A Phase II Trial of Melphalan Based Reduced-Intensity Conditioning for Transplantation of T-Replete HLA-Haploidentical Peripheral Blood Stem Cells with Posttransplant Cyclophosphamide in Patients with Hematologic Malignancies.

Melhem M Solh,Gabriel Hinojosa,Xu Zhang,Asad Bashey,Scott R Solomon,H Kent Holland,Justin Laporte,Lawrence E Morris,Debra A Hoppensteadt

doi:10.1155/2021/8868142

Abstract

T-replete haploidentical donor transplants using posttransplant cyclophosphamide (haplo) have greatly expanded donor availability and are increasingly utilized. Haplo were originally performed using truly nonmyeloablative conditioning and a bone marrow graft. We have also developed myeloablative conditioning and peripheral blood stem cell (PBSC) grafts for use with haplo. However, some patients may not tolerate myeloablative conditioning but may still benefit from a more dose-intensified preparative regimen to control malignancy and diminish graft rejection. To this end, we enrolled 25 patients on a prospective phase II trial utilizing a regimen of fludarabine 30 mg/m2/day × 5 days and Melphalan 140 mg/m2 on day -1 (flu/Mel) followed by infusion of unmanipulated PBSC graft from a haploidentical donor. GVHD prophylaxis included cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil on day 35, and tacrolimus on day 180. Median age was 57 years (range from 35 to 68). Transplantation diagnosis included AML (n = 11), ALL (n = 4), MDS/MPD (n = 6), NHL/CLL (n = 3), and MM (n = 1). Using the refined Disease Risk Index (DRI), patients were low (n = 1), intermediate (n = 13), and high/very high (n = 11). 22 out of 25 patients engrafted with a median time to neutrophil and platelet engraftment of 18 days and 36 days, respectively. All engrafting patients achieved full peripheral blood T-lymphocyte and myeloid donor chimerism at day 30. The 180-day cumulative incidence for acute GVHD grades II–IV and III-IV was seen in 20% (95% CI 8%–37%) and 8% (95% CI 2%–22%), respectively. The 2-year cumulative incidence of chronic GVHD was 16% (95% CI 5%–33%) (moderate-severe 12% (95% CI 3%–27%)). After a median follow-up of 28.3 months, the estimated 2-year OS, DFS, NRM, and relapse were 56% (95%CI 33–74%), 44% (95%CI 23%–64%), 20% (95% CI 8%–37%), and 36% (95% CI 17%–55%), respectively. Among patients with high/very high risk DRI, 2-year OS was 53% compared to 69% for low/intermediate DRI. When compared with a contemporaneous cohort of patients at our center receiving haploidentical transplant with nonablative fludarabine, Cytoxan, and total body irradiation flu/Cy/TBI regimen, the outcomes were statistically similar to the 2-year OS at 56% vs. 63% p=0.75 and DFS at 44% vs. 46% p=0.65.

Highlights

Allogeneic hematopoietic stem cell transplant is considered a curative modality for many patients with high risk hematologic malignancies
In order to reduce the risks of relapse and graft rejection, we have developed approaches to use myeloablative conditioning and peripheral blood stem cell (PBSC) grafts for haplo with PTCY in two consecutive published phase II trials. e first study with busulfan based conditioning established that myeloablative haploidentical transplantation can yield full donor chimerism at day 30, grades III-IV acute graft versus host disease (GVHD) rate of 10%, and a 1-year overall survival (OS) of 69% and disease-free survival (DFS) of 50% [3]
Our study reports the outcomes of a conditioning regimen of fludarabine plus melphalan followed by infusion of HLAmismatched haploidentical peripheral blood stem cells in the setting of posttransplant cyclophosphamide

Summary

Introduction

Allogeneic hematopoietic stem cell transplant (allo-HSCT) is considered a curative modality for many patients with high risk hematologic malignancies. Transplantation using a matched related sibling, if available, is considered the standard choice for patients with high risk malignancies requiring allo-HSCT [1]. One explanation for the high rate of relapse, as in other nonmyeloablative HSCT trials, is that the transplantation conditioning used may not be intense enough to achieve sufficient control of malignancy prior to the development of an effective graft-versusmalignancy effect. E second myeloablative study with TBI based conditioning showed much lower rates of BK virus hemorrhagic cystitis, full donor chimerism at day 30, a one-year NRM under 10%, and a 2-year DFS of 73% [4]. Despite the success of this approach, a significant limitation of full-intensity myeloablative regimens is that they are poorly tolerated in elderly patients older than 60 years or those with significant comorbidities. ere remains a need for a preparative regimen for haplo transplants that is more intense than standard nonablative haplo conditioning (flu/low-dose TBI) but more tolerable than fully myeloablative conditioning regimens as a means of decreasing relapse and preventing graft failure among haplo-HSCT patients

Methods

Results

Conclusion