Allogeneic Hematopoietic Cell Transplantation From Donor- Sources of Matched-sibling, Matched-unrelated, or Haploidentical- Family Donors Using Uniform Conditioning Regimen of Busulfan, Fludarabine, and Antithymocyte Globulin for Acute Myeloid Leukemia in Remission - an Observational Study

1.0 STUDY OBJECTIVES

To evaluate the effect of various clinical variables including HLA-disparity and NK cell-related variables upon outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with acute myeloid leukemia (AML) in the first complete remission (CR). The donors for allogeneic HCT include HLA-matched siblings, matched unrelated donors, and haploidentical family donors. Uniform conditioning regimen of busulfan, fludarabine, and antithymocyte globulin (ATG) will be used regardless of donor-sources.

The endpoints of the study are engraftment, secondary graft failure, acute and chronic graft- versus-host disease (GVHD), immune recovery, infections, leukemia recurrence, non-relapse mortality, and relapse-free (RFS) and overall survival (OS) of patients.

2.0 BACKGROUND INFORMATION

2.1. Allogeneic HCT is now considered the standard treatment procedure for patients with intermediate- or high-risk AML who achieve CR after induction chemotherapy. Numerous factors have been described to affect allogeneic HCT outcomes and include patient age, performance status, disease risk, HCT methodology (conditioning therapy, GVHD prophylaxis), graft (bone marrow vs. peripheral blood mononuclear cells, cell dose), donor-patient HLA- disparity, and donor-patient natural killer cell alloreactivity. Of those, HLA-disparity was considered the most important determinant of HCT outcomes and, therefore, traditionally, allogeneic HCT was performed from HLA-matched sibling (MSD) or unrelated donors (MUD). Recent innovations in HCT mothodologies, such as reduced-intensity conditioning (RIC), anti- thymocyte globulin (ATG) in conditioning regimen, and post-transplantation cyclophosphamide made HCT from HLA-haploidentical family donors (HFD) feasible. In fact, HFD-HCT using aforementioned approaches resulted in consistent donor cell engraftment and low rates of acute and chronic GVHD and non-relapse mortality (NRM). Currently, in many institutions including ours, HFD-HCT is performed as a part of routine clinical practice for patients with AML in remission when they have no HLA-matched sibling or unrelated donor available. Successful HCT from HFD showed that HLA-haplotype barrier between the donor and patient, i.e., 3-4 mismatches/8 HLA-A, -B, -C, and DR antigen can be overcome for successful allogeneic HCT, which contradicts the traditional concept of allogeneic HCT, whereby >1 antigen mismatch was considered the most important cause for increased graft failure, increased acute and chronic GVHD, delayed immune reconstitution, and NRM. Incorporation of ATG in the conditioning regimen is probably one of major factors that attenuated HLA-disparity effect in HFD-HCT. In unrelated donor HCT, HLA-mismatch between donor and patient was not a significant determinant for HCT outcomes when ATG was used in conditioning regimen. Furthermore, GVHD-modulating effect of ATG was well- documented in a randomized trial of unrelated donor-HCT using myeloablative conditioning, where the inclusion of ATG-Fresenius 20 mg/kg/day 1-3 days before donor cell transplantation was shown to decrease grade III-IV acute GVHD (24.5% to 11.7%; P=0.054) and extensive chronic GVHD (42.6% to 12.2%; P<0.0001). Likewise, in a randomized trial of MS-HCT using myeloablative conditioning and peripheral blood grafting, inclusion of ATG-Fresenius 10 mg/kg/day 1-3 days before transplantation resulted in decrease in grade II-IV acute GVHD (18.1% to 10.8%; P=0.13) and chronic GVHD (68.7% to 32.2%; P<0.001). In our phase 2 study of allogeneic HCT in AML in remission, patients undergoing MU- and HF-HCT received same RIC containing busulfan, fludarabine, and ATG (Thymoglobulin, 9 mg/kg), while patients undergoing MS-HCT received myeloablative busulfan-cyclophosphamide conditioning (71%) or RIC containing lower dose of ATG (29%; Thymoglobulin 4.5 mg/kg). Surprisingly, the 2-year cumulative incidence of moderate-to-severe chronic GVHD higher for MS-HCT (40%) that for MUD- or HFD-HCT (both 22%; P=0.02), which suggested that ATG in the conditioning rather than HLA-disparity is stronger determinant for chronic GVHD occurrence . These data showed that ATG added to the conditioning regimen can decrease GVHD, especially chronic GVHD, in HLA-mismatched, as well as matched-donor HCT settings. A Japanese registry study showed that the significance of HLA-allele mismatch in terms of grade III-IV acute GVHD and survival in unrelated donor HCT changed over the years with less impact in recent cohort of patients (after 2002) than in previous cohort of patients (before 2002).