Abstract
The objective of this study was to examine the effect of commonly used conditioning regimens on transplantation outcomes for acute myeloid leukemia (AML; n=1258) and myelodysplastic syndrome (MDS; n=951) transplanted in the US between 2009 and 2014. The median age of the study population was 58 years (18 - 83). Patients with AML were in first or subsequent remission and those with MDS had refractory anemia with unilineage or multilineage dysplasia, 5q- syndrome or refractory anemia with excess blasts at transplantation. Eighty-one percent of patients with AML had intermediate disease risk index (DRI). In contrast, 53% of patients with MDS had high DRI and 22%, very high DRI. Fifty-eight percent of patients reported performance scores of 90 or 100, and 48% had HCT-comorbidity score of 2 or less. A third of patients (35%) received grafts from HLA-matched siblings, 55% from HLA-matched and 10% from HLA-mismatched adult unrelated donors. Peripheral blood was the predominant stem cell source (90%) regardless of donor type. Graft-versus-host disease (GVHD) prophylaxis included a calcineurin inhibitor with methotrexate or mycophenolate; 73% received tacrolimus with methotrexate and 19%, tacrolimus with mycophenolate. All patients received non-irradiation transplant conditioning regimens, 57% being myeloablative (MAC), and 43% were reduced intensity (RIC). ATG was the predominant agent (98%) for in vivo T cell depletion. Cox regression models were built to study the effect of conditioning regimens on transplant outcomes after adjusting for other factors significantly associated with outcomes (Table 1). Fludarabine/busulfan with/without ATG was the predominant conditioning regimen (64%). Treatment failure (relapse or death; inverse of relapse-free survival), relapse and overall survival differed by conditioning regimen. Treatment failure was higher after RIC fludarabine/busulfan (Flu/Bu2) with/without ATG than after MAC fludarabine/busulfan (Flu/Bu4) without ATG conditioning due to higher relapse risks. However, compared to Flu/Bu4 with ATG, treatment failure did not differ with Flu/Bu2 with ATG (p=0.17) or without ATG (p=0.84). Although relapse risks were higher after Flu/Bu4 with ATG than without ATG, there were no differences in mortality or treatment failure risks. Treatment failure, relapse and overall survival were not different after Flu/Bu4 and busulfan/ cyclophosphamide (MAC) . But when ATG was added to Flu/Bu4, treatment failure (HR 1.22, p=0.05), relapse (HR 1.47, p=0.003) and overall mortality (HR 1.27, p=0.02) were higher compared to busulfan/ cyclophosphamide . Fludarabine/melphalan (Flu/Mel) with or without ATG accounted for only 12% of regimens and all were RIC regimens. Relapse (HR 2.32, p<0.0001) and treatment failure (HR 1.33, p=0.01) were higher with Flu/Bu2 compared to Flu/Mel. The addition of ATG also led to higher relapse (HR 2.13, p=0.004) with Flu/Bu2 compared to Flu/Mel but there were no differences in treatment failure (p=0.24) or overall survival (p=0.73). Among patients who received Flu/Mel, the addition of ATG was associated with higher mortality (HR 1.49, p=0.03). The 3-year probabilities of relapse-free and overall survival, adjusted for age, performance score, HCT-comorbidity score, disease and DRI are shown in Figure 1 and 2, respectively. In conclusion, Flu/Bu4 without ATG or busulfan/ cyclophosphamide regimens are optimal for patients with AML in remission and MDS. RIC regimens should be reserved for patients unable to tolerate MAC. Flu/Mel without ATG appears to be the optimal RIC regimen.
Funded in part by a research grant from medac GmbH, Wedel, Germany
No relevant conflicts of interest to declare.
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