A Phase I Study of Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide and/or Bendamustine

Background The nearly universal donor accessibility afforded by haploidentical bone marrow transplantation (haplo-BMT) is salient for our program, as half of the patients undergoing hematopoietic cell transplantation (HCT) are ethnic or racial minorities. This highlights the need for effective haplo-BMT regimens and improvements in graft-versus-host disease (GvHD) prophylaxis. Balancing GvHD prevention with the maintenance of graft-versus-leukemia (GvL) is an ongoing challenge in the field of HCT. We have previously shown in mice that bendamustine (BEN) can safely replace cyclophosphamide (CY) as post-transplant (PT) GvHD prophylaxis following haplo-BMT, with comparable protection from GvHD and superior GvL effects. Based on our preclinical data, we have initiated a Phase I/II study to replace PT-CY (given on days +3 and +4) with PT-BEN following haplo-BMT. Methods Phase I is a standard 3 + 3 dose escalation design with six dose level cohorts. The first three cohorts (1-3) consist of a combination of sequentially reduced doses of CY and increased doses of BEN on day +4 post-BMT with the dose of CY on day +3 remaining unchanged. The next three cohorts (4-6) will involve progressive substitution of CY with BEN on day +3. We are enrolling patients ages 8-60 years with a diagnosis of acute leukemia, chronic myeloid leukemia, myelodysplastic syndrome, Hodgkin's or non-Hodgkin's lymphoma who do not have a readily available HLA-matched (10/10) donor. Myeloablative busulfan, fludarabine, and melphalan or TBI and fludarabine are used as conditioning regimens. Engraftment, immune reconstitution, T-cell receptor β (TRB) diversity, GvHD, infections, relapse, non-relapse mortality (NRM), event-free survival (EFS) and overall survival (OS) are monitored. Patients undergoing haplo-BMT (using the same conditioning regimens) who do not wish to receive PT-BEN are consented as PT-CY controls for the clinical endpoints and immune reconstitution studies. Results We have enrolled through Cohort 2 with no dose-limiting toxicities. Cohort 2 of PT-BEN had significantly earlier neutrophil engraftment than PT-CY controls (median day +13 compared to +17), with >5-fold higher neutrophil to lymphocyte ratios through day +100. PT-BEN patients displayed higher CD4 to CD8 ratio and demonstrated significantly greater TRB diversity than PT-CY only patients through 1 year following transplant. Patients receiving PT-BEN had a trend toward a lower incidence of CMV reactivation, 33% compared to 100% in PT-CY controls. No PT-BEN patient has developed grade III-IV acute GvHD or chronic GvHD. Conclusions PT-BEN has been well-tolerated, with patients demonstrating early engraftment. Preliminary data with PT-BEN indicate potential differences in immune reconstitution and TRB diversity. This may be advantageous in viral control, as well as in GvHD and GvL responses.