Targeted Therapy With Venetoclax and Daratumumab as Part of HSCT Preparative Regimen in Children With Chemorefractory Acute Myeloid Leukemia.

The long-term outcome of allogeneic hematopoietic stem cell transplantation (HSCT) in chemorefractory acute myeloid leukemia (AML) remains suboptimal because of a high relapse rate. Enhancement of conditioning regimens by the incorporation of targeted anti-leukemia agents is a potential approach to improve the efficacy of HSCT. In a pilot trial and extended access cohort, we evaluated the safety and potential value of adding combinations of venetoclax and daratumumab to a preparative regimen among children with chemorefractory acute myeloid leukemia grafted with αß T-cell-depleted peripheral blood stem cells. All 20 patients had active disease status of AML at the time of transplantation. The preparative regimen included myeloablative conditioning based on either total body irradiation or treosulfan. A haploidentical related donor was used as a graft source for all patients. Engraftment was not compromised, and no excess toxicity was noted. Minimal residual disease-negative complete remission was achieved in 17 patients (85%). The cumulative incidence of grade II to IV acute graft-versus-host disease (GVHD) was 17%, and the cumulative incidence of chronic GVHD was 7%. At 2 years, nonrelapse mortality was 10%, relapse incidence was 46%, event-free survival was 44%, and overall survival was 65%. Our data show the possibility of safely adding targeted agents to conditioning regimens; however, no evidence of a significant improvement in long-term transplantation outcomes in this cohort of patients was observed.

A Conditioning Regimen with Plerixafor Is Safe and Improves the Outcome of TCRαß+ and CD19+ Cell-Depleted Stem Cell Transplantation in Patients with Wiskott-Aldrich Syndrome.

Our initial experience with hematopoietic stem cell transplantation (HSCT) from a matched unrelated donor (MUD; n = 12) or a haploidentical related donor (n = 6) with T cell receptor (TCR)αß+/CD19+ graft depletion in patients with Wiskott-Aldrich syndrome (WAS) (n = 18) showed a dramatic decrease in the incidence of graft-versus-host disease (GVHD) and transplantation-related mortality, with an increased overall survival (OS) of 88.9%. Unfortunately, the treatment was associated with mixed myeloid donor chimerism and secondary graft dysfunction (severe thrombocytopenia, n = 2; graft rejection, n = 5). To improve the outcome, we hypothesized that the addition of G-CSF and plerixafor to the conditioning chemotherapy would result in more complete donor stem cell engraftment. This trial was registered at www.clinicaltrials.gov (NCT03019809). A study group of patients with WAS (n = 16) underwent TCRαß+/CD19+-depleted HSCT (MUD, n = 6; haploidentical, n = 10). The conditioning regimen was treosulfan-fludarabine-rabbit antithymocyte globulin-melphalan (or thiophosphamide in 1 patient) with G-CSF (10 µg/kg/day for 5 days starting on day -8) and plerixafor (240 µg/kg/day for 3 days starting on day -6). The clinical outcomes in this study were compared to those in a historical dataset (n = 18). No patients had grade III/IV acute GVHD in either the study or the historical control group. Importantly, in the patients with WAS, there was no statistical significance in OS between those who underwent HSCT from haploidentical donors and those who underwent HSCT from MUDs (93.8% versus 88.5%; P = .612). All patients in the study group had full donor chimerism in whole blood and in the CD3+ compartments. The OS was 93.8%, and there were no cases of graft dysfunction. This study demonstrates the efficacy of adding G-CSF/plerixafor to the conditioning regimen before HSCT with TCRαß+/C D19+ graft depletion in patients with WAS.