Non-T-Cell-Depleted HLA-Haploidentical Hematopoietic Stem Cell Transplantation for Children with Hematological Malignancies: Single-Center Pilot Study
Authors: Mochizuki Kazuhiro , Kikuta Atsushi , Ito Masaki , Sano Hideki , Kobayashi Shogo , Ohto Hitoshi , Hosoya Mitsuaki 
Published: April 2020

Abstract
Allogeneic hematopoietic stem cell transplantation is the only curative approach for a number of patients with hematological malignancies. For patients who do not have an HLA-identical related or unrelated donor, a related haploidentical transplantation is an alternative option. Recent advances in effective T-cell depletion of stem cells have significantly decreased graft-versus-host disease (GVHD) and early transplantationrelated mortality (TRM). However, the problems related to delayed immune reconstitution causing infectious complications and relapse remain, limiting the efficacy of haploidentical transplantation. Here, we report the results of ten children with hematological malignancies who received non-T-cell-depleted haploidentical hematopoietic stem cell transplantation. Malignancies included acute lymphoblastic leukemia (ALL, n = 6), acute myeloid leukemia (n = 2), chronic myeloid leukemia (n = 1) and Epstein Barr virus (EBV)-associated peripheral T cell lymphoma (n = 1). Median patient age was 5 years, and all patients presented with clinical and biologic features that indicated a very high risk of relapse with conventional chemotherapy. At the time of transplantation, seven patients were in remission, and two of these were urgent cases with primary graft failure of the first cord blood transplantation. The remaining three patients were not in remission. HLA disparity was two loci mismatches in one case and three loci mismatches in nine cases. The conditioning regimen consisted of the myeloablative method in five cases and reduced intensity conditioning in five cases. GVHD prophylaxis was conducted with tacrolimus and short-term methotrexate (sMTX) in the initial two cases and the remaining eight cases were given a combination of tacrolimus, sMTX and prednisolone (PSL). The stem cell source for the initial two cases was peripheral blood stem cells mobilized with G-CSF, and that for the remaining eight cases was bone marrow. Nine (90%) of the ten patients engrafted showed myeloid and platelet recovery on days +15 and +31 (median), respectively. All of these patients achieved full donor chimerism by day +30, and it persisted, except in one patient who relapsed. Acute GVHD of Grades II–IV and III–IV occurred in six (66.7%) and two (22.2%) patients, respectively, all of which responded to temporary augmentation of PSL. Chronic GVHD occurred in five (62.5%) patients, three of whom had extensive GVHD. Although one of these developed steroid refractory chronic GVHD, it was not difficult to control the symptoms of GVHD of the remaining patients. Infectious complications, including cytomegalovirus (CMV) antigenemia (n = 2), interstitial pneumonia associated with CMV (n = 1), temporary elevation of EBVDNA (n = 1), zoster (n = 1), invasive aspergillus infection (n = 1) and sepsis (n = 1), were observed. TRM occurred in two patients, and one patient with ALL relapsed on day +472 after transplantation. The Karnofsky performance scales of six of the eight survivors were 100%, and more than half of the evaluable patients were expected to discontinue immunosuppressive therapy within 2 years after transplantation. Because only one patient had relapsed by the time of the last follow-up, we believe that our GVHD prophylactic regimen suppresses the incidence of both acute and chronic GVHD to an acceptable level, while preserving the graft-versus-leukemia effect. Median follow-up of the eight patients who survived event-free was 34 months (range, 3 to 95 months). The 5-year probability of overall survival and event-free survival (EFS) were 77.6% and 66.6%, respectively. In the analysis of disease status at transplantation, encouraging results were obtained in patients who received the transplantation while in remission, with the rate of engraftment and 5-year probability of EFS at 100% and 80%, respectively. Although the number of patients in this series was small, the results described here indicate the feasibility of non-T-cell-depleted haploidentical stem cell transplantation for children with hematological malignancies who do not have an HLA-identical donor.