Irradiation- and busulfan-free stem cell transplantation in Fanconi anemia using an anti-CD117 antibody: a phase 1b trial.

Current hematopoietic stem cell transplantation (HSCT) conditioning strategies cause widespread tissue damage and systemic toxicities, especially in patients with DNA-repair deficiencies such as Fanconi anemia (FA). We have developed an alternative conditioning approach that incorporates the anti-CD117 antibody, briquilimab, which targets host hematopoietic stem and progenitor cells in place of genotoxic irradiation- and busulfan-based chemotherapy. Here we report a phase 1b clinical trial in patients with FA and bone marrow failure, evaluating safety and efficacy of briquilimab-based conditioning in combination with rabbit anti-thymocyte globulin, cyclophosphamide, fludarabine and rituximab immunosuppression and T cell receptor (TCR)αβ+ T cell-depleted and CD19+ B cell-depleted haploidentical HSCT. Primary endpoints of the trial included safety and engraftment, and secondary endpoints included pharmacokinetic measures and hematological and immunological recovery. All three patients have each undergone 2 years of follow-up to complete the phase 1b analysis. No treatment-emergent adverse events or acute graft-versus-host disease was observed. Patients experienced minimal toxicities, with typical mucositis and no veno-occlusive disease. Median neutrophil engraftment was 11 days (range 11-13 days) with robust donor chimerism up to 2 years post-HSCT (99-100%), meeting the primary endpoints of the study. Briquilimab cleared in each patient before HSCT without the need for adjustment. Red blood cell, platelet and lymphocyte recovery was comparable to previous reports with TCRαβ+ T cell-depleted and CD19+ B cell-depleted grafts. All patients are alive and well with resolution of earlier chromosomal breakage abnormalities in peripheral blood lymphocytes post treatment. These data demonstrate the broad potential of this protocol in maintaining HSCT efficacy while reducing toxicity. The phase 2 trial is ongoing (ClinicalTrials.gov identifier: NCT04784052 ).