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Sample records for allogeneic hct patients

  1. Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT

    PubMed Central

    Ryan, Christine E.; Sahaf, Bita; Logan, Aaron C.; O’Brien, Susan; Byrd, John C.; Hillmen, Peter; Brown, Jennifer R.; Dyer, Martin J. S.; Mato, Anthony R.; Keating, Michael J.; Jaglowski, Samantha; Clow, Fong; Rezvani, Andrew R.; Styles, Lori; Coutre, Steven E.

    2016-01-01

    Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton’s tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism–associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL <1/10 000 white blood cells, which persisted even after ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell–mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre–germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD. PMID:27802969

  2. Patient age, remission status and HCT-CI in a combined score are prognostic for patients with AML undergoing allogeneic hematopoietic cell transplantation in CR1 and CR2.

    PubMed

    Michelis, F V; Messner, H A; Atenafu, E G; McGillis, L; Lambie, A; Uhm, J; Alam, N; Seftel, M D; Gupta, V; Kuruvilla, J; Lipton, J H; Kim, D D

    2015-11-01

    For AML, older age, advanced disease and increased hematopoietic cell transplant comorbidity index (HCT-CI) are associated with worse prognosis following allogeneic hematopoietic cell transplantation (HCT). This single-center retrospective study investigated the influence of pre-transplant characteristics on outcomes of 387 patients undergoing allogeneic HCT for AML in CR1 and CR2. The multivariable analysis model for overall survival (OS) included age (hazard ratio (HR)=2.24 for ages 31-64 years and HR=3.23 for age ⩾65 years compared with age ⩽30 years, P=0.003), remission status (HR=1.49 for CR2 compared with CR1, P=0.005) and HCT-CI score (HR=1.47 for ⩾3 compared with <3, P=0.005). Transplant year was significantly associated with OS (P=0.001) but this did not influence the model. A weighted score was developed with age ⩽30, CR1 and HCT-CI score <3 receiving 0 points each, and CR2 and HCT-CI score ⩾3 receiving 1 point each. Ages 31-64 received 2 points, age ⩾65 received 3 points. Scores were grouped as follows: scores 0-1 (low risk, n=36), score 2 (intermediate-low risk, n=147), score 3 (intermediate-high risk, n=141) and scores 4-5 (high risk, n=63) with 3-year OS of 71%, 55%, 42% and 29% for scores 0-1, 2, 3 and 4-5, respectively (P<0.0001). The score predicted nonrelapse mortality (P=0.03) but not cumulative incidence of relapse (P=0.18). This model should be validated for the pre-HCT assessment of AML patients in CR1 and CR2.

  3. CMV reactivation after allogeneic HCT and relapse risk: evidence for early protection in acute myeloid leukemia.

    PubMed

    Green, Margaret L; Leisenring, Wendy M; Xie, Hu; Walter, Roland B; Mielcarek, Marco; Sandmaier, Brenda M; Riddell, Stanley R; Boeckh, Michael

    2013-08-15

    The association between cytomegalovirus (CMV) reactivation and relapse was evaluated in a large cohort of patients with acute myeloid leukemia (AML) (n = 761), acute lymphoblastic leukemia (ALL) (n = 322), chronic myeloid leukemia (CML) (n = 646), lymphoma (n = 254), and myelodysplastic syndrome (MDS) (n = 371) who underwent allogeneic hematopoietic cell transplantation (HCT) between 1995 and 2005. In multivariable models, CMV pp65 antigenemia was associated with a decreased risk of relapse by day 100 among patients with AML (hazard ratio [HR] = 0.56; 95% confidence interval [CI], 0.3-0.9) but not in patients with ALL, lymphoma, CML, or MDS. The effect appeared to be independent of CMV viral load, acute graft-versus-host disease, or ganciclovir-associated neutropenia. At 1 year after HCT, early CMV reactivation was associated with reduced risk of relapse in all patients, but this did not reach significance for any disease subgroup. Furthermore, CMV reactivation was associated with increased nonrelapse mortality (HR = 1.31; 95% CI, 1.1-1.6) and no difference in overall mortality (HR = 1.05; 95% CI, 0.9-1.3). This report demonstrates a modest reduction in early relapse risk after HCT associated with CMV reactivation in a large cohort of patients without a benefit in overall survival.

  4. Risk Factors and Impact of non-Aspergillus mold infections (NAMI) following Allogeneic HCT: A CIBMTR Infection & Immune Reconstitution analysis

    PubMed Central

    Riches, Marcie L.; Trifilio, Steven; Chen, Min; Ahn, Kwang Woo; Langston, Amelia; Lazarus, Hillard M.; Marks, David I.; Martino, Rodrigo; Maziarz, Richard T.; Papinicolou, Genofeva A.; Wingard, John R.; Young, Jo-Anne H.; Bennett, Charles L.

    2015-01-01

    Risk factors for non-Aspergillus mold infection (NAMI) and the impact on transplant outcome are poorly assessed in the current era of antifungal agents. Outcomes of 124 patients receiving allogeneic HCT diagnosed with either mucormycosis [n=72] or fusariosis [n=52] between days 0-365 after HCT are described and compared to a control cohort (n=11856). Patients with NAMI had more advanced disease [mucormycois 25%, fusariosis 23%, controls 18%; p = 0.004] and were more likely to have a KPS<90% at HCT [mucormycosis 42%, fusariosis 38%, controls 28%; p=0.048]. The 1-year survival after HCT was 22% (15–29%) for cases and was significantly inferior compared to controls [65%(64–65%); p < 0.001]. Survival from infection was similarly dismal regardless of mucormycosis [15% (8-25%)] and fusariosis [21% (11-33%)]. In multivariable analysis, NAMI was associated with a 6-fold higher risk of death (p<0.0001) regardless of the site or timing of infection. Risk factors for mucormycosis include preceding acute GVHD, prior aspergillus infection, and older age. For fusariosis, increased risks including receipt of cord blood, prior CMV infection, and transplant prior to May 2002. In conclusion, NAMI occurs infrequently, is associated with high mortality, and appears with similar frequency in the current antifungal era. PMID:26524262

  5. Plasma biomarkers of risk for death in a multicenter phase 3 trial with uniform transplant characteristics post–allogeneic HCT

    PubMed Central

    Abu Zaid, Mohammad; Wu, Juan; Wu, Cindy; Logan, Brent R.; Yu, Jeffrey; Cutler, Corey; Antin, Joseph H.; Paczesny, Sophie

    2017-01-01

    A phase 3 clinical trial (BMT CTN 0402) comparing tacrolimus/sirolimus (Tac/Sir) vs tacrolimus/methotrexate (Tac/Mtx) as graft-versus-host disease (GVHD) prophylaxis after matched-related allogeneic hematopoietic cell transplantation (HCT) recently showed no difference between study arms in acute GVHD-free survival. Within this setting of a prospective, multicenter study with uniform GVHD prophylaxis, conditioning regimen, and donor source, we explored the correlation of 10 previously identified biomarkers with clinical outcomes after allogeneic HCT. We measured biomarkers from plasma samples collected in 211 patients using enzyme-linked immunosorbent assay (Tac/Sir = 104, Tac/Mtx = 107). High suppression of tumorigenicity-2 (ST2) and T-cell immunoglobulin mucin-3 (TIM3) at day 28 correlated with 2-year nonrelapse mortality in multivariate analysis (P = .0050, P = .0075, respectively) and in a proportional hazards model with time-dependent covariates (adjusted hazard ratio: 2.43 [1.49–3.95], P = .0038 and 4.87 [2.53–9.34], P < .0001, respectively). High ST2 and TIM3 correlated with overall survival. Chemokine (C-X-C motif) ligand 9 (CXCL9) levels above the median were associated with chronic GVHD compared with levels below the median in a time-dependent proportional hazard analysis (P = .0069). Low L-Ficolin was associated with hepatic veno-occlusive disease (P = .0053, AUC = 0.80). We confirmed the correlation of plasma-derived proteins, previously assessed in single-center cohorts, with clinical outcomes after allogeneic HCT within this prospective, multicenter study. PMID:27827824

  6. Allogeneic Marrow Transplantation in Patients With Severe Systemic Sclerosis

    PubMed Central

    Nash, Richard A.; McSweeney, Peter A.; Nelson, J. Lee; Wener, Mark; Georges, George E.; Langston, Amelia A.; Shulman, Howard; Sullivan, Keith M.; Lee, Julie; Henstorf, Gretchen; Storb, Rainer; Furst, Daniel E.

    2010-01-01

    Objective To evaluate the safety and efficacy of allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning in patients with severe systemic sclerosis (SSc). Methods Eligibility criteria for the study included SSc patients with features indicative of a poor prognosis. The myeloablative conditioning regimen included busulfan, cyclophosphamide, and antithymocyte globulin. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine and methotrexate. Bone marrow was transplanted from HLA-identical siblings. Results Two patients with diffuse cutaneous SSc and lung involvement who were refractory to conventional immunosuppressive treatment were enrolled in the study. In patient 1, there were no complications related to the conditioning regimen, and GVHD did not develop after transplantation. At 5 years after HCT, there was nearly complete resolution of the scleroderma and marked improvement in physical functioning. Internal organ function improved (lung) or remained stable. On examination of serial skin biopsy samples, there was resolution of the dermal fibrosis. Patient 2 experienced skin toxicity from the conditioning regimen and hypertensive crisis that was likely related to high-dose corticosteroids given for treatment of GVHD. Although this patient experienced an improvement in scleroderma and overall functioning, a fatal opportunistic infection developed 17 months after HCT. Conclusion Allogeneic HCT may result in sustained remission of SSc. GVHD and opportunistic infections are the major risks associated with allogeneic HCT for SSc, as for allogeneic HCT in general. PMID:16732546

  7. Allogeneic hematopoietic cell transplantation in patients with AML not achieving remission: potentially curative therapy.

    PubMed

    Gyurkocza, B; Lazarus, H M; Giralt, S

    2017-02-27

    Patients with acute myeloid leukemia (AML) who fail to achieve complete remission (CR) have a dismal prognosis. Although data suggest that durable remissions can be achieved in approximately 30% of patients with refractory or relapsed AML after allogeneic hematopoietic cell transplantation (HCT), only a small fraction of those patients are offered this therapeutic option. Importantly, patients with primary refractory AML have distinctly better outcomes following allogeneic HCT than those with refractory relapse. Access to suitable donors could be one of the main barriers in these situations. However, with recent developments in the field of allogeneic HCT, such as alternative donor sources, high-resolution HLA-typing, reduced intensity conditioning regimens and improvements in supportive care, this approach has the potential to offer long-term survival for patients with refractory and relapsed AML and should be considered as early after diagnosis as possible. Incorporating novel agents into the conditioning regimen or as post-transplant maintenance therapy could further improve outcomes and render older or medically infirm patients with refractory or relapsed AML eligible for allogeneic HCT. In this review, we summarize existing data on allogeneic HCT in patients with refractory or relapsed AML and explore novel approaches with the potential to improve outcomes in this patient population.Bone Marrow Transplantation advance online publication, 27 February 2017; doi:10.1038/bmt.2017.8.

  8. Second allogeneic hematopoietic cell transplantation for Patients with Fanconi anemia and Bone Marrow Failure

    PubMed Central

    Ayas, Mouhab; Eapen, Mary; Le-Rademacher, Jennifer; Carreras, Jeanette; Abdel-Azim, Hisham; Alter, Blanche P.; Anderlini, Paolo; Battiwalla, Minoo; Bierings, Marc; Buchbinder, David K.; Bonfim, Carmem; Camitta, Bruce M.; Fasth, Anders L.; Gale, Robert Peter; Lee, Michelle A.; Lund, Troy C.; Myers, Kasiani C.; Olsson, Richard F.; Page, Kristin M.; Prestidge, Tim D.; Radhi, Mohamed; Shah, Ami J.; Schultz, Kirk R.; Wirk, Baldeep; Wagner, John E.; Deeg, H. Joachim

    2015-01-01

    Second allogeneic hematopoietic cell transplantation (HCT) is the only salvage option for those for develop graft failure after their first HCT. Data on outcomes after second HCT in Fanconi anemia (FA) are scarce. We report outcomes after second allogeneic HCT for FA (n=81). The indication for second HCT was graft failure after the first HCT. Transplants occurred between 1990 and 2012. The timing of second transplantation predicted subsequent graft failure and survival. Graft failure was high when the second transplant occurred less than 3 months from the first. The 3-month probability of graft failure was 69% when the interval between first and second transplant was less than 3 months compared to 23% when the interval was longer (p<0.001). Consequently, survival rates were substantially lower when the interval between first and second transplant was less than 3 months, 23% at 1-year compared to 58%, when the interval was longer (p=0.001). The corresponding 5-year probabilities of survival were 16% and 45%, respectively (p=0.006). Taken together, these data suggest that fewer than half of FA patients undergoing a second HCT for graft failure are long-term survivors. There is an urgent need to develop strategies to lower graft failure after first HCT. PMID:26116087

  9. Financial impact of allogeneic hematopoietic cell transplantation on patients and families over 2 years: results from a multicenter pilot study.

    PubMed

    Denzen, E M; Thao, V; Hahn, T; Lee, S J; McCarthy, P L; Rizzo, J D; Ammi, M; Drexler, R; Flesch, S; James, H; Omondi, N; Murphy, E; Pederson, K; Majhail, N S

    2016-09-01

    Hematopoietic cell transplantation (HCT) is a procedure that can significantly influence the socioeconomic wellbeing of patients, caregivers and their families. Among 30 allogeneic HCT recipients and their caregivers enrolled on a pilot study evaluating the feasibility of studying financial impact of HCT, 16 agreed to participate in the long-term phase, completed a baseline questionnaire and received phone interviews at 6, 12, 18 and 24 months post HCT. Analyses showed that by 2 years post HCT, 54% of patients who previously contributed to household earnings had not returned to work and 80% of patients/caregivers reported transplant as having moderate to great impact on household income. However, patients' levels of confidence in their abilities to meet household financial obligations increased from baseline to 2 years. A relatively large proportion of patients reported inability to pay for medical care through this time period. Case studies demonstrated that patients' individual perceptions of the financial impact of HCT varies considerably, regardless of actual income. We demonstrate the feasibility of conducting a study to evaluate the financial impact of allogeneic HCT through 2 years post transplantation. Some patients/caregivers continue to experience a significant long-term financial burden after this procedure. Our study lays the foundation for a larger evaluation of patient/caregiver financial burden associated with HCT.

  10. Financial Impact of Allogeneic Hematopoietic Cell Transplantation on Patients and Families over 2-years: Results from a Multicenter Pilot Study

    PubMed Central

    Denzen, Ellen M.; Thao, Viengneesee; Hahn, Theresa; Lee, Stephanie J.; McCarthy, Philip L.; Rizzo, J. Douglas; Ammi, Monique; Drexler, Rebecca; Flesch, Susan; James, Heather; Omondi, Nancy; Murphy, Elizabeth; Pederson, Kate; Majhail, Navneet S.

    2016-01-01

    Hematopoietic cell transplantation (HCT) is a procedure that can significantly influence the socioeconomic wellbeing of patients, caregivers and their families. Among 30 allogeneic HCT recipients and their caregivers enrolled on a pilot study evaluating the feasibility of studying financial impact of HCT, 16 agreed to participate in the long-term phase, completed a baseline questionnaire and received phone interviews at 6, 12, 18 and 24 months post-HCT. Analyses showed that by 2-years post-HCT, 54% of patients who previously contributed to household earnings had not returned to work and 80% of patients/caregivers reported transplant as having moderate to great impact on household income. However, patients’ level of confidence in their ability to meet household financial obligations increased from baseline to 2-years. A relatively large proportion of patients reported inability to pay for medical care through this time period. Case studies demonstrated patient individual perception of financial impact of HCT varies considerably, regardless of actual income. We demonstrate the feasibility of conducting a study to evaluate financial impact of allogeneic HCT through 2-years post-transplantation. Some patients/caregivers continue to experience significant long-term financial burden after this procedure. Our study lays the foundation for a larger evaluation of patient/caregiver financial burden associated with HCT. PMID:27088381

  11. Patient education in allogeneic hematopoietic cell transplant: what patients wish they had known about quality of life.

    PubMed

    Jim, H S L; Quinn, G P; Gwede, C K; Cases, M G; Barata, A; Cessna, J; Christie, J; Gonzalez, L; Koskan, A; Pidala, J

    2014-02-01

    Quality of life (QOL) is increasingly recognized as an important clinical outcome of hematopoietic cell transplantation (HCT), but patient education is often overlooked. The aim of the current qualitative study was to examine education regarding post-HCT QOL from the patient's perspective. Allogeneic HCT recipients participated in one of four focus groups. Participants were asked to recall what they had been told about post-HCT QOL as they were preparing for transplant, how their QOL differed from what they expected and how to educate future patients about post-HCT QOL. Verbatim transcripts were coded for both a priori and emergent themes using content analysis. A total of 24 patients participated (54% female, mean age 51, range 23-73 years). Participants frequently expressed the desire for additional education regarding post-HCT QOL, particularly late complications. They noted that late complications were often unexpected, had a profound impact on their QOL and threatened their ongoing sense of recovery. They emphasized that the timing, content and format of education regarding QOL should be flexible to meet their diverse needs. Findings from the current study draw attention to the importance of patient education regarding post-HCT QOL as well as additional QOL research designed with patient education in mind.

  12. Comparable outcomes post allogeneic hematopoietic cell transplant for patients with de novo or secondary acute myeloid leukemia in first remission.

    PubMed

    Michelis, F V; Atenafu, E G; Gupta, V; Kim, D D; Kuruvilla, J; Lipton, J H; Loach, D; Seftel, M D; Uhm, J; Alam, N; Lambie, A; McGillis, L; Messner, H A

    2015-07-01

    Secondary AML (sAML) has a poor prognosis with conventional chemotherapy alone. Allogeneic hematopoietic cell transplantation (HCT) is beneficial for high-risk AML. Data comparing outcomes of transplants for patients with de novo and sAML are limited. We compared outcomes of patients transplanted for de novo and sAML in first complete remission and investigated the effect of age, HCT comorbidity index (HCT-CI) and karyotype in both groups. A total of 264 patients with de novo (n=180) and sAML (n=84) underwent allogeneic HCT between 1999 and 2013. Median age at transplant was 51 years (range 18-71), median follow-up of survivors was 77 months. Evaluation of all patients demonstrated no significant difference between de novo and sAML for overall survival (P=0.18), leukemia-free survival (P=0.17), cumulative incidence of relapse (P=0.51) and non-relapse mortality (P=0.42). Multivariable and propensity score analyses confirmed the comparable outcomes between de novo and sAML post transplant. Although sAML demonstrates outcomes inferior to de novo AML treated with chemotherapy alone, outcomes following allogeneic HCT are comparable between the two groups.

  13. Reduced-intensity conditioning allogeneic hematopoietic-cell transplantation for older patients with acute myeloid leukemia

    PubMed Central

    Goyal, Gaurav; Gundabolu, Krishna; Vallabhajosyula, Saraschandra; Silberstein, Peter T.; Bhatt, Vijaya Raj

    2016-01-01

    Elderly patients (>60 years) with acute myeloid leukemia have a poor prognosis with a chemotherapy-alone approach. Allogeneic hematopoietic-cell transplantation (HCT) can improve overall survival (OS). However, myeloablative regimens can have unacceptably high transplant-related mortality (TRM) in an unselected group of older patients. Reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning regimens preserve the graft-versus-leukemia effects but reduce TRM. NMA regimens result in minimal cytopenia and may not require stem cell support for restoring hematopoiesis. RIC regimens, intermediate in intensity between NMA and myeloablative regimens, can cause prolonged myelosuppresion and usually require stem cell support. A few retrospective and prospective studies suggest a possibility of lower risk of relapse with myeloablative HCT in fit older patients with lower HCT comorbidity index; however, RIC and NMA HCTs have an important role in less-fit patients and those with significant comorbidities because of lower TRM. Whether early tapering of immunosuppression, monitoring of minimal residual disease, and post-transplant maintenance therapy can improve the outcomes of RIC and NMA HCT in elderly patients will require prospective trials. PMID:27247754

  14. Treosulfan, Fludarabine and 2 Gy Total Body Irradiation Followed by Allogeneic Hematopoietic Cell Transplantation in Patients with MDS and AML

    PubMed Central

    Gyurkocza, Boglarka; Gutman, Jonathan; Nemecek, Eneida R.; Bar, Merav; Milano, Filippo; Ramakrishnan, Aravind; Scott, Bart; Fang, Min; Wood, Brent; Pagel, John M.; Baumgart, Joachim; Delaney, Colleen; Maziarz, Richard T.; Sandmaier, Brenda M.; Estey, Elihu H.; Appelbaum, Frederick R.; Storer, Barry E.; Deeg, H. Joachim

    2014-01-01

    Allogeneic hematopoietic cell transplantation (HCT) offers curative therapy for many patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics. In this prospective phase II trial we assessed the efficacy and toxicity of treosulfan, fludarabine and 2 Gy total body irradiation (TBI) as conditioning for allogeneic HCT in patients with MDS or AML. Ninety-six patients with MDS (n=36; 15 RMCD; 10 RAEB-1; 10 RAEB-2; 1 CMML-1) or AML (n=60; 35 CR1; 18 CR2; 3 advanced CR; 4 refractory relapse) were enrolled; median age was 51 (range: 1–60) years. Twelve patients had undergone a prior HCT with high intensity conditioning. Patients received intravenous (IV) treosulfan, 14 g/m2/day on days −6 to −4, IV fludarabine, 30 mg/m2/day on days −6 to −2, and 2 Gy TBI on day 0, followed by infusion of hematopoietic cells from related (n=27) or unrelated (n=69) donors. Graft-vs.-host disease prophylaxis consisted of tacrolimus and methotrexate. With a median follow-up of 30 months, the 2-year overall survival (OS), relapse incidence and non-relapse mortality were 73%, 27% and 8%, respectively. The incidences of grades II–IV (III–IV) acute and chronic graft-versus-host disease were 59% (10%) and 47%, respectively. Two-year OS was not significantly different between MDS patients with poor risk and good/intermediate risk cytogenetics (69% and 85%, respectively), or between AML patients with unfavorable and favorable/intermediate risk cytogenetics (64% and 76%, respectively). In AML patients, minimal residual disease (MRD; n=10) at the time of HCT predicted higher relapse incidence (70% vs. 18%) and lower OS (41% vs. 79%) at 2 years, when compared to patients without MRD. In conclusion, treosulfan, fludarabine and low-dose TBI provided effective conditioning for allogeneic HCT in patients with MDS or AML, and resulted in low relapse incidence, regardless

  15. Role of reduced-intensity conditioning allogeneic hematopoietic cell transplantation in older patients with de novo acute myeloid leukemia.

    PubMed

    Yamasaki, Satoshi; Hirakawa, Akihiro; Aoki, Jun; Uchida, Naoyuki; Fukuda, Takahiro; Ogawa, Hiroyasu; Ohashi, Kazuteru; Kondo, Tadakazu; Eto, Tetsuya; Kanamori, Heiwa; Okumura, Hirokazu; Iwato, Koji; Ichinohe, Tatsuo; Kanda, Junya; Onizuka, Makoto; Kuwatsuka, Yachiyo; Yanada, Masamitsu; Atsuta, Yoshiko; Takami, Akiyoshi; Yano, Shingo

    2017-02-01

    Reduced-intensity conditioning (RIC) regimens extend the therapeutic use of allogeneic hematopoietic cell transplantation (HCT) to older patients. The survival trend in 2325 patients aged >50 years presenting with de novo acute myeloid leukemia (AML) who underwent first reduced-intensity HCT (RIC-HCT) was assessed by retrospectively analyzing outcomes between 2000 and 2013. The annual number of RIC-HCTs in Japan was higher in the 2008-2013 period (n = 205/year [1229/6 years]) than in the 2000-2007 period (n = 137/year [1096/8 years]). Overall and disease-free survival were higher in the 2008-2013 period (P < 0.001) because of the improvement in transplant-related mortality (TRM). Survival regarding RIC-HCT for AML has improved over time, with an increased number of RIC-HCTs in patients with a Karnofsky performance status (KPS) ≥80. However, TRM remains high and the relapse rate has not improved over time. Multivariate analyses showed that a KPS ≥80 and complete remission at HCT were associated with less TRM and relapse, and better survival regardless of age ≥65 years. Accurate timing and prospective identification of patients at risk of TRM may aid the development of risk-adapted strategies for RIC-HCT in AML patients regardless of age.

  16. Survival of AML patients relapsing after allogeneic hematopoietic cell transplantation: a CIBMTR study

    PubMed Central

    Bejanyan, Nelli; Weisdorf, Daniel J.; Logan, Brent R.; Wang, Hai-Lin; Devine, Steven M.; de Lima, Marcos; Bunjes, Donald W.; Zhang, Mei-Jie

    2015-01-01

    Acute myeloid leukemia (AML) relapse after allogeneic hematopoietic cell transplantation (alloHCT) remains a major therapeutic challenge. We studied outcomes of 1788 AML patients relapsing after alloHCT (1990–2010) during first or second complete remission (CR) to identify factors associated with longer post-relapse survival. Median time of post HCT relapse was 7 months (mo; range, 1–177). At relapse, 1231 patients (69%) received intensive therapy, including chemotherapy (CT) alone (n=660), donor lymphocyte infusion (DLI)±CT (n=202; %), or 2nd alloHCT±CT ±DLI (n=369), with subsequent CR rates of 29%. Median follow-up after relapse was 39 mo (range, <1–193). Survival for all patients was 23% at 1 year post-relapse; however, 3-yr overall survival correlated with time from HCT to relapse (4% for relapse during 1–6 mo period, 12% during 6 mo-2 yr, 26% during 2–3 yr, and 38% for ≥3 yr). In multivariable analysis, lower mortality was significantly associated with longer time from alloHCT to relapse (RR 0.55 for 6 mo-2 yr, RR 0.39 for 2–3 yr, and RR 0.28 for ≥3 yr; p<0.0001) and a 1st HCT using reduced-intensity conditioning (RR=0.77; 95% CI 0.66–0.88, p=0.0002). In contrast, inferior survival was associated with age >40 yr (RR=1.42, 95% CI 1.24–1.64; p<0.0001), active GVHD at relapse (RR=1.25, 95% CI 1.13–1.39; p<0.0001), adverse cytogenetics (RR=1.37, 95% CI 1.09–1.71; p=0.0062), mismatched URD (RR=1.61, 95% CI 1.22–2.13; p=0.0008), and use of cord blood for 1st HCT (RR=1.23, 95% CI 1.06–1.42; p=0.0078). AML relapse after alloHCT predicted poor survival; however, patients who relapsed ≥6 mo after their initial alloHCT had better survival and may benefit from intensive therapy such as 2nd alloHCT±DLI. PMID:25460355

  17. Serum proteomic profiling and haptoglobin polymorphisms in patients with GVHD after allogeneic hematopoietic cell transplantation

    PubMed Central

    McGuirk, Joseph; Hao, Gang; Hou, Weijian; Abhyankar, Sunil; Williams, Casey; Yan, Weisi; Yuan, Jianda; Guan, Xiuqin; Belt, Robert; Dejarnette, Shaun; Wieman, Jeffery; Yan, Ying

    2009-01-01

    We studied serum proteomic profiling in patients with graft versus host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) by two-dimensional gel electrophoresis (2-DE) and mass spectrometry analysis. The expression of a group of proteins, haptoglobin (Hp), alpha-1-antitrypsin, apolipoprotein A-IV, serum paraoxonase and Zn-alpha-glycoprotein were increased and the proteins, clusterin precursor, alpha-2-macroglobulin, serum amyloid protein precursor, sex hormone-binding globulin, serotransferrin and complement C4 were decreased in patients with extensive chronic GVHD (cGVHD). Serum haptoglobin (Hp) levels in patients with cGVHD were demonstrated to be statistically higher than in patients without cGVHD and normal controls (p < 0.01). We used immunoblotting and PCR in combination with 2-DE gel image analysis to determine Hp polymorphisms in 25 allo-HCT patients and 16 normal donors. The results demonstrate that patients with cGVHD had a higher incidence of HP 2-2 phenotype (43.8%), in comparison to the patients without cGVHD (0%) and normal donors (18.7%), suggesting the possibility that specific Hp polymorphism may play a role in the development of cGVHD after allo-HCT. In this study, quantitative serum Hp levels were shown to be related to cGVHD development. Further, the data suggest the possibility that specific Hp polymorphisms may be associated with cGVHD development and warrant further investigation. PMID:19379511

  18. Brentuximab vedotin enables successful reduced-intensity allogeneic hematopoietic cell transplantation in patients with relapsed or refractory Hodgkin lymphoma

    PubMed Central

    Palmer, Joycelynne M.; Thomas, Sandra H.; Tsai, Ni-Chun; Farol, Len; Nademanee, Auayporn; Forman, Stephen J.; Gopal, Ajay K.

    2012-01-01

    Brentuximab vedotin induces an overall response rate of 75% in patients with relapsed/refractory Hodgkin lymphoma, but its impact on future allogeneic transplantation (allo-HCT) is not known. We retrospectively examined the records of 18 patients with relapsed/refractory Hodgkin lymphoma who were treated on brentuximab vedotin clinical trials to evaluate the efficacy and safety of subsequent reduced-intensity allo-HCT. Seventeen patients had previous autologous transplant; 6 were in complete remission, and 8 were in partial remission before allo-HCT with 12 grafts from unrelated or mismatched donors. The 1-year overall survival was 100%, progression-free survival was 92.3%, and nonrelapse mortality was 0% (median follow-up, 14 months). The incidence of acute GVHD was 27.8% and chronic GVHD was 56.3%. Brentuximab vedotin before reduced-intensity allo-HCT does not appear to adversely affect engraftment, GVHD, or survival and may provide sufficient disease control to enable reduced-intensity allo-HCT. PMID:22611160

  19. Comparison of Reduced-Intensity and Myeloablative Conditioning Regimens for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia and Acute Lymphoblastic Leukemia: A Meta-Analysis

    PubMed Central

    Ismail, Nor-Azimah; Mohd-Idris, Mohd-Razif; Jamaluddin, Fariza Wan; Tumian, NorRafeah; Sze-Wei, Ernie Yap; Muhammad, Norasiah; Nai, Ming Lai

    2014-01-01

    Currently, the indications to perform reduced-intensity conditioning allogeneic hematopoietic stem cell transplant (RIC-HCT) are based on data derived mainly from large registry and single-centre retrospective studies. Thus, at the present time, there is limited direct evidence supporting the current practice in selecting patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) for RIC versus myeloablative conditioning (MAC) transplants. To determine the relationship between dose intensity of conditioning regimen and survival outcomes after allografting in AML/ALL patients, we performed a meta-analysis of 23 clinical trials reported between 1990 and 2013 involving 15,258 adult patients that compare survival outcomes after RIC-HCT versus MAC-HCT. RIC-HCT resulted in comparable <2-year and 2–6 year overall survival (OS) rates post-transplantation even though the RIC-HCT recipients were older and had more active disease than MAC-HCT recipients. The 2–6 year progression-free survival (PFS), nonrelapse mortality, acute graft-versus-host disease (GvHD) and chronic GvHD rates were reduced after RIC-HCT, but relapse rate was increased. Similar outcomes were observed regardless of disease type and status at transplantation. Odds ratio for all outcomes remained comparable with or without performing separate analyses for the year of HCT and for retrospective versus prospective studies. Among RIC-HCT recipients, survival rates were superior if patients were in CR at transplantation. Significant inter-study heterogeneity for aGvHD data and publication bias for PFS data were observed. This meta-analysis showed no OS benefit of MAC-HCT over RIC-HCT across the entire cohort of patients suggesting that RIC-HCT could be an effective therapeutic option for AML/ALL patients who are ineligible for MAC-HCT and CR status is preferred before RIC-HCT. PMID:25072307

  20. Kinetics of iron removal by phlebotomy in patients with iron overload after allogeneic hematopoietic cell transplantation

    PubMed Central

    Eisfeld, Ann-Kathrin; Krahl, Rainer; Jaekel, Nadja; Niederwieser, Dietger; Al-Ali, Haifa Kathrin

    2012-01-01

    Excess body iron could persist for years after allogeneic hematopoietic cell transplantation (HCT) with possible deleterious sequels. An iron depletive therapy with phlebotomy seems rational. Kinetics of iron removal by phlebotomy without erythropoietin support in non-thalassemic adult patients with iron overload after HCT and the impact of pre- and post-HCT hemochromatosis (HFE) genotype on iron mobilization were investigated. Patients and methods: Phlebotomy was initiated in 61 recipients of allografts due to hematologic malignancies (median age 48 years) after a median of 18 months. The prephlebotomy median serum ferritin (SF) was 1697ng/ml and the median number of blood transfusions 28 units. Alanine aminotransferase (ALT)/aspartate aminotransferase (AST), alkaline phosphates (AP), and bilirubin were elevated in 55.7%, 64% and 11.5% patients respectively. HFE-genotype was elucidated by polymerase chain reaction using hybridization probes and melting curve analysis. Results: Phlebotomy was well-tolerated irrespective of age or conditioning. A negative iron balance in 80% of patients (median SF 1086 ng/ml) and a rise in hemoglobin were observed (p<0.0001). Higher transfusional burden and SF were associated with a greater iron mobilization per session (p=0.02). In 58% of patients, a plateau after an initial steady decline in SF was followed by a second decline under further phlebotomy. The improvement in ALT (p=0.002), AST (p=0.03), AP (p=0.01), and bilirubin (p<0.0001) did not correlate with the decline in SF. Mutant HFE-gene variants were detected in 14/55 (25%) pre-HCT and 22/55 (40%) patients post-HCT. Overall, dissimilar pre- and posttransplantational HFE-genotypes were detected in 20/55 (40%) patients. Posttransplantational mutant HFE variants correlated with a slower decline in SF (p=0.007). Conclusions: Phlebotomy is a convenient therapy of iron overload in survivors of HCT. A negative iron balance and a rise in hemoglobin were observed in the majority of

  1. Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Myelofibrosis With Prior exposure to JAK1/2 Inhibitors

    PubMed Central

    Shanavas, Mohamed; Popat, Uday; Michaelis, Laura C; Fauble, Veena; McLornan, Donal; Klisovic, Rebecca; Mascarenhas, John; Tamari, Roni; Arcasoy, Murat O; Davies, James; Gergis, Usama; Ukaegbu, Oluchi C; Kamble, Rammurti T; Storring, John M; Majhail, Navneet S; Romee, Rizwan; Verstovsek, Srdan; Pagliuca, Antonio; Vasu, Sumithira; Ernst, Brenda; Atenafu, Eshetu G; Hanif, Ahmad; Champlin, Richard; Hari, Paremeswaran; Gupta, Vikas

    2016-01-01

    The impact of JAK1/2 inhibitor therapy prior to allogeneic hematopoietic cell transplantation (HCT) has not been studied in a large cohort in myelofibrosis (MF). In this retrospective multicenter study, we analyzed outcomes of patients who underwent HCT for MF with prior exposure to JAK1/2 inhibitors. One hundred consecutive patients from participating centers were analyzed, and based on clinical status and response to JAK1/2 inhibitors at the time of HCT, patients were stratified into five groups: (a) clinical improvement (n=23), (b) stable disease (n=31), (c) new cytopenia/increasing blasts/intolerance (n=15), (d) progressive disease: splenomegaly (n=18), and (e) progressive disease: leukemic transformation (LT) (n=13). Overall survival (OS) at two years was 61% (95%CI, 49–71). This was 91% (95% CI, 69–98) for those who experienced clinical improvement, and 32% (95% CI, 8–59) for those who developed LT on JAK1/2 inhibitors. In multivariable analysis, response to JAK1/2 inhibitors (p=0.03), DIPSS score (p=0.003), and donor type (p=0.006) were independent predictors of survival. Among the 66 patients who remained on JAK1/2 inhibitors until stopped for HCT, two patients developed serious adverse events necessitating delaying of HCT, and another 8 patients had symptoms with lesser severity. Adverse events were more common in patients who started tapering or abruptly stopped their regular dose ≥6 days prior to conditioning therapy. We conclude that prior exposure to JAK1/2 inhibitors did not adversely affect post-transplant outcomes. Our data suggest that JAK1/2 inhibitors should be continued near to the start of conditioning therapy. The favorable outcomes of patients who experienced clinical improvement with JAK1/2 inhibitor therapy prior to HCT were particularly encouraging, and need further prospective validation. PMID:26493563

  2. Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease.

    PubMed

    Bachanova, V; Marks, D I; Zhang, M-J; Wang, H; de Lima, M; Aljurf, M D; Arellano, M; Artz, A S; Bacher, U; Cahn, J-Y; Chen, Y-B; Copelan, E A; Drobyski, W R; Gale, R P; Greer, J P; Gupta, V; Hale, G A; Kebriaei, P; Lazarus, H M; Lewis, I D; Lewis, V A; Liesveld, J L; Litzow, M R; Loren, A W; Miller, A M; Norkin, M; Oran, B; Pidala, J; Rowe, J M; Savani, B N; Saber, W; Vij, R; Waller, E K; Wiernik, P H; Weisdorf, D J

    2014-03-01

    The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKIs), mostly imatinib; 39% (RIC) and 49% (MAC) were minimal residual disease (MRD)(neg) pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%; P=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (P=0.058). Overall survival (OS) was similar (RIC 39% (95% confidence interval (CI) 27-52) vs 35% (95% CI 27-44); P=0.62). Patients MRD(pos) pre-HCT had higher risk of relapse with RIC vs MAC (hazard ratio (HR) 1.97; P=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre-RIC HCT had superior OS (55%) compared with a similar MRD population after MAC (33%; P=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; P=0.057), but absence of pre-HCT TKI (HR 1.88; P=0.018), RIC (HR 1.891; P=0.054) and pre-HCT MRD(pos) (HR 1.6; P=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRD(neg) status is preferred pre-HCT.

  3. Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: Impact of tyrosine kinase inhibitor and minimal residual disease

    PubMed Central

    Bachanova, Veronika; Marks, David I.; Zhang, Mei-Jie; Wang, Hailin; de Lima, Marcos; Aljurf, Mahmoud D.; Arellano, Martha; Artz, Andrew S.; Bacher, Ulrike; Cahn, Jean-Yves; Chen, Yi-Bin; Copelan, Edward A.; Drobyski, William R.; Gale, Robert Peter; Greer, John P; Gupta, Vikas; Hale, Gregory A.; Kebriaei, Partow; Lazarus, Hillard M.; Lewis, Ian D.; Lewis, Victor A.; Liesveld, Jane L.; Litzow, Mark R.; Loren, Alison W.; Miller, Alan M.; Norkin, Maxim; Oran, Betul; Pidala, Joseph; Rowe, Jacob M.; Savani, Bipin N.; Saber, Wael; Vij, Ravi; Waller, Edmund K.; Wiernik, Peter H.; Weisdorf, Daniel J.

    2014-01-01

    The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Ph+ acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type, and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKI), mostly imatinib; 39% (RIC) and 49% (MAC) were MRDneg pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%;p=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (p=0.058). Overall survival was similar (RIC 39% [95% CI:27–52] vs. 35% [95% CI:270–44];p=0.62). Patients MRDpos pre-HCT had higher risk of relapse with RIC versus MAC (HR 1.97;p=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre-RIC HCT had superior OS (55%) compared to a similar MRDneg population after MAC (33%; p=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; p=0.057), but absence of pre-HCT TKI (HR 1.88;p=0.018), RIC (HR 1.891;p=0.054) and pre-HCT MRDpos (HR 1.6; p=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRDneg status is preferred pre-HCT. PMID:23989431

  4. Allogeneic, but not autologous, hematopoietic cell transplantation improves survival only among younger adults with acute lymphoblastic leukemia in first remission: an individual patient data meta-analysis.

    PubMed

    Gupta, Vikas; Richards, Sue; Rowe, Jacob

    2013-01-10

    Hematopoietic cell transplantation (HCT) and prolonged chemotherapy are standard postremission strategies for adult acute lymphoblastic leukemia in first complete remission, but the optimal strategy remains controversial. There are no randomized trials of allogeneic HCT. In the present study, updated individual patient data were collected and analyzed from studies with information on availability of matched sibling donor (used to mimic randomization) and from randomized trials of autograft versus chemotherapy. Data from 13 studies including 2962 patients, excluding Philadelphia chromosome-positive patients, showed a survival benefit for having a matched sibling donor for patients < 35 years of age (OR = 0.79; 95% CI, 0.70-0.90, P = .0003) but not for those ≥ 35 years of age (OR = 1.01; 95% CI, 0.85-1.19, P = .9; heterogeneity P = .03) because of the higher absolute risk of nonrelapse mortality for older patients. No differences were seen by risk group. There was a trend toward inferior survival for autograft versus chemotherapy (OR = 1.18; 95% CI, 0.99-1.41; P = .06). No beneficial effect of autografting was seen compared with chemotherapy in this analysis. We conclude that matched sibling donor myeloablative HCT improves survival only for younger patients, with an absolute benefit of approximately 10% at 5 years. Improved chemotherapy outcomes and reduced nonrelapse mortality associated with allogeneic HCT may change the relative effects of these treatments in the future.

  5. Autologous versus allogeneic transfusion: patients' perceptions and experiences

    PubMed Central

    Graham, I D; Fergusson, D; Dokainish, H; Biggs, J; McAuley, L; Laupacis, A

    1999-01-01

    BACKGROUND: Preoperative autologous donation is one way to decrease a patient's exposure to allogeneic blood transfusion. This study was designed to determine patients' perceptions about the autologous blood donation process and their experiences with transfusion. METHODS: To assess patient perception, a questionnaire was administered a few days before surgery to patients undergoing elective cardiac and orthopedic surgery in a Canadian teaching hospital. All patients attending the preoperative autologous donation clinic during a 10-month period were eligible. A convenience sample of patients undergoing the same types of surgery who had not predonated blood were selected from preadmission clinics. Patient charts were reviewed retrospectively to assess actual transfusion practice in all cases. RESULTS: A total of 80 patients underwent cardiac surgery (40 autologous donors, 40 nondonors) and 73 underwent orthopedic surgery (38 autologous donors, 35 nondonors). Of the autologous donors, 75 (96%) attended all scheduled donation appointments, 73 (93%) said that they were "very likely" or "likely" to predonate again, and 75 (96%) said that they would recommend autologous donation to others. There was little difference in preoperative symptoms between the autologous donors and the nondonors, although the former were more likely than the latter to report that their overall health had remained the same during the month before surgery (30 [75%] v. 21 [52%] for the cardiac surgery patients and 30 [79%] v. 18 [51%] for the orthopedic surgery patients). When the autologous donors were asked what they felt their chances would have been of receiving at least one allogeneic blood transfusion had they not predonated, the median response was 80%. When they were asked what their chances were after predonating their own blood, the median response was 0%. The autologous donors were significantly less likely to receive allogeneic blood transfusions (6 [15%] for cardiac surgery and 3 [8

  6. White blood cell recovery after allogeneic hematopoietic cell transplantation predicts clinical outcome.

    PubMed

    Kim, Haesook T; Frederick, David; Armand, Philippe; Andler, Emily; Kao, Grace; Cutler, Corey; Koreth, John; Alyea, Edwin P; Antin, Joseph H; Soiffer, Robert J; Ritz, Jerome; Ho, Vincent T

    2014-06-01

    To determine whether outcome after allogeneic hematopoietic cell transplantation (HCT) could be estimated by using peripheral white blood cell count (WBC) as a metric that integrates several aspects of HCT recovery, we conducted a retrospective study of 1,109 adult patients who underwent first allogeneic HCT from 2003 through 2009. WBC at 1-3 months after HCT was categorized as low (<2), normal (2-10), and high (>10 × 10(9) cells/L). Overall survival (OS) and progression-free survival (PFS) were lower for patients with low or high WBC at 1-3 months after HCT (P < 0.0001). We developed a predictive three-group risk model based on the pattern of WBC recovery early after HCT. Five-year OS was 47, 30, and 15% (P < 0.0001) and 5-year PFS was 39, 22, and 14% for patients in the three different risk groups (P < 0.0001). The pattern of WBC recovery early after HCT provides prognostic information for relapse, nonrelapse mortality, progression-free survival, and overall survival. A scoring system based on the trajectory of the WBC in the first 3 months after HCT can effectively stratify patients into three groups with different PFS and OS. If validated, this system could be useful in the clinical management of patients after HCT, and to stratify patients enrolled on HCT clinical trials.

  7. Long-term survival of patients with CLL after allogeneic transplantation: a report from the European Society for Blood and Marrow Transplantation.

    PubMed

    van Gelder, M; de Wreede, L C; Bornhäuser, M; Niederwieser, D; Karas, M; Anderson, N S; Gramatzki, M; Dreger, P; Michallet, M; Petersen, E; Bunjes, D; Potter, M; Beelen, D; Cornelissen, J J; Yakoub-Agha, I; Russell, N H; Finke, J; Schoemans, H; Vitek, A; Urbano-Ispízua, Á; Blaise, D; Volin, L; Chevallier, P; Caballero, D; Putter, H; van Biezen, A; Henseler, A; Schönland, S; Kröger, N; Schetelig, J

    2017-03-01

    Even with the availability of targeted drugs, allogeneic hematopoietic cell transplantation (allo-HCT) is the only therapy with curative potential for patients with CLL. Cure can be assessed by comparing long-term survival of patients to the matched general population. Using data from 2589 patients who received allo-HCT between 2000 and 2010, we used landmark analyses and methods from relative survival analysis to calculate excess mortality compared with an age-, sex- and calendar year-matched general population. Estimated event-free survival, overall survival and non-relapse mortality (NRM) 10 years after allo-HCT were 28% (95% confidence interval (CI), 25-31), 35% (95% CI, 32-38) and 40% (95% CI, 37-42), respectively. Patients who passed the 5-year landmark event-free survival (N=394) had a 79% probability (95% CI, 73-85) of surviving the subsequent 5 years without an event. Relapse and NRM contributed equally to treatment failure. Five-year mortality for 45- and 65-year-old reference patients who were event-free at the 5-year landmark was 8% and 47% compared with 3% and 14% in the matched general population, respectively. The prospect of long-term disease-free survival remains an argument to consider allo-HCT for young patients with high-risk CLL, and programs to understand and prevent late causes of failure for long-term survivors are warranted, especially for older patients.

  8. Up-to-date tools for risk assessment before allogeneic hematopoietic cell transplantation.

    PubMed

    Elsawy, M; Sorror, M L

    2016-10-01

    Cure of malignant and non-malignant hematological diseases is potentially possible after allogeneic hematopoietic stem cell transplantation (HCT). Accurate evaluation of the risk-benefit ratio for an individual patient could improve the decision-making process about transplant, which ultimately would increase the likelihood of success. Several transplant-related models were designed in an effort to optimize decision-making about suitable candidates for allogeneic HCT. In 1998, The European Society for Blood and Marrow Transplantation (EBMT) developed a five-component pretransplantation risk scoring system for patients with CML. The EBMT score was later tested in patients with various hematological disorders, and it was shown to stratify risks of mortality after allogeneic HCT. More recent research efforts focused on models that assess health status before HCT. A HCT-specific comorbidity index was designed to assign weights to 17 relevant comorbidities that were shown to independently predict non-relapse mortality. Performance status scales and comprehensive geriatric assessment tools might uncover additional overall health limitations that affect long-term survival among older recipients of allogeneic HCT. Other models include the pretransplantation assessment of mortality score that summarizes the impacts of eight different pretransplantation patient- and disease-specific variables into a 50-point model that predicts survival. The disease-risk index captures the impact of primary diagnoses and disease status on relapse and survival following allogeneic HCT. The values and limitations of each model are discussed herein. We also provide insight on how to use these models in the clinic to decide about offering allogeneic HCT with the most suitable conditioning regimen intensity.

  9. Eltrombopag for Treatment of Thrombocytopenia after Allogeneic Hematopoietic Cell Transplantation.

    PubMed

    Tanaka, Takashi; Inamoto, Yoshihiro; Yamashita, Takuya; Fuji, Shigeo; Okinaka, Keiji; Kurosawa, Saiko; Kim, Sung-Won; Tanosaki, Ryuji; Fukuda, Takahiro

    2016-05-01

    Persistent thrombocytopenia is a common complication after allogeneic hematopoietic cell transplantation (HCT). Eltrombopag is an oral thrombopoietin receptor agonist whose efficacy against persistent thrombocytopenia after allogeneic HCT has not been well characterized. This retrospective study evaluated the safety and efficacy of eltrombopag in 12 consecutive patients with persistent thrombocytopenia after allogeneic HCT. Eltrombopag was started at 12.5 mg once daily and the dose was increased by 12.5 mg daily every week until platelet counts exceeded 50,000/μL. Five patients had prolonged isolated thrombocytopenia (PIT) and 7 patients had secondary failure of platelet recovery (SFPR). The cumulative incidence rate of successful platelet recovery to ≥50,000/μL without transfusion support was 60% in PIT patients and 71% in SFPR patients. No patients discontinued the drug because of adverse events or intolerability. Notably, the rate of platelet recovery was higher (100% versus 58%; P = .0017) and recovery was faster (median, 33 days versus 137 days; P = .0078) in patients with normal numbers of bone marrow megakaryocytes before starting eltrombopag than in those with decreased numbers of megakaryocytes. Eltrombopag is a promising treatment for both PIT and SFPR after allogeneic HCT. The number of megakaryocytes in bone marrow before eltrombopag treatment may predict the response to eltrombopag.

  10. Factors associated with hematopoietic cell transplantation (HCT) among patients in a population-based study of myelodysplastic syndrome (MDS) in Minnesota.

    PubMed

    Smith, Angela R; Warlick, Erica D; Roesler, Michelle A; Poynter, Jenny N; Richardson, Michaela; Nguyen, Phuong; Cioc, Adina; Hirsch, Betsy; Ross, Julie A

    2015-10-01

    Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by dysplastic changes in the bone marrow, ineffective erythropoiesis, and an increased risk of developing acute myeloid leukemia. Treatment planning for patients with MDS is a complex process, and we sought to better characterize hematopoietic cell transplantation (HCT) outcomes and the factors that play into decision-making regarding referral of adults with MDS for definitive therapy with HCT. Patients enrolled in a population-based study of MDS between April 2010 and January 2013 who underwent HCT within the first year after enrollment were included in this analysis. Age- and risk-matched MDS patient controls also enrolled during that time period were used as a comparison. Survival was significantly better in the HCT group (48 vs. 21 %, log-rank p value 0.009). Non-HCT patients were more likely to have comorbidities, and HCT patients were more likely to have a college degree and an income >$80,000. All three of these variables were independently associated with HCT, but none impacted survival. Patients with MDS in our study who underwent HCT had better survival than a comparable group of patients who did not undergo HCT. With refined treatment techniques, more patients may be able to be considered for this therapy. More work needs to be done to determine why education and income appear to impact the decision to pursue HCT, but these factors may impact referral to an academic center where aggressive therapy like HCT is more likely to be considered.

  11. Reduced-intensity allogeneic transplant in patients older than 55 years: unrelated umbilical cord blood is safe and effective for patients without a matched related donor.

    PubMed

    Majhail, Navneet S; Brunstein, Claudio G; Tomblyn, Marcie; Thomas, Avis J; Miller, Jeffrey S; Arora, Mukta; Kaufman, Dan S; Burns, Linda J; Slungaard, Arne; McGlave, Philip B; Wagner, John E; Weisdorf, Daniel J

    2008-03-01

    The lower morbidity and mortality of reduced-intensity conditioning (RIC) regimens have allowed allogeneic hematopoietic cell transplantation (HCT) in older patients. Unrelated umbilical cord blood (UCB) has been investigated as an alternative stem cell source to suitably HLA matched related (MRD) and adult volunteer unrelated donors. We hypothesized that RIC HCT using UCB would be safe and efficacious in older patients, and compared the treatment-related mortality (TRM) and overall survival (OS) of RIC HCT in patients older than 55 years using either MRD (n = 47) or, in patients with no 5 of 6 or 6 of 6 HLA compatible related donors, UCB (n = 43). RIC regimen consisted of total-body irradiation (TBI; 200 cGy) and either cyclophosphamide and fludarabine (n = 69), or busulfan and fludarabine (n = 16) or busulfan and cladribine (n = 5). The median age of MRD and UCB cohorts was 58 (range, 55-70) and 59 (range, 55-69) years, respectively. acute myelogenous leukemia/myelodysplastic syndrome (AML/MDS) (50%) was the most common diagnosis. All MRD grafts were 6 of 6 HLA matched to the recipient. Among patients undergoing UCB HCT, 88% received 2 UCB units to optimize cell dose and 93% received 1-2 HLA mismatched grafts. The median follow-up for survivors was 27 (range: 12-61) months. The 3-year probabilities of progression-free survival (PFS; 30% versus 34%, P = .98) and OS (43% versus 34%, P = .57) were similar for recipients of MRD and UCB. The cumulative incidence of grade II-IV acute graft-versus-host (aGVHD) disease (42% versus 49%, P = .20) and TRM at 180-days (23% versus 28%, P = .36) were comparable. However, UCB recipients had a lower incidence of chronic graft-versus-host disease (cGVHD) at 1 year (40% versus 17%, P = .02). On multivariate analysis, graft type had no impact on TRM or survival, and the HCT comorbidity index score was the only factor independently predictive for these endpoints. Our study supports the use of HLA mismatched UCB as an alternative

  12. Reduced Intensity Allogeneic Transplant In Patients Older Than 55 Years: Unrelated Umbilical Cord Blood Is Safe And Effective For Patients Without A Matched Related Donor

    PubMed Central

    Majhail, Navneet S; Brunstein, Claudio G; Tomblyn, Marcie; Thomas, Avis J; Miller, Jeffrey S; Arora, Mukta; Kaufman, Dan S; Burns, Linda J; Slungaard, Arne; McGlave, Philip B; Wagner, John E; Weisdorf, Daniel J

    2009-01-01

    The lower morbidity and mortality of reduced-intensity conditioning (RIC) regimens have allowed allogeneic hematopoietic cell transplantation (HCT) in older patients. Unrelated umbilical cord blood (UCB) has been investigated as an alternative stem cell source to suitably HLA matched related (MRD) and adult volunteer unrelated donors. We hypothesized that RIC HCT using UCB would be safe and efficacious in older patients and compared the transplant related mortality (TRM) and overall survival of RIC HCT in patients older than 55 years using either MRD (n=47) or, in patients with no 5/6 or 6/6 HLA compatible related donors, UCB (n=43). RIC regimen consisted of total-body irradiation (200 cGy) and either cyclophosphamide and fludarabine (n=69), or busulfan and fludarabine (n=16) or busulfan and cladribine (n=5). The median age of MRD and UCB cohorts was 58 (range, 55-70) and 59 (range, 55-69) years, respectively. AML/MDS (50%) was the most common diagnosis. All MRD grafts were 6 of 6 HLA matched to the recipient. Among patients undergoing UCB HCT, 88% received two UCB units to optimize cell dose and 93% received 1-2 HLA mismatched grafts. The median followup for survivors was 27 (range, 12-61) months. The 3-year probabilities of progression-free survival (30% vs. 34%, p=0.98) and overall survival (43% vs. 34%, p=0.57) were similar for recipients of MRD and UCB. The cumulative incidence of grade 2-4 acute graft-versus-host disease (42% vs. 49%, p=0.20) and TRM at 180-days (23% vs. 28%, p=0.36) were comparable. However, UCB recipients had a lower incidence of chronic graft-versus-host disease at 1-year (40% vs. 17%, p=0.02). On multivariate analysis, graft type had no impact on TRM or survival and HCT comorbidity index score was the only factor independently predictive for these endpoints. Our study supports the use of HLA mismatched UCB as an alternative graft source for older patients who need a transplant but do not have a MRD. The use of RIC and UCB extends the

  13. Ipilimumab for Patients with Relapse after Allogeneic Transplantation

    PubMed Central

    Davids, Matthew S.; Kim, Haesook T.; Bachireddy, Pavan; Costello, Caitlin; Liguori, Rebecca; Savell, Alexandra; Lukez, Alexander P.; Avigan, David; Chen, Yi-Bin; McSweeney, Peter; LeBoeuf, Nicole R.; Rooney, Michael S.; Bowden, Michaela; Zhou, Chensheng W.; Granter, Scott R.; Hornick, Jason L.; Rodig, Scott J.; Hirakawa, Masahiro; Severgnini, Mariano; Hodi, F. Stephen; Wu, Catherine J.; Ho, Vincent T.; Cutler, Corey; Koreth, John; Alyea, Edwin P.; Antin, Joseph H.; Armand, Philippe; Streicher, Howard; Ball, Edward D.; Ritz, Jerome; Bashey, Asad; Soiffer, Robert J.

    2016-01-01

    BACKGROUND Loss of donor-mediated immune antitumor activity after allogeneic hematopoietic stem-cell transplantation (HSCT) permits relapse of hematologic cancers. We hypothesized that immune checkpoint blockade established by targeting cytotoxic T-lymphocyte–associated protein 4 with ipilimumab could restore antitumor reactivity through a graft-versus-tumor effect. METHODS We conducted a phase 1/1b multicenter, investigator-initiated study to determine the safety and efficacy of ipilimumab in patients with relapsed hematologic cancer after allogeneic HSCT. Patients received induction therapy with ipilimumab at a dose of 3 or 10 mg per kilogram of body weight every 3 weeks for a total of 4 doses, with additional doses every 12 weeks for up to 60 weeks in patients who had a clinical benefit. RESULTS A total of 28 patients were enrolled. Immune-related adverse events, including one death, were observed in 6 patients (21%), and graft-versus-host disease (GVHD) that precluded further administration of ipilimumab was observed in 4 patients (14%). No responses that met formal response criteria occurred in patients who received a dose of 3 mg per kilogram. Among 22 patients who received a dose of 10 mg per kilogram, 5 (23%) had a complete response, 2 (9%) had a partial response, and 6 (27%) had decreased tumor burden. Complete responses occurred in 4 patients with extramedullary acute myeloid leukemia and 1 patient with the myelodysplastic syndrome developing into acute myeloid leukemia. Four patients had a durable response for more than 1 year. Responses were associated with in situ infiltration of cytotoxic CD8+ T cells, decreased activation of regulatory T cells, and expansion of subpopulations of effector T cells in the blood. CONCLUSIONS Our early-phase data showed that administration of ipilimumab was feasible in patients with recurrent hematologic cancers after allogeneic HSCT, although immune-mediated toxic effects and GVHD occurred. Durable responses were

  14. Allogeneic Hematopoietic Cell Transplantation for Children with Sickle Cell Disease Is Beneficial and Cost-Effective: A Single-Center Analysis.

    PubMed

    Arnold, Staci D; Jin, Zhezhen; Sands, Stephen; Bhatia, Monica; Kung, Andrew L; Satwani, Prakash

    2015-07-01

    Limited data exist regarding health care utilization (HCU) in patients receiving allogeneic hematopoietic cell transplantation (alloHCT) for sickle cell disease. Financial data from 2002 to 2011 were analyzed for 26 alloHCT patients and 48 control subjects (referred but without alloHCT). HCU of alloHCT was determined over 3 time periods: pre-alloHCT, during alloHCT (day 0 to day +365), and post-alloHCT. The median total cost per patient during the alloHCT year was $413,000 inpatient and $18,000 outpatient. Post-alloHCT HCU decreased when compared with pre-alloHCT and control subjects. The median cost of post-alloHCT outpatient visits per patient was significantly less when compared with pre-alloHCT (P = .044). The median cost of post-alloHCT inpatient visits per patient approached significance when compared with those pre-alloHCT (P = .079). Sixteen post-alloHCT patients, 19 control subjects, and 14 unaffected siblings were surveyed using Pediatric Quality of Life Inventory and EuroQOL questionnaires; however, the questionnaire scores across all 3 patient groups were not statistically significant (P = .2638). When adjusted for health-related quality of life, the analysis suggested alloHCT has a positive impact on health-related quality of life over control subjects. These pilot data support our hypothesis that alloHCT in children with sickle cell disease reduces HCU compared with control subjects without alloHCT.

  15. Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50-75 with Intermediate-2 and High Risk Myelodysplastic Syndrome Blood and Marrow Transplant Clinical Trials Network #1102 Study Rationale, Design and Methods

    PubMed Central

    Saber, Wael; Le Rademacher, Jennifer; Sekeres, Mikkael; Logan, Brent; Lewis, Moira; Mendizabal, Adam; Leifer, Eric; Appelbaum, Frederick R.; Horowitz, Mary M; Nakamura, Ryotaro; Cutler, Corey S.

    2014-01-01

    The introduction of reduced intensity conditioning regimens (RIC) made it possible to offer allogeneic hematopoietic cell transplantation (alloHCT) to older patients with myelodysplastic syndromes (MDS). However, the relative risks and benefits of alloHCT compared to novel non-transplant therapies continue to be the source of considerable uncertainty. We will perform a prospective biologic assignment trial to compare RIC alloHCT to non-transplant therapies based on donor availability. Primary outcome is 3-year overall survival. Secondary outcomes include leukemia-free survival, quality of life, and cost-effectiveness. Four hundred patients will be enrolled over roughly 3 years. Planned subgroup analyses will evaluate key biologic questions, such as the impact of age & response to hypomethylating agents on treatment effects. Findings from this study potentially may set a new standard of care for older MDS patients who are considered candidates for alloHCT. PMID:24972249

  16. Autologous or Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Chemotherapy-Sensitive Mantle-Cell Lymphoma: Analysis of Transplantation Timing and Modality

    PubMed Central

    Fenske, Timothy S.; Zhang, Mei-Jie; Carreras, Jeanette; Ayala, Ernesto; Burns, Linda J.; Cashen, Amanda; Costa, Luciano J.; Freytes, César O.; Gale, Robert P.; Hamadani, Mehdi; Holmberg, Leona A.; Inwards, David J.; Lazarus, Hillard M.; Maziarz, Richard T.; Munker, Reinhold; Perales, Miguel-Angel; Rizzieri, David A.; Schouten, Harry C.; Smith, Sonali M.; Waller, Edmund K.; Wirk, Baldeep M.; Laport, Ginna G.; Maloney, David G.; Montoto, Silvia; Hari, Parameswaran N.

    2014-01-01

    Purpose To examine the outcomes of patients with chemotherapy-sensitive mantle-cell lymphoma (MCL) following a first hematopoietic stem-cell transplantation (HCT), comparing outcomes with autologous (auto) versus reduced-intensity conditioning allogeneic (RIC allo) HCT and with transplantation applied at different times in the disease course. Patients and Methods In all, 519 patients who received transplantations between 1996 and 2007 and were reported to the Center for International Blood and Marrow Transplant Research were analyzed. The early transplantation cohort was defined as those patients in first partial or complete remission with no more than two lines of chemotherapy. The late transplantation cohort was defined as all the remaining patients. Results Auto-HCT and RIC allo-HCT resulted in similar overall survival from transplantation for both the early (at 5 years: 61% auto-HCT v 62% RIC allo-HCT; P = .951) and late cohorts (at 5 years: 44% auto-HCT v 31% RIC allo-HCT; P = .202). In both early and late transplantation cohorts, progression/relapse was lower and nonrelapse mortality was higher in the allo-HCT group. Overall survival and progression-free survival were highest in patients who underwent auto-HCT in first complete response. Multivariate analysis of survival from diagnosis identified a survival benefit favoring early HCT for both auto-HCT and RIC allo-HCT. Conclusion For patients with chemotherapy-sensitive MCL, the optimal timing for HCT is early in the disease course. Outcomes are particularly favorable for patients undergoing auto-HCT in first complete remission. For those unable to achieve complete remission after two lines of chemotherapy or those with relapsed disease, either auto-HCT or RIC allo-HCT may be effective, although the chance for long-term remission and survival is lower. PMID:24344210

  17. Allogeneic Hematopoietic Stem Cell Transplantation is Underutilized in Older Patients with Myelodysplastic Syndromes.

    PubMed

    Getta, Bartlomiej M; Kishtagari, Ashwin; Hilden, Patrick; Tallman, Martin S; Maloy, Molly; Gonzales, Patrick; Castro-Malaspina, Hugo; Perales, Miguel-Angel; Giralt, Sergio; Tamari, Roni; Klimek, Virginia

    2017-03-20

    Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative treatment for myelodysplastic syndrome (MDS). The proportion of MDS patients referred for transplant evaluation, those undergoing transplantation and the reasons for not undergoing transplant are unknown. In this retrospective analysis, pre-defined HCT eligibility and indications criteria were applied to 362 unselected patients with newly diagnosed MDS seen by Leukemia faculty between 2008 and 2015 at Memorial Sloan Kettering Cancer Center. Two hundred ninety four patients (81%) were deemed eligible for transplant and among these, transplant was considered indicated in 244 (83%). Of these, 158/244 (65%) were referred for transplant evaluation at a median of 3.9 months from diagnosis. Overall 120/362 (33%) underwent transplant at a median of 7.7 months from diagnosis. Metastatic solid organ malignancy was the major reason for transplant ineligibility (54%), and death due to MDS, which occurred in 41% of candidates who were not transplanted, was the major reason for not undergoing transplant. Factors associated with a lower likelihood of referral for transplant evaluation included age ≥65 (p<0.001), ≥2 co-morbidities (p=0.008), intermediate-1/low risk MDS (p<0.001), <5% blasts at diagnosis (overall p<0.001), having medicare/medicaid health insurance (p<0.001), not being married (p=0.017) and diagnosis between 2008-2011 (p=0.035). On multivariate analysis adjusting for all of the previous, diagnosis between 2008-2011 (p<0.001), age ≥65 (p=0.001) and <5% blasts at diagnosis (overall p=0.031) were associated with a lower likelihood of referral for transplant evaluation. Factors associated with a lower likelihood of undergoing transplant included age ≥65 (p<0.001), ≥2 co-morbidities (p=0.003), intermediate-1/low risk MDS (p<0.001), <5% blasts (overall p<0.001), very low/low/intermediate risk IPSS-R karyotype (p=0.018) and having medicare/medicaid health insurance (p<0.001). In

  18. Hematopoietic cell transplantation activity of Turkey in 2014: Ongoing increase in HCT rates.

    PubMed

    Tekgündüz, Emre; Şencan, İrfan; Kapuağası, Arif; Ünal, Doğan; Öztürk, Murat; Gümüş, Eyüp; Göker, Hakan; Tavil, Emine Betül; Ertem, Mehmet; Çetin, Mustafa; Arat, Mutlu; Soysal, Teoman; Karakaşlı, Osman; Sur, Halil Yılmaz; Yeşilipek, Akif; Ferhanoğlu, Burhan; Uçkan, Duygu; İlhan, Osman; Altuntaş, Fevzi

    2016-02-01

    Hematopoietic cell transplantation is an established treatment option with curative potential for a variety of clinical conditions. The last decade especially witnessed a remarkable increase in HCT activity in Turkey. In 2014, 696 pediatric and 2631 adult (total 3327) HCT were performed in Turkey. Corresponding transplant rates per 10 million inhabitants for autologous-HCT and allogeneic-HCT were 226 and 202, respectively. Total HCT procedures in Turkey increased 177% in the last 5 years and 791% in the last 14 years. This report focuses mainly on HCT activity of Turkey in 2014 based on the national HCT registry and presents a general picture of national HCT activity.

  19. Osteonecrosis in children after allogeneic hematopoietic cell transplantation: study of prevalence, risk factors and longitudinal changes using MR imaging.

    PubMed

    Sharma, S; Leung, W-H; Deqing, P; Yang, J; Rochester, R; Britton, L; Neel, M D; Ness, K K; Kaste, S C

    2012-08-01

    Osteonecrosis after hematopoietic SCT (HCT) has seldom been addressed in pediatric populations. At our institution, since January 2002, children undergoing allogeneic HCT (alloHCT) receive yearly follow-up magnetic resonance imaging (MR) of hips and knees. To estimate the prevalence, longitudinal changes and associated risk factors for osteonecrosis after alloHCT, we reviewed MRs for children who underwent single alloHCT during the study period. We analyzed 149 of 344 patients who had post-HCT MR imaging performed (84 males; median age 11 years (range, 0.5-21 years)), median follow-up time was 32.6 months (range, 2.8-97.2 months). In all, 44 (29.5%) developed osteonecrosis of hips and/or knees; of those, 20 (45%) had at least 30% epiphyseal involvement. In 23 (52%), osteonecrosis lesions were identified in the first and in 43 (98%) by the third yearly scan. Knees were more frequently involved than hips; severity of osteonecrosis was greater in hips. Those who had pre-alloHCT osteonecrosis, two patients' hips and six patients' knees resolved completely; three patients' osteonecrosis lesions regressed after alloHCT. On risk factor analysis, age at time of alloHCT (P=0.051) and osteonecrosis identified by MRs before alloHCT (P=0.001) were the primary risk factors. This analysis shows that preventive strategies for osteonecrosis in this population should focus on measures to minimize risk factors before alloHCT.

  20. Psychosocial adjustment of pediatric patients after allogeneic stem cell transplantation.

    PubMed

    Felder-Puig, R; Peters, C; Matthes-Martin, S; Lamche, M; Felsberger, C; Gadner, H; Topf, R

    1999-07-01

    The purpose of this study was to assess the psychosocial adjustment of patients who had been treated with allogeneic stem cell transplantation (SCT) in our clinic. Selection criteria for patients were to be aged 14-30 years at the time of the follow-up, to be at least 2 years post-SCT and to have a very good knowledge of German. Among 31 eligible patients, 26 participated (84% response rate). The patients were between 15 and 27 years old and were on average 7 years (range 2-13) post-SCT. Research instruments consisted of a demographic questionnaire and various subscales of established psychological measures for which data from a sample of bone cancer survivors and population norms were available. About 35% of patients showed high levels of anxiety, 62% appeared to be extremely sensitive and vulnerable, and 35% showed strong, unfulfilled needs in their love lives. In the other domains tested (self-esteem, family and peer relationships, school/vocational performance, etc), no noticeable differences were found between the subjects and comparable populations. There was no significant association between psychosocial outcome and demographic features or clinical data. Our results suggest that patients who underwent SCT in their childhood or adolescence are at risk of developing long-term emotional or social problems. Due to the retrospective design of our study and the small sample size, no predictive factors for psychosocial distress could be identified.

  1. Increased Foxp3(+)Helios(+) Regulatory T Cells and Decreased Acute Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation in Patients Receiving Sirolimus and RGI-2001, an Activator of Invariant Natural Killer T Cells.

    PubMed

    Chen, Yi-Bin; Efebera, Yvonne A; Johnston, Laura; Ball, Edward D; Avigan, David; Lekakis, Lazaros J; Bachier, Carlos R; Martin, Paul; Duramad, Omar; Ishii, Yasuyuki; Han, Semi; Jung, Yu-Jin; Lee, Dana; Kunkel, Lori; Negrin, Robert S; Bui, Jack D

    2017-04-01

    Regulatory T (Treg) cells play a central role in immune tolerance and prevention of aberrant immune responses. Several studies have suggested that the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) can be ameliorated by increasing Tregs. We have developed an approach of in vivo expansion of Tregs with RGI-2001, a novel liposomal formulation of a synthetic derivative of alpha-galactosylceramide, a naturally occurring ligand that binds to CD1 and activates and expands invariant natural killer cells. In preclinical studies, a single intravenous infusion of RGI-2001 expanded Treg and could ameliorate GVHD in a mouse model of allogeneic HCT. To explore the role of RGI-2001 in clinical HCT, we initiated a phase 2A clinical trial (n = 29), testing 2 different doses of RGI-2001 administered as a single infusion on day 0 of allogeneic HCT. RGI-2001 was well tolerated and without infusion reactions or cytokine release syndrome. A subset of patients (8 of 29, 28%) responded to RGI-2001 by inducing a markedly increased number of cells with a Treg phenotype. The Treg had a high Ki-67 index and were almost exclusively Helios(+) and Foxp3(+), indicating that their accumulation was due to expansion of natural Treg. Notably, the incidence of grade 2 to 4 GVHD in the 8 patients who responded to RGI-2001 was 12.5%, compared with 52.4% in the 21 patients who did not respond. No grade 3 or 4 GVHD was observed in the responder group, compared with a 9.5% incidence among nonresponders. Immunosuppression with sirolimus was also associated with a low incidence of GVHD, suggesting that RGI-2001 may have synergized with sirolimus to promote Treg expansion.

  2. Financial burden in recipients of allogeneic hematopoietic cell transplantation.

    PubMed

    Khera, Nandita; Chang, Yu-hui; Hashmi, Shahrukh; Slack, James; Beebe, Timothy; Roy, Vivek; Noel, Pierre; Fauble, Veena; Sproat, Lisa; Tilburt, Jon; Leis, Jose F; Mikhael, Joseph

    2014-09-01

    Although allogeneic hematopoietic cell transplantation (HCT) is an expensive treatment for hematological disorders, little is known about the financial consequences for the patients who undergo this procedure. We analyzed factors associated with its financial burden and its impact on health behaviors of allogeneic HCT recipients. A questionnaire was retrospectively mailed to 482 patients who underwent allogeneic HCT from January 2006 to June 2012 at the Mayo Clinic, to collect information regarding current financial concerns, household income, employment, insurance, out-of-pocket expenses, and health and functional status. A multivariable logistic regression analysis identified factors associated with financial burden and treatment nonadherence. Of the 268 respondents (56% response rate), 73% reported that their sickness had hurt them financially. All patients for whom the insurance information was available (missing, n = 13) were insured. Forty-seven percent of respondents experienced financial burden, such as household income decreased by >50%, selling/mortgaging home, or withdrawing money from retirement accounts. Three percent declared bankruptcy. Younger age and poor current mental and physical functioning increased the likelihood of financial burden. Thirty-five percent of patients reported deleterious health behaviors because of financial constraints. These patients were likely to be younger, have lower education, and with a longer time since HCT. Being employed decreased the likelihood of experiencing financial burden and treatment nonadherence due to concern about costs. A significant proportion of allogeneic HCT survivors experience financial hardship despite insurance coverage. Future research should investigate potential interventions to help at-risk patients and prevent adverse financial outcomes after this life-saving procedure.

  3. Up-front allogeneic hematopoietic cell transplantation in acute myeloid leukemia arising from the myelodysplastic syndrome.

    PubMed

    Choi, Yunsuk; Kim, Sung-Doo; Park, Young-Hoon; Lee, Jae Seok; Kim, Dae-Young; Lee, Jung-Hee; Lee, Kyoo-Hyung; Seol, Miee; Lee, Young-Shin; Kang, Young-Ah; Jeon, Mijin; Jung, Ah Rang; Lee, Je-Hwan

    2015-01-01

    In patients with secondary acute myeloid leukemia (s-AML) arising from the myelodysplastic syndrome (MDS), treatment outcome is unsatisfactory. We compared up-front allogeneic hematopoietic cell transplantation (HCT) to induction chemotherapy (IC) as an initial treatment in patients with s-AML arising from MDS. This retrospective study included 85 patients who were diagnosed with s-AML arising from MDS; 11 patients proceeded to up-front HCT without IC (HCT group) and 74 received IC (IC group) as an initial treatment for s-AML, 28 of whom subsequently underwent HCT. In the IC group, 41.9% achieved complete remission (CR) compared to 81.8% in the HCT group (p = 0.013). The HCT group showed a significantly longer event-free survival (EFS) than the IC group (median 29.2 vs. 5.2 months, p = 0.042). Overall survival of the HCT group was higher than that of the IC group, but the difference was not statistically significant (median 34.6 vs. 7.6 months, p = 0.149). After adjustment for other clinical factors, outcome in the HCT group was significantly better than in the IC group in terms of CR rate (hazard ratio, HR, 11.195; p = 0.007) and EFS (HR, 0.384; p = 0.029). Up-front HCT is a viable option in s-AML arising from MDS if an appropriate donor is available.

  4. Late-Onset Cerebral Toxoplasmosis After Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Khalaf, Ahmed M.; Hashim, Mahmoud A.; Alsharabati, Mohammed; Fallon, Kenneth; Cure, Joel K.; Pappas, Peter; Mineishi, Shin; Saad, Ayman

    2017-01-01

    Patient: Male, 44 Final Diagnosis: Cerebral toxoplasmosis after HSCT Symptoms: Hemiparesis • muscle weakness Medication: — Clinical Procedure: — Specialty: Hematology Objective: Unusual clinical course Background: Toxoplasmosis is an uncommon but potentially fatal complication following allogeneic hematopoietic stem cell transplantation (HCT). Post-transplant toxoplasmosis is often a reactivation of prior infection and typically occurs within the first 6 months of transplant. Herein, we report that cerebral toxoplasmosis may occur 22 months after allogeneic hematopoietic stem cell transplantation. Case Report: We describe a case of cerebral toxoplasmosis that occurred 22 months after an allogeneic HCT while the patient was on aerosolized pentamidine for Pneumocystis jiroveci pneumonia (PCP) prophylaxis. The disease was only diagnosed after brain biopsy because of atypical MRI appearance of the cerebral lesion and negative Toxoplasma gondii IgG antibody test result in the cerebrospinal fluid (CSF). The patient received pyrimethamine and sulfadiazine treatment, with dramatic improvement after several months. The patient is alive 2 years after infection diagnosis, with no evidence of disease and is off Toxoplasma prophylaxis. Conclusions: Cerebral toxoplasmosis can occur late after allogeneic HCT while patients are on immunosuppression therapy, with atypical features on imaging studies and negative Toxoplasma gondii IgG antibody test result in the CSF. Pre-transplant serologic screening for T. gondii antibodies in allogeneic transplant candidates is warranted. Brain biopsy can be a helpful diagnostic tool for cerebral lesions. PMID:28280256

  5. Factors associated with improved outcomes after second allogeneic hematopoietic cell transplantation for relapsed pediatric leukemia.

    PubMed

    Menon, Neethu N; Jenkins, Lydia M; Cui, Haiyan; Jenkins, Craig; Anwer, Faiz; Yeager, Andrew M; Katsanis, Emmanuel

    2016-03-01

    A second allogeneic (allo) hematopoietic cell transplant (HCT) is an important therapeutic consideration for patients relapsing after their first. We conducted a retrospective review of 41 pediatric patients with leukemia that underwent a second allo-HCT at our institution. Overall, 53.7 and 43.9 % of patients were alive and disease-free at 1 and 5 years, respectively, after the second allo-HCT. The factors affecting outcome by both univariate and multivariate analysis were interval between transplants and the use of a myeloablative conditioning (MAC) regimen prior to second transplant. Outcomes were inferior in patients who received their second transplant <6 months from their first HCT when compared to patients in whom the interval between HCTs was 6-12 or more than 12 months. Interval between HCTs was also significant when each type of leukemia (acute lymphoblastic leukemia (ALL) n = 21, acute myelogenous leukemia (AML) n = 11, and chronic myelogenous leukemia (CML) n = 7) was analyzed separately. In univariate analysis, use of the same donor and use of a matched sibling donor resulted in significant improved outcome. There was not a significant association between disease-free survival (DFS) and age, remission status, use of total body irradiation (TBI) before second HCT, or type of leukemia. Second allogeneic HCT can be a curative therapeutic option for leukemia patients relapsing after their first transplant. As more targeted therapies have become available, patients that relapse after first HCT are more likely to achieve remission. Therefore, it is anticipated that there will be more candidates for second HCT with improved performance and remission status, ultimately leading to a better outcome with the second HCT.

  6. Late-Onset Cerebral Toxoplasmosis After Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Khalaf, Ahmed M; Hashim, Mahmoud A; Alsharabati, Mohammed; Fallon, Kenneth; Cure, Joel K; Pappas, Peter; Mineishi, Shin; Saad, Ayman

    2017-03-10

    BACKGROUND Toxoplasmosis is an uncommon but potentially fatal complication following allogeneic hematopoietic stem cell transplantation (HCT). Post-transplant toxoplasmosis is often a reactivation of prior infection and typically occurs within the first 6 months of transplant. Herein, we report that cerebral toxoplasmosis may occur 22 months after allogeneic hematopoietic stem cell transplantation. CASE REPORT We describe a case of cerebral toxoplasmosis that occurred 22 months after an allogeneic HCT while the patient was on aerosolized pentamidine for Pneumocystis jiroveci pneumonia (PCP) prophylaxis. The disease was only diagnosed after brain biopsy because of atypical MRI appearance of the cerebral lesion and negative Toxoplasma gondii IgG antibody test result in the cerebrospinal fluid (CSF). The patient received pyrimethamine and sulfadiazine treatment, with dramatic improvement after several months. The patient is alive 2 years after infection diagnosis, with no evidence of disease and is off Toxoplasma prophylaxis. CONCLUSIONS Cerebral toxoplasmosis can occur late after allogeneic HCT while patients are on immunosuppression therapy, with atypical features on imaging studies and negative Toxoplasma gondii IgG antibody test result in the CSF. Pre-transplant serologic screening for T. gondii antibodies in allogeneic transplant candidates is warranted. Brain biopsy can be a helpful diagnostic tool for cerebral lesions.

  7. Long-term survival outcomes of reduced-intensity allogeneic or autologous transplantation in relapsed grade 3 follicular lymphoma.

    PubMed

    Klyuchnikov, E; Bacher, U; Woo Ahn, K; Carreras, J; Kröger, N M; Hari, P N; Ku, G H; Ayala, E; Chen, A I; Chen, Y-B; Cohen, J B; Freytes, C O; Gale, R P; Kamble, R T; Kharfan-Dabaja, M A; Lazarus, H M; Martino, R; Mussetti, A; Savani, B N; Schouten, H C; Usmani, S Z; Wiernik, P H; Wirk, B; Smith, S M; Sureda, A; Hamadani, M

    2016-01-01

    Grade 3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade 3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs autologous hematopoietic cell transplantation (auto-HCT) in the rituximab era. A total of 197 patients undergoing first reduced-intensity conditioning (RIC) allo-HCT or first auto-HCT during 2000-2012 were included. Rituximab-naive patients were excluded. Allo-HCT recipients were younger, more heavily pretreated and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, PFS and overall survival (OS) for auto-HCT vs allo-HCT groups were 4% vs 27% (P<0.001), 61% vs 20% (P<0.001), 36% vs 51% (P=0.07) and 59% vs 54% (P=0.7), respectively. On multivariate analysis, auto-HCT was associated with reduced risk of NRM (relative risk (RR)=0.20; P=0.001). Within the first 11 months post HCT, auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11 months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; P=0.003) and inferior PFS (RR=3.2; P=0.005). In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.42; P=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; P=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors.

  8. Long-term survival outcomes of reduced-intensity allogeneic or autologous transplantation in relapsed grade 3 follicular lymphoma

    PubMed Central

    Klyuchnikov, Evgeny; Bacher, Ulrike; Ahn, Kwang Woo; Carreras, Jeanette; Kröger, Nicolaus M.; Hari, Parameswaran N.; Ku, Grace H.; Ayala, Ernesto; Chen, Andy I.; Chen, Yi-Bin; Cohen, Jonathon B.; Freytes, César O.; Gale, Robert Peter; Kamble, Rammurti T.; Kharfan-Dabaja, Mohamed A.; Lazarus, Hillard M.; Martino, Rodrigo; Mussetti, Alberto; Savani, Bipin N.; Schouten, Harry C.; Usmani, Saad Z.; Wiernik, Peter H.; Wirk, Baldeep; Smith, Sonali M.; Sureda, Anna; Hamadani, Mehdi

    2015-01-01

    Grade-3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade-3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs. autologous hematopoietic cell transplantation (auto-HCT) in the rituximab-era. A total of 197 patients undergoing first RIC allo-HCT or first auto-HCT during 2000-2012 were included. Rituximab-naïve patients were excluded. Allo-HCT recipients were younger; more heavily pretreated, and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, progression-free survival (PFS) and overall survival (OS) for auto-HCT vs. allo-HCT groups were 4% vs. 27% (p<0.001); 61% vs. 20% (p<0.001); 36% vs. 51% (p=0.07) and 59% vs. 54% (p=0.7), respectively. On multivariate analysis auto-HCT was associated with reduced risk of NRM (RR=0.20; p=0.001). Within the first 11months post-HCT auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; p=0.003) and inferior PFS (RR=3.2; p=0.005). In the first 24 months post-HCT, auto-HCT was associated with improved OS (RR=0.42; p=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; p=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors. PMID:26437062

  9. Feasibility of Frequent Patient-Reported Outcome Surveillance in Patients Undergoing Hematopoietic Cell Transplantation

    PubMed Central

    Wood, William A.; Deal, Allison M.; Abernethy, Amy; Basch, Ethan; Battaglini, Claudio; Kim, Yoon Hie; Whitley, Julia; Shatten, Charlotte; Serody, Jon; Shea, Thomas; Reeve, Bryce B.

    2012-01-01

    Patient-reported outcomes (PROs), including symptoms and health-related quality of life (HRQOL), provide a patient-centered description of hematopoietic cell transplantation (HCT)-related toxicity. These data characterize the patient experience after HCT and may have prognostic usefulness for long-term outcomes after HCT. We conducted a study of 32 patients after HCT (10 autologous HCT recipients, 11 full-intensity conditioning allogeneic HCT recipients, and 11 reduced-intensity conditioning allogeneic HCT recipients) to determine the feasibility of weekly electronic PRO collection from HCT until day (D) + 100. We used questions from the PRO version of the Common Terminology Criteria for Adverse Events to capture symptoms, and the Patient-Reported Outcomes Measurement Information System Global Health scale to measure physical and mental HRQOL. The vast majority (94%) of patients used the electronic PRO system, with only 6% opting for paper-and-pencil only. The median weekly percentage of participants who completed the surveys was 100% in all cohorts through hospital discharge, and remained 100% for the autologous HCT and reduced-intensity allogeneic HCT cohorts through D+100. Patients were satisfied with the electronic system, giving high marks for readability, comfort, and questionnaire length. Symptom severity varied by absolute level and type of symptom across the 3 cohorts, with the full-intensity allogeneic HCT cohort exhibiting the greatest median overall symptom severity, peaking at D+7. Median physical health HRQOL scores decreased with time in the 3 cohorts, and HRQOL was generally correlated with overall symptom severity. Our results demonstrate the feasibility of frequent electronic PROs in the early post-HCT period. Future studies in larger populations to explore predictive models using frequent PRO data for outcomes, including long-term HRQOL and survival, are warranted. PMID:23253558

  10. Risk for Clostridium difficile Infection After Allogeneic Hematopoietic Cell Transplant Remains Elevated in the Postengraftment Period

    PubMed Central

    Dubberke, Erik R.; Reske, Kimberly A.; Olsen, Margaret A.; Bommarito, Kerry M.; Seiler, Sondra; Silveira, Fernanda P.; Chiller, Tom M.; DiPersio, John; Fraser, Victoria J.

    2017-01-01

    Background Clostridium difficile infection (CDI) is a frequent cause of diarrhea among allogeneic hematopoietic cell transplant (HCT) recipients. It is unknown whether risk factors for CDI vary by time posttransplant. Methods We performed a 3-year prospective cohort study of CDI in allogeneic HCT recipients. Participants were enrolled during their transplant hospitalizations. Clinical assessments were performed weekly during hospitalizations and for 12 weeks posttransplant, and monthly for 30 months thereafter. Data were collected through patient interviews and chart review, and included CDI diagnosis, demographics, transplant characteristics, medications, infections, and outcomes. CDI cases were included if they occurred within 1 year of HCT and were stratified by time from transplant. Multivariable logistic regression was used to determine risk factors for CDI. Results One hundred eighty-seven allogeneic HCT recipients were enrolled, including 63 (34%) patients who developed CDI. 38 (60%) CDI cases occurred during the preengraftment period (days 0-30 post-HCT) and 25 (40%) postengraftment (day >30). Lack of any preexisting comorbid disease was significantly associated with lower risk of CDI preengraftment (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.9). Relapsed underlying disease (OR, 6.7; 95% CI, 1.3-33.1), receipt of any high-risk antimicrobials (OR, 11.8; 95% CI, 2.9-47.8), and graft-versus-host disease (OR, 7.8; 95% CI, 2.0-30.2) were significant independent risk factors for CDI postengraftment. Conclusions A large portion of CDI cases occurred during the postengraftment period in allogeneic HCT recipients, suggesting that surveillance for CDI should continue beyond the transplant hospitalization and preengraftment period. Patients with continued high underlying severity of illness were at increased risk of CDI postengraftment.

  11. Allogeneic hematopoietic cell transplantation in adult patients with acute lymphoblastic leukemia.

    PubMed

    Marks, David I; Alonso, Laura; Radia, Rohini

    2014-12-01

    This review discusses the use of prognostic factors, patient and donor selection, choice of conditioning regimens, and timing of transplant. It also describes the management of Philadelphia-positive acute lymphocytic leukemia (ALL) and central nervous system disease. All aggressively treated adults with ALL should be considered for allogeneic transplantation and tissue typed at diagnosis. We further suggest that eligible patients be entered into clinical trials (that incorporate transplantation); these unselected prospective outcome data are essential to evaluate the true value of allogeneic transplantation in adults with ALL.

  12. Tailored strategy for AML patients receiving allogeneic peripheral blood stem cell transplantation.

    PubMed

    Sohn, Sang Kyun; Kim, Jong Gwang; Kim, Dong Hwan

    2006-10-01

    Considering the heterogeneity of acute myelogenous leukemia (AML), along with the pros and cons of allogeneic peripheral blood stem cell transplantation (PBSCT), a tailored strategy is needed to minimize the transplant-related mortality and maximize the transplant outcomes in AML patients exhibiting certain factors that have an impact on the post-transplant quality of life and outcomes. The factors that need to be considered when tailoring a strategy in an allogeneic PBSCT setting include the recipient's performance status and co-morbid disease include AML risk stratification, disease status, expected severity of graft-versus-host disease, and the necessity of a graft-versus-leukemia effect. Accordingly, this review article describes a possible tailoring strategy for AML patients receiving allogeneic PBSCT based on certain factors influencing the transplant outcome.

  13. Allogeneic Hematopoietic Cell Transplantation for Myeloma: When and in Whom Does It Work.

    PubMed

    Bashir, Qaiser; Qazilbash, Muzaffar H

    2017-03-11

    The growing list of available therapies for patients with multiple myeloma has resulted in tremendously high response rates and prolonged survival. However, the cure remains elusive. A continued effort at developing strategies to utilize all available treatment modalities in the most effective manner is needed. Allogeneic hematopoietic cell transplantation (allo-HCT) is a robust platform, associated with high response rates, and provides a unique foundation on which immune therapies and novel agents can be employed to improve clinical outcomes. Patients with high-risk myeloma and those relapsing after novel agent-based therapies or early after an autologous HCT should be considered for allo-HCT, ideally in a clinical trial setting. Results from several ongoing studies are expected to provide important information that will help determine the place of allo-HCT in the myeloma treatment algorithm.

  14. The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease.

    PubMed

    Staffas, Anna; Burgos da Silva, Marina; van den Brink, Marcel R M

    2017-02-23

    Hematopoietic cell transplantation (HCT) is a critical treatment of patients with high-risk hematopoietic malignancies, hematological deficiencies, and other immune diseases. In allogeneic HCT (allo-HCT), donor-derived T cells recognize host tissues as foreign, causing graft-versus-host disease (GVHD) which is a main contributor to morbidity and mortality. The intestine is one of the organs most severely affected by GVHD and research has recently highlighted the importance of bacteria, particularly the gut microbiota, in HCT outcome and in GVHD development. Loss of intestinal bacterial diversity is common during the course of HCT and is associated with GVHD development and treatment with broad-spectrum antibiotics. Loss of intestinal diversity and outgrowth of opportunistic pathogens belonging to the phylum Proteobacteria and Enterococcus genus have also been linked to increased treatment-related mortality including GVHD, infections, and organ failure after allo-HCT. Experimental studies in allo-HCT animal models have shown some promising results for prebiotic and probiotic strategies as prophylaxis or treatment of GVHD. Continuous research will be important to define the relation of cause and effect for these associations between microbiota features and HCT outcomes. Importantly, studies focused on geographic and cultural differences in intestinal microbiota are necessary to define applicability of new strategies targeting the intestinal microbiota.

  15. T-cell-depleted allogeneic transplant without donor leukocyte infusions results in excellent long-term survival in patients with multiply relapsed Lymphoma. Predictors for survival after transplant relapse

    PubMed Central

    KENKRE, VAISHALEE P.; HOROWITZ, SARAH; ARTZ, ANDREW S.; LIAO, CHUANHONG; COHEN, KENNETH S.; GODLEY, LUCY A.; KLINE, JUSTIN P.; SMITH, SONALI M.; STOCK, WENDY; VAN BESIEN, KOEN

    2013-01-01

    We analyzed 67 patients with lymphoma who received alemtuzumab-based conditioning regimens for allogeneic stem cell transplant and no post-transplant DLI. The median age was 54 (24–70), 43% had unrelated donors, 34% had chemotherapy refractory disease, and 25% had an elevated LDH. With a median follow-up for survivors of 35 months, the estimated 3-year progression-free survival (PFS) and overall survival (OS) were 30% and 47%, respectively. Chemosensitivity by CT and pre-transplant LDH were independent prognostic factors for both overall survival and progression-free survival. Patient age, performance status, donor type, lymphoma subtype, disease sensitivity by PET, and conditioning regimen did not correlate with PFS and OS. Patients who relapsed greater than 6 months after allogeneic transplant were frequently able to re-enter a subsequent durable remission. Our experience confirms the curative potential of alemtuzumab-containing RIC regimens for allogeneic HCT in patients with relapsed lymphoma without prophylactic DLI. An elevated pre-transplant LDH and chemorefractory disease prior to transplant confer a worse prognosis, while PET scan findings do not have this same implication. Patients who relapse greater than 6 months after their transplant are likely to achieve a subsequent remission with any of a variety of interventions, suggesting that GVL effects can be operative even after recurrence. Our outcomes challenge the utility of the common practice of prophylactic DLI after T-depleted transplant for lymphoma. PMID:21142785

  16. Estimating Demand and Unmet Need for Allogeneic Hematopoietic Cell Transplantation in the United States Using Geographic Information Systems

    PubMed Central

    Besse, Kelsey L.; Preussler, Jaime M.; Murphy, Elizabeth A.; Denzen, Ellen M.; Lill, Michael C.; Chell, Jeffrey W.; Senneka, Mary K.; Majhail, Navneet S.; Williams, Eric P.

    2015-01-01

    Purpose: Allogeneic hematopoietic cell transplantation (HCT) is an increasingly used therapy for many patients with hematologic malignancies and other marrow failure or immune system disorders. The purpose of this study was to quantify and visualize both the demand and unmet need for HCT. Methods: HCT use for 2012 was described using the Center for International Blood and Marrow Transplant Research registry. Potential demand for HCT was calculated using 2012 SEER data and published literature for HCT-treatable conditions. Point locations of transplant centers were geocoded using geographic information system (GIS) software; Thiessen polygons were created to establish adult (age 20 to 74 years) and pediatric (age 0 to 19 years) market areas. Market-area population estimates were calculated using 2012 population estimates by age aggregated by census block. Results: US market areas for HCTs were identified separately for transplant centers treating adult (n = 62) and pediatric patients (n = 52). Overall HCT demand among adults was 16,096, with an unmet need for HCTs of 10,276 patients. For pediatric patients, the total demand was 4,561, with an unmet need of 3,213 potential recipients. Evaluation of adult and pediatric market areas indicated that the largest unmet needs tended to be in areas with large populations. Conclusion: Market-area maps and statistics developed using GIS will help communicate the unmet need for HCT, inform policy, and assist transplant centers in planning for the anticipated growth in HCT use. PMID:25784576

  17. Controversies in autologous and allogeneic hematopoietic cell transplantation in peripheral T/NK-cell lymphomas.

    PubMed

    Shustov, Andrei

    2013-03-01

    Peripheral T-cell and NK-cell lymphomas (PT/NKCL) are a heterogeneous group of lymphoid neoplasms with poor outcomes. There is no consensus on the best front line therapy or management of relapsed/refractory disease. The use of autologous and allogeneic hematopoietic cell transplantation (HCT) has been studied in both settings to improve outcomes. Multiple retrospective and several prospective trials were reported. While at first sight the outcomes in the relapsed/refractory setting appear similar in B-cell and T-cell lymphomas when treated with high dose therapy (HDT) and autologous HCT, it is becoming obvious that only specific subtypes of PTCL benefit from this approach (i.e. anaplastic large cell lymphoma [ALCL] and angioimmunoblastic lymphoma [AITL] in second CR). In less favorable histologies, HDT seems to provide limited benefit, with the majority of patients experiencing post-transplant relapse. The use of autologous HCT to consolidate first remission has been evaluated in several prospective trials. Again, the best results were observed in ALCL, but the superiority of this approach over chemotherapy alone needs confirmation in randomized trials. In less favorable histologies, high-dose consolidation resulted in low survival rates comparable to those obtained with chemotherapy alone, and without randomized trials it is hard to recommend this strategy to all patients with newly diagnosed PT/NKCL. Allogeneic HCT might provide potent and potentially curative graft-vs-lymphoma effect and overcome chemotherapy resistance. Only a few studies have been reported to date on allogeneic HCT in PT/NKCL. Based on available data, eligible patients benefit significantly from this approach, with 50% or more patients achieving long-term disease control or cure, although at the expense of significant treatment related mortality (TRM). Reduced-intensity conditioning regimens appear to have lower TRM and might extend this approach to older patients. With the recent approval of

  18. Allogeneic hematopoietic cell transplantation for primary immune deficiency diseases: current status and critical needs.

    PubMed

    Griffith, Linda M; Cowan, Morton J; Kohn, Donald B; Notarangelo, Luigi D; Puck, Jennifer M; Schultz, Kirk R; Buckley, Rebecca H; Eapen, Mary; Kamani, Naynesh R; O'Reilly, Richard J; Parkman, Robertson; Roifman, Chaim M; Sullivan, Kathleen E; Filipovich, Alexandra H; Fleisher, Thomas A; Shearer, William T

    2008-12-01

    Allogeneic hematopoietic cell transplantation (HCT) has been used for 40 years to ameliorate or cure primary immune deficiency (PID) diseases, including severe combined immunodeficiency (SCID) and non-SCID PID. There is a critical need for evaluation of the North American experience of different HCT approaches for these diseases to identify best practices and plan future investigative clinical trials. Our survey of incidence and prevalence of PID in North American practice sites indicates that such studies are feasible. A conference of experts in HCT treatment of PID has recommended (1) a comprehensive cross-sectional and retrospective analysis of HCT survivors with SCID; (2) a prospective study of patients with SCID receiving HCT, with comparable baseline and follow-up testing across participating centers; (3) a pilot study of newborn screening for SCID to identify affected infants before compromise by infection; and (4) studies of the natural history of disease in patients who do or do not receive HCT for the non-SCID diseases of Wiskott-Aldrich syndrome and chronic granulomatous disease. To accomplish these goals, collaboration by a consortium of institutions in North America is proposed. Participation of immunologists and HCT physicians having interest in PID and experts in laboratory methods, clinical outcomes assessment, databases, and analysis will be required for the success of these studies.

  19. Brentuximab vedotin is associated with improved progression-free survival after allogeneic transplantation for Hodgkin lymphoma

    PubMed Central

    Chen, Robert; Palmer, Joycelynne M.; Tsai, Ni-Chun; Thomas, Sandra H.; Siddiqi, Tanya; Popplewell, Leslie; Farol, Len; Nademanee, Auayporn; Forman, Stephen J.

    2014-01-01

    We previously reported that BV enabled successful reduced-intensity allogeneic hematopoietic cell transplantation (RIC-alloHCT) in patients with relapsed Hodgkin lymphoma, after a median follow-up of 14.4 months. We now provide an updated report on 21 patients who were treated from 2009–2012 with BV prior to RIC-alloHCT with a uniform fludarabine/melphalan conditioning regimen and donor source after a median follow-up of 29.9 months. We have also retrospectively compared the patient characteristics and outcomes of these BV pre-treated patients to 23 patients who received fludarabine/melphalan RIC-alloHCT without prior BV, in the time period before the drug was available (2003–2009, pre-BV era). Patients who were treated with BV prior to RIC-alloHCT had a lower median HCT-specific comorbidity index (HCT-CI) and a reduced number of peri-transplant toxicities. There were also improvements in 2-year PFS (59.3% versus 26.1%) and cumulative incidence of relapse/progression (23.8% versus 56.5%). PMID:25008328

  20. Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Immunosuppressants in Allogeneic Hematopoietic Cell Transplantation: Part II.

    PubMed

    McCune, Jeannine S; Bemer, Meagan J; Long-Boyle, Janel

    2016-05-01

    Part I of this article included a pertinent review of allogeneic hematopoietic cell transplantation (alloHCT), the role of postgraft immunosuppression in alloHCT, and the pharmacokinetics, pharmacodynamics, and pharmacogenomics of the calcineurin inhibitors and methotrexate. In this article (Part II), we review the pharmacokinetics, pharmacodynamics, and pharmacogenomics of mycophenolic acid (MPA), sirolimus, and the antithymocyte globulins (ATG). We then discuss target concentration intervention (TCI) of these postgraft immunosuppressants in alloHCT patients, with a focus on current evidence for TCI and on how TCI may improve clinical management in these patients. Currently, TCI using trough concentrations is conducted for sirolimus in alloHCT patients. Several studies demonstrate that MPA plasma exposure is associated with clinical outcomes, with an increasing number of alloHCT patients needing TCI of MPA. Compared with MPA, there are fewer pharmacokinetic/dynamic studies of rabbit ATG and horse ATG in alloHCT patients. Future pharmacokinetic/dynamic research of postgraft immunosuppressants should include '-omics'-based tools: pharmacogenomics may be used to gain an improved understanding of the covariates influencing pharmacokinetics as well as proteomics and metabolomics as novel methods to elucidate pharmacodynamic responses.

  1. RECIPIENT PRETRANSPLANT INOSINE MONOPHOSPHATE DEHYDROGENASE ACTIVITY IN NONMYELOABLATIVE HCT

    PubMed Central

    Bemer, Meagan J.; Risler, Linda J.; Phillips, Brian R.; Wang, Joanne; Storer, Barry E.; Sandmaier, Brenda M.; Duan, Haichuan; Raccor, Brianne S.; Boeckh, Michael J.; McCune, Jeannine S.

    2014-01-01

    Mycophenolic acid, the active metabolite of mycophenolate mofetil (MMF), inhibits inosine monophosphate dehydrogenase (IMPDH) activity. IMPDH is the rate-limiting enzyme involved in de novo synthesis of guanosine nucleotides and catalyzes the oxidation of inosine 5’- monophosphate (IMP) to xanthosine 5’-monophosphate (XMP). We developed a highly sensitive liquid chromatography–mass spectrometry method to quantitate XMP concentrations in peripheral blood mononuclear cells (PMNC) isolated from the recipient pretransplant and used this method to determine IMPDH activity in 86 nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) patients. The incubation procedure and analytical method yielded acceptable within-sample and within-individual variability. Considerable between-individual variability was observed (12.2-fold). Low recipient pretransplant IMPDH activity was associated with increased day +28 donor T-cell chimerism, more acute graft-versus-host disease (GVHD), lower neutrophil nadirs, and more cytomegalovirus reactivation, but not with chronic GVHD, relapse, non-relapse mortality, or overall mortality. We conclude that quantitation of the recipient’s pretransplant IMPDH activity in PMNC lysate could provide a useful biomarker to evaluate a recipient’s sensitivity to MMF, but confirmatory studies are needed. Further trials should be conducted to confirm our findings and to optimize postgrafting immunosuppression in nonmyeloablative HCT recipients. PMID:24923537

  2. Extramedullary Relapse Following Total Marrow and Lymphoid Irradiation in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

    SciTech Connect

    Kim, Ji Hyun; Stein, Anthony; Schultheiss, Timothy E.; Palmer, Joycelynne; Liu, An; Rosenthal, Joseph; Forman, Stephen J.

    2014-05-01

    Purpose: Approximately 5% to 20% of patients who undergo total body irradiation (TBI) in preparation for hematopoietic cell transplantation (HCT) can develop extramedullary (EM) relapse. Whereas total marrow and lymphoid irradiation (TMLI) provides a more conformally targeted radiation therapy for patients, organ sparing has the potential to place the patient at a higher risk for EM relapse than TBI. This study evaluated EM relapse in patients treated with TMLI at our institution. Methods and Materials: Patients eligible for analysis had been enrolled in 1 of 3 prospective TMLI trials between 2006 and 2012. The TMLI targeted bones, major lymph node chains, liver, spleen, testes, and brain, using image-guided tomotherapy with total dose ranging from 12 to 15 Gy. Results: A total of 101 patients with a median age of 47 years were studied. The median follow-up was 12.8 months. Incidence of EM relapse and bone marrow (BM) relapse were 12.9% and 25.7%, respectively. Of the 13 patients who had EM relapse, 4 also had BM relapse, and 7 had EM disease prior to HCT. There were a total of 19 EM relapse sites as the site of initial recurrence: 11 soft tissue, 6 lymph node, 2 skin. Nine of these sites were within the target region and received ≥12 Gy. Ten initial EM relapse sites were outside of the target region: 5 sites received 10.1 to 11.4 Gy while 5 sites received <10 Gy. Pretransplantation EM was the only significant predictor of subsequent EM relapse. The cumulative incidence of EM relapse was 4% at 1 year and 11.4% at 2 years. Conclusions: EM relapse incidence was as frequent in regions receiving ≥10 Gy as those receiving <10 Gy. EM relapse rates following TMLI that included HCT regimens were comparable to published results with regimens including TBI and suggest that TMLI is not associated with an increased EM relapse risk.

  3. Allogeneic stem cell transplantation for sickle cell disease. A study of patients' decisions.

    PubMed

    van Besien, K; Koshy, M; Anderson-Shaw, L; Talishy, N; Dorn, L; Devine, S; Yassine, M; Kodish, E

    2001-09-01

    Allogeneic stem cell transplantation is increasingly considered as a curative though risky treatment option for adults with sickle cell disease. Little is known about attitudes of adult patients and their health care providers regarding the risks and benefits of transplantation. A survey of 100 patients and their health care providers was undertaken. Assessment of risk was by a reference gamble paradigm. Comparison was made of the characteristics of those accepting substantial risk vs those not accepting risk, as well as assessment of agreement on risks recommended by health care providers and accepted by patients. Sixty-three of 100 patients were willing to accept some short-term risk of mortality in exchange for the certainty of cure. Fifteen patients were willing to accept more than 35% mortality risk. No differences in patient or disease-related variables were identified between those accepting risk and those not accepting risk. There was no agreement between the recommendations of health care providers and the risk accepted by patients. A substantial proportion of adults with sickle cell disease are interested in curative treatment, at the expense of considerable risk. The decision to accept risk is influenced by individual patient values that cannot be easily quantified and that do not correlate with the assessment of the health care provider. Given the substantial interest in curative therapy, education about and consultation for allogeneic stem cell transplantation in sickle cell patients should be encouraged.

  4. Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Patients with Hematologic Malignancies Who Relapse following Autologous Transplantation: A Multi-Institutional Prospective Study from the Cancer and Leukemia Group B (CALGB trial 100002)

    PubMed Central

    Bashey, Asad; Owzar, Kouros; Johnson, Jeffrey L.; Edwards, Peggy S.; Kelly, Michael; Baxter-Lowe, Lee-Ann; Devine, Steven; Farag, Sherif; Hurd, David; Ball, Edward; McCarthy, Philip; Lister, John; Shea, Thomas C.; Linker, Charles

    2013-01-01

    We prospectively treated 80 patients with relapse of malignancy or secondary myelodysplasia after autologous hematopoietic cell transplantation (AHCT) with allogeneic hematopoietic cell transplantation (allo-HCT) using a reduced-intensity conditioning (RIC) regimen of fludarabine 150 mg/m2 plus intravenous busulfan 6.4 mg/kg. Both sibling (MSD) and unrelated donors (MUD) were allowed. Patients transplanted from MUD donors received more intensive graft-versus-host disease (GVHD) prophylaxis, including rabbit anti-thymocyte globulin 10 mg/kg, mycophenolate mofetil, and an extended schedule of tacrolimus. With a median follow-up of 3.1 years (0.9 to 5.8), TRM at 6 months and 2 years was 8% and 23% respectively. Neither TRM nor the rates of acute GVHD were different in those with sibling or MUD donors. Donor CD3 cell chimerism > 90% at day +30 was achieved more often in patients with MUD than with MSD donors, 70% versus 23% (p<0.0001). Median EFS was higher in patients who achieved early full donor chimerism (14.2 versus 8 mo, p = 0.0395). Allo-HCT using this RIC regimen can be performed with low TRM in patients who have received a prior AHCT. Efforts to improve early donor CD3 chimerism may improve EFS. PMID:20674758

  5. Some aspects of allogeneic stem cell transplantation in patients with myelodysplastic syndrome: advances and controversy.

    PubMed

    Blau, Olga; Blau, Igor Wolfgang

    2014-01-01

    Myelodysplastic syndrome (MDS) is a heterogeneous group of myeloid disorders. MDS remains a disease of elderly patients; moreover, the incidence of high risk MDS is proportionally greater in elderly patients, with increased frequency of secondary acute myeloid leukemia, as well as adverse cytogenetic abnormalities. Allogeneic stem cell transplantation is a therapeutic approach with known curative potential for patients with MDS that allows the achievement of long-term disease control. Numerous controversies still exist regarding transplantation in MDS: timing of transplantation, disease status at transplantation and comorbidity, conditioning intensity, pretransplant therapy, and stem cell source. Various transplant modalities of different intensities and alternative donor sources are now in use. Current advances in transplant technology are allowing the consideration of older patients. This should result in a greater number of older patients benefiting from this potentially curative treatment modality. Despite advances in transplantation technology, there is still considerable morbidity and mortality associated with this approach. Nevertheless, with the introduction of reduced-intensity conditioning and thereby reduced early mortality, transplant numbers in MDS patients have significantly increased. Moreover, recent new developments with innovative drugs, including hypomethylating agents, have extended the therapeutic alternatives for MDS patients. Hypomethylating agents allow the delay of allogeneic stem cell transplantation by serving as an effective and well-tolerated means to reduce disease burden.

  6. How I treat late effects in adults after allogeneic stem cell transplantation

    PubMed Central

    Griffith, Michelle L.; Jagasia, Shubhada; Lee, Stephanie J.

    2011-01-01

    More than 25 000 allogeneic hematopoietic stem cell transplantations (allo-HCTs) are expected to be performed worldwide in 2010, a number that has been increasing yearly. With broadening indications, more options for allo-HCT, and improvement in survival, by 2020 there may be up to half a million long-term survivors after allo-HCT worldwide. These patients have increased risks for various late complications, which can cause morbidity and mortality. Most long-term survivors return to the care of their local hematologists/oncologists or primary care physicians, who may not be familiar with specialized monitoring recommendations for this patient population. The purpose of this article is to describe practical approaches to screening for and managing these late effects, with the goal of reducing preventable morbidity and mortality associated with allo-HCT. PMID:21193694

  7. Fecal microbiota transplantation for fulminant Clostridium difficile infection in an allogeneic stem cell transplant patient.

    PubMed

    Neemann, K; Eichele, D D; Smith, P W; Bociek, R; Akhtari, M; Freifeld, A

    2012-12-01

    We present a case of severe Clostridium difficile infection (CDI) in a non-neutropenic allogeneic hematopoietic stem cell transplant recipient who was treated successfully with fecal microbiota therapy after standard pharmacologic therapy had failed. Following naso-jejunal instillation of donor stool, the patient's symptoms resolved within 48 h. Bowel resection was averted. This is the first case in the literature, to our knowledge, to describe fecal microbiota therapy in a profoundly immunocompromised host with severe CDI. We propose that fecal microbiota therapy be considered as a therapeutic option in immunosuppressed patients with refractory severe CDI.

  8. A patient with progressive multiple myeloma treated successfully with arsenic trioxide after allogeneic bone marrow transplantation.

    PubMed

    Gesundheit, B; Shapira, M Y; Ackerstein, A; Resnik, I B; Bitan, M; Or, R

    2007-01-01

    Multiple myeloma (MM) is an incurable progressive disease. Many therapeutic options are available to delay progression, including autologous and allogeneic bone marrow transplantation. At advanced stages, MM is often refractory to treatment. We report a heavily pretreated patient with graft-versus-host disease after bone marrow transplantations, treated at a terminal stage with a modified protocol for arsenic trioxide (ATO). This patient with poor clinical status tolerated the treatment very well. He had a remarkable clinical response and achieved complete remission. The mechanisms of ATO are presented and the potential role of ATO for MM is discussed.

  9. Long Term Incidence of Secondary Malignancies Following Allogeneic Hematopoietic Cell Transplantation: a Single Center Experience.

    PubMed

    Michelis, Fotios V; Kotchetkov, Rouslan; Grunwald, Rebecca M; Azeem, Aamir; Atenafu, Eshetu G; Lipton, Jeffrey H; Loach, David; Gupta, Vikas; Kuruvilla, John; Kim, Dennis D; Viswabandya, Auro; Deotare, Uday; Messner, Hans A

    2017-02-27

    To review the emergence of secondary malignancies (SM) in recipients of allogeneic hematopoietic cell transplantation (HCT). We documented the occurrence of SM in 2415 allogeneic HCT recipients, ages 18-71, in a single center over four decades. SM was seen in 209 patients, including 58 with non-metastatic squamous cell (SCC) and basal cell carcinoma (BCC) of the skin. Cumulative incidence of SM was 6.3% at 10 years, 13.5% at 20 years and 17.6% at 30 years post-HCT. Median age at diagnosis of SM was 61 years (range 21-85). By multivariable analysis, older age at HCT was the only independent prognostic factor for SM (HR=1.39 for age 41-55 and HR=1.92 for age >55 compared to age ≤40, p=0.001). The rate of SM (excluding non-metastatic SCC/BCC of skin) after HCT was 2.07 times higher (p=0.01) compared to the general population. Overall survival (OS) following diagnosis of SM (excluding non-metastatic SCC/BCC of skin) was 58% at 5 years and 50% at 10 years post-diagnosis. ECOG score was the only independent predictor of OS on multivariable analysis, with over 2 fold increased risk of death for patients with an ECOG score of 1 and over 6 fold for ECOG 2-4, compared to ECOG score 0 (p<0.0001). Forty (19%) of the 209 patients diagnosed with SM subsequently developed another new malignancy. OS was 68% and 51% at 5 and 10 years, respectively. The survival of SM patients post-HCT is favorable, thus warranting diligent long-term cancer screening and standard of care treatment. ECOG status of these patients is a predominant prognostic factor.

  10. FLT3 mutational status is an independent risk factor for adverse outcomes after allogeneic transplantation in AML

    PubMed Central

    Li, Yumeng; Braun, Thomas; Chang, Lawrence; Bixby, Dale; Hanauer, David A.; Chughtai, Komal A.; Gatza, Erin; Couriel, Daniel; Goldstein, Steven; Pawarode, Attaphol; Reddy, Pavan; Riwes, Mary; Connelly, James; Harris, Andrew; Kitko, Carrie; Levine, John; Yanik, Greg

    2015-01-01

    Allogeneic HCT has been increasingly used in the setting of FLT3 mutated AML. However, its role in conferring durable relapse-free intervals remains in question. Herein, we sought to investigate FLT3 mutational status on transplant outcomes. We conducted a retrospective cohort study of 262 consecutive AML patients who underwent first-time allogeneic HCT (2008-2014), of whom 171 had undergone FLT3-ITD mutational testing. FLT3 mutated AML was associated with nearly twice the relapse risk (RR) compared with those without FLT3 mutation 3 years post-HCT (63% vs. 37%, P<0.001), and with a shorter median time to relapse (100 vs. 121 days). FLT3 mutational status remained significantly associated with this outcome after controlling for patient, disease, and transplant-related risk factors (P<0.05). Multivariate analysis showed a significant association of FLT3 mutation with increased 3-year RR (HR 3.63, 95% CI: 2.13, 6.19, P<0.001), and inferior disease-free survival (HR 2.05, 95% CI: 1.29, 3.27, P<0.01) and overall survival (HR 1.92, 95% CI: 1.14, 3.24, P<0.05). These data demonstrate high risk of early relapse after allogeneic HCT for FLT3 mutated AML that translates into adverse disease-free and overall survival outcomes. Additional targeted and coordinated interventions are needed to maintain durable remission after allogeneic HCT in this high-risk population. PMID:26191952

  11. Induction of tolerance to parental parathyroid grafts using allogeneic thymus tissue in patients with DiGeorge anomaly.

    PubMed

    Chinn, Ivan K; Markert, M Louise

    2011-06-01

    DiGeorge anomaly can affect both thymic and parathyroid function. Although athymia is corrected by allogeneic thymus transplantation, treatment options for hypoparathyroidism have been unsatisfactory. Parathyroid transplantation offers the potential for definitive cure but remains challenging because of graft rejection. Some allogeneic parathyroid grafts have functioned in adult recipients in the context of immunosuppression for renal transplantation. Other efforts have attempted to reduce the allogenicity of the parathyroid grafts through manipulation of the parathyroid tissues before transplantation (by using encapsulation or special culture techniques). Recently, we demonstrated the efficacy of parental parathyroid transplantation when combined with allogeneic thymus transplantation in an infant with complete DiGeorge anomaly. The recipient developed tolerance toward the parathyroid donor. The parathyroid graft has functioned for 5 years after transplantation without the need for continued immunosuppression or calcium supplementation. We observed that matching of the allogeneic thymus graft to the parathyroid donor HLA class II alleles that are unshared with the recipient appears to be associated with the induction of tolerance toward the parathyroid graft. Further work is needed to determine the optimal means for using combined allogeneic thymus and parental parathyroid transplantation to correct hypoparathyroidism in patients with both complete and partial DiGeorge anomaly.

  12. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia.

    PubMed

    Dhédin, Nathalie; Huynh, Anne; Maury, Sébastien; Tabrizi, Reza; Beldjord, Kheira; Asnafi, Vahid; Thomas, Xavier; Chevallier, Patrice; Nguyen, Stéphanie; Coiteux, Valérie; Bourhis, Jean-Henri; Hichri, Yosr; Escoffre-Barbe, Martine; Reman, Oumedaly; Graux, Carlos; Chalandon, Yves; Blaise, Didier; Schanz, Urs; Lhéritier, Véronique; Cahn, Jean-Yves; Dombret, Hervé; Ifrah, Norbert

    2015-04-16

    Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome-negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10(-3) (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678.

  13. Adenoviral Infections in Adult Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Single Center Experience

    PubMed Central

    Yilmaz, Musa; Chemaly, Roy F.; Han, Xiang Y.; Thall, Peter F.; Fox, Patricia S.; Tarrand, Jeffrey J.; De Lima, Marcos J.; Hosing, Chitra M.; Popat, Uday R.; Shpall, Elizabeth; Champlin, Richard E.; Qazilbash, Muzaffar H.

    2014-01-01

    Disseminated adenoviral infection (AI) is associated with profound immunosuppression and poor outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). A better understanding of AI in allo-HCT recipients can serve a basis to develop more effective management strategies. We evaluated all adult patients who received allo-HCT at M.D. Anderson Cancer Center between 1999 and 2008. Among the 2879 allo-HCT patients, 73 (2.5%) were diagnosed with AI. Enteritis (26%) and pneumonia (24%) were the most common clinical manifestations; pneumonia was the most common cause of adenovirus-associated death. A multivariable Bayesian logistic regression showed that, when the joint effects of all covariates were accounted for, a cord blood transplant, absolute lymphocyte count (ALC) ≤ 200/mm3, and male gender were associated with a higher probability of disseminated AI. The overall survival was significantly worse for patients with AI that was disseminated rather than localized (median of 5 months versus 28 months, respectively, p<0.001) and for patients with ALC ≤ 200/mm3 (p<0.001). Disseminated AI, in patients who received allo-HCT, is a significant cause of morbidity and mortality. Strategies for early diagnosis and intervention are essential, especially for high-risk patients. PMID:23503529

  14. Allogeneic bone marrow mesenchymal stem cell transplantation in patients with UDCA-resistant primary biliary cirrhosis.

    PubMed

    Wang, Li; Han, Qin; Chen, Hua; Wang, Ke; Shan, Guang-liang; Kong, Fang; Yang, Yun-jiao; Li, Yong-zhe; Zhang, Xuan; Dong, Fen; Wang, Qian; Xu, Dong; Hu, Zhao-jun; Wang, Shi-hua; Keating, Armand; Bi, Ya-lan; Zhang, Feng-chun; Zhao, Robert Chun-hua

    2014-10-15

    The objective of this study was to evaluate the safety and efficacy of allogeneic bone marrow mesenchymal stromal/stem cell transplantation (BM-MSCT) for patients with ursodeoxycholic acid (UDCA)-resistant primary biliary cirrhosis (PBC). Ten patients were enrolled in this trial of BM-MSCT. All patients were permitted to concurrently continue their previous UDCA treatment. The efficacy of BM-MSCT in UDCA-resistant PBC was assessed at various time points throughout the 12-month follow up. No transplantation-related side effects were observed. The life quality of the patients was improved after BM-MSCT as demonstrated by responses to the PBC-40 questionnaire. Serum levels of ALT, AST, γ-GT, and IgM significantly decreased from baseline after BM-MSCT. In addition, the percentage of CD8+ T cells was reduced, while that of CD4+CD25+Foxp3+ T cells was increased in peripheral lymphocytic subsets. Serum levels of IL-10 were also elevated. Notably, the optimal therapeutic outcome was acquired in 3 to 6 months and could be maintained for 12 months after BM-MSCT. In conclusion, allogeneic BM-MSCT in UDCA-resistant PBC is safe and appears to be effective.

  15. Pediatric donor cell leukemia after allogeneic hematopoietic stem cell transplantation in AML patient from related donor.

    PubMed

    Bobadilla-Morales, Lucina; Pimentel-Gutiérrez, Helia J; Gallegos-Castorena, Sergio; Paniagua-Padilla, Jenny A; Ortega-de-la-Torre, Citlalli; Sánchez-Zubieta, Fernando; Silva-Cruz, Rocio; Corona-Rivera, Jorge R; Zepeda-Moreno, Abraham; González-Ramella, Oscar; Corona-Rivera, Alfredo

    2015-01-01

    Here we present a male patient with acute myeloid leukemia (AML) initially diagnosed as M5 and with karyotype 46,XY. After induction therapy, he underwent a HLA-matched allogeneic hematopoietic stem cell transplantation, and six years later he relapsed as AML M1 with an abnormal karyotype //47,XX,+10[2]/47,XX,+11[3]/48,XX,+10,+11[2]/46,XX[13]. Based on this, we tested the possibility of donor cell origin by FISH and molecular STR analysis. We found no evidence of Y chromosome presence by FISH and STR analysis consistent with the success of the allogeneic hematopoietic stem cell transplantation from the female donor. FISH studies confirmed trisomies and no evidence of MLL translocation either p53 or ATM deletion. Additionally 28 fusion common leukemia transcripts were evaluated by multiplex reverse transcriptase-polymerase chain reaction assay and were not rearranged. STR analysis showed a complete donor chimerism. Thus, donor cell leukemia (DCL) was concluded, being essential the use of cytological and molecular approaches. Pediatric DCL is uncommon, our patient seems to be the sixth case and additionally it presented a late donor cell leukemia appearance. Different extrinsic and intrinsic mechanisms have been considered to explain this uncommon finding as well as the implications to the patient.

  16. Is ABO mismatch another risk factor for allogeneic hematopoietic stem cell transplantation in pediatric thalassemic patients?

    PubMed

    Atay, Didem; Erbey, Fatih; Akcay, Arzu; Ozturk, Gulyuz

    2015-09-01

    The ABO incompatibility between donor and recipient is not considered a barrier to successful allogeneic HSCT. Nevertheless, conflicting data still exist about the influence of ABO incompatibility on transplant outcome in pediatric patients with thalassemia. Fifty-one children with beta-thalassemia major who underwent allogeneic HSCT were enrolled this study. Twenty-three of them (45%) received an ABO-incompatible transplant [minor ABO mismatch: six (26%), major ABO mismatch: fourteen (61%), and bidirectional mismatch: three (13%)]. In this study, ABO incompatibility did not significantly impair GVHD, VOD, neutrophil and platelet engraftment, TRM, OS and TFS. Particularly in major and bidirectional ABO-mismatched patients, a delayed erythroid recovery was recorded as compared to the group receiving an ABO-compatible graft (median time, 31 and 38 days vs. 19.5 days; p: 0.02 and p: 0.03). Median time to red cell transfusion independence was significantly longer in major ABO-incompatible patients (median time, 87 days vs. 32 days; p: 0.001). Therefore, whenever feasible, major ABO-mismatched donors should be avoided in HSCT recipients, to prevent delayed erythroid recovery with prolonged RBC transfusion needs and impaired quality of life.

  17. Relapse after Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndromes: Analysis of Late Relapse Using Comparative Karyotype and Chromosome Genome Array Testing

    PubMed Central

    Fang, Min; Scott, Bart L.; Flowers, Mary E.D.; Gooley, Ted; Deeg, H. Joachim

    2016-01-01

    Relapse is a major cause of failure after allogeneic hematopoietic cell transplantation (HCT) in patients with myelodysplastic syndromes (MDS). We analyzed the relapse pattern in 1007 patients who underwent transplantation for MDS to identify factors that may determine the timing of relapse. Overall, 254 patients relapsed: 213 before 18 months and 41 later than 18 months after HCT, a time point frequently used in clinical trials. The hazard of relapse declined progressively with time since transplantation. A higher proportion of patients with early relapse had high-risk cytogenetics compared with patients with late relapse (P =.009). Patients with late relapse had suggestively longer postrelapse survival than patients who relapsed early, although the difference was not statistically significant (P =.07). Among 41 late relapsing patients, sequential cytogenetic data were available in 36. In 41% of these, new clonal abnormalities in addition to pre-HCT findings were identified at relapse; in 30% pre-HCT abnormalities were replaced by new clones, in 17.3% the same clone was present before HCT and at relapse, and in 9.7%, no abnormalities were present either before HCT or at relapse. Comparative chromosomal genomic array testing in 3 patients with late relapse showed molecular differences not detectable by cytogenetics between the pre-HCT clones and the clones at relapse. These data show that late relapses are not infrequent in patients who undergo transplantation for MDS. The pattern of new cytogenetic alterations at late relapse is similar to that observed in patients with early relapse and supports the concept that MDS relapse early and late after HCT is frequently due to the emergence of clones not detectable before HCT. PMID:25953732

  18. Therapy of relapsed leukemia after allogeneic hematopoietic cell transplantation with T cells specific for minor histocompatibility antigens

    PubMed Central

    Fujii, Nobuharu; Akatsuka, Yoshiki; Chaney, Colette N.; Mito, Jeffrey K.; Loeb, Keith R.; Gooley, Ted A.; Brown, Michele L.; Koo, Kevin K. W.; Rosinski, Kellie V.; Ogawa, Seishi; Matsubara, Aiko; Appelbaum, Frederick R.; Riddell, Stanley R.

    2010-01-01

    The adoptive transfer of donor T cells that recognize recipient minor histocompatibility antigens (mHAgs) is a potential strategy for preventing or treating leukemic relapse after allogeneic hematopoietic cell transplantation (HCT). A total of 7 patients with recurrent leukemia after major histocompatibility complex (MHC)–matched allogeneic HCT were treated with infusions of donor-derived, ex vivo–expanded CD8+ cytotoxic T lymphocyte (CTL) clones specific for tissue-restricted recipient mHAgs. The safety of T-cell therapy, in vivo persistence of transferred CTLs, and disease response were assessed. Molecular characterization of the mHAgs recognized by CTL clones administered to 3 patients was performed to provide insight into the antileukemic activity and safety of T-cell therapy. Pulmonary toxicity of CTL infusion was seen in 3 patients, was severe in 1 patient, and correlated with the level of expression of the mHAg-encoding genes in lung tissue. Adoptively transferred CTLs persisted in the blood up to 21 days after infusion, and 5 patients achieved complete but transient remissions after therapy. The results of these studies illustrate the potential to selectively enhance graft-versus-leukemia activity by the adoptive transfer of mHAg-specific T-cell clones and the challenges for the broad application of this approach in allogeneic HCT. This study has been registered at http://clinicaltrials.gov as NCT00107354. PMID:20071660

  19. Population Pharmacokinetics and Dose Optimization of Mycophenolic Acid in HCT Recipients Receiving Oral Mycophenolate Mofetil

    PubMed Central

    Li, H; Mager, D E; Sandmaier, B M; Maloney, D G; Bemer, M J; McCune, J S

    2012-01-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. 4,496 MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance and volume of the central compartment were 24.2 L/hr and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA clearance by 33.8%. The optimal LSS was immediately before and at 0.25, 1.25, 2, and 4hr after oral MMF administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation. PMID:23382105

  20. Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil.

    PubMed

    Li, H; Mager, D E; Sandmaier, B M; Maloney, D G; Bemer, M J; McCune, J S

    2013-04-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety-six MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance (CL) and volume of the central compartment were 24.2 L/hour and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA CL by 33.8%. The optimal LSS was immediately before and at 0.25 hours, 1.25 hours, 2 hours, and 4 hours after oral mycophenolate mofetil administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation.

  1. Immunogenicity of Decidual Stromal Cells in an Epidermolysis Bullosa Patient and in Allogeneic Hematopoietic Stem Cell Transplantation Patients

    PubMed Central

    Carlson, Lena-Maria; Erkers, Tom; Nava, Silvia; Molldén, Pia; Gustafsson, Britt; Qian, Hua; Li, Xiaoguang; Hashimoto, Takashi; Sadeghi, Behnam; Alheim, Mats; Ringdén, Olle

    2015-01-01

    Allogeneic mesenchymal stromal cells (MSCs) are widely used in regenerative medicine, but little is known about their immunogenicity. In this study, we monitored the therapeutic and immunogenic effects of decidual stromal cells (DSCs) from term placentas when used as a therapy for generalized severe junctional epidermolysis bullosa (JEB) (previously termed Herlitz JEB), a lethal condition caused by the lack of functional laminin-332. An 11-month-old JEB patient was treated with five infusions of allogeneic DSCs within a 3-month period. Amniotic membranes (AMs) were applied to severe wounds. After the treatment, wounds started to heal in the middle of the blisters, but the improvements were transient. After two infusions of DSCs, the JEB patient had developed multispecific anti-HLA class-I antibodies. No antibodies to laminin-332 were detected, but the patient had high levels of anti-bovine serum albumin antibodies, which could bind to DSCs. Peripheral blood mononuclear cells (PBMCs) from the patient had a higher proliferative response to DSCs than to third-party PBMCs, which contrasts with the pattern observed in healthy donors. Human DSCs and MSCs induced similar xenoreactivity in mice. Two of 16 allogeneic stem cell-transplanted patients, treated with DSCs for graft-versus-host disease or hemorrhagic cystitis, showed a positive flow cytometric crossmatch test. One patient had anti-HLA antibodies before DSC infusion, whereas the other had no anti-HLA antibodies at any time. AM and DSC infusions may have improved the healing process in the JEB patient, but DSCs appeared to induce anti-HLA antibodies. The risk of alloimmunization by DSCs seems to be low in immunocompromised patients. PMID:25658253

  2. Pretransplant β2-Microglobulin Is Associated with the Risk of Acute Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplant.

    PubMed

    Costa-Lima, Carolina; Miranda, Eliana Cristina Martins; Colella, Marcos Paulo; Aranha, Francisco Jose Penteado; de Souza, Carmino Antonio; Vigorito, Afonso Celso; De Paula, Erich Vinicius

    2016-07-01

    The risk of acute graft-versus-host disease (aGVHD) can be reliably estimated by the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), which can be further refined by the incorporation of pre-hematopoietic cell transplantation (HCT) serum levels of inflammatory biomarkers such as ferritin and albumin. β2-Microglobulin (β2-m) is a key component of the MHC class I complex, which is independently associated with mortality and frailty in the general population. We took advantage of our institutional protocol that includes measurement of pre-HCT β2-m serum levels in the most patients to investigate whether pre-transplant β2-m levels were associated with the risk of aGVHD. One hundred three consecutive patients submitted to allogeneic HCT, of which 26 developed grades II to IV aGVHD, were included in the analysis. β2-m was significantly associated with age and HCT-CI. Higher levels of β2-m were observed in patients who developed aGVHD (P = .008). In the multivariate Cox regression model, β2-m and HCT-CI remained independently associated with the risk of developing aGVHD. In conclusion, the association between β2-m and the occurrence of aGVHD suggests that the measurement of this protein before HCT might represent an additional element for risk stratification of aGVHD.

  3. Comorbidity-Age Index: A Clinical Measure of Biologic Age Before Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Sorror, Mohamed L.; Storb, Rainer F.; Sandmaier, Brenda M.; Maziarz, Richard T.; Pulsipher, Michael A.; Maris, Michael B.; Bhatia, Smita; Ostronoff, Fabiana; Deeg, H. Joachim; Syrjala, Karen L.; Estey, Elihu; Maloney, David G.; Appelbaum, Frederick R.; Martin, Paul J.; Storer, Barry E.

    2014-01-01

    Purpose Age has long been used as a major factor for assessing suitability for allogeneic hematopoietic cell transplantation (HCT). The HCT-comorbidity index (HCT-CI) was developed as a measure of health status to predict mortality risk after HCT. Whether age, comorbidities, or both should guide decision making for HCT is unknown. Patients and Methods Data from 3,033 consecutive recipients of HLA-matched grafts from five institutions contributed to this analysis. Patients were randomly divided into a training set to develop weights for age intervals and a validation set to assess the performance of prognostic models. Results In the training set, patients age 20 to 39 years, 40 to 49 years, 50 to 59 years, and ≥ 60 years had hazard ratios for nonrelapse mortality (NRM) of 1.21 (P = .29), 1.48 (P = .04), 1.75 (P = .004), and 1.84 (P = .005), respectively, compared with those age younger than 20 years. Consequently, age ≥ 40 years was assigned a weight of 1 to be added to the HCT-CI to constitute a composite comorbidity/age index. In the validation set, the composite comorbidity/age score had statistically significantly higher c-statistic estimates for prediction of NRM (0.664 v 0.556; P < .001) and survival (0.682 v 0.560; P < .001) compared with age, respectively. Patients with comorbidity/age scores of 0 to 2 had comparable mortality risks regardless of conditioning regimens. Patients with scores of 3 to 4 and ≥ 5 had statistically significant higher mortality risks after high-dose versus nonmyeloablative regimens. Conclusion Age is a poor prognostic factor. The proposed composite measure allows integration of both comorbidities and age into clinical decision making and comparative-effectiveness research of HCT. PMID:25154831

  4. Impact of MRD and TKI on allogeneic hematopoietic cell transplantation for Ph+ALL: a study from the adult ALL WG of the JSHCT.

    PubMed

    Nishiwaki, S; Imai, K; Mizuta, S; Kanamori, H; Ohashi, K; Fukuda, T; Onishi, Y; Takahashi, S; Uchida, N; Eto, T; Nakamae, H; Yujiri, T; Mori, S; Nagamura-Inoue, T; Suzuki, R; Atsuta, Y; Tanaka, J

    2016-01-01

    To assess the impact of minimal residual disease (MRD) and tyrosine kinase inhibitor (TKI) administration on allogeneic hematopoietic cell transplantation (allo-HCT) for Ph-positive ALL (Ph+ALL), we retrospectively analyzed data from a registry database for 432 adult Ph+ALL patients in first CR (CR1) who received pre-transplant TKI administration. Negative MRD (MRD(-)) at allo-HCT was achieved in 277 patients. OS in patients transplanted in MRD(-) was significantly better than that in patients transplanted in MRD(+) (MRD(-): 67% vs MRD(+): 55% at 4 years; P=0.001). MRD(-) at allo-HCT was a significant risk factor for survival along with age at allo-HCT in multivariate analyses. Incidence of relapse in patients transplanted in MRD(-) was significantly lower than that in patients transplanted in MRD(+) (MRD(-): 19% vs MRD(+): 29% at 4 years; P=0.006). In multivariate analyses, MRD(+) at allo-HCT was a significant risk factor for relapse. A post-transplant TKI was administered to 103 patients. In subanalyses regarding the effect of post-transplant TKI administration, post-transplant TKI administration was a significant risk factor for relapse in multivariate analyses (P<0.0001). MRD status at allo-HCT is one of the most important predictive factors for Ph+ALL patients transplanted in CR1.

  5. Allogeneic hematopoietic cell transplantation without fluconazole and fluoroquinolone prophylaxis.

    PubMed

    Heidenreich, D; Kreil, S; Nolte, F; Reinwald, M; Hofmann, W-K; Klein, S A

    2016-01-01

    Fluoroquinolone (FQ) and fluconazole prophylaxis is recommended for patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). However, due to an uncertain scientific basis and the increasing emergence of resistant germs, this policy should be questioned. Therefore, FQ and fluconazole prophylaxis was omitted in alloHCT at our center. In this retrospective analysis, all consecutive patients (n = 63) who underwent first alloHCT at our institution from September 2010 to September 2013 were included. Patients neither received FQ nor fluconazole prophylaxis. Day 100 mortality, incidence of febrile neutropenia, bacterial infections, and invasive fungal diseases (IFD) were assessed. Sixteen patients who started conditioning under antimicrobial treatment/prophylaxis due to pre-existing neutropenia (3/16), IFD (12/16), or aortic valve replacement (1/16) were excluded from the analysis. Finally, 47 patients were transplanted without prophylaxis as intended. Day 100 mortality was 9 %. Febrile neutropenia occurred in 62 % (29/47); 17/47 patients (36 %) experienced a blood stream infection (BSI) with detection of Gram-positive bacteria in 14 patients, Gram-negative bacteria in five patients, and candida in one patient, respectively. Coagulase-negative staphylococci were the most frequently isolated Gram-positive bacteria; 12/21 isolated Gram-positive and 3/6 Gram-negative bacteria were FQ resistant. In 21 % (10/47) of the patients, IFD (1x proven, 1x probable, and 8x possible) were diagnosed. To conclude, all three criteria, day 100 mortality, the incidence of IFD, and BSI, are in the range of published data for patients transplanted with FQ and fluconazole prophylaxis. These data demonstrate that alloHCT is feasible without FQ and fluconazole prophylaxis.

  6. Nutritional status of patients submitted to transplantation of allogeneic hematopoietic stem cells: a retrospective study

    PubMed Central

    Ferreira, Érika Elias; Guerra, Daiane Cristina; Baluz, Kátia; de Resende Furtado, Wander; da Silva Bouzas, Luis Fernando

    2014-01-01

    Objective This study aimed to describe and compare the nutritional status of adult patients submitted to allogeneic hematopoietic stem cell transplantation at two different time points (admission and discharge). Methods A retrospective, descriptive and quantitative study was performed based on clinical, laboratory and nutritional data obtained from medical records of adult patients of both genders submitted to allogeneic hematopoietic stem cell transplantation in a bone marrow transplantation reference center in Rio de Janeiro in the period from 2010 to 2013. Statistical analysis was performed using the SPSS software (version 22.0). Results Sixty-four patients were evaluated. The mean age was 42.1 ± 3.2 years and the most prevalent disease was acute myeloid leukemia (39%). There was a high prevalence of gastrointestinal symptoms including nausea (100%), vomiting (97%) and mucositis (93%). Between admission and discharge there was a significant decrease in the median weight (−2.5 kg; 71.5 vs. 68.75 kg; p-value < 0.001), body mass index (−0.9 kg/m2; 24.8 vs. 24.4 kg/m2; p-value < 0.001), and serum albumin levels (−0.2 g/dL; 3.7 vs. 3.6 g/dL; p-value = 0.024). The survival time after hematopoietic stem cell transplantation correlated negatively with C-reactive protein at discharge (CC = −0.72; p-value < 0.001) and positively with serum albumin levels (CC = 0.56; p-value = 0.004) and with high total protein level at discharge (CC = 0.53; p-value = 0.006). Conclusion Our results suggest that patients submitted to allogeneic hematopoietic stem cell transplantation have compromised nutritional status during the hospital stay for transplantation. PMID:25453651

  7. Allogeneic nonmyeloablative hematopoietic cell transplantation in metastatic colon cancer: tumor-specific T cells directed to a tumor-associated antigen are generated in vivo during GVHD.

    PubMed

    Carnevale-Schianca, Fabrizio; Cignetti, Alessandro; Capaldi, Antonio; Vitaggio, Katiuscia; Vallario, Antonella; Ricchiardi, Alberto; Sperti, Elisa; Ferraris, Renato; Gatti, Marco; Grignani, Giovanni; Rota-Scalabrini, Delia; Geuna, Massimo; Fizzotti, Marco; Sangiolo, Dario; Sottile, Antonino; De Rosa, Giovanni; Bucci, Anna Rosa; Lambertenghi-Deliliers, Giorgio; Benedetti, Edoardo; Nash, Richard; Aglietta, Massimo

    2006-05-01

    A pilot study was conducted to evaluate safety and activity of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) in colorectal carcinoma (CRC) and to determine whether a T-cell response to a tumor-associated antigen (TAA) was induced. Fifteen patients with metastatic CRC underwent HCT from human leukocyte antigen (HLA)-matched siblings after a nonmyeloablative conditioning regimen. All patients engrafted with a median donor T-cell chimerism of 72% at day +56. Eight patients experienced grades II to IV acute graft-versus-host disease (GVHD). Despite progressive disease before HCT, partial remission and disease stabilization longer than 90 days were observed in 1 and 3 patients, respectively. Induction of TAA-specific T cells was evaluated with a carcinoembryonic antigen (CEA)-specific HLA-A(*)0201 pentamer in 6 patients with CRC. CEA-specific CD8(+) T cells were detected in 3 of 3 patients concomitant with GHVD onset, but not in 3 of 3 patients without GVHD. They were also not detected in 9 of 9 control patients with GVHD who received transplants for diagnoses other than CRC. Antitumor activity of CEA-specific T cells was also validated in vitro. In one patient, the induction of CEA-specific T cells was associated with a decrease of serum CEA levels and a partial response. Thus, graft-versus-host reactions associated with allogeneic HCT can trigger the generation of T cells specific for CEA, and this may be associated with a clinical response.

  8. Making the genomic leap in HCT: application of second-generation sequencing to clinical advances in hematopoietic cell transplantation.

    PubMed

    Li, Yun R; Levine, John E; Hakonarson, Hakon; Keating, Brendan J

    2014-06-01

    Recent developments in second-generation sequencing (SGS) technologies provide an avenue for achieving rapid and accurate high-throughput analysis of human and microbial genomic diversity. SGS technologies have the potential to transform existing medical management of complex and life-threatening medical conditions by enabling clinicians to develop disease-targeted clinical care plans for each patient. In this review, we outline how innovative SGS-based approaches can improve the care of recipients of allogeneic hematopoietic cell transplantation (HCT), a life-saving procedure that carries a 1-year mortality risk of over 30%. We specifically evaluate foreseeable applications of SGS-based technology in facilitating rapid, phase-sensitive human leukocyte antigen (HLA) typing, assessment of non-HLA genomic compatibility, identifying patients at high risk for adverse drug reactions, and post-HCT monitoring for engraftment, minimal residual disease and infection. We conclude that innovative SGS approaches have the capacity to revolutionize the HCT recipient risk assessment process, support non-invasive clinical monitoring and improve patient outcomes, thereby setting the stage for a new era of genomically informed patient-centered medicine.

  9. Pretransplant NPM1 MRD levels predict outcome after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia.

    PubMed

    Kayser, S; Benner, A; Thiede, C; Martens, U; Huber, J; Stadtherr, P; Janssen, J W G; Röllig, C; Uppenkamp, M J; Bochtler, T; Hegenbart, U; Ehninger, G; Ho, A D; Dreger, P; Krämer, A

    2016-07-29

    The objective was to evaluate the prognostic impact of pre-transplant minimal residual disease (MRD) as determined by real-time quantitative polymerase chain reaction in 67 adult NPM1-mutated acute myeloid leukemia patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Twenty-eight of the 67 patients had a FLT3-ITD (42%). Median age at transplantation was 54.7 years, median follow-up for survival from time of allografting was 4.9 years. At transplantation, 31 patients were in first, 20 in second complete remission (CR) and 16 had refractory disease (RD). Pre-transplant NPM1 MRD levels were measured in 39 CR patients. Overall survival (OS) for patients transplanted in CR was significantly longer as compared to patients with RD (P=0.004), irrespective of whether the patients were transplanted in first or second CR (P=0.74). There was a highly significant difference in OS after allogeneic HSCT between pre-transplant MRD-positive and MRD-negative patients (estimated 5-year OS rates of 40 vs 89%; P=0.007). Multivariable analyses on time to relapse and OS revealed pre-transplant NPM1 MRD levels >1% as an independent prognostic factor for poor survival after allogeneic HSCT, whereas FLT3-ITD had no impact. Notably, outcome of patients with pre-transplant NPM1 MRD positivity >1% was as poor as that of patients transplanted with RD.

  10. Sequential myeloablative autologous stem cell transplantation and reduced intensity allogeneic hematopoietic cell transplantation is safe and feasible in children, adolescents and young adults with poor-risk refractory or recurrent Hodgkin and non-Hodgkin lymphoma.

    PubMed

    Satwani, P; Jin, Z; Martin, P L; Bhatia, M; Garvin, J H; George, D; Chaudhury, S; Talano, J; Morris, E; Harrison, L; Sosna, J; Peterson, M; Militano, O; Foley, S; Kurtzberg, J; Cairo, M S

    2015-02-01

    The outcome of children, adolescents and young adults (CAYA) with poor-risk recurrent/refractory lymphoma is dismal (⩽30%). To overcome this poor prognosis, we designed an approach to maximize an allogeneic graft vs lymphoma effect in the setting of low disease burden. We conducted a multi-center prospective study of myeloablative conditioning (MAC) and autologous stem cell transplantation (AutoSCT), followed by a reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (AlloHCT) in CAYA, with poor-risk refractory or recurrent lymphoma. Conditioning for MAC AutoSCT consisted of carmustine/etoposide/cyclophosphamide, RIC consisted of busulfan/fludarabine. Thirty patients, 16 Hodgkin lymphoma (HL) and 14 non-Hodgkin lymphoma (NHL), with a median age of 16 years and median follow-up of 5years, were enrolled. Twenty-three patients completed both MAC AutoSCT and RIC AlloHCT. Allogeneic donor sources included unrelated cord blood (n=9), unrelated donor (n=8) and matched siblings (n=6). The incidence of transplant-related mortality following RIC AlloHCT was only 12%. In patients with HL and NHL, 10 year EFS was 59.8% and 70% (P=0.613), respectively. In summary, this approach is safe, and long-term EFS with this approach is encouraging considering the poor-risk patient characteristics and the use of unrelated donors for RIC AlloHCT in the majority of cases.

  11. Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin's lymphoma.

    PubMed

    Herbaux, Charles; Gauthier, Jordan; Brice, Pauline; Drumez, Elodie; Ysebaert, Loic; Doyen, Hélène; Fornecker, Luc; Bouabdallah, Krimo; Manson, Guillaume; Ghesquières, Hervé; Tabrizi, Reza; Hermet, Eric; Lazarovici, Julien; Thiebaut-Bertrand, Anne; Chauchet, Adrien; Demarquette, Hélène; Boyle, Eileen; Houot, Roch; Yakoub-Agha, Ibrahim; Morschhauser, Franck

    2017-03-07

    Allogeneic hematopoietic cell transplantation (allo-HCT) is indicated for patients with relapsed and refractory Hodgkin lymphoma (HL). While long-term disease control can be achieved, relapse remains frequent. The programmed death 1 (PD-1) blocking antibody nivolumab has shown substantial therapeutic activity and an acceptable safety profile in relapsed and refractory HL who did not receive allo-HCT. However, PD-1-blocking strategy can increase the risk of Graft Versus Host Disease (GVHD) in murine models. We retrospectively assessed the efficacy and toxicity of nivolumab as a single agent in 20 HL patients relapsing after allo-HCT. GVHD occurred in six patients (30%) after nivolumab initiation. All six patients had prior history of acute GVHD. These nivolumab-induced GVHD were managed by standard treatment of acute GVHD. Two patients died of GVHD, one of progressive disease and one of the complications related to a second allo-HCT. Overall response rate was 95%. At a median follow-up of 370 days, one-year progression-free and overall survival rates were 58.2% [95%CI, 33.1 - 76.7] and 78.7% [95%CI, 52.4 - 91.5], respectively. Among 13 patients still in response, six received a single dose of nivolumab and seven remain on nivolumab. Compared to standard options in this indication, our results show that nivolumab is effective with an acceptable safety profile.

  12. Allogeneic stem cell transplantation for patients with advanced rhabdomyosarcoma: a retrospective assessment

    PubMed Central

    Thiel, U; Koscielniak, E; Blaeschke, F; Grunewald, T G P; Badoglio, M; Diaz, M A; Paillard, C; Prete, A; Ussowicz, M; Lang, P; Fagioli, F; Lutz, P; Ehninger, G; Schneider, P; Santucci, A; Bader, P; Gruhn, B; Faraci, M; Antunovic, P; Styczynski, J; Krüger, W H; Castagna, L; Rohrlich, P; Ouachée-Chardin, M; Salmon, A; Peters, C; Bregni, M; Burdach, S

    2013-01-01

    Background: Allogeneic haematopoietic stem cell transplantation (allo-SCT) may provide donor cytotoxic T cell-/NK cell-mediated disease control in patients with rhabdomyosarcoma (RMS). However, little is known about the prevalence of graft-vs-RMS effects and only a few case experiences have been reported. Methods: We evaluated allo-SCT outcomes of 30 European Group for Blood and Marrow Transplantation (EBMT)-registered patients with advanced RMS regarding toxicity, progression-free survival (PFS) and overall survival (OS) after allo-SCT. Twenty patients were conditioned with reduced intensity and ten with high-dose chemotherapy. Twenty-three patients were transplanted with HLA-matched and seven with HLA-mismatched grafts. Three patients additionally received donor lymphocyte infusions (DLIs). Median follow-up was 9 months. Results: Three-year OS was 20% (s.e.±8%) with a median survival time of 12 months. Cumulative risk of progression was 67% (s.e.±10%) and 11% (s.e.±6%) for death of complications. Thirteen patients developed acute graft-vs-host disease (GvHD) and five developed chronic GvHD. Eighteen patients died of disease and four of complications. Eight patients survived in complete remission (CR) (median: 44 months). No patients with residual disease before allo-SCT were converted to CR. Conclusion: The use of allo-SCT in patients with advanced RMS is currently experimental. In a subset of patients, it may constitute a valuable approach for consolidating CR, but this needs to be validated in prospective trials. PMID:24149176

  13. Outcome of allogeneic hematopoietic stem cell transplantation in adult patients with acute myeloid leukemia harboring trisomy 8.

    PubMed

    Konuma, Takaaki; Kondo, Tadakazu; Yamashita, Takuya; Uchida, Naoyuki; Fukuda, Takahiro; Ozawa, Yukiyasu; Ohashi, Kazuteru; Ogawa, Hiroyasu; Kato, Chiaki; Takahashi, Satoshi; Kanamori, Heiwa; Eto, Tetsuya; Nakaseko, Chiaki; Kohno, Akio; Ichinohe, Tatsuo; Atsuta, Yoshiko; Takami, Akiyoshi; Yano, Shingo

    2017-03-01

    Trisomy 8 (+8) is one of the most common cytogenetic abnormalities in adult patients with acute myeloid leukemia (AML). However, the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in adult patients with AML harboring +8 remains unclear. To evaluate, the outcome and prognostic factors in patients with AML harboring +8 as the only chromosomal abnormality or in association with other abnormalities, we retrospectively analyzed the Japanese registration data of 631 adult patients with AML harboring +8 treated with allogeneic HSCT between 1990 and 2013. In total, 388 (61%) patients were not in remission at the time of HSCT. With a median follow-up of 38.5 months, the probability of overall survival and the cumulative incidence of relapse at 3 years were 40 and 34%, respectively. In the multivariate analysis, two or more additional cytogenetic abnormalities and not being in remission at the time of HSCT were significantly associated with a higher overall mortality and relapse. Nevertheless, no significant impact on the outcome was observed in cases with one cytogenetic abnormality in addition to +8. Although more than 60% of the patients received HSCT when not in remission, allogeneic HSCT offered a curative option for adult patients with AML harboring +8.

  14. Allogeneic peripheral blood stem cell rescue of late graft failure after bone marrow transplantation in patients with aplastic anemia.

    PubMed Central

    Chung, Ik-Joo; Lee, Je-Jung; Park, Moo-Rim; Kook, Hoon; Cho, Sang-Hee; Hwang, Tai-Ju; Kim, Hyeoung-Joon

    2002-01-01

    We investigated the effect and outcome of allogeneic peripheral blood stem cell (PBSC) rescue for aplastic anemia (AA) patients with graft failure after allogeneic bone marrow transplantation (BMT). Seven (28%) of 25 AA patients who received BMT from HLA-identical sibling donors developed late graft failure at a median of 7 months (range, 2.0-9.3 months) after transplantation. The patients with graft failure were treated with PBSC collected from the original donor after mobilization with granulocyte-colony stimulating factor (G-CSF). The median boost dose of peripheral blood mononuclear cells was 3.1 x 10(8)/kg (range, 1.4-11.9 x 10(8)/kg). Median times to reach an absolute neutrophil count greater than 0.5 x 10(9)/L and a platelet count greater than 50 x 10(9)/L were 7 days (range, 4-14 days) and 9 days (range, 3-41 days), respectively. There was sustained graft function in 6 of 7 patients, with a median follow-up duration of 3.3 yr (range, 1.0-6.2 yr). Grade-I acute graft-versus-host disease (GVHD) occurred in 2 patients, while extensive chronic GVHD developed in 3 patients. This report shows that G-CSF-mobilized allogeneic PBSC rescue is very effective in achieving complete and sustained engraftment in patients with AA after graft failure. However, more efficacious measures to prevent extensive chronic GVHD remain to be developed. PMID:12172040

  15. Immune Reconstitution and Graft-Versus-Host Reactions in Rat Models of Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Zinöcker, Severin; Dressel, Ralf; Wang, Xiao-Nong; Dickinson, Anne M.; Rolstad, Bent

    2012-01-01

    Allogeneic hematopoietic cell transplantation (alloHCT) extends the lives of thousands of patients who would otherwise succumb to hematopoietic malignancies such as leukemias and lymphomas, aplastic anemia, and disorders of the immune system. In alloHCT, different immune cell types mediate beneficial graft-versus-tumor (GvT) effects, regulate detrimental graft-versus-host disease (GvHD), and are required for protection against infections. Today, the “good” (GvT effector cells and memory cells conferring protection) cannot be easily separated from the “bad” (GvHD-causing cells), and alloHCT remains a hazardous medical modality. The transplantation of hematopoietic stem cells into an immunosuppressed patient creates a delicate environment for the reconstitution of donor blood and immune cells in co-existence with host cells. Immunological reconstitution determines to a large extent the immune status of the allo-transplanted host against infections and the recurrence of cancer, and is critical for long-term protection and survival after clinical alloHCT. Animal models continue to be extremely valuable experimental tools that widen our understanding of, for example, the dynamics of post-transplant hematopoiesis and the complexity of immune reconstitution with multiple ways of interaction between host and donor cells. In this review, we discuss the rat as an experimental model of HCT between allogeneic individuals. We summarize our findings on lymphocyte reconstitution in transplanted rats and illustrate the disease pathology of this particular model. We also introduce the rat skin explant assay, a feasible alternative to in vivo transplantation studies. The skin explant assay can be used to elucidate the biology of graft-versus-host reactions, which are known to have a major impact on immune reconstitution, and to perform genome-wide gene expression studies using controlled combinations of minor and major histocompatibility between the donor and the recipient

  16. Erythropoietin therapy after allogeneic hematopoietic cell transplantation: a prospective, randomized trial.

    PubMed

    Jaspers, Aurélie; Baron, Frédéric; Willems, Evelyne; Seidel, Laurence; Hafraoui, Kaoutar; Vanstraelen, Gaetan; Bonnet, Christophe; Beguin, Yves

    2014-07-03

    We conducted a prospective randomized trial to assess hemoglobin (Hb) response to recombinant human erythropoietin (rhEPO) therapy after hematopoietic cell transplantation (HCT). Patients (N = 131) were randomized (1:1) between no treatment (control arm) or erythropoietin at 500 U/kg per week (EPO arm). Patients were also stratified into 3 cohorts: patients undergoing myeloablative HCT with rhEPO to start on day (D)28, patients given nonmyeloablative HCT (NMHCT) with rhEPO to start on D28, and patients also given NMHCT but with rhEPO to start on D0. The proportion of complete correctors (ie, Hb ≥13 g/dL) before D126 posttransplant was 8.1% in the control arm (median not reached) and 63.1% in the EPO arm (median, 90 days) (P < .001). Hb levels were higher and transfusion requirements decreased (P < .001) in the EPO arm, but not during the first month in the nonmyeloablative cohort starting rhEPO on D0. There was no difference in rates of thromboembolic events or other complications between the 2 arms. This is the first randomized trial to demonstrate that rhEPO therapy hastens erythroid recovery and decreases transfusion requirements when started one month after allogeneic HCT. There was no benefit to start rhEPO earlier after NMHCT.

  17. YKL-40 in allogeneic hematopoietic cell transplantation after acute myeloid leukemia and myelodysplastic syndrome

    PubMed Central

    Kornblit, Brian; Wang, Tao; Lee, Stephanie J.; Spellman, Stephen R.; Zhu, Xiaochun; Fleischhauer, Katharina; Müller, Carlheinz; Verneris, Michael R.; Müller, Klaus; Johansen, Julia S.; Vindelov, Lars; Garred, Peter

    2016-01-01

    YKL-40, also called chitinase3-like-1 protein, is an inflammatory biomarker which has been associated with disease severity in inflammatory and malignant diseases, including acute myeloid leukemia (AML), multiple myeloma and lymphomas. The objective of the current study was to assess the prognostic value of pre-transplant recipient and donor plasma YKL-40 concentrations in patients with AML (n=624) or myelodysplastic syndrome (MDS) (n=157) treated with allogeneic hematopoietic cell transplantation (HCT). In recipients, the plasma YKL-40 concentrations were increased when the HCT-comorbidity index was ≥5 (p=0.028). There were no significant associations between plasma YKL-40 concentrations in recipients and any outcome measures. In donors with YKL-40 plasma concentrations above the age adjusted 95th percentile a trend towards increased grade II-IV acute graft versus host disease in recipients was observed (adjusted hazard ratio 1.39 (95% confidence interval 1.00–1.94), P=0.050), with no significant associations with overall survival, treatment-related mortality or relapse. In conclusion, our study shows that YKL-40 does not aid risk stratification of patients undergoing allogeneic HCT, but suggests that YKL-40 may aid donor selection when multiple, otherwise equal, donors are available. PMID:27427920

  18. The clinical impact of cytomegalovirus infection following allogeneic hematopoietic cell transplantation: Why the quest for meaningful prophylaxis still matters.

    PubMed

    Chan, Shawna T; Logan, Aaron C

    2017-02-02

    Latent infection with human cytomegalovirus (CMV) is common. Functional immunity effectively contains such latent infections; however, CMV reactivation may cause significant complications in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). In spite of the universal implementation of post-transplant screening for CMV viremia and the institution of pre-emptive antiviral management, CMV disease still occurs in a small portion of patients. Moreover, interactions between CMV and the immune system have significant implications for the incidence of graft-versus-host disease, the recurrence of malignancy, and non-relapse mortality following alloHCT, even in the era of pre-emptive antiviral management. CMV serostatus thus remains an important consideration for patients undergoing alloHCT. We review the clinical impact of CMV in the setting of alloHCT, interactions between CMV serostatus, viral reactivation, and transplant outcomes, as well as current and evolving strategies for prevention and treatment of CMV-related complications that may have significant impact for alloHCT recipients.

  19. Allogeneic Hematopoietic Cell Transplantation for Aggressive NK Cell Leukemia. A Center for International Blood and Marrow Transplant Research Analysis.

    PubMed

    Hamadani, Mehdi; Kanate, Abraham S; DiGilio, Alyssa; Ahn, Kwang Woo; Smith, Sonali M; Lee, Jong Wook; Ayala, Ernesto; Chao, Nelson; Hari, Parameswaran; Bolaños-Meade, Javier; Gress, Ronald; Smedegaard Anderson, Niels; Chen, Yi-Bin; Farooq, Umar; Schiller, Gary; Yared, Jean; Sureda, Anna; Fenske, Timothy S; Olteanu, Horatiu

    2017-02-01

    Aggressive NK cell leukemia (ANKL) is an exceedingly rare form of leukemia and carries a poor prognosis, with a median survival of only 2 months. Using the Center for International Blood and Marrow Transplant Research database, we evaluated outcomes of allogeneic hematopoietic cell transplantation (alloHCT) in patients with ANKL. Twenty-one patients with a centrally confirmed diagnosis of ANKL were included. Median patient age was 42 years and 15 patients (71%) were Caucasian. Fourteen patients (67%) were in complete remission (CR) at the time of alloHCT, and 5 patients had active disease. Median follow-up of survivors was 25 months (range, 12 to 116). The 2-year estimates of nonrelapse mortality, relapse/progression, progression-free (PFS), and overall survival (OS) were 21%, 59%, 20%, and 24%, respectively. The 2-year PFS of patients in CR at the time of alloHCT was significantly better than that of patients with active disease at transplantation (30% versus 0%; P = .001). The 2-year OS in similar order was 38% versus 0% (P < .001). In conclusion, this registry analysis that included majority non-Asian patient population shows that alloHCT can provide durable disease control in a subset of ANKL patients. Achieving CR before transplantation appears to be a prerequisite for successful transplantation outcomes.

  20. SCID patients with ARTEMIS vs RAG deficiencies following HCT: increased risk of late toxicity in ARTEMIS-deficient SCID.

    PubMed

    Schuetz, Catharina; Neven, Benedicte; Dvorak, Christopher C; Leroy, Sandrine; Ege, Markus J; Pannicke, Ulrich; Schwarz, Klaus; Schulz, Ansgar S; Hoenig, Manfred; Sparber-Sauer, Monika; Gatz, Susanne A; Denzer, Christian; Blanche, Stephane; Moshous, Despina; Picard, Capucine; Horn, Biljana N; de Villartay, Jean-Pierre; Cavazzana, Marina; Debatin, Klaus-Michael; Friedrich, Wilhelm; Fischer, Alain; Cowan, Morton J

    2014-01-09

    A subgroup of severe combined immunodeficiencies (SCID) is characterized by lack of T and B cells and is caused by defects in genes required for T- and B-cell receptor gene rearrangement. Several of these genes are also involved in nonhomologous end joining of DNA double-strand break repair, the largest subgroup consisting of patients with T(-)B(-)NK(+)SCID due to DCLRE1C/ARTEMIS defects. We postulated that in patients with ARTEMIS deficiency, early and late complications following hematopoietic cell transplantation might be more prominent compared with patients with T(-)B(-)NK(+)SCID caused by recombination activating gene 1/2 (RAG1/2) deficiencies. We analyzed 69 patients with ARTEMIS and 76 patients with RAG1/2 deficiencies who received transplants from either HLA-identical donors without conditioning or from HLA-nonidentical donors without or with conditioning. There was no difference in survival or in the incidence or severity of acute graft-versus-host disease regardless of exposure to alkylating agents. Secondary malignancies were not observed. Immune reconstitution was comparable in both groups, however, ARTEMIS-deficient patients had a significantly higher occurrence of infections in long-term follow-up. There is a highly significant association between poor growth in ARTEMIS deficiency and use of alkylating agents. Furthermore, abnormalities in dental development and endocrine late effects were associated with alkylation therapy in ARTEMIS deficiency.

  1. Major non-ABO incompatibility caused by anti-Jk(a) in a patient before allogeneic hematopoietic stem cell transplantation.

    PubMed

    Kim, M Y; Chaudhary, P; Shulman, I A; Pullarkat, V

    2013-01-01

    A 49-year-old white man with blood group AB, D+ was found to have alloanti-Jk(a) and -K when he developed a delayed hemolytic transfusion reaction before allogeneic hematopoietic stem cell transplant (HSCT). Given that his stem cell donor was blood group O, D+, Jk(a+), K-, rituximab was added to his conditioning regimen of fludarabine and melphalan to prevent hemolysis of engrafting Jk(a+) donor red blood cells. The patient proceeded to receive a peripheral blood stem cell transplant from a matched unrelated donor with no adverse events. To our knowledge, this is the first case of successful management of major non-ABO incompatibility caused by anti-Jk(a) in a patient receiving an allogeneic HSCT reported in the literature.

  2. Catheter-Related Candidemia Caused by Candida lipolytica in a Patient Receiving Allogeneic Bone Marrow Transplantation

    PubMed Central

    D'Antonio, Domenico; Romano, Ferdinando; Pontieri, Eugenio; Fioritoni, Giuseppe; Caracciolo, Claudia; Bianchini, Stefano; Olioso, Paola; Staniscia, Tommaso; Sferra, Roberta; Boccia, Stefania; Vetuschi, Antonella; Federico, Giovanni; Gaudio, Eugenio; Carruba, Giuseppe

    2002-01-01

    Candida lipolytica was recovered from the blood and the central venous catheter in a patient receiving allogeneic bone marrow transplantation. Two C. lipolytica strains from different geographical areas and the ATCC 9773 strain of C. lipolytica were used as controls. C. lipolytica was identified by standard methods. MICs indicated antifungal susceptibilities to amphotericin B, fluconazole, and itraconazole for all strains. In vitro testing and scanning electron microscopy showed that C. lipolytica was capable of producing large amounts of viscid slime material in glucose-containing solution, likely responsible for the ability of the yeast to adhere to catheter surfaces. Restriction fragment length polymorphisms revealed an identical profile for all clinical isolates, unrelated to those observed for the control strains. This finding suggested the absence of microevolutionary changes in the population of the infecting strain, despite the length of the sepsis and the potential selective pressure of amphotericin B, which had been administered to the patient for about 20 days. The genomic differences that emerged between the isolates and the control strains were indicative of a certain degree of genetic diversity between C. lipolytica isolates from different geographical areas. PMID:11923360

  3. Survival improvements in adolescents and young adults after myeloablative allogeneic transplantation for acute lymphoblastic leukemia.

    PubMed

    Wood, William A; Lee, Stephanie J; Brazauskas, Ruta; Wang, Zhiwei; Aljurf, Mahmoud D; Ballen, Karen K; Buchbinder, David K; Dehn, Jason; Freytes, Cesar O; Lazarus, Hillard M; Lemaistre, Charles F; Mehta, Paulette; Szwajcer, David; Joffe, Steven; Majhail, Navneet S

    2014-06-01

    Adolescents and young adults (AYAs, ages 15 to 40 years) with cancer have not experienced survival improvements to the same extent as younger and older patients. We compared changes in survival after myeloablative allogeneic hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia (ALL) among children (n = 981), AYAs (n = 1218), and older adults (n = 469) who underwent transplantation over 3 time periods: 1990 to 1995, 1996 to 2001, and 2002 to 2007. Five-year survival varied inversely with age group. Survival improved over time in AYAs and paralleled that seen in children; however, overall survival did not change over time for older adults. Survival improvements were primarily related to lower rates of early treatment-related mortality in the most recent era. For all cohorts, relapse rates did not change over time. A subset of 222 AYAs between the ages of 15 and 25 at 46 pediatric or 49 adult centers were also analyzed to describe differences by center type. In this subgroup, there were differences in transplantation practices among pediatric and adult centers, although HCT outcomes did not differ by center type. Survival for AYAs undergoing myeloablative allogeneic HCT for ALL improved at a similar rate as survival for children.

  4. Disseminated aspergillosis caused by Aspergillus ustus in a patient following allogeneic peripheral stem cell transplantation.

    PubMed

    Iwen, P C; Rupp, M E; Bishop, M R; Rinaldi, M G; Sutton, D A; Tarantolo, S; Hinrichs, S H

    1998-12-01

    The first case of disseminated aspergillosis caused by Aspergillus ustus in an allogeneic peripheral stem cell transplant patient is described. The patient, a 46-year-old female with a history of myelodysplastic syndrome, underwent high-dose chemotherapy and total body irradiation prior to transplantation. She was released from the hospital 49 days posttransplant (p.t.) in a stable condition with an absolute neutrophil count (ANC) of 2,700 cells per microl. Multiple antimicrobial agents, including itraconazole (ITR), were prescribed during hospitalization and at the time of discharge. Three days after discharge, the patient was readmitted with hemorrhagic cystitis, persistent thrombocytopenia, and bilateral pulmonary consolidation, although no fever was present. The ANC at the time of readmission was 3,500. Upon detection of a pulmonary nodule (day 67 p.t.), a bronchoalveolar lavage was performed; the lavage fluid was positive for both cytomegalovirus and parainfluenza virus and negative for fungus. The patient was placed on ganciclovir. A biopsy specimen from a leg lesion also noted on day 67 p.t. revealed septate hyphae consistent with Aspergillus species, and a culture subsequently yielded Aspergillus ustus. Confirmation detection of A. ustus was made by demonstration of characteristic reproductive structures with the presence of Hülle cells. On day 67 p.t., ITR was discontinued and liposomal amphotericin B (AMB) was initiated. The patient's condition worsened, and she died 79 days p.t. At the time of autopsy, septate hyphae were present in heart, thyroid, and lung tissues, with lung tissue culture positive for A. ustus. In vitro susceptibility testing indicated probable resistance to AMB but not to ITR. This case supports the need for the development of rapid methods to determine antifungal susceptibility.

  5. Design and Validation of an Augmented Hematopoietic Cell Transplantation-Comorbidity Index Comprising Pre-transplant Ferritin, Albumin and Platelet Count for Prediction of Outcomes after Allogeneic Transplantation

    PubMed Central

    Vaughn, Jennifer E.; Storer, Barry; Armand, Philippe; Raimondi, Roberto; Gibson, Christopher; Rambaldi, Alessandro; Ciceri, Fabio; Oneto, Rosi; Bruno, Benedetto; Martin, Paul J.; Sandmaier, Brenda M.; Storb, Rainer; Sorror, Mohamed L.

    2015-01-01

    Purpose Pre-transplant values of serum ferritin, albumin and peripheral blood counts were previously suggested to provide prognostic information about hematopoietic cell transplantation (HCT) outcomes. Whether these “biomarkers” have prognostic value independent of each other and the HCT-comorbidity index (HCT-CI) is unknown. Patients and Methods We analyzed data from 3917 allogeneic HCT recipients at multiple sites in the US and Italy using multivariate models including each biomarker and the HCT-CI. Data from all sites were then randomly divided into a training set (n=2352) to develop weights for the relevant biomarkers to be added to the HCT-CI scores and a validation set (n=1407) to validate an augmented HCT-CI compared to the original index. Results Multivariate analysis with data from one site showed that ferritin, albumin and platelets-- not neutrophils or hemoglobin--were independently associated with increased non-relapse mortality (NRM) and decreased overall survival. Findings were validated in data from the other sites. Subsequently, in a training set from all sites, ferritin >2500 mg/dL (HR:1.69); albumin 3–3.5 g/dL (HR:1.61) and <3.0 g/dL (HR:2.27); and platelets 50–<100,000 (HR:1.28), 20–<50,000 (HR:1.29) and <20,000 (HR:1.55) were statistically significantly associated with NRM. Weights were assigned to these laboratory values following the same equation used to design the original index. In the validation set, The addition of the biomarkers to the original index to develop an augmented HCT-CI resulted in a statistically significant increase in higher c-statistic estimate for prediction of NRM. (p=0.0007). Conclusion Ferritin, albumin, and platelet counts are important prognostic markers that further refine the discriminative power of the HCT-CI for transplant outcomes. PMID:25862589

  6. Development of allogeneic NK cell adoptive transfer therapy in metastatic melanoma patients: in vitro preclinical optimization studies.

    PubMed

    Besser, Michal J; Shoham, Tsipi; Harari-Steinberg, Orit; Zabari, Naama; Ortenberg, Rona; Yakirevitch, Arkadi; Nagler, Arnon; Loewenthal, Ron; Schachter, Jacob; Markel, Gal

    2013-01-01

    Natural killer (NK) cells have long been considered as potential agents for adoptive cell therapy for solid cancer patients. Until today most studies utilized autologous NK cells and yielded disappointing results. Here we analyze various modular strategies to employ allogeneic NK cells for adoptive cell transfer, including donor-recipient HLA-C mismatching, selective activation and induction of melanoma-recognizing lysis receptors, and co-administration of antibodies to elicit antibody-dependent cell cytotoxicity (ADCC). We show that NK cell activation and induction of the relevant lysis receptors, as well as co-administration of antibodies yield substantial anti-cancer effects, which are functionally superior to HLA-C mismatching. Combination of the various strategies yielded improved effects. In addition, we developed various clinically-compatible ex vivo expansion protocols that were optimized according to fold expansion, purity and expression of lysis receptors. The main advantages of employing allogeneic NK cells are accessibility, the ability to use a single donor for many patients, combination with various strategies associated with the mechanism of action, e.g. antibodies and specific activation, as well as donor selection according to HLA or CD16 genotypes. This study rationalizes a clinical trial that combines adoptive transfer of highly potent allogeneic NK cells and antibody therapy.

  7. Different effects of lansoprazole and rabeprazole on the plasma voriconazole trough levels in allogeneic hematopoietic cell transplant recipients.

    PubMed

    Yasu, Takeo; Konuma, Takaaki; Kato, Seiko; Kurokawa, Yosuke; Takahashi, Satoshi; Tojo, Arinobu

    2016-10-01

    Voriconazole (VRC) is widely used as prophylaxis and in the treatment of invasive fungal disease (IFD) after allogeneic hematopoietic cell transplantation (HCT). We retrospectively examined the results of VRC therapeutic drug monitoring (TDM) in allogeneic HCT recipients. A total of 474 samples were obtained from 59 adult patients who received VRC during the first 100 days following HCT between 2009 and 2014 in our institute. Seventeen patients received VRC for prophylaxis of IFD, and 42 received VRC for the empirical or preemptive therapy for IFD. A total of 299 samples (63 %) were obtained during the administration of the intravenous form of VRC. The median VRC daily dose based on the actual body weight was 6.68 mg/kg/day (range, 1.92-10.41 mg/kg/day). The median VRC trough level was 0.99 mg/l (range, <0.09-5.45 mg/l). The multivariate analysis using a logistic regression model demonstrated significantly higher VRC trough levels (≥1.0 mg/l) in males (P < 0.001), empirical or preemptive therapy (P = 0.002), VRC daily dose based on the actual body weight ≥7 mg/kg/day (P < 0.001), and concomitant use of lansoprazole as compared to rabeprazole (P < 0.001). The concomitant use of calcineurin inhibitors and corticosteroids had no effects on VRC trough levels in multivariate analysis. These data suggest that lansoprazole and rabeprazole have different effects on the plasma VRC trough levels in the allogeneic HCT recipients.

  8. Inoculation Site from a Cutaneous Melanoma Patient Treated with an Allogeneic Therapeutic Vaccine: A Case Report

    PubMed Central

    Aris, Mariana; Bravo, Alicia Inés; Barrio, María Marcela; Mordoh, José

    2015-01-01

    We have developed a therapeutic vaccine consisting of a mixture of lethally-irradiated allogeneic cutaneous melanoma cell lines with BCG and GM-CSF as adjuvants. The CSF-470 vaccine is currently being assayed in a Phase II–III trial against medium-dose IFN-α2b. All vaccinated patients immunized intradermally developed large edematous erythema reactions, which then transformed into subcutaneous nodules active for several months. However, vaccine injection sites were not routinely biopsied. We describe the case of a female patient, previously classified as stage III, but who, due to the simultaneous discovery of bone metastases only received one vaccination was withdrawn from the study, and continued her treatment elsewhere. This patient developed a post-vaccination nodule which was surgically removed 7 weeks later, and allowed to analyze the reactivity and immune profiling of the inoculation site. An inflammatory reaction with zones of fibrosis, high irrigation, and brisk lymphoid infiltration, primarily composed of CD8+ and CD20+ lymphocytes, was observed. There were no remaining BCG bacilli, and scarce CD4+ and Foxp3+ T cells were determined. MART-1 Ag was found throughout the vaccination site. CD11c+ Ag presenting cells were either dispersed or forming dense nests. Some CD11c+ cells proliferated; most of them contained intracellular MART-1 Ag, and some interacted with CD8+ lymphocytes. These observations suggest a potent, long-lasting local inflammatory response with recruitment of Ag-presenting cells that incorporate melanoma Ags, probably leading to Ag presentation to naïve T cells. PMID:25870600

  9. Impact of Pretransplantation (18)F-fluorodeoxy Glucose-Positron Emission Tomography Status on Outcomes after Allogeneic Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma.

    PubMed

    Bachanova, Veronika; Burns, Linda J; Ahn, Kwang Woo; Laport, Ginna G; Akpek, Görgün; Kharfan-Dabaja, Mohamed A; Nishihori, Taiga; Agura, Edward; Armand, Philippe; Jaglowski, Samantha M; Cairo, Mitchell S; Cashen, Amanda F; Cohen, Jonathon B; D'Souza, Anita; Freytes, César O; Gale, Robert Peter; Ganguly, Siddhartha; Ghosh, Nilanjan; Holmberg, Leona A; Inwards, David J; Kanate, Abraham S; Lazarus, Hillard M; Malone, Adriana K; Munker, Reinhold; Mussetti, Alberto; Norkin, Maxim; Prestidge, Tim D; Rowe, Jacob M; Satwani, Prakash; Siddiqi, Tanya; Stiff, Patrick J; William, Basem M; Wirk, Baldeep; Maloney, David G; Smith, Sonali M; Sureda, Anna M; Carreras, Jeanette; Hamadani, Mehdi

    2015-09-01

    Assessment with (18)F-fluorodeoxy glucose (FDG)-positron emission tomography (PET) before hematopoietic cell transplantation (HCT) for lymphoma may be prognostic for outcomes. Patients with chemotherapy-sensitive non-Hodgkin lymphoma (NHL) undergoing allogeneic HCT reported to the Center of International Blood and Marrow Transplantation Registry between 2007 and 2012 were included. Pre-HCT PET status (positive versus negative) was determined by the reporting transplantation centers. We analyzed 336 patients; median age was 55 years and 60% were males. Follicular lymphoma (n = 104) was more common than large cell (n = 85), mantle cell (n = 69), and mature natural killer or T cell lymphoma (n = 78); two thirds of the cohort received reduced-intensity conditioning; one half had unrelated donor grafts. Patients underwent PET scanning a median of 1 month (range, .07 to 2.83 months) before HCT; 159 were PET positive and 177 were PET negative. At 3 years, relapse/progression, progression-free survival (PFS), and overall survival (OS) in PET-positive versus PET-negative groups were 40% versus 26%; P = .007; 43% versus 47%; P = .47; and 58% versus 60%; P = .73, respectively. On multivariate analysis, a positive pretransplantation PET was associated with an increased risk of relapse/progression (risk ratio [RR], 1.86; P = .001) but was not associated with increased mortality (RR, 1.29, 95% confidence interval [CI], .96 to 1.7; P = .08), therapy failure (RR, 1.32; 95% CI, .95 to 1.84; P = .10), or nonrelapse mortality (RR, .75; 95% CI, .48 to 1.18; P = .22). PET status conferred no influence on graft-versus-host disease. A positive PET scan before HCT is associated with increased relapse risk but should not be interpreted as a barrier to a successful allograft. PET status does not appear to predict survival after allogeneic HCT for NHL.

  10. Impact of Pretransplantation 18F-fluorodeoxy Glucose—Positron Emission Tomography Status on Outcomes after Allogeneic Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma

    PubMed Central

    Bachanova, Veronika; Burns, Linda J.; Ahn, Kwang Woo; Laport, Ginna G.; Akpek, Görgün; Kharfan-Dabaja, Mohamed A.; Nishihori, Taiga; Agura, Edward; Armand, Philippe; Jaglowski, Samantha M.; Cairo, Mitchell S.; Cashen, Amanda F.; Cohen, Jonathon B.; D'Souza, Anita; Freytes, César O.; Gale, Robert Peter; Ganguly, Siddhartha; Ghosh, Nilanjan; Holmberg, Leona A.; Inward, David J.; Kanate, Abraham S.; Lazarus, Hillard M.; Malone, Adriana K.; Munker, Reinhold; Mussetti, Alberto; Norkin, Maxim; Prestidge, Tim D.; Rowe, Jacob M.; Satwani, Prakash; Siddiqi, Tanya; Stiff, Patrick J.; William, Basem M.; Wirk, Baldeep; Maloney, David G.; Smith, Sonali M.; Sureda, Anna M.; Carreras, Jeanette; Hamadani, Mehdi

    2015-01-01

    Assessment with 18F-fluorodeoxy glucose (FDG)—positron emission tomography (PET) before hematopoietic cell transplantation (HCT) for lymphoma may be prognostic for outcomes. Patients with chemotherapy-sensitive non—Hodgkin lymphoma (NHL) undergoing allogeneic HCT reported to the Center of International Blood and Marrow Transplantation Registry between 2007 and 2012 were included. Pre-HCT PET status (positive versus negative) was determined by the reporting transplantation centers. We analyzed 336 patients; median age was 55 years and 60% were males. Follicular lymphoma (n = 104) was more common than large cell (n = 85), mantle cell (n = 69), and mature natural killer or T cell lymphoma (n = 78); two thirds of the cohort received reduced-intensity conditioning; one half had unrelated donor grafts. Patients underwent PET scanning a median of 1 month (range, .07 to 2.83 months) before HCT; 159 were PET positive and 177 were PET negative. At 3 years, relapse/progression, progression-free survival (PFS), and overall survival (OS) in PET-positive versus PET-negative groups were 40% versus 26%; P = .007; 43% versus 47%; P = .47; and 58% versus 60%; P = .73, respectively. On multivariate analysis, a positive pretransplantation PET was associated with an increased risk of relapse/progression (risk ratio [RR], 1.86; P = .001) but was not associated with worse OS (RR, 1.29, 95% confidence interval [CI], .96 to 1.7; P = .08), PFS (RR, 1.32; 95% CI, .95 to 1.84; P = .10), or nonrelapse mortality (RR, .75; 95% CI, .48 to 1.18; P = .22). PET status conferred no influence on graft-versus-host disease. A positive PET scan before HCT is associated with increased relapse risk but should not be interpreted as a barrier to a successful allograft. PET status does not appear to predict survival after allogeneic HCT for NHL. PMID:25983043

  11. Assessing the Influence of Different Comorbidities Indexes on the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in a Developing Country

    PubMed Central

    Teixeira, Gustavo Machado; Bittencourt, Henrique; Rezende, Suely Meireles

    2015-01-01

    Although the application of Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) has enabled better prediction of transplant-related mortality (TRM) in allogeneic hematopoietic stem cell transplants (AHSCT), data from developing countries are scarce. This study prospectively evaluated the HCT-CI and the Adult Comorbidity Evaluation (ACE-27), in its original and in a modified version, as predictors of post-transplant complications in adults undergoing a first related or unrelated AHSCT in Brazil. Both bone marrow (BM) and peripheral blood stem cells (PBSC) as graft sources were included. We analyzed the cumulative incidence of granulocyte and platelet recovery, sinusoidal obstructive syndrome, acute and chronic graft-versus-host disease, relapse and transplant-related mortality, and rates of event-free survival and overall survival. Ninety-nine patients were assessed. Median age was 38 years (18–65 years); HCT-CI ≥ 3 accounted for only 8% of cases; hematologic malignancies comprised 75.8% of the indications for AHSCT. There was no association between the HCT-CI or the original or modified ACE-27 with TRM or any other studied outcomes after AHSCT. These results show that, in the population studied, none of the comorbidity indexes seem to be associated with AHSCT outcomes. A significantly low frequency of high-risk (HCT-CI ≥ 3) in this Brazilian population might justify these results. PMID:26394228

  12. Epidemiology of complementary and alternative medicine therapy use in allogeneic hematopoietic stem cell transplant survivorship patients in Australia.

    PubMed

    Lindsay, Julian; Kabir, Masrura; Gilroy, Nicole; Dyer, Gemma; Brice, Lisa; Moore, John; Greenwood, Matthew; Hertzberg, Mark; Gottlieb, David; Larsen, Stephen R; Hogg, Megan; Brown, Louisa; Huang, Gillian; Tan, Jeff; Ward, Christopher; Kerridge, Ian

    2016-12-01

    In addition to prescribed conventional medicines, many allogeneic hematopoietic stem cell transplant (HSCT) survivors also use complementary and alternative medical therapies (CAM), however, the frequency and types of CAMs used by allogeneic HSCT survivors remain unclear. Study participants were adults who had undergone an allogeneic HSCT between 1st January 2000 and 31st December 2012. Participants completed a 402-item questionnaire regarding the use of CAM, medical complications, specialist referrals, medications and therapies, infections, vaccinations, cancer screening, lifestyle, and occupational issues and relationship status following stem cell transplantation. A total of 1475 allogeneic HSCT were performed in the study period. Of the 669 recipients known to be alive at study sampling, 583 were contactable and were sent study packs. Of 432 participants who returned the completed survey (66% of total eligible, 76% of those contacted), 239 (54.1%) HSCT survivors used at least one form of CAM. These included dietary modification (13.6%), vitamin therapy (30%), spiritual or mind-body therapy (17.2%), herbal supplements (13.5%), manipulative and body-based therapies (26%), Chinese medicine (3.5%), reiki (3%), and homeopathy (3%). These results definitively demonstrate that a large proportion of HSCT survivors are using one or more form of CAM therapy. Given the potential benefits demonstrated by small studies of specific CAM therapies in this patient group, as well as clearly documented therapies with no benefit or even toxicity, this result shows there is a large unmet need for additional studies to ascertain efficacy and safety of CAM therapies in this growing population.

  13. Similar and Promising Outcomes in Lymphoma Patients Treated with Myeloablative or Nonmyeloablative Conditioning and Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Tomblyn, Marcie; Brunstein, Claudio; Burns, Linda J.; Miller, Jeffrey S.; MacMillan, Margaret; DeFor, Todd E.; Weisdorf, Daniel J.

    2008-01-01

    We compared the outcomes of 141 consecutive patients who received allogeneic transplantation with either myeloablative (MA) or nonmyeloablative/reduced intensity (NMA) conditioning for non-Hodgkin and Hodgkin lymphoma at the University of Minnesota. All patients were transplanted between 1997 and 2004. NMA transplant recipients were older and received umbilical cord blood grafts more frequently (MA: 6 [9%]; NMA: 33 [43%], P < .001). NMA patients had more advanced disease and 30 (39%) patients had undergone prior autologous transplantation. The 4-year overall survival (OS) (MA: 46% versus NMA: 49%; p = .34) and the 3-year progression-free survival (PFS) (MA: 44% versus NMA: 31%; P = 0.82) were similar after MA or NMA conditioning. However, MA conditioning resulted in significantly higher 1-year treatment-related mortality (TRM) (MA: 43% versus NMA: 17%; P < .01) but a lower risk of relapse at 3 years (MA: 11% versus NMA: 36%; P < .01). We conclude that similar transplant outcomes are achieved after allogeneic hematopoietic stem cell transplantation using MA conditioning in younger patients and NMA conditioning in older patients or those with prior autologous transplantation not eligible for MA conditioning. Modifications to refine patient assignment to the preferred conditioning intensity and reduce relapse risks with NMA approaches are needed. PMID:18410896

  14. Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Progression Free Survival for Patients with Chronic Myelomonocytic Leukemia

    PubMed Central

    Kongtim, Piyanuch; Popat, Uday; Jimenez, Antonio; Gaballa, Sameh; Fakih, Riad El; Rondon, Gabriela; Chen, Julianne; Bueso-Ramos, Carlos; Borthakur, Gautam; Pemmaraju, Naveen; Garcia-Manero, Guillermo; Kantarjian, Hagop; Alousi, Amin; Hosing, Chitra; Anderlini, Paolo; Khouri, Issa F.; Kebriaei, Partow; Andersson, Borje S.; Oran, Betul; Rezvani, Katayoun; Marin, David; Shpall, Elizabeth J.; Champlin, Richard E.; Ciurea, Stefan O.

    2016-01-01

    The treatment of patients with chronic myelomonocytic leukemia (CMML) with transplant has not been optimized. We retrospectively reviewed the data for 83 consecutive patients with CMML (47 with CMML-1/2 and 36 with CMML progressed to acute myeloid leukemia) who received an allogeneic stem cell transplant at our institution between April 1991 and December 2013 to identify factors associated with improved survival and determine whether treatment with hypomethylating agents before transplant improves progression-free survival. The median age of the cohort was 57 years. Seventy-eight patients received induction treatment before transplant, with 37 receiving hypomethylating agents and 41 receiving cytotoxic chemotherapy. Patients treated with a hypomethylating agent had a significantly lower cumulative incidence of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; p=0.03), whereas TRM at 1 year post-transplant did not significantly differ between the groups (27% and 30%, respectively; p=0.84). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a hypomethylating agent (43%) than in those treated with other agents (27%; p=0.04). Our data support the use of hypomethylating agents before allogeneic stem cell transplantation for patients with CMML to achieve morphologic remission and improve progression-free survival of these patients. Future studies are needed to confirm these findings. PMID:26343946

  15. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial.

    PubMed

    Platzbecker, U; Wermke, M; Radke, J; Oelschlaegel, U; Seltmann, F; Kiani, A; Klut, I-M; Knoth, H; Röllig, C; Schetelig, J; Mohr, B; Graehlert, X; Ehninger, G; Bornhäuser, M; Thiede, C

    2012-03-01

    This study evaluated azacitidine as treatment of minimal residual disease (MRD) determined by a sensitive donor chimerism analysis of CD34(+) blood cells to pre-empt relapse in patients with CD34(+) myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). At a median of 169 days after HSCT, 20/59 prospectively screened patients experienced a decrease of CD34(+) donor chimerism to <80% and received four azacitidine cycles (75 mg/m(2)/day for 7 days) while in complete hematologic remission. A total of 16 patients (80%) responded with either increasing CD34(+) donor chimerism to ≥80% (n=10; 50%) or stabilization (n=6; 30%) in the absence of relapse. Stabilized patients and those with a later drop of CD34(+) donor chimerism to <80% after initial response were eligible for subsequent azacitidine cycles. A total of 11 patients (55%) received a median of 4 (range, 1-11) additional cycles. Eventually, hematologic relapse occurred in 13 patients (65%), but was delayed until a median of 231 days (range, 56-558) after initial decrease of CD34(+) donor chimerism to <80%. In conclusion, pre-emptive azacitidine treatment has an acceptable safety profile and can substantially prevent or delay hematologic relapse in patients with MDS or AML and MRD after allogeneic HSCT.

  16. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial

    PubMed Central

    Platzbecker, U; Wermke, M; Radke, J; Oelschlaegel, U; Seltmann, F; Kiani, A; Klut, I-M; Knoth, H; Röllig, C; Schetelig, J; Mohr, B; Graehlert, X; Ehninger, G; Bornhäuser, M; Thiede, C

    2012-01-01

    This study evaluated azacitidine as treatment of minimal residual disease (MRD) determined by a sensitive donor chimerism analysis of CD34+ blood cells to pre-empt relapse in patients with CD34+ myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT). At a median of 169 days after HSCT, 20/59 prospectively screened patients experienced a decrease of CD34+ donor chimerism to <80% and received four azacitidine cycles (75 mg/m2/day for 7 days) while in complete hematologic remission. A total of 16 patients (80%) responded with either increasing CD34+ donor chimerism to ⩾80% (n=10; 50%) or stabilization (n=6; 30%) in the absence of relapse. Stabilized patients and those with a later drop of CD34+ donor chimerism to <80% after initial response were eligible for subsequent azacitidine cycles. A total of 11 patients (55%) received a median of 4 (range, 1–11) additional cycles. Eventually, hematologic relapse occurred in 13 patients (65%), but was delayed until a median of 231 days (range, 56–558) after initial decrease of CD34+ donor chimerism to <80%. In conclusion, pre-emptive azacitidine treatment has an acceptable safety profile and can substantially prevent or delay hematologic relapse in patients with MDS or AML and MRD after allogeneic HSCT. PMID:21886171

  17. Current Knowledge and Priorities for Future Research in Late Effects after Hematopoietic Stem Cell Transplantation (HCT) for Severe Combined Immunodeficiency Patients: A Consensus Statement from the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects after Pediatric HCT.

    PubMed

    Heimall, Jennifer; Puck, Jennifer; Buckley, Rebecca; Fleisher, Thomas A; Gennery, Andrew R; Neven, Benedicte; Slatter, Mary; Haddad, Elie; Notarangelo, Luigi D; Baker, K Scott; Dietz, Andrew C; Duncan, Christine; Pulsipher, Michael A; Cowan, Mort J

    2017-03-01

    Severe combined immunodeficiency (SCID) is 1 of the most common indications for pediatric hematopoietic cell transplantation (HCT) in patients with primary immunodeficiency. Historically, SCID was diagnosed in infants who presented with opportunistic infections within the first year of life. With newborn screening (NBS) for SCID in most of the United States, the majority of infants with SCID are now diagnosed and treated in the first 3.5 months of life; however, in the rest of the world, the lack of NBS means that most infants with SCID still present with infections. The average survival for SCID patients who have undergone transplantation currently is >70% at 3 years after transplantation, although this can vary significantly based on multiple factors, including age and infection status at the time of transplantation, type of donor source utilized, manipulation of graft before transplantation, graft-versus-host disease prophylaxis, type of conditioning (if any) utilized, and underlying genotype of SCID. In at least 1 study of SCID patients who received no conditioning, long-term survival was 77% at 8.7 years (range out to 26 years) after transplantation. Although a majority of patients with SCID will engraft T cells without any conditioning therapy, depending on genotype, donor source, HLA match, and presence of circulating maternal cells, a sizable percentage of these will fail to achieve full immune reconstitution. Without conditioning, T cell reconstitution typically occurs, although not always fully, whereas B cell engraftment does not, leaving some molecular types of SCID patients with intrinsically defective B cells, in most cases, dependent on regular infusions of immunoglobulin. Because of this, many centers have used conditioning with alkylating agents including busulfan or melphalan known to open marrow niches in attempts to achieve B cell reconstitution. Thus, it is imperative that we understand the potential late effects of these agents in this patient

  18. Long-term Survival and Late Effects among 1-year Survivors of Second Allogeneic Hematopoietic Cell Transplantation for Relapsed Acute Leukemia and Myelodysplastic Syndromes

    PubMed Central

    Duncan, Christine N.; Majhail, Navneet S.; Brazauskas, Ruta; Wang, Zhiwei; Cahn, Jean-Yves; Frangoul, Haydar A.; Hayashi, Robert J.; Hsu, Jack W.; Kamble, Rammurti T.; Kasow, Kimberly A.; Khera, Nandita; Lazarus, Hillard M.; Loren, Alison W.; Marks, David I.; Maziarz, Richard T.; Mehta, Paulette; Myers, Kasiani C.; Norkin, Maxim; Pidala, Joseph A.; Porter, David L.; Reddy, Vijay; Saber, Wael; Savani, Bipin N.; Schouten, Harry C.; Steinberg, Amir; Wall, Donna A.; Warwick, Anne B.; Wood, William A.; Yu, Lolie C.; Jacobsohn, David A.; Sorror, Mohamed L.

    2014-01-01

    We analyzed the outcomes of patients who survived disease-free for 1-year or more following second allogeneic hematopoietic cell transplantation (HCT) for relapsed acute leukemia or myelodysplastic syndromes between 1980 and 2009. A total of 1285 patients received a second allogeneic transplant following disease relapse; among these 325 survived relapse-free at 1-year after the second HCT. The median time from first to second HCT was 17 and 24 months for children and adults, respectively. A myeloablative preparative regimen was used in the second transplant in 62% of children and 45% of adult patients. The overall 10-year conditional survival rates after second transplantation in this cohort of patients who had survived disease-free for at least one year were 55% in children and 39% in adults. Relapse was the leading cause of mortality (77% and 54% of deaths in children and adults, respectively). In multivariate analyses, only disease status prior to second HCT was significantly associated with higher risk for overall mortality (HR 1.71 for patients with disease not in complete remission prior to second HCT, P<0.01). Chronic graft-versus-host disease (GVHD) developed in 43% and 75% of children and adults following second transplant. Chronic GVHD was the leading cause of non-relapse mortality followed by organ failure and infection. The cumulative incidence of developing at least one of the studied late effects at 10-years after second HCT was 63% in children and 55% in adults. The most frequent late effects in children were growth disturbance (10-year cumulative incidence 22%) and cataracts (20%), and in adults were cataracts (20%) and avascular necrosis (13%). Among patients with acute leukemia and myelodysplastic syndromes who receive a second allogeneic HCT for relapse and survive disease-free for at least 1-year, many can be expected to survive long term. However, they continue to be at risk for relapse and non-relapse morbidity and mortality. Novel approaches

  19. Long-term survival and late effects among one-year survivors of second allogeneic hematopoietic cell transplantation for relapsed acute leukemia and myelodysplastic syndromes.

    PubMed

    Duncan, Christine N; Majhail, Navneet S; Brazauskas, Ruta; Wang, Zhiwei; Cahn, Jean-Yves; Frangoul, Haydar A; Hayashi, Robert J; Hsu, Jack W; Kamble, Rammurti T; Kasow, Kimberly A; Khera, Nandita; Lazarus, Hillard M; Loren, Alison W; Marks, David I; Maziarz, Richard T; Mehta, Paulette; Myers, Kasiani C; Norkin, Maxim; Pidala, Joseph A; Porter, David L; Reddy, Vijay; Saber, Wael; Savani, Bipin N; Schouten, Harry C; Steinberg, Amir; Wall, Donna A; Warwick, Anne B; Wood, William A; Yu, Lolie C; Jacobsohn, David A; Sorror, Mohamed L

    2015-01-01

    We analyzed the outcomes of patients who survived disease-free for 1 year or more after a second allogeneic hematopoietic cell transplantation (HCT) for relapsed acute leukemia or myelodysplastic syndromes between 1980 and 2009. A total of 1285 patients received a second allogeneic transplant after disease relapse; among these, 325 were relapse free at 1 year after the second HCT. The median time from first to second HCT was 17 and 24 months for children and adults, respectively. A myeloablative preparative regimen was used in the second transplantation in 62% of children and 45% of adult patients. The overall 10-year conditional survival rates after second transplantation in this cohort of patients who had survived disease-free for at least 1 year was 55% in children and 39% in adults. Relapse was the leading cause of mortality (77% and 54% of deaths in children and adults, respectively). In multivariate analyses, only disease status before second HCT was significantly associated with higher risk for overall mortality (hazard ratio, 1.71 for patients with disease not in complete remission before second HCT, P < .01). Chronic graft-versus-host disease (GVHD) developed in 43% and 75% of children and adults after second transplantation. Chronic GVHD was the leading cause of nonrelapse mortality, followed by organ failure and infection. The cumulative incidence of developing at least 1 of the studied late effects within 10 years after second HCT was 63% in children and 55% in adults. The most frequent late effects in children were growth disturbance (10-year cumulative incidence, 22%) and cataracts (20%); in adults they were cataracts (20%) and avascular necrosis (13%). Among patients with acute leukemia and myelodysplastic syndromes who receive a second allogeneic HCT for relapse and survive disease free for at least 1 year, many can be expected to survive long term. However, they continue to be at risk for relapse and nonrelapse morbidity and mortality. Novel

  20. Comparison of characteristics of bacterial bloodstream infection between adult patients with allogeneic and autologous hematopoietic stem cell transplantation.

    PubMed

    Hong, Junshik; Moon, Song Mi; Ahn, Hee Kyung; Sym, Sun Jin; Park, Yoon Soo; Park, Jinny; Cho, Yong Kyun; Cho, Eun Kyung; Shin, Dong Bok; Lee, Jae Hoon

    2013-06-01

    Although autologous and allogeneic hematopoietic stem cell transplantation (HSCT) are fundamentally different procedures, a tailored approach to bacterial bloodstream infection (BSI) according to the type of HSCT has not yet been suggested. We evaluated the characteristics of BSI after HSCT, with a focus on comparison of BSIs between recipients of autologous HSCT (auto-HSCT) and allogeneic HSCT (allo-HSCT). Among 134 patients (59 received allo-HSCT and 75 received auto-HSCT) who underwent HSCT, BSIs were reported earlier in patients who underwent auto-HSCT, compared with those who underwent allo-HSCT (mean 12.1 ± 3.4 days versus 32.8 ± 27.1 days, P = .006). Among patients receiving allo-HSCT, postneutrophil-engraftment bacterial BSI showed an association with grade ≥ 2 acute graft-versus-host disease (GVHD). In patients who underwent auto-HSCT, results of multivariate analysis showed that not receiving prophylactic antibiotics (P = .004) and having elevated serum C-reactive protein (P = .034) were risk factors of BSI. Elevated CRP (P = .01) and acute GVHD ≥ grade 2 (P = .002) were independent risk factors in patients who underwent allo-HSCT. Those differences originated mainly from the impact of acute GVHD-related postengraftment BSIs of patients who underwent allo-HSCT. To establish the best defense strategy against BSI, the distinctive natures of bacterial BSI after HSCT between auto-HSCT and allo-HSCT should be considered.

  1. Rare case of disseminated fusariosis in a young patient with graft vs. host disease following an allogeneic transplant

    PubMed Central

    Tanase, Alina; Colita, Anca; Ianosi, Gabriel; Neagoe, Daniela; Branisteanu, Daciana Elena; Calina, Daniela; Docea, Anca Oana; Tsatsakis, Aristidis; Ianosi, Simona Laura

    2016-01-01

    Fusarium infection is a severe fungal infection caused by fungi of the genus Fusarium. It most commonly occurs in immunocompromised patients with malignant hematological comorbidities or secondary to hematopoietic stem cell transplant. The classical route of contamination is through inhalation but infection may also occur through contiguity with a skin lesion. This report describes the case of a 24-year-old woman who developed graft-vs.-host disease (GVHD) at 220 days after receiving an allogeneic stem cell transplant from a sibling donor for Hodgkin disease. On day 330 after transplant the patient presented with fever and several painful subcutaneous, tender, red nodules with ulcerative and necrotic features on the pelvic region and right leg, extensive glass infiltrative lesions in the lungs and pansinusitis; however, the patient did not have onychomycosis. Following skin biopsy, culture of cutaneous lesions, computed tomography (CT) scanning of the lungs and CT scanning and magnetic resonance imaging of facial sinuses the patient was diagnosed with disseminated Fusarium species infection. Despite intensive treatment with voriconazole, the patient succumbed with respiratory insufficiency on day 400 after transplant. This case is noteworthy because the patient did not have any additional risk associated with the allogeneic transplant; there was no transplant mismatch, no severe neutropenia and no prior clinical signs of onychomycosis. The association of skin lesions with GVHD lesions increased the initial immunosuppression and delayed diagnosis. PMID:27698695

  2. Allogeneic Transplantation for Relapsed Waldenström Macroglobulinemia and Lymphoplasmacytic Lymphoma.

    PubMed

    Cornell, Robert F; Bachanova, Veronika; D'Souza, Anita; Woo-Ahn, Kwang; Martens, Michael; Huang, Jiaxing; Al-Homsi, A Samer; Chhabra, Saurabh; Copelan, Edward; Diaz, Miguel-Angel; Freytes, Cesar O; Gale, Robert Peter; Ganguly, Siddhartha; Hamadani, Mehdi; Hildebrandt, Gerhard; Kamble, Rammurti T; Kharfan-Dabaja, Mohamed; Kindwall-Keller, Tamila; Lazarus, Hillard M; Marks, David I; Nishihori, Taiga; Olsson, Richard F; Saad, Ayman; Usmani, Saad; Vesole, David H; Yared, Jean; Mark, Tomer; Nieto, Yago; Hari, Parameswaran

    2017-01-01

    Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is characterized by lymphoplasmacytic proliferation, lymph node and spleen enlargement, bone marrow involvement, and IgM production. Treatment varies based on the extent and biology of disease. In some patients, the use of allogeneic hematopoietic cell transplantation (alloHCT) may have curative potential. We evaluated long-term outcomes of 144 patients who received adult alloHCT for WM/LPL. Data were obtained from the Center for International Blood and Marrow Transplant Research database (2001 to 2013). Patients received myeloablative(n = 67) or reduced-intensity conditioning (RIC; n = 67). Median age at alloHCT was 53 years, and median time from diagnosis to transplantation was 41 months. Thirteen percent (n = 18) failed prior autologous HCT. About half (n = 82, 57%) had chemosensitive disease at the time of transplantation, whereas 22% had progressive disease. Rates of progression-free survival, overall survival, relapse, and nonrelapse mortality at 5 years were 46%, 52%, 24%, and 30%, respectively. Patients with chemosensitive disease and better pretransplant disease status experienced significantly superior overall survival. There were no significant differences in progression-free survival based on conditioning (myeloablative, 50%, versus RIC, 41%) or graft source. Conditioning intensity did not impact treatment-related mortality or relapse. The most common causes of death were primary disease and graft-versus-host disease (GVHD). AlloHCT yielded durable survival in select patients with WM/LPL. Strategies to reduce mortality from GVHD and post-transplant relapse are necessary to improve this approach.

  3. Long-term therapeutic efficacy of allogenic bone marrow transplantation in a patient with mucopolysaccharidosis IVA.

    PubMed

    Chinen, Yasutsugu; Higa, Takeshi; Tomatsu, Shunji; Suzuki, Yasuyuki; Orii, Tadao; Hyakuna, Nobuyuki

    Mucopolysaccharidosis IVA (MPS IVA) is one of the lysosomal storage diseases. It is caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to accumulation of the specific glycosaminoglycans keratan sulfate and chondroitin-6-sulfate. This accumulation has a direct impact on cartilage and bone development, resulting in systemic skeletal dysplasia. There is no curative therapy for this skeletal dysplasia. This report describes long-term therapeutic efficacy in a 15-year-old boy with a severe form of MPS IVA who received successful allogeneic bone marrow transplantation (BMT) from his HLA-identical carrier sister. The level of the GALNS enzyme in the recipient's lymphocytes reached almost half of normal level within two years after BMT. For the successive 9+ years post-BMT, GALNS activity in his lymphocytes maintained the same level as the donor's, and the level of urinary uronic acid was reduced. Lumbar bone mineral density increased around 50% one year later post-BMT and was kept consistent. Radiographs showed that the figures of trochanter major and minor appeared, while the epiphyseal dysplasia in the femoral cap was almost unchanged. Loud snoring and apnea disappeared. Vital capacity increased to around 20% for the first two years and was maintained. Activity of daily life (ADL) was improved in work/study efficacy, respiratory status, sleep, joint pain, and frequency of infection. In conclusion, the long-term study of hematopoetic stem cell transplantation has shown clinical improvements in respiratory function, radiograph findings, ADL, and biochemical findings, suggesting that it is a potential therapeutic option for patients with MPS IVA.

  4. Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors.

    PubMed

    Carnevale-Schianca, Fabrizio; Caravelli, Daniela; Gallo, Susanna; Coha, Valentina; D'Ambrosio, Lorenzo; Vassallo, Elena; Fizzotti, Marco; Nesi, Francesca; Gioeni, Luisa; Berger, Massimo; Polo, Alessandra; Gammaitoni, Loretta; Becco, Paolo; Giraudo, Lidia; Mangioni, Monica; Sangiolo, Dario; Grignani, Giovanni; Rota-Scalabrini, Delia; Sottile, Antonino; Fagioli, Franca; Aglietta, Massimo

    2017-03-01

    Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571.

  5. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation.

    PubMed

    Landgren, Ola; Gilbert, Ethel S; Rizzo, J Douglas; Socié, Gérard; Banks, Peter M; Sobocinski, Kathleen A; Horowitz, Mary M; Jaffe, Elaine S; Kingma, Douglas W; Travis, Lois B; Flowers, Mary E; Martin, Paul J; Deeg, H Joachim; Curtis, Rochelle E

    2009-05-14

    We evaluated 26 901 patients who underwent allogeneic hematopoietic cell transplantation (HCT) at 271 centers worldwide to define patterns of posttransplantation lymphoproliferative disorders (PTLDs). PTLDs developed in 127 recipients, with 105 (83%) cases occurring within 1 year after transplantation. In multivariate analyses, we confirmed that PTLD risks were strongly associated (P < .001) with T-cell depletion of the donor marrow, antithymocyte globulin (ATG) use, and unrelated or HLA-mismatched grafts (URD/HLA mismatch). Significant associations were also confirmed for acute and chronic graft-versus-host disease. The increased risk associated with URD/HLA-mismatched donors (RR = 3.8) was limited to patients with T-cell depletion or ATG use (P = .004). New findings were elevated risks for age 50 years or older at transplantation (RR = 5.1; P < .001) and second transplantation (RR = 3.5; P < .001). Lower risks were found for T-cell depletion methods that remove both T and B cells (alemtuzumab and elutriation, RR = 3.1; P = .025) compared with other methods (RR = 9.4; P = .005 for difference). The cumulative incidence of PTLDs was low (0.2%) among 21 686 patients with no major risk factors, but increased to 1.1%, 3.6%, and 8.1% with 1, 2, and more than 3 major risk factors, respectively. Our findings identify subgroups of patients who underwent allogeneic HCT at elevated risk of PTLDs for whom prospective monitoring of Epstein-Barr virus activation and early treatment intervention may be particularly beneficial.

  6. Screening for Y Chromosome Microdeletion in a Nonobstructive Azoospermic Male Patient with Allogeneic Bone Marrow Transplantation from His Sister

    PubMed Central

    Gurkan, Hakan; Kucukdurmaz, Faruk; Akman, Tolga; Aydın, Filiz; Kadioglu, Ates

    2010-01-01

    Genomic DNA of a patient diagnosed with nonobstructive azoospermia and with the history of allogenic bone marrow transplantation from his sister due to chronic myeloid leukemia was isolated from peripheral blood in order to screen Y chromosome microdeletions. 13 short tagged sites belonging to AZF a, b, and c loci were detected with multiplex polymerase chain reaction technique. Bands were determined in ZFX/ZFY wells, whereas no bands were determined in wells of other STS regions. DNA isolation was done from buccal mucosa smear to obtain genomic DNA from patient's own cells and multiplex polymerase chain reaction technique was performed again. Bands were seen in all wells of 13 STS regions. Y chromosome microdeletion was not detected in the patient. In conclusion, genomic DNA isolation in patients undergoing BMT should be done from patients' own cells. PMID:21209805

  7. Relationship of body mass index and arm anthropometry to outcomes after pediatric allogeneic hematopoietic cell transplantation for hematologic malignancies.

    PubMed

    Hoffmeister, Paul A; Storer, Barry E; Macris, Paula Charuhas; Carpenter, Paul A; Baker, K Scott

    2013-07-01

    Although nutritional status may adversely affect various health outcomes, the relationship between anthropometry and outcomes after hematopoietic cell transplantation (HCT) has not been fully studied in children. We analyzed the impact of pre-HCT body mass index (BMI), arm muscle area, and arm fat area on outcomes in 733 patients age 2-18 years who underwent allogeneic HCT for a hematologic malignancy between 1985 and 2009. We evaluated these 3 variables according to patient group based on age- and sex-adjusted percentiles for BMI, arm muscle area (<5th, 5th-24th, 25th-94th, and ≥95th), and arm fat area (<25th, 25th-94th, and ≥95th). Cox proportional hazards regression models for event-free survival (EFS), relapse, and nonrelapse mortality (NRM) at 100 days and 3 years after HCT, as well as grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD, were performed using the 3 major variables and adjusted for covariates. BMI was <5th percentile in only 3% of patients and ≥95th percentile in 15% of patients, but outcomes for both groups were similar to those for the BMI 25th-94th percentile group. The BMI 5th-24th percentile group had lower EFS (P = .01) and higher relapse (P = .003) at day +100 post-HCT, but these associations did not hold at 3 years post-HCT. Arm muscle area was <5th percentile in 8% of patients, and arm fat area was <25th percentile in 10%. Analysis of arm muscle area showed that the <5th percentile group had lower EFS and higher NRM and relapse rate at day +100 (P = .002, .04, and .01, respectively) and 3 years (P = .0004, .008, and .01, respectively) post-HCT. Arm fat area <25th percentile was associated with lower EFS at day +100 (hazard ratio, 1.5; P = .05), but not at 3 years post-HCT. Anthropometry variables were not associated with acute or chronic GVHD. In conclusion, arm muscle area <5th percentile appears to be a stronger predictor than BMI of poor outcomes after HCT in children with hematologic malignancies.

  8. Patients with mantle-cell lymphoma relapsing after autologous stem cell transplantation may be rescued by allogeneic transplantation.

    PubMed

    Martínez, C; Carreras, E; Rovira, M; Urbano-Ispizua, A; Esteve, J; Perales, M; Fernández, F; Montserrat, E

    2000-09-01

    Two patients with disseminated mantle-cell lymphoma relapsed 24 and 13 months, respectively, after high-dose chemotherapy and autologous stem cell transplantation (autoSCT). Both patients had an HLA-identical sibling and received an allogeneic stem cell transplant (alloSCT) 32 and 18 months after autologous transplant, after conditioning with fractionated 12 Gy total body irradiation plus cyclophosphamide 120 mg/kg. They are both alive and in complete remission 24 months after transplant. Both patients have developed chronic graft-versus-host disease and their Karnofsky performance status is 90%. AlloSCT may offer a useful approach in a subgroup of patients with mantle-cell lymphoma who have relapsed after autologous transplantation.

  9. Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic haematopoietic stem-cell transplantation

    PubMed Central

    Marks, David I; Pagliuca, Antonio; Kibbler, Christopher C; Glasmacher, Axel; Heussel, Claus-Peter; Kantecki, Michal; Miller, Paul JS; Ribaud, Patricia; Schlamm, Haran T; Solano, Carlos; Cook, Gordon

    2011-01-01

    Antifungal prophylaxis for allogeneic haematopoietic stem-cell transplant (alloHCT) recipients should prevent invasive mould and yeast infections (IFIs) and be well tolerated. This prospective, randomized, open-label, multicentre study compared the efficacy and safety of voriconazole (234 patients) versus itraconazole (255 patients) in alloHCT recipients. The primary composite endpoint, success of prophylaxis, incorporated ability to tolerate study drug for ≥100 d (with ≤14 d interruption) with survival to day 180 without proven/probable IFI. Success of prophylaxis was significantly higher with voriconazole than itraconazole (48·7% vs. 33·2%, P <0·01); more voriconazole patients tolerated prophylaxis for 100 d (53·6% vs. 39·0%, P<0·01; median total duration 96 vs. 68 d). The most common (>10%) treatment-related adverse events were vomiting (16·6%), nausea (15·8%) and diarrhoea (10·4%) for itraconazole, and hepatotoxicity/liver function abnormality (12·9%) for voriconazole. More itraconazole patients received other systemic antifungals (41·9% vs. 29·9%, P<0·01). There was no difference in incidence of proven/probable IFI (1·3% vs. 2·1%) or survival to day 180 (81·9% vs. 80·9%) for voriconazole and itraconazole respectively. Voriconazole was superior to itraconazole as antifungal prophylaxis after alloHCT, based on differences in the primary composite endpoint. Voriconazole could be given for significantly longer durations, with less need for other systemic antifungals. PMID:21880032

  10. HEMORRHAGIC CYSTITIS AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION: RISK FACTORS, GRAFT SOURCE, AND SURVIVAL

    PubMed Central

    Lunde, Laura E.; Dasaraju, Sandhyarani; Cao, Qing; Cohn, Claudia S.; Reding, Mark; Bejanyan, Nelli; Trottier, Bryan; Rogosheske, John; Brunstein, Claudio; Warlick, Erica; Young, Jo Anne H.; Weisdorf, Daniel J.; Ustun, Celalettin

    2017-01-01

    Although hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic cell transplantation (alloHCT), its risk factors and effects on survival are not well-known. We evaluated HC in a large cohort (n=1321, 2003 – 2012) receiving alloHCT from all graft sources, including umbilical cord blood (UCB). We compared HC patients with non-HC (control) patients and examined clinical variables at HC onset and resolution. Of these 1321 patients, 219 (16.6%) developed HC at a median of 22 days after alloHCT. BK viruria was detected in 90% of 109 tested HC patients. Median duration of HC was 27 days. At the time of HC diagnosis, acute graft-versus-host disease (GVHD), fever, severe thrombocytopenia, and steroid use were more frequent than at the time of HC resolution. In univariate analysis, male sex, age <20 years, myeloablative conditioning with cyclophosphamide and acute GVHD were associated with HC. In multivariate analysis, HC was significantly more common in males and HLA-mismatched UCB graft recipients. Severe grade HC (grade III–IV) was associated with increased treatment-related mortality (TRM) but not with overall survival at 1 year. HC remains hazardous and therefore better prophylaxis and early interventions to limit its severity are still needed. PMID:26168069

  11. Muscle Cramps and Neuropathies in Patients with Allogeneic Hematopoietic Stem Cell Transplantation and Graft-versus-Host Disease

    PubMed Central

    Kraus, Peter D.; Wolff, Daniel; Grauer, Oliver; Angstwurm, Klemens; Jarius, Sven; Wandinger, Klaus P.; Holler, Ernst; Schulte-Mattler, Wilhelm; Kleiter, Ingo

    2012-01-01

    Objective Graft-versus-host disease (GVHD) is an immune-mediated multisystemic disorder and the leading cause of morbidity after allogeneic hematopoietic stem cell transplantation. Peripheral nervous system manifestations of GVHD are rare but often disabling. Whereas immune-mediated neuropathies are an established feature of GVHD, muscle cramps are not well characterized. Methods In a single-centre retrospective cohort we studied 27 patients (age 23 to 69 years) with GVHD (acute n = 6, chronic n = 21) who complained of symptoms suggestive of peripheral nervous system complications. Clinical, laboratory and neurophysiological findings were evaluated by descriptive statistics and regression analysis to detect factors associated with muscle cramps. Patient’s sera were examined for anti-neuronal antibodies. Results Nine patients had polyneuropathy, 4 had muscle cramps, and 14 had both. Median onset of polyneuropathy and muscle cramps was 6 and 9 months after allogeneic hematopoietic stem cell transplantation, respectively. Neurophysiology revealed a predominantly axonal polyneuropathy in 20 of 26 patients. In 4 of 19 patients electromyography showed signs of myopathy or myositis. Muscle cramps were more frequent during chronic than acute GVHD and affected muscles other than calves in 15 of 18 patients. They typically occurred daily, lasted 1 to 10 minutes with medium to severe pain intensity, compromised daily activity or sleep in 12, and were refractory to therapy in 4 patients. Muscle cramps were less likely with tacrolimus treatment and signs of severe polyneuropathy, but more likely with myopathic changes in electromyography and with incipient demyelinating polyneuropathy, shown by increased high frequency attenuation of the tibial nerve. Serological studies revealed antinuclear or antimitochondrial antibodies in a subset of patients. Two of 16 patients had a serum reactivity against peripheral nervous tissue. Conclusion Muscle cramps are associated with

  12. Platelet and Red Blood Cell Utilization and Transfusion Independence in Umbilical Cord Blood and Allogeneic Peripheral Blood Hematopoietic Cell Transplants

    PubMed Central

    Solh, Melhem; Brunstein, Claudio; Morgan, Shanna; Weisdorf, Daniel

    2010-01-01

    Allogeneic hematopoietic cell transplantation (HCT) recipients have substantial transfusion requirements. Factors associated with increased transfusions and the extent of blood product use in umbilical cord blood (UCB) recipients are uncertain. We reviewed blood product use in 229 consecutive adult recipients of allogeneic HCT at the University of Minnesota: 147 with leukemia, 82 lymphoma or myeloma; 58% received unrelated UCB and 43% sibling donor peripheral blood stem cell (PBSC) grafts. Although neutrophil recovery was prompt (UCB median 17, range 2–45 days, and PBSC 14, range 3–34 days), only 135 of 229 (59% cumulative incidence, CI) achieved RBC independence and 157 (69%) achieved platelet independence by 6 months. Time to platelet independence was prolonged in UCB recipients (median UCB 41 vs. PBSC 14 days) and in patients who had received a prior transplant (median 48 vs. 32 days). Patients who received UCB grafts required more RBC through day 60 post HCT (mean UCB 7.8 (95% CI 6.7–8.9) vs. PBSC 5.2 (3.7–6.7) transfusions, p=0.04), and more platelet transfusions (mean 25.2 (95% CI 22.1–28.2) vs. 12.9 (9.4–16.4), p<0.01) compared to PBSC recipients. Patient receiving myeloablative (MA) conditioning required more RBC and platelet transfusions during the first 2 months post HCT compared to reduced intensity conditioning (RIC) (7.4 vs. 6.2, p=0.3 for RBC; 23.2 vs 17.5, p=0.07 for platelets). Despite prompt neutrophil engraftment, UCB recipients had delayed platelet recovery as well as more prolonged and costly blood product requirements. Enhanced approaches to accelerate multilineage engraftment could limit the transfusion-associated morbidity and costs accompanying UCB allotransplantation. PMID:20813199

  13. Platelet and red blood cell utilization and transfusion independence in umbilical cord blood and allogeneic peripheral blood hematopoietic cell transplants.

    PubMed

    Solh, Melhem; Brunstein, Claudio; Morgan, Shanna; Weisdorf, Daniel

    2011-05-01

    Allogeneic hematopoietic cell transplantation (HCT) recipients have substantial transfusion requirements. Factors associated with increased transfusions and the extent of blood product use in umbilical cord blood (UCB) recipients are uncertain. We reviewed blood product use in 229 consecutive adult recipients of allogeneic HCT at the University of Minnesota: 147 with leukemia, 82 lymphoma or myeloma; 58% received unrelated UCB and 43% sibling donor peripheral blood stem cell (PBSC) grafts. Although neutrophil recovery was prompt (UCB median 17, range: 2-45 days, and PBSC 14, range: 3-34 days), only 135 of 229 (59% cumulative incidence) achieved red blood cell (RBC) independence and 157 (69%) achieved platelet independence by 6 months. Time to platelet independence was prolonged in UCB recipients (median UCB 41 versus PBSC 14 days) and in patients who had received a prior transplant (median 48 versus 32 days). Patients who received UCB grafts required more RBC through day 60 post-HCT (mean UCB 7.8 (95% confidence interval [CI] 6.7-8.9) versus PBSC 5.2 (3.7-6.7) transfusions, P = .04), and more platelet transfusions (mean 25.2 (95% CI 22.1-28.2) versus 12.9 (9.4-16.4), P < .01) compared to PBSC recipients. Patients receiving myeloablative (MA) conditioning required more RBC and platelet transfusions during the first 2 months post-HCT compared to reduced-intensity conditioning (RIC) (7.4 versus 6.2, P = .30 for RBC; 23.2 versus 17.5, P = .07 for platelets). Despite prompt neutrophil engraftment, UCB recipients had delayed platelet recovery as well as more prolonged and costly blood product requirements. Enhanced approaches to accelerate multilineage engraftment could limit the transfusion-associated morbidity and costs accompanying UCB allotransplantation.

  14. A clofarabine-based bridging regimen in patients with relapsed ALL and persistent minimal residual disease (MRD).

    PubMed

    Gossai, N; Verneris, M R; Karras, N A; Gorman, M F; Patel, N J; Burke, M J

    2014-03-01

    In patients with relapsed ALL, minimal residual disease (MRD) identified prior to allogeneic hematopoietic cell transplantation (HCT) is a strong predictor of relapse. We report our experience using a combination of reduced-dosing clofarabine, CY and etoposide as a 'bridge' to HCT in eight patients with high risk or relapsed ALL and pre-HCT MRD. All patients had detectable MRD (>0.01%, flow cytometry) at the start of therapy with all eight achieving MRD reduction following one cycle. The regimen was well tolerated with seven grade 3/4 toxicities occurring among four of the eight patients. Five patients (62.5%) are alive, one died from relapse (12.5%) and two from transplant-related mortality (25%). The combination of reduced-dose clofarabine, CY and etoposide as bridging therapy appears to be well tolerated in patients with relapsed ALL and is effective in reducing pre-HCT MRD.

  15. Toll like receptor polymorphisms in allogeneic hematopoietic cell transplantation

    PubMed Central

    Kornblit, Brian; Enevold, Christian; Wang, Tao; Spellman, Stephen; Haagenson, Mike; Lee, Stephanie J; Müller, Klaus

    2014-01-01

    To assess the impact of the genetic variation in toll-like receptors (TLR) on outcome after allogeneic myeloablative conditioning hematopoietic cell transplantation (HCT) we have investigated 29 single nucleotide polymorphisms (SNP) across 10 TLRs in 816 patients and donors. Only donor genotype of TLR8 rs3764879, which is located on the X chromosome, was significantly associated with outcome at the Bonferroni corrected level P≤0.001. Male hemizygosity and female homozygosity for the minor allele were significantly associated with disease free survival (DFS) (hazard ratio (HR) 1.47 (95% confidence interval (CI) 1.16–1.85); P=0.001). Further analysis stratified by donor sex due to confounding by sex, was suggestive for associations with overall survival (male donor: HR 1.41 (95% CI 1.09–1.83), P=0.010); female donor: (HR 2.78 (95% CI 1.43–5.41), P=0.003), DFS (male donor: HR 1.45 (95% CI 1.12–1.87), P=0.005; female donor: HR 2.34 (95% CI 1.18–4.65), P=0.015) and treatment related mortality (male donor: HR 1.49 (95% CI 1.09–2.04), P=0.012; female donor: HR 3.12 (95% CI 1.44–6.74), P=0.004). In conclusion our findings suggest that the minor allele of TLR8 rs3764879 of the donor is associated with outcome after myeloablative conditioned allogeneic HCT. PMID:25464115

  16. Toll-like receptor polymorphisms in allogeneic hematopoietic cell transplantation.

    PubMed

    Kornblit, Brian; Enevold, Christian; Wang, Tao; Spellman, Stephen; Haagenson, Mike; Lee, Stephanie J; Müller, Klaus

    2015-02-01

    To assess the impact of the genetic variation in toll-like receptors (TLRs) on outcome after allogeneic myeloablative conditioning hematopoietic cell transplantation (HCT), we investigated 29 single nucleotide polymorphisms across 10 TLRs in 816 patients and donors. Only donor genotype of TLR8 rs3764879, which is located on the X chromosome, was significantly associated with outcome at the Bonferroni-corrected level P ≤ .001. Male hemizygosity and female homozygosity for the minor allele were significantly associated with disease-free survival (hazard ratio [HR], 1.47 [95% confidence interval {CI}, 1.16 to 1.85]; P = .001). Further analysis stratified by donor sex due to confounding by sex was suggestive for associations with overall survival (male donor: HR, 1.41 [95% CI, 1.09 to 1.83], P = .010; female donor: HR, 2.78 [95% CI, 1.43 to 5.41], P = .003), disease-free survival (male donor: HR, 1.45 [95% CI, 1.12 to 1.87], P = .005; female donor: HR, 2.34 [95% CI, 1.18 to 4.65], P = .015), and treatment-related mortality (male donor: HR, 1.49 [95% CI, 1.09 to 2.04], P = .012; female donor: HR, 3.12 [95% CI, 1.44 to 6.74], P = .004). In conclusion, our findings suggest that the minor allele of TLR8 rs3764879 of the donor is associated with outcome after myeloablative conditioned allogeneic HCT.

  17. Dose Escalation of Total Marrow Irradiation With Concurrent Chemotherapy in Patients With Advanced Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation

    SciTech Connect

    Wong, Jeffrey Y.C.; Forman, Stephen; Somlo, George; Liu An; Schultheiss, Timothy; Radany, Eric; Palmer, Joycelynne; Stein, Anthony

    2013-01-01

    Purpose: We have demonstrated that toxicities are acceptable with total marrow irradiation (TMI) at 16 Gy without chemotherapy or TMI at 12 Gy and the reduced intensity regimen of fludarabine/melphalan in patients undergoing hematopoietic cell transplantation (HCT). This article reports results of a study of TMI combined with higher intensity chemotherapy regimens in 2 phase I trials in patients with advanced acute myelogenous leukemia or acute lymphoblastic leukemia (AML/ALL) who would do poorly on standard intent-to-cure HCT regimens. Methods and Materials: Trial 1 consisted of TMI on Days -10 to -6, etoposide (VP16) on Day -5 (60 mg/kg), and cyclophosphamide (CY) on Day -3 (100 mg/kg). TMI dose was 12 (n=3 patients), 13.5 (n=3 patients), and 15 (n=6 patients) Gy at 1.5 Gy twice daily. Trial 2 consisted of busulfan (BU) on Days -12 to -8 (800 {mu}M min), TMI on Days -8 to -4, and VP16 on Day -3 (30 mg/kg). TMI dose was 12 (n=18) and 13.5 (n=2) Gy at 1.5 Gy twice daily. Results: Trial 1 had 12 patients with a median age of 33 years. Six patients had induction failures (IF), and 6 had first relapses (1RL), 9 with leukemia blast involvement of bone marrow ranging from 10%-98%, 5 with circulating blasts (24%-85%), and 2 with chloromas. No dose-limiting toxicities were observed. Eleven patients achieved complete remission at Day 30. With a median follow-up of 14.75 months, 5 patients remained in complete remission from 13.5-37.7 months. Trial 2 had 20 patients with a median age of 41 years. Thirteen patients had IF, and 5 had 1RL, 2 in second relapse, 19 with marrow blasts (3%-100%) and 13 with peripheral blasts (6%-63%). Grade 4 dose-limiting toxicities were seen at 13.5 Gy (stomatitis and hepatotoxicity). Stomatitis was the most frequent toxicity in both trials. Conclusions: TMI dose escalation to 15 Gy is possible when combined with CY/VP16 and is associated with acceptable toxicities and encouraging outcomes. TMI dose escalation is not possible with BU/VP16 due to

  18. [Development of acute myeloid leukemia from donor cells after allogeneic peripheral blood stem cell transplantation in a female patient with acute monoblastic leukemia].

    PubMed

    2011-01-01

    Development of leukemia from donor cells is a rare complication of allogeneic blood stem cells (BSC). The paper describes a case of evolving acute myeloid leukemia of a graft in a patient with resistant acute monoblastic leukemia after related allogeneic peripheral BSC transplantation. The rarity of this complication, difficulties in providing evidence for the donor origin of a leukemic clone demonstrate a need for all-round careful dynamic assessment of the hematopoietic system after allogeneic transplantation, by applying the current cytogenetic (fluorescence in situ hybridization) and molecular (hypervariable genomic region amplification test using the polymerase chain reaction, hypervariable number of tandem repeats (VNTR), and short number of tandem repeats (STR)) techniques, which permits errors to be avoided in the assessment of a clinical situation and in the diagnosis of leukemia from donor cells. There is no developed policy for treatment of acute graft-versus-leukemia.

  19. Acute Myeloid Leukaemia of Donor Cell Origin Developing 17 Years after Allogenic Hematopoietic Cell Transplantation for Acute Promyelocytic Leukaemia

    PubMed Central

    Jiménez, Pilar; Alvarez, J. Carlos; Garrido, Pilar; Lorente, J. Antonio; Palacios, Jorge; Ruiz-Cabello, Francisco

    2012-01-01

    Donor cell leukaemia (DCL) is a rare complication of allogenic hematopoietic cell transplantation (HCT). We report the case of a female patient with acute promyelocytic leukaemia (APL), FAB type M3, who developed acute myeloid leukaemia (AML) type M5 of donor origin 17 years after allogenic bone marrow transplantation (BMT) from her HLA-matched sister. Morphology and immunophenotyping showed differences with the initial leukaemia, and short tandem repeat (STR) analysis confirmed donor-type haematopoiesis. Interphase fluorescence in situ hybridisation (FISH) showed an 11q23 deletion. Given that the latency period between transplant and development of leukaemia was the longest reported to date, we discuss the mechanisms underlying delayed leukaemia onset. PMID:23675279

  20. Outcome of Second Allogeneic Hematopoietic Cell Transplantation after Relapse of Myeloid Malignancies following Allogeneic Hematopoietic Cell Transplantation: A Retrospective Cohort on Behalf of the Grupo Español de Trasplante Hematopoyetico.

    PubMed

    Orti, Guillermo; Sanz, Jaime; Bermudez, Arancha; Caballero, Dolores; Martinez, Carmen; Sierra, Jorge; Cabrera Marin, José R; Espigado, Ildefonso; Solano, Carlos; Ferrà, Christelle; García-Noblejas, Ana; Jimenez, Santiago; Sampol, Antonia; Yañez, Lucrecia; García-Gutiérrez, Valentin; Pascual, Maria Jesus; Jurado, Manuel; Moraleda, José M; Valcarcel, David; Sanz, Miguel A; Carreras, Enric; Duarte, Rafael F

    2016-03-01

    Allogeneic stem cell transplantation (allo-HCT) represents the most effective immunotherapy for acute myeloid leukemia (AML) and myeloid malignancies. However, disease relapse remains the most common cause of treatment failure. By performing a second allo-HCT, durable remission can be achieved in some patients. However, a second allo-HCT is of no benefit for the majority of patients, so this approach requires further understanding. We present a retrospective cohort of 116 patients diagnosed with AML, myelodysplastic syndromes, and myeloproliferative disorders who consecutively underwent a second allo-HCT for disease relapse. The median age was 38 years (range, 4 to 69 years). Sixty-three patients were alive at last follow-up. The median follow-up of the whole cohort was 193 days (range, 2 to 6724 days) and the median follow-up of survivors was 1628 days (range, 52 to 5518 days). Overall survival (OS) at 5 years was 32% (SE ± 4.7%). Multivariate analysis identified active disease status (P < .001) and second allo-HCT < 430 days (the median of the time to second transplantation) after the first transplantation (P < .001) as factors for poor prognosis, whereas the use of an HLA-identical sibling donor for the second allo-HCT was identified as a good prognostic factor (P < .05) for OS. The use of myeloablative conditioning (P = .01), active disease (P = .02), and a donor other than an HLA-identical sibling (others versus HLA-identical siblings) (P = .009) were factors statistically significant for nonrelapse mortality in multivariate analysis. Time to second transplantation was statistically significant (P = .001) in the relapse multivariate analysis, whereas multivariate analysis identified active disease status (P < .001) and time to second transplantation (P < .001) as poor prognosis factors for disease-free survival. This study confirms active disease and early relapse as dismal prognostic factors for a second allo-HCT. Using a different donor at second allo-HCT

  1. Association of fludarabine pharmacokinetic/dynamic biomarkers with donor chimerism in nonmyeloablative HCT recipients

    PubMed Central

    McCune, Jeannine S.; Mager, Donald E.; Bemer, Meagan J.; Sandmaier, Brenda M.; Storer, Barry E.; Heimfeld, Shelly

    2015-01-01

    Purpose Fludarabine monophosphate (fludarabine) is an integral component of many reduced-intensity conditioning regimens for hematopoietic cell transplantation (HCT). Fludarabine’s metabolite, 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A), undergoes cellular uptake and activation to form the active cytotoxic metabolite fludarabine triphosphate (F-ara-ATP), which inhibits cellular DNA synthesis in CD4+ and CD8+ cells. In this study, we evaluated whether fludarabine-based pharmacologic biomarkers were associated with clinical outcomes in HCT recipients. Methods Participants with hematologic diseases were conditioned with fludarabine and low-dose total body irradiation (TBI) followed by allogeneic HCT and post-grafting immunosuppression. After fludarabine administration, we evaluated pharmacological biomarkers for fludarabine – F-ara-A area under the curve (AUC) and the ratio of circulating CD4+ and CD8+ cells (CD4+/CD8+ ratio) after fludarabine administration – in 102 patients; F-ara-ATP accumulation rate in enriched CD4+ and CD8+ cells was evaluated in 34 and 36 patients, respectively. Results Interpatient variability in the pharmacological biomarkers was high, ranging from 3.7-fold (F-ara-A AUC) to 39-fold (F-ara-ATP in CD8+ cells). Circulating CD8+ cells were more sensitive to fludarabine administration. A population pharmacokinetic-based sampling schedule successfully allowed for estimation of F-ara-A AUC in this outpatient population. There was poor correlation between the F-ara-AUC and the F-ara-ATP accumulation rate in CD4+ (R2=0.01) and CD8+ cells (R2=0.00). No associations were seen between the four biomarkers and clinical outcomes (day +28 donor T-cell chimerism, acute graft-versus-host disease (GVHD), neutrophil nadirs, cytomegalovirus reactivation, chronic GVHD, relapse, non-relapse mortality, or overall mortality). Conclusions Considerable interpatient variability exists in pharmacokinetic and fludarabine-based biomarkers, but these biomarkers

  2. Dose-independent confusion induced by voriconazole in a patient with Asian ancestry after allogeneic hematopoietic stem cell transplant.

    PubMed

    Hui, John

    2016-02-01

    This is the case of a 71-year-old man with Asian ancestry who had myelodysplastic syndrome admitted for allogeneic hematopoietic stem cell transplant. This case suggests that voriconazole-induced confusion is probably dose-independent and reversible with no residual symptoms after discontinuation of voriconazole. Patient can experience confusion even voriconazole is ordered according to package insert and serum voriconazole level is within therapeutic range (1-6 µg/mL). The onset of confusion can be delayed and sudden after seven days of voriconazole therapy. Genotyping of CYP2C19 can be tested for Asian populations since 15-20% of them could be poor metabolizers of voriconazole.

  3. CD34-selected allogeneic hematopoietic stem cell transplantation for patients with relapsed, high-risk multiple myeloma

    PubMed Central

    Smith, Eric; Devlin, Sean M.; Orlando, Evelyn; Landau, Heather; Lesokhin, Alex M.; Chung, David J.; Hassoun, Hani; Lendvai, Nikoletta; Landgren, Ola; Giralt, Sergio; Chari, Ajai; Jagannath, Sundar; Koehne, Guenther

    2016-01-01

    We report results of a retrospective analysis of 44 patients with relapsed and high-risk multiple myeloma (MM) undergoing allogeneic CD34-selected hematopoietic stem-cell transplantation (CD34-selected HSCT) from human leukocyte antigen (HLA)-compatible donors. Patients had multiply relapsed disease including relapse at <15 months after autologous transplant and most patients (28/44; 65%) also had high-risk cytogenetics. Before transplant, patients received busulfan (0.8 mg/kg X 10 doses), melphalan (70 mg/m2 X 2 days), fludarabine (25 mg/m2 X 5 days), and rabbit anti-thymocyte globulin (2.5 mg/kg X 2 days). Patients with 10/10 HLA-matched donors were treated prophylactically with low doses of donor lymphocyte infusions (0.5 to 1 X 106 CD3+/kg) starting at 4–6 months post CD34-selected HSCT. Acute (grade II–IV) graph-versus-host disease (GVHD) and transplant-related mortality at 12 months were 2% and 18%, respectively. Chronic GVHD was not observed in any patient. Overall and progression-free survival at 2 years was 54% and 31%, respectively. By multivariate analyses, the outcomes of CD34-selected HSCT were influenced by presence of extramedullary disease, disease status prior to CD34-selected HSCT and age. This study demonstrates notable safety and efficacy of CD34-selected HSCT in patients with multiply relapsed MM including those with high-risk cytogenetics. PMID:26325439

  4. Allogenic stem cell transplantation as salvage therapy for patients relapsing after autologous transplantation: experience from a single institution.

    PubMed

    Martínez, C; Carreras, E; Rovira, M; Urbano-Ispizua, A; Esteve, J; Fernández-Avilés, F; Perales, M; Rives, S; Gómez, M; Montserrat, E

    2001-05-01

    The prognosis of patients relapsing after an autologous transplant (autoSCT) is very poor. Allogenic stem cell transplantation (alloSCT) offers the possibility of curing some of these patients, at the cost, however, of a high transplant related mortality (TRM). The aim of this study was to analyze the outcome of 14 consecutive patients with hematologic malignancies, from a single institution, who underwent alloSCT for progressive disease after autoSCT. Patients had relapsed at a median of 11.5 months (range 2-72) after autoSCT and they underwent alloSCT at a median of 25.5 months (range 7-73) from the first transplant. Ten patients received HLA-identical related peripheral blood progenitor cells, three patients underwent matched-unrelated donor marrow transplants, and one patient received a mismatched related transplant. Conditioning regimens consisted of total body irradiation plus cyclophosphamide (n=5) or melphalan (n=1), or high-dose combination chemotherapy (n=8). Cyclosporin A and methotrexate were administered as graft-versus-host disease (GVHD) prophylaxis. Eight patients (57%) developed grade II-IV acute GVHD. All evaluable patients (n=6) presented extensive chronic GVHD. Overall survival at 1 year was 16% (median 3.5 months, 95% CI 0.7-10.3). Ten patients (71%) died from transplant related complications at a median of 3.5 months (range 0.7-11). Only one patient died of recurrent disease. Three patients remain alive and in complete remission at the time of this report (4, 20 and 20 months, respectively). In conclusion, alloSCT offers the possibility of a sustained control of the disease in some patients who relapse after an autoSCT. However, the procedure is associated with a high transplant-related mortality. Better results might be obtained by carefully selecting patients and by reducing the intensity of the preparative regimen.

  5. Pharmacokinetics, Pharmacodynamics and Pharmacogenomics of Immunosuppressants in Allogeneic Haematopoietic Cell Transplantation: Part I.

    PubMed

    McCune, Jeannine S; Bemer, Meagan J

    2016-05-01

    Although immunosuppressive treatments and target concentration intervention (TCI) have significantly contributed to the success of allogeneic haematopoietic cell transplantation (alloHCT), there is currently no consensus on the best immunosuppressive strategies. Compared with solid organ transplantation, alloHCT is unique because of the potential for bidirectional reactions (i.e. host-versus-graft and graft-versus-host). Postgraft immunosuppression typically includes a calcineurin inhibitor (cyclosporine or tacrolimus) and a short course of methotrexate after high-dose myeloablative conditioning, or a calcineurin inhibitor and mycophenolate mofetil after reduced-intensity conditioning. There are evolving roles for the antithymyocyte globulins (ATGs) and sirolimus as postgraft immunosuppression. A review of the pharmacokinetics and TCI of the main postgraft immunosuppressants is presented in this two-part review. All immunosuppressants are characterized by large intra- and interindividual pharmacokinetic variability and by narrow therapeutic indices. It is essential to understand immunosuppressants' pharmacokinetic properties and how to use them for individualized treatment incorporating TCI to improve outcomes. TCI, which is mandatory for the calcineurin inhibitors and sirolimus, has become an integral part of postgraft immunosuppression. TCI is usually based on trough concentration monitoring, but other approaches include measurement of the area under the concentration-time curve (AUC) over the dosing interval or limited sampling schedules with maximum a posteriori Bayesian personalization approaches. Interpretation of pharmacodynamic results is hindered by the prevalence of studies enrolling only a small number of patients, variability in the allogeneic graft source and variability in postgraft immunosuppression. Given the curative potential of alloHCT, the pharmacodynamics of these immunosuppressants deserves to be explored in depth. Development of

  6. Prognostic impact of viral reactivations in acute myeloid leukemia patients undergoing allogeneic stem cell transplantation in first complete response

    PubMed Central

    Guenounou, Sarah; Borel, Cécile; Bérard, Emilie; Yon, Edwige; Fort, Marylise; Mengelle, Catherine; Bertoli, Sarah; Sarry, Audrey; Tavitian, Suzanne; Huguet, Françoise; Attal, Michel; Récher, Christian; Huynh, Anne

    2016-01-01

    Abstract Cytomegalovirus (CMV) serological status of donor and recipient as well as CMV reactivation have been associated with a lower risk of relapse in acute myeloid leukemia (AML) patients after allogeneic stem cell transplantation (alloSCT). Since immunosuppression following transplant allows resurgence of many other viruses, we retrospectively evaluated the impact of viral reactivations on relapse and survival in a cohort of 136 AML patients undergoing alloSCT in first remission from sibling (68%) or unrelated (32%) donors. Myeloablative and reduced-intensity conditioning regimen were given to 71 and 65 patients, respectively. Including CMV reactivations, at least 1 viral reactivation was recorded in 76 patients. Viral reactivations were associated with a lower risk of relapse (adjusted HR 0.14; 95% CI 0.07–0.30; P < 0.01), better disease-free survival (aHR 0.29; 95% CI 0.16–0.54; P < 0.01) but higher non relapse mortality. This translated into a better overall survival (aHR 0.44; 95%CI 0.25–0.77; P < 0.01) in patients who experienced viral reactivation. Thus, viral reactivations, including but not limited to CMV reactivation, are associated with a better outcome particularly with regard to the risk of relapse in AML patients undergoing alloSCT. New guidelines regarding the choice of donor according to the CMV serostatus are needed. PMID:27902595

  7. TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation.

    PubMed

    Middeke, Jan M; Herold, Sylvia; Rücker-Braun, Elke; Berdel, Wolfgang E; Stelljes, Matthias; Kaufmann, Martin; Schäfer-Eckart, Kerstin; Baldus, Claudia D; Stuhlmann, Reingard; Ho, Anthony D; Einsele, Hermann; Rösler, Wolf; Serve, Hubert; Hänel, Mathias; Sohlbach, Kristina; Klesse, Christian; Mohr, Brigitte; Heidenreich, Falk; Stölzel, Friedrich; Röllig, Christoph; Platzbecker, Uwe; Ehninger, Gerhard; Bornhäuser, Martin; Thiede, Christian; Schetelig, Johannes

    2016-03-01

    Treatment success in patients with acute myeloid leukaemia (AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation (HSCT). Samples of 97 patients with AML and adverse-risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three-year probabilities of overall survival (OS) and event-free survival for patients with TP53 wild type were 33% [95% confidence interval (CI), 21% to 45%] and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) (P = 0·002 and P = 0·007) for those with mutated TP53, respectively. In multivariate analysis, the TP53-mutation status had a negative impact on OS (Hazard Ratio = 1·7; P = 0·066). Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML.

  8. Pre-transplant weight loss predicts inferior outcome after allogeneic stem cell transplantation in patients with myelodysplastic syndrome.

    PubMed

    Radujkovic, Aleksandar; Becker, Natalia; Benner, Axel; Penack, Olaf; Platzbecker, Uwe; Stölzel, Friedrich; Bornhäuser, Martin; Hegenbart, Ute; Ho, Anthony D; Dreger, Peter; Luft, Thomas

    2015-10-27

    Allogeneic stem cell transplantation (alloSCT) represents a curative therapeutic option for patients with myelodysplastic syndrome (MDS), but relapse and non-relapse mortality (NRM) limit treatment efficacy. Based on our previous observation in acute myeloid leukemia we investigated the impact of pre-transplant weight loss on post-transplant outcome in MDS patients. A total of 111 patients diagnosed with MDS according to WHO criteria transplanted between 2000 and 2012 in three different transplant centers were included into the analysis. Data on weight loss were collected from medical records prior to conditioning therapy and 3-6 months earlier. Patient, disease and transplant characteristics did not differ between patients with weight loss (2-5%, n = 17; > 5%, n = 17) and those without (n = 77). In a mixed effect model, weight loss was associated with higher risk MDS (p = 0.046). In multivariable analyses, pre-transplant weight loss exceeding 5% was associated with a higher incidence of relapse (p < 0.001) and NRM (p = 0.007). Pre-transplant weight loss of 2-5% and > 5% were independent predictors of worse disease-free (p = 0.023 and p < 0.001, respectively) and overall survival (p = 0.043 and p < 0.001, respectively). Our retrospective study suggests that MDS patients losing weight prior to alloSCT have an inferior outcome after transplantation. Prospective studies addressing pre-transplant nutritional interventions are highly warranted.

  9. Survey of experts on therapeutic policies and proposals for the optimal timing for allogeneic peripheral blood stem cell transplantation in transfusion-dependent patients with myelodysplastic syndrome-refractory anemia

    PubMed Central

    Moon, Joon Ho; Lee, Yoo Jin; Park, Sung Woo; Kim, Ji Yoon

    2016-01-01

    Background Most hypomethylating agent (HMA) responders with myelodysplastic syndrome (MDS) eventually need allogeneic stem cell transplantation (SCT) because they often acquire resistance to HMAs within two years of treatment. Considering the nature of MDS and the poor outcomes of SCT when performed after confirming the progression of MDS to acute myeloid leukemia (AML), allogeneic SCT should be performed with caution in patients with low-risk MDS. Methods To address low-risk MDS, the Korean AML/MDS working party group designed a survey for 34 MDS experts in Korea on therapeutic HMA and allogeneic SCT policies for low-risk MDS. The level of consensus was defined as the percentage of agreement among the experts. Results With regard to the optimal time for allogeneic SCT for HMA responders with MDS-RA, 76% experts agreed that allogeneic SCT should be performed when a patient has a low platelet count. With regard to the relapse pattern that was most commonly found during HMA treatment in responding patients with MDS-RA, 54% experts agreed that the most common pattern that indicated HMA failure was the gradual worsening of cytopenia. Conclusion The optimal time to perform allogeneic SCT in RA patients who achieved hematologic complete remission during HMA treatment is when the platelet count decreases. However, these suggestions need to be evaluated in larger future studies. Therefore, careful decisions should be taken at each step of allogeneic SCT to maximize the outcomes for patients with MDS-RA and iron overload. PMID:27104191

  10. Protein C and procollagen III peptide levels in patients with hepatic dysfunction after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Pihusch, M; Wegner, H; Goehring, P; Salat, C; Pihusch, V; Andreesen, R; Kolb, H-J; Holler, E; Pihusch, R

    2005-10-01

    Veno-occlusive disease (VOD) is one of the most serious complications following hematopoietic stem cell transplantation (HSCT) and is associated with a high mortality. We conducted a large trial on the clinical significance of protein C (PC) and procollagen III peptide (PNPIII) levels, which have been described as possible diagnostic markers of VOD. In total, 350 patients undergoing allogeneic HSCT were included. PC and PNPIII levels were analyzed prior to conditioning and weekly until 8 weeks after the HSCT. Signs of VOD and other transplantation-related complications (graft-versus-host disease (GVHD), toxicity, microangiopathic hemolytic anemia, infection) were recorded weekly throughout the trial. Patients showed a significant drop of the PC levels in VOD (70.3 vs 96.3%, P<0.001) and with increasing severity of aGVHD. Steroids increased the PC levels (69.4% vs 109.4%, P<0.001). The highest PNPIII levels were registered in patients with VOD (mean 6.3 IU/ml). Patients with aGVHD showed an elevation of PNPIII, especially patients with hepatic aGVHD. PC levels during conditioning do not predict VOD (98.5 vs 76.5%, NS). Although PC and PNPIII may play a role in the pathogenesis of VOD they cannot discriminate between complications with jaundice and are only of limited help in the differential diagnosis of VOD.

  11. Results of allogeneic stem cell transplantation in the Spanish MDS registry: prognostic factors for low risk patients.

    PubMed

    Díez Campelo, M; Sánchez-Barba, M; de Soria, V Gómez-García; Martino, R; Sanz, G; Insunza, A; Bernal, T; Duarte, R; Amigo, M L; Xicoy, B; Tormo, M; Iniesta, F; Bailén, A; Benlloch, L; Córdoba, I; López-Villar, O; Del Cañizo, M C

    2014-10-01

    Although new agents have been approved for the treatment of MDS, the only curative approach is allogeneic hematopoietic stem cell transplantation (HSCT) and thus, in particular circumstances this procedure has been proposed as a treatment option for low risk patients. We have retrospectively analyzed the results of HSCT in 291 patients from the Spanish MDS registry with special attention to low risk MDS (LR-MDS) in order to define the variables that could impact their clinical evolution after transplantation. At 2 years OS was 51% and EFS was 50% (95% CI 0.7-4.5 years for OS and 95% CI 0.1-3.9 years for EFS). Among 43 LR-MDS, transplant-related mortality was 28%. At 3 years, OS was 67% (95% CI 264.7-8927.2 days for OS) and EFS was 64% (95% CI 0-9697.2 days for EFS). In the multivariate analysis only cytogenetics retained statistical significant effect on both OS (p=.047) and EFS (p=.046). Conditioning regimen could improve outcome among this subset of patients (OS 86% and RFS 100% for patients receiving RIC regimen). The present study confirms that specific disease characteristic as well as transplant characteristics have a significant impact on transplant outcome. Regarding low risk patients a non-myeloablative conditioning would be preferable especially in cases without high-risk cytogenetics.

  12. Brentuximab vedotin in refractory CD30+ lymphomas: a bridge to allogeneic transplantation in approximately one quarter of patients treated on a Named Patient Programme at a single UK center

    PubMed Central

    Gibb, Adam; Jones, Craig; Bloor, Adrian; Kulkarni, Samar; Illidge, Tim; Linton, Kim; Radford, John

    2013-01-01

    The CD30-targeted agent brentuximab vedotin has shown impressive activity in relapsed/refractory Hodgkin lymphoma and anaplastic large cell lymphoma in phase II studies. We have treated 24 patients with relapsed/refratory disease enrolled onto a Named Patient Programme during 2010-11 at a single UK center. Overall response rate across all histologies was 67% (Hodgkin 72%; anaplastic large cell 60%), complete response rate 25% (Hodgkin 17%; anaplastic large cell 60%), median progression-free survival 5.1 months, and toxicity mild to moderate in the majority of cases. Six patients proceeded to allogeneic transplantation and one patient awaits this procedure. These results are similar to phase II data and show that brentuximab vedotin provides a bridge to allogeneic transplantation in approximately one quarter of patients refractory to conventional salvage therapies. Best response was seen after four doses, so consideration of allogeneic transplantation should be made early and scheduled following the first assessment indicating response. PMID:23065511

  13. Allogeneic Hematopoietic Cell Transplant for Acute Myeloid Leukemia: No Impact of Pre-transplant Extramedullary Disease on Outcome

    PubMed Central

    Goyal, Sagun D.; Zhang, Mei-Jie; Wang, Hai-Lin; Akpek, Görgün; Copelan, Edward A.; Freytes, César; Gale, Robert Peter; Hamadani, Mehdi; Inamoto, Yoshihiro; Kamble, Rammurti T.; Lazarus, Hillard M.; Marks, David I.; Nishihori, Taiga; Olsson, Richard F.; Reshef, Ran; Ritchie, David S.; Saber, Wael; Savani, Bipin N.; Seber, Adriana; Shea, Thomas C.; Tallman, Martin S.; Wirk, Baldeep; Bunjes, Donald W.; Devine, Steven M.; de Lima, Marcos; Weisdorf, Daniel J.; Uy, Geoffrey L.

    2015-01-01

    The impact of extramedullary disease (EMD) in AML on the outcomes of allogeneic hematopoietic cell transplantation (alloHCT) is unknown. Using data from the Center for International Blood and Marrow Transplant Research (CIBMTR) we compared the outcomes of patients who had EMD of AML at any time prior to transplant to a cohort of AML patients without EMD. We reviewed data AML from 9,797 patients including 814 with EMD from 310 reporting centers and 44 different countries who underwent alloHCT between and 1995–2010. The primary outcome was overall survival (OS) after alloHCT. Secondary outcomes included leukemia-free survival (LFS), relapse rate, and treatment-related mortality (TRM). In a multivariate analysis, the presence of EMD did not affect either OS (HR 1.00, 95% CI 0.91–1.09), LFS (0.98, 0.89–1.09), TRM (RR 0.92, 95% CI 0.80–1.16, p=0.23) or relapse (RR =1.03, 95% CI, 0.92–1.16; p=0.62). Furthermore, the outcome of patients with EMD was not influenced by the location, timing of EMD, or intensity of conditioning regimen. The presence of EMD in AML does not affect transplant outcomes and should not be viewed as an independent adverse prognostic feature. PMID:25915806

  14. Health-related quality of life following hematopoietic cell transplantation: Patient education, evaluation, and intervention

    PubMed Central

    Pidala, Joseph; Anasetti, Claudio; Jim, Heather

    2009-01-01

    Summary Health-related quality of life (QOL) is a vital concern in the pre-treatment consent process and post-treatment care of recipients of hematopoietic cell transplantation (HCT). We propose that comprehensive care of such patients requires an integration of knowledge of the impact of HCT on QOL, assessment of QOL, as well as resources available for intervention. This knowledge may significantly improve patient care when incorporated into daily clinical practice in the transplant setting. As a framework for this approach, this article reviews the literature on QOL after allogeneic and autologous HCT for adults with hematological malignancies. We then discuss evidence in support of the beneficial impact of clinical QOL assessment, and finally evaluate behavioral interventions that show promise to maintain or improve QOL after HCT. PMID:19919651

  15. Fungal Colonization of the Respiratory Tract in Allogeneic and Autologous Hematopoietic Stem Cell Transplant Recipients: A Study of 573 Transplanted Patients

    PubMed Central

    Markowski, Jarosław; Helbig, Grzegorz; Widziszowska, Agnieszka; Likus, Wirginia; Kyrcz-Krzemień, Sławomira; Jarosz, Urszula; Dziubdziela, Włodzimierz; Markiewicz, Mirosław

    2015-01-01

    Background Fungal colonization and infections remain a major cause of infection morbidity and mortality following hematopoietic stem cell transplantation (HSCT) in patients with hematological malignancies. The aim of this study was to analyze the spectrum of fungal microflora of the respiratory tract (oral cavity, pharynx, epiglottis, and sputum) in patients undergoing HSCT and to evaluate the relationship between HSCT type and incidence of mycotic colonization and infections. Material/Methods Retrospective analysis of fungal isolates collected from the respiratory tract (oral cavity, pharynx, epiglottis, and sputum) of 573 patients undergoing HSCT was performed. Results The overall rate of fungal colonization in patients undergoing HSCT was 8.7%. Patients undergoing allogeneic HSCT were statistically significantly more often colonized (12.95%) compared to autologous HSCT recipients (4.7%). Colonizing cultures were mainly C. albicans and C. krusei, and sporadically C. glabrata, C. famata, Aspergillus spp. and Saccharomyces cerevisiae. C. albicans was the most frequent species found in isolates from the pharynx, sputum, and oral cavity collected from patients undergoing HSCT. Aspergillosis was more common after allogeneic than after autologous HSCT. The pharynx was the most frequently colonized site. Conclusions Allogeneic HSCT recipients are more susceptible to fungal infections compared to the autologous group. Selection of species during prophylaxis and antifungal therapy requires developing more effective prevention and treatment strategies based on new antifungal drugs and microbe-specific diagnoses. PMID:25907308

  16. Monitoring MRD with flow cytometry: an effective method to predict relapse for ALL patients after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Zhao, Xiao-Su; Liu, Yan-Rong; Zhu, Hong-Hu; Xu, Lan-Ping; Liu, Dai-Hong; Liu, Kai-Yan; Huang, Xiao-Jun

    2012-02-01

    This study evaluated the prognostic value of minimal residual disease (MRD) monitoring by four-color flow cytometry (FCM) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). MRD was examined with four-color FCM at different time points in 139 patients (including pediatric and adult patients) with ALL after allo-HSCT. Real-time quantitative polymerase chain reaction (RQ-PCR) was applied to evaluate the MRD of Philadelphia chromosome-positive ALL (Ph+ ALL) patients. Patients who were FCM-positive (FCM+) after transplantation had a lower event-free survival (EFS) of 0.54 and a higher cumulative incidence of relapse (CIR) of 0.54 compared to an EFS of 0.80 and a CIR of 0.08 in FCM-negative (FCM-) patients (EFS, p < 0.001; CIR, p < 0.001). Similar results were obtained in high-risk patients and Ph+ ALL patients. Moreover, a FCM+ status after the second month post-HSCT (defined as MRD positive) proved to be a predictor of leukemia relapse. Multivariate analysis for EFS, OS and CIR showed that MRD status after transplantation was an independent prognostic factor (p < 0.001, p = 0.013, and p < 0.001, respectively). A good correlation was found between the MRD results of FCM and RQ-PCR (n = 126 pairs, Spearman r = 0.8139, p < 0.001). MRD monitoring by four-color FCM post-transplantation is an important tool for relapse prediction in ALL patients. Prompt and appropriate pre-emptive anti-leukemia treatment could be considered based on the status of MRD after HSCT.

  17. Forum for debate: Safety of allogeneic blood transfusion alternatives in the surgical/critically ill patient.

    PubMed

    Muñoz Gómez, M; Bisbe Vives, E; Basora Macaya, M; García Erce, J A; Gómez Luque, A; Leal-Noval, S R; Colomina, M J; Comin Colet, J; Contreras Barbeta, E; Cuenca Espiérrez, J; Garcia de Lorenzo Y Mateos, A; Gomollón García, F; Izuel Ramí, M; Moral García, M V; Montoro Ronsano, J B; Páramo Fernández, J A; Pereira Saavedra, A; Quintana Diaz, M; Remacha Sevilla, Á; Salinas Argente, R; Sánchez Pérez, C; Tirado Anglés, G; Torrabadella de Reinoso, P

    2015-12-01

    In recent years, several safety alerts have questioned or restricted the use of some pharmacological alternatives to allogeneic blood transfusion in established indications. In contrast, there seems to be a promotion of other alternatives, based on blood products and/or antifibrinolytic drugs, which lack a solid scientific basis. The Multidisciplinary Autotransfusion Study Group and the Anemia Working Group España convened a multidisciplinary panel of 23 experts belonging to different healthcare areas in a forum for debate to: 1) analyze the different safety alerts referred to certain transfusion alternatives; 2) study the background leading to such alternatives, the evidence supporting them, and their consequences for everyday clinical practice, and 3) issue a weighted statement on the safety of each questioned transfusion alternative, according to its clinical use. The members of the forum maintained telematics contact for the exchange of information and the distribution of tasks, and a joint meeting was held where the conclusions on each of the items examined were presented and discussed. A first version of the document was drafted, and subjected to 4 rounds of review and updating until consensus was reached (unanimously in most cases). We present the final version of the document, approved by all panel members, and hope it will be useful for our colleagues.

  18. The Impact of HLA and KIR Ligand Mismatching on Unrelated Allogeneic Hematopoietic Stem Cell Transplantation in Korean Adult Patients

    PubMed Central

    Park, Hyewon; Rho, Eun Youn; In, Ji Won; Kim, Inho; Yoon, Sung-Soo; Park, Seonyang; Shin, Sue; Park, Kyoung Un

    2015-01-01

    Background The impact of HLA and KIR ligand mismatching on the outcome of hematopoietic stem cell transplantation (HSCT) remains unclear. Previous reports have identified considerable ethnic differences in the impact of HLA and KIR ligand mismatches, as well as KIR ligand status, on HSCT; however, to date, no data has been acquired in Korean adult patients. Methods We investigated the association of high-resolution HLA matching on five loci (HLA-A, -B, -C, -DRB1, and -DQB1), KIR ligand mismatching, and KIR ligand status on the outcome of allogeneic HSCT from unrelated donors in 154 Korean adult patients treated at Seoul National University Hospital. Results In a multivariate analysis, less than 9/10 allelic matches in five HLA loci was an independent risk factor for acute graft-versus-host disease (GVHD) (grade II to IV) (P=0.019, odds ratio [OR]=2.7). In addition, HLA-A allele mismatching was increasingly prevalent in patients with acute GVHD compared to patients without (61.9% vs. 34.5%, P=0.06). For KIR ligand status, the patient and donor combination of both C1/C1 ligands showed better event-free and overall survival than combinations with C2 ligand patients or donors (P=0.048, P=0.034, respectively) by log-rank test. Conclusions Korean adult transplant patients with less than 9 of 10 HLA allele matches in the HLA-A, -B, -C, -DRB1, and DQB1 loci have a higher likelihood of developing acute GVHD (grade II to IV). Impact of KIR ligand status on clinical outcome should be further studied in a larger patient population. PMID:25553290

  19. Role of allogeneic transplantation in patients with chronic lymphocytic leukemia in the era of novel therapies: a review

    PubMed Central

    Nathan, Sunita

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia and is characterized by a highly variable clinical course. In the past decade, several prognostic risk factors have been identified facilitating the classification of CLL into various risk groups. Patients with poor risk disease, such as poor cytogenetics or relapsing after purine-based analogues, had limited therapeutic options, with allogeneic hematopoietic cell transplantation (allo-SCT) the only known therapy with curative potential. More recently, the introduction of novel agents inhibiting the B-cell receptor pathway, and the early success with chimeric antigen receptor T cells offers an effective and relatively safe option for this poor prognostic group which holds promise in the future. Alternatively, the use of reduced intensity conditioning regimens in the allo-SCT setting has led to a significant decrease in nonrelapse mortality to 16–23%, making it an attractive therapeutic option. No recent guidelines have been developed since these novel therapies became available regarding the optimal time to allo-SCT in this patient population. The advent of these novel and highly active therapeutic agents, therefore, warrants a reappraisal of the role and timing of allo-SCT in patients with CLL. In this article, we summarize the literature regarding the novel therapeutic agents available today as well as focus on the efficacy and safety of allo-SCT. PMID:25324955

  20. Admission of hematopoietic cell transplantation patients to the intensive care unit at the Pontificia Universidad Católica de Chile Hospital.

    PubMed

    Escobar, Karen; Rojas, Patricio; Ernst, Daniel; Bertin, Pablo; Nervi, Bruno; Jara, Veronica; Garcia, Maria Jose; Ocqueteau, Mauricio; Sarmiento, Mauricio; Ramirez, Pablo

    2015-01-01

    Patients undergoing hematopoietic cell transplantation (HCT) can have complications that require management in the intensive care unit (ICU). We conducted a retrospective study of patients undergoing HCT between 2007 and 2011 with admission to the ICU. We analyzed 97 patients, with an average age of 37 (range, 15 to 68). The main indications for HCT were hematologic malignancies (84%, n = 82). Ninety percent (n = 87) received myeloablative conditioning. Thirty-one percent were admitted (autologous transplant recipients 15%, allogeneic transplant recipients 34%, and umbilical cord blood [UCB] transplant recipients 48%) with an average length of stay of 19 days (range, 1 to 73 days). The average time between transplantation and transfer was 15 days. The main causes of admission were acute respiratory failure (63%) and septic shock (20%). ICU mortality was 20% for autologous transplantations and 64% for allogeneic transplantations (adult donor and UCB combined). On average, patients died 108 days after the transplantation (range, 4 to 320 days). One-year overall survival, comparing patients entering the ICU with those never admitted, was 16% versus 82% (P < .0001) for allogeneic transplantations (adult donor and UCB combined) and 80% versus 89% (P = not significant) for autologous transplantations. Acute graft-versus-host disease was significantly associated with death in ICU after UCB HCT. ICU support is satisfactory in about one half of patients admitted, characterized by a short and medium term prognosis not as unfavorable as has been previously reported.

  1. Nonmyeloablative allogeneic hematopoietic cell transplantation

    PubMed Central

    Storb, Rainer; Sandmaier, Brenda M.

    2016-01-01

    Most hematological malignancies occur in older patients. Until recently these patients and those with comorbidities were not candidates for treatment with allogeneic hematopoietic transplantation because they were unable to tolerate the heretofore used high-dose conditioning regimens. The finding that many of the cures achieved with allogeneic hematopoietic transplantation were due to graft-versus-tumor effects led to the development of less toxic and well-tolerated reduced intensity and nonmyeloablative regimens. These regimens enabled allogeneic engraftment, thereby setting the stage for graft-versus-tumor effects. This review summarizes the encouraging early results seen with the new regimens and discusses the two hurdles that need to be overcome for achieving even greater success, disease relapse and graft-versus-host disease. PMID:27132278

  2. Longitudinal analyses of leukemia-associated antigen-specific CD8(+) T cells in patients after allogeneic stem cell transplantation.

    PubMed

    Rücker-Braun, Elke; Link, Cornelia S; Schmiedgen, Maria; Tunger, Antje; Vizjak, Petra; Teipel, Raphael; Wehner, Rebekka; Kühn, Denise; Fuchs, Yannik F; Oelschlägel, Uta; Germeroth, Lothar; Schmitz, Marc; Bornhäuser, Martin; Schetelig, Johannes; Heidenreich, Falk

    2016-11-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment approach for patients with acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). Graft versus leukemia (GVL) effects, which are exerted by donor T cells directed against leukemic-associated antigens (LAAs), are considered to play a crucial role in disease eradication. Although the expansion of cytotoxic T lymphocytes (CTLs) specific for cytomegalovirus (CMV) in response to an infection has been shown in multiple studies, data on CTLs mediating GVL effects are limited. To evaluate a potential increase or decrease of T lymphocytes specific for LAAs in the setting of allogeneic HSCT, we monitored leukemia-specific CD8(+) T cells throughout the first year after HSCT in 18 patients using streptamer technology. A broad panel of promising LAAs was selected: Wilms tumor protein, proteinase 3, receptor for hyaluronan acid-mediated motility, apoptosis regulator Bcl-2, survivin, nucleophosmin, and fibromodulin. T cells specifically directed against AML- or CLL-associated antigens were found at very low frequencies in peripheral blood. Substantial frequencies of LAA-specific T cells could not be measured at any time point by flow cytometry. In contrast, abundant CMV-pp65-specific T cells were detected in CMV-seropositive patient-recipient pairs and an increase prompted by CMV infection could be demonstrated. In conclusion, T lymphocytes with specificities for the aforementioned LAAs can only be detected in minimal quantities in the early phase after allogeneic HSCT.

  3. Graft Immune Cell Composition Associates with Clinical Outcome of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with AML.

    PubMed

    Impola, Ulla; Larjo, Antti; Salmenniemi, Urpu; Putkonen, Mervi; Itälä-Remes, Maija; Partanen, Jukka

    2016-01-01

    Complications of allogeneic hematopoietic stem cell transplantation (HSCT) have been attributed to immune cells transferred into the patient with the graft. However, a detailed immune cell composition of the graft is usually not evaluated. In the present study, we determined the level of variation in the composition of immune cells between clinical HSCT grafts and whether this variation is associated with clinical outcome. Sizes of major immune cell populations in 50 clinical grafts from a single HSCT Centre were analyzed using flow cytometry. A statistical comparison between cell levels and clinical outcomes of HSCT was performed. Overall survival, acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD), and relapse were used as the primary endpoints. Individual HSCT grafts showed considerable variation in their numbers of immune cell populations, including CD123(+) dendritic cells and CD34(+) cells, which may play a role in GVHD. Acute myeloid leukemia (AML) patients who developed aGVHD were transplanted with higher levels of effector CD3(+) T, CD19(+) B, and CD123(+) dendritic cells than AML patients without aGVHD, whereas grafts with a high CD34(+) content protected against aGVHD. AML patients with cGVHD had received grafts with a lower level of monocytes and a higher level of CD34(+) cells than those without cGVHD. There is considerable variation in the levels of immune cell populations between HSCT grafts, and this variation is associated with outcomes of HSCT in AML patients. A detailed analysis of the immune cell content of the graft can be used in risk assessment of HSCT.

  4. Safety and immunogenicity of the tetravalent protein-conjugated meningococcal vaccine (MCV4) in recipients of related and unrelated allogeneic hematopoietic stem cell transplantation.

    PubMed

    Mahler, Michelle B; Taur, Ying; Jean, Raymond; Kernan, Nancy A; Prockop, Susan E; Small, Trudy N

    2012-01-01

    Given the high morbidity and mortality associated with meningococcal disease, in 2007 the Advisory Committee of Immunization Practices recommended immunization of all children ages 11-18 with a protein-conjugated meningococcal vaccine. There are limited data on the immunogenicity of this vaccine after allogeneic hematopoietic stem cell transplantation (allo-HCT). Since 2007, we have immunized 48 patients with the MCV4 vaccine. Two vaccinated patients who lacked follow-up titers were excluded from this analysis. Stem cells were derived from an HLA-identical sibling (n = 17) or an alternative donor (n = 29). The median time to vaccination was 2.34 years after allo-HCT. Only 7 patients responded to all 4 serogroups, and 16 patients responded to none of the serogroups. The response to serogroups A, C, Y, and W-135 was 52%, 30%, 46%, and 33%, respectively. The ability to respond to 2 or more serogroups was not affected by age, diagnosis, time to vaccination, or history of graft-versus-host disease. Receipt of a T cell-depleted graft was associated with a poorer response (P = .044). Eight of 16 patients who received a second MCV4 vaccination responded to all 4 serogroups. This retrospective study suggests that response to a single MCV4 vaccination is poor after allo-HCT. Administration of a 2-dose series, as currently recommended for patients with asplenia, complement deficiency, and HIV infection, should be evaluated in this patient population.

  5. Relationship between neurocognitive functioning and medication management ability over the first 6 months following allogeneic stem cell transplantation.

    PubMed

    Mayo, S; Messner, H A; Rourke, S B; Howell, D; Victor, J C; Kuruvilla, J; Lipton, J H; Gupta, V; Kim, D D; Piescic, C; Breen, D; Lambie, A; Loach, D; Michelis, F V; Alam, N; Uhm, J; McGillis, L; Metcalfe, K

    2016-06-01

    Although neurocognitive impairment has been established as a major issue among cancer survivors, the real-world consequences of this impairment are unclear. This study investigated the relationship between neurocognitive functioning and medication management ability over time among 58 patients treated with allogeneic hematopoietic stem cell transplantation (HCT). Participants completed a neuropsychological test battery and a simulated medication management task at three time points: pre-transplant (T0), Day 100 (T1) and 6 months post transplant (T2). Neurocognitively impaired participants performed worse on the medication management task than neurocognitively normal participants at each time point, and were more likely to score in the impaired range of medication management ability post transplant (72% vs 20%, P<0.001 at T1; 67% vs 23%, P=0.013 at T2). In multivariate analyses, worse performance in executive functioning/working memory consistently predicted impaired medication management ability, even when controlling for sociodemographic and clinical confounders (odds ratio=0.89, 95% confidence interval (0.80, 0.98), P=0.023). Lower physical symptom distress also predicted impaired medication management ability, but this effect decreased over time. Self-reported cognitive problems were not correlated with medication management ability at any time point. Findings suggest that poor neurocognitive functioning, particularly in the domain of executive functioning/working memory, is associated with worse medication management ability within the first 6 months after allogeneic HCT.

  6. Association between Allogeneic or Autologous Blood Transfusion and Survival in Patients after Radical Prostatectomy: A Systematic Review and Meta-Analysis

    PubMed Central

    Yuan, Xiao-Hua

    2017-01-01

    Background A number of studies have investigated the effect of perioperative blood transfusion (PBT) for patients after radical prostatectomy (RP), with some reporting conflicting results. A systematic review of the literature and a meta-analysis were conducted to explore the association between PBT (autologous or allogeneic) and biochemical recurrence-free survival (BRFS), overall survival (OS) and cancer-specific survival (CSS) in patients undergoing RP. Methods The PubMed, Medline, Cochrane Library, and Embase databases were searched for published controlled clinical studies on perioperative allogeneic or autologous blood transfusion (BT) and patient survival after RP. STATA software version 12.0 was used for data analysis. We used hazard ratios (HRs) and 95% confidence intervals (CIs) to test the correlation between BT and patient survival after RP. Results Data from a total of 26,698 patients in ten published studies were included in the meta-analysis. The meta-analysis results showed that autologous BT was not associated with BRFS (HR: 1.06; 95% CI: 0.96–1.18; Z = 1.17; P = 0.24), OS (HR: 0.86; 95% CI: 0.71–1.04; Z = 1.58; P = 0.11), or CSS (HR: 0.98; 95% CI: 0.49–1.96; Z = 0.05; P = 0.96). Allogeneic BT exhibited a significant association with worse BRFS (HR: 1.09; 95% CI: 1.01–1.16; Z = 2.37; P = 0.02), OS (HR: 1.43; 95% CI: 1.24–1.64; Z = 4.95; P<0.01) and CSS (HR: 1.74; 95% CI: 1.18–2.56; Z = 2.81; P = 0.005). Conclusion Our data showed an association between allogeneic BT and reduced BRFS, OS and CSS in patients after RP. These findings indicate that perioperative blood conservation strategies are important for decreasing the allogeneic BT rate. PMID:28135341

  7. Severe regimen-related toxicity occurring in a patient with XYY syndrome receiving allogeneic peripheral blood stem cell transplantation.

    PubMed

    Shibata, S; Kami, M; Kishi, Y; Hamaki, T; Ueyama, J-I; Miyakoshi, S; Morinaga, S-I; Hirabayashi, N; Kanda, Y; Mutou, Y

    2002-07-01

    A 23-year-old man with chronic myelocytic leukemia (CML) in the first chronic phase underwent allogeneic peripheral blood stem cell transplantation (PBSCT) from his HLA-identical sibling. Pretransplant evaluations showed that he had a low risk of transplantation-related mortality and that the interval between the diagnosis of CML and PBSCT was only 6 months. However, he developed a variety of complications, including acute renal failure requiring hemodialysis, severe hepatic damage, hemorrhagic cystitis, and gastrointestinal hemorrhage leading to hypovolemic shock. Pathological examination of the colonic mucosa showed vascular endothelial damage and thrombotic lesions, leading to the diagnosis of thrombotic microangiopathy. Later, we found that he had the constitutional abnormality XYY. XYY syndrome is a frequent congenital abnormality, and mental disorders and congenital abnormalities of kidney and liver are common manifestations. Considering his clinical course, it was interesting that complications were severe in the organs which are frequently involved in cases of XYY syndrome. These organs may have poor function or poor reserves and may be more vulnerable to endothelial damage caused by high-dose cytotoxic chemotherapy. Patients with XYY syndrome might have a high risk of transplantation-related mortality.

  8. Allogeneic hematopoietic stem cell transplant in adult patients with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes.

    PubMed

    Sharma, Prashant; Shinde, Shivani S; Damlaj, Moussab; Hefazi Rorghabeh, Mehrdad; Hashmi, Shahrukh K; Litzow, Mark R; Hogan, William J; Gangat, Naseema; Elliott, Michelle A; Al-Kali, Aref; Tefferi, Ayalew; Patnaik, Mrinal M

    2017-04-01

    MDS/MPN (myelodysplastic syndrome/myeloproliferative neoplasm) overlap syndromes are myeloid malignancies for which allogeneic hematopoietic stem cell transplant (allo-HSCT) is potentially curative. We describe transplant outcomes of 43 patients - 35 with chronic myelomonocytic leukemia, CMML (of which 17 had blast transformation, BT) and eight with MDS/MPN-unclassifiable (MDS/MPN,U). At median follow-up of 21 months, overall survival (OS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 55%, 29%, and 25% respectively in CMML without BT and 47%, 40%, and 34% respectively in CMML with BT. Higher HSCT-comorbidity index (HSCT-CI >3 versus ≤3; p = 0.015) and splenomegaly (p = 0.006) predicted worse OS in CMML without BT. In CMML with BT, engraftment failure (p = 0.006) and higher HSCT-CI (p = 0.03) were associated with inferior OS, while HSCT within 1-year of diagnosis was associated with improved OS (p = 0.045). In MDS/MPN,U, at median follow-up of 15 months, OS, CIR, and NRM were 62%, 30%, and 14%, respectively.

  9. Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases.

    PubMed

    Koç, O N; Peters, C; Aubourg, P; Raghavan, S; Dyhouse, S; DeGasperi, R; Kolodny, E H; Yoseph, Y B; Gerson, S L; Lazarus, H M; Caplan, A I; Watkins, P A; Krivit, W

    1999-11-01

    Human bone marrow contains mesenchymal stem cells (MSCs) that can differentiate into various cells of mesenchymal origin. We developed an efficient method of isolating and culture expanding a homogenous population of MSCs from bone marrow and determined that MSCs express alpha-L-iduronidase, arylsulfatase-A and B, glucocerebrosidase, and adrenoleukodystrophy protein. These findings raised the possibility that MSCs may be useful in the treatment of storage disorders. To determine if donor derived MSCs are transferred to the recipients with lysosomal or peroxisomal storage diseases by allogeneic hematopoietic stem cell (HSC) transplantation, we investigated bone marrow derived MSCs of 13 patients 1-14 years after allogeneic transplantation. Highly purified MSCs were genotyped either by fluorescence in situ hybridization using probes for X and Y-chromosomes in gender mis-matched recipients or by radiolabeled PCR amplification of polymorphic simple sequence repeats. Phenotype was determined by the measurement of disease specific protein/enzyme activity in purified MSCs. We found that MSCs isolated from recipients of allogeneic HSC transplantation are not of donor genotype and have persistent phenotypic defects despite successful donor type hematopoietic engraftment. Whether culture expanded normal MSCs can be successfully transplanted into patients with storage diseases and provide therapeutic benefit needs to be determined.

  10. Determining Toxoplasma high-risk autologous and allogeneic hematopoietic stem cell transplantation patients by systematic pre-transplant PCR screening of stem cell originated buffy coat.

    PubMed

    Caner, Ayşe; Dönmez, Ayhan; Döşkaya, Mert; Değirmenci, Aysu; Tombuloğlu, Murat; Cağirgan, Seçkin; Guy, Edward; Francis, Janet; Soyer, Nur Akad; Gürüz, Yüksel

    2012-12-01

    The diagnosis of Toxoplasma infection or disease in hematopoietic stem cell transplantation (HSCT) patients is achieved mainly by PCR screening; however screening did not find wide field of use in practice due to costly expenditures of PCR. This study aimed to determine patients at high risk of Toxoplasma infection or disease before transplantation by stem cell originated buffy coat PCR and subsequently to screen them. Buffy coats collected from 12 autologous and 18 allogeneic HSCT patients' donors were investigated by PCR before transplantation. After transplantation, blood and sera collected at fixed time intervals were screened by two PCR methods and serological assays. Screening results first time assessed a toxoplasmosis incidence level as 25% in autologous HSCT patients and increased incidence level in allogeneic HSCT patients to 22%. Importantly, buffy coat PCR was first time performed before transplantation, to determine the risk of toxoplasmosis. Buffy coat PCR results showed that four patients were at high risk of toxoplasmosis before transplantation. After transplantation, these patients experienced toxoplasmosis. In conclusion, for the determination of patients at risk of toxoplasmosis, clinicians should consider buffy coat PCR in combination with serology before transplantation. After transplantation, PCR screening can be initiated in high risk patients upon clinical suspicion.

  11. Total Body Irradiation without Chemotherapy as Conditioning for an Allogeneic Hematopoietic Cell Transplantation for Adult Acute Myeloid Leukemia

    PubMed Central

    Altouri, Sultan; Allan, David; Atkins, Harry; Huebsch, Lothar; Maze, Dawn; Samant, Rajiv; Bredeson, Christopher

    2016-01-01

    Current therapies for acute myeloid leukemia (AML), failing induction, are rarely effective. We report our experience in 4 patients with AML who received 16 Gy TBI prior to allogeneic hematopoietic cell transplantation (alloHCT), between June 2010 and May 2011. Patients were 20 to 55 years of age, 2 with relapsed disease and 2 with AML failing induction. An HLA-matched graft from related or unrelated donor was infused on day 0. All but one, who received a CD34+-selected graft, received methotrexate and tacrolimus +/− antithymocyte globulin, as GVHD prophylaxis. The other patient received tacrolimus alone. Neutrophil and platelet engraftment occurred at a median of 18 and 14 days, respectively. Patients were discharged at a median of 28 days. There were no unexpected toxicities in the first 30 days. One patient had cytomegalovirus (CMV) viremia and anorexia, at two months. One patient had grade 2 acute GVHD of the skin. One patient developed chronic GVHD of the eyes, mouth, skin, joints, and lung at 4 months. Two patients died from relapse of their leukemia at days 65 and 125. Two patients remain in remission beyond day 1500. 16 Gy TBI followed by an alloHCT for AML, failing induction, is feasible and tolerable. PMID:27957357

  12. Immune reconstitution post allogeneic transplant and the impact of immune recovery on the risk of infection.

    PubMed

    Mehta, Rohtesh S; Rezvani, Katayoun

    2016-11-16

    Infection is the leading cause of non-relapse mortality after allogeneic haematopoietic cell transplantation (HCT). This occurs as a result of dysfunction to the host immune system from the preparative regimen used prior to HCT, combined with a delay in reconstitution of the donor-derived immune system after HCT. In this article, we elaborate on the process of immune reconstitution post-HCT that begins with the innate system and is followed by recovery of adaptive immunity. Simultaneously, we describe how the tempo of immune reconstitution influences the risk of various infections. We explain some of the key differences in immune reconstitution and the consequent risk of infections in recipients of peripheral blood stem cell, bone marrow or umbilical cord blood grafts. Other factors that impact on immune recovery are also highlighted. Finally, we allude to various strategies that are being tested to enhance immune reconstitution post-HCT.

  13. Correlation and Agreement of Handheld Spirometry with Laboratory Spirometry in Allogeneic Hematopoietic Cell Transplant Recipients.

    PubMed

    Cheng, Guang-Shing; Campbell, Angela P; Xie, Hu; Stednick, Zach; Callais, Cheryl; Leisenring, Wendy M; Englund, Janet A; Chien, Jason W; Boeckh, Michael

    2016-05-01

    Early detection of subclinical lung function decline may help identify allogeneic hematopoietic cell transplant (HCT) recipients who are at increased risk for late noninfectious pulmonary complications, including bronchiolitis obliterans syndrome. We evaluated the use of handheld spirometry in this population. Allogeneic HCT recipients enrolled in a single-center observational trial performed weekly spirometry with a handheld spirometer for 1 year after transplantation. Participants performed pulmonary function tests in an outpatient laboratory setting at 3 time points: before transplantation, at day 80 after transplantation, and at 1 year after transplantation. Correlation between the 2 methods was assessed by Pearson and Spearman correlations; agreement was assessed using Bland-Altman plots. A total of 437 subjects had evaluable pulmonary function tests. Correlation for forced expiratory volume in 1 second (FEV1) was r = .954 (P < .0001) at day 80 and r = .931 (P < .0001) at 1 year when the handheld and laboratory tests were performed within 1 day of each other. Correlation for handheld forced expiratory volume in 6 seconds (FEV6) with laboratory forced vital capacity was r = .914 (P < .0001) at day 80 and r = .826 (P < .0001) at 1 year. The bias, or the mean difference (handheld minus laboratory), for FEV1 at day 80 and 1 year was -.13 L (limits of agreement, -.63 to .37) and -.10 L (limits of agreement, -.77 to .56), respectively. FEV6 showed greater bias at day 80 (-.51 L [limits of agreement, -1.44 to .42]) and 1 year (-.40 L [limits of agreement, -1.81 to 1.01]). Handheld spirometry correlated well with laboratory spirometry after allogeneic HCT and may be useful for self-monitoring of patients for early identification of airflow obstruction.

  14. An exploratory analysis of mitochondrial haplotypes and allogeneic hematopoietic cell transplantation outcomes.

    PubMed

    Ross, Julie A; Tolar, Jakub; Spector, Logan G; DeFor, Todd; Lund, Troy C; Weisdorf, Daniel J; Langer, Erica; Hooten, Anthony J; Thyagarajan, Bharat; Gleason, Michelle K; Wagner, John E; Robien, Kimberly; Verneris, Michael R

    2015-01-01

    Certain mitochondrial haplotypes (mthaps) are associated with disease, possibly through differences in oxidative phosphorylation and/or immunosurveillance. We explored whether mthaps are associated with allogeneic hematopoietic cell transplantation (HCT) outcomes. Recipient (n = 437) and donor (n = 327) DNA were genotyped for common European mthaps (H, J, U, T, Z, K, V, X, I, W, and K2). HCT outcomes for mthap matched siblings (n = 198), all recipients, and all donors were modeled using relative risks (RR) and 95% confidence intervals and compared with mthap H, the most common mitochondrial haplotypes. Siblings with I and V were significantly more likely to die within 5 years (RR = 3.0; 95% confidence interval [CI], 1.2 to 7.9; and RR = 4.6; 95% CI, 1.8 to 12.3, respectively). W siblings experienced higher acute graft-versus-host disease (GVHD) grades II to IV events (RR = 2.1; 95% CI, 1.1 to 2.4) with no events for those with K or K2. Similar results were observed for all recipients combined, although J recipients experienced lower GVHD and higher relapse. Patients with I donors had a 2.7-fold (1.2 to 6.2) increased risk of death in 5 years, whereas few patients with K2 or W donors died. No patients with K2 donors and few patients with U donors relapsed. Mthap may be an important consideration in HCT outcomes, although validation and functional studies are needed. If confirmed, it may be feasible to select donors based on mthap to increase positive or decrease negative outcomes.

  15. The Impact of Methylenetetrahydrofolate Reductase C677T Polymorphism on Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation with Methotrexate Prophylaxis

    PubMed Central

    Shin, Dong-Yeop; Koh, Youngil; Yoon, Sung-Soo; Seong, Moon-Woo; Park, Sung Sup; Kim, Jin Hee; Lee, Yun-Gyoo; Kim, Inho

    2016-01-01

    Pharmacogenomics can explain the inter-individual differences in response to drugs, including methotrexate (MTX) used for acute graft-versus-host disease (aGVHD) prophylaxis during hematopoietic stem cell transplantation (HSCT). In real-world practice, preplanned MTX dose is arbitrarily modified according to observed toxicity which can lead to unexpected and severe aGVHD development. We aimed to validate the influence of MTHFR C677T polymorphism on the outcomes of allogenic HSCT in a relatively under-represented homogenous Asian population. A total of 177 patients were divided into 677TT group versus 677C-carriers (677CT+677CC), and clinical outcomes along with baseline characteristics were analyzed and compared. Although there was a tendency towards increased peak liver function test results and accordingly greater delta values between the highest and the baseline in 677TT group, we found no associations between genotypes and hepatotoxicity. However, the incidence of acute liver GVHD (≥ grade 2) was significantly higher in the 677TT group than in the 677CC + 677CT group (P = 0.016). A total of 25 patients (14.1%) expired due to transplantation related mortality (TRM) during the first 180 days after HSCT. Patients carrying 677TT genotype were more likely to experience early TRM than 677C-carriers. The same pattern was observed in the cumulative TRM rate, and 677TT genotype patients were more prone to cumulative TRM (P = 0.010). This translated into shorter OS for patients with 677TT compared to 677C-carriers (P = 0.010). The 3-year survival after HSCT was 29.9% for 677TT cases and 47.1% for 677C-carriers. The multivariate analysis identified 677TT genotype (HR = 1.775. 95% CI 1.122–2.808, P = 0.014) and non-CR state (HR = 2.841. 95% CI 1.627–4.960, P<0.001) as predictors for survival. In conclusion, the MTHFR 677TT genotype appears to be associated with acute liver GVHD, and represent a risk factor for TRM and survival in patients undergoing HSCT with MTX as

  16. Radiolabeled Anti-CD45 Antibody with Reduced-Intensity Conditioning and Allogeneic Transplantation for Younger Patients with Advanced Acute Myeloid Leukemia or Myelodysplastic Syndrome

    PubMed Central

    Mawad, Raya; Gooley, Ted A.; Rajendran, Joseph G.; Fisher, Darrell R.; Gopal, Ajay K.; Shields, Andrew T.; Sandmaier, Brenda M.; Sorror, Mohamed L.; Deeg, H. Joachim; Storb, Rainer; Green, Damian J.; Maloney, David G.; Appelbaum, Frederick R.; Press, Oliver W.; Pagel, John M.

    2014-01-01

    We treated patients under age 50 years with 131I-anti-CD45 antibody combined with fludarabine and 2 Gy total body irradiation to create an improved hematopoietic cell transplantation (HCT) strategy for advanced acute myeloid leukemia or high-risk myelodysplastic syndrome patients. Fifteen patients received 332–1,561 mCi of 131I, delivering an average of 27 Gy to bone marrow, 84 Gy to spleen, and 21 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no dose-limiting toxicity was observed. Marrow doses were arbitrarily capped at 43 Gy to avoid radiation-induced stromal damage; however no graft failure or evidence of stromal damage was observed. Twelve patients (80%) developed Grade II graft-versus-host disease (GVHD), one patient developed Grade III GVHD, and no patients developed Grade IV GVHD during the first 100 days after HCT. Of the 12 patients with chronic GVHD data, 10 developed chronic GVHD, generally involving the skin and mouth. Six patients (40%) are surviving after a median of 5.0 years (range, 4.2 to 8.3 years). The estimated survival at 1 year was 73% among the 15 treated patients. Eight patients relapsed, 7 of whom subsequently died. The median time to relapse among these 8 patients was 54 days (range, 26 to 1364 days). No cases of non-relapse mortality were observed in the first year after transplant. However, two patients died in remission from complications of chronic GVHD and cardiomyopathy, at 18 months and 14 months after transplant, respectively. This study suggests that patients may tolerate myeloablative doses >28 Gy delivered to the liver using 131I-anti-CD45 antibody in addition to standard reduced intensity conditioning. Moreover, the arbitrary limit of 43 Gy to the marrow may be unnecessarily conservative, and continued escalation of targeted radioimmunotherapy doses may be feasible to further reduce relapse. PMID:24858425

  17. T-cell receptor excision circle levels after allogeneic stem cell transplantation are predictive of relapse in patients with acute myeloid leukemia and myelodysplastic syndrome.

    PubMed

    Uzunel, Mehmet; Sairafi, Darius; Remberger, Mats; Mattsson, Jonas; Uhlin, Michael

    2014-07-15

    In this retrospective study, 209 patients with malignant disease were analyzed for levels of T-cell receptor excision circles (TRECs) for the first 24 months after allogeneic stem cell transplantation. CD3(+) cells were separated by direct antibody-coupled magnetic beads, followed by DNA extraction according to a standard protocol. The δRec-ψJα signal joint TREC was measured with real-time quantitative PCR. Patients were grouped based on malignant disease: chronic myeloid leukemia, chronic lymphatic leukemia, acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndrome (MDS). Patients were further subdivided based on TREC levels below (low-TREC) or above (high-TREC) median at each time point. TREC levels were then correlated to relapse incidence and relapse-free survival (RFS). For patients with AML, low TREC levels 2 months post-transplantation were correlated to high relapse incidence at 5 years (P<0.05). In patients with chronic leukemia, high TREC levels were correlated with improved RFS (P<0.05). For patients with MDS, high TREC levels at 9 months post-transplantation were associated with higher RFS at 5 years (P<0.02) and lower relapse incidence (P<0.02). This study shows the potential use of TREC measurement in blood to predict relapse in patients with AML and MDS after allogeneic hematopoietic stem cell transplantation.

  18. Late effects in patients with Fanconi anemia following allogeneic hematopoietic stem cell transplantation from alternative donors

    PubMed Central

    Anur, Praveen; Friedman, Danielle N; Sklar, Charles; Oeffinger, Kevin; Castiel, Mercedes; Kearney, Julia; Singh, Bhuvanesh; Prockop, Susan E; Kernan, Nancy A; Scaradavou, Andromachi; Kobos, Rachel; Curran, Kevin; Ruggiero, Julianne; Zakak, Nicole; O’Reilly, Richard J; Boulad, Farid

    2016-01-01

    Hematopoietic stem cell transplantation (HSCT) is curative for hematological manifestations of Fanconi anemia (FA). We performed a retrospective analysis of 22 patients with FA and aplastic anemia, myelodysplastic syndrome or acute myelogenous leukemia who underwent a HSCT at Memorial Sloan Kettering Cancer Center and survived at least one year post-HSCT. Patients underwent either a total body irradiation (TBI) (N=18) or busulfan (N=4) based cytoreduction followed by T-cell depleted transplants from alternative donors. Twenty patients were alive at time of study with a 5 and 10 year overall survival of 100% and 84% and no evidence of chronic GVHD. Among the 18 patients receiving a TBI-based regimen, 11 (61%) had persistent hemochromatosis, four (22%) developed hypothyroidism, seven (39%) had insulin resistance and five (27%) developed hypertriglyceridemia after transplant. Eleven of 16 evaluable patients (68%), receiving TBI, developed gonadal dysfunction. Two patients who received a TBI-based regimen died of squamous cell carcinoma. One patient developed hemochromatosis, hypothyroidism, and gonadal dysfunction after Busulfan-based cytoreduction. TBI appears to be a risk factor for malignant and endocrine late effects in the FA host. Multidisciplinary follow-up of patients with FA (including cancer screening) is essential for early detection and management of late complications, and improving long-term outcomes. PMID:26999465

  19. Pregnancy after allogeneic hematopoietic stem cell transplantation in a Fanconi anemia patient

    PubMed Central

    Atashkhoei, Simin; Fakhari, Solmaz; Bilehjani, Eissa; Farzin, Haleh

    2017-01-01

    Pregnancy in patients with Fanconi anemia (FA) is rare. However, there are reports of successful pregnancy in Fanconi patients after bone marrow transplantation (BMT, hematopoietic stem cell transplantation). We describe the case of a term pregnant woman with FA who was treated with BMT 2 years earlier. She underwent successful delivery with cesarean section using spinal anesthesia without any complications. PMID:28138266

  20. Making strides and meeting challenges in pediatric allogeneic hematopoietic cell transplantation clinical trials in the United States: Past, present and future.

    PubMed

    Satwani, Prakash; Kahn, Justine; Jin, Zhezhen

    2015-11-01

    Over the past 20years, the field of pediatric allogeneic hematopoietic cell transplantation has made ground-breaking strides in the successful treatment of patients with both malignant and non-malignant diseases. As the field advances, so does the need for high-quality studies including randomized controlled trials, aimed at answering clinically important questions about optimizing care and outcomes of children undergoing alloHCT. In an effort to actively address emerging clinical questions, three main cooperative groups in the U.S. have joined forces to develop and implement multiple clinical trials for pediatric alloHCT patients. These groups include the Blood and Marrow Transplant Clinical Trials Network, the Children's Oncology Group and the Pediatric Blood and Marrow Transplant Consortium. Though the field of stem cell transplantation continues to advance, conducting clinical trials in the pediatric population is a unique challenge and as a result, optimal outcomes have yet to be reached in this population. Because of the limited number of pediatric transplant patients at each institution in the U.S., trials aimed at answering important clinical questions still struggle to accrue acceptable numbers of patients in an appropriate amount of time and thus gathering statistically useful data has posed a challenge for the field. In an effort to mitigate some of the challenges associated with obtaining statistically and clinically meaningful information about pediatric alloHCT, the implementation of new cooperative group trials is active and ongoing.

  1. Review of stem-cell transplantation for myelodysplastic syndromes in older patients in the context of the Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome emanating from the Centers for Medicare and Medicaid Services.

    PubMed

    Giralt, Sergio A; Horowitz, Mary; Weisdorf, Daniel; Cutler, Corey

    2011-02-10

    Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem-cell disorders that result in varying degrees of cytopenia and risk of transformation into acute leukemia. Allogeneic stem-cell transplantation (SCT) is the only known cure for this disease. The treatment is routinely used for younger patients, but only a minority of patients older than the age of 60 undergo this procedure. The overall MDS incidence is 3.3 per 100,000, but the incidence in patients older than age 70 is between 15 and 50 per 100,000. The median age at presentation is 76 years. Medicare-age patients 65 or older represent 80% of the total population receiving an MDS diagnosis. In the United States, one of the obstacles to SCT for older patients with MDS has been lack of third party reimbursement. On August 4, 2010, the Centers for Medicare and Medicaid Services released their Decision Memo for Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Myelodysplastic Syndrome. This memo states: "Allogeneic HSCT for MDS is covered by Medicare only for beneficiaries with MDS participating in an approved clinical study that meets the criteria below…. " In this review, we will summarize what is known regarding the role of allogeneic SCT in older patients as well as other elements that should be included within clinical trials that can provide the evidence necessary to demonstrate that allogeneic SCT should be a covered benefit for Medicare beneficiaries.

  2. Immunity of patients surviving 20 to 30 years after allogeneic or syngeneic bone marrow transplantation.

    PubMed

    Storek, J; Joseph, A; Espino, G; Dawson, M A; Douek, D C; Sullivan, K M; Flowers, M E; Martin, P; Mathioudakis, G; Nash, R A; Storb, R; Appelbaum, F R; Maloney, D G

    2001-12-15

    The duration of immunodeficiency following marrow transplantation is not known. Questionnaires were used to study the infection rates in 72 patients surviving 20 to 30 years after marrow grafting. Furthermore, in 33 of the 72 patients and in 16 donors (siblings who originally donated the marrow) leukocyte subsets were assessed by flow cytometry. T-cell receptor excision circles (TRECs), markers of T cells generated de novo, were quantitated by real-time polymerase chain reaction. Immunoglobulin G(2) (IgG(2)) and antigen-specific IgG levels were determined by enzyme-linked immunosorbent assay. Infections diagnosed more than [corrected] 15 years after transplantation occurred rarely. The average rate was 0.07 infections per patient-year (one infection every 14 years), excluding respiratory tract infections, gastroenteritis, lip sores, and hepatitis C. The counts of circulating monocytes, natural killer cells, B cells, CD4 T cells, and CD8 T cells in the patients were not lower than in the donors. The counts of TREC(+) CD4 T cells in transplant recipients younger than age 18 years (at the time of transplantation) were not different from the counts in their donors. In contrast, the counts of TREC(+) CD4 T cells were lower in transplant recipients age 18 years or older, even in those with no history of clinical extensive chronic graft-versus-host disease, compared with their donors. The levels of total IgG(2) and specific IgG against Haemophilus influenzae and Streptococcus pneumoniae were similar in patients and donors. Overall, the immunity of patients surviving 20 to 30 years after transplantation is normal or near normal. Patients who received transplants in adulthood have a clinically insignificant deficiency of de novo-generated CD4 T cells, suggesting that in these patients the posttransplantation thymic insufficiency may not be fully reversible.

  3. Posaconazole plasma concentration in pediatric patients receiving antifungal prophylaxis after allogeneic hematopoietic stem cell transplantation.

    PubMed

    Heinz, Werner J; Cabanillas Stanchi, Karin M; Klinker, Hartwig; Blume, Olivia; Feucht, Judith; Hartmann, Ulrike; Feuchtinger, Tobias; Lang, Peter; Handgretinger, Rupert; Döring, Michaela

    2016-02-01

    Posaconazole has been proven to be effective for antifungal prophylaxis in adults after hematopoietic stem cell transplantation (HSCT). Due to low gastrointestinal resorption of posaconazole suspension, bioavailability is impaired. Fatty food improves the uptake of posaconazole, but insufficient data on the pharmacokinetics of posaconazole in pediatric patients are available so far. The single-center analysis investigated 161 posaconazole serum concentrations in 27 pediatric patients after HSCT receiving 12 mg·kg BW(-1)·d(-1) posaconazole suspension depending on age, gender, and intestinal graft-versus-host (iGvHD) disease, and the influence of posaconazole on cyclosporine A plasma concentrations. To improve the uptake of posaconazole, one patient cohort received higher fat nutrition with the drug administration. A comparison of the regular nutrition and higher-fat nutrition groups revealed the following values: 31 (27.4%) versus 8 (16.7%) < 500 ng/ml; 12 (10.6%) versus 7 (14.6%) 500-700 ng/ml; 8 (7.1%) versus 6 (12.5%) 700-1000 ng/ml; 51 (45.1%) versus 21 (43.8%) 1000-2000 ng/ml; and 11 (9.7%) versus 6 (12.5%) > 2000 ng/ml. The mean posaconazole concentrations in patients with regular nutrition was 1123 ± 811 ng/ml and with higher-fat nutrition was 1191 ± 673 ng/ml. Posaconazole levels in patients with iGvHD were significantly lower (P = 0.0003) than in patients without GvHD. The majority of samples showed a sufficient posaconazole concentration above 700 ng/ml. Posaconazole levels were slightly higher in patients with higher-fat nutrition and significantly lower in patients with iGvHD. Cyclosporine A levels were not significantly higher during posaconazole administration.

  4. Association of Macroeconomic Factors With Nonrelapse Mortality After Allogeneic Hematopoietic Cell Transplantation for Adults With Acute Lymphoblastic Leukemia: An Analysis From the Acute Leukemia Working Party of the EBMT

    PubMed Central

    Labopin, Myriam; Ibatici, Adalberto; Browne, Paul; Czerw, Tomasz; Socie, Gerard; Unal, Ali; Kyrcz-Krzemien, Slawomira; Bacigalupo, Andrea; Goker, Hakan; Potter, Mike; Furness, Caroline L.; McQuaker, Grant; Beelen, Dietrich; Milpied, Noel; Campos, Antonio; Craddock, Charles; Nagler, Arnon; Mohty, Mohamad

    2016-01-01

    Purpose. From a global perspective, the rates of allogeneic hematopoietic cell transplantation (alloHCT) are closely related to the economic status of a country. However, a potential association with outcome has not yet been documented. The goal of this study was to evaluate effects of health care expenditure (HCE), Human Development Index (HDI), team density, and center experience on nonrelapse mortality (NRM) after HLA-matched sibling alloHCT for adults with acute lymphoblastic leukemia (ALL). Patients and Methods. A total of 983 patients treated with myeloablative alloHCT between 2004 and 2008 in 24 European countries were included. Results. In a univariate analysis, the probability of day 100 NRM was increased for countries with lower current HCE (8% vs. 3%; p = .06), countries with lower HDI (8% vs. 3%; p = .02), and centers with less experience (8% vs. 5%; p = .04). In addition, the overall NRM was increased for countries with lower current HCE (21% vs. 17%; p = .09) and HDI (21% vs. 16%; p = .03) and for centers with lower activity (21% vs. 16%; p = .07). In a multivariate analysis, the strongest predictive model for day 100 NRM included current HCE greater than the median (hazard ratio [HR], 0.39; p = .002). The overall NRM was mostly predicted by HDI greater than the median (HR, 0.65; p = .01). Both lower current HCE and HDI were associated with decreased probability of overall survival. Conclusion. Both macroeconomic factors and the socioeconomic status of a country strongly influence NRM after alloHCT for adults with ALL. Our findings should be considered when clinical studies in the field of alloHCT are interpreted. Implications for Practice: Results of allogeneic hematopoietic cell transplantation (alloHCT) and other advanced oncological procedures may vary among countries and be related to various economic factors. This study, which included a homogenous population of patients with acute lymphoblastic leukemia, demonstrated significant associations of

  5. Associations between gastrointestinal toxicity, micro RNA and cytokine production in patients undergoing myeloablative allogeneic stem cell transplantation.

    PubMed

    Pontoppidan, Peter L; Jordan, Karina; Carlsen, Anting Liu; Uhlving, Hilde Hylland; Kielsen, Katrine; Christensen, Mette; Ifversen, Marianne; Nielsen, Claus Henrik; Sangild, Per; Heegaard, Niels Henrik Helweg; Heilmann, Carsten; Sengeløv, Henrik; Müller, Klaus

    2015-03-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is a procedure with a high risk of treatment related mortality. The primary aim of the present study was to examine associations between markers of gastrointestinal toxicity, markers of systemic inflammation, and plasma levels of microRNA (miRNA) -155 and -146a during the first month after HSCT. The secondary aim was to characterize the impact of the toxic-inflammatory response on the function of circulating leukocytes during immune recovery. Thirty HSCT patients were included. Gastrointestinal injury was monitored by toxicity scores, lactulose-mannitol test and plasma citrulline, as a measure of the enterocyte population. Nadir of citrulline and maximum of oral toxicity scores, intestinal permeability, CRP and plasma levels of IL-6 and IL-10 was seen at day +7 post-HSCT. miRNA-155 and mi-RNA-146a showed an inverse relation with significantly elevated miRNA-155 and decreased miRNA-146a levels, from day 0 to day +28 compared with pre-conditioning levels. Citrulline levels below the median at day +7 were associated with higher spontaneous production of IL-6 and TNF-α as well as higher in vitro stimulated production of IL-17A at day +21. This study is the first to demonstrate that toxic responses to chemotherapy are accompanied by differential regulation of miRNAs with opposing effects on immune regulation. We find that a proinflammatory miRNA profile is sustained during the first three weeks after the transplantation, indicating that these miRNAs may play a role in the regulation of the inflammatory environment during immune reconstitution after HSCT.

  6. Busulfan and total body irradiation as antihematopoietic stem cell agents in the preparation of patients with congenital bone marrow disorders for allogenic bone marrow transplantation

    SciTech Connect

    Parkman, R.; Rappeport, J.M.; Hellman, S.; Lipton, J.; Smith, B.; Geha, R.; Nathan, D.G.

    1984-10-01

    The capacity of busulfan and total body irradiation to ablate hematopoietic stem cells as preparation for the allogeneic bone marrow transplantation of patients with congenital bone marrow disorders was studied. Fourteen patients received 18 transplants; busulfan was used in the preparatory regimen of eight transplants and total body irradiation in the regimens of six transplants. Sustained hematopoietic ablation was achieved in six of eight patients prepared with busulfan and in all six patients prepared with total body irradiation. Three patients prepared with total body irradiation died with idiopathic interstitial pneumonitis, whereas no patients receiving busulfan developed interstitial pneumonitis. The optimal antihematopoietic stem cell agent to be used for the preparation of patients with congenital bone marrow disorder for bone marrow transplantation is not certain.

  7. [18F]FHBG PET/CT Imaging of CD34-TK75 Transduced Donor T Cells in Relapsed Allogeneic Stem Cell Transplant Patients: Safety and Feasibility

    PubMed Central

    Eissenberg, Linda G; Rettig, Michael P; Ritchey, Julie K; Prior, Julie L; Schwarz, Sally W; Frye, Jennifer; White, Brian S; Fulton, Robert S; Ghobadi, Armin; Cooper, Matthew L; Couriel, Daniel R; Seegulam, Muhammad Esa; Piwnica-Worms, David; Dehdashti, Farrokh; Cornetta, Kenneth; DiPersio, John F

    2015-01-01

    Described herein is a first-in-man attempt to both genetically modify T cells with an imagable suicide gene and track these transduced donor T cells in allogeneic stem cell transplantation recipients using noninvasive positron emission tomography/computerized tomography (PET/CT) imaging. A suicide gene encoding a human CD34-Herpes Simplex Virus-1-thymidine kinase (CD34-TK75) fusion enabled enrichment of retrovirally transduced T cells (TdT), control of graft-versus-host disease and imaging of TdT migration and expansion in vivo in mice and man. Analysis confirmed that CD34-TK75-enriched TdT contained no replication competent γ-retrovirus, were sensitive to ganciclovir, and displayed characteristic retroviral insertion sites (by targeted sequencing). Affinity-purified CD34-TK75+-selected donor T cells (1.0–13 × 105)/kg were infused into eight patients who relapsed after allogeneic stem cell transplantation. Six patients also were administered 9-[4-(18F)fluoro-3-hydroxymethyl-butyl]guanine ([18F]FHBG) to specifically track the genetically modified donor T cells by PET/CT at several time points after infusion. All patients were assessed for graft-versus-host disease, response to ganciclovir, circulating TdT cells (using both quantitative polymerase chain reaction and [18F]FHBG PET/CT imaging), TdT cell clonal expansion, and immune response to the TdT. This phase 1 trial demonstrated that genetically modified T cells and [18F]FHBG can be safely infused in patients with relapsed hematologic malignancies after allogeneic stem cell transplantation. PMID:25807290

  8. A Trial of Alemtuzumab Adjunctive Therapy in Allogeneic Hematopoietic Cell Transplantation with Minimal Conditioning for Severe Combined Immunodeficiency

    PubMed Central

    Dvorak, Christopher C.; Horn, Biljana N.; Puck, Jennifer M.; Adams, Stuart; Veys, Paul; Czechowicz, Agnieszka; Cowan, Morton J.

    2014-01-01

    For infants with severe combined immunodeficiency (SCID) the ideal conditioning regimen before allogeneic hematopoietic cell transplantation (HCT) would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with alemtuzumab monotherapy to overcome NK-cell mediated immunologic barriers to engraftment. We enrolled 4 patients who received CD34-selected haploidentical cells, two of whom failed to engraft donor T cells. The 2 patients who engrafted had delayed T cell reconstitution, despite rapid clearance of circulating alemtuzumab. Although well-tolerated, alemtuzumab failed to overcome immunologic barriers to donor engraftment. Furthermore, alemtuzumab may slow T cell development in patients with SCID in the setting of a T-cell depleted graft. PMID:24977928

  9. A trial of alemtuzumab adjunctive therapy in allogeneic hematopoietic cell transplantation with minimal conditioning for severe combined immunodeficiency.

    PubMed

    Dvorak, Christopher C; Horn, Biljana N; Puck, Jennifer M; Adams, Stuart; Veys, Paul; Czechowicz, Agnieszka; Cowan, Morton J

    2014-09-01

    For infants with SCID the ideal conditioning regimen before allogeneic HCT would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with alemtuzumab monotherapy to overcome NK-cell mediated immunologic barriers to engraftment. We enrolled four patients who received CD34-selected haploidentical cells, two of whom failed to engraft donor T cells. The two patients who engrafted had delayed T-cell reconstitution, despite rapid clearance of circulating alemtuzumab. Although well-tolerated, alemtuzumab failed to overcome immunologic barriers to donor engraftment. Furthermore, alemtuzumab may slow T-cell development in patients with SCID in the setting of a T-cell depleted graft.

  10. Dendritic cell count in the graft predicts relapse in patients with hematologic malignancies undergoing an HLA-matched related allogeneic peripheral blood stem cell transplant.

    PubMed

    Rajasekar, Reena; Lakshmi, Kavitha M; George, Biju; Viswabandya, Auro; Thirugnanam, Rajasekar; Abraham, Aby; Chandy, Mammen; Srivastava, Alok; Mathews, Vikram

    2010-06-01

    We investigated the impact of the number of infused and reconstituted immunocompetent cells including dendritic cells (DCs) on clinical outcome of patients with hematologic malignancies undergoing an allogeneic peripheral blood stem cell transplantation. Sixty-nine consecutive patients with hematologic malignancies were included in the analysis. The median age of the cohort was 32 years (range: 2-62 years) and there were 39 (57%) males. Twenty-one (30%) patients relapsed with a cumulative incidence of 44 % +/- 14% at a median follow up of 28 months. On a multivariate analysis, a high plasmacytoid dendritic cell (PC) content in the graft was associated with higher risk of relapse. The patients were further categorized based on the median PC counts in the graft as high (> or =2.3 x 10(6)/kg) and low (<2.3 x 10(6)/kg) groups. The baseline characteristics of these 2 groups were comparable. The group that had a high PC content in the graft had significantly higher risk of relapse and lower overall survival (OS) and event-free survival (EFS). Our data suggests that PC content in the graft predicts clinical outcomes such as relapse and survival in patients with hematologic malignancies undergoing an allogeneic HLA matched related peripheral blood stem cell transplantation. There is potential for pretransplant manipulation of this cellular subset in the graft.

  11. Establishment of Definitions and Review Process for Consistent Adjudication of Cause-Specific Mortality After Allogeneic Unrelated Donor Hematopoietic Cell Transplantation

    PubMed Central

    Preus, Leah; Zhu, Xiaochun; Hansen, John A.; Martin, Paul J.; Yan, Li; Liu, Song; Spellman, Stephen; Tritchler, David; Clay, Alyssa

    2015-01-01

    Clinical trials commonly use adjudication committees to refine endpoints, but observational research or genome-wide association studies rarely do. Our goals were to establish definitions of cause-specific death after unrelated donor allogeneic hematopoietic cell transplantation (URD-HCT), estimate discordance between reported and adjudicated cause-specific death, and identify factors contributing to inconsistency in cause-specific deathdetermination. A consensus panel adjudicated cause-specific deathin 1,484 patients who died within 1 year after HCT, derived from 3,532 acute leukemia or myelodysplasia patients after URD-HCT 2000-2011 reported by 151 U.S. transplant centers to CIBMTR. Deaths were classified as disease-related (DRM) or transplant-related (TRM). The panel agreed with >99% of deaths reported by centers as DRM and 80% reported as TRM. Year of transplant (cohort effect) and disease status significantly influenced agreement between panel and centers. Sensitivity analysis of deaths <100 days post-transplant yielded lowest agreement between the panel and centers for myelodysplastic syndrome patients. Standard pre-defined criteria for adjudicating cause-specific deathled to consistent application to similar clinical scenarios and clearer delineation of cause-specific deathcategories. Other studies of competing events like cancer-specific vs treatment-related mortality would benefit from our results. Our detailed algorithm should result in more consistent reporting of cause-specific deathby centers. PMID:26028504

  12. Special considerations for the patient undergoing allogeneic or autologous bone marrow transplantation.

    PubMed

    Hiemenz, J W; Greene, J N

    1993-10-01

    Improvements in the diagnosis, treatment, and prevention of infectious complications of bone marrow transplantation over the past two decades have markedly reduced the morbidity and mortality of this procedure. We are now able to begin early empiric antibiotic coverage with less toxic, but equally effective, antibacterial agents. Once believed to be uniformly fatal, complications such as CMV pneumonia are now considered treatable in at least half the cases with a combination of intravenous immunoglobulin and ganciclovir. Although probably the most controversial, prophylactic therapy has improved the outcome of patients undergoing bone marrow transplantation. The appropriate setting, agents to use, dose, and dose intervals will require further study in coming years. In the introduction to this article, we attempted to outline what is known about the immunobiology of bone marrow transplantation. A clear understanding of this process helps us recognize and anticipate the infectious complications encountered in this population of patients. It may also allow clinicians to focus more on immune augmentation as a means of prevention, as has been attempted with the newly available cytokines and the use of intravenous immunoglobulin infusions. Despite improvements in diagnosis, treatment, and prevention, infectious complications remain the leading cause of morbidity and mortality in the patient undergoing bone marrow transplantation. Future studies are required in this area to build on the successes of the last two decades.

  13. Financial Hardship and Patient-Reported Outcomes after Hematopoietic Cell Transplantation.

    PubMed

    Abel, Gregory A; Albelda, Randy; Khera, Nandita; Hahn, Theresa; Salas Coronado, Diana Y; Odejide, Oreofe O; Bona, Kira; Tucker-Seeley, Reginald; Soiffer, Robert

    2016-08-01

    Although hematopoietic cell transplantation (HCT) is the only curative therapy for many advanced hematologic cancers, little is known about the financial hardship experienced by HCT patients nor the association of hardship with patient-reported outcomes. We mailed a 43-item survey to adult patients approximately 180 days after their first autologous or allogeneic HCT at 3 high-volume centers. We assessed decreases in household income; difficulty with HCT-related costs, such as need to relocate or travel; and 2 types of hardship: hardship_1 (reporting 1 or 2 of the following: dissatisfaction with present finances, difficulty meeting monthly bill payments, or not having enough money at the end of the month) and "hardship_2" (reporting all 3). Patient-reported stress was measured with the Perceived Stress Scale-4, and 7-point scales were provided for perceptions of overall quality of life (QOL) and health. In total, 325 of 499 surveys (65.1%) were received. The median days since HCT was 173; 47% underwent an allogeneic HCT, 60% were male, 51% were > 60 years old, and 92% were white. Overall, 46% reported income decline after HCT, 56% reported hardship_1, and 15% reported hardship_2. In multivariable models controlling for income, those reporting difficulty paying for HCT-related costs were more likely to report financial hardship (odds ratio, 6.9; 95% confidence interval, 3.8 to 12.3). Hardship_1 was associated with QOL below the median (odds ratio, 2.9; 95% confidence interval, 1.7 to 4.9), health status below the median (odds ratio, 2.2; 95% confidence interval, 1.3 to 3.6), and stress above the median (odds ratio, 2.1; 95% confidence interval, 1.3 to 3.5). In this sizable cohort of HCT patients, financial hardship was prevalent and associated with worse QOL and higher levels of perceived stress. Interventions to address patient financial hardship-especially those that ameliorate HCT-specific costs-are likely to improve patient-reported outcomes.

  14. Brentuximab Vedotin in Patients With Hodgkin Lymphoma and a Failed Allogeneic Stem Cell Transplantation: Results From a Named Patient Program at Four Italian Centers

    PubMed Central

    Ricci, Francesca; Dalto, Serena; Mazza, Rita; Malagola, Michele; Patriarca, Francesca; Viviani, Simonetta; Russo, Domenico; Giordano, Laura; Castagna, Luca; Corradini, Paolo; Santoro, Armando

    2015-01-01

    Background. Brentuximab vedotin (BV) has demonstrated an extraordinary efficacy in heavily pretreated classical Hodgkin lymphoma (cHL) patients, targeting CD30-positive cells; however, limited data have been reported on the efficacy of BV in cHL patients failing allogeneic stem cell transplantation (allo-SCT). The aim of this study was to retrospectively evaluate the efficacy and safety of BV in a multicenter setting of cHL relapsing or progressing after allo-SCT. Methods. Sixteen BV-naïve patients with recurrent cHL after allo-SCT were included in a compassionate use program and treated with intravenous BV at the dose of 1.8 mg/kg of body weight every 3 weeks for a maximum of 16 cycles. Results. The objective response rate was 69%. Five patients (31%) had complete remission, and 6 (37%) had partial remission. Stable disease was observed in 4 patients (25%), and progressive disease was observed in 1 (6%). After median follow-up of 26 months (range: 5–30 months), median progression-free survival (PFS), overall survival (OS), and duration of response were 7, 25, and 5 months, respectively. The 2-year PFS and OS were 20% and 61%, respectively. Grade 3–4 hematological adverse events included anemia (15%), thrombocytopenia (12%), and neutropenia (18%). Grade 3 peripheral sensory neuropathy occurred in 2 patients (12%). Conclusion. BV therapy is an effective and safe approach for achieving transient disease control in cHL patients with failed allo-SCT. To improve disease control, future studies should explore the combination of BV with targeted agents. PMID:25669663

  15. A trial of plerixafor adjunctive therapy in allogeneic hematopoietic cell transplantation with minimal conditioning for severe combined immunodeficiency.

    PubMed

    Dvorak, Christopher C; Horn, Biljana N; Puck, Jennifer M; Czechowicz, Agnieszka; Shizuru, Judy A; Ko, Rose M; Cowan, Morton J

    2014-09-01

    For infants with SCID, the ideal conditioning regimen before allogeneic HCT would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with G-CSF plus plerixafor given to the host to mobilize HSC from their niches. We enrolled six patients who received CD34-selected haploidentical cells and one who received T-replete matched unrelated BM. All patients receiving G-CSF and plerixafor had generally poor CD34(+) cell and Lin(-) CD34(+) CD38(-) CD90(+) CD45RA(-) HSC mobilization, and developed donor T cells, but no donor myeloid or B-cell engraftment. Although well tolerated, G-CSF plus plerixafor alone failed to overcome physical barriers to donor engraftment.

  16. Quality of life in chronic myeloid leukaemia patients after haematopoietic cell transplantation pretreated with second-generation tyrosine kinase inhibitors

    PubMed Central

    Gil, Lidia; Jakitowicz, Karolina; Prejzner, Witold; Komarnicki, Mieczysław; Hellmann, Andrzej

    2016-01-01

    Aim of the study The majority of patients with chronic myeloid leukaemia (CML) respond to tyrosine kinase inhibitors (TKI), while allogeneic haematopoietic cell transplantation (HCT) is indicated in selected clinical situations. HCT carries the risk of severe complications, while the toxicity profile of dasatinib and nilotinib may lead to adverse reactions affecting the quality of life (QoL). We present the results of observational analysis of CML patients who underwent HCT after exposure to second-generation TKI (TKI2), with respect to their quality of life assessed comparatively after transplantation. Material and methods Eligible subjects included 19 patients. The quality of life and global health assessment were performed with a questionnaire comparing the signs and symptoms present during the TKI2-therapy with those related to post-transplant complications, including psychosocial problems. Results and conclusions Most patients had no/few problems with exhausting activities, no/few difficulties during long-distance walks, and do not/rarely rest in the daytime. Seventeen (89.5%) patients reported at least one symptom related to TKI2-therapy and most of them disappeared after HCT. Thirteen (68.4%) patients noted no serious complication after HCT. Most patients claimed to have a very good QoL and general health compared to the period prior to HCT. We found statistically significant improvement in global health (p = 0.016) and QoL (p = 0.043) after HCT. From the survivors perspective, HCT influence positively general health and QoL comparing to TKI2-therapy period. Further studies on larger group of patients will more precisely define the QoL level and possible predictors of changes in QoL, to assess which group of patients needs psychological support.

  17. Umbilical Cord Blood Transplantation Outcomes in Acute Myelogenous Leukemia/Myelodysplastic Syndrome Patients Aged ≥70 Years.

    PubMed

    Sandhu, Karamjeet S; Brunstein, Claudio; DeFor, Todd; Bejanyan, Nelli; Arora, Mukta; Warlick, Erica; Weisdorf, Daniel; Ustun, Celalettin

    2016-02-01

    The maximum age of patients receiving allogeneic hematopoietic stem cell transplantation (alloHCT) has been moving up over time. However, the availability of a suitable HLA-matched sibling donor may limit access of this patient population to alloHCT. We retrospectively investigated the outcomes of umbilical cord blood transplantation (UCBT) after reduced-intensity conditioning regimens in patients aged ≥70 years with myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) between 2010 and 2014. During this period 70 patients with AML/MDS were referred to our center for alloHCT consideration. Twenty-two patients (33%) received alloHCT: 10 UCBT, 9 HLA full-matched sibling donor transplantation, 2 haploidentical alloHCT, and 1 unrelated donor alloHCT. In UCBT, cumulative incidences of nonrelapse mortality and relapse were 20% and 30% at 2 years, respectively. The cumulative incidence of acute graft-versus-host disease (GVHD) at day +100 and chronic GVHD at 2 years was 10%. Seven patients had viral reactivation/infections. Rates of overall survival and disease-free survival were 60% and 50% at 2 years, respectively. Moreover, these outcomes seemed to be similar to that of patients aged 60 to 69 years receiving UCBT (n = 60) and patients aged ≥70 years receiving HLA full-matched sibling donor transplantation (n = 9). These results suggest that UCBT is feasible in selected AML/MDS patients aged ≥70 years. In fact, UCBT shortens the required time for an unrelated donor search and thus increases the chance of proceeding with alloHCT, which might contribute to higher rates of alloHCT in the referral group. Outcomes of UCBT are promising; however, larger studies with a longer follow-up are needed.

  18. Cytogenetic Evolution in Myeloid Neoplasms at Relapse after Allogeneic Hematopoietic Cell Transplantation: Association with Previous Chemotherapy and Effect on Survival.

    PubMed

    Ertz-Archambault, Natalie; Kosiorek, Heidi; Slack, James L; Lonzo, Melissa L; Greipp, Patricia T; Khera, Nandita; Kelemen, Katalin

    2017-02-09

    Cytogenetic evolution (CGE) in patients with myeloid neoplasms who relapsed after an allogeneic (allo) hematopoietic cell transplantation (HCT) has been evaluated by only few studies. The effect of the CGE on survival of relapsed allo-HCT recipients is not clear. The effect of previously received chemotherapy to induce CGE in this patient population has not been studied. The aims of our study are to (1) characterize the patterns of cytogenetic change in patients with myeloid neoplasms who relapsed after an allo-HCT, (2) evaluate the effect of CGE on survival, and (3) explore the association of CGE with previous chemotherapy (including the lines of salvage therapy, type of induction, and conditioning therapy). Of 49 patients with a myeloid malignancy (27 acute myeloid leukemia [AML], 19 myelodysplastic syndrome [MDS]/myeloproliferative neoplasm [MPN], and 3 chronic myelogenous leukemia) who relapsed after an allo-HCT, CGE was observed in 25 (51%), whereas 24 patients had unchanged cytogenetic findings at relapse. The CGE group carried more cytogenetic abnormalities at original diagnosis. The most frequent cytogenetic change was the acquisition of 3 or more new chromosomal abnormalities followed by acquisition of unbalanced abnormalities, aneuploidy, and emergence of apparently new clones unrelated to the original clone. The CGE cohort had higher proportion of MDS and MPN and fewer patients with de novo AML. Disease risk assessment category showed a trend to higher frequency of high-risk patients in the CGE group, though the difference was not statistically significant. Time from diagnosis to transplantation and time from transplantation to relapse were not different between the CGE and non-CGE groups. CGE and non-CGE cohorts had similar exposures to salvage therapy and to induction chemotherapy, as well as similar conditioning regimens; thus, no particular type of chemotherapy emerged as a predisposing factor to CGE. CGE was associated with significantly shortened

  19. Metabolic Serum Profiles for Patients Receiving Allogeneic Stem Cell Transplantation: The Pretransplant Profile Differs for Patients with and without Posttransplant Capillary Leak Syndrome

    PubMed Central

    Reikvam, Håkon; Grønningsæter, Ida-Sofie; Ahmed, Aymen Bushra; Hatfield, Kimberley; Bruserud, Øystein

    2015-01-01

    Allogeneic stem cell transplantation is commonly used in the treatment of younger patients with severe hematological diseases, and endothelial cells seem to be important for the development of several posttransplant complications. Capillary leak syndrome is a common early posttransplant complication where endothelial cell dysfunction probably contributes to the pathogenesis. In the present study we investigated whether the pretreatment serum metabolic profile reflects a risk of posttransplant capillary leak syndrome. We investigated the pretransplant serum levels of 766 metabolites for 80 consecutive allotransplant recipients. Patients with later capillary leak syndrome showed increased pretherapy levels of metabolites associated with endothelial dysfunction (homocitrulline, adenosine) altered renal regulation of fluid and/or electrolyte balance (betaine, methoxytyramine, and taurine) and altered vascular function (cytidine, adenosine, and methoxytyramine). Additional bioinformatical analyses showed that capillary leak syndrome was also associated with altered purine/pyrimidine metabolism (i.e., metabolites involved in vascular regulation and endothelial functions), aminoglycosylation (possibly important for endothelial cell functions), and eicosanoid metabolism (also involved in vascular regulation). Our observations are consistent with the hypothesis that the pretransplant metabolic status can be a marker for posttransplant abnormal fluid and/or electrolyte balance. PMID:26609191

  20. Metabolic bone diseases in patients after allogeneic hematopoietic stem cell transplantation: report from the Consensus Conference on Clinical Practice in chronic graft-versus-host disease.

    PubMed

    Hautmann, Anke Heidewig; Elad, Sharon; Lawitschka, Anita; Greinix, Hildegard; Bertz, Hartmut; Halter, Joerg; Faraci, Maura; Hofbauer, Lorenz Christian; Lee, Stephanie; Wolff, Daniel; Holler, Ernst

    2011-09-01

    With improved outcome of allogeneic stem cell transplantation (allo-SCT) for hematologic malignancies, long-term complications gain greater importance. Skeletal complications such as osteoporosis or avascular necrosis (AVN) occur frequently in allogeneic recipients with a cumulative incidence of diminished bone mineral density of 24-50% between 2 and 12 months after allo-SCT and a cumulative incidence of AVN in as many as 19% of patients 3 years after allo-SCT. Here, we present a review as part of the German, Austrian, and Swiss Consensus Conference on clinical practice in chronic graft-versus-host disease, held 2009 in Regensburg. The Consensus Conference aimed to achieve a consensus on the current evidence of diagnosis, prevention, and therapeutic options of late complications after allo-SCT summarizing and discussing the literature on these topics. In this report, we provide recommendations for metabolic bone diseases agreed upon by the working party. This includes guidelines for diagnosis, prevention, and therapeutic options in patients with low bone mass or AVN.

  1. Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation

    PubMed Central

    Lee, Stephanie J.; Ahn, Kwang Woo; Spellman, Stephen; Wang, Hai-Lin; Aljurf, Mahmoud; Askar, Medhat; Dehn, Jason; Fernandez Viña, Marcelo; Gratwohl, Alois; Gupta, Vikas; Hanna, Rabi; Horowitz, Mary M.; Hurley, Carolyn K.; Inamoto, Yoshihiro; Kassim, Adetola A.; Nishihori, Taiga; Mueller, Carlheinz; Oudshoorn, Machteld; Petersdorf, Effie W.; Prasad, Vinod; Robinson, James; Saber, Wael; Schultz, Kirk R.; Shaw, Bronwen; Storek, Jan; Wood, William A.; Woolfrey, Ann E.; Anasetti, Claudio

    2014-01-01

    We examined current outcomes of unrelated donor allogeneic hematopoietic cell transplantation (HCT) to determine the clinical implications of donor-recipient HLA matching. Adult and pediatric patients who had first undergone myeloablative-unrelated bone marrow or peripheral blood HCT for acute myelogenous leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome between 1999 and 2011 were included. All had high-resolution typing for HLA-A, -B, -C, and -DRB1. Of the total (n = 8003), cases were 8/8 (n = 5449), 7/8 (n = 2071), or 6/8 (n = 483) matched. HLA mismatch (6-7/8) conferred significantly increased risk for grades II to IV and III to IV acute graft vs host disease (GVHD), chronic GVHD, transplant-related mortality (TRM), and overall mortality compared with HLA-matched cases (8/8). Type (allele/antigen) and locus (HLA-A, -B, -C, and -DRB1) of mismatch were not associated with overall mortality. Among 8/8 matched cases, HLA-DPB1 and -DQB1 mismatch resulted in increased acute GVHD, and HLA-DPB1 mismatch had decreased relapse. Nonpermissive HLA-DPB1 allele mismatch was associated with higher TRM compared with permissive HLA-DPB1 mismatch or HLA-DPB1 match and increased overall mortality compared with permissive HLA-DPB1 mismatch in 8/8 (and 10/10) matched cases. Full matching at HLA-A, -B, -C, and -DRB1 is required for optimal unrelated donor HCT survival, and avoidance of nonpermissive HLA-DPB1 mismatches in otherwise HLA-matched pairs is indicated. PMID:25161269

  2. An operational definition of primary refractory acute myeloid leukemia allowing early identification of patients who may benefit from allogeneic stem cell transplantation.

    PubMed

    Ferguson, Paul; Hills, Robert K; Grech, Angela; Betteridge, Sophie; Kjeldsen, Lars; Dennis, Michael; Vyas, Paresh; Goldstone, Anthony H; Milligan, Donald; Clark, Richard E; Russell, Nigel H; Craddock, Charles

    2016-11-01

    Up to 30% of adults with acute myeloid leukemia fail to achieve a complete remission after induction chemotherapy - termed primary refractory acute myeloid leukemia. There is no universally agreed definition of primary refractory disease, nor have the optimal treatment modalities been defined. We studied 8907 patients with newly diagnosed acute myeloid leukemia, and examined outcomes in patients with refractory disease defined using differing criteria which have previously been proposed. These included failure to achieve complete remission after one cycle of induction chemotherapy (RES), less than a 50% reduction in blast numbers with >15% residual blasts after one cycle of induction chemotherapy (REF1) and failure to achieve complete remission after two courses of induction chemotherapy (REF2). 5-year overall survival was decreased in patients fulfilling any criteria for refractory disease, compared with patients achieving a complete remission after one cycle of induction chemotherapy: 9% and 8% in patients with REF1 and REF2 versus 40% (P<0.0001). Allogeneic stem cell transplantation improved survival in the REF1 (HR 0.58 (0.46-0.74), P=0.00001) and REF2 (HR 0.55 (0.41-0.74), P=0.0001) cohorts. The utilization of REF1 criteria permits the early identification of patients whose outcome after one course of induction chemotherapy is very poor, and informs a novel definition of primary refractory acute myeloid leukemia. Furthermore, these data demonstrate that allogeneic stem cell transplantation represents an effective therapeutic modality in selected patients with primary refractory acute myeloid leukemia.

  3. [Current attitudes to the elimination of infection foci from the oral cavity of adult patients qualified for allogeneic hematopoietic stem cell transplantation].

    PubMed

    Bogusławska-Kapała, Agnieszka; Struzycka, Izabela; Hałaburda, Kazimierz

    2013-11-01

    Oral cavity is often the source of local and/or general complications in patients treated by allogeneic hematopoietic stem cell transplantation (alloHSCT). According to the literature dental treatment of an adult patient prior to transplantation is based on empiric protocols elaborated by oncological clinics for their individual needs. Suggested rules often differs between each other. I this article we present different attitude to the important problem of either removing or leaving the potential dentogenic foci of infection. The analysis of the literature suggest that the most appropriate procedure is to eliminate all potential and existing sources of infection before transplantation, as long as it is possible by the amount of time remaining before beginning the conditioning chemo/radiotherapy and by the general condition of a patient. In another case dental treatment should be postponed until the posttransplantation period.

  4. Does quality of life impact the decision to pursue stem cell transplantation for elderly patients with advanced MDS?

    PubMed

    El-Jawahri, A; Kim, H T; Steensma, D P; Cronin, A M; Stone, R M; Watts, C D; Chen, Y-B; Cutler, C S; Soiffer, R J; Abel, G A

    2016-08-01

    The factors that influence utilization of reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HCT) among medically fit older patients with advanced myelodysplastic syndromes (MDS) are largely unknown. The MDS Transplant-Associated Outcomes (MDS-TAO) study is an ongoing prospective observational study at the Dana-Farber Cancer Institute and Massachusetts General Hospital that enrolls transplant-eligible fit patients aged 60-75 years with advanced MDS and follows them through RIC HCT vs non-HCT treatment. In this analysis of 127 patients enrolled from May 2011 to June 2014, we examined the influence of age, gender, cytogenetics, International Prognostic Scoring System (IPSS) category, performance status, distance from HCT center and baseline patient-reported quality of life (QOL) from the EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire) on the likelihood of receiving RIC HCT using competing risk regression modeling. With a median follow-up of 16 months, 44 patients (35%) had undergone RIC HCT. In multivariable analyses, age (hazard ratio (HR) 0.87 per year, 95% confidence interval (CI): 0.81-0.92, P<0.001) and higher IPSS (intermediate-2/high; HR 2.29, 95% CI: 1.25-4.19, P=0.007) were significantly predictive of receipt of RIC HCT; neither global QOL score nor any QOL subscales scores were predictive. These data suggest that baseline patient-reported QOL has little influence on the decision to undergo RIC HCT for older patients with advanced MDS.

  5. Radiolabeled anti-CD45 antibody with reduced-intensity conditioning and allogeneic transplantation for younger patients with advanced acute myeloid leukemia or myelodysplastic syndrome.

    PubMed

    Mawad, Raya; Gooley, Ted A; Rajendran, Joseph G; Fisher, Darrell R; Gopal, Ajay K; Shields, Andrew T; Sandmaier, Brenda M; Sorror, Mohamed L; Deeg, Hans Joachim; Storb, Rainer; Green, Damian J; Maloney, David G; Appelbaum, Frederick R; Press, Oliver W; Pagel, John M

    2014-09-01

    We treated patients under age 50 years with iodine-131 ((131)I)-anti-CD45 antibody combined with fludarabine and 2 Gy total body irradiation to create an improved hematopoietic cell transplantation (HCT) strategy for advanced acute myeloid leukemia or high-risk myelodysplastic syndrome patients. Fifteen patients received 332 to 1561 mCi of (131)I, delivering an average of 27 Gy to bone marrow, 84 Gy to spleen, and 21 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no dose-limiting toxicity was observed. Marrow doses were arbitrarily capped at 43 Gy to avoid radiation-induced stromal damage; however, no graft failure or evidence of stromal damage was observed. Twelve patients (80%) developed grade II graft-versus-host disease (GVHD), 1 patient developed grade III GVHD, and no patients developed grade IV GVHD during the first 100 days after HCT. Of the 12 patients with chronic GVHD data, 10 developed chronic GVHD, generally involving the skin and mouth. Six patients (40%) are surviving after a median of 5.0 years (range, 4.2 to 8.3 years). The estimated survival at 1 year was 73% among the 15 treated patients. Eight patients relapsed, 7 of whom subsequently died. The median time to relapse among these 8 patients was 54 days (range, 26 to 1364 days). No cases of nonrelapse mortality were observed in the first year after transplantation. However, 2 patients died in remission from complications of chronic GVHD and cardiomyopathy, at 18 months and 14 months after transplantation, respectively. This study suggests that patients may tolerate myeloablative doses >28 Gy delivered to the liver using (131)I-anti-CD45 antibody in addition to standard reduced-intensity conditioning. Moreover, the arbitrary limit of 43 Gy to the marrow may be unnecessarily conservative, and continued escalation of targeted radioimmunotherapy doses may be feasible to further reduce relapse.

  6. Outcome of Allogeneic Stem Cell Transplantation Following Reduced-Intensity Conditioninig Regimen in Patients With Idiopathic Myelofibrosis: the G.I.T.M.O. Experience

    PubMed Central

    Patriarca, Francesca; Bacigalupo, Andrea; Sperotto, Alessandra; Isola, Miriam; Bruno, Barbara; van Lint, Maria Teresa; Iori, Anna Paola; Di Bartolomeo, Paolo; Musso, Maurizio; Pioltelli, Pietro; Visani, Giuseppe; Iacopino, Pasquale; Fanin, Renato; Bosi., Alberto

    2010-01-01

    Background: Allogeneic stem cell transplantation (SCT) is a potentially curative treatment for myelofibrosis (MI), though limited by a high rate of transplant-related mortality (TRM). In the present study we evaluate the outcome of MI patients undergoing an allogenic SCT after reduced intensity conditioning (RIC) regimens, and the impact of prognostic factors. Design and methods: Fifty two patients were transplanted in 26 Italian centres between 1998 and 2006. We analyzed the influence of patient and disease clinical features before SCT and of transplant procedures on TRM and overall survival (OS) by means of univariate and multivariate analyses. Results: At SCT, median age was 52,5 years (32–68) and 89% of the patients had an intermediate or high Dupriez score. Conditioning regimens were based on fludarabine plus busulphan in 27% of patients, thiotepa plus cyclophosphamide in 46% and miscellaneous drug combinations in the other 27% of cases. Stem cells came from matched sibling donors for 75% of the patients and mismatched sibling or unrelated donors for the remaining 25%. The cumulative incidence of engraftment at day 90 after transplant was 83% (95% CI, 0.87–0.97). The estimated 1-year TRM was 30%. The estimated 3-year event-free-survival (EFS) and OS after hematopoietic SCT was 44% and 38% respectively. In multivariate analysis, an higher leukocyte count and circulating blasts in the peripheral blood before SCT significantly reduced EFS and OS respectively. Interpretation and conclusions: We conclude that the extension of the disease before transplantation based on the presence of circulating blasts and high leukocyte counts significantly affected the outcome after HSCT PMID:21415963

  7. The costs and cost-effectiveness of allogeneic peripheral blood stem cell transplantation versus bone marrow transplantation in pediatric patients with acute leukemia.

    PubMed

    Lin, Yu-Feng; Lairson, David R; Chan, Wenyaw; Du, Xianglin L; Leung, Kathryn S; Kennedy-Nasser, Alana A; Martinez, Caridad A; Gottschalk, Stephen M; Bollard, Catherine M; Heslop, Helen E; Brenner, Malcolm K; Krance, Robert A

    2010-09-01

    In a retrospective study, we evaluated the cost and cost-effectiveness of allogeneic peripheral blood stem cell transplantation (PBSCT) (n = 30) compared with bone marrow transplantation (BMT) (n = 110) in children with acute leukemia after 1 year of follow-up. Treatment success was defined as disease-free survival at 1 year posttransplantation. For patients at standard risk for disease, the treatment success rate was 57.1% for PBSCT recipients and 80.3% for BMT recipients (P = not significant [NS]). The average total cost per treatment success at 1 year in the standard-risk disease group was $512,294 for PBSCT recipients and $352,885 for BMT recipients (P = NS). For patients with high-risk disease, the treatment success rate was 18.8% for PBSCT recipients and 23.5% for BMT recipients (P = NS). The cumulative average cost was $457,078 in BMT recipients and $377,316 in PBSCT recipients (P = NS). Point estimates of the incremental cost-effectiveness ratio (ICER) indicate that in patients with standard-risk disease, allogeneic BMT had lower costs and greater effectiveness than PBSCT (ICER, -$687,108; 95% confidence interval [CI], $2.4 million to dominated). For patients with high-risk disease, BMT was more effective and more costly, and it had an ICER of $1.69 million (95% CI, $29.7 million to dominated) per additional treatment success. The comparative economic evaluation provides support for BMT in standard-risk patients, but much uncertainty precludes a clear advantage of either treatment option in patients with high-risk disease. More studies using larger and randomized controlled trials are needed to confirm the long-term cost-effectiveness of each procedure.

  8. Cyclophosphamide followed by intravenous targeted busulfan for allogeneic hematopoietic cell transplantation: pharmacokinetics and clinical outcomes

    PubMed Central

    Rezvani, Andrew R.; McCune, Jeannine S.; Storer, Barry E.; Batchelder, Ami; Kida, Aiko; Deeg, H. Joachim; McDonald, George B.

    2013-01-01

    Targeted busulfan/cyclophosphamide (TBU/CY) for allogeneic hematopoietic cell transplantation (HCT) carries a high risk of sinusoidal obstruction syndrome (SOS) in patients transplanted for myelofibrosis. We tested the hypothesis that reversing the sequence of administration (from TBU/CY to CY/TBU) will reduce SOS and day +100 non-relapse mortality (NRM). We enrolled 51 patients with myelofibrosis (n=20), acute myeloid leukemia (AML, n=20), or myelodysplastic syndrome (MDS, n=11) in a prospective trial of CY/TBU conditioning for HCT. Cyclophosphamide 60 mg/kg/day IV for two days was followed by daily IV BU for four days, targeted to a concentration at steady state (Css) of 800–900 ng/mL. CY/TBU-conditioned patients had higher exposure to CY (p<0.0001) and lower exposure to 4-hydroxyCY (p<0.0001) compared to TBU/CY-conditioned patients. Clinical outcomes were compared with controls (n=271) conditioned with TBU/CY for the same indications. In patients with myelofibrosis, CY/TBU conditioning was associated with a significantly reduced incidence of SOS (0% vs. 30% after TBU/CY, p=0.006), while SOS incidence was low in both cohorts with AML/MDS. Day +100 mortality was significantly lower in the CY/TBU cohort (2% vs. 13%, p=0.01). CY/TBU conditioning markedly impacted CY pharmacokinetics and was associated with significantly lower incidences of SOS and day +100 mortality, suggesting that CY/TBU is superior to TBU/CY as conditioning for patients with myelofibrosis. PMID:23583825

  9. Veno-occlusive disease (VOD) of the liver in Korean patients following allogeneic bone marrow transplantation (BMT): efficacy of recombinant human tissue plasminogen activator (rt-PA) treatment.

    PubMed

    Lee, J H; Lee, K H; Choi, J S; Zang, D Y; Kim, S B; Kim, S W; Suh, C; Lee, J S; Kim, W K; Lee, Y S; Kim, S H

    1996-04-01

    Veno-occlusive disease (VOD) of the liver is a clinical syndrome characterized by hyperbilirubinemia, painful hepatomegaly, and fluid retention. In the bone marrow transplantation (BMT) setting, VOD is caused by dose-intensive chemotherapy and/or radiotherapy used to prepare patients for transplant. VOD occurs in up to 50% of the patients who undergo BMT and is usually associated with a high mortality rate. Until recently, there was no proven effective medical therapy for this condition once it was clinically apparent. We report here on the frequency and treatment result of VOD with rt-PA in our allogeneic BMT patients. Eight patients (median age 28.5 years) underwent allogeneic BMT from December, 1993 to June, 1995 in Asan Medical Center. Six leukemia patients were prepared for BMT with busulfan and cyclophosphmide, while two aplastic anemia patients received cyclophosphamide and antithymocyte globulin. VOD was defined as having two of the following features before day 20 posttransplant: jaundice (bilirubin > or = 2 mg/dL), tender hepatomegaly and/or right upper quadrant pain, ascites and/or unexplained weight gain (> 2% from baseline). All patients who were diagnosed with VOD received rt-PA (10-20 mg/day) and heparin (10,000 U/day). Three (37.5%) of the eight patients developed VOD that occurred between 6 and 10 days posttransplant. All three patients developed jaundice, weight gain, and tender hepatomegaly. Ascites and renal insufficiency occurred in two patients and pleural effusion in one patient. rt-PA and heparin were begun 6 to 26 days posttransplant and rt-PA was administered for 7 to 14 days. All three patients responded to the therapy; bilirubin levels began to decrease at 4 to 13 days from the start of therapy. They are all alive at day 111, 316, and 548 days posttransplant. None of the patients had significant hemorrhagic complications after rt-PA treatment. Prolonged administration of rt-PA was feasible without bleeding episode and it seems that rt

  10. Immunosuppressive Total Lymphoid Irradiation-Based Reconditioning Regimens Enable Engraftment After Graft Rejection or Graft Failure in Patients Treated With Allogeneic Hematopoietic Stem Cell Transplantation

    SciTech Connect

    Heinzelmann, Frank; Lang, Peter J.; Ottinger, Hellmut; Faul, Christoph; Bethge, Wolfgang; Handgretinger, Rupert; Bamberg, Michael; Belka, Claus

    2008-02-01

    Purpose: To retrospectively evaluate the efficacy of total lymphoid irradiation (TLI)-based reconditioning regimens in patients with graft failure or graft rejection after allogeneic hematopoietic stem cell transplantation. Methods and Materials: The results of 14 patients (7 adults and 7 children) with a variety of hematologic malignant diseases treated with a TLI-based reconditioning regimen with 7-Gy single-dose application plus anti-T-lymphocyte antibody OKT3 (n = 11) and/or antithymocyte globulin (n = 7)/fludarabine (n = 9), followed by an infusion of peripheral blood stem cells (n = 13) or bone marrow stem cells (n = 1) from related or unrelated donors, were retrospectively analyzed. Results: Of the 14 recipients, the data from 11 were evaluable for engraftment after TLI-based reconditioning because 3 adults died early (at Day 2, 5, and 15) after the second transplantation of infectious complications. Engraftment in 4 adults was seen after a median of 12 days (range, 10-18) and occurred after a median of 10 days (range, 9-32) in the 7 children. TLI-based reconditioning was well-tolerated with no severe toxicity. The median overall survival and disease-free survival for the whole cohort was 140 days (range, 5-1,268). After a median follow-up of 681 days, the disease-free survival and overall survival rate was 85.7% and 85.7%, respectively, in the children. Despite engraftment in the 4 remaining adults, 1 died of fatal graft-vs.-host disease, 1 of infectious complications, 1 of disease relapse, and 1 of acute respiratory distress syndrome. Conclusions: In patients with graft failure or graft rejection after allogeneic hematopoietic stem cell transplantation, TLI-based reconditioning regimens allow sustained engraftment, paralleled by a favorable toxicity profile, potentially leading to long-term survival.

  11. Benefit of allogeneic transplantation in patients age ≥ 60 years with acute myeloid leukemia is limited to those in first complete remission at time of transplant.

    PubMed

    Michelis, Fotios V; Messner, Hans A; Atenafu, Eshetu G; Kim, Dennis D; Kuruvilla, John; Lipton, Jeffrey H; Uhm, Jieun; Loach, David; Gupta, Vikas

    2014-04-01

    We evaluated the impact of age and remission status on 242 consecutive patients who underwent allogeneic hematopoietic cell transplantation for acute myeloid leukemia (AML) in our program between 1999 and 2011. Median age of all patients was 48 years (range, 18 to 71). Based on age and remission status, patients were divided into 4 groups: first complete remission (CR1) age <60 years (n = 116), second complete remission (CR2) age <60 years (n = 78), CR1 age ≥60 years (n = 32), and CR2 age ≥60 years (n = 16). Donors were matched related (n = 155, 64%) or matched unrelated (n = 87, 36%). Median follow-up of survivors was 65 months (range, 12 to 145). In a univariate analysis, 3-year overall survival rates of the 4 groups were 57%, 43%, 39%, and 16% (P = .003), respectively. In a multivariable analysis, hazard ratios of nonrelapse mortality and survival were 2.08 (P = .06) and 1.52 (P = .23), respectively, in patients ≥60 years in CR2 compared with ≥ 60 years in CR1. Although a plateau in survival was observed for patients ≥60 years in CR1 similar to those <60 years in CR1 and CR2, no long-term survivors were seen in patients ≥60 years in CR2. Our data suggest disappointing outcomes in AML patients ≥60 years of age transplanted in CR2. Therefore, if a transplant is indicated, early referral is recommended in patients ≥60 years with AML.

  12. Current Status of Allogeneic Hematopoietic Cell Transplantation for MDS

    PubMed Central

    Xu, Feng; Deeg, H. Joachim

    2011-01-01

    Hematopoietic cell transplantation (HCT) offers potentially curative therapy for patients with myelodysplastic syndromes (MDS). However, as most patients with MDS are in the 7th or 8th decade of life, only few of these were transplanted in the past, using high-dose conditioning regimens. The development of reduced-intensity conditioning has allowed to offer HCT also to older patients and those with clinically relevant comorbid conditions. Dependent upon disease status and the type of clonal chromosomal abnormalities present at the time of HCT, some 25%–75% of patients will be cured of their disease and survive long-term. Recent results with HLA matched unrelated donors are comparable to those with HLA genotypically identical siblings. The increasing use of cord blood and HLA haploidentical donors is expected to make HCT available to a growing number of patients. However, post-transplant relapse and graft-versus-host disease remain problems requiring further investigation. PMID:22571701

  13. Cost minimization analysis of preoperative erythropoietin vs autologous and allogeneic blood donation in total joint arthroplasty.

    PubMed

    Green, William Scott; Toy, Pearl; Bozic, Kevin J

    2010-01-01

    Autologous blood donation and erythropoietin (EPO) have been shown to be effective in reducing allogeneic blood transfusion, but the cost-effectiveness of these interventions remains unclear. A cost minimization analysis was performed, comparing the total costs of allogeneic blood transfusion strategy and autologous and allogeneic blood transfusion strategy for 161 primary total hip arthroplasty (THA) and 195 total knee arthroplasty (TKA) patients. An EPO cost minimization model was constructed using a previously published algorithm for blood management after total joint arthroplasty. The least costly strategy was autologous blood donation in combination with allogeneic blood for THA and TKA patients at $856 and $892 per patient, respectively. The most costly strategy was allogeneic only at $1769 and $1352 per THA and TKA patient, respectively. The EPO strategy model predicted costs similar to the autologous and allogeneic. A strategy that combines autologous blood donation with EPO for patients who cannot donate autologous blood may provide the greatest cost savings and minimize allogeneic blood transfusion.

  14. Treatment with Hypomethylating Agents before Allogeneic Stem Cell Transplant Improves Progression-Free Survival for Patients with Chronic Myelomonocytic Leukemia.

    PubMed

    Kongtim, Piyanuch; Popat, Uday; Jimenez, Antonio; Gaballa, Sameh; El Fakih, Riad; Rondon, Gabriela; Chen, Julianne; Bueso-Ramos, Carlos; Borthakur, Gautam; Pemmaraju, Naveen; Garcia-Manero, Guillermo; Kantarjian, Hagop; Alousi, Amin; Hosing, Chitra; Anderlini, Paolo; Khouri, Issa F; Kebriaei, Partow; Andersson, Borje S; Oran, Betul; Rezvani, Katayoun; Marin, David; Shpall, Elizabeth J; Champlin, Richard E; Ciurea, Stefan O

    2016-01-01

    The treatment of patients with chronic myelomonocytic leukemia (CMML) with transplant has not been optimized. We retrospectively reviewed the data for 83 consecutive patients with CMML (47 with CMML-1/2 and 36 with CMML progressed to acute myeloid leukemia) who received an allogeneic stem cell transplant (allo-SCT) at our institution between April 1991 and December 2013 to identify factors associated with improved survival and determine whether treatment with hypomethylating agents before transplant improves progression-free survival (PFS). The median age of the cohort was 57 years. Seventy-eight patients received induction treatment before transplant, with 37 receiving hypomethylating agents and 41 receiving cytotoxic chemotherapy. Patients treated with a hypomethylating agent had a significantly lower cumulative incidence of relapse at 3 years post-transplant (22%) than those treated with other agents (35%; P = .03), whereas treatment-related mortality at 1 year post-transplant did not significantly differ between the groups (27% and 30%, respectively; P = .84). The lower relapse rate resulted in a significantly higher 3-year PFS rate in patients treated with a hypomethylating agent (43%) than in those treated with other agents (27%; P = .04). Our data support the use of hypomethylating agents before allo-SCT for patients with CMML to achieve morphologic remission and improve PFS of these patients. Future studies are needed to confirm these findings.

  15. ABO mismatch is associated with increased non-relapse mortality after allogeneic hematopoietic cell transplantation

    PubMed Central

    Logan, Aaron C.; Wang, Zhiyu; Alimoghaddam, Kamran; Wong, Ruby M.; Lai, Tze; Negrin, Robert S.; Grumet, Carl; Logan, Brent R.; Zhang, Mei-Jie; Spellman, Stephen R.; Lee, Stephanie J.; Miklos, David B.

    2015-01-01

    We evaluated ABO associated outcomes in 1,737 patients who underwent allogeneic hematopoietic cell transplant (allo-HCT) at Stanford University between January 1986 and July 2011. Grafts were 61% ABO matched, 18% major mismatched (MM), 17% minor MM, and 4% bidirectional MM. Median follow-up was 6 years. In multivariate analysis, OS was inferior in minor MM HCT (median 2.1 vs 6.3 years; HR 1.56; 95%CI 1.19-2.05; p=0.001) in comparison with ABO matched grafts. ABO minor MM was associated with an increase in early NRM (18% vs 13%; HR 1.48, 95%CI 1.06-2.06; p=0.02). In an independent Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 435 lymphoma patients receiving mobilized peripheral blood grafts, impairment of OS (HR 1.55; 95%CI 1.07 – 2.25; p=0.021) and increased NRM (HR 1.72; 95%CI 1.11 – 2.68; p=0.03) was observed in recipients of ABO minor MM grafts. A second independent analysis of a CIBMTR dataset including 5,179 patients with AML and MDS identified a non-significant trend toward decreased OS in recipients of ABO minor MM grafts and also found ABO major MM to be significantly associated with decreased OS (HR 1.19, 95% CI 1.08 – 1.31, p<0.001) and increased NRM (HR 1.23, 95%CI 1.08 – 1.4, p=0.002). ABO minor and major MM are risk factors for worse transplant outcomes, although the associated hazards may not be uniform across different transplant populations. Further study is warranted to determine which patient populations are at greatest risk, and whether this risk can be modified by anti-B-cell therapy or other peri-transplant treatments. PMID:25572032

  16. Personalized Home-based Interval Exercise Training May Improve Cardiorespiratory Fitness in Cancer Patients Preparing to Undergo Hematopoietic Cell Transplantation

    PubMed Central

    Wood, William A; Phillips, Brett; Smith-Ryan, Abbie E; Wilson, Doug; Deal, Allison M; Bailey, Charlotte; Meeneghan, Mathew; Reeve, Bryce B; Basch, Ethan M; Bennett, Antonia V; Shea, Thomas C; Battaglini, Claudio L

    2016-01-01

    Impaired cardiorespiratory fitness is associated with inferior survival in patients preparing to undergo hematopoietic cell transplantation (HCT). Exercise training based on short, higher-intensity intervals has the potential to efficiently improve cardiorespiratory fitness. We studied home-based interval exercise training (IET) in 40 patients prior to autologous (N=20) or allogeneic (N=20) HCT. Each session consisted of 5, three-minute intervals of walking, jogging, or cycling at 65-95% maximal heart rate (MHR) with 3 minutes of low intensity exercise (<65% MHR) between intervals. Participants were asked to perform sessions at least 3 times weekly. The duration of the intervention was at least 6 weeks, depending on each patient’s scheduled transplantation date. Cardiorespiratory fitness was assessed from a peak oxygen consumption test (VO2peak) and a 6 minute walk (6MWD) before and after the intervention period. For the autologous HCT cohort, improvements in VO2peak (p=0.12) and 6MWD (p=0.19) were not statistically significant. For the allogeneic cohort, the median VO2peak improvement was 3.7ml/kg*min (p=0.005) and the median 6MWD improvement was 34 meters (p=0.006). Home-based, interval exercise training can be performed prior to HCT and has the potential to improve cardiorespiratory fitness. PMID:26999467

  17. Fludarabine and busulfan as a reduced-toxicity myeloablative conditioning regimen in allogeneic hematopoietic stem cell transplantation for acute leukemia patients

    PubMed Central

    DAI, ZHIMING; LIU, JIE; ZHANG, WANG-GANG; CAO, XINGMEI; ZHANG, YANG; DAI, ZHIJUN

    2016-01-01

    The optimal conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute leukemia remains undefined. We evaluated the outcomes in 30 patients with acute leukemia who underwent allo-HSCT from human leukocyte antigen-matched donors after conditioning with busulfan and fludarabine (BuFlu). The regimen comprised injection of busulfan 3.2 mg/kg daily on 4 consecutive days and fludarabine 30 mg/m2 daily for 4 doses. All 30 patients achieved hematopoiesis reconstitution with full donor chimerism confirmed by short tandem repeat DNA analysis. The most common regimen-related toxicity was mucositis (86.7%), followed by cytomegalovirus infection (80%). Serious regimen-related toxicities were rare. Acute graft vs. host disease (aGVHD) was detected in 46.7% of the patients; 33.4% had grade I–II aGVHD and 13.3% had grade III–IV aGVHD. Chronic GVHD (cGVHD) was noted in 20% of the patients. The overall survival and disease-free survival rates were 66.7 and 53%, respectively, with a median follow-up of 25 months for surviving patients. Therefore, BuFlu was an effective conditioning regimen with a low rate of transplant-related adverse effects and increased antileukemic effects in patients with acute leukemia undergoing allo-HSCT. PMID:27073687

  18. Myeloablative allogeneic hematopoietic stem cell transplantation in patients who experience relapse after autologous stem cell transplantation for lymphoma: a report of the International Bone Marrow Transplant Registry.

    PubMed

    Freytes, César O; Loberiza, Fausto R; Rizzo, J Douglas; Bashey, Asad; Bredeson, Christopher N; Cairo, Mitchell S; Gale, Robert Peter; Horowitz, Mary M; Klumpp, Thomas R; Martino, Rodrigo; McCarthy, Philip L; Molina, Arturo; Pavlovsky, Santiago; Pecora, Andrew L; Serna, Derek S; Tsai, Tsuong; Zhang, Mei-Jie; Vose, Julie M; Lazarus, Hillard M; van Besien, Koen

    2004-12-01

    Myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasingly used in patients with lymphoma who experience disease relapse after autologous hematopoietic stem cell transplantation (auto-HSCT) because the allograft is tumor free and may induce a graft-versus-tumor effect. We analyzed 114 patients treated with this approach from 1990 to 1999 to assess disease progression, progression-free survival (PFS), and overall survival (OS). Cumulative incidence of disease progression at 3 years was 52%, whereas treatment-related mortality was 22%, lower than previously reported. Three-year probabilities of OS and PFS were 33% and 25%, respectively. With prolonged follow-up, however, nearly all patients experienced disease progression, and 5-year probabilities were 24% and 5%, respectively. Complete remission at the time of allo-HSCT and use of total body irradiation (TBI) in patients with non-Hodgkin lymphoma (NHL) were associated with lower rates of disease progression and higher rates of OS. In summary, allo-HSCT is feasible for patients with lymphoma who have relapses after auto-HSCT and can result in prolonged survival for some, but it is usually not curative. Most likely to benefit are patients who have HLA-matched sibling donors, are in remission, and have good performance status.

  19. Value of surveillance blood culture for early diagnosis of occult bacteremia in patients on corticosteroid therapy following allogeneic hematopoietic stem cell transplantation.

    PubMed

    Chizuka, A; Kami, M; Kanda, Y; Murashige, N; Kishi, Y; Hamaki, T; Kim, S-W; Hori, A; Kojima, R; Mori, S-I; Tanosaki, R; Gomi, H; Takaue, Y

    2005-03-01

    Bloodstream infection (BSI) is a significant complication following allogeneic hematopoietic stem cell transplantation (allo-SCT). Corticosteroids mask inflammatory responses, delaying the initiation of antibiotics. We reviewed medical records of 69 allo-SCT patients who had been on >0.5 mg/kg prednisolone to investigate the efficacy of weekly surveillance blood cultures. A total of 36 patients (52%) had positive cultures, 25 definitive BSI and 11 probable BSI. Pathogens in definitive BSI were Staphylococcus epidermidis (n=7), S. aureus (n=4), Entrococcus faecalis (n=3), Pseudomonas aeruginosa (n=5), Acenitobacter lwoffii (n=4), and others (n=10). The median interval from the initiation of corticosteroids to the first positive cultures was 24 days (range, 1-70). At the first positive cultures, 15 patients with definitive BSI were afebrile. Four of them remained afebrile throughout the period of positive surveillance cultures. Patients with afebrile BSI tended to be older (P=0.063), and had in-dwelling central venous catheters less frequently than febrile patients (P<0.0001). Bloodstream pathogens were directly responsible for death in two patients with afebrile BSI. This study demonstrates that cortisosteroid frequently masks inflammatory reactions in allo-SCT recipients given conrticosteroids, and that surveillance blood culture is only diagnostic clue for 'occult' BSI.

  20. Low CD34 dose is associated with poor survival after reduced-intensity conditioning allogeneic transplantation for acute myeloid leukemia and myelodysplastic syndrome.

    PubMed

    Törlén, Johan; Ringdén, Olle; Le Rademacher, Jennifer; Batiwalla, Minoo; Chen, Junfang; Erkers, Tom; Ho, Vincent; Kebriaei, Partow; Keever-Taylor, Carolyn; Kindwall-Keller, Tamila; Lazarus, Hillard M; Laughlin, Mary J; Lill, Michael; O'Brien, Tracey; Perales, Miguel-Angel; Rocha, Vanderson; Savani, Bipin N; Szwajcer, David; Valcarcel, David; Eapen, Mary

    2014-09-01

    Reduced-intensity conditioning/nonmyeloablative conditioning regimens are increasingly used in allogeneic hematopoietic cell transplantation (HCT). Reports have shown CD34(+) dose to be important for transplantation outcome using myeloablative conditioning. The role of CD34(+) dose of peripheral blood progenitor cells (PBPC) has not been previously analyzed in a large population undergoing reduced-intensity conditioning/nonmyeloablative HCT. We studied 1054 patients, ages 45 to 75 years, with acute myeloid leukemia or myelodysplastic syndrome who underwent transplantation between 2002 and 2011. Results of multivariate analysis showed that PBPC from HLA-matched siblings containing <4 × 10(6) CD34(+)/kg was associated with higher nonrelapse mortality (hazard ratio [HR], 2.03; P = .001), overall mortality (HR, 1.48; P = .008), and lower neutrophil (odds ratio [OR], .76; P = .03) and platelet (OR, .76; P = .03) recovery. PBPC from unrelated donors with CD34(+) dose < 6 × 10(6) CD34(+)/kg was also associated with higher nonrelapse (HR, 1.38; P = .02) and overall mortality (HR, 1.20; P = .05). In contrast to reports after myeloablative HCT, CD34(+) dose did not affect relapse or graft-versus-host disease with either donor type. An upper cell dose limit was not associated with adverse outcomes. These data suggest that PBPC CD34(+) doses >4 × 10(6) CD34(+)/kg and >6 × 10(6) CD34(+)/kg are optimal for HLA-matched sibling and unrelated donor HCT, respectively.

  1. Vascular and perivascular niches, but not the osteoblastic niche, are numerically restored following allogeneic hematopoietic stem cell transplantation in patients with aplastic anemia.

    PubMed

    Wu, Liangliang; Mo, Wenjian; Zhang, Yuping; Zhou, Ming; Li, Yumiao; Zhou, Ruiqing; Xu, Shiling; Pan, Shiyi; Deng, Hui; Mao, Ping; Wang, Shunqing

    2017-03-16

    Bone marrow (BM) niches, including the osteoblastic, vascular, and perivascular niches, are numerically impaired in patients with aplastic anemia (AA). It remains unclear whether these niches are numerically restored in AA patients after allogenic hematopoietic stem cell transplantation (allo-HSCT). To investigate changes in BM niches, we monitored 52 patients with AA who had undergone allo-HSCT and performed immunohistochemical studies of BM niches using antibodies against CD34, CD146, and osteopontin. After allo-HSCT, patients with AA exhibited a remarkable increase in the number of cellular elements in the BM niches, including the vascular and perivascular cells. However, no significant differences in endosteal cells were detected. We explored the cause of this restoration by analyzing the origin of BM mesenchymal stem cells (BM-MSCs) and the expression of cytokines in BM plasma. STR-PCR revealed that the BM-MSCs were derived from the host, not the donor. In addition, significantly elevated levels of vascular endothelial growth factor (VEGF) were found after allo-HSCT. Our data indicates that vascular and perivascular niches are numerically restored, but the endosteal niche remains numerically impaired in patients with AA after allo-HSCT, and that levels of VEGF, but not donor-derived BM-MSCs, may correlate with the restoration of BM niches.

  2. Decision analysis of allogeneic hematopoietic stem cell transplantation for patients with myelodysplastic syndrome stratified according to the revised international prognostic scoring system (IPSS-R).

    PubMed

    Della Porta, M G; Jackson, C H; Alessandrino, E P; Rossi, M; Bacigalupo, A; van Lint, M T; Bernardi, M; Allione, B; Bosi, A; Guidi, S; Santini, V; Malcovati, L; Ubezio, M; Milanesi, C; Todisco, E; Voso, M T; Musto, P; Onida, F; Iori, A P; Cerretti, R; Grillo, G; Molteni, A; Pioltelli, P; Borin, L; Angelucci, E; Oldani, E; Sica, S; Pascutto, C; Ferretti, V; Santoro, A; Bonifazi, F; Cazzola, M; Rambaldi, A

    2017-03-21

    Allogeneic hematopoietic stem cell transplantation (allo-SCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Crucial questions in clinical decision making include the definition of optimal timing of the procedure and the benefit of cytoreduction before transplant in high risk patients. We carried out a decision analysis on 1728 MDS who received supportive care, transplantation or hypomethylating agents (HMAs). Risk assessment was based on the revised International Prognostic Scoring System (IPSS-R). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of different treatment policies on survival. Life expectancy increased when transplantation was delayed from the initial stages to intermediate IPSS-R risk (gain of life expectancy 5.3, 4.7 and 2.8 years for patients aged ⩽55, 60 and 65 years, respectively), and then decreased for higher risks. Modelling decision analysis on IPSS-R vs original IPSS changed transplantation policy in 29% of patients, resulting in a 2-year gain in life expectancy. In advanced stages, HMAs given before transplant is associated with a 2-year gain of life expectancy, especially in older patients. These results provide a preliminary evidence to maximize the effectiveness of allo-SCT in MDS.Leukemia accepted article preview online, 21 March 2017. doi:10.1038/leu.2017.88.

  3. Assessment of CD4 T-lymphocyte reactivity by the Cylex ImmuKnow assay in patients following allogeneic hematopoietic SCT.

    PubMed

    Gesundheit, B; Budowski, E; Israeli, M; Shapira, M Y; Resnick, I B; Bringer, R; Azar, Y; Samuel, S; Dray, L; Amar, A; Kristt, D; Or, R

    2010-03-01

    After allogeneic hematopoietic SCT (alloHSCT), immunosuppressed patients are susceptible to opportunistic infections, and uncontrolled function of the graft can result in GVHD. Accurate immune monitoring may help early detection and treatment of these severe complications. Between October 2005 and November 2007, a total of 170 blood samples were collected from 40 patients after alloHSCT in the Hadassah Hebrew University Medical Center and from 13 healthy controls. We utilized the Cylex ImmuKnow assay for CD4 ATP levels to compare known clinically immunocompromised vs immunocompetent patients after alloHSCT. We also compared the reconstitution of WBC count to the ImmuKnow results and clinical status. The patients' clinical course correlated with the stratification of immune response established by the ImmuKnow assay for solid organ transplantation (immunocompetent vs immunocompromised), and this often differed from their WBC count. On the basis of our observations, we conclude that the ImmuKnow assay is a simple and fast immune-monitoring technique for patients undergoing alloHSCT, with potential to predict clinical course and facilitate prompt management of post-HSCT complications. The assay should be evaluated prospectively in clinical trials.

  4. Minimal Residual Disease as a Predictive Factor for Relapse after Allogeneic Hematopoietic Stem Cell Transplant in Adult Patients with Acute Myeloid Leukemia in First and Second Complete Remission

    PubMed Central

    Grubovikj, Rada M.; Alavi, Asif; Koppel, Ahrin; Territo, Mary; Schiller, Gary J.

    2012-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for patients with high-risk leukemia, but disease recurrence remains the leading cause of treatment failure. Our objective was to determine the impact of minimal residual disease (MRD) by any technique in adult patients with acute myeloid leukemia (AML) in morphologic first and second complete remission undergoing allo-SCT. Fifty nine patients were eligible for the study of 160 patients transplanted over ten years. For the MRD assessment we used multiparametric flow cytometry, cytogenetics and fluorescent in situ hybridization; 19 patients (32.2%) were identified as MRD positive. Patients with MRD had a consistently worse outcome over those without MRD, with 3-years leukemia-free survival (LFS) of 15.8% vs. 62.4% and overall survival (OS) of 17.5% vs. 62.3%. Relapse rate was significantly higher in MRD-positive patients; 3 years relapse rate in MRD-positive patients was 57.9% vs. 15.1% in MRD-negative patients. Detection of MRD in complete remission was associated with increased overall mortality (HR = 3.3; 95% CI: 1.45–7.57; p = 0.0044) and relapse (HR = 5.26; 95% CI: 2.0–14.0; p = 0.001), even after controlling for other risk factors. Our study showed that for patients in morphologic complete remission the presence of MRD predicts for significantly increased risk of relapse and reduced LFS and OS. PMID:24213327

  5. The Activating NKG2C Receptor Is Significantly Reduced in NK Cells after Allogeneic Stem Cell Transplantation in Patients with Severe Graft-versus-Host Disease.

    PubMed

    Kordelas, Lambros; Steckel, Nina-Kristin; Horn, Peter A; Beelen, Dietrich W; Rebmann, Vera

    2016-10-27

    Natural killer (NK) cells play a central role in the innate immune system. In allogeneic stem cell transplantation (alloSCT), alloreactive NK cells derived by the graft are discussed to mediate the elimination of leukemic cells and dendritic cells in the patient and thereby to reduce the risk for leukemic relapses and graft-versus-host reactions. The alloreactivity of NK cells is determined by various receptors including the activating CD94/NKG2C and the inhibitory CD94/NKG2A receptors, which both recognize the non-classical human leukocyte antigen E (HLA-E). Here we analyze the contribution of these receptors to NK cell alloreactivity in 26 patients over the course of the first year after alloSCT due to acute myeloid leukemia, myelodysplastic syndrome and T cell Non-Hodgkin-Lymphoma. Our results show that NK cells expressing the activating CD94/NKG2C receptor are significantly reduced in patients after alloSCT with severe acute and chronic graft-versus-host disease (GvHD). Moreover, the ratio of CD94/NKG2C to CD94/NKG2A was reduced in patients with severe acute and chronic GvHD after receiving an HLA-mismatched graft. Collectively, these results provide evidence for the first time that CD94/NKG2C is involved in GvHD prevention.

  6. Autoimmune hemolytic anemia after allogeneic hematopoietic stem cell transplantation: analysis of 533 adult patients who underwent transplantation at King's College Hospital.

    PubMed

    Wang, Meng; Wang, Wenjia; Abeywardane, Ayesha; Adikarama, Malinthi; McLornan, Donal; Raj, Kavita; de Lavallade, Hugues; Devereux, Stephen; Mufti, Ghulam J; Pagliuca, Antonio; Potter, Victoria T; Mijovic, Aleksandar

    2015-01-01

    Autoimmune hemolytic anemia (AIHA) is a recognized complication of hematopoietic stem cell transplantation (HSCT); it is often refractory to treatment and carries a high mortality. To improve understanding of the incidence, risk factors, and clinical outcome of post-transplantation AIHA, we analyzed 533 patients who received allogeneic HSCT, and we identified 19 cases of AIHA after HSCT (overall incidence, 3.6%). The median time to onset, from HSCT to AIHA, was 202 days. AIHA was associated with HSCT from unrelated donors (hazard ratio [HR], 5.28; 95% confidence interval [CI], 1.22 to 22.9; P = .026). In the majority (14 of 19; 74%) of AIHA patients, multiple agents for treatment were required, with only 9 of 19 (47%) patients achieving complete resolution of AIHA. Patients with post-transplantation AIHA had a higher overall mortality (HR, 2.48; 95% CI, 1.33 to 4.63; P = .004), with 36% (4 of 11 cases) of deaths attributable to AIHA.

  7. [The role of pre-transplant debulking treatment in patients undergoing allogeneic stem cell transplantation for high-risk myelodysplastic syndrome].

    PubMed

    Gauthier, Jordan; Damaj, Gandhi; Yakoub-Agha, Ibrahim

    2015-04-01

    Treatment of myelodysplastic syndromes (MDS) remains unsatisfactory. Variable success in the correction of blood cytopenias, reduction of the proportion of marrow myeloblasts, and normalization of cytogenetics has been achieved with a variety of treatment strategies, including the use of immunosuppressive drugs, differentiating agents, conventional chemotherapy, and hypomethylating agents (HMAs) However, in general, responses have not been complete and have been of limited duration; prolongation of survival, if achieved, on average has been in the range of months. Currently, allogeneic hematopoietic stem-cell transplantation (allo-SCT) remains the only approach with curative potential for patients with higher risk/advanced MDS. Yet, despite the beneficial effects of allo-SCT, post-transplant relapse is a major cause of failure. Debulking prior to transplant treatment in patients with MDS is a matter of debate. The achievement of complete remission (CR) before allo-SCT improves post-transplantation outcome, although it is not clear whether this reflects the selection of patients with more responsive disease or is related to a reduction in disease burden. Higher CR rates in patients with MDS are obtained with induction chemotherapy (ICT) than with hypomethylating agents (HMAs), although HMAs may be active in patients with complex karyotypes in whom ICT almost invariably fails. Furthermore, HMAs have a good toxicity profile compared with ICT and may therefore be considered especially in older patients and in patients with comorbidities. However, all interventions aimed at reducing disease burden before allo-SCT expose patients to the risk of complications, which may prevent them from undergoing transplantation. Therefore, up-front allo-SCT is an option, particularly for patients with life-threatening cytopenias. In the absence of prospective randomized trials, the main therapeutic approaches are discussed in this review.

  8. Allogeneic Stem Cell Transplantation for Patients Age ≥ 70 Years with Myelodysplastic Syndrome: A Retrospective Study of the MDS Subcommittee of the Chronic Malignancies Working Party of the EBMT.

    PubMed

    Heidenreich, Silke; Ziagkos, Dimitris; de Wreede, Liesbeth C; van Biezen, Anja; Finke, Jürgen; Platzbecker, Uwe; Niederwieser, Dietger; Einsele, Hermann; Bethge, Wolfgang; Schleuning, Michael; Beelen, Dietrich W; Tischer, Johanna; Nagler, Arnon; Glass, Bertram; Maertens, Johan; Yáñez, Lucrecia; Beguin, Yves; Sill, Heinz; Scheid, Christof; Stelljes, Matthias; Ganser, Arnold; Zachée, Pierre; Selleslag, Dominik; de Witte, Theo; Robin, Marie; Kröger, Nicolaus

    2017-01-01

    In this retrospective analysis we evaluated the outcome of 313 patients aged ≥ 70 years in the registry of the European Group for Blood and Marrow Transplantation with myelodysplastic syndrome (MDS; n = 221) and secondary acute myeloid leukemia (n = 92) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from related (n = 79) or unrelated (n = 234) donors. Median age at HSCT was 72 years (range, 70 to 78). Conditioning regimen was nonmyeloablative (n = 54), reduced intensity (n = 207), or standard intensity (n = 52). Allogeneic HSCT for MDS patients ≥ 70 years was increasingly performed over time. Although during 2000 to 2004 only 16 patients received HSCT, during 2011 to 2013 the number of transplantations increased to 181. The cumulative incidence of nonrelapse mortality at 1 year and relapse at 3 years was 32% and 28%, respectively, with a 3-year overall survival rate of 34%. Good performance, determined by Karnofsky performance status, and recipients' seronegativity for cytomegalovirus was associated with 3-year estimated overall survival rates of 43% (P = .01) and 46% (P = .002), respectively. Conditioning intensity did not impact survival. After careful patient selection, allogeneic HSCT can be offered to patients older than 70 years with MDS.

  9. A Prospective Study of an Alemtuzumab Containing Reduced-intensity Allogeneic Stem Cell Transplantation Program in Patients with Poor-Risk and Advanced Lymphoid Malignancies

    PubMed Central

    Sauter, Craig S.; Chou, Joanne F.; Papadopoulos, Esperanza B.; Perales, Miguel-Angel; Jakubowski, Ann A.; Young, James W.; Scordo, Michael; Giralt, Sergio; Castro-Malaspina, Hugo

    2015-01-01

    Reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (allo-SCT) have used alemtuzumab to abrogate the risk of graft-versus-host disease (GVHD). Thirty-eight advanced lymphoma patients underwent a prospective phase II study of melphalan, fludarabine and alemtuzumab containing RIC allo-SCT from 20 matched related and 18 unrelated donors with cyclosporin-A as GVHD prophylaxis. The cumulative incidence of grade II-IV acute GVHD at 3 months was 10.5% and three evaluable patients experienced chronic GVHD. Progression-free (PFS) and overall (OS) survival at 5 years is 25% (95% CI: 13-40) and 44% (95% CI: 28-59%) respectively. Previous high-dose therapy and autologous stem cell transplantation (HDT-ASCT) and elevated LDH at the time of allo-SCT resulted in inferior OS. Within this cohort of high-risk lymphoma patients, alemtuzumab containing RIC resulted in a low risk of GVHD and a high incidence of POD, especially in those with poor-risk features defined by elevated LDH pre-allo-SCT and previous HDT-ASCT. PMID:24528216

  10. Comparison of total body irradiation plus cyclophosphamide with busulfan plus cyclophosphamide as conditioning regimens in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplant.

    PubMed

    Eroglu, Celalettin; Pala, Cigdem; Kaynar, Leylagül; Yaray, Kadir; Aksozen, M Tarkan; Bankir, Mehmet; Zararsız, Gökmen; Orhan, Okan; Gündog, Mete; Yıldız, Oguz G; Eser, Bülent; Cetin, Mustafa; Unal, Ali

    2013-11-01

    Conditioning regimens used during stem cell transplant provide prolonged control or cure of the disease in patients with acute lymphoblastic leukemia (ALL). In this study, we present a comparison of treatment results for 95 patients with ALL who underwent allogeneic hematopoietic stem cell transplant (AHSCT) with total body irradiation plus cyclophosphamide (TBI + Cy) or busulfan plus cyclophosphamide (Bu + Cy) as conditioning regimen. Median age was 25 (range: 9-54) years. Median follow-up was 24 (range: 3-107) months. Median overall survival (OS) was found to be 29 months. Median event-free survival (EFS) was 9 months. Median OS was 37 months in the TBI + Cy arm, while it was 12 months in the Bu + Cy arm, suggesting a significant advantage favoring the TBI + Cy arm (p = 0.003). Median EFS was 13 months in the TBI + Cy arm, while it was 4 months in the Bu + Cy arm, indicating a significant difference (p = 0.006). In univariate and multivariate analysis, it was found that high OS and EFS were significantly correlated with TBI + Cy conditioning regimen and lack of transplant-related mortality (p < 0.05). The TBI + Cy conditioning regimen was found to be superior to the Bu + Cy regimen in patients with ALL undergoing AHSCT regarding both OS and EFS.

  11. Cytoreductive treatment with clofarabine/ara-C combined with reduced-intensity conditioning and allogeneic stem cell transplantation in patients with high-risk, relapsed, or refractory acute myeloid leukemia and advanced myelodysplastic syndrome.

    PubMed

    Buchholz, Stefanie; Dammann, Elke; Stadler, Michael; Krauter, Juergen; Beutel, Gernot; Trummer, Arne; Eder, Matthias; Ganser, Arnold

    2012-01-01

    The combination of cytoreductive chemotherapy with reduced-intensity conditioning (RIC) is a highly effective antileukemic therapy. Purpose of this retrospective analysis was to evaluate the antileukemic efficacy and toxicity of clofarabine-based chemotherapy followed by RIC and allogeneic stem cell transplantation (SCT) for high-risk, relapsed, or refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). From May 2007 until October 2009, a total of 27 patients underwent allogeneic SCT after treatment with clofarabine and ara-C for 5d and RIC (4Gy TBI/cyclophosphamide/ATG). Prophylaxis of graft-versus-host disease (GvHD) consisted of cyclosporine and mycophenolate mofetil. Unmanipulated G-CSF mobilized PBSC (n=26) or bone marrow cells (n=1) were transplanted from unrelated (n=21) or matched related (n=6) donors. Non-hematological toxicities of this regimen mainly affected liver and skin and were all reversible. Seven patients relapsed within a median time of 5.7 months. The overall survival (OS) and relapse-free survival rates were 56% and 52% at 2 yr, respectively. In this cohort of patients, cytoreduction with clofarabine/ara-C (ClAraC) followed by RIC allogeneic SCT was well tolerated and showed good antileukemic efficacy even in patients with high-risk AML or MDS, with engraftment and GvHD-incidence comparable to other RIC regimens.

  12. Fourth European Conference on Infections in Leukaemia (ECIL-4): guidelines for diagnosis, prevention, and treatment of invasive fungal diseases in paediatric patients with cancer or allogeneic haemopoietic stem-cell transplantation.

    PubMed

    Groll, Andreas H; Castagnola, Elio; Cesaro, Simone; Dalle, Jean-Hugues; Engelhard, Dan; Hope, William; Roilides, Emmanuel; Styczynski, Jan; Warris, Adilia; Lehrnbecher, Thomas

    2014-07-01

    Invasive opportunistic fungal diseases (IFDs) are important causes of morbidity and mortality in paediatric patients with cancer and those who have had an allogeneic haemopoietic stem-cell transplantation (HSCT). Apart from differences in underlying disorders and comorbidities relative to those of adults, IFDs in infants, children, and adolescents are unique with respect to their epidemiology, the usefulness of diagnostic methods, the pharmacology and dosing of antifungal agents, and the absence of interventional phase 3 clinical trials for guidance of evidence-based decisions. To better define the state of knowledge on IFDs in paediatric patients with cancer and allogeneic HSCT and to improve IFD diagnosis, prevention, and management, the Fourth European Conference on Infections in Leukaemia (ECIL-4) in 2011 convened a group that reviewed the scientific literature on IFDs and graded the available quality of evidence according to the Infectious Diseases Society of America grading system. The final considerations and recommendations of the group are summarised in this manuscript.

  13. Therapeutic vaccination with an interleukin-2-interferon-gamma-secreting allogeneic tumor vaccine in patients with progressive castration-resistant prostate cancer: a phase I/II trial.

    PubMed

    Brill, Thomas H; Kübler, Hubert R; Pohla, Heike; Buchner, Alexander; Fend, Falko; Schuster, Tibor; van Randenborgh, Heiner; Paul, Roger; Kummer, Tania; Plank, Christian; Eisele, Bernd; Breul, Jürgen; Hartung, Rudolf; Schendel, Dolores J; Gansbacher, Bernd

    2009-12-01

    Immunotherapy with whole cell cancer vaccines has been tested in various tumor types. This study investigated the safety profile and antitumor activity of an allogeneic prostate carcinoma cell line, LNCaP, expressing recombinant human interleukin-2 and human interferon-gamma. Thirty HLA-A*0201-matched patients with progressive, castration-resistant prostate cancer received four intradermal injections on days 1, 15, 29, and 92, and then every 90 days, as long as no tumor progression occurred. Three patients received a dose level of 7.5 million cells, and 27 patients received 15 million cells per injection. The primary study criteria were safety and the difference in prostate-specific antigen doubling time (PSA-DT), determined in the pretreatment phase (before the start of vaccination) and in the trial treatment phase (during vaccination). No dose-limiting or autoimmune toxicity was seen. During vaccination there was a significant prolongation of the PSA-DT compared with the prevaccination period (prolongation from 63 to 114 days; p < 0.01; intention to treat). In addition, results showed a period of PSA stabilization of at least 12 weeks, together with stable bone scans in 12 of 30 patients, and 3 patients sustained a >50% decrease in PSA versus baseline. The median overall survival time from first vaccination was 32 months (mean value, 34 months). Immune monitoring revealed T cell stimulation in the majority of patients. This vaccine strategy was found to be safe and well tolerated and was accompanied by prolongation of PSA-DT. The results of this trial warrant clinical development of this vaccine.

  14. Posaconazole oral suspension primary prophylaxis in acute leukemia and allogeneic stem cell transplant patients: can it be used without measurement of plasma concentration?

    PubMed

    Girmenia, Corrado; Annino, Luciana; Mariotti, Benedetta; Fanci, Rosa; Minotti, Clara; Spadea, Antonio; Carotti, Alessandra; Piedimonte, Monica; Chierichini, Anna; Cerchiara, Elisabetta; Caselli, Desiree; Cupelli, Luca; Arcioni, Francesco; Bertaina, Alice; Ribersani, Michela; Proia, Anna; Mengarelli, Andrea; Perriello, Vincenzo; Torelli, Giovanni Fernando; Di Gioia, Massimo; Del Principe, Maria Ilaria; Cassetta, Maria Iris; Fallani, Stefania; Novelli, Andrea

    2016-07-01

    Posaconazole oral suspension (PCZ-susp) can display a variable degree of inter and intra-individual absorption. However, there is no agreement on the need of plasma-posaconazole-concentration (PPC) monitoring as a routine practice in patients receiving PCZ-susp. In this prospective, multicenter study we evaluated the variability of PPCs in hematologic patients receiving PCZ-susp prophylaxis with the aim to define conditions at different risk of subtherapeutic PPCs. Overall, 103 acute leukemia (AL) patients submitted to intensive chemotherapy (115 courses) and 46 allogeneic stem cell transplant (allo-SCT) recipients (47 courses) receiving PCZ-susp prophylaxis were considered. The adequacy of PPC pattern after the steady state (≥day 7 of treatment) in courses with two or more PPC measurements was defined as follows: inadequate pattern: PPC < 0.5 mcg/ml at least once; borderline pattern: PPC always ≥0.5mcg/ml but < 0.7 mcg/ml at least once; adequate pattern: PPC always ≥0.7 mcg/ml. The PPC pattern was evaluable in 83 and 37 AL and allo-SCT patients, respectively. It was adequate, borderline and inadequate in 63.9%, 14.5%, and 21.7% of courses, respectively, in AL, and in 62.2%, 10.8%, and 27.0% of courses, respectively, in allo-SCT. In both groups, an inadequate PPC pattern was associated with the development of diarrhea. In absence of diarrhea, the probability of an inadequate PPC pattern was 11.9% in AL and 17.2% in allo-SCT patients. PCZ-susp might be used without stringent need of PPC monitoring in patients without diarrhea.

  15. Iron overload in patients receiving allogeneic hematopoietic stem cell transplantation: quantification of iron burden by a superconducting quantum interference device (SQUID) and therapeutic effectiveness of phlebotomy.

    PubMed

    Busca, Alessandro; Falda, Michele; Manzini, Paola; D'Antico, Sergio; Valfrè, Adriano; Locatelli, Franco; Calabrese, Roberto; Chiappella, Annalisa; D'Ardia, Stefano; Longo, Filomena; Piga, Antonio

    2010-01-01

    Iron overload (IO) is a known adverse prognostic factor in patients who undergo allogeneic hematopoietic stem cell transplantation (HSCT) for thalassemia and appears to play a similar role in patients with other hematologic disorders. The estimation of IO is based primarily on serum ferritin level; however, many confounding factors can result in ferritin overestimation, especially in HSCT recipients. The aim of the present study was to quantify IO after HSCT using a superconducting quantum interference device (SQUID), and to evaluate the impact of IO on hepatic function and infections. In addition, the feasibility of iron depletion was investigated. A total of 102 consecutive allogeneic HSCT recipients admitted to our outpatient department between December 2005, and December 2007, were analyzed. Primary diagnosis included acute leukemia/myelodysplastic syndrome in 61% of cases. Assessment of IO after HSCT included serum ferritin; in those with hyperferritinemia (ferritin>1000 ng/mL), liver iron concentration (LIC) was evaluated by SQUID magnetic susceptometry. Iron removal therapy was offered to patients with moderate IO (LIC 1000-2000 microg Fe/g wet weight [ww]) or severe IO (LIC >2,000 microg Fe/g ww). Fifty-seven patients had a ferritin level <1000 ng/mL: the median time between HSCT and assessment of ferritin level was 1006 days (range, 93-5239 days), significantly different from the median time of 183 days (range, 78-2957 days) in the 45 patients with a ferritin level >1000 ng/mL. Out of 42 patients evaluated by SQUID, 29 had moderate to severe IO (median LIC value, 1493 microg Fe/g ww [range, 1030-3253]). In a multivariate analysis, a significant correlation was found between a ferritin level >1000 ng/mL and the presence of at least one abnormal liver function test (LFT) ORo=6.8; 95% CI=2.2-20.6). In addition, the rate of proven/probable invasive fungal disease was significantly higher in the patients with hyperferritinemia (13% vs 0%; P=.006). Nineteen of

  16. Assessment of nephrotoxicity of high-cumulative dose of liposomal amphotericin B in a pediatric patient who underwent allogeneic bone marrow transplantation.

    PubMed

    Cesaro, Simone; Zignol, Matteo; Burlina, Alberto B; Tridello, Gloria; Visintin, Gianluca; Messina, Chiara

    2006-03-01

    We describe a 9-yr-old boy who received the highest cumulative dose so far reported of liposomal amphotericin B. The patient underwent an allogeneic bone marrow transplantation (BMT) for adrenoleucodystrophy, after a conditioning regimen with busulfan, thiothepa and cyclophosphamide. Rabbit antithymoglobulin, cyclosporin and prednisone were used as prophylaxis against graft vs. host disease (GVHD). Post-transplant Epstein-Bar-virus-related lymphoma was diagnosed on day +68 and was treated with donor-derived lymphocytes. The patient developed a severe form of GVHD, and a progressive worsening of his neurological status because of progression of his underlying disease. Death from septic shock occurred 23 months after BMT. During prolonged hospitalization, 19,750 mg of liposomal amphotericin B, about 1000 mg/kg, were given for prophylactic or empirical therapeutic purposes without significant nephrotoxicity. This case suggests that liposomal amphotericin B is safe and well-tolerated even if is administered for long periods and a cumulative dose fivefold greater than the nephrotoxic threshold of amphotericin B deoxycholate is achieved.

  17. Successful pregnancy and delivery via in vitro fertilization with cryopreserved and thawed embryo transfer in an acute myeloid leukemia patient after allogeneic bone marrow transplantation.

    PubMed

    Nakajima, Yuki; Kuwabara, Hideyuki; Kishimoto, Kumiko; Numata, Ayumi; Motohashi, Kenji; Tachibana, Takayoshi; Tanaka, Masatsugu; Yamashita, Naoki; Ishigatsubo, Yoshiaki; Fujisawa, Shin

    2015-04-01

    As the number of young long-term survivors of hematopoietic stem cell transplantation (HSCT) for acute leukemia continues to increase, post-transplant infertility is becoming a significant concern. HSCT, particularly with cyclophosphamide and total body irradiation conditioning, is known to cause secondary premature ovarian failure, resulting in infertility. To preserve post-transplant fertility, several methods have been proposed, including in vitro fertilization (IVF) with embryo cryopreservation. Due to the aggressiveness of acute leukemia, however, patients have little chance to undergo egg harvesting and IVF before they must begin receiving chemotherapy. To the best of our knowledge, there have been no detailed reports of successful pregnancy after HSCT using IVF with embryo cryopreservation and transfer in a patient with acute myeloid leukemia. Here, we report the case of a 42-year-old woman with acute myeloid leukemia who became pregnant 2 years and 2 months after allogeneic bone marrow transplantation via IVF-embryo transfer with an egg collected after induction therapy and delivered a full-term healthy infant.

  18. Efficacy of mouth rinse in preventing oral mucositis in patients receiving high-dose cytarabine for allogeneic hematopoietic stem cell transplantation.

    PubMed

    Mori, Takehiko; Hasegawa, Kaori; Okabe, Ai; Tsujimura, Natsuki; Kawata, Yusuke; Yashima, Tomoko; Kobayashi, Naoko; Kondo, Sakiko; Aisa, Yoshinobu; Kato, Jun; Tsunoda, Kazuyuki; Nagai, Tetsuo; Nakagawa, Taneaki; Shigematsu, Naoyuki; Kubo, Atsushi; Ikeda, Yasuo; Okamoto, Shinichiro

    2008-12-01

    High-dose cytarabine is one of the major components of the conditioning regimen for hematopoietic stem cell transplantation (HSCT), and frequently causes severe oral mucositis. We have recently demonstrated that cytarabine is excreted into the saliva in patients receiving high-dose cytarabine, and proposed that it might locally and directly contribute to the development of oral mucositis. Therefore, this study was performed to assess whether removing the excreted cytarabine in the saliva by intensive mouth rinse during high-dose cytarabine infusion could reduce the incidence of oral mucositis. Fifteen patients with hematologic malignancies undergoing allogeneic HSCT who received total body irradiation (12 Gy) and high-dose cytarabine at a dose of 3 g/m(2) every 12 h for 4 days as a conditioning were evaluated. Patients were instructed to rinse their mouths using ice-cold water every 10 min, starting simultaneously with the 2-h cytarabine infusion and continuing up to 1 h after completion of each infusion. Oral mucositis was graded on a daily basis according to the National Cancer Institute, Common Toxicity Criteria. Thirty-five patients who previously underwent the same conditioning without mouth rinse served as controls. The incidence of Grades 2-3 and Grade 3 oral mucositis was significantly reduced in patients who performed mouth rinse as compared with the controls (40 vs. 80%, P = 0.009; 0 vs. 25. 7%, P = 0.02). In conclusion, mouth rinse during and shortly after high-dose cytarabine infusion could be an effective and inexpensive measure in reducing the incidence of moderate to severe oral mucositis caused by high-dose cytarabine. This finding strongly suggests the role of cytarabine excretion in the saliva in the development of cytarabine-associated oral mucositis.

  19. Screening with spirometry is a useful predictor of later development of noninfectious pulmonary syndromes in patients undergoing allogeneic stem cell transplantation.

    PubMed

    Thompson, Philip A; Lim, Andrew; Panek-Hudson, Yvonne; Tacey, Mark; Hijazi, Ramzi; Ng, Ashley P; Szer, Jeff; Ritchie, David; Bajel, Ashish

    2014-06-01

    Noninfectious pulmonary syndromes (NIPS) frequently complicate allogeneic stem cell transplantation (allo-SCT). The most common and serious is the bronchiolitis obliterans syndrome, characterized by irreversible fixed airflow obstruction, impaired quality of life, and a high mortality. Treatment for established symptomatic disease is relatively ineffective. We therefore sought to identify potential predictive factors for development of NIPS, which may identify patients at risk in whom earlier intervention may be of benefit. Spirometry and diffusing capacity for carbon monoxide were performed before allo-SCT, day 100, and 1 year after allo-SCT. We retrospectively analyzed spirometry in consecutive patients having allo-SCT from 2004 to 2010, along with computed tomography and bronchoalveolar lavage results to identify cases of NIPS. Cases of bronchiolitis obliterans syndrome were defined as per current National Institutes of Health consensus guidelines. Spirometry results and baseline variables were compared between patients with and without NIPS to identify early predictors and risk factors for NIPS. Of 235 assessable patients, 23 (9.8%) developed NIPS. Median time of onset was day 367 (interquartile range [IQR], 144 to 544 days). Changes in forced expiratory volume in 1 second (ΔFEV1.0) was the best predictor of later NIPS development. Median ΔFEV1.0 from pretransplant to day 100 in patients later developing NIPS was -12% (IQR, -25% to -1%) versus -1% (IQR, -7% to +6%) in unaffected patients, P = .002. From pretransplant to 1 year, ΔFEV1.0 was -19% (IQR, -37% to -6%) versus -3% (IQR, -10% to +4%) in patients later developing NIPS and unaffected patients, respectively, P < .001. Busulfan-based, but not total body irradiation-based, conditioning increased the risk of NIPS (hazard ratio, 9.4 [3.4 to 23.9], P < .001). No cases of NIPS were seen in the 53 patients who received in vivo T cell depletion with antithymocyte globulin (ATG, Genzyme Transplant, Cambridge

  20. Unrelated donor allogeneic hematopoietic stem cell transplantation for patients with hemoglobinopathies using a reduced-intensity conditioning regimen and third-party mesenchymal stromal cells.

    PubMed

    Kharbanda, Sandhya; Smith, Angela R; Hutchinson, Stephanie K; McKenna, David H; Ball, James B; Lamb, Lawrence S; Agarwal, Rajni; Weinberg, Kenneth I; Wagner, John E

    2014-04-01

    Allogeneic hematopoietic stem cell transplantation for patients with a hemoglobinopathy can be curative but is limited by donor availability. Although positive results are frequently observed in those with an HLA-matched sibling donor, use of unrelated donors has been complicated by poor engraftment, excessive regimen-related toxicity, and graft-versus-host disease (GVHD). As a potential strategy to address these obstacles, a pilot study was designed that incorporated both a reduced-intensity conditioning and mesenchymal stromal cells (MSCs). Six patients were enrolled, including 4 with high-risk sickle cell disease (SCD) and 2 with transfusion-dependent thalassemia major. Conditioning consisted of fludarabine (150 mg/m(2)), melphalan (140 mg/m(2)), and alemtuzumab (60 mg for patients weighing > 30 kg and .9 mg/kg for patients weighing <30 kg). Two patients received HLA 7/8 allele matched bone marrow and 4 received 4-5/6 HLA matched umbilical cord blood as the source of HSCs. MSCs were of bone marrow origin and derived from a parent in 1 patient and from an unrelated third-party donor in the remaining 5 patients. GVHD prophylaxis consisted of cyclosporine A and mycophenolate mofetil. One patient had neutropenic graft failure, 2 had autologous hematopoietic recovery, and 3 had hematopoietic recovery with complete chimerism. The 2 SCD patients with autologous hematopoietic recovery are alive. The remaining 4 died either from opportunistic infection, GVHD, or intracranial hemorrhage. Although no infusion-related toxicity was seen, the cotransplantation of MSCs was not sufficient for reliable engraftment in patients with advanced hemoglobinopathy. Although poor engraftment has been observed in nearly all such trials to date in this patient population, there was no evidence to suggest that MSCs had any positive impact on engraftment. Because of the lack of improved engraftment and unacceptably high transplant-related mortality, the study was prematurely terminated

  1. Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice

    PubMed Central

    Shono, Yusuke; Docampo, Melissa D.; Peled, Jonathan U.; Perobelli, Suelen M.; Velardi, Enrico; Tsai, Jennifer J.; Slingerland, Ann E.; Smith, Odette M.; Young, Lauren F.; Gupta, Jyotsna; Lieberman, Sophia R.; Jay, Hillary V.; Ahr, Katya F.; Rodriguez, Kori A. Porosnicu; Xu, Ke; Calarfiore, Marco; Poeck, Hendrik; Caballero, Silvia; Devlin, Sean M.; Rapaport, Franck; Dudakov, Jarrod A.; Hanash, Alan M.; Gyurkocza, Boglarka; Murphy, George F.; Gomes, Camilla; Liu, Chen; Moss, Eli L.; Falconer, Shannon B.; Bhatt, Ami S.; Taur, Ying; Pamer, Eric G.

    2016-01-01

    After allogeneic hematopoietic stem cell transplantation (allo-HSCT), intestinal bacteria modulate risks of infection and graft-versus-host disease (GVHD). Neutropenic fever is common and treated with a choice of clinically equivalent antibiotics that target obligately anaerobic bacteria (anaerobes) to varying degrees. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam was associated with increased GVHD-related mortality at 5 years (21.5% in imipenem-cilastatin-treated patients vs. 13.1% in untreated patients, p=0.025, and 19.8% in piperacillin-tazobactam-treated patients vs. 11.9% in untreated patients, p=0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (p=0.78 and p=0.98, respectively). Analysis of stool microbiota composition showed that piperacillin-tazobactam administration was associated with increased compositional perturbation. Studies in mouse models demonstrated similar effects of these antibiotics, as well as aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactm compared to aztreonam (p<0.01 and p<0.05, respectively). We found pathological evidence for increased GVHD in the colon of imipenem-cilastatin-treated mice (p<0.05), but no differences in short-chain fatty acid concentrations or regulatory T cells numbers. Notably, imipenem-cilastatin treatment of mice with GVHD led to loss of the protective lining of mucus in the colon (p<0.01) and intestinal barrier function was compromised (p<0.05). Sequencing of mouse stool specimens showed expansion of Akkermansia muciniphila (p<0.001), a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation can contribute to murine GVHD. We demonstrate an underappreciated risk for antibiotics with activity against anaerobes to exacerbate colonic GVHD after

  2. Utilization of TREC and KREC quantification for the monitoring of early T- and B-cell neogenesis in adult patients after allogeneic hematopoietic stem cell transplantation

    PubMed Central

    2013-01-01

    Background After hematopoietic stem cell transplantation (HSCT) T- and B-cell reconstitution from primary lymphoid organs are a prerequisite for an effective early lymphocyte reconstitution and a long-term survival for adult patients suffering from acute leukemia. Here, we asked whether quantification of T cell receptor excision circle, (TREC) and kappa-deleting recombination excision circle (KREC) before and within six month after allogeneic HSCT could be used to measure the thymic and bone marrow outputs in such patients. Methods We used a duplex real time PCR assay to quantify the absolute copy counts of TREC and KREC, and correlated the data with absolute cell counts of CD3+CD4+ T-cell and CD19+ B-cell subsets determined by flow cytometry, respectively. Results By comparing two recently proposed naïve T cell subsets, CD31+ naive and CD31- naive T cells, we found a better correlation for the CD31+ subset with TREC level post alloHSCT, in line with the assumption that it contained T cells recently derived from the thymus, indicating that TREC levels reflected real thymic de novo production. Transitional as well as naïve B cells highly correlated with KREC levels, which suggested an association of KREC levels with ongoing bone marrow B cell output. CD45RO+ memory T cells and CD27+ memory B cells were significantly less correlated with TREC and KREC recovery, respectively. Conclusion We conclude that simultaneous TREC/ KREC quantification is as a suitable and practicable method to monitor thymic and bone marrow output post alloHSCT in adult patients diagnosed with acute leukemia. PMID:23941115

  3. Induction of anti-tumour lymphocytes in cancer patients after brief exposure to supernatants from cultures of anti-CD3-stimulated allogeneic lymphocytes.

    PubMed Central

    Baxevanis, C. N.; Tsiatas, M. L.; Cacoullos, N. T.; Spanakos, G.; Liacos, C.; Missitzis, I.; Papadhimitriou, S. I.; Papamichail, M.

    1997-01-01

    The present study investigated the ability of supernatants collected from cultures of healthy donor-derived peripheral blood mononuclear cells (HD-PBMCs) stimulated with anti-CD3 monoclonal antibody (MAb) (allogeneic CD3 supernatants; ACD3S) to induce, upon brief exposure, tumour-reactive cytotoxic lymphocytes in cancer patients' PBMCs. ACD3S enhanced natural killer (NK) and lymphokine-activated killer (LAK) cell-mediated cytotoxicity. ACD3S contained increased levels of interleukins (IL) 1, 2, 6, 7 and 12, as well as of granulocyte-macrophage colony-stimulating factor (GM-CSF), gamma-interferon (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha). MAbs against these cytokines significantly reduced the ACD3S-induced cytotoxicity. ACD3S-induced cytotoxicity was not inhibited by anti-CD4, CD8 and MHC class I MAbs, but was markedly reduced in the presence of MAb against CD18. In contrast to HD-PBMC, ACD3S derived from cancer patients' lymphocytes exhibited lower levels of the above-mentioned cytokines and exerted reduced biological activity. In conclusion, ACD3S are able to activate, upon short-term incubation, tumour-reactive lymphocytes from cancer patients' PBMCs that lyse a variety of tumour targets, including autologous tumours. ACD3S contain high levels of certain cytokines that positively influence the induction of autologous tumour-reactive lymphocytes. Such supernatants can be collected easily from healthy donors and stored until use in clinical trials for adoptive cellular therapy of cancer. They may also be indicated in the construction of cytokine cocktails that have the ability to induce anti-tumour cytotoxicity. PMID:9376269

  4. Development of a modified prognostic index of patients with aggressive adult T-cell leukemia-lymphoma aged 70 years or younger: a possible risk-adapted management strategies including allogeneic transplantation.

    PubMed

    Fuji, Shigeo; Yamaguchi, Takuhiro; Inoue, Yoshitaka; Utsunomiya, Atae; Moriuchi, Yukiyoshi; Uchimaru, Kaoru; Owatari, Satsuki; Miyagi, Takashi; Taguchi, Jun; Choi, Ilseung; Otsuka, Eiichi; Nakachi, Sawako; Yamamoto, Hisashi; Kurosawa, Saiko; Tobinai, Kensei; Fukuda, Takahiro

    2017-03-24

    Adult T-cell leukemia-lymphoma is a distinct type of peripheral T-cell lymphoma caused by human T-cell lymphotropic virus type I. Although allogeneic stem cell transplantation after chemotherapy is a recommended treatment option for patients with aggressive adult T-cell leukemia-lymphoma, there is no consensus about indications for allogeneic stem cell transplantation because there is no established risk stratification system for transplant eligible patients. We conducted a nationwide survey of patients with aggressive adult T-cell leukemia-lymphoma to construct a new large database that includes 1,792 patients aged 70 years or younger with aggressive adult T-cell leukemia-lymphoma who were diagnosed between 2000 and 2013 and received intensive first-line chemotherapy. We randomly divided patients into two groups (training and validation sets). Acute type, poor performance status, high soluble interleukin-2 receptor level (> 5,000 U/mL), high adjusted calcium level (≥ 12 mg/dL), and high C-reactive protein level (≥ 2.5 mg/dL) were independent adverse prognostic factors using the training set. We used these five variables to divide patients into three risk groups. In the validation set, medial overall survival was 626 days, 322 days, and 197 days for the low-, intermediate-, and high-risk groups, respectively. In the intermediate- and high-risk groups, transplanted recipients had significantly better overall survival than non-transplanted patients. We developed a new promising risk stratification system to identify patients aged 70 years or younger with aggressive adult T-cell leukemia-lymphoma who may benefit from upfront allogeneic stem cell transplantation. Prospective studies are warranted to confirm the benefit of this treatment strategy.

  5. Dangers resulting from DNA profiling of biological materials derived from patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) with regard to forensic genetic analysis.

    PubMed

    Jacewicz, R; Lewandowski, K; Rupa-Matysek, J; Jędrzejczyk, M; Berent, J

    The study documents the risk that comes with DNA analysis of materials derived from patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in forensic genetics. DNA chimerism was studied in 30 patients after allo-HSCT, based on techniques applied in contemporary forensic genetics, i.e. real-time PCR and multiplex PCR-STR with the use of autosomal DNA as well as Y-DNA markers. The results revealed that the DNA profile of the recipient's blood was identical with the donor's in the majority of cases. Therefore, blood analysis can lead to false conclusions in personal identification as well as kinship analysis. An investigation of buccal swabs revealed a mixture of DNA in the majority of recipients. Consequently, personal identification on the basis of stain analysis of the same origin may be impossible. The safest (but not ideal) material turned out to be the hair root. Its analysis based on autosomal DNA revealed 100% of the recipient's profile. However, an analysis based on Y-chromosome markers performed in female allo-HSCT recipients with male donors demonstrated the presence of donor DNA in hair cells - similarly to the blood and buccal swabs. In the light of potential risks arising from DNA profiling of biological materials derived from persons after allotransplantation in judicial aspects, certain procedures were proposed to eliminate such dangers. The basic procedures include abandoning the approach based exclusively on blood collection, both for kinship analysis and personal identification; asking persons who are to be tested about their history of allo-HSCT before sample collection and profile entry in the DNA database, and verification of DNA profiling based on hair follicles in uncertain cases.

  6. Immunological effects of nilotinib prophylaxis after allogeneic stem cell transplantation in patients with advanced chronic myeloid leukemia or philadelphia chromosome-positive acute lymphoblastic leukemia

    PubMed Central

    Shouval, Roni; Eldror, Shiran; Lev, Atar; Davidson, Jacqueline; Rosenthal, Esther; Volchek, Yulia; Shem-Tov, Noga; Yerushalmi, Ronit; Shimoni, Avichai; Somech, Raz; Nagler, Arnon

    2017-01-01

    Allogeneic stem cell transplantation remains the standard treatment for resistant advanced chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia. Relapse is the major cause of treatment failure in both diseases. Post-allo-SCT administration of TKIs could potentially reduce relapse rates, but concerns regarding their effect on immune reconstitution have been raised. We aimed to assess immune functions of 12 advanced CML and Ph+ ALL patients who received post-allo-SCT nilotinib. Lymphocyte subpopulations and their functional activities including T-cell response to mitogens, NK cytotoxic activity and thymic function, determined by quantification of the T cell receptor (TCR) excision circles (TREC) and TCR repertoire, were evaluated at several time points, including pre-nilotib-post-allo-SCT, and up to 365 days on nilotinib treatment. NK cells were the first to recover post allo-SCT. Concomitant to nilotinib administration, total lymphocyte counts and subpopulations gradually increased. CD8 T cells were rapidly reconstituted and continued to increase until day 180 post SCT, while CD4 T cells counts were low until 180−270 days post nilotinib treatment. T-cell response to mitogenic stimulation was not inhibited by nilotinib administration. Thymic activity, measured by TREC copies and surface membrane expression of 24 different TCR Vβ families, was evident in all patients at the end of follow-up after allo-SCT and nilotinib treatment. Finally, nilotinib did not inhibit NK cytotoxic activity. In conclusion, administration of nilotinib post allo-SCT, in attempt to reduce relapse rates or progression of Ph+ ALL and CML, did not jeopardize immune reconstitution or function following transplantation. PMID:27880933

  7. Analysis of transgene-specific immune responses that limit the in vivo persistence of adoptively transferred HSV-TK–modified donor T cells after allogeneic hematopoietic cell transplantation

    PubMed Central

    Berger, Carolina; Flowers, Mary E.; Warren, Edus H.; Riddell, Stanley R.

    2006-01-01

    The introduction of an inducible suicide gene such as the herpes simplex virus thymidine kinase (HSV-TK) might allow exploitation of the antitumor activity of donor T cells after allogeneic hematopoietic cell transplantation (HCT) without graft versus host disease. However, HSV-TK is foreign, and immune responses to gene-modified T cells could lead to their premature elimination. We show that after the infusion of HSV-TK–modified donor T cells to HCT recipients, CD8+ and CD4+ T-cell responses to HSV-TK are rapidly induced and coincide with the disappearance of transferred cells. Cytokine flow cytometry using an overlapping panel of HSV-TK peptides allowed rapid detection and quantitation of HSV-TK–specific T cells in the blood and identified multiple immunogenic epitopes. Repeated infusion of modified T cells boosted the induced HSV-TK–specific T cells, which persisted as memory cells. These studies demonstrate the need for nonimmunogenic suicide genes and identify a strategy for detection of CD4+ and CD8+ T-cell responses to transgene products that should be generally applicable to monitoring patients on gene therapy trials. The potency of gene-modified T cells to elicit robust and durable immune responses imply this approach might be used for vaccination to elicit T-cell responses to viral or tumor antigens. PMID:16282341

  8. Features of Epstein-Barr virus reactivation after allogeneic hematopoietic cell transplantation in Korean children living in an area of high seroprevalence against Epstein-Barr virus.

    PubMed

    Han, Seung Beom; Bae, E Young; Lee, Jae Wook; Jang, Pil Sang; Lee, Dong-Gun; Chung, Nack-Gyun; Jeong, Dae Chul; Cho, Bin; Lee, Soon Ju; Kang, Jin Han; Kim, Hack-Ki

    2014-08-01

    The present study was conducted to investigate Epstein-Barr virus (EBV) reactivation after hematopoietic cell transplantation (HCT) in Korean children living in an area of a high seroprevalence against EBV and to determine the impact of recipient age on EBV reactivation. Medical records of 248 children and adolescents who had received allogeneic HCT were retrospectively reviewed. The trends of EBV reactivation and post-transplant lymphoproliferative disorders (PTLDs) were evaluated and compared between younger (≤10 years old) and older (11-20 years old) groups. EBV reactivation occurred in 177 cases (71.4 %) and high-level EBV reactivation, defined as a virus DNA titer of 300,000 copies/mL or higher, occurred in 21 cases (8.5 %). PTLD was diagnosed in five cases (2.0 %), and one of these patients died. The EBV reactivation rate was not significantly different between the two age groups; however, high-level reactivation and PTLD were more significantly frequent in the older than in the younger group (P = 0.030 and P = 0.026, respectively). In conclusion, older children and adolescents are more likely to experience high-level EBV reactivation and PTLDs, and higher EBV DNA titers than those previously reported may be a predictor of PTLD in areas with a high seroprevalence against EBV.

  9. Image-Guided Total-Marrow Irradiation Using Helical Tomotherapy in Patients With Multiple Myeloma and Acute Leukemia Undergoing Hematopoietic Cell Transplantation

    SciTech Connect

    Wong, Jeffrey Y.C. Rosenthal, Joseph; Liu An; Schultheiss, Timothy; Forman, Stephen; Somlo, George

    2009-01-01

    Purpose: Total-body irradiation (TBI) has an important role in patients undergoing hematopoietic cell transplantation (HCT), but is associated with significant toxicities. Targeted TBI using helical tomotherapy results in reduced doses to normal organs, which predicts for reduced toxicities compared with standard TBI. Methods and Materials: Thirteen patients with multiple myeloma were treated in an autologous tandem transplantation Phase I trial with high-dose melphalan, followed 6 weeks later by total-marrow irradiation (TMI) to skeletal bone. Dose levels were 10, 12, 14, and 16 Gy at 2 Gy daily/twice daily. In a separate allogeneic HCT trial, 8 patients (5 with acute myelogenous leukemia, 1 with acute lymphoblastic leukemia, 1 with non-Hodgkin's lymphoma, and 1 with multiple myeloma) were treated with TMI plus total lymphoid irradiation plus splenic radiotherapy to 12 Gy (1.5 Gy twice daily) combined with fludarabine/melphalan. Results: For the 13 patients in the tandem autologous HCT trial, median age was 54 years (range, 42-66 years). Median organ doses were 15-65% that of the gross target volume dose. Primarily Grades 1-2 acute toxicities were observed. Six patients reported no vomiting; 9 patients, no mucositis; 6 patients, no fatigue; and 8 patients, no diarrhea. For the 8 patients in the allogeneic HCT trial, median age was 52 years (range, 24-61 years). Grades 2-3 nausea, vomiting, mucositis, and diarrhea were observed. In both trials, no Grade 4 nonhematologic toxicity was observed, and all patients underwent successful engraftment. Conclusions: This study shows that TMI using helical tomotherapy is clinically feasible. The reduced acute toxicities observed compare favorably with those seen with standard TBI. Initial results are encouraging and warrant further evaluation as a method to dose escalate with acceptable toxicity or to offer TBI-containing regimens to patients unable to tolerate standard approaches.

  10. Resistin and Visfatin Expression in HCT-116 Colorectal Cancer Cell Line

    PubMed Central

    Ghaemmaghami, Sara; Mohaddes, Seyed Mojtaba; Hedayati, Mehdi; Gorgian Mohammadi, Masumeh; Dehbashi, Golnoosh

    2013-01-01

    Adipocytokines, hormones secreted from adipose tissue, have been shown to be associated with many cancers such as breast, prostate and colorectal cancer. Recent studies have indicated that resistin and visfatin, two of these adipokines have high level plasma concentrations in colorectal cancer patients and may be promising biomarkers for colorectal cancer. The aim of this study was to identify whether the colorectal cancer cell line, HCT-116, itself is the source of these two adipokines secretion. Resistin and visfatin expression were investigated in HCT-116 by RT – PCR at mRNA level and confirmed by ELISA at protein level. Visfatin showed a high expression at both mRNA and protein levels in HCT-116. Conversely, resistin was not expressed in either cell lysate or supernatant. These results showed that HCT-116 colorectal cancer cells secrete and express visfatin endogenously. However, they are not the main source of resistin and the high level of resistin in colorectal cancer may be due to monocytes and other inflammatory cells which increase in proinflammation status of cancer. Taken together, visfatin may act on colorectal cancer cell in an autocrine manner while resistin may act in a paracrine manner. PMID:24551805

  11. Bloodstream infection caused by Acinetobacter junii in a patient with acute lymphoblastic leukaemia after allogenic haematopoietic cell transplantation.

    PubMed

    Cayô, Rodrigo; Yañez San Segundo, Lucrecia; Pérez del Molino Bernal, Inmaculada Concepción; García de la Fuente, Celia; Bermúdez Rodríguez, Maria Aranzazu; Calvo, Jorge; Martínez-Martínez, Luis

    2011-03-01

    Acinetobacter junii is a rare human pathogen associated with bacteraemia in neonates and paediatric oncology patients. We present a case of A. junii causing bacteraemia in an adult transplant patient with leukaemia. The correct identification of Acinetobacter species can highlight the clinical significance of the different species of this genus.

  12. Fulvic Acid Attenuates Resistin-Induced Adhesion of HCT-116 Colorectal Cancer Cells to Endothelial Cells

    PubMed Central

    Huang, Wen-Shih; Yang, Jen-Tsung; Lu, Chien-Chang; Chang, Shun-Fu; Chen, Cheng-Nan; Su, Yu-Ping; Lee, Ko-Chao

    2015-01-01

    A high level of serum resistin has recently been found in patients with a number of cancers, including colorectal cancer (CRC). Hence, resistin may play a role in CRC development. Fulvic acid (FA), a class of humic substances, possesses pharmacological properties. However, the effect of FA on cancer pathophysiology remains unclear. The aim of this study was to investigate the effect of resistin on the endothelial adhesion of CRC and to determine whether FA elicits an antagonistic mechanism to neutralize this resistin effect. Human HCT-116 (p53-negative) and SW-48 (p53-positive) CRC cells and human umbilical vein endothelial cells (HUVECs) were used in the experiments. Treatment of both HCT-116 and SW-48 cells with resistin increases the adhesion of both cells to HUVECs. This result indicated that p53 may not regulate this resistin effect. A mechanistic study in HCT-116 cells further showed that this resistin effect occurs via the activation of NF-κB and the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Co-treating cells with both FA and resistin revealed that FA significantly attenuated the resistin-increased NF-κB activation and ICAM-1/VCAM-1 expression and the consequent adhesion of HCT-116 cells to HUVECs. These results demonstrate the role of resistin in promoting HCT-116 cell adhesion to HUVECs and indicate that FA might be a potential candidate for the inhibition of the endothelial adhesion of CRC in response to resistin. PMID:26690142

  13. Serum citrulline as a biomarker of gastrointestinal function during hematopoietic cell transplantation (HCT) in children

    PubMed Central

    Gosselin, Kerri B.; Feldman, Henry A.; Sonis, Andrew L.; Bechard, Lori J.; Kellogg, Mark D.; Gura, Kathleen; Venick, Robert; Gordon, Catherine M.; Guinan, Eva C.; Duggan, Christopher

    2014-01-01

    Objective We sought to determine if serum citrulline (CIT), an amino acid produced by small bowel enterocytes, was associated with clinical and biochemical markers of gastrointestinal function in children undergoing hematopoietic cell transplantation (HCT). Methods We conducted a multi-center, prospective cohort study of 26 children to define time-related changes in serum CIT over the course of HCT. Markers of gastrointestinal function including oral energy intake, emesis, stool volume, presence of graft-versus-host disease (GVHD), oral mucositis severity, and cytokine and neurohormone levels were measured. Weekly serum CIT concentrations were obtained from 10 days prior until 30 days after HCT. Results Mean baseline CIT concentration was 22.7 µmol/L (95% CI 17.7 – 27.6) on day −10, which decreased to a nadir of 7.5 µmol/L (95% CI 3.1 – 18.0, p = 0.017) on day +8 following HCT before returning to baseline by day 30. After adjustment for IL-6 level (1.0% lower CIT per 10% increase in IL-6, p=0.004), presence of acute graft-versus-host disease (GVHD), (27% lower CIT, p=0.025) and oral energy intake (2.1% lower CIT per 10% decrease in energy intake, p=0.018), the nadir shifted to day +10, when mean CIT concentration was lower in patients with severe oral mucositis (6.7 µmol/L, 95% CI 3.4–13.1) than in those without severe mucositis (11.9 µmol/L, 95% CI 5.8–24.4, p=0.003). Change in CIT was not correlated with stool volume, C-reactive protein, TNF-alpha, leptin, or ghrelin. Conclusion In children undergoing HCT, serum CIT correlates with measures of gastrointestinal function (oral mucositis severity, dietary intake, acute GVHD) and may reflect mucosal injury to the gastrointestinal tract. PMID:24614125

  14. Seven-year follow-up of allogeneic transplant using BCNU, etoposide, cytarabine and melphalan chemotherapy in patients with Hodgkin lymphoma after autograft failure: importance of minimal residual disease.

    PubMed

    Sobol, Urszula; Rodriguez, Tulio; Smith, Scott; Go, Aileen; Vimr, Ross; Parthasarathy, Mala; Guo, Rong; Stiff, Patrick

    2014-06-01

    Abstract Allogeneic transplant using reduced intensity conditioning is a therapeutic option for patients with Hodgkin lymphoma (HL) who relapse after an autograft. This was a prospective study of 31 consecutive eligible patients with HL who relapsed after an autograft and underwent an allograft using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning. At a median follow-up of 7 years the progression-free survival (PFS) was 36% (95% confidence interval [CI] 19-54%) and overall survival (OS) was 42% (95% CI 23-59%). In multivariate analysis only residual disease at the time of transplant predicted outcome, with a 4-year PFS and OS of 62% and 75% for patients with minimal residual disease versus 8% and 8% for patients with gross residual disease, respectively (p = 0.005 and p = 0.001, respectively). This benefit seemed to be irrespective of chemosensitivity, with an OS for patients with chemorefractory yet minimal disease of 71% at 4 years. BEAM allogeneic transplant is effective in producing long-term remissions after autograft failure. Regardless of chemosensitivity, minimizing tumor burden pre-transplant may improve long-term outcome.

  15. Impact of FAB classification on predicting outcome in acute myeloid leukemia, not otherwise specified, patients undergoing allogeneic stem cell transplantation in CR1: An analysis of 1690 patients from the acute leukemia working party of EBMT.

    PubMed

    Canaani, Jonathan; Beohou, Eric; Labopin, Myriam; Socié, Gerard; Huynh, Anne; Volin, Liisa; Cornelissen, Jan; Milpied, Noel; Gedde-Dahl, Tobias; Deconinck, Eric; Fegueux, Nathalie; Blaise, Didier; Mohty, Mohamad; Nagler, Arnon

    2017-04-01

    The French, American, and British (FAB) classification system for acute myeloid leukemia (AML) is extensively used and is incorporated into the AML, not otherwise specified (NOS) category in the 2016 WHO edition of myeloid neoplasm classification. While recent data proposes that FAB classification does not provide additional prognostic information for patients for whom NPM1 status is available, it is unknown whether FAB still retains a current prognostic role in predicting outcome of AML patients undergoing allogeneic stem cell transplantation. Using the European Society of Blood and Bone Marrow Transplantation registry we analyzed outcome of 1690 patients transplanted in CR1 to determine if FAB classification provides additional prognostic value. Multivariate analysis revealed that M6/M7 patients had decreased leukemia free survival (hazard ratio (HR) of 1.41, 95% confidence interval (CI), 1.01-1.99; P = .046) in addition to increased nonrelapse mortality (NRM) rates (HR, 1.79; 95% CI, 1.06-3.01; P = .028) compared with other FAB types. In the NPM1(wt) AML, NOS cohort, FAB M6/M7 was also associated with increased NRM (HR, 2.17; 95% CI, 1.14-4.16; P = .019). Finally, in FLT3-ITD(+) patients, multivariate analyses revealed that specific FAB types were tightly associated with adverse outcome. In conclusion, FAB classification may predict outcome following transplantation in AML, NOS patients.

  16. A non-myeloablative conditioning regimen in allogeneic stem cell transplantation from related and unrelated donors in elderly patients.

    PubMed

    Tsirigotis, Panagiotis; Bitan, Reuven OrMenachem; Resnick, Igor B; Samuel, Simcha; Ackerstein, Aliza; Eladì, Sharon; Gesundheit, Benjamin; Zilberman, Irina; Miron, Svetlana; Leubovic, Alexander; Slavin, Shimon; Shapira, Michael Y

    2006-06-01

    We describe our experience with the use of a single non-myeloablative preparative regimen in stem-cell transplantation (NST) in 37 heavily pretreated patients > or =55 years. The conditioning regimen consisted of fludarabine, low-dose busulfan, and antithymocyte globulin. Acute graft-versus-host disease (GVHD) grade III-IV and chronic GVHD developed in 15.6% and 44.4% of cases, respectively. With a median follow-up period of 22 (range 3-113) months, the 1-year overall survival and disease-free-survival were 55% and 53%, respectively, while the overall non-relapse mortality was 35%. In conclusion, reduced intensity stem cell transplantation is feasible and effective in patients > or =55 years. Age per se, should no longer be considered as a contra-indication to stem cell transplantation.

  17. Allogeneic and Autologous Bone Marrow Transplantation in CHAMPUS 1989-1993 A Total Patient Treatment Episode Analysis.

    DTIC Science & Technology

    1993-10-22

    AUTOLOGOUS BONE MARROW TRANSPLANTATION IN CHAMPUS 1989-1993 A TOTAL PATIENT TREATMENT EPISODE ANALYSIS DR. SCOTT A. OPTENBERG, GM-15 Chief, Health Care...Analysis Division Directorate of Health Care Studies and Analyses DR. JAMES M. THOMPSON, LTC, USAF, MC (RET) Former Director, Bone Marrow...Department of the Air Force position unless so designated by other authorized documents. Authors’ current addresses: Directorate of Health Care

  18. Hematopoietic cell transplantation as curative therapy for patients with myelofibrosis: Long-term success in all age groups

    PubMed Central

    Deeg, H. Joachim; Bredeson, Christopher; Farnia, Stephanie; Ballen, Karen; Gupta, Vikas; Mesa, Ruben A.; Popat, Uday; Saber, Wael; Seftel, Matthew; Tamari, Roni; Pertersdorf, Effie

    2015-01-01

    Myeloproliferative neoplasms (MPN) are chronic marrow disorders with variable prognosis. Most patients with Polycythemia Vera, Essential Thrombocythemia or even Primary Myelofibrosis (PMF) are successfully managed by conservative strategies for years or even decades, and recent data suggest that even in patients with high-risk disease, in particular those with PMF, life expectancy can be extended by treatment with JAK2 inhibitors. However, none of those modalities are curative, and once marrow failure develops, the disease “accelerates” or transforms to acute leukemia, the only treatment option able to effectively treat and, in fact, cure MPN is allogeneic hematopoietic cell transplantation (HCT). Outcome is superior if HCT is performed before leukemic transformation occurs. Several reports document survival in unmaintained remission beyond 10 years. The most recent analyses show reduced regimen-related mortality (less than 10% or even 5% at day 100), and progressively improved survival with both HLA-identical sibling and unrelated donors. The development of low/reduced intensity conditioning regimens has contributed to the improved success rate and has allowed to successfully carry out HCT in patients in the 7th and even 8th decade of life. We propose, therefore, that HCT should be offered to fit patients in these age groups and should be covered by their respective insurance carriers. PMID:26371371

  19. Outcome of myeloablative allogeneic peripheral blood hematopoietic stem cell transplantation for refractory/relapsed AML patients in NR status.

    PubMed

    Liu, Na; Ning, Hong-Mei; Hu, Liang-Ding; Jiang, Min; Xu, Chen; Hu, Jiang-Wei; Wang, Jun; Li, Yu-Hang; Li, Bo-Tao; Lou, Xiao; Yang, Fan; Chen, Jian-Lin; Su, Yong-Feng; Li, Meng; Wang, Hong-Ye; Ren, Jing; Feng, Yue-Qian; Zhang, Bin; Wang, Dan-Hong; Chen, Hu

    2015-12-01

    To further find effective method to improve the long term survival of refractory or relapsed acute myeloid leukemia (AML) patients, we retrospectively analyzed the outcomes of myeloablative hematopoietic stem cell transplantation (HSCT) for 133 consecutive patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) therapy related AML(t-AML) in not remission status. The overall 3-year OS and DFS were 40.9% and 35.6% respectively. The variables associated with improved long term DFS were a bone marrow blast cell count less than 20% and an intensified conditioning regimen. In addition, the t-AML group had higher rates of relapse and III-IV acute GVHD than the primary AML group. The unrelated donor group had similar OS and DFS with sibling groups. Our study suggested that decreasing bone marrow blast cell counts before HSCT and strengthening the conditioning regimen may improve long-term DFS for refractory/relapsed AML patients, and unrelated donor group can get similar effect when compared to the sibling group.

  20. Replenishment of type VII collagen and re-epithelialization of chronically ulcerated skin after intradermal administration of allogeneic mesenchymal stromal cells in two patients with recessive dystrophic epidermolysis bullosa.

    PubMed

    Conget, Paulette; Rodriguez, Fernando; Kramer, Susanne; Allers, Carolina; Simon, Valeska; Palisson, Francis; Gonzalez, Sergio; Yubero, Maria J

    2010-05-01

    In animal models it has been shown that mesenchymal stromal cells (MSC) contribute to skin regeneration and accelerate wound healing. We evaluated whether allogeneic MSC administration resulted in an improvement in the skin of two patients with recessive dystrophic epidermolysis bullosa (RDEB; OMIM 226600). Patients had absent type VII collagen immunohistofluorescence and since birth had suffered severe blistering and wounds that heal with scarring. Vehicle or 0.5 x 10(6) MSC were infused intradermally in intact and chronic ulcerated sites. One week after intervention, in MSC-treated skin type VII collagen was detected along the basement membrane zone and the dermal-epidermal junction was continuous. Re-epithelialization of chronic ulcerated skin was observed only near MSC administration sites. In both patients the observed clinical benefit lasted for 4 months. Thus intradermal administration of allogeneic MSC associates with type VII collagen replenishment at the dermal-epidermal junction, prevents blistering and improves wound healing in unconditioned patients with RDEB.

  1. Allogeneic versus autologous blood transfusion and survival after radical prostatectomy

    PubMed Central

    Chalfin, Heather J.; Frank, Steven M.; Feng, Zhaoyong; Trock, Bruce J.; Drake, Charles G.; Partin, Alan W.; Humphreys, Elizabeth; Ness, Paul M.; Jeong, Byong C.; Lee, Seung B.; Han, Misop

    2016-01-01

    BACKGROUND Potential adverse effects of blood transfusion (BT) remain controversial, especially for clinical outcomes after curative cancer surgery. Some postulate that immune modulation after allogeneic BT predisposes to recurrence and death, but autologous superiority is not established. This study assessed whether BT is associated with long-term prostate cancer recurrence and survival a large single-institutional radical prostatectomy (RP) database. STUDY DESIGN AND METHODS Between 1994 and 2012, a total of 11,680 patients had RP with available outcome and transfusion data. A total of 7443 (64%) had complete covariate data. Clinical variables associated with biochemical recurrence-free survival (BRFS), cancer-specific survival (CSS), and overall survival (OS) were identified with Cox proportional hazards models for three groups: no BT (reference, 27.7%, n = 2061), autologous BT only (68.8%, n = 5124), and any allogeneic BT (with or without autologous, 3.5%, n = 258). RESULTS Median (range) follow-up was 6 (1–18) years. Kaplan-Meier analysis showed significantly decreased OS (but not BRFS or PCSS) in the allogeneic group versus autologous and no BT groups (p = 0.006). With univariate analysis, any allogeneic BT had a hazard ratio (HR) of 2.29 (range, 1.52–3.46; p < 0.0001) for OS, whereas autologous BT was not significant (HR, 1.04 [range, 0.82–1.32], p = 0.752). In multivariable models, neither autologous nor allogeneic BT was independently associated with BRFS, CSS, or OS, and a dose response was not observed for allogeneic units and BRFS. CONCLUSION Although allogeneic but not autologous BT was associated with decreased long-term OS, after adjustment for confounding clinical variables, BT was not independently associated with OS, BRFS, or CSS regardless of transfusion type. Notably, no association was observed between allogeneic BT and cancer recurrence. Observed differences in OS may reflect confounding. PMID:24601996

  2. Serial monitoring of Mucorales DNA load in serum samples of a patient with disseminated mucormycosis after allogeneic bone marrow transplantation.

    PubMed

    Shigemura, Tomonari; Nakazawa, Yozo; Matsuda, Kazuyuki; Sano, Kenji; Yaguchi, Takashi; Motobayashi, Mitsuo; Saito, Shoji; Noda, Shunsuke; Kobayashi, Norimoto; Agematsu, Kazunaga; Honda, Takayuki; Koike, Kenichi

    2014-08-01

    Mucormycosis is a fatal complication in immunocompromised patients, and is additionally difficult to diagnose due to the lack of useful serum biomarkers. Using a quantitative PCR approach, we retrospectively analyzed Mucorales DNA load in sera collected serially from a 3-year-old patient with chronic granulomatous disease, who died of multi-organ failure probably due to dissemination of Rhizomucor pusillus, which was detected from necropsy specimens. Mucorales DNA load was below the detection limit on days 9, 2, and 4 after unrelated bone marrow transplantation. Rhizomucor DNA was first detected on day 14 (1.6 × 10(3) copies/mL), and subsequently fluctuated between 1.3 × 10(3) and 37.2 × 10(3) copies/mL until day 43. Rhizomucor achieved a peak value of 940.0 × 10(3) copies/mL on day 48 the day before death. The detection or fluctuation of Rhizomucor DNA appeared to be associated with corticosteroid dosages or C-reactive protein levels. This specific, noninvasive, and highly quantitative assay may be useful for the early diagnosis of mucormycosis and prediction of disease progression.

  3. Randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation: blood and marrow transplant clinical trials network protocol.

    PubMed

    Yanik, Gregory A; Horowitz, Mary M; Weisdorf, Daniel J; Logan, Brent R; Ho, Vincent T; Soiffer, Robert J; Carter, Shelly L; Wu, Juan; Wingard, John R; Difronzo, Nancy L; Ferrara, James L; Giralt, Sergio; Madtes, David K; Drexler, Rebecca; White, Eric S; Cooke, Kenneth R

    2014-06-01

    Idiopathic pneumonia syndrome (IPS) is a diffuse, noninfectious lung injury that occurs acutely after allogeneic hematopoietic cell transplantation (HCT). IPS-related mortality has been historically high (>50%) despite treatment with systemic corticosteroids and supportive care measures. We have now examined the role of tumor necrosis factor inhibition in a randomized, double-blind, placebo-controlled trial of corticosteroids with etanercept or placebo. Thirty-four subjects (≥18 years) with IPS after HCT were randomized to receive methylprednisolone (2 mg/kg/day) plus etanercept (0.4 mg/kg twice weekly × 4 weeks; n = 16) or placebo (n = 18). No active infections and a pathogen-negative bronchoscopy were required at study entry. Response (alive, with complete discontinuation of supplemental oxygen support) and overall survival were examined. This study, originally planned to accrue 120 patients, was terminated prematurely due to slow accrual. In the limited number of patients examined, there were no differences in response rates at day 28 of study. Ten of 16 patients (62.5% [95% confidence interval {CI}, 35.4% to 84.8%]) receiving etanercept and 12 of 18 patients (66.7% [95% CI, 41.0% to 86.7%]) receiving placebo met the day 28 response definition (P = 1.00). The median survival was 170 days (95% CI, 11 to 362) with etanercept versus 64 days (95% CI, 26 to 209) with placebo (P = .51). Among responders, the median time to discontinuation of supplemental oxygen was 9 days (etanercept) versus 7 days (placebo). Therapy was well tolerated, with 1 toxicity-related death from infectious pneumonia in the placebo arm. The treatment of IPS with corticosteroids in adult HCT recipients was associated with high early response rates (>60%) compared with historical reports, with poor overall survival. The addition of etanercept did not lead to further increases in response, although the sample size of this truncated trial preclude a definitive conclusion.

  4. Randomized, Double-Blind, Placebo-Controlled Trial of Soluble Tumor Necrosis Factor Receptor: Enbrel (Etanercept) for the Treatment of Idiopathic Pneumonia Syndrome after Allogeneic Stem Cell Transplantation: Blood and Marrow Transplant Clinical Trials Network Protocol

    PubMed Central

    Yanik, Gregory A.; Horowitz, Mary M.; Weisdorf, Daniel J.; Logan, Brent R.; Ho, Vincent T.; Soiffer, Robert J.; Carter, Shelly L.; Wu, Juan; Wingard, John R.; Difronzo, Nancy L.; Ferrara, James L.; Giralt, Sergio; Madtes, David K.; Drexler, Rebecca; White, Eric S.; Cooke, Kenneth R.

    2014-01-01

    Idiopathic pneumonia syndrome (IPS) is a diffuse, noninfectious lung injury that occurs acutely after allogeneic hematopoietic cell transplantation (HCT). IPS-related mortality has been historically high (>50%) despite treatment with systemic corticosteroids and supportive care measures. We have now examined the role of tumor necrosis factor inhibition in a randomized, double-blind, placebo-controlled trial of corticosteroids with etanercept or placebo. Thirty-four subjects (≥18 years) with IPS after HCT were randomized to receive meth-ylprednisolone (2 mg/kg/day) plus etanercept (0.4 mg/kg twice weekly ≥ 4 weeks; n = 16) or placebo (n = 18). No active infections and a pathogen-negative bronchoscopy were required at study entry. Response (alive, with complete discontinuation of supplemental oxygen support) and overall survival were examined. This study, originally planned to accrue 120 patients, was terminated prematurely due to slow accrual. In the limited number of patients examined, there were no differences in response rates at day 28 of study. Ten of 16 patients (62.5% [95% confidence interval {CI}, 35.4% to 84.8%]) receiving etanercept and 12 of 18 patients (66.7% [95% CI, 41.0% to 86.7%]) receiving placebo met the day 28 response definition (P = 1.00). The median survival was 170 days (95% CI, 11 to 362) with etanercept versus 64 days (95% CI, 26 to 209) with placebo (P = .51). Among responders, the median time to discontinuation of supplemental oxygen was 9 days (etanercept) versus 7 days (placebo). Therapy was well tolerated, with 1 toxicity-related death from infectious pneumonia in the placebo arm. The treatment of IPS with corticosteroids in adult HCT recipients was associated with high early response rates (>60%) compared with historical reports, with poor overall survival. The addition of etanercept did not lead to further increases in response, although the sample size of this truncated trial preclude a definitive conclusion. PMID:24607553

  5. Phase II Study of Haploidentical Natural Killer Cell Infusion for Treatment of Relapsed or Persistent Myeloid Malignancies Following Allogeneic Hematopoietic Cell Transplantation.

    PubMed

    Shaffer, Brian C; Le Luduec, Jean-Benoit; Forlenza, Christopher; Jakubowski, Ann A; Perales, Miguel-Angel; Young, James W; Hsu, Katharine C

    2016-04-01

    We conducted a phase 2 study to determine the efficacy of HLA-haploidentical related donor natural killer (NK) cells after cyclophosphamide-based lymphodepletion in patients with relapsed or progressive acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) following allogeneic hematopoietic cell transplantation (HCT). Eight patients (2 with MDS and 6 with AML) were treated with cyclophosphamide 50 mg/kg on day -3 and day -2 before infusion of NK cells isolated from a haploidentical related donor. One patient also received fludarabine 25 mg/m2/day for 4 days. Six doses of 1 million units of interleukin-2 (IL-2) were administered on alternating days beginning on day -1. The median number of NK cells infused was 10.6 × 10(6)/kg (range, 4.3 to 22.4 × 10(6)/kg), and the median number of CD3 cells infused was 2.1 × 10(3)/kg (range, 1.9 to 40 × 10(3)/kg). NK infusions were well tolerated, with a median time to neutrophil recovery of 19 days (range, 7 days to not achieved) and no incidence of graft-versus-host disease after NK infusion. One patient with AML and 1 patient with MDS achieved a complete response, but relapsed at 1.7 and 1.8 months, respectively. One patient with MDS experienced resolution of dysplastic features but persistence of clonal karyotype abnormalities; this patient was stable at 65 months after NK cell therapy. The median duration of survival was 12.9 months (range, 0.8 to 65.3 months). Chimerism analysis of CD3(-)/CD56(+) peripheral blood cells did not detect any circulating haploidentical NK cells after infusion. NK phenotyping was performed in 7 patients during and after IL-2 infusion. We found a slight trend toward greater expression of KIR2DL2/2DL3/2DS2 (5% versus 28%; P = .03) at 14 days in patients who survived longer than 6 months from NK cell infusion (n = 4) compared with those who died within 6 months of NK cell therapy (n = 3). In summary, our data support the safety of haploidentical NK cell infusion after allogeneic HCT.

  6. Recombinant human erythropoietin therapy in critically ill patients: a dose-response study [ISRCTN48523317

    PubMed Central

    Georgopoulos, Dimitris; Matamis, Dimitris; Routsi, Christina; Michalopoulos, Argiris; Maggina, Nina; Dimopoulos, George; Zakynthinos, Epaminondas; Nakos, George; Thomopoulos, George; Mandragos, Kostas; Maniatis, Alice

    2005-01-01

    Introduction The aim of this study was to assess the efficacy of two dosing schedules of recombinant human erythropoietin (rHuEPO) in increasing haematocrit (Hct) and haemoglobin (Hb) and reducing exposure to allogeneic red blood cell (RBC) transfusion in critically ill patients. Method This was a prospective, randomized, multicentre trial. A total of 13 intensive care units participated, and a total of 148 patients who met eligibility criteria were enrolled. Patients were randomly assigned to receive intravenous iron saccharate alone (control group), intravenous iron saccharate and subcutaneous rHuEPO 40,000 units once per week (group A), or intravenous iron saccharate and subcutaneous rHuEPO 40,000 units three times per week (group B). rHuEPO was given for a minimum of 2 weeks or until discharge from the intensive care unit or death. The maximum duration of therapy was 3 weeks. Results The cumulative number of RBC units transfused, the average numbers of RBC units transfused per patient and per transfused patient, the average volume of RBCs transfused per day, and the percentage of transfused patients were significantly higher in the control group than in groups A and B. No significant difference was observed between group A and B. The mean increases in Hct and Hb from baseline to final measurement were significantly greater in group B than in the control group. The mean increase in Hct was significantly greater in group B than in group A. The mean increase in Hct in group A was significantly greater than that in control individuals, whereas the mean increase in Hb did not differ significantly between the control group and group A. Conclusion Administration of rHuEPO to critically ill patients significantly reduced the need for RBC transfusion. The magnitude of the reduction did not differ between the two dosing schedules, although there was a dose response for Hct and Hb to rHuEPO in these patients. PMID:16277712

  7. (GT)n Repeat Polymorphism in Heme Oxygenase-1 (HO-1) Correlates with Clinical Outcome after Myeloablative or Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation

    PubMed Central

    Køllgaard, Tania; Kornblit, Brian; Petersen, Jesper; Klausen, Tobias Wirenfeldt; Mortensen, Bo Kok; Brændstrup, Peter; Sengeløv, Henrik; Høgdall, Estrid; Müller, Klaus; Vindeløv, Lars; Andersen, Mads Hald; thor Straten, Per

    2016-01-01

    Allogeneic hematopoietic cell transplantation (HCT) is a treatment for various hematologic diseases where efficacy of treatment is in part based on the graft versus tumour (GVT) activity of cells in the transplant. The cytoprotective enzyme heme oxygenase-1 (HO-1) is a rate-limiting enzyme in heme degradation and it has been shown to exert anti-inflammatory functions. In humans a (GT)n repeat polymorphism regulates the expression of HO-1. We conducted fragment length analyses of the (GT)n repeat in the promotor region of the gene for HO-1 in DNA from donors and recipients receiving allogeneic myeloablative- (MA) (n = 110) or nonmyeloablative- (NMA-) (n = 250) HCT. Subsequently, we compared the length of the (GT)n repeat with clinical outcome after HCT. We demonstrated that transplants from a HO-1high donor after MA-conditioning (n = 13) is associated with higher relapse incidence at 3 years (p = 0.01, n = 110). In the NMA-conditioning setting transplantation of HO-1low donor cells into HO-1low recipients correlated significantly with decreased relapse related mortality (RRM) and longer progression free survival (PFS) (p = 0.03 and p = 0.008, respectively). Overall, our findings suggest that HO-1 may play a role for the induction of GVT effect after allogeneic HCT. PMID:27997582

  8. Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty

    PubMed Central

    Golpanian, Samuel; DiFede, Darcy L.; Pujol, Marietsy V.; Lowery, Maureen H.; Levis-Dusseau, Silvina; Goldstein, Bradley J.; Schulman, Ivonne H.; Longsomboon, Bangon; Wolf, Ariel; Khan, Aisha; Heldman, Alan W.; Goldschmidt-Clermont, Pascal J.; Hare, Joshua M.

    2016-01-01

    Frailty is a syndrome associated with reduced physiological reserves that increases an individual's vulnerability for developing increased morbidity and/or mortality. While most clinical trials have focused on exercise, nutrition, pharmacologic agents, or a multifactorial approach for the prevention and attenuation of frailty, none have studied the use of cell-based therapies. We hypothesize that the application of allogeneic human mesenchymal stem cells (allo-hMSCs) as a therapeutic agent for individuals with frailty is safe and efficacious. The CRATUS trial comprises an initial non-blinded phase I study, followed by a blinded, randomized phase I/II study (with an optional follow-up phase) that will address the safety and pre-specified beneficial effects in patients with the aging frailty syndrome. In the initial phase I protocol, allo-hMSCs will be administered in escalating doses via peripheral intravenous infusion (n=15) to patients allocated to three treatment groups: Group 1 (n=5, 20 million allo-hMSCs), Group 2 (n=5, 100 million allo-hMSCs), and Group 3 (n=5, 200 million allo-hMSCs). Subsequently, in the randomized phase, allo-hMSCs or matched placebo will be administered to patients (n=30) randomly allocated in a 1:1:1 ratio to one of two doses of MSCs versus placebo: Group A (n=10, 100 million allo-hMSCs), Group B (n=10, 200 million allo-hMSCs), and Group C (n=10, placebo). Primary and secondary objectives are, respectively, to demonstrate the safety and efficacy of allo-hMSCs administered in frail older individuals. This study will determine the safety of intravenous infusion of stem cells and compare phenotypic outcomes in patients with aging frailty. PMID:26933813

  9. Non-comparative evaluation of the safety of aerosolized amphotericin B lipid complex in patients undergoing allogeneic hematopoietic stem cell transplantation.

    PubMed

    Alexander, B D; Dodds Ashley, E S; Addison, R M; Alspaugh, J A; Chao, N J; Perfect, J R

    2006-03-01

    Allogeneic hematopoietic stem cell transplant (HSCT) recipients are at increased risk for invasive fungal infections (IFIs) over prolonged periods of time. Aerosolized amphotericin B lipid complex (ABLC) has shown promise in lung transplant recipients as a convenient means of delivering protective drug to the upper airways avoiding systemic toxicities. The safety and tolerability of aerosolized ABLC in 40 subjects undergoing allogeneic HSCT was prospectively investigated in an open-labeled, non-comparative study. Subjects received aerosolized ABLC treatment once daily for 4 days, then once weekly for 13 weeks; fluconazole was administered daily as standard of care through post-transplant day 100. Pulmonary mechanics were measured before and after each dose of inhaled ABLC; adverse events (AEs) and the development of IFI were also monitored. Cough, nausea, taste disturbance, or vomiting followed 2.2% of 458 total inhaled ABLC administrations; 5.2% of inhaled ABLC administrations were associated with >or=20% decrease in pulmonary function measurements (forced expiratory volume in 1 second or forced vital capacity) and none required treatment with bronchodilators or withdrawal from study. Four mild AEs were considered possibly or probably related to study treatment; no deaths or withdrawals from treatment were attributed to study drug. Of 3 proven IFIs occurring during the study period, only 1, a catheter-related case of disseminated fusariosis, occurred while the subject was receiving study medication. Aerosolized ABLC was well tolerated in allogeneic HSCT recipients. With only 1 of 40 subjects developing IFI while receiving treatment, the combination of fluconazole and inhaled ABLC warrants further study as antifungal prophylaxis following allogeneic HSCT.

  10. ABO mismatch is associated with increased nonrelapse mortality after allogeneic hematopoietic cell transplantation.

    PubMed

    Logan, Aaron C; Wang, Zhiyu; Alimoghaddam, Kamran; Wong, Ruby M; Lai, Tze; Negrin, Robert S; Grumet, Carl; Logan, Brent R; Zhang, Mei-Jie; Spellman, Stephen R; Lee, Stephanie J; Miklos, David B

    2015-04-01

    We evaluated ABO associated outcomes in 1737 patients who underwent allogeneic hematopoietic cell transplantation (allo-HCT) at Stanford University between January 1986 and July 2011. Grafts were 61% ABO matched, 18% major mismatched (MM), 17% minor MM, and 4% bidirectional MM. Median follow-up was 6 years. In multivariate analysis, overall survival (OS) was inferior in minor MM hematopoietic cell transplantations (median 2.1 versus 6.3 years; hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.19 to 2.05; P = .001) in comparison with ABO-matched grafts. ABO minor MM was associated with an increase in early nonrelapse mortality (NRM) (18% versus 13%; HR, 1.48; 95% CI, 1.06 to 2.06; P = .02). In an independent Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 435 lymphoma patients receiving mobilized peripheral blood grafts, impairment of OS (HR, 1.55; 95% CI, 1.07 to 2.25; P = .021) and increased NRM (HR, 1.72; 95% CI, 1.11 to 2.68; P = .03) were observed in recipients of ABO minor-MM grafts. A second independent analysis of a CIBMTR data set including 5179 patients with acute myeloid leukemia and myelodysplastic syndrome identified a nonsignificant trend toward decreased OS in recipients of ABO minor-MM grafts and also found ABO major MM to be significantly associated with decreased OS (HR, 1.19; 95% CI, 1.08 to 1.31; P < .001) and increased NRM (HR, 1.23; 95% CI, 1.08 to 1.4; P = .002). ABO minor and major MM are risk factors for worse transplantation outcomes, although the associated hazards may not be uniform across different transplantation populations. Further study is warranted to determine which patient populations are at greatest risk, and whether this risk can be modified by anti-B cell therapy or other peri-transplantation treatments.

  11. High-dose immunosuppressive therapy and autologous HCT for relapsing-remitting MS

    PubMed Central

    Hutton, George J.; Racke, Michael K.; Popat, Uday; Devine, Steven M.; Steinmiller, Kaitlyn C.; Griffith, Linda M.; Muraro, Paolo A.; Openshaw, Harry; Sayre, Peter H.; Stuve, Olaf; Arnold, Douglas L.; Wener, Mark H.; Georges, George E.; Wundes, Annette; Kraft, George H.; Bowen, James D.

    2017-01-01

    Objective: To evaluate the safety, efficacy, and durability of multiple sclerosis (MS) disease stabilization after high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT). Methods: High-Dose Immunosuppression and Autologous Transplantation for Multiple Sclerosis (HALT-MS) is a phase II clinical trial of HDIT/HCT for patients with relapsing-remitting (RR) MS who experienced relapses with disability progression (Expanded Disability Status Scale [EDSS] 3.0–5.5) while on MS disease-modifying therapy. The primary endpoint was event-free survival (EFS), defined as survival without death or disease activity from any one of: disability progression, relapse, or new lesions on MRI. Participants were evaluated through 5 years posttransplant. Toxicities were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events (AE). Results: Twenty-five participants were evaluated for transplant and 24 participants underwent HDIT/HCT. Median follow-up was 62 months (range 12–72). EFS was 69.2% (90% confidence interval [CI] 50.2–82.1). Progression-free survival, clinical relapse-free survival, and MRI activity-free survival were 91.3% (90% CI 74.7%–97.2%), 86.9% (90% CI 69.5%–94.7%), and 86.3% (90% CI 68.1%–94.5%), respectively. AE due to HDIT/HCT were consistent with expected toxicities and there were no significant late neurologic adverse effects noted. Improvements were noted in neurologic disability with a median change in EDSS of −0.5 (interquartile range −1.5 to 0.0; p = 0.001) among participants who survived and completed the study. Conclusion: HDIT/HCT without maintenance therapy was effective for inducing long-term sustained remissions of active RRMS at 5 years. ClinicalTrials.gov identifier: NCT00288626. Classification of evidence: This study provides Class IV evidence that participants with RRMS experienced sustained remissions with toxicities as expected from HDIT/HCT. PMID:28148635

  12. Allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia who had central nervous system involvement: a study from the Adult ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation.

    PubMed

    Shigematsu, Akio; Kako, Shinichi; Mitsuhashi, Kenjiro; Iwato, Koji; Uchida, Naoyuki; Kanda, Yoshinobu; Fukuda, Takahiro; Sawa, Masashi; Senoo, Yasushi; Ogawa, Hiroyasu; Miyamura, Koichi; Takada, Satoru; Nagamura-Inoue, Tokiko; Morishima, Yasuo; Ichinohe, Tatsuo; Atsuta, Yoshiko; Mizuta, Shuichi; Tanaka, Junji

    2017-02-14

    The prognosis for adult acute lymphoblastic leukemia (ALL) patients with central nervous system (CNS) involvement (CNS+) who received allogeneic hematopoietic stem cell transplantation (allo-SCT) remains unclear. We retrospectively compared the outcomes of allo-SCT for patients with CNS involvement and for patients without CNS involvement (CNS-) using a database in Japan. The eligibility criteria for this study were as follows: diagnosis of ALL, aged more than 16 years, allo-SCT between 2005 and 2012, and first SCT. Data for 2582 patients including 136 CNS+ patients and 2446 CNS- patients were used for analyses. As compared with CNS- patients, CNS+ patients were younger, had worse disease status at SCT and had poorer performance status (PS) at SCT (P < 0.01). Incidence of relapse was higher in CNS+ patients (P = 0.02), and incidence of CNS relapse was also higher (P < 0.01). The probability of 3-year overall survival (OS) was better in CNS- patients (P < 0.01) by univariate analysis. However, in patients who received SCT in CR, there was no difference in the probability of OS between CNS+ and CNS- patients (P = 0.38) and CNS involvement did not have an unfavorable effect on OS by multivariate analysis. CNS+ patients who achieved CR showed OS comparable to that of CNS- patients.

  13. [Human Herpesvirus-6 Encephalitis in Allogeneic Hematopoietic Stem Cell Transplantation].

    PubMed

    Ogata, Masao

    2015-07-01

    The reactivation of human herpesvirus-6B (HHV-6B) is common after allogeneic hematopoietic cell transplantation (allo-HCT), and it is sporadically associated with the development of HHV-6 encephalitis. HHV-6 encephalitis typically develops around 2-6 weeks after allo-HCT, and it is characterized by short-term memory loss. Magnetic resonance imaging typically shows bilateral signal abnormalities in the limbic system. The incidence of HHV-6 encephalitis is reportedly 0-11.6% after bone marrow or peripheral blood stem cell transplantation and 4.9-21.4% after cord blood transplantation. The mortality of HHV-6 encephalitis is high, and survivors are often left with serious sequelae. Antiviral therapy using foscarnet or ganciclovir is recommended for the treatment of HHV-6 encephalitis, but the efficacy of the currently available treatment is insufficient once HHV-6 encephalitis has developed. The elucidation of the pathogenesis of HHV-6 encephalitis and the establishment of preventative therapy are needed to overcome this disease.

  14. Dendritic cell-mediated immune humanization of mice: implications for allogeneic and xenogeneic stem cell transplantation.

    PubMed

    Salguero, Gustavo; Daenthanasanmak, Anusara; Münz, Christian; Raykova, Ana; Guzmán, Carlos A; Riese, Peggy; Figueiredo, Constanca; Länger, Florian; Schneider, Andreas; Macke, Laura; Sundarasetty, Bala Sai; Witte, Torsten; Ganser, Arnold; Stripecke, Renata

    2014-05-15

    De novo regeneration of immunity is a major problem after allogeneic hematopoietic stem cell transplantation (HCT). HCT modeling in severely compromised immune-deficient animals transplanted with human stem cells is currently limited because of incomplete maturation of lymphocytes and scarce adaptive responses. Dendritic cells (DC) are pivotal for the organization of lymph nodes and activation of naive T and B cells. Human DC function after HCT could be augmented with adoptively transferred donor-derived DC. In this study, we demonstrate that adoptive transfer of long-lived human DC coexpressing high levels of human IFN-α, human GM-CSF, and a clinically relevant Ag (CMV pp65 protein) promoted human lymphatic remodeling in immune-deficient NOD.Rag1(-/-).IL-2rγ(-/-) mice transplanted with human CD34(+) cells. After immunization, draining lymph nodes became replenished with terminally differentiated human follicular Th cells, plasma B cells, and memory helper and cytotoxic T cells. Human Igs against pp65 were detectable in plasma, demonstrating IgG class-switch recombination. Human T cells recovered from mice showed functional reactivity against pp65. Adoptive immunotherapy with engineered DC provides a novel strategy for de novo immune reconstitution after human HCT and a practical and effective tool for studying human lymphatic regeneration in vivo in immune deficient xenograft hosts.

  15. [The impact of donor naive and memory T cell subsets on patient outcome following allogeneic stem cell transplantation: relationship between infused donor CD4+/CCR7+ T cell subsets and acute graft-versus-host disease].

    PubMed

    Choufi, B; Thiant, S; Trauet, J; Cliquennois, M; Cherrel, M; Boulanger, F; Coiteux, V; Magro, L; Labalette, M; Yakoub-Agha, I

    2014-06-01

    In a previous prospective study on 62 patients who underwent an HLA-matched allogeneic stem cell transplantation, we have observed that proportion of donor-derived CCR7(+)/CD4(+) T cells in the graft provided a predictive indicator of acute GVHD without interfering on chronic GVHD and relapse rate. Here we present our results on a confirmatory cohort of 137 consecutive patients. Indeed patients who received more than 76% of CCR7(+)/CD4(+) T cells in the graft developed more often acute GVHD be it of low or high grade than those who did not. Determination of the CCR7(+)/CCR7(neg) ratio of CD4(+) T cells in the graft provides a predictive indicator of acute GVHD and could help to define strategies of partial selective T cell depleted transplantation.

  16. PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS OF INOSINE MONOPHOSPHATE DEHYDROGENASE (IMPDH) ACTIVITY IN MMF-TREATED HCT RECIPIENTS

    PubMed Central

    Li, Hong; Mager, Donald E.; Sandmaier, Brenda M.; Storer, Barry E.; Boeckh, Michael J.; Bemer, Meagan J.; Phillips, Brian R.; Risler, Linda J.; McCune, Jeannine S.

    2014-01-01

    A novel approach to personalizing postgrafting immunosuppression in hematopoietic cell transplant (HCT) recipients is evaluating inosine monophosphate dehydrogenase (IMPDH) activity as a drug-specific biomarker of mycophenolic acid (MPA)-induced immunosuppression. This prospective study evaluated total MPA, unbound MPA, and total MPA glucuronide plasma concentrations and IMPDH activity in peripheral blood mononuclear cells (PMNC) at five time points after the morning dose of oral mycophenolate mofetil (MMF) on day +21 in 56 nonmyeloablative HCT recipients. Substantial interpatient variability in the pharmacokinetics and pharmacodynamics was observed and accurately characterized by the population pharmacokinetic/dynamic model. IMPDH activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration in most patients. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory Emax model with an IC50 = 3.23 mg/L total MPA and 57.3 ng/mL unbound MPA. The day +21 IMPDH area under the effect curve (AUEC) was associated with cytomegalovirus reactivation, non-relapse mortality, and overall mortality. In conclusion, a pharmacokinetic/dynamic model was developed that relates plasma MPA concentrations with PMNC IMPDH activity after an MMF dose in HCT recipients. Future studies should validate this model and confirm that day +21 IMPDH AUEC is a predictive biomarker. PMID:24727337

  17. [Prophylactic, preemptive and curative use of donor lymphocyte infusion in patients undergoing allogeneic stem cell transplantation: guidelines of the SFGM-TC].

    PubMed

    Guillaume, T; Porcheron, S; Audat, F; Bancillon, N; Berceanu, A; Charbonnier, A; Dulery, R; Edy, N; El Cheikh, J; Hermet, E; Maurer, N; Paul, F; Konopacki-Potet, J; Turlure, P; Wallart, A; Boulanger, F; Dhédin, N; Suarez, F; Yakoub-Agha, I

    2014-08-01

    In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapy (SFGM-TC) set up the fourth annual series of workshops which brought together practitioners from all member centers and took place in September 2013 in Lille. Here, we report our recommendations regarding the use of donor lymphocyte injection (DLI) in the prophylactic, pre-emptive and curative settings. This work has been limited to allogeneic stem cell transplantations from an HLA-matched (10/10) or -one antigen-mismatched (9/10) donor.

  18. Second reduced intensity conditioning allogeneic transplant as a rescue strategy for acute leukaemia patients who relapse after an initial RIC allogeneic transplantation: analysis of risk factors and treatment outcomes.

    PubMed

    Vrhovac, R; Labopin, M; Ciceri, F; Finke, J; Holler, E; Tischer, J; Lioure, B; Gribben, J; Kanz, L; Blaise, D; Dreger, P; Held, G; Arnold, R; Nagler, A; Mohty, M

    2016-02-01

    Limited therapeutic options are available after relapse of acute leukaemia following first reduced intensity conditioning haematopoietic stem cell transplantation (RIC1). A retrospective study on European Society for Blood and Marrow Transplantation (EBMT) registry data was performed on 234 adult patients with acute leukaemia who received a second RIC transplantation (RIC2) from 2000 to 2012 as a salvage treatment for relapse following RIC1. At the time of RIC2, 167 patients (71.4%) had relapsed or refractory disease, 49 (20.9%) were in second CR and 18 (7.7%) in third or higher CR. With a median follow-up of 21 (1.5-79) months after RIC2, 51 patients are still alive. At 2 years, the cumulative incidence of non-relapse mortality (NRM), relapse incidence (RI), leukaemia-free survival (LFS) and overall survival (OS) were 22.4% (95% confidence interval (CI): 17-28.4), 63.9% (56.7-70.1), 14.6% (8.8-18.5) and 20.5% (14.9-26.1), respectively. In patients with acute myelogenous, biphenotypic and undifferentiated leukaemia (representing 89.8% of all patients), duration of remission following RIC1 >225 days, presence of CR at RIC2, patient's Karnofsky performance status >80 at RIC2 and non-myeloablative conditioning were found to be the strongest predictors of patients' favourable outcome.

  19. C19orf48 Encodes a Minor Histocompatibility Antigen Recognized by CD8+ Cytotoxic T Cells from Renal Cell Carcinoma Patients

    PubMed Central

    Tykodi, Scott S.; Fujii, Nobuharu; Vigneron, Nathalie; Lu, Sharon M.; Mito, Jeffrey K.; Miranda, Maureen X.; Chou, Jeffrey; Voong, Lilien N.; Thompson, John A.; Sandmaier, Brenda M.; Cresswell, Peter; Van den Eynde, Benoît; Riddell, Stanley R.; Warren, Edus H.

    2009-01-01

    Purpose Tumor regression has been observed in some patients with metastatic renal cell carcinoma (RCC) after nonmyeloablative allogeneic hematopoietic cell transplantation (HCT). Cellular and molecular characterization of antigens recognized by tumor-reactive T cells isolated from responding patients could potentially provide insight into the mechanisms of tumor regression. Experimental Design CD8+ cytotoxic T lymphocyte (CTL) clones that recognized a novel RCC-associated minor histocompatibility (H) antigen presented by HLA-A*0201 were isolated from two patients with metastatic RCC who experienced tumor regression or stable disease following nonmyeloablative allogeneic HCT. These clones were used to screen a cDNA library and isolate the unique cDNA encoding the antigen. Results An alternative open reading frame in the C19orf48 gene located on chromosome 19q13 encodes the HLA-A*0201-restricted minor H antigen recognized by the RCC-reactive T cells. Differential T cell recognition of donor- and recipient-derived target cells is attributable to a nonsynonymous single nucleotide polymorphism within the nucleotide interval that encodes the antigenic peptide. Assays for gene expression and CTL recognition demonstrated that the C19orf48-encoded peptide is widely expressed in renal tumors and solid tumors of other histologies. The antigenic peptide can be processed for CTL recognition via both TAP-dependent and TAP-independent pathways. Conclusions Donor T cell responses against the HLA-A*0201-restricted minor H antigen encoded by C19orf48 may contribute to RCC regression after MHC-matched allogeneic HCT. PMID:18698046

  20. Pre-Operative Autologous Blood Donation Does Not Affect Pre-Incision Hematocrit in Adolescent Idiopathic Scoliosis Patients. A Retrospective Cohort of a Prospective Randomized Trial

    PubMed Central

    Verma, Kushagra; Peters, Austin; Lonner, Baron S.; Errico, Thomas

    2016-01-01

    Background Pre-donation of autologous blood prior to spine fusion for adolescent idiopathic scoliosis (AIS) has been used in deformity surgery. The effect of pre-donation on pre-operative hematocrit (Hct) remains debated. Multiple factors may influence pre-operative Hct including intravascular volume status, patient factors, and timing of pre-operative blood donation. The purpose of this study was to determine if pre-donation significantly lowers pre-incision Hct in AIS patients. Methods A retrospective cohort study of a Level-1 prospective randomized trial was conducted. 125 patients from the homogeneous population were included. AIS patients undergoing a posterior only spinal fusion for AIS were separated into two groups based on their pre-operative blood donation history. Demographic variables, pre-incision Hct, and transfusion rates were compared between the two groups using the Student's T-test. Results Pre-donation and non pre-donation groups had 28 and 97 patients, respectively. Pre-donation group was 75% female (21F, 7M) and non pre-donation group was 78% female (76F, 21M). There was no difference between pre-donation and non pre-donation groups in mean age (15.6 ± 2.2 vs 14.8 ± 2.2, p = 0.081), BMI (23.1 ± 4.2 vs 21.7 ± 5.3, p = 0.219), and pre-incision Hct (32.8 ± 3.4 vs 33.8 ± 3.1, p = 0.628). The overall transfusion rates were equivalent (32.1± 48.0% vs 25.8 ± 44.0%, p = 0.509), however, the rate of allogenic transfusion for the pre-donation group was significantly lower (3.6 ± 18.9% vs 25.8 ± 44.0%, p = 0.011). Conclusions This study supports the use of pre-donation for AIS, without a significant drop in pre-incision Hct. Patients that donate are also much less likely to be exposed to allogenic blood. There may be a surgeon bias to recommend pre-donation in patients with a larger BMI and older age. Future studies are needed from a larger population of patients including those with non-AIS pathology. Level of evidence: Level III. PMID:27652198

  1. Cannabidiol for the Prevention of Graft-versus-Host-Disease after Allogeneic Hematopoietic Cell Transplantation: Results of a Phase II Study.

    PubMed

    Yeshurun, Moshe; Shpilberg, Ofer; Herscovici, Corina; Shargian, Liat; Dreyer, Juliet; Peck, Anat; Israeli, Moshe; Levy-Assaraf, Maly; Gruenewald, Tsipora; Mechoulam, Raphael; Raanani, Pia; Ram, Ron

    2015-10-01

    Graft-versus-host-disease (GVHD) is a major obstacle to successful allogeneic hematopoietic cell transplantation (alloHCT). Cannabidiol (CBD), a nonpsychotropic ingredient of Cannabis sativa, possesses potent anti-inflammatory and immunosuppressive properties. We hypothesized that CBD may decrease GVHD incidence and severity after alloHCT. We conducted a phase II study. GVHD prophylaxis consisted of cyclosporine and a short course of methotrexate. Patients transplanted from an unrelated donor were given low-dose anti-T cell globulin. CBD 300 mg/day was given orally starting 7 days before transplantation until day 30. Forty-eight consecutive adult patients undergoing alloHCT were enrolled. Thirty-eight patients (79%) had acute leukemia or myelodysplastic syndrome and 35 patients (73%) were given myeloablative conditioning. The donor was either an HLA-identical sibling (n = 28), a 10/10 matched unrelated donor (n = 16), or a 1-antigen-mismatched unrelated donor (n = 4). The median follow-up was 16 months (range, 7 to 23). No grades 3 to 4 toxicities were attributed to CBD. None of the patients developed acute GVHD while consuming CBD. In an intention-to-treat analysis, we found that the cumulative incidence rates of grades II to IV and grades III to IV acute GVHD by day 100 were 12.1% and 5%, respectively. Compared with 101 historical control subjects given standard GVHD prophylaxis, the hazard ratio of developing grades II to IV acute GVHD among subjects treated with CBD plus standard GVHD prophylaxis was .3 (P = .0002). Rates of nonrelapse mortality at 100 days and at 1 year after transplantation were 8.6% and 13.4%, respectively. Among patients surviving more than 100 days, the cumulative incidences of moderate-to-severe chronic GVHD at 12 and 18 months were 20% and 33%, respectively. The combination of CBD with standard GVHD prophylaxis is a safe and promising strategy to reduce the incidence of acute GVHD. A randomized double-blind controlled study is warranted

  2. Treatment of Oral Mucositis in Hematologic Patients Undergoing Autologous or Allogeneic Transplantation of Peripheral Blood Stem Cells: a Prospective, Randomized Study with a Mouthwash Containing Camelia Sinensis Leaf Extract

    PubMed Central

    Carulli, Giovanni; Rocco, Melania; Panichi, Alessia; Chios, Chiara Feira; Ciurli, Ester; Mannucci, Chiara; Sordi, Elisabetta; Caracciolo, Francesco; Papineschi, Federico; Benedetti, Edoardo; Petrini, Mario

    2013-01-01

    Oral mucositis is an important side effect of hematopoietic stem cell transplantation (HCST), mainly due to toxicity of conditioning regimens. It produces significant pain and morbidity. The present study reports a prospective, randomized, non-blinded study testing the efficacy of a new mouthwash, called Baxidil Onco® (Sanitas Farmaceutici Srl, Tortona, Italy) in 60 hematologic patients undergoing HCST (28 autologous, 32 allogeneic). Baxidil Onco®, used three times a day from Day -1 to Day +30, in addition to standard prophylactic schedules, was administered to 14 patients undergoing autologous and 14 patients undergoing allogeneic HCST. The remaining 32 patients (14 autologous and 18 HCST) were treated only with standard prophylactic schedules and served as control. In our study, the overall incidence of oral mucositis, measured according to the World Health Organization 0-4 scale, was 50% in the Baxidl Onco® group versus 82% in the control group (P=0.022). In addition, a significant reduction in scale 2-4 oral mucositis was observed in the Baxidil Onco® group (25% vs 56.2%; P=0.0029). The results obtained indicate that incidence, severity and duration of oral mucositis induced by conditioning regimens for HCST can be significantly reduced by oral rinsing with Baxidil Onco®, in addition to the standard prophylaxis scheme. Since Camelia Sinensin extract, which is used to produce green tea, is the main agent in this mouthwash, we hypothesize that the anti-oxidative properties of polyphenolic compounds of tea might exert protective effects on oral mucosa. PMID:23888242

  3. Design and Validation of an Augmented Hematopoietic Cell Transplantation-Comorbidity Index Comprising Pretransplant Ferritin, Albumin, and Platelet Count for Prediction of Outcomes after Allogeneic Transplantation.

    PubMed

    Vaughn, Jennifer E; Storer, Barry E; Armand, Philippe; Raimondi, Roberto; Gibson, Christopher; Rambaldi, Alessandro; Ciceri, Fabio; Oneto, Rosi; Bruno, Benedetto; Martin, Paul J; Sandmaier, Brenda M; Storb, Rainer; Sorror, Mohamed L

    2015-08-01

    Pretransplant values of serum ferritin, albumin, and peripheral blood counts were previously suggested to provide prognostic information about hematopoietic cell transplantation (HCT) outcomes. Whether these "biomarkers" have prognostic value independent of each other and the HCT-comorbidity index (HCT-CI) is unknown. We analyzed data from 3917 allogeneic HCT recipients at multiple sites in the United States and Italy using multivariate models including each biomarker and the HCT-CI. Data from all sites were then randomly divided into a training set (n = 2352) to develop weights for the relevant biomarkers to be added to the HCT-CI scores and a validation set (n = 1407) to validate an augmented HCT-CI compared with the original index. Multivariate analysis with data from one site showed that ferritin, albumin, and platelets-not neutrophils or hemoglobin-were independently associated with increased nonrelapse mortality (NRM) and decreased overall survival. Findings were validated in data from the other sites. Subsequently, in a training set from all sites, ferritin >2500 mg/dL (hazard ratio [HR], 1.69); albumin 3 to 3.5 g/dL (HR, 1.61) and <3.0 g/dL (HR, 2.27); and platelets 50 to <100,000 (HR, 1.28), 20 to <50,000 (HR, 1.29), and <20,000 (HR, 1.55) were statistically significantly associated with NRM. Weights were assigned to these laboratory values following the same equation used to design the original index. In the validation set, the addition of the biomarkers to the original index to develop an augmented HCT-CI resulted in a statistically significant increase in a higher c-statistic estimate for prediction of NRM (P = .0007). Ferritin, albumin, and platelet counts are important prognostic markers that further refine the discriminative power of the HCT-CI for transplant outcomes.

  4. A Safety and Feasibility Study of an Allogeneic Colon Cancer Cell Vaccine Administered with a Granulocyte–Macrophage Colony Stimulating Factor–Producing Bystander Cell Line in Patients with Metastatic Colorectal Cancer

    PubMed Central

    Zheng, Lei; Edil, Barish H.; Soares, Kevin C.; El-Shami, Khaled; Uram, Jennifer N.; Judkins, Carol; Zhang, Zhe; Onners, Beth; Laheru, Daniel; Pardoll, Drew; Jaffee, Elizabeth M.; Schulick, Richard D.

    2014-01-01

    Background Despite recent advances in earlier detection and improvements in chemotherapy, the 5-year survival rate of patients with metastatic colorectal carcinoma remains poor. Immunotherapy is a potentially effective therapeutic approach to the treatment of colorectal carcinoma. Preclinical studies have supported the antitumor activity of immunization with a granulocyte–macrophage colony-stimulating factor (GM-CSF) producing murine colon tumor cell vaccine. Methods A novel colorectal cancer vaccine composed of irradiated, allogeneic human colon cancer cells and GM-CSF-producing bystander cells was developed and tested in combination with a single intravenous low dose of cyclophosphamide in a phase 1 study of patients with metastatic colorectal cancer. Results A total of nine patients were enrolled onto and treated in this study. Six patients had a history of colorectal adenocarcinoma hepatic metastases and underwent curative metastasectomy, while three other patients had unresectable stage IV disease. This study demonstrates the safety and feasibility of this vaccine administered in patients with metastatic colorectal cancer. At last follow-up, the six patients who underwent curative metastasectomy survived longer than 36 months, and four of these six patients were without disease recurrence. Immunologic correlate results suggest that the GM-CSF-producing colon cancer vaccine enhances the production of anti-MUC1 antibodies. Conclusions This vaccine is feasible and safe. Future investigation of the efficacy and antitumor immunity of this vaccine is warranted. PMID:24943235

  5. Effectivity of a strategy in elderly AML patients to reach allogeneic stem cell transplantation using intensive chemotherapy: Long-term survival is dependent on complete remission after first induction therapy.

    PubMed

    von dem Borne, P A; de Wreede, L C; Halkes, C J M; Marijt, W A F; Falkenburg, J H F; Veelken, H

    2016-07-01

    Intensive chemotherapy followed by allogeneic stem cell transplantation (alloSCT) can cure AML. Most studies on alloSCT in elderly AML report results of highly selected patient cohorts. Hardly any data exist on the effectiveness of prospective strategies intended to bring as many patients as possible to transplant. Between 2006 and 2011 we implemented a treatment algorithm for all newly diagnosed AML patients aged 61-75 years, consisting of intensive chemotherapy cycles to induce complete remission, followed by alloSCT. 44 of 60 (73%) newly diagnosed elderly AML patients started with chemotherapy. By meticulously following our algorithm in almost all patients, we could induce complete remission (CR) in 66% of patients starting with chemotherapy, and transplant 32% of these patients in continuous CR. Main reasons for failure were early relapse (16%), early death (14%), primary refractory disease (9%), and patient or physician decision to stop treatment (16%). Patients in continuous CR after first induction benefit most with 36% long-term survival. Patients not in CR after first induction benefit less; although additional chemotherapy induces CR in 45% of these patients, only 23% are transplanted and no long-term survival is observed, mainly due to relapse. Long-term survival in the group of 44 patients is 9% (median 4.5 years after alloSCT). Considering that 27% of patients do not start with chemotherapy and 64% of patients starting with chemotherapy do not reach alloSCT, the reasons for failure presented here should be used as a guide to develop new treatment algorithms to improve long-term survival in elderly AML patients.

  6. CNS infections in patients with hematological disorders (including allogeneic stem-cell transplantation)—Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO)

    PubMed Central

    Schmidt-Hieber, M.; Silling, G.; Schalk, E.; Heinz, W.; Panse, J.; Penack, O.; Christopeit, M.; Buchheidt, D.; Meyding-Lamadé, U.; Hähnel, S.; Wolf, H. H.; Ruhnke, M.; Schwartz, S.; Maschmeyer, G.

    2016-01-01

    Infections of the central nervous system (CNS) are infrequently diagnosed in immunocompetent patients, but they do occur in a significant proportion of patients with hematological disorders. In particular, patients undergoing allogeneic hematopoietic stem-cell transplantation carry a high risk for CNS infections of up to 15%. Fungi and Toxoplasma gondii are the predominant causative agents. The diagnosis of CNS infections is based on neuroimaging, cerebrospinal fluid examination and biopsy of suspicious lesions in selected patients. However, identification of CNS infections in immunocompromised patients could represent a major challenge since metabolic disturbances, side-effects of antineoplastic or immunosuppressive drugs and CNS involvement of the underlying hematological disorder may mimic symptoms of a CNS infection. The prognosis of CNS infections is generally poor in these patients, albeit the introduction of novel substances (e.g. voriconazole) has improved the outcome in distinct patient subgroups. This guideline has been developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) with the contribution of a panel of 14 experts certified in internal medicine, hematology/oncology, infectious diseases, intensive care, neurology and neuroradiology. Grades of recommendation and levels of evidence were categorized by using novel criteria, as recently published by the European Society of Clinical Microbiology and Infectious Diseases. PMID:27052648

  7. CNS infections in patients with hematological disorders (including allogeneic stem-cell transplantation)-Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO).

    PubMed

    Schmidt-Hieber, M; Silling, G; Schalk, E; Heinz, W; Panse, J; Penack, O; Christopeit, M; Buchheidt, D; Meyding-Lamadé, U; Hähnel, S; Wolf, H H; Ruhnke, M; Schwartz, S; Maschmeyer, G

    2016-07-01

    Infections of the central nervous system (CNS) are infrequently diagnosed in immunocompetent patients, but they do occur in a significant proportion of patients with hematological disorders. In particular, patients undergoing allogeneic hematopoietic stem-cell transplantation carry a high risk for CNS infections of up to 15%. Fungi and Toxoplasma gondii are the predominant causative agents. The diagnosis of CNS infections is based on neuroimaging, cerebrospinal fluid examination and biopsy of suspicious lesions in selected patients. However, identification of CNS infections in immunocompromised patients could represent a major challenge since metabolic disturbances, side-effects of antineoplastic or immunosuppressive drugs and CNS involvement of the underlying hematological disorder may mimic symptoms of a CNS infection. The prognosis of CNS infections is generally poor in these patients, albeit the introduction of novel substances (e.g. voriconazole) has improved the outcome in distinct patient subgroups. This guideline has been developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) with the contribution of a panel of 14 experts certified in internal medicine, hematology/oncology, infectious diseases, intensive care, neurology and neuroradiology. Grades of recommendation and levels of evidence were categorized by using novel criteria, as recently published by the European Society of Clinical Microbiology and Infectious Diseases.

  8. Busulfan and fludarabine conditioning regimen given at hematological nadir of cytoreduction fludarabine, cytarabine, and idarubicin chemotherapy in patients with refractory acute myeloid leukemia undergoing allogeneic stem cell transplantation: a single arm pilot consort study.

    PubMed

    Tang, Wei; Fan, Xing; Wang, Ling; Hu, Jiong

    2015-04-01

    To improve the outcome of allogeneic stem cell transplantation in refractory acute myeloid leukemia (AML), we conducted a single-arm phase II clinical trial to evaluate the efficacy and feasibility of conditioning regimen following cytoreduction chemotherapy with 7-day interval. Adult patients with refractory AML were enrolled in the study and received fludarabine, cytarabine, and idarubicin (FLAG-IDA) as cytoreductive chemotherapy followed by busulfan and fludarabine (Flu-BU) conditioning regimen and transfusion of mobilized peripheral stem cells from human leukocyte antigen-matched sibling or unrelated donor. The primary endpoint of the study was 2-year leukemia-free survival (LFS) and secondary endpoints included complete-remission rate, 2-year overall survival (OS), nonrelapse mortality (NRM), and relapse rate. A total of 16 patients were enrolled with median age of 36 (16-60), which included 9 primary induction failure, 2 early relapse, and 5 with relapse/refractory disease. The median cycles of previous chemotherapy were 4 (3-10) with a median of 55% (1%-90%) blasts in bone marrow. Six patients received transplantation from matched sibling and 10 from matched unrelated donors. After transplantation, 15 patients achieved bone marrow remission (11 complete remissions [CRs] and 4 bone marrow remissions without platelet recovery) at day +28. A total of 8 patients remained alive in CR with median LFS of 29.5 months (9.5-40.5 months). Four patients relapsed and 3 of them died of disease and another 4 patients died because of transplantation-related toxicity. The 2-year NRM and relapse rates were 25.0% ± 10.8% and 33.4% ± 13.8%, respectively with 2-year OS at 53.5% ± 13.1% and LFS at 50.0% ± 12.5%. Based on the Simon 2-stage design, 5 out of first eligible 14 patients remained leukemia-free for more than 2 years after allogeneic hematopoietic stem cell transplantation; thus, the null hypothesis of the study will be rejected and the study protocol

  9. Downregulation of caveolin-1 increases the sensitivity of drug-resistant colorectal cancer HCT116 cells to 5-fluorouracil

    PubMed Central

    Li, Zhaoyang; Wang, Ning; Huang, Changxin; Bao, Yanhong; Jiang, Yiqian; Zhu, Guiting

    2017-01-01

    Colorectal cancer is the third most common type of cancer in men and women. Chemotherapy is an important treatment strategy for patients with terminal stage cancer. However, the development of drug resistance hampers the effectiveness of chemotherapy. Therefore, an effective therapeutic approach to target chemoresistance-associated cellular molecules is required. In the present study, drug-resistant human colorectal cancer HCT116 cells were developed by treating HCT116 cells with increasing concentrations of 5-fluorouracil (5-FU). The present study indicated that the drug-resistance cells (DRC) were resistant to 5-FU compared with parental HCT116 cells by detecting cell survival using an MTT assay. Additionally, the expression of the chemoresistance-associated protein caveolin-1 (Cav-1) was assessed by reverse transcription-quantitative polymerase chain reaction and western blotting. The results revealed that the Cav-1 expression level was significantly higher in DRC compared with that in the parental HCT116 cells. Next, Cav-1 was silenced by small interfering RNA (siRNA) or was inhibited with its specific inhibitor methyl β-cyclodextrin (MCD). MTT assay demonstrated that Cav-1 siRNA and MCD resensitized DRC to 5-FU. These data reveal that Cav-1 was involved in the development of resistance, suggesting that Cav-1 is a potential target for the treatment of colorectal cancer chemoresistance. In addition, 5-FU combined with Cav-1 siRNA or its specific inhibitor may increase the effectiveness of the treatment strategy. PMID:28123586

  10. 21 CFR 1271.265 - Receipt, predistribution shipment, and distribution of an HCT/P.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... distribution of an HCT/P. 1271.265 Section 1271.265 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Practice § 1271.265 Receipt, predistribution shipment, and distribution of an HCT/P. (a) Receipt. You must evaluate each incoming HCT/P for the presence and significance of microorganisms and inspect for damage...

  11. 21 CFR 1271.265 - Receipt, predistribution shipment, and distribution of an HCT/P.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... distribution of an HCT/P. 1271.265 Section 1271.265 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Practice § 1271.265 Receipt, predistribution shipment, and distribution of an HCT/P. (a) Receipt. You must evaluate each incoming HCT/P for the presence and significance of microorganisms and inspect for damage...

  12. 21 CFR 1271.265 - Receipt, predistribution shipment, and distribution of an HCT/P.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... distribution of an HCT/P. 1271.265 Section 1271.265 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Practice § 1271.265 Receipt, predistribution shipment, and distribution of an HCT/P. (a) Receipt. You must evaluate each incoming HCT/P for the presence and significance of microorganisms and inspect for damage...

  13. 21 CFR 1271.265 - Receipt, predistribution shipment, and distribution of an HCT/P.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... distribution of an HCT/P. 1271.265 Section 1271.265 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Practice § 1271.265 Receipt, predistribution shipment, and distribution of an HCT/P. (a) Receipt. You must evaluate each incoming HCT/P for the presence and significance of microorganisms and inspect for damage...

  14. 21 CFR 1271.265 - Receipt, predistribution shipment, and distribution of an HCT/P.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... distribution of an HCT/P. 1271.265 Section 1271.265 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF... Practice § 1271.265 Receipt, predistribution shipment, and distribution of an HCT/P. (a) Receipt. You must evaluate each incoming HCT/P for the presence and significance of microorganisms and inspect for damage...

  15. [Plastic repair using the demineralized matrix of flat allogeneic bone in an operation for ventral hernia].

    PubMed

    Isaĭchev, B A; Chikaleva, V I

    1990-11-01

    Investigations were performed in experiments on 36 dogs. Clinico-morphological results of plasty of artificial defects of the anterior abdominal wall by demineralized matrix of a flat allogeneic bone have shown good taking by tissues. In clinic the demineralized matrix of flat allogeneic bone (scapula, skull fornix) was used in ventral hernias in 36 patients. No recurrent hernias were noted in these patients within 20 months after operation.

  16. Allogeneic hematopoietic cell transplantation after conditioning with I-131-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome.

    SciTech Connect

    Pagel, John M.; Gooley, T. A.; Rajendran, Joseph G.; Fisher, Darrell R.; Wilson, Wendy A.; Sandmaier, B. M.; Matthews, D. C.; Deeg, H. Joachim; Gopal, Ajay K.; Martin, P. J.; Storb, R.; Press, Oliver W.; Appelbaum, Frederick R.

    2009-12-24

    We conducted a study to estimate the maximum tolerated dose (MTD) of I-131-anti-CD45 antibody (Ab; BC8) that can be combined with a standard reduced-intensity conditioning regimen before allogeneic hematopoietic cell transplantation. Fifty-eight patients older than 50 years with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) were treated with (131)I-BC8 Ab and fludarabine plus 2 Gy total body irradiation. Eighty-six percent of patients had AML or MDS with greater than 5% marrow blasts at the time of transplantation. Treatment produced a complete remission in all patients, and all had 100% donor-derived CD3(+) and CD33(+) cells in the blood by day 28 after the transplantation. The MTD of I-131-BC8 Ab delivered to liver was estimated to be 24 Gy. Seven patients (12%) died of nonrelapse causes by day 100. The estimated probability of recurrent malignancy at 1 year is 40%, and the 1-year survival estimate is 41%. These results show that CD45-targeted radiotherapy can be safely combined with a reduced-intensity conditioning regimen to yield encouraging overall survival for older, high-risk patients with AML or MDS. This study was registered at www.clinicaltrials.gov as #NCT00008177.

  17. Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome.

    PubMed

    Pagel, John M; Gooley, Theodore A; Rajendran, Joseph; Fisher, Darrell R; Wilson, Wendy A; Sandmaier, Brenda M; Matthews, Dana C; Deeg, H Joachim; Gopal, Ajay K; Martin, Paul J; Storb, Rainer F; Press, Oliver W; Appelbaum, Frederick R

    2009-12-24

    We conducted a study to estimate the maximum tolerated dose (MTD) of (131)I-anti-CD45 antibody (Ab; BC8) that can be combined with a standard reduced-intensity conditioning regimen before allogeneic hematopoietic cell transplantation. Fifty-eight patients older than 50 years with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) were treated with (131)I-BC8 Ab and fludarabine plus 2 Gy total body irradiation. Eighty-six percent of patients had AML or MDS with greater than 5% marrow blasts at the time of transplantation. Treatment produced a complete remission in all patients, and all had 100% donor-derived CD3(+) and CD33(+) cells in the blood by day 28 after the transplantation. The MTD of (131)I-BC8 Ab delivered to liver was estimated to be 24 Gy. Seven patients (12%) died of nonrelapse causes by day 100. The estimated probability of recurrent malignancy at 1 year is 40%, and the 1-year survival estimate is 41%. These results show that CD45-targeted radiotherapy can be safely combined with a reduced-intensity conditioning regimen to yield encouraging overall survival for older, high-risk patients with AML or MDS. This study was registered at www.clinicaltrials.gov as #NCT00008177.

  18. Prospective study of percutaneous cryoablation combined with allogenic NK cell immunotherapy for advanced renal cell cancer.

    PubMed

    Lin, Mao; Xu, Kecheng; Liang, Shuzhen; Wang, Xiaohua; Liang, Yinqing; Zhang, Mingjie; Chen, Jibing; Niu, LiZhi

    2017-03-05

    In this study, the clinical efficacy of cryosurgery combined with allogenic NK cell immunotherapy for advanced renal cell cancer was evaluated. From July to December 2016, we enrolled 60 patients who met the enrollment criteria and divided them into two groups: (1) the simple cryoablation group (n=30); and (2) the cryoablation combined with allogenic NK cells group (n=30). The clinical efficacy, quality of life, immune function, and other related indicators were evaluated. Combining allogeneic NK cells with cryoablation had a synergistic effect, not only enhancing the immune function and improving the quality of life of the patients, but also significantly exhibiting good clinical efficacy of the patients. This study is the first clinical trial that has evaluated the safety and efficacy of allogenic NK cells combined with cryosurgery for the treatment of renal cell cancer.

  19. Cell salvage for minimising perioperative allogeneic blood transfusion

    PubMed Central

    Carless, Paul A; Henry, David A; Moxey, Annette J; O’Connell, Dianne; Brown, Tamara; Fergusson, Dean A

    2014-01-01

    Background Concerns regarding the safety of transfused blood have prompted reconsideration of the use of allogeneic (from an unrelated donor) red blood cell (RBC) transfusion, and a range of techniques to minimise transfusion requirements. Objectives To examine the evidence for the efficacy of cell salvage in reducing allogeneic blood transfusion and the evidence for any effect on clinical outcomes. Search methods We identified studies by searching CENTRAL (The Cochrane Library 2009, Issue 2), MEDLINE (1950 to June 2009), EMBASE (1980 to June 2009), the internet (to August 2009) and bibliographies of published articles. Selection criteria Randomised controlled trials with a concurrent control group in which adult patients, scheduled for non-urgent surgery, were randomised to cell salvage (autotransfusion) or to a control group who did not receive the intervention. Data collection and analysis Data were independently extracted and the risk of bias assessed. Relative risks (RR) and weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated. Data were pooled using a random-effects model. The primary outcomes were the number of patients exposed to allogeneic red cell transfusion and the amount of blood transfused. Other clinical outcomes are detailed in the review. Main results A total of 75 trials were included. Overall, the use of cell salvage reduced the rate of exposure to allogeneic RBC transfusion by a relative 38% (RR 0.62; 95% CI 0.55 to 0.70). The absolute reduction in risk (ARR) of receiving an allogeneic RBC transfusion was 21% (95% CI 15% to 26%). In orthopaedic procedures the RR of exposure to RBC transfusion was 0.46 (95% CI 0.37 to 0.57) compared to 0.77 (95% CI 0.69 to 0.86) for cardiac procedures. The use of cell salvage resulted in an average saving of 0.68 units of allogeneic RBC per patient (WMD −0.68; 95% CI −0.88 to −0.49). Cell salvage did not appear to impact adversely on clinical outcomes. Authors’ conclusions

  20. Sirolimus for Refractory Autoimmune Hemolytic Anemia after Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report and Literature Review of the Treatment of Post-Transplant Autoimmune Hemolytic Anemia.

    PubMed

    Park, Jeong A; Lee, Hyun-Hee; Kwon, Hyun-Seop; Baik, Chung-Ryul; Song, Sae-Am; Lee, Jung Nye

    2016-01-01

    Autoimmune hemolytic anemia (AIHA) may occur after any type of allogeneic hematopoietic stem cell transplantation (HCT), even ABO-matched transplantation. It tends to be refractory to standard corticosteroid treatment and requires multiple transfusions. Though, there is no consensus regarding the optimal treatment for post-transplant severe AIHA. We present a pediatric patient with refractory AIHA after umbilical cord blood transplantation. She developed severe AIHA at 3months after transplantation and was unresponsive to multiple treatment modalities, including corticosteroids, intravenous immunoglobulin, plasma exchange and rituximab, resulting in persistent transfusion dependency. Sirolimus, a mammalian target of rapamycin inhibitor, was started on day 67 after the onset of AIHA, and this patient was successfully rescued without any complications. Sirolimus induces apoptosis in autoreactive lymphocytes, increases regulatory T cells and has been reported to have a positive effect on AIHA following solid organ transplantation (SOT). We reviewed the literature regarding post-transplant AIHA in the PubMed database and evaluated the treatment outcome of sirolimus in AIHA after SOT.

  1. A Standardized Nursing Intervention Protocol for HCT Patients

    ClinicalTrials.gov

    2015-06-03

    Chronic Myeloproliferative Disorders; Leukemia; Lymphoma; Multiple Myeloma and Plasma Cell Neoplasm; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Neoplasms; Psychosocial Effects of Cancer and Its Treatment; Therapy-related Toxicity

  2. REDUCED INTENSITY HEMATOPOIETIC CELL TRANSPLANTATION FOR PATIENTS WITH PRIMARY MYELOFIBROSIS: A COHORT ANALYSIS FROM THE CENTER FOR INTERNATIONAL BLOOD AND MARROW TRANSPLANT RESEARCH

    PubMed Central

    Gupta, Vikas; Malone, Adriana K.; Hari, Parameswaran N.; Ahn, Kwang Woo; Hu, Zhen-Huan; Gale, Robert Peter; Ballen, Karen K.; Hamadani, Mehdi; Olavarria, Eduardo; Gerds, Aaron T.; Waller, Edmund K.; Costa, Luciano J.; Antin, Joseph H.; Kamble, Rammurti T.; van Besien, Koen M.; Savani, Bipin N.; Schouten, Harry C.; Szer, Jeffrey; Cahn, Jean-Yves; de Lima, Marcos J.; Wirk, Baldeep; Aljurf, Mahmoud D.; Popat, Uday; Bejanyan, Nelli; Litzow, Mark R.; Norkin, Maxim; Lewis, Ian D.; Hale, Gregory A.; Woolfrey, Ann E.; Miller, Alan M.; Ustun, Celalettin; Jagasia, Madan H.; Lill, Michael; Maziarz, Richard T.; Cortes, Jorge; Kalaycio, Matt E.; Saber, Wael

    2014-01-01

    We evaluated the outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced intensity conditioning (RIC). Median age at HCT was 55 years. Donors were: matched sibling donor (MSD), 34%; HLA-well-matched unrelated donors (URD), 45%; and partially/mismatched URD, 21%. Risk stratification according to Dynamic International Prognostic Scoring System (DIPSS): low, 12%; intermediate-1, 49%; intermediate-2, 37%; and high, 1%. The probability of survival at 5-years was 47% (95% CI 40–53). In a multivariate analysis, donor type was the only independent factor associated with survival. Adjusted probabilities of survival at 5-years for MSD, well matched URD and partially matched/mismatched URD were 56% (95% CI 44–67), 48% (95% CI 37–58), and 34% (95% CI 21–47), respectively (p=0.002). Relative risks (RR) for NRM for well-matched URD and partially matched/mismatched URD were 3.92 (p=0.006) and 9.37 (p<0.0001), respectively. A trend towards increased NRM (RR 1.7, p=0.07) and inferior survival (RR 1.37, p=0.10) was observed in DIPSS-intermediate-2/high-risk patients compared to DIPSS-low/intermediate-1 risk patients. RIC HCT is a potentially curative option for patients with MF, and donor type is the most important factor influencing survival in these patients. PMID:24161923

  3. Isolated extramedullary cutaneous relapse despite concomitant severe graft-vs.-host disease and tissue chimerism analysis in a patient with acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation: A case report

    PubMed Central

    Kantarcioglu, Bulent; Bekoz, Huseyin Saffet; Ogret, Yeliz Duvarci; Cakir, Asli; Kivanc, Demet; Oguz, Fatma Savran; Sargin, Deniz

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with acute lymphoblastic leukemia (ALL). The curative potential of allo-HSCT for ALL is, in part, due to the graft-vs.-leukemia (GVL) effect, in addition to the intensive conditioning chemo-radiotherapy. However, relapse remains the major cause of treatment failure following allo-HSCT for ALL. In the allo-HSCT setting, testing for genetic markers of hematopoietic chimerism has become a part of the routine diagnostic program. Routine chimerism analysis is usually performed in peripheral blood or bone marrow; in fact, little is known about the value of tissue chimerism in patients with extramedullary relapse (EMR) after the allo-HSCT setting. The present study reports on, a case of a patient with ALL who experienced isolated cutaneous EMR despite ongoing graft-vs.-host disease (GVHD), and the results of peripheral blood and skin tissue chimerism studies using multiplex polymerase chain reaction (PCR) of short tandem repeats (STR-PCR). The present case demonstrates that, although complete remission and/or chimerism may be achieved in the bone marrow, chimerism achieved at the tissue level, and the subsequent GVL effect, may be limited, despite concomitant severe GVHD following allo-HSCT. Our tissue chimerism analysis results provide a good example of how skin tissue may be a ‘sanctuary’ site for effector cells of GVL, despite active GVHD and complete hematopoetic chimerism. PMID:28105353

  4. A reappraisal of ICU and long-term outcome of allogeneic hematopoietic stem cell transplantation patients and reassessment of prognosis factors: results of a 5-year cohort study (2009-2013).

    PubMed

    Platon, L; Amigues, L; Ceballos, P; Fegueux, N; Daubin, D; Besnard, N; Larcher, R; Landreau, L; Agostini, C; Machado, S; Jonquet, O; Klouche, K

    2016-02-01

    Epidemiology and prognosis of complications related to allogeneic hematopoietic stem cell transplant (HSCT) recipients requiring admission to intensive care unit (ICU) have not been reassessed precisely in the past few years. We performed a retrospective single-center study on 318 consecutive HSCT patients (2009-2013), analyzing outcome and factors prognostic of ICU admission. Among these patients, 73 were admitted to the ICU. In all, 32 patients (40.3%) died in ICU, 46 at hospital discharge (63%) and 61 (83.6%) 1 year later. Survivors had a significantly lower sequential organ failure assessment (SOFA) score, serum lactate and bilirubin upon ICU admission. Catecholamine support, mechanical ventilation (MV) and/or renal replacement therapy during ICU stay, a delayed organ support and an active graft versus host disease (GvHD) significantly worsen the outcome. By multivariate analysis, the worsening of SOFA score from days 1 to 3, the need for MV and the occurrence of an active GvHD were predictive of mortality. In conclusion, the incidence of HSCT-related complications requiring an admission to an ICU was at 22%, with an ICU mortality rate of 44%, and 84% 1 year later. A degradation of SOFA score at day 3 of ICU, need of MV and occurrence of an active GvHD are main predictive factors of mortality.

  5. Blood concentration of cyclosporine during early post-transplant period may have influence on the occurrence of chronic graft versus host disease in patients who received allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Park, Silvia; Kim, Kihyun; Jang, Jun Ho; Kim, Seok Jin; Kim, Won Seog; Jung, Chul Won

    2016-01-01

    Introduction It has rarely been studied that how the blood level of CsA affect the incidence of chronic GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods A total of 183 patients who underwent allo-HSCT from an HLA-matched or haplo matched family donors between 2006 and 2014 were reviewed. Results The average monthly CsA blood concentration (CsAavr, ng/ml) was calculated in each patient: 0-1, 1-2, and 2-3 months after allo-HSCT. CsAavr at the first month showed significant association with the occurrence of moderate to severe cGVHD in multivariate analysis adjusted for gender, age, total body irradiation, anti-thymocyte globulin, acute GVHD ≥ grade 2 and CsAavr levels of other periods. The risk of cGVHD development was lowest in patients with CsAavr of 200-250 ng/ml when compared to those with CsAavr of ≥ 250 or < 200 ng/ml (p=0.003). Conclusions CsA level between 200 and 250 mg/ml during the first month after transplantation was significantly associated with the decreased risk of moderate to severe cGVHD. PMID:27494893

  6. Is there still a role for allogeneic stem-cell transplantation in multiple myeloma?

    PubMed Central

    Bensinger, William I.

    2007-01-01

    Despite significant improvements in survival for multiple myeloma patients through autologous stem-cell transplantation (SCT) and the introduction of novel drugs, the disease remains incurable for all but a small fraction of patients. Only allogeneic SCT is potentially curative, due in part to a graft-versus-myeloma effect. High transplant-related mortality with allogeneic SCT is currently the major limitation to wider use of this potentially curative modality. Mortality can be reduced through the use of lower-intensity conditioning regimens which allow engraftment of allogeneic stem cells, but this comes at a cost of higher rates of disease progression and relapse. Promising studies to improve outcomes of allogeneic transplants include the use of more intensive non-myeloablative conditioning regimens, tandem transplants, peripheral blood cells, graft engineering to improve the graft-versus-myeloma activity while reducing graft-versus-host disease (GVHD), post-transplant maintenance, and targeted conditioning therapies such as bone-seeking radioisotopes. PMID:18070719

  7. Allogeneic stem cell transplantation in patients with atypical chronic myeloid leukaemia: a retrospective study from the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

    PubMed

    Onida, Francesco; de Wreede, Liesbeth C; van Biezen, Anja; Eikema, Diderik-Jan; Byrne, Jenny L; Iori, Anna P; Schots, Rik; Jungova, Alexandra; Schetelig, Johannes; Finke, Jürgen; Veelken, Hendrik; Johansson, Jan-Erik; Craddock, Charles; Stelljes, Matthias; Theobald, Matthias; Holler, Ernst; Schanz, Urs; Schaap, Nicolaas; Bittenbring, Jörg; Olavarria, Eduardo; Chalandon, Yves; Kröger, Nicolaus

    2017-03-28

    Atypical chronic myeloid leukaemia (aCML) is an aggressive malignancy for which allogeneic haematopoietic stem cell transplantation (allo-HSCT) represents the only curative option. We describe transplant outcomes in 42 patients reported to the European Society for Blood and Marrow Transplantation (EBMT) registry who underwent allo-HSCT for aCML between 1997 and 2006. Median age was 46 years. Median time from diagnosis to transplant was 7 months. Disease status was first chronic phase in 69%. Donors were human leucocyte antigen (HLA)-identical siblings in 64% and matched unrelated (MUD) in 36%. A reduced intensity conditioning was employed in 24% of patients. T-cell depletion was applied in 87% and 26% of transplants from MUD and HLA-identical siblings, respectively. According to the EBMT risk-score, 45% of patients were 'low-risk', 31% 'intermediate-risk' and 24% 'high-risk'. Following allo-HSCT, 87% of patients achieved complete remission. At 5 years, relapse-free survival was 36% and non-relapse mortality (NRM) was 24%, while relapse occurred in 40%. Patient age and the EBMT score had an impact on overall survival. Relapse-free survival was higher in MUD than in HLA-identical sibling HSCT, with no difference in NRM. In conclusion, this study confirmed that allo-HSCT represents a valid strategy to achieve cure in a reasonable proportion of patients with aCML, with young patients with low EBMT risk score being the best candidates.

  8. Upfront allogeneic stem cell transplantation after reduced-intensity/nonmyeloablative conditioning for patients with myelodysplastic syndrome: a study by the Société Française de Greffe de Moelle et de Thérapie Cellulaire.

    PubMed

    Damaj, Gandhi; Mohty, Mohammad; Robin, Marie; Michallet, Mauricette; Chevallier, Patrice; Beguin, Yves; Nguyen, Stephanie; Bories, Pierre; Blaise, Didier; Maillard, Natacha; Rubio, Marie Therese; Fegueux, Nathalie; Cornillon, Jerome; Clavert, Aline; Huynh, Anne; Adès, Lionel; Thiébaut-Bertrand, Anne; Hermine, Olivier; Vigouroux, Stephane; Fenaux, Pierre; Duhamel, Alain; Yakoub-Agha, Ibrahim

    2014-09-01

    Cytoreduction before allogeneic stem cell transplantation (allo-SCT) for patients with myelodysplastic syndromes remains a debatable issue. After excluding patients who had received preconditioning induction chemotherapy, we analyzed 128 consecutive patients with myelodysplastic syndrome who received reduced-intensity or nonmyeloablative conditioning (RIC/NMA) allo-SCT. Among them, 40 received azacitidine (AZA) before transplant (AZA group) and 88 were transplanted up front (best supportive care [BSC] group). At diagnosis, 55 patients had intermediate 2 or high-risk scores per the International Prognostic Scoring System and 33 had a high cytogenetic risk score. Progression to a more advanced disease before allo-SCT was recorded in 22 patients. Source of stem cells were blood (n = 112) or marrow (n = 16) from sibling (n = 78) or HLA-matched unrelated (n = 50) donors. With a median follow-up of 60 months, 3-year overall survival, relapse-free survival, cumulative incidence of relapse, and nonrelapse mortality were, respectively, 53% versus 53% (P = .69), 37% versus 42% (P = .78), 35% versus 36% (P = .99), and 20% versus 23% (P = .74), for the AZA group and BSC group, respectively. Multivariate analysis confirmed the absence of statistical differences in outcome between the AZA and BSC groups, after adjusting for potential confounders using the propensity score approach. The absence of cytoreduction before RIC/NMA allo-SCT did not seem to alter the outcome. However, our results emphasize the need to perform prospective protocols to delineate the role of debulking strategy and to identify subsets of patients who may benefit from this approach.

  9. Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: a retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation

    PubMed Central

    Martino, Rodrigo; Parody, Rocio; Fukuda, Takahiro; Maertens, Johan; Theunissen, Koen; Ho, Aloysius; Mufti, Ghulam J.; Kroger, Nicolaus; Zander, Arnold R.; Heim, Dominik; Paluszewska, Monika; Selleslag, Dominik; Steinerova, Katerina; Ljungman, Per; Cesaro, Simone; Nihtinen, Anna; Cordonnier, Catherine; Vazquez, Lourdes; López-Duarte, Monica; Lopez, Javier; Cabrera, Rafael; Rovira, Montserrat; Neuburger, Stefan; Cornely, Oliver; Hunter, Ann E.; Marr, Kieren A.; Dornbusch, Hans Jürgen; Einsele, Hermann

    2006-01-01

    In this retrospective study, we analyzed the outcomes of 129 patients who underwent an allogeneic hematopoietic stem cell transplantation (allo-HSCT) and had a history of probable or proven invasive aspergillosis (IA), of whom 57 (44%) received a reduced-intensity conditioning (RIC). Overall, 27 patients with IA progressed after the allo-HSCT (cumulative incidence [CumInc] at 2 years, 22%). The variables that increased the 2-year CumInc of IA progression were (1) longer duration of neutropenia after transplantation; (2) advanced status of the underlying disease; and (3) less than 6 weeks from start of systemic anti-Aspergillus therapy and the allo-HSCT. In addition, (4) conventional myeloablative conditioning increased the risk of progression early after transplantation (before day 30) only, while 3 variables increased the risk beyond day 30 were (5) cytomegalovirus disease; (6) bone marrow or cord blood as source of stem cells; and (7) grades II to IV acute graft-versus-host disease (GVHD). A risk model for progression was generated, defined as low (0-1 risk factors, 6% incidence), intermediate (2-3 risk factors, 27% incidence), or high risk (≥ 3 risk factors, 72% incidence [P < .001]). These findings may help in the interpretation and design of future studies on secondary prophylaxis of IA after an allo-HSCT. PMID:16720833

  10. Allogeneic stem cell transplantation after conditioning with treosulfan, etoposide and cyclophosphamide for patients with ALL: a phase II-study on behalf of the German Cooperative Transplant Study Group and ALL Study Group (GMALL).

    PubMed

    Kröger, N; Bornhäuser, M; Stelljes, M; Pichlmeier, U; Trenschel, R; Schmid, C; Arnold, R; Martin, H; Heinzelmann, M; Wolschke, C; Meyer, R G; Bethge, W; Kobbe, G; Ayuk, F; Gökbuget, N; Hölzer, D; Zander, A; Beelen, D

    2015-12-01

    TBI-based preparative regimens are considered as standard conditioning therapy for allogeneic stem cell transplantation (AHSC) in patients with ALL. We investigated toxicity and efficacy of a non-TBI-based regimen consisting of treosulfan, etoposide and cyclophosphamide for ALL within a prospective study. Major inclusion criteria were CR and non-eligibility for TBI. Fifty patients with a median age of 46.5 years (range, 18-64) were included. Donors were HLA-identical sibling (n=8), matched (n=42) or mismatched (n=10) unrelated. The toxicity was moderate, resulting in a cumulative incidence of non-relapse mortality (NRM) at 1 year of 8% (90% confidence interval: 2-15%). Acute GvHD grade II-IV and grade III/IV was noted in 53% and 14%, respectively. Chronic GvHD at one year was seen in 41%. After a median follow-up of 24 months the cumulative incidence of relapse was 36% (90% confidence interval: 24-48) and 51% (90% confidence interval: 37-65) at 1 and 2 years, respectively. The estimated 2-year disease-free and overall survivals were 36 and 48%, respectively. Treosulfan, etoposide and cyclophosphamide followed by AHSC has a favorable toxicity profile with low NRM and therefore represents a potential alternative regimen for ALL in 1. CR (NCT00682305).

  11. Challenges in Determining Genotypes for Pharmacogenetics in Allogeneic Hematopoietic Cell Transplant Recipients.

    PubMed

    Langman, Loralie J; Nesher, Lior; Shah, Dimpy P; Azzi, Jacques M; Shpall, Elizabeth J; Rezvani, Katy; Black, John L; Chemaly, Roy F

    2016-09-01

    As part of a pharmacogenetic study, paired blood and oral fluid samples were tested for the IL28B polymorphism (rs12979860) before and after hematopoietic cell transplantation (HCT) to evaluate changes in the genotype and investigate the utility of genotyping in oral fluid in HCT recipients. In 54 patients with leukemia >18 years of age, samples were collected approximately 7 days before HCT and 60 days after HCT. IL28B polymorphism testing was performed using real-time PCR with allele-specific probes. Twenty-four patients had the same genotype as their donors. In 30 patients, the genotype was different from that of the donor. In the oral fluid samples, 4 retained the recipient's genotype, and 18 had a genotype that matched that of the donor. In the remaining 8 patients, the results could not be characterized and appeared to be a combination of both, suggesting mixed proportions of donor and recipient cells. The assumption was that the sloughed epithelial cells of the mouth are of recipient origin. However, oral fluid is a mixture that contains varying numbers of cells of the recipient and immunomodulatory cells from the donor. Therefore, the use of oral fluid after HCT for clinical pharmacogenetics purposes needs further investigation.

  12. Procaine Induces Epigenetic Changes in HCT116 Colon Cancer Cells

    PubMed Central

    Samy, Mariam B.; Said, Osama A. M.; El-Zawahri, Mokhtar M.

    2016-01-01

    Colon cancer is the third most commonly diagnosed cancer in the world, and it is the major cause of morbidity and mortality throughout the world. The present study aimed at treating colon cancer cell line (HCT116) with different chemotherapeutic drug/drug combinations (procaine, vorinostat “SAHA,” sodium phenylbutyrate, erlotinib, and carboplatin). Two different final concentrations were applied: 3 μM and 5 μM. Trypan blue test was performed to assess the viability of the cell before and after being treated with the drugs. The data obtained showed that there was a significant decrease in the viability of cells after applying the chemotherapeutic drugs/drug combinations. Also, DNA fragmentation assay was carried out to study the effect of these drugs on the activation of apoptosis-mediated DNA degradation process. The results indicated that all the drugs/drug combinations had a severe effect on inducing DNA fragmentation. Global DNA methylation quantification was performed to identify the role of these drugs individually or in combination in hypo- or hypermethylating the CpG dinucleotide all over the genome of the HCT116 colon cancer cell line. Data obtained indicated that different combinations had different effects in reducing or increasing the level of methylation, which might indicate the effectiveness of combining drugs in treating colon cancer cells. PMID:27843649

  13. Sequential chemotherapy followed by reduced-intensity conditioning and allogeneic haematopoietic stem cell transplantation in adult patients with relapse or refractory acute myeloid leukaemia: a survey from the Acute Leukaemia Working Party of EBMT.

    PubMed

    Ringdén, Olle; Labopin, Myriam; Schmid, Christoph; Sadeghi, Behnam; Polge, Emmanuelle; Tischer, Johanna; Ganser, Arnold; Michallet, Mauricette; Kanz, Lothar; Schwerdtfeger, Rainer; Nagler, Arnon; Mohty, Mohamad

    2017-02-01

    This study analysed the outcome of 267 patients with relapse/refractory acute myeloid leukaemia (AML) who received sequential chemotherapy including fludarabine, cytarabine and amsacrine followed by reduced-intensity conditioning (RIC) and allogeneic haematopoietic stem cell transplantation (HSCT). The transplants in 77 patients were from matched sibling donors (MSDs) and those in 190 patients were from matched unrelated donors. Most patients (94·3%) were given anti-T-cell antibodies. The incidence of acute graft-versus-host disease (GVHD) of grades II-IV was 32·1% and that of chronic GVHD was 30·2%. The 3-year probability of non-relapse mortality (NRM) was 25·9%, that of relapse was 48·5%, that of GVHD-free and relapse-free survival (GRFS) was 17·8% and that of leukaemia-free survival (LFS) was 25·6%. In multivariate analysis, unrelated donor recipients more frequently had acute GVHD of grades II-IV [hazard ratio (HR) = 1·98, P = 0·017] and suffered less relapses (HR = 0·62, P = 0·01) than MSD recipients. Treatment with anti-T-cell antibodies reduced NRM (HR = 0·35, P = 0·01) and improved survival (HR = 0·49, P = 0·01), GRFS (HR = 0·37, P = 0·0004) and LFS (HR = 0·46, P = 0·005). Thus, sequential chemotherapy followed by RIC HSCT and use of anti-T-cell antibodies seems promising in patients with refractory AML.

  14. Risk factors in interstitial pneumonitis following allogenic bone marrow transplantation

    SciTech Connect

    Pino Y Torres, J.L.; Bross, D.S.; Lam, W.C.; Wharam, M.D.; Santos, G.W.; Order, S.E.

    1982-08-01

    Total body irradiation is part of the preparatory regimen for allogeneic bone marrow transplantation because of its cytotoxic and immunosuppressive properties. A major toxicity of bone marrow transplantation has been interstitial pneumonitis, which may be, in part, related to the lung irradiation. One hundred and sixty-one consecutive patients receiving allogeneic bone marrow transplantation for leukemia and aplastic anemia at Johns Hopkins Hospital (1968-1979) were retrospectively studied. The present study demonstrated that lung shielding to 600 rad maximum in single dose total body irradiation, fractionation of total body irradiation in comparison to single dose total body irradiation, and absence of graft versus host disease in the leukemia patients, each reduced the risk of interstitial pneumonitis. Total body irradiation significantly reduced the leukemia recurrence rate and/or the failure of remission induction.

  15. Acquisition of 5-fluorouracil resistance induces epithelial-mesenchymal transitions through the Hedgehog signaling pathway in HCT-8 colon cancer cells

    PubMed Central

    LIU, YANJUN; DU, FANGFANG; ZHAO, QIANNAN; JIN, JIAN; MA, XIN; LI, HUAZHONG

    2015-01-01

    Colon cancer has a high incidence in individuals >60-years-old. The commonly used chemotherapeutic agent, 5-fluorouracil (5-FU), has gradually lost its potency in treating colorectal cancer following the acquisition of resistance. Drug resistance is usually associated with epithelial-mesenchymal transitions (EMTs) in cancer cells. In the present study, the EMT phenotypes of two colon cancer cell lines, wild-type (HCT-8/WT) and 5-FU-resistant (HCT-8/5-FU), were characterized following the analysis of cellular migration, proliferation, morphology and molecular changes. In order to further clarify the mechanism of EMT in HCT-8/5-FU cells, the effect of EMT pathway inhibitors upon drug sensitivity was investigated. The results revealed that the Hedgehog signaling pathway inhibitor, GDC0449, reversed drug resistance. Therefore, inhibition of the Hedgehog pathway may provide a novel chemotherapeutic strategy for the treatment of patients with 5-FU-resistant colon cancer. PMID:26137127

  16. Upfront allogeneic blood stem cell transplantation for patients with high-risk myelodysplastic syndrome or secondary acute myeloid leukemia using a FLAMSA-based high-dose sequential conditioning regimen.

    PubMed

    Saure, Christian; Schroeder, Thomas; Zohren, Fabian; Groten, Anke; Bruns, Ingmar; Czibere, Akos; Galonska, Lars; Kondakci, Mustafa; Weigelt, Christian; Fenk, Roland; Germing, Ulrich; Haas, Rainer; Kobbe, Guido

    2012-03-01

    Patients suffering from high-risk myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) secondary to MDS (sAML) are characterized by poor response to conventional cytotoxic chemotherapy. The purpose of our prospective single-center study was to examine the safety and efficacy of an allogeneic hematopoietic stem cell transplantation (HSCT) following a sequential conditioning regimen as first-line therapy for previously untreated patients with high-risk MDS or sAML. Between November 2003 and June 2010, 30 patients (20 high-risk MDS, 10 sAML) received fludarabine (4 × 30 mg/m(2)), amsacrine (4 × 100 mg/m(2)), and Ara-C (4 × 2 g/m(2), FLAMSA). After 2 to 3 days of rest, patients received high-dose melphalan alone (200 mg/m(2) for patients with an age <50 years, 150 mg/m(2) for patients with an age between 50 and 60 years, and 100 mg/m(2) for patients with an age >60 years; n = 24) or melphalan and thiotepa (10 mg/kg, Mel/Thio, n = 6). Following these high-dose conditioning regimens, a median number of 7.7 × 10(6) CD34(+) cells/kg body weight (range: 2.9 × 10(6)-17.2 × 10(6)) were transplanted from 13 related or 17 unrelated donors. Antithymocyte globulin (Fresenius 30-60 mg/kg) as well as tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. All patients except 1 with primary graft failure achieved complete remission after HSCT. After a median follow-up time of 28 months (range: 7-81), 21 patients (70%) were alive and free of disease. Overall, 4 patients relapsed. At 2 years, overall survival, event-free survival, and treatment-related mortality were 70%, 63%, and 30%, respectively. Because of undue toxicity, thiotepa is no longer part of the conditioning regimen. Our results add to the body of evidence that a FLAMSA-based sequential conditioning therapy is effective for previously untreated patients with high-risk MDS or sAML.

  17. Serum thymus and activation-regulated chemokine level monitoring may predict disease relapse detected by PET scan after reduced-intensity allogeneic stem cell transplantation in patients with Hodgkin lymphoma.

    PubMed

    Farina, Lucia; Rezzonico, Francesca; Spina, Francesco; Dodero, Anna; Mazzocchi, Arabella; Crippa, Flavio; Alessi, Alessandra; Dalto, Serena; Viviani, Simonetta; Corradini, Paolo

    2014-12-01

    Patients with relapsed and refractory Hodgkin lymphoma (HL) may experience long-term survival after allogeneic stem cell transplantation (alloSCT), but disease recurrence represents the main cause of treatment failure. Positron-emission tomography (PET)-positive patients after alloSCT have a dismal outcome. Serum thymus and activation-regulated chemokine (TARC) is produced by Reed-Sternberg cells and may be a marker of disease. Our study aimed at assessing whether TARC levels after alloSCT correlated with disease status and whether TARC monitoring could increase the ability to predict relapse. Twenty-four patients were evaluated in a prospective observational study. TARC serum level and PET were assessed before and after alloSCT during the follow-up (median, 30 months; range, 2 to 54). Before alloSCT, the median TARC level was 721 pg/mL (range, 209 to 1332) in PET-negative patients and 2542 pg/mL (range, 94 to 13,870) in PET-positive patients. After alloSCT, TARC was 620 pg/mL (range, 12 to 4333) in persistently PET-negative patients compared with 22,397 pg/mL (range, 602 to 106,578) in PET-positive patients (P < .0001). In 7 patients who relapsed after alloSCT, TARC level increased progressively even before PET became positive, with a median fold increase of 3.19 (range, 1.66 to 7.11) at relapse. The cut-off value of 1726 pg/mL had a sensitivity of 100% and a specificity of 71% for PET positivity. Patients with at least 1 TARC value above 1726 pg/mL during the first year after alloSCT had a worse progression-free survival (P = .031). In conclusion, TARC was correlated with disease status and its monitoring may be able to predict PET positivity after alloSCT, thus potentially allowing an early immune manipulation.

  18. 131I-Anti-CD45 Antibody Plus Busulfan and Cyclophosphamide before Allogeneic Hematophoietic Cell Transplantation for Treatment of Acute Myeloid Leukemia in First Remission

    SciTech Connect

    Pagel, John M.; Appelbaum, Frederick R.; Eary, Janet F.; Rajendran, Joseph G.; Fisher, Darrell R.; Gooley, Ted; Ruffner, Katherine; Nemecek, Eneida; Sickle, Eileen; Durack, Larry; Carreras, Jeanette; Horowitz, Mary; Press, Oliver W.; Gopal, Ajay K.; Martin, Paul J.; Bernstein, Irwin D.; Matthews, Dana C.

    2006-03-01

    In an attempt to improve outcomes for patients with acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT), we conducted a Phase I/II study in which targeted irradiation delivered by 131I-anti-CD45 antibody was combined with targeted busulfan (BU; area-under-curve, 600-900 ng/ml) and cyclophosphamide (CY; 120 mg/kg). Fifty-two of 59 patients (88%) receiving a trace 131I-labeled dose of 0.5 mg/kg anti-CD45 murine antibody had higher estimated absorbed radiation in bone marrow and spleen than in any other organ. Forty-six patients were treated with 102-298 mCi 131I delivering an estimated 5.3-19 (mean 11.3) Gy to marrow, 17-72 (mean 29.7) Gy to spleen, and 3.5 Gy (n=4) to 5.25 Gy (n=42) to the liver. The estimated 3-year non-relapse mortality and disease-free survival (DFS) were 21% and 61%, respectively. These results were compared to those from 509 similar International Bone Marrow Transplant Registry patients transplanted using BU/CY alone. After adjusting for differences in age and cytogenetics-risk, the hazard of mortality among all antibody-treated patients was 0.65 times that of the Registry patients (95% CI 0.39-1.08; p=.09). The addition of targeted hematopoietic irradiation to conventional BU/CY is feasible and well tolerated, and Phase II results are sufficiently encouraging to warrant further study.

  19. Early lymphocyte recovery at 28 d post-transplant is predictive of reduced risk of relapse in patients with acute myeloid leukemia transplanted with peripheral blood stem cell grafts.

    PubMed

    Michelis, Fotios V; Messner, Hans A; Loach, David; Uhm, Jieun; Gupta, Vikas; Lipton, Jeffrey H; Seftel, Matthew D; Kuruvilla, John; Kim, Dennis D

    2014-10-01

    Allogeneic hematopoietic cell transplantation (HCT) is potentially curative for acute myeloid leukemia (AML). Impact of lymphocyte recovery on post-transplant outcomes has been suggested but reports are conflicting. We evaluated the impact of lymphocyte recovery at 28 d post-HCT in 191 AML patients using peripheral blood stem cells as graft. Patients were divided into those with absolute lymphocyte count (ALC) ≥ 0.5 × 10(9) /L (n = 111, 58%; high ALC group) and those with ALC < 0.5 × 10(9) /L (n = 80, 42%; low ALC group), at day 28 post-transplant. With a median follow-up of 49 months, overall survival (OS) was significantly improved in the high ALC group (59% at 3 yr) vs. patients with low ALC (40% at 3 yr, P = 0.03). Cumulative incidence of relapse (CIR) was significantly lower in the high ALC group (16% at 3 yr) vs. low ALC group (36% at 3 yr, P = 0.001). Multivariable analysis for CIR demonstrated high ALC group as an independent factor decreasing relapse risk (P = 0.03, HR = 0.49, 95% CI = 0.26-0.92). Multivariable analysis for OS and non-relapse mortality did not demonstrate ALC ≥ 0.5 × 10(9) /L at 28 d post-transplant to be predictive. We conclude that lymphocyte recovery with ALC ≥ 0.5 × 10(9) /L at day 28 post-transplant is associated with less relapse in AML patients undergoing allogeneic peripheral blood HCT, but without survival benefit.

  20. Haploidentical T Cell-Replete Transplantation with Post-Transplantation Cyclophosphamide for Patients in or above the Sixth Decade of Age Compared with Allogeneic Hematopoietic Stem Cell Transplantation from an Human Leukocyte Antigen-Matched Related or Unrelated Donor.

    PubMed

    Blaise, Didier; Fürst, Sabine; Crocchiolo, Roberto; El-Cheikh, Jean; Granata, Angela; Harbi, Samia; Bouabdallah, Reda; Devillier, Raynier; Bramanti, Stephania; Lemarie, Claude; Picard, Christophe; Chabannon, Christian; Weiller, Pierre-Jean; Faucher, Catherine; Mohty, Bilal; Vey, Norbert; Castagna, Luca

    2016-01-01

    It has recently been shown that a T cell-replete allogeneic (allo) hematopoietic stem cell transplantation (HSCT) from a haploidentical donor (haplo-ID) could be a valid treatment for hematological malignancies. However, little data exist concerning older populations. We provided transplantation to 31 patients over the age of 55 years from a haplo-ID and compared their outcomes with patients of the same ages who underwent transplantation from a matched related (MRD) or an unrelated donor (UD). All 3 groups were comparable, except for their conditioning. Patients in haplo-ID group received 2 days of post-transplantation high-dose cyclophosphamide followed by cyclosporine A and mycophenolate mofetil, whereas patients in other groups received pretransplantation antithymocyte globulin, cyclosporine A, and additional mycophenolate mofetil in case of 1-antigen mismatch. All patients but 1 in the haplo-ID group engrafted. The incidence of grades 2 to 4 acute graft-versus-host disease (GVHD) was not statistically different between recipients from haplo-ID (cumulative incidence, 23%) and MRD (cumulative incidence, 21%) transplantations but it was lower than after UD HSCT (cumulative incidence, 44%). No patient in the haplo-ID group developed severe chronic GVHD, compared with cumulative incidences of 16% and 14% after MRD (P = .02) and UD (P = .03) grafts, respectively. The cumulative incidences of relapse were similar in the 3 groups, whereas nonrelapse mortality after UD HSCT was 3-fold higher than after haplo-ID or MRD HSCT. Overall, 2-year overall survival (70%), progression-free survival (67%), and progression and severe chronic GVHD-free survival (67%) probabilities after haplo-ID did not statistically differ from MRD transplantation (78%, 64%, and 51%, respectively), although they were higher than after UD transplantation (51% [P = .08], 38% [P = .02], and 31% [P = .007]). We conclude that T cell-replete haplo-ID HSCT followed by post-transplantation high

  1. Allogeneic hematopoietic stem cell transplantation for neuromyelitis optica.

    PubMed

    Greco, Raffaella; Bondanza, Attilio; Vago, Luca; Moiola, Lucia; Rossi, Paolo; Furlan, Roberto; Martino, Gianvito; Radaelli, Marta; Martinelli, Vittorio; Carbone, Maria Rosaria; Lupo Stanghellini, Maria Teresa; Assanelli, Andrea; Bernardi, Massimo; Corti, Consuelo; Peccatori, Jacopo; Bonini, Chiara; Vezzulli, Paolo; Falini, Andrea; Ciceri, Fabio; Comi, Giancarlo

    2014-03-01

    Neuromyelitis optica is a rare neurological autoimmune disorder characterized by a poor prognosis. Immunosuppression can halt disease progression, but some patients are refractory to multiple treatments, experiencing frequent relapses with accumulating disability. Here we report on durable clinical remissions after allogeneic hematopoietic stem cell transplantation in 2 patients suffering from severe forms of the disease. Immunological data evidenced disappearance of the pathogenic antibodies and regeneration of a naive immune system of donor origin. These findings correlated with evident clinical and radiological improvement in both patients, warranting extended clinical trials to investigate this promising therapeutic option.

  2. Anti-thymocyte globulin could improve the outcome of allogeneic hematopoietic stem cell transplantation in patients with highly aggressive T-cell tumors

    PubMed Central

    Yang, J; Cai, Y; Jiang, J L; Wan, L P; Yan, S K; Wang, C

    2015-01-01

    The early experiment result in our hospital showed that anti-thymocyte globulin (ATG) inhibited the proliferation of lymphoid tumor cells in the T-cell tumors. We used the ATG as the part of the conditioning regimen and to evaluate the long-term anti-leukemia effect, the safety and complication in the patients with highly aggressive T-cell lymphomas. Twenty-three patients were enrolled into this study. At the time of transplant, six patients reached first or subsequent complete response, three patients had a partial remission and 14 patients had relapsed or primary refractory disease. The conditioning regimen consisted of ATG, total body irradiation, toposide and cyclophosphamide. The complete remission rate after transplant was 95.7%. At a median follow-up time of 25 months, 16 (69.6%) patients are alive and free from diseases, including nine patients in refractory and progressive disease. Seven patients died after transplant, five from relapse and two from treatment-related complications. The incidence of grades II–IV acute graft-vs-host disease (GvHD) was 39.1%. The maximum cumulative incidence of chronic GvHD was 30%. The most frequent and severe conditioning-related toxicities observed in 8 out of 23 patients were grades III/IV infections during cytopenia. Thus, ATG-based conditioning is a feasible and effective alternative for patients with highly aggressive T-cell tumors. PMID:26230956

  3. Age and Modified European LeukemiaNet Classification to Predict Transplant Outcomes: An Integrated Approach for Acute Myelogenous Leukemia Patients Undergoing Allogeneic Stem Cell Transplantation.

    PubMed

    Oran, Betül; Jimenez, Antonio M; De Lima, Marcos; Popat, Uday R; Bassett, Roland; Andersson, Borje S; Borthakur, Gautam; Bashir, Qaiser; Chen, Julianne; Ciurea, Stefan O; Jabbour, Elias; Cortes, Jorge; Kebriaei, Partow; Khouri, Issa F; Qazilbash, Muzaffar H; Ravandi, Farhad; Rondon, Gabriela; Lu, Xinyan; Shpall, Elizabeth J; Champlin, Richard E

    2015-08-01

    We evaluated the prognostic significance of a modified European LeukemiaNet (ELN) classification for patients with acute myelogenous leukemia (AML) undergoing hematopoietic stem cell transplantation (HSCT) while in first complete remission (CR1). We analyzed 464 AML patients with matched related (n = 211, 45.5%), matched unrelated (n = 176, 37.9%), and mismatched donors (n = 77, 16.6%). Patients were classified into 4 modified ELN risk groups (favorable, intermediate-I, intermediate-II, and adverse) separately for 354 patients age < 60 years and 110 patients age ≥ 60 years. In this modified version of ELN classification, patients with normal cytogenetic were classified by FLT3-ITD mutational status: favorable risk if FLT3-ITDwild and intermediate-I if FLT3-ITDmut. The best outcomes occurred in the ELN favorable and intermediate-II groups in younger AML patients and in the favorable and intermediate-I groups in older AML patients. Older AML patients had worse transplant outcomes within each modified ELN risk group except intermediate-I when compared with younger patients; leukemia-free survival at 3 years was 67.8% versus 49.8% in favorable, 53.4% versus 50.7% in intermediate-I, 65.7% versus 20.2% in intermediate-II, and 44.6% versus 23.8% in adverse group younger and older patients, respectively. Among lesion-specific abnormalities, del5q/-5 and abnl(17p) had the worse transplant outcomes, with 3-year leukemia-free survival rates of 18.4% and 20% in younger CR1 patients. In conclusion, the modified ELN prognostic classification developed for chemotherapy outcomes also identifies prognostic groups for HSCT, which is useful for a selection of patients for post-transplant strategies to improve outcomes.

  4. Comparison of umbilical cord blood allogeneic stem cell transplantation vs. auto-SCT for adult acute myeloid leukemia patients in second complete remission at transplant: a retrospective study on behalf of the SFGM-TC.

    PubMed

    Chevallier, Patrice; Labopin, Myriam; Socie, Gerard; Rubio, Marie-There; Blaise, Didier; Vigouroux, Stephane; Huynh, Anne; Michallet, Mauricette; Bay, Jacques-Olivier; Maury, Sébastien; Yakoub-Agha, Ibrahim; Fegueux, Nathalie; Deconinck, Eric; Contentin, Nathalie; Maillard, Natacha; Bulabois, Claude-Eric; Francois, Sylvie; Oumedaly, Reman; Raus, Nicole; Mohty, Mohamad

    2015-05-01

    This retrospective study considered the outcomes of 181 patients with acute myeloid leukemia (AML) transplanted in second complete remission (CR2) between January 2005 and April 2012 and who received either a myeloablative autologous stem cell transplant (Auto-SCT; n = 82; median age: 48 years; median follow-up: 45 months) or an umbilical cord blood (UCB) allogeneic SCT (n = 99, median age: 46 years; median follow-up: 36 months; conditioning regimens: myeloablative n = 21, reduced n = 78; single unit n = 37, double units n = 62). Although the Auto group showed a significant better prognostic profile at transplant, with longer median interval between diagnosis and time of graft, higher incidence of good-risk cytogenetics and lower number of previously transplanted patients, 3-year OS and LFS were similar between both groups (Auto: 59 ± 6% vs. 50 ± 6%, P = 0.45; and 57 ± 6% vs. 46 ± 6%, P = 0.37). In multivariate analysis, UCB allo-SCT was associated with lower relapse incidence (HR: 0.3, 95% CI: 0.11-0.82, P = 0.02), but higher non-relapse mortality (NRM) (HR: 4.16; 95% CI: 1.46-11.9, P = 0.008). Results from this large study suggest that UCB allo-SCT provides better disease control than auto-SCT, which is especially important in the setting of high-risk disease. However, this disease control advantage is counterbalanced by higher toxicity, highlighting the need for novel approaches aiming to decrease NRM after UCB allo-SCT.

  5. Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy

    PubMed Central

    Michael, W.; Schüpbach, M.; Mandel, Hanna; Casali, Carlo; Orchard, Kim; Collin, Matthew; Valcarcel, David; Rovelli, Attilio; Filosto, Massimiliano; Dotti, Maria T.; Marotta, Giuseppe; Pintos, Guillem; Barba, Pere; Accarino, Anna; Ferra, Christelle; Illa, Isabel; Beguin, Yves; Bakker, Jaap A.; Boelens, Jaap J.; de Coo, Irenaeus F. M.; Fay, Keith; Sue, Carolyn M.; Nachbaur, David; Zoller, Heinz; Sobreira, Claudia; Pinto Simoes, Belinda; Hammans, Simon R.; Savage, David; Martí, Ramon; Chinnery, Patrick F.; Elhasid, Ronit; Gratwohl, Alois; Hirano, Michio

    2015-01-01

    Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10–41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262–1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation

  6. Allogeneic haematopoietic stem cell transplantation for mitochondrial neurogastrointestinal encephalomyopathy.

    PubMed

    Halter, Joerg P; Michael, W; Schüpbach, M; Mandel, Hanna; Casali, Carlo; Orchard, Kim; Collin, Matthew; Valcarcel, David; Rovelli, Attilio; Filosto, Massimiliano; Dotti, Maria T; Marotta, Giuseppe; Pintos, Guillem; Barba, Pere; Accarino, Anna; Ferra, Christelle; Illa, Isabel; Beguin, Yves; Bakker, Jaap A; Boelens, Jaap J; de Coo, Irenaeus F M; Fay, Keith; Sue, Carolyn M; Nachbaur, David; Zoller, Heinz; Sobreira, Claudia; Pinto Simoes, Belinda; Hammans, Simon R; Savage, David; Martí, Ramon; Chinnery, Patrick F; Elhasid, Ronit; Gratwohl, Alois; Hirano, Michio

    2015-10-01

    Haematopoietic stem cell transplantation has been proposed as treatment for mitochondrial neurogastrointestinal encephalomyopathy, a rare fatal autosomal recessive disease due to TYMP mutations that result in thymidine phosphorylase deficiency. We conducted a retrospective analysis of all known patients suffering from mitochondrial neurogastrointestinal encephalomyopathy who underwent allogeneic haematopoietic stem cell transplantation between 2005 and 2011. Twenty-four patients, 11 males and 13 females, median age 25 years (range 10-41 years) treated with haematopoietic stem cell transplantation from related (n = 9) or unrelated donors (n = 15) in 15 institutions worldwide were analysed for outcome and its associated factors. Overall, 9 of 24 patients (37.5%) were alive at last follow-up with a median follow-up of these surviving patients of 1430 days. Deaths were attributed to transplant in nine (including two after a second transplant due to graft failure), and to mitochondrial neurogastrointestinal encephalomyopathy in six patients. Thymidine phosphorylase activity rose from undetectable to normal levels (median 697 nmol/h/mg protein, range 262-1285) in all survivors. Seven patients (29%) who were engrafted and living more than 2 years after transplantation, showed improvement of body mass index, gastrointestinal manifestations, and peripheral neuropathy. Univariate statistical analysis demonstrated that survival was associated with two defined pre-transplant characteristics: human leukocyte antigen match (10/10 versus <10/10) and disease characteristics (liver disease, history of gastrointestinal pseudo-obstruction or both). Allogeneic haematopoietic stem cell transplantation can restore thymidine phosphorylase enzyme function in patients with mitochondrial neurogastrointestinal encephalomyopathy and improve clinical manifestations of mitochondrial neurogastrointestinal encephalomyopathy in the long term. Allogeneic haematopoietic stem cell transplantation

  7. Long term impact of hyperleukocytosis in newly diagnosed acute myeloid leukemia patients undergoing allogeneic stem cell transplantation: an analysis from the acute leukemia working party of the EBMT.

    PubMed

    Canaani, Jonathan; Labopin, Myriam; Socié, Gerard; Nihtinen, Anne; Huynh, Anne; Cornelissen, Jan; Deconinck, Eric; Gedde-Dahl, Tobias; Forcade, Edouard; Chevallier, Patrice; Bourhis, Jean Henri; Blaise, Didier; Mohty, Mohamad; Nagler, Arnon

    2017-03-28

    Up to 20% of acute myeloid leukemia (AML) patients present initially with hyperleukocytosis, placing them at increased risk for early mortality during induction. Yet, it is unknown whether hyperleukocytosis still retains prognostic value for AML patients undergoing hematopoietic stem cell transplantation (HSCT). Furthermore, it is unknown whether hyperleukocytosis holds prognostic significance when modern molecular markers such as FLT3-ITD and NPM1 are accounted for. To determine whether hyperleukocytosis is an independent prognostic factor influencing outcome in transplanted AML patients we performed a retrospective analysis using the registry of the acute leukemia working party of the EBMT. A cohort of 357 patients with hyperleukocytosis (159 patients with WBC 50K-100K, 198 patients with WBC≥100K) was compared to 918 patients without hyperleukocytosis. Patients with hyperleukocytosis were younger, had an increased rate of favorable risk cytogenetics, and more likely to be FLT3 and NPM1 mutated. In multivariate analysis, hyperleukocytosis was independently associated with increased relapse incidence (hazard ratio [HR] of 1.55, 95% confidence interval [CI], 1.14 - 2.12; p=0.004), decreased leukemia-free survival (HR of 1.38, 95% CI, 1.07 - 1.78; p=0.013), and inferior overall survival (HR of 1.4, 95% CI, 1.07 - 1.84; p=0.013). Hyperleukocytosis retains a significant prognostic role for AML patients undergoing HSCT. This article is protected by copyright. All rights reserved.

  8. MODIFYING LIGNIN IN CONIFERS: THE ROLE OF HCT DURING TRACHEARY ELEMENT FORMATION IN PINUS RADIATA

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The enzyme hydroxycinnamoyl-CoA: shikimate hydroxycinnamoyltransferase (HCT) is involved in the production of methoxylated monolignols that are precursors to guaiacyl and syringyl lignin in angiosperm species. We identified and cloned a putative HCT gene from Pinus radiata, a coniferous gymnosperm, ...

  9. [Increased efficacy of allogenic bone marrow transplantation].

    PubMed

    Fedotenkov, A G; Danilova, L A; Ignasheva, L P

    1982-08-01

    Experiments made in vivo and vitro have demonstrated that conservation of allogeneic hemopoietic tissue with glycerin brings about a decrease in transplatation, homologous activity of T lymphocytes. Allogeneic bone marrow conserved with glycerin compares very favourably with freshly prepared allogeneic bone marrow since the transplant-versus-host reaction is attenuated under the effect of glycerin. Moreover, it shows a higher proliferative activity. The glycerin-induced reduction of the inactivating effect of lymphocytes against non-syngeneic colony-forming units enables the conserved bone marrow to be transplanted from several donors.

  10. Similar Survival for Patients Undergoing Reduced-Intensity Total Body Irradiation (TBI) Versus Myeloablative TBI as Conditioning for Allogeneic Transplant in Acute Leukemia

    SciTech Connect

    Mikell, John L.; Waller, Edmund K.; Switchenko, Jeffrey M.; Rangaraju, Sravanti; Ali, Zahir; Graiser, Michael; Hall, William A.; Langston, Amelia A.; Esiashvili, Natia; Khoury, H. Jean; Khan, Mohammad K.

    2014-06-01

    Purpose: Hematopoietic stem cell transplantation (HSCT) is the mainstay of treatment for adults with acute leukemia. Total body irradiation (TBI) remains an important part of the conditioning regimen for HCST. For those patients unable to tolerate myeloablative TBI (mTBI), reduced intensity TBI (riTBI) is commonly used. In this study we compared outcomes of patients undergoing mTBI with those of patients undergoing riTBI in our institution. Methods and Materials: We performed a retrospective review of all patients with acute leukemia who underwent TBI-based conditioning, using a prospectively acquired database of HSCT patients treated at our institution. Patient data including details of the transplantation procedure, disease status, Karnofsky performance status (KPS), response rates, toxicity, survival time, and time to progression were extracted. Patient outcomes for various radiation therapy regimens were examined. Descriptive statistical analysis was performed. Results: Between June 1985 and July 2012, 226 patients with acute leukemia underwent TBI as conditioning for HSCT. Of those patients, 180 had full radiation therapy data available; 83 had acute lymphoblastic leukemia and 94 had acute myelogenous leukemia; 45 patients received riTBI, and 135 received mTBI. Median overall survival (OS) was 13.7 months. Median relapse-free survival (RFS) for all patients was 10.2 months. Controlling for age, sex, KPS, disease status, and diagnosis, there were no significant differences in OS or RFS between patients who underwent riTBI and those who underwent mTBI (P=.402, P=.499, respectively). Median length of hospital stay was shorter for patients who received riTBI than for those who received mTBI (16 days vs 23 days, respectively; P<.001), and intensive care unit admissions were less frequent following riTBI than mTBI (2.22% vs 12.69%, respectively, P=.043). Nonrelapse survival rates were also similar (P=.186). Conclusions: No differences in OS or RFS were seen between

  11. Allogeneic marrow transplantation following cyclophosphamide and escalating doses of hyperfractionated total body irradiation in patients with advanced lymphoid malignancies: A phase I/II trial

    SciTech Connect

    Demirer, T.; Petersen, F.B.; Appelbaum, F.R.

    1995-07-15

    The purpose of this investigation was to define the maximum tolerated dose (MTD) of unshielded total body irradiation (TBI) delivered from dual {sup 60}C sources at an exposure rate of 0.08 Gy/min and given in thrice daily fractions of 1.2 Gy in patients with advanced lymphoid malignancies. Forty-four patients with a median age of 28 (range 6-48) years were entered into a Phase I/II study. All patients received cyclophosphamide (Cy), 120 mg/kg administered over 2 days before TBI. Marrow from human leukocyte antigen (HLA) identical siblings was infused following the last dose of TBI. An escalation-deescalation schema designed to not exceed an incidence of 25% of Grade 3-4 regimen-related toxicities (RRTs) was used. The first dose level tested was 13.2 Gy followed by 14.4 Gy. None of the four patients at the dose level of 13.2 Gy developed Grade 3-4 RRT. Two of the first eight patients receiving 14.4 Gy developed Grade 3-4 RRT, establishing this as the MTD. An additional 32 patients were evaluated at the 14.4 Gy level to confirm these initial observations. Of 40 patients receiving 14.4 Gy, 13 (32.5%) developed Grade 3-4 RRTs; 46% in adults and 12% in children. The primary dose limiting toxicity was Grade 3-4 hepatic toxicity, which occurred in 12.5% of patients. Noninfectious Grade 3-4 interstitial pneumonia syndrome occurred in 5% of patients. The actuarial probabilities of event-free survival, relapse, and nonrelapse mortality at 2 years were 0.10, 0.81, and 0.47, respectively, for patients who received 14.4 Gy of TBI. The outcome for patients receiving 14.4 Gy of TBI was not different from previous studies of other CY and TBI regimens in patients with advanced lymphoid malignancies. These data showed that the incidence of Grade 3-4 RRTs in adults was greater than the 25% maximum set as the goal of this study, suggesting that 13.2 Gy is a more appropriate dose of TBI for adults, while 14.4 Gy is an appropriate dose for children. 36 refs., 1 fig., 3 tabs.

  12. Clinical Allogeneic and Autologous Islet Cell Transplantation: Update

    PubMed Central

    2011-01-01

    Islet cell transplantation is categorized as a β-cell replacement therapy for diabetic patients who lack the ability to secrete insulin. Allogeneic islet cell transplantation is for the treatment of type 1 diabetes, and autologous islet cell transplantation is for the prevention of surgical diabetes after a total pancreatectomy. The issues of allogeneic islet cell transplantation include poor efficacy of islet isolation, the need for multiple donor pancreata, difficulty maintaining insulin independence and undesirable side effects of immunosuppressive drugs. Those issues have been solved step by step and allogeneic islet cell transplantation is almost ready to be the standard therapy. The donor shortage will be the next issue and marginal and/or living donor islet cell transplantation might alleviate the issue. Xeno-islet cell transplantation, β-cell regeneration from human stem cells and gene induction of the naïve pancreas represent the next generation of β-cell replacement therapy. Autologous islet cell transplantation after total pancreatectomy for the treatment of chronic pancreatitis with severe abdominal pain is the standard therapy, even though only limited centers are able to perform this treatment. Remote center autologous islet cell transplantation is an attractive option for hospitals performing total pancreatectomies without the proper islet isolation facilities. PMID:21785738

  13. Cyclin-dependent kinase 5 activity is required for allogeneic T-cell responses after hematopoietic cell transplantation in mice

    PubMed Central

    Pareek, Tej K.; Eid, Saada; Ganguly, Sudipto; Tyler, Megan; Huang, Alex Y.; Letterio, John J.

    2017-01-01

    Molecular intermediates in T-cell activation pathways are crucial targets for the therapy and prevention of graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (allo-HCT). We recently identified an essential role for cyclin-dependent kinase 5 (Cdk5) in T-cell activation and effector function, but the contribution of Cdk5 activity to the development of GVHD has not been explored. Using an established, preclinical, murine, GVHD model, we reveal that Cdk5 activity is increased in key target organs early after allo-HCT. We then generated chimeric mice (Cdk5+/+C or Cdk5−/−C) using hematopoietic progenitors from either embryonic day 16.5 Cdk5+/+ or Cdk5−/− embryos to enable analyses of the role of Cdk5 in GVHD, as germ line Cdk5 gene deletion is embryonically lethal. The immunophenotype of adult Cdk5−/−C mice is identical to control Cdk5+/+C mice. However, transplantation of donor Cdk5−/−C bone marrow and T cells dramatically reduced the severity of systemic and target organ GVHD. This phenotype is attributed to decreased T-cell migration to secondary lymphoid organs (SLOs), reduced in vivo proliferation within these organs, and fewer cytokine-producing donor T cells during GVHD development. Moreover, these defects in Cdk5−/− T-cell function are associated with altered CCR7 signaling following ligation by CCL19, a receptor:ligand interaction critical for T-cell migration into SLOs. Although Cdk5 activity in donor T cells contributed to graft-versus-tumor effects, pharmacologic inhibition of Cdk5 preserved leukemia-free survival. Collectively, our data implicate Cdk5 in allogeneic T-cell responses after HCT and as an important new target for therapeutic intervention. PMID:28064242

  14. Antibiotic-mediated modification of the intestinal microbiome in allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Whangbo, J; Ritz, J; Bhatt, A

    2016-01-01

    Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for many patients with severe benign and malignant hematologic disorders. The success of allogeneic HSCT is limited by the development of transplant-related complications such as acute graft-versus-host disease (GvHD). Early pre-clinical studies suggested that intestinal microflora contribute to the pathogenesis of acute GvHD, and that growth suppression or eradication of intestinal bacteria prevented the development of acute GvHD even in MHC-mismatched transplants. These observations led to the practice of gut decontamination (GD) with oral non-absorbable antibiotics in patients undergoing allogeneic HSCT as a method of acute GvHD prophylaxis. Microbiome studies in the modern sequencing era are beginning to challenge the benefit of this practice. In this review, we provide a historical perspective on the practice of GD and highlight findings from the limited number of clinical trials evaluating the use of GD for acute GvHD prevention in allogeneic HSCT patients. In addition, we examine the role of the gut microbiota in allogeneic HSCT in the context of recent studies linking the microflora to regulation of intestinal immune homeostasis. We discuss the implications of these findings for future strategies to reduce acute GvHD risk by selective manipulation of the microbiota. PMID:27526283

  15. Induction of late graft-versus-host disease in a patient post-allogeneic stem cell transplantation by progesterone in conjunction with donor lymphocyte infusion.

    PubMed

    Gesundheit, Benjamin; Shapira, Michael Y; Maly, Alexander; Samuel, Simcha; Budowski, Einat; Or, Reuven

    2008-03-01

    Patients after stem cell transplantation (SCT), often develop graft-versus-host disease (GVHD) which, although potentially dangerous, is associated with the beneficial graft-versus-leukemia (GVL) effect. Where there is high risk of disease recurrence, donor lymphocyte infusions (DLI) are given to provide long-term disease control. We present a patient treated with DLI 4 years post-SCT, who developed acute GVHD after administration of progesterone to induce menstruation. This rare allergic reaction warrants further investigation.

  16. Non-intensive treatment with low-dose 5-aza-2'-deoxycytidine (DAC) prior to allogeneic blood SCT of older MDS/AML patients.

    PubMed

    Lübbert, M; Bertz, H; Rüter, B; Marks, R; Claus, R; Wäsch, R; Finke, J

    2009-11-01

    Novel, non-intensive treatment options in older MDS/AML patients planned for allografting, with the goal of down-staging the underlying disease and bridging time to transplantation, are presently being developed. 5-azacytidine and decitabine (DAC) are of particular interest, as they can be given repetitively, with very limited non-hematologic toxicity and result in responses both in MDS and AML even at low doses. We describe 15 consecutive patients (median age 69 years, range 60-75 years) with MDS (n=10) or AML (n=5) who all received first-line treatment with DAC and subsequent allografting (from sibling donor in four patients, unrelated donor in 11) after reduced-intensity conditioning with the FBM regimen. Successful engraftment was attained in 14/15 patients, all of whom achieved a CR, with a median duration of 5 months (range 1+ to 51+). Six of these 14 patients are alive (4 with complete donor chimerism), 8 have died either from relapse (n=4) or treatment-related complications while in CR (n=4). We conclude that allografting after low-dose DAC and subsequent conditioning with FBM is feasible, with no unexpected toxicities and appears as a valid alternative to standard chemotherapy ('InDACtion instead of induction') in elderly patients with MDS/AML.

  17. Quality of life assessment in patients undergoing reduced intensity conditioning allogeneic as compared to autologous transplantation: results of a prospective study.

    PubMed

    Díez-Campelo, M; Pérez-Simón, J A; González-Porras, J R; García-Cecilia, J M; Salinero, M; Caballero, M D; Cañizo, M C; Ocio, E M; Miguel, J F San

    2004-10-01

    The aim was to analyze quality-of-life (QOL) during the first year post transplant in 47 patients undergoing reduced-intensity conditioning (RIC) allotransplantation, and to compare these with a similar subgroup of patients receiving autologous stem cell transplantation (ASCT). We used self-reported questionnaires. Each answer scored from 0 (not at all) to 4 (very much), with higher scores indicating worse functioning. Mean value of physical categories among RIC transplants ranged between 1.23 and 0.77 indicating that patients scored very low for physical symptoms. Patients undergoing ASCT had higher scores in questionnaires performed early after transplant and then gradually improved (P < 0.001). Overall, when we compared physical functioning scores, allo-RIC did significantly better (P = 0.049). Nevertheless, while allo-RIC scores were significantly better for the first three questionnaires, ASCT patients did better in the last two questionnaires. These findings are in accordance with the toxicities observed in both subgroups which are lower in the RIC group early after transplant. No significant differences were observed between either subgroup for any of the functional, social/ family, psychological distress and satisfaction with doctor/nurse relationship items. We have observed similar QOL among patients undergoing RIC-allo as compared to ASCT although GVHD remains an important 'event' in QOL.

  18. Association of mannose-binding lectin levels and invasive fungal disease in hematologic malignancy patients receiving myelosuppressive chemotherapy or allogeneic hematopoietic stem cell transplantation.

    PubMed

    Riwes, M M; Leather, H; Neal, D; Bennett, C; Sugrue, M; Cline, C; Stokes, J; Hiemenz, J; Hsu, J; Wingard, J R

    2016-09-01

    Several studies have suggested an association of mannose-binding lectin (MBL) deficiency with infections. In this study, we investigated the association between MBL deficiency and invasive fungal disease (IFD) in hematologic malignancy patients receiving myelosuppressive chemotherapy or hematopoietic stem cell transplant. MBL levels were quantified at the start of treatment in 152 patients who were followed for 6 months and scored as developing IFD or not. Forty-five patients (29.6%) developed IFD, of which 21 (46.7% of IFD cases and 13.8% of patients) were proven or probable IFD. Fifty-nine (38.8%) had MBL levels <1000 ng/mL. The rates of all IFD in patients with MBL levels below and above 1000 ng/mL were 33.9% and 26.9%, respectively (P=0.356). The rates of proven or probable IFD in patients with MBL levels below and above 1000 ng/mL were 11.9% and 15.1%, respectively (P=0.579). MBL levels <1000 ng/mL were not predictors of death (P=0.233). As expected, IFD was associated with death (P<0.0001). Our findings indicate that MBL levels <1000 ng/mL were not associated with an increased risk of developing IFD or overall survival.

  19. Second line azacitidine for elderly or infirmed patients with acute myeloid leukemia (AML) not eligible for allogeneic hematopoietic cell transplantation-a retrospective national multicenter study.

    PubMed

    Ram, Ron; Gatt, Moshe; Merkel, Drorit; Helman, Ilana; Inbar, Tsofia; Nagler, Arnon; Avivi, Irit; Ofran, Yishai

    2017-04-01

    Elderly and infirm patients with acute myeloid leukemia (AML) with either induction refractory or relapse disease may benefit from treatment with azacitidine. We retrospectively reviewed the data from five tertiary centers in Israel, treated between 2009 and 2015. Thirty-four patients (median age 74 years) were identified. Sixty-two percent of the patients had relapsed disease and 38% had refractory disease. Median time of follow-up was 12.1 months. Out of a total of 327 courses, incidence of infectious episodes was 6%. Eighteen percent experienced major bleeding. Thirty-two percent of the patients achieved morphologic complete remission, and 26% had stabilization of disease during at least three courses. At 12 and 18 months after the first course of azacitidine, 33 and 10% of the patients were progression-free, respectively. Incidences of overall survival at 12 and 24 months were 54.5 and 16%, respectively. Age <75 years was associated with better overall survival. Normal leukocyte count at the first dose of azacitidine and standard doses of azacitidine were both associated with a better progression-free and overall survival. We conclude that azacitidine is feasible in patients who have failed induction chemotherapy and may be associated with prolongation of survival. A prospective trial to validate these results is warranted.

  20. CD34 cell selection of peripheral blood progenitor cells using the CliniMACS device for allogeneic transplantation: clinical results in 102 patients.

    PubMed

    Ringhoffer, Mark; Wiesneth, Markus; Harsdorf, Stephanie; Schlenk, Richard F; Schmitt, Anita; Reinhardt, Peter P; Moessner, Margit; Grimminger, Wolfgang; Mertens, Thomas; Reske, Sven N; Döhner, Hartmut; Bunjes, Donald

    2004-08-01

    The present study investigated the effects of CD34(+) cell selection in 102 patients using the CliniMACS device. Patients were at high risk for the development of graft versus host disease (GvHD) because of age, or the use of a haploidentical, mismatched or unrelated donor (UD). The median age of the patients was 44 years. The CliniMACS procedure yielded 8.0 x 10(6) CD34(+) cells/kg and the number of residual T cells was 1.3 x 10(4)/kg (median). The median follow up was 20.6 months. The probability of graft failure was 7%. The rate of acute GvHD was low (compatible family donors 10%, UDs 17%, and haploidentical donors 26%) with no patient enduring more than grade II disease. The cumulative incidence of chronic GvHD at the median follow up after transplant was 15% for the compatible family donor group, 40% for the UD group and 78% in the group transplanted from a haploidentical donor Treatment failure was mainly because of transplant-related mortality, especially aspergillus infection, and not due to relapse. The probability of disease-free survival, stratified for the risk of treatment failure, was 27% for the high risk, 46% for the intermediate risk and 83% for the low risk group.

  1. Characterization of sphere-forming HCT116 clones by whole RNA sequencing

    PubMed Central

    Chung, Eunkyung; Oh, Inkyung

    2016-01-01

    Purpose To determine CD133+ cells defined as cancer stem cells (CSCs) in colon cancer, we examined whether CD133+ clones in HCT116 demonstrate known features of CSCs like sphere-forming ability, chemodrug-resistance, and metastatic potential. Methods Magnetic cell isolation and cell separation demonstrated that <1% of HCT116 cells expressed CD133, with the remaining cells being CD133- clones. In colon cancer cells, radioresistance is also considered a CSC characteristic. We performed clonogenic assay using 0.4 Gy γ-irradiation. Results Interestingly, there were no differences between HCT116 parental and HCT116 CD133+ clones when the cells comprised 0.5% of the total cells, and CD133- clone demonstrated radiosensitive changes compared with parental and CD133+ clones. Comparing gene expression profiles between sphere-forming and nonforming culture conditions of HCT116 subclones by whole RNA sequencing failed to obtain specific genes expressed in CD133+ clones. Conclusion Despite no differences of gene expression profiles in monolayer attached culture conditions of each clone, sphere-forming conditions of whole HCT116 subclones, parental, CD133+, and CD133- increased 1,761 coding genes and downregulated 1,384 genes related to CSCs self-renewal and survival. Thus, spheroid cultures of HCT116 cells could be useful to expand colorectal CSCs rather than clonal expansion depending on CD133 expressions. PMID:27073788

  2. 21 CFR 1271.25 - What information is required for establishment registration and HCT/P listing?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... registration and HCT/P listing? 1271.25 Section 1271.25 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... HCT/P listing? (a) Your establishment registration Form FDA 3356 must include: (1) The legal name(s... registration and HCT/P listing form is true and accurate, to the best of his or her knowledge. (b) Your...

  3. 21 CFR 1271.21 - When do I register, submit an HCT/P list, and submit updates?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false When do I register, submit an HCT/P list, and... Listing § 1271.21 When do I register, submit an HCT/P list, and submit updates? (a) You must register and submit a list of every HCT/P that your establishment manufactures within 5 days after...

  4. 21 CFR 1271.25 - What information is required for establishment registration and HCT/P listing?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... registration and HCT/P listing? 1271.25 Section 1271.25 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... HCT/P listing? (a) Your establishment registration Form FDA 3356 must include: (1) The legal name(s... registration and HCT/P listing form is true and accurate, to the best of his or her knowledge. (b) Your...

  5. Fluctuating lymphocyte chimerism, tolerance and anti-tumor response in a patient with refractory lymphoma receiving nonmyeloablative conditioning and a haploidentical related allogeneic bone marrow transplant.

    PubMed

    Toh, Han C; Spitzer, Thomas R; Preffer, Frederic; Alexander, Stephen I; McAfee, Steve; Dombkowski, David; Clark, Jeffrey S; Colby, Christine; Saidman, Susan; Sackstein, Robert; Sykes, Megan

    2002-12-01

    A 51-year-old patient with refractory non-Hodgkin lymphoma (NHL) received non-myeloablative conditioning and a two of six (A, B, DR) human leucocyte antigen (HLA) mismatched donor BMT. Post-BMT lymphocytes showed fluctuating T- and natural killer (NK)-cell chimerism, which culminated in mainly donor lymphocytes by Day + 100. Changes in lymphocyte chimerism correlated with anti-donor and anti-host responses in mixed lymphocyte reaction (MLR). On Day + 100, a strong anti-host response was observed in MLR in the absence of graft-versus-host disease (GVHD), together with near complete regression of the patient's lymphoma. A mild chronic GVHD later developed and, eventually, by 680 days post-BMT, the lymphoma had relapsed and MLR reflected a state of global immune unresponsiveness. These observations demonstrate evolving host-versus-graft and graft-versus-host tolerance that correlates with fluctuating lymphoid chimerism and graft-versus-lymphoma (GVL) effects, in the absence of severe GVHD. Eventual lymphoma relapse temporally correlated with a generalised immunosuppressed state.

  6. The bone marrow microenvironment is similarly impaired in allogeneic hematopoietic stem cell transplantation patients with early and late poor graft function.

    PubMed

    Kong, Y; Wang, Y-T; Hu, Y; Han, W; Chang, Y-J; Zhang, X-H; Jiang, Z-F; Huang, X-J

    2016-02-01

    Poor graft function (PGF), including early and late PGF, is a serious complication following allotransplant. We recently reported that bone marrow microenvironment abnormalities may occur in cases of late PGF. Whether these abnormalities occur in early PGF remains unknown. To answer this question, we performed a nested case-control study comparing cellular elements of the bone marrow microenvironment in 10 subjects with early PGF, 30 subjects with late PGF and 40 subjects without PGF. Bone marrow endosteal cells, perivascular cells and endothelial cells were analyzed by flow cytometry and by hematoxylin-eosin and immunohistochemical staining in situ. Subjects with early and late PGF had similar abnormalities in these cell types compared with transplant recipients without PGF. However, none of the aforementioned elements of the bone marrow microenvironment were significantly different between early and late PGF patients. Our data suggest that similar abnormalities in the bone marrow microenvironment may occur in early and late PGF post allotransplant. Cellular approaches, such as the administration of mesenchymal stem cells, promise to be beneficial therapeutic strategies in patients with early or late PGF.

  7. Curative treatment for severe sickle cell disease: allogeneic transplantation.

    PubMed

    Oshrine, Benjamin; Talano, Julie-An

    2015-04-01

    Sickle cell disease is an inherited hematologic disorder that in its severe form can result in substantial morbidity and early mortality. Patients with this disorder can suffer from severe pain, lung disease, and strokes, resulting in chronic debilitating conditions, end organ dysfunction, and organ failure. The health care costs of caring for these chronically ill patients are substantial. Allogeneic transplantation is a modality that has the potential to cure these patients. To date, matched sibling donor transplantation is widely accepted as a standard of care for pediatric patients. Utilizing alternative donors for transplant is still under investigation, as is transplant for adult patients with sickle cell disease. This review focuses on the most recent data for hematopoietic cell transplantation for patients with sickle cell disease.

  8. Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer.

    PubMed

    Miller, Jeffrey S; Soignier, Yvette; Panoskaltsis-Mortari, Angela; McNearney, Sarah A; Yun, Gong H; Fautsch, Susan K; McKenna, David; Le, Chap; Defor, Todd E; Burns, Linda J; Orchard, Paul J; Blazar, Bruce R; Wagner, John E; Slungaard, Arne; Weisdorf, Daniel J; Okazaki, Ian J; McGlave, Philip B

    2005-04-15

    We previously demonstrated that autologous natural killer (NK)-cell therapy after hematopoietic cell transplantation (HCT) is safe but does not provide an antitumor effect. We hypothesize that this is due to a lack of NK-cell inhibitory receptor mismatching with autologous tumor cells, which may be overcome by allogeneic NK-cell infusions. Here, we test haploidentical, related-donor NK-cell infusions in a nontransplantation setting to determine safety and in vivo NK-cell expansion. Two lower intensity outpatient immune suppressive regimens were tested: (1) low-dose cyclophosphamide and methylprednisolone and (2) fludarabine. A higher intensity inpatient regimen of high-dose cyclophosphamide and fludarabine (Hi-Cy/Flu) was tested in patients with poor-prognosis acute myeloid leukemia (AML). All patients received subcutaneous interleukin 2 (IL-2) after infusions. Patients who received lower intensity regimens showed transient persistence but no in vivo expansion of donor cells. In contrast, infusions after the more intense Hi-Cy/Flu resulted in a marked rise in endogenous IL-15, expansion of donor NK cells, and induction of complete hematologic remission in 5 of 19 poor-prognosis patients with AML. These findings suggest that haploidentical NK cells can persist and expand in vivo and may have a role in the treatment of selected malignancies used alone or as an adjunct to HCT.

  9. Spinal fluid lymphocytes responsive to autologous and allogeneic cells in multiple sclerosis and control individuals.

    PubMed Central

    Birnbaum, G; Kotilinek, L; Schwartz, M; Sternad, M

    1984-01-01

    Spinal fluid lymphocytes from multiple sclerosis (MS) patients and controls were stimulated with either autologous non-T cells or with allogeneic non-T cells followed by stimulation with autologous non-T lymphocytes. Cells responding to these stimuli were cloned and their proliferative responses to autologous and allogeneic MS and normal non-T cells were measured. Large numbers of clones with specific patterns of reaction to both autologous and allogeneic cells were obtained from lymphocytes in MS cerebrospinal fluid (CSF), but only occasionally from cells in control CSF. Patterns of responses among clones from a particular CSF were similar and often identical, which suggested that cells in MS CSF were relatively restricted in their specificities. Surface antigen phenotyping of the clones showed them to be predominantly OKT4+, with 13% OKT8+ and 11% OKT4+8+. Peripheral T cells that were stimulated and cultured in parallel with CSF cells were different in that they usually did not give rise to as many clones nor were their patterns of response similar. Many CSF clones were heteroclitic, that is they responded to particular allogeneic cells but not autologous cells. Lymphocytes in MS CSF thus appear to represent a selected population of cells with a high frequency of responsiveness to autologous and allogeneic antigens. Such responses may be evidence for immune regulation within the central nervous system or could represent responses to altered-self antigens. PMID:6237121

  10. Donor lymphocyte infusion after allogeneic stem cell transplantation.

    PubMed

    Castagna, Luca; Sarina, Barbara; Bramanti, Stefania; Perseghin, Paolo; Mariotti, Jacopo; Morabito, Lucio

    2016-06-01

    Allogeneic stem cell transplantation (allo-SCT) is considered the cornerstone in the treatment of several malignant and not malignant hematological diseases. However, relapse of hematological disease after allo-SCT is considered the most challenging point in the field. The risk can be reduced through optimal patients, donor and disease selection before allo-SCT, but harnessing donor immune system is an appealing way to treat or avoid disease relapse. Donor lymphocyte infusion (DLI) is a simple and effective therapy after allo-SCT. In this paper, the efficacy of DLI will be analyzed in different hematological diseases, focusing also on their therapeutic or pre-emptive use.

  11. A myeloablative conditioning regimen for patients with impaired cardiac function undergoing allogeneic stem cell transplantation: reduced cyclophosphamide combined with etoposide and total body irradiation.

    PubMed

    Yoshimi, Akihide; Nannya, Yasuhito; Sakata-Yanagimoto, Mamiko; Oshima, Kumi; Takahashi, Tsuyoshi; Kanda, Yoshinobu; Motokura, Toru; Chiba, Shigeru; Kurokawa, Mineo

    2008-08-01

    To circumvent the cardiac toxicity of high-dose cyclophosphamide (CY) in the myeloablative conditioning for those with cardiac comorbidity, we developed a new cardiac sparing conditioning regimen (VP/rCY/TBI) composed of 12 Gy of total body irradiation (TBI), etoposide (VP-16) (40 mg/kg), and reduced CY (40 mg/kg). We assessed the feasibility of this regimen by retrospectively comparing the outcome of VP/rCY/TBI recipients (n = 18) with that of CY/TBI recipients (n = 140). VP/rCY/TBI recipients had significantly higher cumulative dose of anthracyclines, lower ejection fraction (EF), and poorer Karnofsky performance scales (KPS) than CY/TBI recipients. The cumulative incidences of disease progression were 34.9% in VP/rCY/TBI recipients and 19.0% in CY/TBI recipients (P = 0.33). Despite poorer KPS and more cardiac comorbidity in the VP/rCY/TBI recipients, no difference in the nonprogression mortality rates was observed among recipients of the two regimens (17.5 and 14.3%, respectively, P = 0.96). Severe cardiac toxicity within 28 days after transplantation occurred in 5.9 and 3.6% of VP/rCY/TBI and CY/TBI recipients, respectively (P = 0.64). Graft rejection was not observed in VP/rCY/TBI recipients. There is a possibility that VP/rCY/TBI regimen can be safely administered for patients with pretransplantation cardiac comorbidity while preserving antineoplastic effects. These observations merit further prospective study.

  12. A Limited Sampling Schedule to Estimate Individual Pharmacokinetic Parameters of Fludarabine in Hematopoietic Cell Transplant Patients

    PubMed Central

    Salinger, David H.; Blough, David K.; Vicini, Paolo; Anasetti, Claudio; O’Donnell, Paul V.; Sandmaier, Brenda M.; McCune, Jeannine S.

    2009-01-01

    Purpose Fludarabine monophosphate (fludarabine) is frequently administered to patients receiving a reduced-intensity conditioning regimen for allogeneic hematopoietic cell transplant (HCT) in an ambulatory care setting. These patients experience significant interpatient variability in clinical outcomes, potentially due to pharmacokinetic variability in 2-fluoroadenine (F-ara-A) plasma concentrations. To test such hypotheses, patient compliance with the blood sampling should be optimized by the development of a minimally intrusive limited sampling schedule (LSS) to characterize F-ara-A pharmacokinetics. To this end, we sought to create the first F-ara-A population pharmacokinetic model and subsequently a LSS. Experimental Design A retrospective evaluation of F-ara-A pharmacokinetics was conducted after one or more doses of daily IV fludarabine in 42 adult HCT recipients. NONMEM software was used to estimate the population pharmacokinetic parameters and compute the area under the concentration-time curve (AUC). Results A two compartment model best fit the data. A LSS was constructed using a simulation approach, seeking to minimize the scaled mean square error (sMSE) for the AUC for each simulated individual. The LSS times chosen were: 0.583 hour (hr), 1.5 hr, 6.5 hr and 24 hr after the start of the 30 minute fludarabine infusion. Conclusion The pharmacokinetics of F-ara-A in an individual HCT patient can be accurately estimated by obtaining 4 blood samples (using the LSS) and maximum a posteriori (MAP) Bayesian estimation. Conclusions These are essential tools for prospective pharmacodynamic studies seeking to determine if clinical outcomes are related to F-ara-A pharmacokinetics in patients receiving IV fludarabine in the ambulatory clinic. PMID:19671874

  13. Allogeneic and autologous mode of stem cell transplantation in regenerative medicine: which way to go?

    PubMed

    Mamidi, Murali Krishna; Dutta, Susmita; Bhonde, Ramesh; Das, Anjan Kumar; Pal, Rajarshi

    2014-12-01

    Stem cell transplantation is a generic term covering different techniques. However there is argument over the pros and cons of autologous and allogeneic transplants of mesenchymal stem cells (MSCs) for regenerative therapy. Given that the MSCs have already been proven to be safe in patients, we hypothesize that allogeneic transplantation could be more effective and cost-effective as compared to autologous transplantation specifically in older subjects who are the likely victims of degenerative diseases. This analysis is based on the scientific logic that allogeneic stem cells extracted in large numbers from young and healthy donors could be physiologically, metabolically and genetically more stable. Therefore stem cells from young donors may be expected to exhibit higher vigor in secreting trophic factors leading to activation of host tissue-specific stem cells and also be more efficient in remodeling the micro-environmental niche of damaged tissue.

  14. Murine allogeneic CD19 CAR T cells harbor potent antileukemic activity but have the potential to mediate lethal GVHD.

    PubMed

    Jacoby, Elad; Yang, Yinmeng; Qin, Haiying; Chien, Christopher D; Kochenderfer, James N; Fry, Terry J

    2016-03-10

    Acute lymphoblastic leukemia (ALL) persisting or relapsing following bone marrow transplantation (BMT) has a dismal prognosis. Success with chimeric antigen receptor (CAR) T cells offers an opportunity to treat these patients with leukemia-redirected donor-derived T cells, which may be more functional than T cells derived from patients with leukemia but have the potential to mediate graft-versus-host disease (GVHD). We, together with others, have previously demonstrated tumor-specific T-cell dysfunction in the allogeneic environment. Here, we studied CAR T-cell function following BMT using an immunocompetent murine model of minor mismatched allogeneic transplantation followed by donor-derived CD19-CAR T cells. Allogeneic donor-derived CD19-CAR T cells eliminated residual ALL with equal potency to those administered after syngeneic BMT. Surprisingly, allogeneic CAR T cells mediated lethal acute GVHD with early mortality, which is atypical for this minor mismatch model. We demonstrated that both allogeneic and syngeneic CAR T cells show initial expansion as effector T cells, with a higher peak but rapid deletion of allogeneic CAR T cells. Interestingly, CAR-mediated acute GVHD was only seen in the presence of leukemia, suggesting CAR-target interactions induced GVHD. Indeed, serum interleukin (IL)-6 was elevated only in the presence of both leukemia and CAR T cells, and IL-6 neutralization ameliorated the severity of GVHD in a delayed donor lymphocyte infusion model. Finally, allogeneic CD4(+) CAR T cells were responsible for GVHD, which correlated with their ability to produce IL-6 upon CAR stimulation. Altogether, we demonstrate that donor-derived allogeneic CAR T cells are active but have the capacity to drive GVHD.

  15. Disseminated histoplasmosis in allogeneic bone marrow transplant: a diagnosis not to be missed.

    PubMed

    Haydoura, S; Wallentine, J; Lopansri, B; Ford, C D; Saad, D; Burke, J P

    2014-10-01

    Immunosuppressed patients are at highest risk for disseminated histoplasmosis, but only a few cases have been reported in hematopoietic stem cell transplant recipients. We report a case of disseminated histoplasmosis in an allogeneic bone marrow transplant recipient residing in a non-endemic area. Diagnosis was first suspected based on a peripheral blood smear.

  16. Maintenance of the stemness in CD44(+) HCT-15 and HCT-116 human colon cancer cells requires miR-203 suppression.

    PubMed

    Ju, Sy-Yeuan; Chiou, Shih-Hwa; Su, Yeu

    2014-01-01

    The purpose of this study was to isolate cancer stem cells (CSCs, also called tumor-initiating cells, TICs) from established human colorectal carcinoma (CRC) cell lines, characterize them extensively and dissect the mechanism for their stemness. Freshly isolated CD44(+) and CD44(-) cells from the HCT-15 human colon cancer cell line were subjected to various analyses. Interestingly, CD44(+) cells exhibited higher soft agar colony-forming ability and in vivo tumorigenicity than CD44(-) cells. In addition, the significant upregulation of the protein Snail and the downregulation of miR-203, a stemness inhibitor, in CD44(+) cells suggested that this population possessed higher invasion/metastasis and differentiation potential than CD44(-) cells. By manipulating the expression of CD44 in HCT-15 and HCT-116 cells, we found that the levels of several EMT activators and miR-203 were positively and negatively correlated with those of CD44, respectively. Further analyses revealed that miR-203 levels were repressed by Snail, which was shown to bind to specific E-box(es) present in the miR-203 promoter. In agreement, silencing miR-203 expression in wild-type HCT-116 human colon cancer cells also resulted in an increase of their stemness. Finally, we discovered that c-Src kinase activity was required for the downregulation of miR-203 in HCT-15 cells, which was stimulated by the interaction between hyaluronan (HA) and CD44. Taken together, CD44 is a critical molecule for modulating stemness in CSCs. More importantly, we show for the first time that the downregulation of miR-203 by HA/CD44 signaling is the main reason for stemness-maintenance in colon cancer cells.

  17. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin’s lymphoma. Results of the HDR-ALLO study – a prospective clinical trial by the Grupo Español de Linfomas/Trasplante de Médula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation

    PubMed Central

    Sureda, Anna; Canals, Carme; Arranz, Reyes; Caballero, Dolores; Ribera, Josep Maria; Brune, Mats; Passweg, Jacob; Martino, Rodrigo; Valcárcel, David; Besalduch, Joan; Duarte, Rafael; León, Angel; Pascual, Maria Jesus; García-Noblejas, Ana; Corral, Lucia López; Xicoy, Bianca; Sierra, Jordi; Schmitz, Norbert

    2012-01-01

    Background Although Hodgkin’s lymphoma is a highly curable disease with modern chemotherapy protocols, some patients are primary refractory or relapse after first-line chemotherapy or even after high-dose therapy and autologous stem cell transplantation. We investigated the potential role of allogeneic stem cell transplantation in this setting. Design and Methods In this phase II study 92 patients with relapsed Hodgkin’s lymphoma and an HLA-identical sibling, a matched unrelated donor or a one antigen mismatched, unrelated donor were treated with salvage chemotherapy followed by reduced intensity allogeneic transplantation. Fourteen patients showed refractory disease and died from progressive lymphoma with a median overall survival after trial entry of 10 months (range, 6–17). Seventy-eight patients proceeded to allograft (unrelated donors, n=23). Fifty were allografted in complete or partial remission and 28 in stable disease. Fludarabine (150 mg/m2 iv) and melphalan (140 mg/m2 iv) were used as the conditioning regimen. Anti-thymocyte globulin was additionally used as graft-versus-host-disease prophylaxis for recipients of grafts from unrelated donors. Results The non-relapse mortality rate was 8% at 100 days and 15% at 1 year. Relapse was the major cause of failure. The progression-free survival rate was 47% at 1 year and 18% at 4 years from trial entry. For the allografted population, the progression-free survival rate was 48% at 1 year and 24% at 4 years. Chronic graft-versus-host disease was associated with a lower incidence of relapse. Patients allografted in complete remission had a significantly better outcome. The overall survival rate was 71% at 1 year and 43% at 4 years. Conclusions Allogeneic stem cell transplantation can result in long-term progression-free survival in heavily pre-treated patients with Hodgkin’s lymphoma. The reduced intensity conditioning approach significantly reduced non-relapse mortality; the high relapse rate represents

  18. Incidence and risk factors for life-threatening bleeding after allogeneic stem cell transplant.

    PubMed

    Labrador, Jorge; López-Corral, Lucia; Vazquez, Lourdes; Sánchez-Guijo, Fermin; Guerrero, Carmen; Sánchez-Barba, Mercedes; Lozano, Francisco S; Alberca, Ignacio; Del Cañizo, María C; Caballero, Dolores; González-Porras, Jose R

    2015-06-01

    Bleeding is a frequent complication after allogeneic haematopoietic stem cell transplantation (HSCT) and may affect survival. The purpose of this study was to determine the incidence and risk factors for life-threatening bleeding after HSCT by retrospective evaluation of 491 allogeneic HSCT recipients. With a median follow-up of 33 months, 126 out of 491 allogeneic HSCT recipients experienced a haemorrhagic event (25·7%) and 46 patients developed a life-threatening bleeding episode (9·4%). Pulmonary and gastrointestinal bleeding were the most common sites for life-threatening bleeding, followed by central nervous system. In multivariate analyses, the presence of severe thrombocytopenia after day +28 and the development of grade III-IV acute graft-versus-host disease (GVHD) or thrombotic microangiopathy (TMA) retained their association with life-threatening bleeding events. The overall survival at 3 years among patients without bleeding was 67·1% for only 17·1% for patients with life-threatening bleeding (P < 0·001). In conclusion, life-threatening bleeding is a common complication after allogeneic HSCT. Prolonged severe thrombocytopenia, acute grade III-IV GVHD and TMA were associated with its development.

  19. Management of infections complicating allogeneic hematopoietic stem cell transplantation.

    PubMed

    Hiemenz, John W

    2009-07-01

    The use of allogeneic hematopoietic stem cell transplantation for the treatment of hematologic malignancies, as well as some benign hematologic disorders, has continued to grow over the last 10 years. The availability of this procedure to an increasing number of patients has been facilitated by the use of newer techniques, including reduced intensity conditioning (RIC) regimens, peripheral blood stem cells (PBSCs) and cord blood as donor sources, graft manipulation such as selective T-cell depletion, and other in vitro and in vivo attempts to reduce the risk and severity of graft-versus-host disease (GVHD) after transplantation without losing the potential benefits of a graft-versus-tumor effect for patients with hematologic malignancies. The underlying theme of many of these newer techniques has been to minimize the severity and duration of transplant-related immune suppression, thus reducing the risk of morbidity and mortality from infectious complications. This article reviews immune suppression and recovery that occur after allogeneic stem cell transplantation, with changes in the epidemiology, and some of the recent advances that have been made in management of infectious complications.

  20. Endocrinopathies after Allogeneic and Autologous Transplantation of Hematopoietic Stem Cells

    PubMed Central

    Muscogiuri, Giovanna; Palomba, Stefano; Serio, Bianca; Sessa, Mariarosaria; Giudice, Valentina; Ferrara, Idalucia; Tauchmanovà, Libuse; Colao, Annamaria; Selleri, Carmine

    2014-01-01

    Early and late endocrine disorders are among the most common complications in survivors after hematopoietic allogeneic- (allo-) and autologous- (auto-) stem cell transplant (HSCT). This review summarizes main endocrine disorders reported in literature and observed in our center as consequence of auto- and allo-HSCT and outlines current options for their management. Gonadal impairment has been found early in approximately two-thirds of auto- and allo-HSCT patients: 90–99% of women and 60–90% of men. Dysfunctions of the hypothalamus-pituitary-growth hormone/insulin growth factor-I axis, hypothalamus-pituitary-thyroid axis, and hypothalamus-pituitary-adrenal axis were documented as later complicances, occurring in about 10, 30, and 40–50% of transplanted patients, respectively. Moreover, overt or subclinical thyroid complications (including persistent low-T3 syndrome, chronic thyroiditis, subclinical hypo- or hyperthyroidism, and thyroid carcinoma), gonadal failure, and adrenal insufficiency may persist many years after HSCT. Our analysis further provides evidence that main recognized risk factors for endocrine complications after HSCT are the underlying disease, previous pretransplant therapies, the age at HSCT, gender, total body irradiation, posttransplant derangement of immune system, and in the allogeneic setting, the presence of graft-versus-host disease requiring prolonged steroid treatment. Early identification of endocrine complications can greatly improve the quality of life of long-term survivors after HSCT. PMID:24883377

  1. Chlamydia pneumoniae respiratory infection after allogeneic stem cell transplantation.

    PubMed

    Geisler, William M; Corey, Lawrence

    2002-03-27

    Chlamydia pneumoniae is a common cause of upper and lower respiratory tract infections in immunocompetent patients; however, its role as a respiratory pathogen in immunocompromised hosts has been infrequently recognized. We describe C. pneumoniae lower respiratory tract infection in a 19-year-old male after allogeneic stem cell transplantation. The patient developed fever on day +14, and a subsequent computed tomography scan of the chest revealed a right lateral pleural-based opacity, which was then resected during thoracoscopy. Diagnosis was made by culture and staining of the resected tissue with C. pneumoniae-specific monoclonal antibodies, and azithromycin was administered. To the best of our knowledge, this is the first report of C. pneumoniae respiratory infection after stem cell or marrow transplantation. C. pneumoniae often coexists with other etiologic agents of pneumonia in immunocompromised patients. Considering the infrequency of infections from this organism in this clinical setting, one must still rule out other more likely respiratory pathogens.

  2. 21 CFR 1271.65 - How do I store an HCT/P from a donor determined to be ineligible, and what uses of the HCT/P are...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false How do I store an HCT/P from a donor determined to be ineligible, and what uses of the HCT/P are not prohibited? 1271.65 Section 1271.65 Food and Drugs... TISSUE-BASED PRODUCTS Donor Eligibility § 1271.65 How do I store an HCT/P from a donor determined to...

  3. 21 CFR 1271.65 - How do I store an HCT/P from a donor determined to be ineligible, and what uses of the HCT/P are...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false How do I store an HCT/P from a donor determined to be ineligible, and what uses of the HCT/P are not prohibited? 1271.65 Section 1271.65 Food and Drugs... TISSUE-BASED PRODUCTS Donor Eligibility § 1271.65 How do I store an HCT/P from a donor determined to...

  4. 21 CFR 1271.65 - How do I store an HCT/P from a donor determined to be ineligible, and what uses of the HCT/P are...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false How do I store an HCT/P from a donor determined to be ineligible, and what uses of the HCT/P are not prohibited? 1271.65 Section 1271.65 Food and Drugs... TISSUE-BASED PRODUCTS Donor Eligibility § 1271.65 How do I store an HCT/P from a donor determined to...

  5. [Eight years using the "Mexican method" for allogeneic hematopoietic stem cell transplants].

    PubMed

    Ruiz-Argüelles, Guillermo J; Gómez-Almaguer, David; Ruiz-Delgado, Guillermo J; del Carmen Tarin-Arzaga, Luz

    2007-01-01

    In the past eight years, in Mexico and in other developing countries, over 350 patients have undergone allogeneic hematopoietic stem cell transplants using a non-myeloablative conditioning regimen developed in Mexico and based on international standards. The so called "Mexican method" to conduct allogeneic stem cell transplants is endowed with certain advantages which make it affordable and in turn, available to individuals living in resource-poor countries. The best results using this method have been observed among patients with stage 1 chronic myelogenous leukemia and aplastic anemia. The less favourable results have been observed among patients with acute lymphoblastic leukemia; mild to moderate results have been reported among patients with acute myelogenous leukemia. The "Mexican method" to conduct hematopoietic cells allografting has resulted not only in turning this method accessible to patients in developing countries, but also it has witnessed an increase in the academic activities of physicians from these countries involved in the field.

  6. Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index: A CIBMTR® Study

    PubMed Central

    Sorror, Mohamed L.; Logan, Brent R.; Zhu, Xiaochun; Rizzo, J. Douglas; Cooke, Kenneth R.; McCarthy, Philip L; Ho, Vincent T.; Horowitz, Mary M.; Pasquini, Marcelo C.

    2015-01-01

    Prospective validation of the hematopoietic cell transplantation-comorbidity index (HCT-CI) using contemporary patients treated with HCT across the Unites States is necessary to confirm its widespread applicability. We performed a prospective observational study including all patients (8115 recipients of allogeneic and 11,652 recipients of autologous HCT) who underwent first HCT that was reported to the CIBMTR between 2007 and 2009. In proportional hazards models, increased HCT-CI scores were independently associated with increases in hazard ratios for NRM (p<0.0001) and overall mortality (p<0.0001) among recipients of allogeneic HCT. HCT-CI Scores of ≥3 were uniformly associated with higher risks for outcomes in both allogeneic and autologous HCT, and all subgroups regardless of diagnoses, age, and conditioning intensity. Recipients of allogeneic HCT with scores of 1–2 who were aged <18 or were treated with lower intensity conditioning regimens had similar outcomes compared to those with score 0. Higher risks for overall mortality, but not for NRM, were observed among recipients of autologous HCT with scores of 1–2 versus 0. Our results confirm the validity the HCT-CI in both allogeneic and autologous HCT. The index should be used as a valid standard-of-care health measure in counseling patients for HCT, in clinical trial design, and in adjusting outcome analyses. PMID:25862591

  7. Parainfluenza virus type 3 Ab in allogeneic hematopoietic cell transplant recipients: factors influencing post-transplant Ab titers and associated outcomes.

    PubMed

    Seo, S; Xie, H; Karron, R A; Thumar, B; Englund, J A; Leisenring, W M; Stevens-Ayers, T; Boeckh, M; Campbell, A P

    2014-09-01

    Parainfluenza virus type 3 (PIV-3) can cause severe respiratory illness among hematopoietic cell transplantation (HCT) recipients. Factors associated with PIV-3-specific Ab level, and the association between PIV-3 Ab levels and clinical outcomes in HCT recipients who acquire PIV-3 infection, are unknown. We evaluated PIV-3-specific hemagglutination inhibition Ab levels and clinical outcomes among 172 patients with PIV-3 infection following HCT. In a multivariable linear regression model, high post-transplantation Ab levels were independently associated with higher pre-transplantation recipient titer (mean difference 0.38 (95% confidence interval (CI), 0.26, 0.50), P<0.001). Significant associations between pre-HCT Ab titers in both patients and donors and occurrence of lower respiratory tract disease (LRD) after HCT were not observed. In conclusion, low pre-transplantation titers are associated with low Ab levels after HCT. The relationship between PIV-3 Ab levels and outcomes remain uncertain. Further study is needed to prospectively evaluate the dynamics of PIV-3-specific Ab responses and the relative contribution of PIV-3-specific Ab to protection from infection acquisition and progression to LRD.

  8. Carnosine inhibits KRAS-mediated HCT116 proliferation by affecting ATP and ROS production.

    PubMed

    Iovine, Barbara; Iannella, Maria Luigia; Nocella, Francesca; Pricolo, Maria Rosaria; Bevilacqua, Maria Assunta

    2012-02-28

    Carnosine is a natural dipeptide that has generated particular interest for its antioxidant, anti-aging and especially for its antiproliferative properties. In this study, we demonstrate that carnosine inhibits the proliferation of human HCT116 colon cancer cells. In this cell line, the activating KRAS mutation induces mitochondrial ROS, the signaling molecules for cell proliferation. We observed that 50-100 mM carnosine decreases ATP and ROS concentration and induces cell cycle arrest in G1 phase. In HCT116 cells these effects are related to decreased ERK1/2 phosphorylation and increased p21waf1 protein. Our findings support the concept that carnosine could inhibit HCT116 cell growth via its antioxidant activity and its ability to affect glycolysis.

  9. Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international blood and marrow transplant research.

    PubMed

    Gupta, Vikas; Malone, Adriana K; Hari, Parameswaran N; Ahn, Kwang Woo; Hu, Zhen-Huan; Gale, Robert Peter; Ballen, Karen K; Hamadani, Mehdi; Olavarria, Eduardo; Gerds, Aaron T; Waller, Edmund K; Costa, Luciano J; Antin, Joseph H; Kamble, Rammurti T; van Besien, Koen M; Savani, Bipin N; Schouten, Harry C; Szer, Jeffrey; Cahn, Jean-Yves; de Lima, Marcos J; Wirk, Baldeep; Aljurf, Mahmoud D; Popat, Uday; Bejanyan, Nelli; Litzow, Mark R; Norkin, Maxim; Lewis, Ian D; Hale, Gregory A; Woolfrey, Ann E; Miller, Alan M; Ustun, Celalettin; Jagasia, Madan H; Lill, Michael; Maziarz, Richard T; Cortes, Jorge; Kalaycio, Matt E; Saber, Wael

    2014-01-01

    We evaluated outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced-intensity conditioning (RIC). The median age at RIC HCT was 55 yr. Donors were a matched sibling donor (MSD) in 34% of RIC HCTs, an HLA well-matched unrelated donor (URD) in 45%, and a partially matched/mismatched URD in 21%. Risk stratification according to the Dynamic International Prognostic Scoring System (DIPSS) was 12% low, 49% intermediate-1, 37% intermediate-2, and 1% high. The probability of survival at 5 yr was 47% (95% confidence interval [CI], 40% to 53%). In a multivariate analysis, donor type was the sole independent factor associated with survival. Adjusted probabilities of survival at 5-yr were 56% (95% CI, 44% to 67%) for MSD, 48% (95% CI, 37% to 58%) for well-matched URD, and 34% (95% CI, 21% to 47%) for partially matched/mismatched URD (P = .002). The relative risk (RR) for NRM was 3.92 (P = .006) for well-matched URD and 9.37 (P < .0001) for partially matched/mismatched URD. Trends toward increased NRM (RR, 1.7; P = .07) and inferior survival (RR, 1.37; P = .10) were observed in DIPSS intermediate-2/high-risk patients compared with DIPSS low/intermediate-1 risk patients. Our data indicate that RIC HCT is a potentially curative option for patients with MF, and that donor type is the most important factor influencing survival in these patients.

  10. THE IMPACT OF GRAFT VERSUS HOST DISEASE ON RELAPSE RATE IN PATIENTS WITH LYMPHOMA DEPENDS ON THE HISTOLOGICAL SUB-TYPE AND THE INTENSITY OF THE CONDITIONING REGIMEN

    PubMed Central

    Urbano-Ispizua, Alvaro; Pavletic, Steven Z.; Flowers, Mary E.; Klein, John P.; Zhang, Mei-Jie; Carreras, Jeanette; Montoto, Silvia; Perales, Miguel-Angel; Aljurf, Mahmoud D.; Akpek, Görgün; Bredeson, Christopher N.; Costa, Luciano J.; Dandoy, Christopher; Freytes, César O.; Fung, Henry C.; Gale, Robert Peter; Gibson, John; Hamadani, Mehdi; Hayashi, Robert J.; Inamoto, Yoshihiro; Inwards, David J.; Lazarus, Hillard M.; Maloney, David G.; Martino, Rodrigo; Munker, Reinhold; Nishihori, Taiga; Olsson, Richard F.; Rizzieri, David A.; Reshef, Ran; Saad, Ayman; Savani, Bipin N.; Schouten, Harry C.; Smith, Sonali M.; Socié, Gérard; Wirk, Baldeep; Yu, Lolie C.; Saber, Wael

    2015-01-01

    Purpose To analyze the impact of graft versus host disease (GVHD) on the relapse rate of different lymphoma subtypes after allogeneic hematopoietic cell transplantation (allo-HCT). Patients and Methods Adult patients with a diagnosis of Hodgkin lymphoma (HL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), peripheral T-cell lymphoma (PTCL), or mantle cell lymphoma (MCL) undergoing HLA-identical sibling or unrelated donor HCT between 1997 and 2009 were included. Results Two thousand six hundred and eleven cases were included. Reduced-intensity conditioning (RIC) regimen was used in 62.8% of the transplants. In a multivariate analysis of myeloablative cases (n=970), neither acute (aGVHD) nor chronic GVHD (cGVHD) were significantly associated with a lower incidence of relapse/progression in any lymphoma subtype. In contrast, the analysis of RIC cases (n=1641) showed that cGVHD was associated with a lower incidence of relapse/progression in FL (RR 0.51, p=0.049) and in MCL (RR 0.41, p=0.019). Patients with FL or MCL developing both aGVHD and cGVHD had the lowest risk of relapse (RR 0.14, p=0.007; and RR 0.15, p=0.0019, respectively). Of interest, the effect of GVHD on decreasing relapse was similar in patients with sensitive disease and chemoresistant disease. Unfortunately, both aGVHD and cGVHD had a deleterious effect on treatment related mortality (TRM) and overall survival (OS) in FL cases, and did not impact TRM, OS or PFS in MCL. Conclusion This study reinforces the use of RIC allo-HCT as a platform for immunotherapy in follicular and mantle cell lymphoma patients. PMID:25981509

  11. Recipient HLA-C Haplotypes and microRNA 148a/b Binding Sites Have No Impact on Allogeneic Hematopoietic Cell Transplantation Outcomes.

    PubMed

    Hoff, Gretchen A; Fischer, Johannes C; Hsu, Katharine; Cooley, Sarah; Miller, Jeffrey S; Wang, Tao; Haagenson, Michael; Spellman, Stephen; Lee, Stephanie J; Uhrberg, Markus; Venstrom, Jeffrey M; Verneris, Michael R

    2017-01-01

    Natural killer cells are important in graft-versus-leukemia responses after hematopoietic cell transplantation (HCT). A variety of surface receptors dictates natural killer cell function, including killer cell immunoglobulin-like receptor recognition of HLA-C. Previous single-center studies show that HLA-C epitopes, designated C1 and C2, were associated with allogeneic HCT outcomes; specifically, recipients homozygous for the C1 epitope (C1/C1) experienced a survival benefit. Additionally, mismatching at HLA-C was beneficial in recipients possessing at least 1 C2 allele, whereas the opposite was true for homozygous C1 (C1/C1) recipients where HLA-C mismatching resulted in worse outcomes. In this analysis we aimed to validate these findings in a large multicenter study. We also set out to determine whether surface expression of recipient HLA-C, determined by polymorphism in a microRNA (miR-148a/b) binding site within the 3'-region of the HLA-C transcript, was associated with transplant outcomes. In this large registry cohort, we were unable to confirm the prior findings regarding recipient HLA-C epitope status and outcome. Additionally, HLA-C surface expression (ie, surface density), as predicted by the miR-148a/b binding single nucleotide polymorphism, was also not with associated transplant outcomes. Collectively, neither HLA-C surface expression, as determined by miR-148a/b, nor recipient HLA-C epitopes (C1, C2) are associated with allogeneic HCT outcomes.

  12. Progress in hematopoietic stem cell transplantation as allogeneic cellular gene therapy in thalassemia.

    PubMed

    Isgrò, Antonella; Gaziev, Javid; Sodani, Pietro; Lucarelli, Guido

    2010-08-01

    Allogeneic hemopoietic stem cell transplantation (HSCT) represents one of the best cures for thalassemia. Currently, HSCT for thalassemia consists of allogeneic stem cell gene therapy and still awaits autologous genetically modified stem cell transplantation. HSCT for thalassemia has substantially improved over the last two decades, due in large part to improvements in preventive strategies, the effective control of transplant-related complications, and the development of new preparative regimens. A risk classes-based approach to transplantation in thalassemia has led to disease-free survival probability of 87, 85, and 80% in classes 1, 2, and 3 patients, respectively. Adult thalassemia patients, who are higher risk patients for transplant-related toxicity due to an advanced phase of the disease, have a cure rate of 65% with current treatment protocol. Patients who do not have matched family or unrelated donors could benefit from haploidentical mother-to-child transplantation. Overall, the results of this type of transplantation appear encouraging.

  13. Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Ogonek, Justyna; Kralj Juric, Mateja; Ghimire, Sakhila; Varanasi, Pavankumar Reddy; Holler, Ernst; Greinix, Hildegard; Weissinger, Eva

    2016-01-01

    The timely reconstitution and regain of function of a donor-derived immune system is of utmost importance for the recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Of note, new developments such as umbilical cord blood or haploidentical grafts were associated with prolonged immunodeficiency due to delayed immune reconstitution, raising the need for better understanding and enhancing the process of immune reconstitution and finding strategies to further optimize these transplant procedures. Immune reconstitution post-HSCT occurs in several phases, innate immunity being the first to regain function. The slow T cell reconstitution is regarded as primarily responsible for deleterious infections with latent viruses or fungi, occurrence of graft-versus-host disease, and relapse. Here we aim to summarize the major steps of the adaptive immune reconstitution and will discuss the importance of immune balance in patients after HSCT. PMID:27909435

  14. Allogeneic stem cell transplantation for the treatment of refractory scleromyxedema.

    PubMed

    Shayegi, Nona; Alakel, Nael; Middeke, Jan Moritz; Schetelig, J; Mantovani-Löffler, Luisa; Bornhäuser, Martin

    2015-02-01

    Scleromyxedema is a rare disorder of connective tissue with unknown etiology. Its manifestation includes a generalized mucin deposition, which is frequently associated with paraproteinemia. The course of scleromyxedema is progressive and often lethal. As a result of its poorly understood pathogenesis, there is no causative treatment option. The efficacy of cytoreductive agents and autologous stem cell transplantation has been reported, but so far allografting as a treatment option has not yet been documented. Herein, we report on a patient with severe neurologic involvement and refractory course attaining durable remission after receiving an allogeneic hematopoietic cell transplant from an human leukocyte antigen-matched sibling. This case not only illustrates a potential new treatment option for selected patients, but also provides insights into the pathogenesis of this rare disease.

  15. A Unique Case of Allogeneic Fat Grafting Between Brothers

    PubMed Central

    Kim, Samuel; Edelson, Richard L.; Sumpio, Brandon; Kwei, Stephanie

    2016-01-01

    Summary: We present a case of a 65-year-old man with cutaneous T-cell lymphoma treated with radiation therapy and an allogeneic hematopoietic stem cell transplant from his human leukocyte antigen-matched brother. Engraftment was successful, but the patient went on to develop painful, radiation-induced ulcers. The ulcers were fat-allografted using liposuctioned fat from his brother because of the patient’s unique chimeric state. Postprocedure follow-up revealed epithelialization of the ulcer sites and significant improvement in neuropathic pain. Our unique case study supports the use of fat grafting for its restorative purposes and for its ability to alleviate chronic neuropathic pain. Additionally, it appears that our case provides a basis of a general approach to the treatment of radiation-induced ulcers in chimeric patients with lymphoid malignancies. PMID:27757347

  16. NCI, NHLBI first international consensus conference on late effects after pediatric hematopoietic cell transplantation: etiology and pathogenesis of late effects after HCT performed in childhood--methodologic challenges.

    PubMed

    Bhatia, Smita; Davies, Stella M; Scott Baker, K; Pulsipher, Michael A; Hansen, John A

    2011-10-01

    Hematopoietic cell transplantation (HCT) is now a curative option for certain categories of patients with hematologic malignancies and other life-threatening illnesses. Technical and supportive care has resulted in survival rates that exceed 70% for those who survive the first 2 years after HCT. However, long-term survivors carry a high burden of morbidity, including endocrinopathies, musculoskeletal disorders, cardiopulmonary compromise, and subsequent malignancies. Understanding the etiologic pathways that lead to specific post-HCT morbidities is critical to developing targeted prevention and intervention strategies. Understanding the molecular underpinnings associated with graft-versus-host disease (GVHD), organ toxicity, relapse, opportunistic infection, and other long-term complications now recognized as health care concerns will have significant impact on translational research aimed at developing novel targeted therapies for controlling chronic GVHD, facilitating tolerance and immune reconstitution, reducing risk of relapse and secondary malignancies, minimizing chronic metabolic disorders, and improving quality of life. However, several methodological challenges exist in achieving these goals; these issues are discussed in detail in this paper.

  17. Angiogenesis after transplantation of auto- and allogenic cells.

    PubMed

    Fatkhudinov, T Kh; Bol'shakova, G B; Komissarova, S V; Arutyunyan, I V; Rzhaninova, A A; Goldstein, D V

    2010-10-01

    Neoangiogenesis after transplantation of auto- and allogenic mononuclears and multipotent stromal cells from the bone marrow was studied on the model of inflammatory angiogenesis. Transplanted auto- and allogenic cells stimulate the formation of new blood vessels in the granulation tissue, this manifesting in an increase in the quantity and volume density of blood vessels. The most pronounced angiogenesis was observed after transplantation of allogenic mononuclears and multipotent stromal cells. It was associated with intense inflammatory infiltration, with less numerous and mature collagen fibers in the granulation tissue. Injection of allogenic cells led to stimulation and chronization of inflammation, infiltration with inflammatory and poorly differentiated cells, and more pronounced and lasting angiogenesis. However, neither auto-, nor allogenic transplanted labeled cells were detected in the walls of new blood vessels. Hence, it seems that bone marrow mononuclears and multipotent stromal cells stimulated angiogenesis mainly at the expense of production of angiogenic factors, and after transplantation of allogenic cells also by stimulating the inflammation.

  18. Successful allogeneic hematopoietic stem cell transplantation in a boy with X-linked inhibitor of apoptosis deficiency presenting with hemophagocytic lymphohistiocytosis: A case report

    PubMed Central

    Jiang, Ming-Yan; Guo, Xia; Sun, Shu-Wen; Li, Qiang; Zhu, Yi-Ping

    2016-01-01

    X-linked inhibitor of apoptosis (XIAP) deficiency, also known as X-linked lymphoproliferative syndrome type 2 (XLP2), is a rare inherited primary immunodeficiency resulting from the XIAP (also known as BIRC4) mutation. XIAP deficiency is mainly associated with familial hemophagocytic lymphohistiocytosis (HLH) phenotypes, and genetic testing is crucial in diagnosing this syndrome. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only successful strategy for the treatment of this disease; however, a limited number of studies has been published concerning the outcomes of allogeneic HSCT in patients with XIAP deficiency. The present study reported a successful allogeneic HSCT performed to treat XIAP deficiency in a Chinese boy presenting with HLH. Polymerase chain reaction and DNA sequencing were performed to confirm the diagnosis of XIAP deficiency, and allogeneic HSCT was performed. Genetic tests revealed a two-nucleotide deletion (c.1021_1022delAA) in the patient, which was inherited from his mother, and resulted in frameshift mutation and premature stop codon (p.N341fsX348); this is considered to be a disease-causing mutation. The XIAP deficiency patient underwent allogeneic HSCT, receiving busulfan-containing reduced intensity myeloablative conditioning regimen, with a good intermediate follow-up result obtained. Therefore, genetic testing is essential to confirm the diagnosis of XIAP deficiency and detect the carrier of mutation. The present case study may promote the investigation of allogeneic HSCT in patients with XIAP deficiency. PMID:27602064

  19. Cartilage Regeneration in Osteoarthritic Patients by a Composite of Allogeneic Umbilical Cord Blood-Derived Mesenchymal Stem Cells and Hyaluronate Hydrogel: Results From a Clinical Trial for Safety and Proof-of-Concept With 7 Years of Extended Follow-Up.

    PubMed

    Park, Yong-Beom; Ha, Chul-Won; Lee, Choong-Hee; Yoon, Young Cheol; Park, Yong-Geun

    2016-09-09

    : Few methods are available to regenerate articular cartilage defects in patients with osteoarthritis. We aimed to assess the safety and efficacy of articular cartilage regeneration by a novel medicinal product composed of allogeneic human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs). Patients with Kellgren-Lawrence grade 3 osteoarthritis and International Cartilage Repair Society (ICRS) grade 4 cartilage defects were enrolled in this clinical trial. The stem cell-based medicinal product (a composite of culture-expanded allogeneic hUCB-MSCs and hyaluronic acid hydrogel [Cartistem]) was applied to the lesion site. Safety was assessed by the World Health Organization common toxicity criteria. The primary efficacy outcome was ICRS cartilage repair assessed by arthroscopy at 12 weeks. The secondary efficacy outcome was visual analog scale (VAS) score for pain on walking. During a 7-year extended follow-up, we evaluated safety, VAS score, International Knee Documentation Committee (IKDC) subjective score, magnetic resonance imaging (MRI) findings, and histological evaluations. Seven participants were enrolled. Maturing repair tissue was observed at the 12-week arthroscopic evaluation. The VAS and IKDC scores were improved at 24 weeks. The improved clinical outcomes were stable over 7 years of follow-up. The histological findings at 1 year showed hyaline-like cartilage. MRI at 3 years showed persistence of the regenerated cartilage. Only five mild to moderate treatment-emergent adverse events were observed. There were no cases of osteogenesis or tumorigenesis over 7 years. The application of this novel stem cell-based medicinal product appears to be safe and effective for the regeneration of durable articular cartilage in osteoarthritic knees.

  20. Retrospective Study of Incidence and Prognostic Significance of Eosinophilia after Allogeneic Hematopoietic Stem Cell Transplantation: Influence of Corticosteroid Therapy

    PubMed Central

    Yamamoto, Wataru; Ogusa, Eriko; Matsumoto, Kenji; Maruta, Atsuo; Ishigatsubo, Yoshiaki; Kanamori, Heiwa

    2016-01-01

    Objective: The clinical significance of eosinophilia after allogeneic hematopoietic stem cell transplantation is controversial. This study aimed to retrospectively study the impact of eosinophilia on the outcome of allogeneic hematopoietic stem cell transplantation by taking into account the influence of corticosteroid therapy. Materials and Methods: We retrospectively studied 204 patients with acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome who underwent allogeneic hematopoietic stem cell transplantation from January 2001 to December 2010. Results: The median age was 43 years (minimum-maximum: 17-65 years). Myeloablative conditioning was used in 153 patients and reduced intensity conditioning was employed in 51 patients. Donor cells were from bone marrow in 132 patients, peripheral blood in 34, and cord blood in 38. Eosinophilia was detected in 71 patients and there was no significant predictor of eosinophilia by multivariate analysis. There was no relationship between occurrence of eosinophilia and the incidence or grade of acute graft-versus-host disease when the patients were stratified according to corticosteroid treatment. Although eosinophilia was a prognostic factor for 5-year overall survival by univariate analysis, it was not a significant indicator by multivariate analysis. Conclusion: These results suggest that the clinical significance of eosinophilia in patients receiving allogeneic hematopoietic stem cell transplantation should be assessed with consideration of systemic corticosteroid administration. PMID:27094383

  1. Pure red cell aplasia after ABO major-mismatched allogeneic peripheral blood stem cell transplantation successfully treated with plasma exchange and low-dose steroid: two case reports.

    PubMed

    Tsai, Hui-Jen; Lin, Sheng-Fung; Liu, Ta-Chih; Chang, Chao-Sung; Hsiao, Hui-Hua; Chen, Tyen-Po

    2004-03-01

    Pure red cell aplasia (PRCA) is a complication of ABO-incompatible allogeneic stem cell transplantation. The mechanism is not well known, although the isoagglutinin titer before transplantation or cyclosporine use is considered to be the cause. Patients with this complication require more blood transfusions than those without it. There is no standard treatment. We report two cases of PRCA after allogeneic peripheral blood stem cell transplantation that were successfully treated with plasma exchange and low-dose steroid.

  2. Therapy-related acute myeloid leukemia and myelodysplastic syndrome after hematopoietic cell transplantation for lymphoma.

    PubMed

    Yamasaki, S; Suzuki, R; Hatano, K; Fukushima, K; Iida, H; Morishima, S; Suehiro, Y; Fukuda, T; Uchida, N; Uchiyama, H; Ikeda, H; Yokota, A; Tsukasaki, K; Yamaguchi, H; Kuroda, J; Nakamae, H; Adachi, Y; Matsuoka, K-I; Nakamura, Y; Atsuta, Y; Suzumiya, J

    2017-04-03

    Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for lymphoma. The choice between high-dose therapy with autologous HCT and allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed lymphoma. We retrospectively analyzed incidence and risk factors for the development of t-AML/MDS in lymphoma patients treated with autologous or allogeneic HCT. A total of 13 810 lymphoma patients who received autologous (n=9963) or allogeneic (n=3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, lymphoma patients receiving autologous HCT (1.38% at 3 years after autologous HCT) had a significant risk for developing t-AML/MDS compared to allogeneic HCT (0.37% at 3 years after allogeneic HCT, P<0.001). Significant risk factors for the development of t-AML/MDS after autologous and allogeneic HCT were high-stage risk at HCT (P=0.04) or secondary malignancies (P<0.001) and receiving cord blood stem cell (P=0.03) or involved field radiotherapy (P=0.002), respectively. Strategies that carefully select lymphoma patients for autologous HCT, by excluding lymphoma patients with high-stage risk at HCT, may allow the identification of individual lymphoma patients at particular high risk for t-AML/MDS.Bone Marrow Transplantation advance online publication, 3 April 2017; doi:10.1038/bmt.2017.52.

  3. SUCCESSFUL FERTILITY RESTORATION AFTER ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION

    PubMed Central

    Gharwan, Helen; Neary, Nicola M.; Link, Mary; Hsieh, Matthew M.; Fitzhugh, Courtney D.; Sherins, Richard J.; Tisdale, John F.

    2015-01-01

    Objective Myeloablative conditioning regimens given prior to hematopoietic stem cell transplantation (HSCT) frequently cause permanent sterility in men. In patients with sickle cell disease (SCD) we use a nonmyeloablative regimen with sirolimus, alemtuzumab, and low-dose total-body irradiation (300 centigrays) with gonadal shielding preceding allogeneic HSCT. We report here the restoration of azoospermia in a patient with SCD after allogeneic HSCT. We discuss the impact of our patient’s underlying chronic medical conditions and the therapies he had received (frequent blood transfusions, iron chelating drugs, ribavirin, hydroxyurea, opioids), as well as the impact of the nonmyeloablative conditioning regimen on male gonadal function, and we review the literature on this topic. Methods We determined the patient’s reproductive hormonal values and his semen parameters before, during, and after HSCT and infertility treatment. In addition, we routinely measured his serum laboratory parameters pertinent to SCD and infertility, such as iron and ferritin levels. A karyotype analysis was performed to assess the potential presence of Klinefelter syndrome. Finally, imaging studies of the patient’s brain and testes were done to rule out further underlying pathology. Results A 42-year-old man with SCD, transfusional iron overload, and hepatitis C underwent a nonmyeloablative allogeneic HSCT. One year later he desired to father a child but was found to be azoospermic in the context of hypogonadotropic hypogonadism. Restoration of fertility was attempted with human chorionic gonadotropin (2,000 IU) plus human menopausal gonadotropin (75 IU follicle-stimulating hormone) injected subcutaneously 3 times weekly. Within 6 months of treatment, the patient’s serum calculated free testosterone value normalized, and his sperm count and sperm motility improved. After 10 months, he successfully initiated a pregnancy through intercourse. The pregnancy was uncomplicated, and a healthy

  4. Rationale and design of the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy (the POSEIDON-DCM study): a phase I/II, randomized pilot study of the comparative safety and efficacy of transendocardial injection of autologous mesenchymal stem cell vs. allogeneic mesenchymal stem cells in patients with non-ischemic dilated cardiomyopathy.

    PubMed

    Mushtaq, Muzammil; DiFede, Darcy L; Golpanian, Samuel; Khan, Aisha; Gomes, Samirah A; Mendizabal, Adam; Heldman, Alan W; Hare, Joshua M

    2014-12-01

    While accumulating clinical trials have focused on the impact of cell therapy in patients with acute myocardial infarction (MI) and ischemic cardiomyopathy, there are fewer efforts to examine cell-based therapy in patients with non-ischemic cardiomyopathy (NICM). We hypothesized that cell therapy could have a similar impact in NICM. The POSEIDON-DCM trial is a phase I/II trial designed to address autologous vs. allogeneic bone marrow-derived mesenchymal stem cells (MSCs) in patients with NICM. In this study, cells will be administered transendocardially with the NOGA injection-catheter system to patients (n = 36) randomly allocated to two treatment groups: group 1 (n = 18 auto-human mesenchymal stem cells (hMSC)) and group 2 (n = 18 allo-hMSCs). The primary and secondary objectives are, respectively, to demonstrate the safety and efficacy of allo-hMSCS vs. auto-hMSCs in patients with NICM. This study will establish safety of transendocardial injection of stem cells (TESI), compare phenotypic outcomes, and offer promising advances in the field of cell-based therapy in patients with NICM.

  5. Inositol Pyrophosphate Profiling of Two HCT116 Cell Lines Uncovers Variation in InsP8 Levels

    PubMed Central

    Gu, Chunfang; Wilson, Miranda S. C.; Jessen, Henning J.; Saiardi, Adolfo; Shears, Stephen B.

    2016-01-01

    The HCT116 cell line, which has a pseudo-diploid karotype, is a popular model in the fields of cancer cell biology, intestinal immunity, and inflammation. In the current study, we describe two batches of diverged HCT116 cells, which we designate as HCT116NIH and HCT116UCL. Using both gel electrophoresis and HPLC, we show that HCT116UCL cells contain 6-fold higher levels of InsP8 than HCT116NIH cells. This observation is significant because InsP8 is one of a group of molecules collectively known as ‘inositol pyrophosphates’ (PP-InsPs)—highly ‘energetic’ and conserved regulators of cellular and organismal metabolism. Variability in the cellular levels of InsP8 within divergent HCT116 cell lines could have impacted the phenotypic data obtained in previous studies. This difference in InsP8 levels is more remarkable for being specific; levels of other inositol phosphates, and notably InsP6 and 5-InsP7, are very similar in both HCT116NIH and HCT116UCL lines. We also developed a new HPLC procedure to record 1-InsP7 levels directly (for the first time in any mammalian cell line); 1-InsP7 comprised <2% of total InsP7 in HCT116NIH and HCT116UCL lines. The elevated levels of InsP8 in the HCT116UCL lines were not due to an increase in expression of the PP-InsP kinases (IP6Ks and PPIP5Ks), nor to a decrease in the capacity to dephosphorylate InsP8. We discuss how the divergent PP-InsP profiles of the newly-designated HCT116NIH and HCT116UCL lines should be considered an important research opportunity: future studies using these two lines may uncover new features that regulate InsP8 turnover, and may also yield new directions for studying InsP8 function. PMID:27788189

  6. Minimizing the risk of allo-sensitization to optimize the benefit of allogeneic cardiac-derived stem/progenitor cells

    PubMed Central

    Hocine, Hocine R.; Costa, Hicham E. L.; Dam, Noemie; Giustiniani, Jerome; Palacios, Itziar; Loiseau, Pascale; Benssusan, Armand; Borlado, Luis R.; Charron, Dominique; Suberbielle, Caroline; Jabrane-Ferrat, Nabila; Al-Daccak, Reem

    2017-01-01

    Allogeneic human cardiac-derived stem/progenitor cells (hCPC) are currently under clinical investigation for cardiac repair. While cellular immune response against allogeneic hCPC could be part of their beneficial-paracrine effects, their humoral immune response remains largely unexplored. Donor-specific HLA antibodies (DSA-HLA-I/DSA-HLA-II), primary elements of antibody-mediated allograft injury, might present an unidentified risk to allogeneic hCPC therapy. Here we established that the binding strength of anti-HLA monoclonal antibodies delineates hCPC proneness to antibody-mediated injury. In vitro modeling of clinical setting demonstrated that specific DSA-HLA-I of high/intermediate binding strength are harmful for hCPC whereas DSA-HLA-II are benign. Furthermore, the Luminex-based solid-phase assays are suitable to predict the DSA-HLA risk to therapeutic hCPC. Our data indicate that screening patient sera for the presence of HLA antibodies is important to provide an immune-educated choice of allogeneic therapeutic cells, minimize the risk of precipitous elimination and promote the allogeneic reparative effects. PMID:28117403

  7. Intracoronary allogeneic cardiosphere-derived stem cells are safe for use in dogs with dilated cardiomyopathy.

    PubMed

    Hensley, Michael Taylor; Tang, Junnan; Woodruff, Kathleen; Defrancesco, Teresa; Tou, Sandra; Williams, Christina M; Breen, Mathew; Meurs, Kathryn; Keene, Bruce; Cheng, Ke

    2017-03-15

    Cardiosphere-derived cells (CDCs) have been shown to reduce scar size and increase viable myocardium in human patients with mild/moderate myocardial infarction. Studies in rodent models suggest that CDC therapy may confer therapeutic benefits in patients with non-ischaemic dilated cardiomyopathy (DCM). We sought to determine the safety and efficacy of allogeneic CDC in a large animal (canine) model of spontaneous DCM. Canine CDCs (cCDCs) were grown from a donor dog heart. Similar to human CDCs, cCDCs express CD105 and are slightly positive for c-kit and CD90. Thirty million of allogeneic cCDCs was infused into the coronary vessels of Doberman pinscher dogs with spontaneous DCM. Adverse events were closely monitored, and cardiac functions were measured by echocardiography. No adverse events occurred during and after cell infusion. Histology on dog hearts (after natural death) revealed no sign of immune rejection from the transplanted cells.

  8. Second allogeneic transplantation for relapse of malignant disease: retrospective analysis of outcome and predictive factors by the EBMT.

    PubMed

    Ruutu, T; de Wreede, L C; van Biezen, A; Brand, R; Mohty, M; Dreger, P; Duarte, R; Peters, C; Garderet, L; Schönland, S; Gratwohl, A; Niederwieser, D; de Witte, T; Kröger, N

    2015-12-01

    In patients treated with allogeneic stem cell transplantation (SCT) for malignant disease who suffer from a relapse after the transplantation, the role of second allogeneic SCT is often uncertain. In a retrospective analysis, 2632 second allogeneic transplantations carried out for a relapse after the first transplantation were analyzed to define indications and identify predictive factors. Fifteen percent of the patients remained relapse-free until 5 years after the second SCT. Patients with CML had a better survival than patients with other diseases. In a multivariate analysis, factors associated with better survival were low disease burden, longer remission duration after the first transplantation, longer interval between the transplantations, younger age, absence of grade II-IV acute GvHD or chronic GvHD after the first transplantation, and later year of transplantation. The European Society for Blood and Marrow Transplantation risk score predicted the outcome. Using the same donor as in the first transplantation vs another donor had no predictive value for survival. Sibling donor was a favorable predictive factor. In conclusion, second allogeneic SCT offers a reasonable option especially for young patients with a long remission after the first transplantation and a low disease burden. The present findings do not support the usefulness of changing the donor for the second transplantation.

  9. The demanding attention of tuberculosis in allogeneic hematopoietic stem cell transplantation recipients: High incidence compared with general population

    PubMed Central

    Lee, Hyo-Jin; Lee, Dong-Gun; Choi, Su-Mi; Park, Sun Hee; Cho, Sung-Yeon; Choi, Jae-Ki; Kim, Si-Hyun; Choi, Jung-Hyun; Yoo, Jin-Hong; Cho, Byung-Sik; Eom, Ki-Seong; Lee, Seok; Kim, Yoo-Jin; Kim, Hee-Je; Min, Chang-Ki; Kim, Dong-Wook; Lee, Jong-Wook; Min, Woo-Sung; Jung, Jung Im

    2017-01-01

    Background The risk of developing tuberculosis (TB) in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is expected to be relatively high in an intermediate TB burden country. This single-center retrospective study was conducted to investigate risk factors and the incidence of TB after allogeneic HSCT. Methods From January 2004 to March 2011, 845 adult patients were enrolled. Starting April 2009, patients were given isoniazid (INH) prophylaxis based on interferon-γ release assay results. The incidence of TB was analyzed before and after April 2009, and compared it with that of the general population in Korea. Results TB was diagnosed in 21 (2.49%) of the 845 allogeneic HSCT patients. The median time to the development of TB was 386 days after transplantation (range, 49–886). Compared with the general population, the standardized incidence ratio of TB was 9.10 (95% CI; 5.59–14.79). Extensive chronic graft-versus-host disease (GVHD) was associated with the development of TB (P = 0.003). Acute GVHD, conditioning regimen with total body irradiation and conditioning intensity were not significantly related. INH prophylaxis did not reduce the incidence of TB (P = 0.548). Among 21 TB patients, one patient had INH prophylaxis. Conclusion Allogeneic HSCT recipients especially those who suffer from extensive chronic GVHD are at a high risk of developing TB. INH prophylaxis did not statistically change the incidence of TB, however, further well-designed prospective studies are needed. PMID:28278166

  10. Bilateral Maxillary, Sphenoid Sinuses and Lumbosacral Spinal Cord Extramedullary Relapse of CML Following Allogeneic Stem Cell Transplant

    PubMed Central

    Hosseini, Soudabeh; Ansari, Shahla; Vosough, Parvaneh; Bahoush, Gholamreza; Hamidieh, Amir Ali; Chahardouli, Bahram; Shamsizadeh, Morteza; Mehrazma, Mitra; Dorgalaleh, Akbar

    2016-01-01

    Isolated extramedullary relapse of chronic myelogenous leukemia (CML) after allogeneic stem cell transplant is rare. There is a case report of a child who developed a granulocytic sarcoma of the maxillary and sphenoid sinuses and lumbosacral spinal cord mass 18 months after allogeneic bone marrow transplant for CML. He was presented with per orbital edema and neurological deficit of lower extremities and a mass lesion was found on spinal cord imaging. No evidence of hematologic relapse was identified at that time by bone marrow histology or cytogenetic. The patient died 1 month later with a picture of pneumonia, left ventricular dysfunction and a cardiopulmonary arrest on a presumed underlying sepsis with infectious etiology. Granulocytic sarcoma should be considered in the differential diagnosis of mass lesions presenting after allogeneic bone marrow transplantation for CML, even if there is no evidence of bone marrow involvement. PMID:27252811

  11. Perioperative blood transfusion: the role of allogenous and autologous transfusions, and pharmacological agents.

    PubMed

    Chimutengwende-Gordon, Mukai; Khan, Wasim S; Maruthainar, Nimalan

    2010-08-01

    The decision to transfuse patients perioperatively is made on an individual basis and should consider factors such as duration and severity of anaemia, symptoms, physiological parameters and comorbidities. Autologous blood transfusion has the benefit of avoiding some of the immunological and infective complications associated with allogenic blood transfusion. Pharmacological agents as well as anaesthetic and surgical techniques have a role in avoiding the need for blood transfusion.

  12. Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells.

    PubMed

    Sánchez-Martínez, Diego; Lanuza, Pilar M; Gómez, Natalia; Muntasell, Aura; Cisneros, Elisa; Moraru, Manuela; Azaceta, Gemma; Anel, Alberto; Martínez-Lostao, Luis; Villalba, Martin; Palomera, Luis; Vilches, Carlos; García Marco, José A; Pardo, Julián

    2016-01-01

    Mutational status of TP53 together with expression of wild-type (wt) IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) patients. Adoptive cell therapy using allogeneic HLA-mismatched Natural killer (NK) cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs) the most effective stimulus to activate NK cells. Here, we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell-activating receptors (NKG2D and NCRs) and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV) are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells, and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments.

  13. Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells

    PubMed Central

    Sánchez-Martínez, Diego; Lanuza, Pilar M.; Gómez, Natalia; Muntasell, Aura; Cisneros, Elisa; Moraru, Manuela; Azaceta, Gemma; Anel, Alberto; Martínez-Lostao, Luis; Villalba, Martin; Palomera, Luis; Vilches, Carlos; García Marco, José A.; Pardo, Julián

    2016-01-01

    Mutational status of TP53 together with expression of wild-type (wt) IGHV represents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) patients. Adoptive cell therapy using allogeneic HLA-mismatched Natural killer (NK) cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs) the most effective stimulus to activate NK cells. Here, we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell-activating receptors (NKG2D and NCRs) and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based on TP53 and IGHV mutational status. Cells from patients with worse prognosis (mutated TP53 and wt IGHV) are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells, and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments. PMID:27833611

  14. [Aspergillus galactomannan detection in allogenic hematopoietic cell transplantation].

    PubMed

    Rovira Tarrats, Montserrat; Puig de la Bellacasa, Jorge

    2003-09-01

    Invasive aspergillosis has become the leading cause of death after allogeneic hematopoietic stem cell transplantation. This is partially due to the lack of a prompt diagnosis. Recently the detection of Aspergillus galactomannan antigen by means an ELISA technique in serum has been described. The objective of this study was to validate its usefulness in the allogeneic hematopoietic stem cell transplantation setting.

  15. The Role of ABO Incompatibility in Allogeneic Peripheral Blood Stem Cell Transplant.

    PubMed

    Arslan, Önder; Coşkun, Hasan Şanol; Arat, Mutlu; Soydan, Ender; Özcan, Muhit; Gürman, Günhan; Çelebi, Harika; Demirer, Taner; Akan, Hamdi; İlhan, Osnman; Konuk, Nahide; Uysal, Akın; Berksaç, Meral; Koç, Haluk

    2002-09-05

    ABO incompatibility is not a contraindication for allogeneic bone marrow transplantation, but this procedure requires an extra effort for erythrocyte or plasma depletion in certain well established conditions. Some acute or delayed immunohematological complications such as acute or chronic hemolysis and pure red cell aplasia may be encountered. In this study the outcome and transplant related complications of ABO incompatible and identical cases, who have received allogeneic peripheral blood stem cells from their HLA identical siblings were compared with each other. Ninety-one patients (CML 36, AML 37, other 18) were analyzed retrospectively including 51 (60.4%) ABO identical patients and 36 (39.6%) ABO mismatched (MM) patients, who have a bi-directional MM (n= 5), major MM (n= 16), minor MM (n= 9) and Rh MM (n= 6). Median follow up was 13 (0.5-43.0) months. We did not observed any significant differences between two groups (identical vs non-identical) in terms of acute hemolysis preceding stem cell infusion, peritransplant transfusion demand, acute- and chronic graft versus host disease. There was no change in estimated disease free survival and overall survival durations. We did not observed any influence of ABO/Rh incompatibility on short term outcome in allogeneic peripheral blood stem cell transplantation in our series and did not recommend further manipulation of the infused stem cells.

  16. Kinetics of lymphocyte reconstitution after allogeneic bone marrow transplantation: markers of graft-versus-host disease

    PubMed Central

    Zinöcker, Severin; Sviland, Lisbet; Dressel, Ralf; Rolstad, Bent

    2011-01-01

    GVHD causes extensive morbidity and mortality in patients who receive alloHCT. Predictive and reliable markers for GVHD are currently lacking but required to improve the safety and accessibility of alloHCT. We present an experimental rat model of myeloablative total body irradiation and fully mismatched major and minor histoincompatible, T cell-depleted BMT, followed by delayed infusion of donor lymphocytes. This treatment, in contrast to marrow transplantation alone, resulted in severe aGVHD and 100% lethality within 2–6 weeks. We investigated the reconstitution kinetics and phenotypes of donor leukocyte subpopulations as well as the histopathology of selected organs that may correlate with GVHD, with the goal to find potential disease-related markers. We observed histological changes mainly confined to the skin, with degenerative changes in the basal layer. LNs and spleen showed deranged architecture with markedly increased accumulation of lymphocytes, whereas the gut, liver, and lungs appeared normal. Of the lymphocyte markers tested, donor-derived CD62L+ T cells were markedly decreased in animals suffering from GVHD. Furthermore, we observed peripheral depletion of CD4+CD25hiFoxP3+ Treg, which was in contrast to controls. The relative frequency of these lymphocyte subpopulations in blood may therefore serve as accessible cellular markers of aGVHD. We propose that the animal model presented is instructive for the identification of clinically relevant markers of GVHD, which could improve disease diagnosis and management in alloHCT. PMID:21498586

  17. BK virus-hemorrhagic cystitis following allogeneic stem cell transplantation: Clinical characteristics and utility of leflunomide treatment.

    PubMed

    Park, Young Hoon; Lim, Joo Han; Yi, Hyeon Gyu; Lee, Moon Hee; Kim, Chul Soo

    2016-04-18

    BK virus-hemorrhagic cystitis (BKV-HC) is a potential cause of morbidity and mortality in patients having undergone allogeneic stem cell transplantation (Allo-SCT). We analyzed the clinical features of BKV-HC following Allo-SCT and reported the utility of leflunomide therapy for BKV-HC.

  18. 21 CFR 1271.55 - What records must accompany an HCT/P after the donor-eligibility determination is complete; and...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false What records must accompany an HCT/P after the.../P after the donor-eligibility determination is complete; and what records must I retain? (a... HCT/P at all times: (1) A distinct identification code affixed to the HCT/P container,...

  19. 21 CFR 1271.37 - Will establishment registrations and HCT/P listings be available for inspection, and how do I...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Will establishment registrations and HCT/P... § 1271.37 Will establishment registrations and HCT/P listings be available for inspection, and how do I... provided. The following information submitted under the HCT/P requirements is illustrative of the type...

  20. 21 CFR 1271.37 - Will establishment registrations and HCT/P listings be available for inspection, and how do I...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Will establishment registrations and HCT/P... § 1271.37 Will establishment registrations and HCT/P listings be available for inspection, and how do I... provided. The following information submitted under the HCT/P requirements is illustrative of the type...

  1. 21 CFR 1271.55 - What records must accompany an HCT/P after the donor-eligibility determination is complete; and...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false What records must accompany an HCT/P after the.../P after the donor-eligibility determination is complete; and what records must I retain? (a... HCT/P at all times: (1) A distinct identification code affixed to the HCT/P container,...

  2. The Symptom Experience in the First 100 Days Following Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

    PubMed Central

    Bevans, Margaret F.; Mitchell, Sandra A.; Marden, Susan

    2010-01-01

    Goals of Work Despite advances in allogeneic hematopoietic stem cell transplantation (HSCT), post-transplant complications are common and patients’ symptom experience has not been well documented. Purpose To characterize the symptom experience of adult patients pre-transplantation and days 0, 30 and 100 after allogeneic HSCT. Methods Data from 76 participants enrolled in a prospective Health-Related Quality of Life (HRQL) study were used. Symptom occurrence, distress, and clusters were determined based on the 11 symptoms of the Symptom Distress Scale (SDS). Results Participants were on average 40 years old (SD ± 13.5). The majority (54%) received reduced intensity conditioning. Prevalent symptoms included fatigue (68%) and worry (68%) at baseline; appetite change (88%) at day 0; and fatigue at days 30 (90%) and 100 (81%). Participants reported the following symptoms as severely distressing: worry (16%) [baseline], insomnia (32%) [Day 0], appetite change (22%) [Day 30] and fatigue (11%) [Day 100]. The total SDS score was highest at day 0 (M = 26.6 ± 7.6) when the highest number of symptoms were reported [Mdn = 8 (1 - 11)]. Symptoms formed clusters comprised of fatigue, appearance change, and worry at baseline, and fatigue, insomnia and bowel changes at days 0 and 30. Compared to those with low symptom distress, participants with moderate/severe symptom distress reported poorer HRQL. Conclusion Allogeneic HSCT patients present for transplantation with low symptom distress yet experience multiple symptoms and high symptom distress after HSCT conditioning. Understanding the symptom experience of allogeneic HSCT patients can guide management strategies and improve HRQL. PMID:18322708

  3. Cytotoxic effect of fucoidan extracted from Sargassum cinereum on colon cancer cell line HCT-15.

    PubMed

    Somasundaram, Sivasankara Narayani; Shanmugam, Saravanan; Subramanian, Bharathiraja; Jaganathan, Ravindran

    2016-10-01

    The present study was aimed to investigate the antioxidant and cytotoxicity activity against HCT-15 of fucoidan from Sargassum cinereum. Purification of fucoidan was done by DEAE cellulose and dialysis. Physicochemical characterization of fucoidan was analysed by calorimetric assay, FT-IR, HPLC and NMR. The extracted fucoidan contains 65.753% of fucose and 3.7±1.54% of sulphate respectively. HPLC results showed that the fucoidan contains the monosaccharide composition such as fucose, galactose, mannose and xylose. Antioxidant effect of fucoidan in Sargassum Cinereum was determined by DPPH. The maximum DPPH activity was found at the concentration of 100μg, where as the crude extract showed the scavenging activity was 63.58±0.56%. Cytotoxicity effect was done by MTT assay. Fucoidan extract caused about 50% of cell death after 24h of incubation with 75±0.9037μg/ml against HCT-15.

  4. Natural product-based design, synthesis and biological evaluation of Albiziabioside A derivatives that selectively induce HCT116 cell death.

    PubMed

    Wei, Gaofei; Cui, Shanshan; Luan, Weijing; Wang, Shuai; Hou, Zhuang; Liu, Yongxiang; Liu, Yang; Cheng, Maosheng

    2016-05-04

    A series of Albiziabioside A coupled substituents of cinnamoyl derivatives were designed and synthesized. The synthesized compounds were screened for anticancer activity against a panel of six human cancer cell lines using a MTT assay. Synthetic derivatives showed excellent selectivity, as they were toxic against only HCT116 cell line. Some compounds exhibited better anti-cancer activity against HCT116 compared to positive controls, such as 5-fluorouracil and Albiziabioside A. Compound 8n was the most active derivative. Importantly, it was also found that the anti-proliferative activity of 8n could be attributed to the induction of cell cycle arrest and apoptosis in HCT116 cells.

  5. Cellular Uptake of Decitabine by Equilibrative Nucleoside Transporters in HCT116 Cells.

    PubMed

    Ueda, Kumiko; Hosokawa, Mika; Iwakawa, Seigo

    2015-01-01

    DNA hypermethylation, an epigenetic change that silences gene expression without altering nucleotide sequences, plays a critical role in the formation and progression of colorectal cancers as well as in the acquisition of drug resistance. Decitabine (DAC), a DNA methyltransferase 1 inhibitor of nucleoside analogues, has been shown to restore gene expression silenced by hypermethylation. In the present study, the mechanisms underlying both uridine and DAC uptake were examined in the human colon cancer cell line HCT116. Real-time polymerase chain reaction analysis revealed that ENT1 mRNA was the most abundant among the nucleoside transporters examined in HCT116 cells. The ENT1 protein was detected in the membrane fraction, as determined by Western blotting. The uptake of uridine or DAC was time- and concentration-dependent, but also Na(+)-independent. The uptake of these agents was inhibited by S-(4-nitrobenzyl)-6-thioinosine (NBMPR), an inhibitor of equilibrative nucleoside transporters (ENTs), and was also decreased in cells treated with ENT1 small interfering RNA. The uptake of both uridine and DAC was inhibited by uridine, cytidine, adenosine, or inosine, while that of DAC was also inhibited by thymidine. The expression of MAGEA1 mRNA, the DNA of which was methylated in HCT116 cells, was increased by DAC treatment, and this increment was attenuated by concomitant treatment with NBMPR. The IC50 value of DAC was also increased in the presence of NBMPR. These results suggest that DAC is mainly taken up by ENT1 and that this uptake is one of the key determinants of the activity of DAC in HCT116 cells.

  6. Regulation of Adaptive NK Cells and CD8 T Cells by HLA-C Correlates with Allogeneic Hematopoietic Cell Transplantation and with Cytomegalovirus Reactivation.

    PubMed

    Horowitz, Amir; Guethlein, Lisbeth A; Nemat-Gorgani, Neda; Norman, Paul J; Cooley, Sarah; Miller, Jeffrey S; Parham, Peter

    2015-11-01

    Mass cytometry was used to investigate the effect of CMV reactivation on lymphocyte reconstitution in hematopoietic cell transplant patients. For eight transplant recipients (four CMV negative and four CMV positive), we studied PBMCs obtained 6 mo after unrelated donor hematopoietic cell transplantation (HCT). Forty cell-surface markers, distinguishing all major leukocyte populations in PBMC, were analyzed with mass cytometry. This group included 34 NK cell markers. Compared with healthy controls, transplant recipients had higher HLA-C expression on CD56(-)CD16(+) NK cells, B cells, CD33(bright) myeloid cells, and CD4CD8 T cells. The increase in HLA-C expression was greater for CMV-positive HCT recipients than for CMV negative recipients. Present in CMV-positive HCT recipients, but not in CMV-negative HCT recipients or controls, is a population of killer cell Ig-like receptor (KIR)-expressing CD8 T cells not previously described. These CD8 T cells coexpress CD56, CD57, and NKG2C. The HCT recipients also have a population of CD57(+)NKG2A(+) NK cells that preferentially express KIR2DL1. An inverse correlation was observed between the frequencies of CD57(+)NKG2C(+) NK cells and CD57(+)NKG2A(+) NK cells. Although CD57(+)NKG2A(+) NK cells are less abundant in CMV-positive recipients, their phenotype is of a more activated cell than the CD57(+)NKG2A(+) NK cells of controls and CMV-negative HCT recipients. These data demonstrate that HCT and CMV reactivation are associated with an increased expression of HLA-C. This could influence NK cell education during lymphocyte reconstitution. The increased inhibitory KIR expression by proliferating CMV-specific CD8 T cells suggests regulatory interactions between HLA-C and KIR might promote Graft-versus-Leukemia effects following transplantation.

  7. Bottom-up proteomic analysis of single HCT 116 colon carcinoma multicellular spheroids

    PubMed Central

    Feist, Peter; Sun, Liangliang; Liu, Xin; Dovichi, Norman J.; Hummon, Amanda B.

    2016-01-01

    Rationale Proteomic analysis of single multicellular spheroids has not been previously reported. As three-dimensional cell cultures are an increasingly popular model system for biological research, there is interest in obtaining proteomic profiles of these samples. We investigated the proteome of single HCT 116 multicellular spheroids using protocols optimized for small sample sizes. Methods Six biological replicates were analyzed via microscopy for size. Total protein content was assessed via the bicinchoninic acid assay (BCA assay). Five separate biological replicate spheroids were analyzed via mass spectrometry in technical duplicate. An ultra-performance liquid chromatography (UPLC) system coupled with an LTQ Orbitrap Velos was used for peptide separation, analysis, and identification. Results The average diameter of six replicate HCT 116 spheroids was 940 ± 30 μm and the average total protein amount was determined to be 39 ± 4 μg. At least 1300 protein groups were identified in each single LC-MS/MS run with ten percent of the material from single spheroid loaded. Database search results showed variation between spheroid protein group identifications. Pearson correlations show that the disparity in identifications is due to random variations in spectra and protocol. Conclusions We detected more than 1350 protein groups in each replicate HCT 116 spheroid. While some variation was detected between replicates, differences in the number of protein groups identified were determined to be the result of random variations in mass spectra acquisition. PMID:26212283

  8. Methylsulfonylmethane Induces p53 Independent Apoptosis in HCT-116 Colon Cancer Cells