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Rapid donor T-cell engraftment increases the risk of chronic graft-versus-host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes.

ABSTRACT: The risk of graft-rejection after allogeneic hematopoietic cell transplantation using conventional cyclophosphamide-based conditioning is increased in patients with bone marrow failure syndromes (BMFS) who are heavily transfused and often HLA-alloimmunized. Fifty-six patients with BMFS underwent fludarabine-based reduced-intensity conditioning and allogeneic peripheral blood progenitor cell (PBPC) transplantation at a single institution. The conditioning regimen consisted of intravenous cyclophosphamide, fludarabine, and equine antithymocyte globulin. Graft-versus-host disease (GVHD) prophylaxis included cyclosporine A alone or in combination with either mycophenolate mofetil or methotrexate. To reduce the risk of graft-rejection/failure, unmanipulated G-CSF mobilized PBPCs obtained from an HLA-identical or single HLA-antigen mismatched relative were transplanted rather than donor bone marrow. Despite a high prevalence of pretransplant HLA-alloimmunization (41%) and a heavy prior transfusion burden, graft-failure did not occur with all patients having sustained donor lympho-hematopoietic engraftment. The cumulative incidence of grade II-IV acute-GVHD and chronic-GVHD was 51.8% and 72%, respectively; with 87.1% surviving at a median follow-up of 4.5 years. A multivariate analysis showed pretransplant alloimmunization and rapid donor T-cell engraftment (?95% donor by day 30) were both significantly (P < 0.05) associated with the development of chronic-GVHD (adjusted HR 2.13 and 2.99, respectively). These data show fludarabine-based PBPC transplantation overcomes the risk of graft-failure in patients with BMFS, although rapid donor T-cell engraftment associated with this approach appears to increase the risk of chronic-GVHD. (Clinicaltrials.gov identifier: NCT00003838).

SUBMITTER: Pantin J

PROVIDER: S-EPMC4171745 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Rapid donor T-cell engraftment increases the risk of chronic graft-versus-host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes.

Pantin Jeremy J Tian Xin X Shah Avni A AA Kurlander Roger R Ramos Catalina C Cook Lisa L Khuu Hahn H Stroncek David D Leitman Susan S Barrett John J Donohue Theresa T Young Neal S NS Geller Nancy N Childs Richard W RW

American journal of hematology 20130903 10

The risk of graft-rejection after allogeneic hematopoietic cell transplantation using conventional cyclophosphamide-based conditioning is increased in patients with bone marrow failure syndromes (BMFS) who are heavily transfused and often HLA-alloimmunized. Fifty-six patients with BMFS underwent fludarabine-based reduced-intensity conditioning and allogeneic peripheral blood progenitor cell (PBPC) transplantation at a single institution. The conditioning regimen consisted of intravenous cyclopho ...[more]

PMID: 23813900

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Project description:Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative treatment for myelodysplastic syndrome (MDS). The proportion of MDS patients referred for transplantation evaluation, those undergoing transplantation, and the reasons for not undergoing transplantation are unknown. In this retrospective analysis, predefined 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 transplantation and among these, transplantation was considered indicated in 244 (83%). Of these, 158 of 244 (65%) were referred for transplantation evaluation at a median of 3.9 months from diagnosis. Overall 120 of 362 (33%) underwent transplantation at a median of 7.7 months from diagnosis. Metastatic solid-organ malignancy was the major reason for transplantation ineligibility (54%), and death due to MDS, which occurred in 41% of candidates who did not undergo transplantation, was the major reason for not undergoing transplantation. Factors associated with a lower likelihood of referral for transplantation evaluation included age ≥65 (P < .001), ≥2 comorbidities (P = .008), intermediate-1/low risk MDS (P < .001), <5% blasts at diagnosis (overall P < .001), having Medicare/Medicaid health insurance (P < .001), not being married (P = .017), and diagnosis between 2008 and 2011 (P = .035). On multivariate analysis adjusting for all of the previous factors, diagnosis between 2008 and 2011 (P < .001), age ≥65 (P = .001), and <5% blasts at diagnosis (overall P = .031) were associated with a lower likelihood of referral for transplantation evaluation. Factors associated with a lower likelihood of undergoing transplantation included age ≥65 (P < .001), ≥2 comorbidities (P = .003), intermediate-1/low risk MDS (P < .001), <5% blasts (overall P < .001), very low/low/intermediate risk International Prognostic Scoring System-revised karyotype (P = .018), and having Medicare/Medicaid health insurance (P < .001). In multivariate analysis adjusting for all of the previous factors, age ≥65 (P = .021), presence of ≥2 comorbidities (P = .018), and <5% blasts (overall P = .011) were associated with a lower likelihood of undergoing transplantation. The results highlight that transplantation for MDS remains underutilized, particularly for candidates over the age of 65.

Project description:Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of 4 doses, beginning days +60 through +90, to recipients of matched related donor (MRD, n = 25) or matched unrelated donor (MUD, n = 26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n = 6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue the most common adverse events (>10%). In phase II (n = 51), the cumulative incidence of cGVHD at 1 year was 36% (95% confidence interval [CI], 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. One-year cumulative incidence of nonrelapse mortality (NRM) and relapse was 0% and 20% (95% CI, 8% to 36%) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0% to 16%) and 34% (17% to 52%). The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research (CIBMTR) controls. This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD (hazard ratio [HR] = 0.85, P = .64) or MUD cohorts (HR = 0.68, P = .26) on the study compared with CIBMTR controls. B cell activating factor plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD free compared with those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.

Dataset Information

Rapid donor T-cell engraftment increases the risk of chronic graft-versus-host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes.

Publications

Rapid donor T-cell engraftment increases the risk of chronic graft-versus-host disease following salvage allogeneic peripheral blood hematopoietic cell transplantation for bone marrow failure syndromes.

Similar Datasets

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