Results of T Cell Depleted (TCD) Allogeneic Hematopoietic Stem Cell Transplantation (AlloHSCT) from HLA Matched (HLA-M) or Partially Mismatched (HLA-MM) Unrelated Donors (URD) in Patients with Hematologic Malignancies: Sustained Engraftment and Low Incidence of Graft-vs-Host Disease (GvHD).
Authors: Jakubowski Ann A. , Papadopoulos Esperanza B. , Kernan Nancy A. , Boulad Farid , Castro-Malaspina H.R. , Collins Nancy H. , Hsu Katharine , Perales Miguel-Angel , Small Trudy N. , van den Brink Marcel , Young James W. , O’Reilly Richard J. 
Published: October 2019

Abstract
Curative strategies for hematologic malignancies include alloHSCT, which has become a treatment option for older pts, as well as those with more extensive prior therapy and comorbidities. This has stimulated research on the development of less toxic but comparably effective approaches to transplantation at the level of cytoreduction, alternate graft sources, graft manipulation, and GvHD prophylaxis. To this end, between 7/2001 and 12/2005, we administered TCD HSCTs, derived from HLA-M or HLA-MM URDs, to 36 adult pts as treatment for a variety of hematologic malignancies on a clinical trial. The conditioning regimen was designed to reduce regimen related toxicity while preserving adequate immunosuppression to allow for engraftment. The TCD grafts allowed transplantation across HLA disparate pt-donor pairs without the use of additional renal and hepatotoxic GvHD prophylaxis. The conditioning regimen consisted of hyperfractionated total body irradiation (HFTBI) (1375 cGy), thiotepa (5mg/kg) x 2d, fludarabine (25mg/m2) x 5d and antithymocyte globulin (ATG) x 2d. HLA typing was performed by DNA SSOP analyses for A,B,C, DRB1, and DQB1, and donors were matched at ≥8 of 10 alleles. Pts received TCD-PBSC (n=29) or TCD-BM (n=7) from HLA-M (21 pairs) or HLA-MM (15 pairs) URDs. PBSCs were TCD by Isolex 300i CD34+ selection followed by sheep E-rosette depletion, and BMs were depleted with soybean agglutination and sheep E-rosette depletion. The median age was 40.6 (range 18–63)yrs; 10 pts ≥ 50 yrs. Diseases included AML and ALL CR1 (only standard or high risk), AML and ALL CR2, ALL ≥ CR3, acute biphenotypic leukemia, CML in CP, MDS, T-PLL. The median followup is 22 (range 6–55) mos. All evaluable pts engrafted neutrophils, 31 of 35 evaluable pts engrafted platelets. Four pts died of complications prior to platelet engraftment, including one pt with late graft failure. The 100d non-relapse mortality was 20% with most (>50%) deaths due to infection. The incidence of acute (a) grade II–III and chronic (c) GvHD was low for the entire group of 36 pts at 11% and 28%, respectively, when compared to that of unmodified transplantation. The incidence of aGvHD was 14% and 7%, and cGvHD (majority - limited) was 26% and 30% for HLA-M and HLA-MM transplant pairs, respectively. Estimated 3 yr DFS is 60% for both HLA-M and HLA-MM transplants, and 83% for standard risk and 41% for high risk disease pts. Only one pt has relapsed. These results indicate that a transplantation strategy using HFTBI, thiotepa, fludarabine and ATG followed by TCD PBSC or BM, but without posttransplant immunomodulating agents, is well-tolerated in an older patient group (median age 40 yrs) even with HLA-MM URDs. Although this approach appears to provide an antileukemic effect for acute leukemia pts transplanted in remission of acute leukemia, this will need to be confirmed with longer followup.