Abstract
Reduced intensity conditioning (RIC) extends the curative potential of allogeneic hematopoietic cell transplantation (HCT) to patients with hematologic malignancies unsuitable for myeloablative conditioning. We prospectively studied a RIC HCT approach for patients with hematologic malignancies and sibling or unrelated donors (URD) from 2001-2016. Patients received cyclophosphamide (Cy) 50mg/kg/day IV day -6, fludarabine (Flu) 40mg/m2/d IV days -6 to -2 and TBI 200cGy on day -1 +/- anti-thymocyte globulin (ATG) on days -6 to -4 for those without prior autografting or recent multidrug chemotherapy. After identifying potential increased non-relapse mortality from excess fludarabine metabolite (F-ara-A) exposure we reduced the fludarabine dosing to 30 mg/m2/d IV days -6 to -2 in late 2009.
The 292 patients (median age 58: range 19-75); median follow-up 8 years (IQR range 4-12) included 127 with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS), 40 aggressive non-Hodgkin lymphoma (NHL), 11 indolent NHL, 21 Hodgkin Lymphoma (HL), 26 multiple myeloma, 14 chronic myeloid leukemia (CML), 23 chronic lymphocytic leukemia (CLL), 17 acute lymphocytic leukemia (ALL), 13 myeloproliferative neoplasms (MPN). Five year overall survival (OS) was 73% (95% CL, 37-90%) for patients with indolent NHL, 53% (95% CL, 36-67%) for aggressive NHL, 55% (95% CL, 31-74%) for HL, 39% (95% CL, 30-48%) for AML/MDS, 32% (95% CL, 15-50%) for myeloma, 50% (95% CL, 23-72%) for CML, 45% (95% CL, 24-46%) for CLL, 15% (95% CL, 2-39%) for MPN and 34% (95% CL, 12-59%) for those with ALL. By donor source, 5 year OS was 46% (95% CL, 40-53%), 25% (95% CL, 6-50%), 38% (95% CL, 22-54%), and 11% (95% CL, 1-35%) using matched sibling donors (n=225), mismatched (MM) sibling PBSC (n=12), matched marrow unrelated donor (URD) (n=37), and matched peripheral blood URD (n=18) (p<0.01) (Figure 1). Fludarabine dosing (30 vs. 40 mg/m2/day x 5) had no significant influence on OS (45 vs. 40%, p=0.42) or 2 year NRM (25% vs. 26%, p=0.86). NRM (overall 26%; 95% CI 21-31%) was significantly worse with MM sibling or URD (either BM or PBSC) compared to matched sibling BM/PBSC. Relapse at 5 years was significantly worse in patients with myeloma (76%) and Hodgkins (53%), intermediate in AML/MDS (37%), but lowest in aggressive (25%) and particularly indolent NHL (0%).
These results suggest that: 1) this Cy/Flu/TBI RIC conditioning was well tolerated by an older population; 2) indolent and aggressive NHLs responded best to RIC conditioning highlighting the importance of the graft versus lymphoma (GVL) effect; and 3) reduction in fludarabine dosing did not compromise disease control or survival but did not appear to diminish NRM. Diagnosis, donor source, and HCT-CI remain the dominant factors influencing outcomes. Targeted disease treatments or maintenance therapy to limit relapse might be the best approach to improve overall survival.
Brunstein: Novartis: Research Funding; Magenta Therapeutics: Research Funding. MacMillan: Magenta Therapeutics: Research Funding.
