A Myeloablative Conditioning Regimen Is Required to Produce Durable Engraftment and Immune Reconsitution in Related and Unrelated Multi-Antigen HLA Mismatched Pan-T-Cell Depleted Limited T-Cell Add-Back Transplants.
Authors: Hsu Jack W. , Rowley Scott D. , Goldberg Stuart L. , Siegel David S. , Preti Robert A. , Pecora Andrew L. 
Published: October 2019

Multi-antigen HLA mismatched transplantation is associated with a high risk of graft failure and graft-vs.-host disease (GVHD), particularly in the unrelated setting. Strategies used to overcome these barriers include high CD34+ dose and T-cell depletion respectively. However, this often results in increased relapse rates and delayed immune reconstitution. We previously reported on four patients without matched donors who were transplanted using a multi-antigen mismatched, pan T-cell depleted donor graft with limited (1x105 CD3+ cells/kg unrelated donor, 1x106 CD3+ cells/kg related donor) T-cells added back on the day of transplant. Two additional patients have been transplanted using this strategy. The results are summarized in the table below. Post-graft immunosuppression consisted of tacrolimus and prednisone with short course methotrexate. Patients who received a full myeloablative conditioning regimen demonstrated neutrophil engraftment (ANC > 500/uL) at day +15, +15, +16 and +21. One patient had secondary graft failure attributed to resistant herpes infection, and promptly recovered graft function after an additional infusion of CD34+ cells. Of the patients who received a reduced intensity conditioning regimen, one never attained neutrophil engraftment while the other had neutrophil recovery at day +32, but had secondary graft failure at day +107. None of the patients receiving an unrelated donor graft developed GVHD. Of the six patients, there are two survivors at 12 months and 29 months. Analysis of the immune reconstitution of these patients reveal persistent graft function with recovery of T-cell function with absolute CD4+ counts of 225 and 472 cells/μL respectively. Both patients remain in complete remission. In summary, limited T-cell add-back at the time of immune reconstitution in pan T-cell depleted, multi-antigen HLA mismatched grafts can result in engraftment without GVHD, adequate disease control, and immune reconstitution. However, a requirement for this effect is a fully myeloablative conditioning regimen. We postulate that the degree of immuosuppression provided by a reduced intensity conditioning regimen is not enough to overcome the host-vs.-graft reactions, resulting in graft rejection. Further study is warranted among patients requiring mismatched donor transplantation.

Diagnosis Mismatch Stem Cell Source Conditioning WBC > 500 Plt >20k Complications Pt. Status Notes: BC= blast crisis, CR= complete remission, R= relapse, U= unrelated donor, R= related donor, BM= bone marrow, PBSC= peripheral blood stem cell, Bu= busulfan, CY= cyclophosphamide, ATG= rabbit ATG, Flu= fludarabine, Mel= melphalan 2° AML-CR1 B/DR/DQ U-BM Bu/CY/ATG D+14 D+104 EBV, Influenza Alive @ 19 Mo ALL-CR2 B/C U-BM TBI/CY/ATG D+21 - CMV Pneumonia Died D+110, CMV CML-BC A/DQ U-BM Bu/CY/ATG D+25 −/D+17 after CD34 boost Graft failure 2° HSV, CD34 boost D+128 Alive @ 12 Mo 2° AML-CR1 DR/DQ R-PBSC Flu/Bu/ATG D+15 D+24 GVHD gut D+40, Relapse D+118 Died D+212, relapse 2° AML-CR1 B/C U-PBSC Flu/Mel/ATG - - 1° graft failure Died D+42, graft failure AML-R1 A/C U-PBSC Flu/Mel/ATG D+32 - 2° graft failure D+107, melanoma Died D+148, graft failure