Induction of Remission Prior to Transplantation Improves the Disease-Free Survival (DFS) of Patients with Advanced Myelodysplastic Syndromes (MDS) Treated with Myeloablative T - Cell Depleted (TCD) Stem Cell Transplants (SCT) from Histocompatible Unrelated Donors.
Authors: Castro-Malaspina H.R. , Jakubowski Ann A. , Papadopoulos Esperanza B. , Boulad Farid , Young James W. , Kernan Nancy A. , Perales Miguel-Angel , Small Trudy N. , Chiu Michelle , Heller Glenn , Van Den Brink Marcel , Nimer Stephen D. , O’Reilly Richard J. 
Published: April 2020

Disease relapse and transplant-related mortality (TRM) have been the two major problems limiting the success of unrelated donor SCT in patients with advanced MDS (RAEB 1 and 2 and AML evolved from MDS). Induction of remission is an approach that has been used to reduce the incidence of relapse, but its use remains controversial. T cell depletion of allografts has been used to reduce the incidence of graft-versus-host disease and TRM. From 1989 to 2004, 28 patients with advanced MDS underwent bone marrow or peripheral blood SCT from molecularly matched (HLA A, B, C, DRB1 and DQB1 - 18 patients) or partially mismatched (maximum 2 antigen mismatch allowed - 10 patients) volunteer donors following conditioning with myeloablative conditioning with total body irradiation (1375 cGy), thiotepa (10 mg/kg) and cyclophosphamide (120 mg/kg) or fludarabine 125 mg/kg) - 17 patients, or busulfan (8 mg/kg), melphalan (140 mg/kg) and fludarabine (125 mg/kg) - 11 patients. Twenty six patients received chemotherapy (2 low dose and 24 induction doses) prior to conditioning, and 2 patients did not receive any chemotherapy. Prior to transplant, 18 of the 28 treated patients were in hematologic remission (CR), 2 in a second refractory cytopenia phase (RCy2) (20 responders), and 6 had failed to achieve remission or their MDS had relapsed. The marrow grafts were depleted of T cells using the soybean agglutinin method and then sheep red blood cell rosetting (15 patients) and the G-CSF-mobilized peripheral blood stem cell (PBSC) grafts with CD34 selection and E-rosetting (13 patients). Rejection prophylaxis with anti-thymocyte globulin was used in all 28 patients. Posttransplant pharmacologic prophylaxis for GvHD was given only to 1 patient. The median age was 49.9 years (range 4–59.6), 14 patients were ≥ age 50. Two patients died before engraftment and 26 engrafted; 2 of them had late graft failure. Eight patients developed acute GvHD (grades 2 to 4) and 2 chronic GvHD (1 limited). The DFS in these three group of patients was significantly different (p= 0.0004). The DFS at 5 years was 55% for the patients in CR and RCy2, 33% for the failures, and no patients were alive in the untreated group. DFS was worse in patients with high risk IPSS. DFS was slightly better in patients cytoreduced with the busulfan-containing regimen, 72% versus 29% (p = 018). DFS was not statistically different in the recipients of matched (39%) or mismatched (60%) transplants. The cumulative incidence (CI) of relapse at 2-years posttransplant for the responders was 5.5%, for the failures 25%, and for the untreated group 50%. The CI of non-relapse mortality or TRM at 2-years posttransplant for the responders was 33.33%, for the failures was 62.5%, and for the untreated was 50%. All survivors have achieved ≥KPS 90%. These observations confirm the value of induction of remission prior to conditioning as a means to reduce the incidence of disease relapse in the posttransplant period and show that T cell depletion decreases the TRM in these patients receiving unrelated stem cell transplants.