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Results of a 2-arm, phase 2 clinical trial using post-transplantation cyclophosphamide for the prevention of graft-versus-host disease in haploidentical donor and mismatched unrelated donor hematopoietic stem cell transplantation.

ABSTRACT: High-dose, post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD) has improved outcomes in haploidentical (HAPLO) stem cell transplantation (SCT). However, it remains unclear whether this strategy is effective in SCT from 1-antigen human leukocyte antigen (HLA)-mismatched unrelated donors (9/10 MUD) and how the outcomes of these patients compare with those of haploidentical transplantation recipients.A parallel, 2-arm, nonrandomized phase 2 clinical trial was conducted of melphalan-based reduced-intensity conditioning with PTCy, tacrolimus, and mycophenolate mofetil to prevent GVHD in patients with high-risk hematologic malignancies who underwent HAPLO (n = 60) or 9/10 MUD (n = 46) SCT.The 1-year overall and progression-free survival rates were 70% and 60%, respectively, in the HAPLO arm and 60% and 47%, respectively, in the 9/10 MUD arm. The day +100 cumulative incidence of grade II to IV acute GVHD and grade III to IV acute GVHD was 28% and 3%, respectively, in the HAPLO arm and 33% and 13%, respectively, in the 9/10 MUD arm. The 2-year cumulative incidence of chronic GVHD was 24% in the HAPLO arm and 19% in the 9/10 MUD arm. The 1-year cumulative incidence of nonrelapse mortality was 21% in the HAPLO arm and 31% in the 9/10 MUD arm, and the 1-year relapse rate was 19% in the HAPLO arm and 25% in the 9/10 MUD arm.Although this was a nonrandomized study and could not serve as a direct comparison between the 2 groups, the authors conclude that PTCy-based GVHD prophylaxis is effective for both HAPLO and 9/10 MUD SCTs. Prospective randomized trials will be required to compare the efficacies of alternative donor options for patients lacking HLA-matched donors. Cancer 2016;122:3316-3326. © 2016 American Cancer Society.

SUBMITTER: Gaballa S

PROVIDER: S-EPMC5459484 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Results of a 2-arm, phase 2 clinical trial using post-transplantation cyclophosphamide for the prevention of graft-versus-host disease in haploidentical donor and mismatched unrelated donor hematopoietic stem cell transplantation.

Gaballa Sameh S Ge Isabell I El Fakih Riad R Brammer Jonathan E JE Kongtim Piyanuch P Tomuleasa Ciprian C Wang Sa A SA Lee Dean D Petropoulos Demetrios D Cao Kai K Rondon Gabriela G Chen Julianne J Hammerstrom Aimee A Lombardi Lindsey L Alatrash Gheath G Korbling Martin M Oran Betul B Kebriaei Partow P Ahmed Sairah S Ahmed Sairah S Shah Nina N Rezvani Katayoun K Marin David D Bashir Qaiser Q Alousi Amin A Nieto Yago Y Qazilbash Muzaffar M Hosing Chitra C Popat Uday U Shpall Elizabeth J EJ Khouri Issa I Champlin Richard E RE Ciurea Stefan O SO

Cancer 20160712 21

<h4>Background</h4>High-dose, post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD) has improved outcomes in haploidentical (HAPLO) stem cell transplantation (SCT). However, it remains unclear whether this strategy is effective in SCT from 1-antigen human leukocyte antigen (HLA)-mismatched unrelated donors (9/10 MUD) and how the outcomes of these patients compare with those of haploidentical transplantation recipients.<h4>Methods</h4>A parallel, 2-arm, nonrando ...[more]

PMID: 27404668

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Project description:BackgroundAllogeneic hematopoietic cell transplantation (allo-HCT) using a mismatched unrelated donor (MMUD) and cord blood transplantation (CBT) are valid alternatives for patients without a fully human leukocyte antigen (HLA)-matched donor. Here, we compared the allo-HCT outcomes of CBT versus single-allele-mismatched MMUD allo-HCT with post-transplant cyclophosphamide (PTCy) in acute myeloid leukemia.MethodsPatients who underwent a first CBT without PTCy (N = 902) or allo-HCT from a (HLA 9/10) MMUD with PTCy (N = 280) were included in the study. A multivariate regression analysis was performed for the whole population. A matched-pair analysis was carried out by propensity score-based 1:1 matching of patients (177 pairs) with known cytogenetic risk.ResultsThe incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at 6 months was 36% versus 32% (p = 0.07) and 15% versus 11% (p = 0.16) for CBT and MMUD cohorts, respectively. CBT was associated with a higher incidence of graft failure (11% vs. 4%, p < 0.01) and higher 2-year non-relapse mortality (NRM) (30% vs. 16%, p < 0.01) compared to MMUD. In the multivariate analysis, CBT was associated with a higher risk of, NRM (HR = 2.09, 95% CI 1.46-2.99, p < 0.0001), and relapse (HR = 1.35, 95% CI 1-1.83, p = 0.05), which resulted in worse leukemia-free survival (LFS) (HR = 1.68, 95% CI 1.34-2.12, p < 0.0001), overall survival (OS) (HR = 1.7, 95% CI 1.33-2.17, p < 0.0001), and GVHD-free, relapse-free survival (GRFS) (HR = 1.49, 95% CI 1.21-1.83, p < 0.0001) compared to MMUD. The risk of grade II-IV acute GVHD (p = 0.052) and chronic GVHD (p = 0.69) did not differ significantly between the cohorts. These results were confirmed in a matched-pair analysis.ConclusionsCBT was associated with lower LFS, OS, and GRFS due to higher NRM, compared to MMUD allo-HCT with PTCy. In the absence of a fully matched donor, 9/10 MMUD with PTCy may be preferred over CBT.

Project description:High-dose post-transplantation cyclophosphamide (PTCy) is an effective platform for prevention of severe graft-versus-host disease (GVHD) after allogeneic bone marrow (BM) transplantation with mismatched unrelated donors (mMUDs). Previous studies evaluating PTCy with mMUDs favored BM allografts over peripheral blood stem cell transplantation (PBSCT) due to concerns that PBSCT may be associated with an increased risk of acute and chronic GVHD. In addition, haploidentical PBSCT is associated with high rates of cytokine release syndrome (CRS), which is another concern with mMUD PBSCT. This study was conducted to determine the feasibility and safety of using mMUD PBSCT with PTCy as GVHD prophylaxis. Patients who received mMUD PBSCT using a PTCy-based GVHD prophylaxis at Johns Hopkins Hospital as part of a prospective clinical trial of mMUD and non-first-degree relative haploidentical transplantation with PTCy (ClinicalTrials.gov identifier NCT01203722) were included. All patients underwent T cell-replete PBSCT between November 2012 and August 2020. Statistical analyses were performed using the Kaplan-Meier method and proportional subdistribution hazard regression model for competing risks. The 29 patients in the study had a median age of 54 years, with 10 patients (34%) age ≥60 years. Nineteen grafts (66%) were matched for 9/10 HLA loci, 6 (21%) were match for 8/10, and 4 (14%) were matched for 7/10. No primary or secondary graft failure occurred. The median time to neutrophil recovery (≥500/µL) was 17 days, and that to platelet recovery (≥20,000/µL) was 28 days. Full donor chimerism was achieved in all patients by day +60. The cumulative incidence (CuI) of grade II-IV acute GVHD at 180 days was 15% (90% confidence interval [CI], 3% to 26%). There were no cases of severe chronic GVHD, 3 cases of mild chronic GVHD, and 1 case of moderate chronic GVHD. The CuI of nonrelapse mortality (NRM) was 7% (90% CI, NA to 18%) at 1 year. Eighteen patients (62%) experienced mild CRS (grade 1-2), and 1 patient (3%) experienced severe CRS (grade 3-5). At 1 year, the CuI of relapse was 29% (90% CI, 8% to 50%), overall survival was 93% (90% CI, 85% to 100%), progression-free survival was 64% (90% CI, 46% to 88%), GVHD-free relapse-free survival was 41% (90% CI, 23% to 73%), and chronic GVHD-free relapse-free survival was 64% (90% CI, 46% to 88%). Our data indicate that mMUD PBSCT using PTCy-based GVHD prophylaxis is safe and feasible. All patients engrafted, and rates of NRM (7%) and acute GVHD (15%) at 1 year were low. There was only 1 case (3%) of severe CRS. Compared with previously published outcomes, mMUD PBSCT using PTCy-based GVHD prophylaxis has a safety and efficacy profile that may not be different from that of PBSCT from matched donors. These results further solidify that all patients who require blood or BM transplantation should be able to find an acceptable donor.

Dataset Information

Results of a 2-arm, phase 2 clinical trial using post-transplantation cyclophosphamide for the prevention of graft-versus-host disease in haploidentical donor and mismatched unrelated donor hematopoietic stem cell transplantation.

Publications

Results of a 2-arm, phase 2 clinical trial using post-transplantation cyclophosphamide for the prevention of graft-versus-host disease in haploidentical donor and mismatched unrelated donor hematopoietic stem cell transplantation.

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