Reduced intensity vs. myeloablative conditioning with fludarabine and PK-guided busulfan in allogeneic stem cell transplantation for patients with AML/MDS

Abstract

Conditioning regimens contribute significantly to outcomes following allogeneic stem cell transplantation (allo-SCT). Reduced-intensity conditioning (RIC) regimens provide lower toxicity at the cost of reduced efficacy compared with myeloablative conditioning (MAC) regimens. However, because pre-transplant prognostic variables often determine the conditioning regimen, studies of RIC vs. MAC have been inconclusive. We present a retrospective analysis of 242 acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) patients, 112 of whom were in 56 pairs matched using propensity scores, to account for variation that may confound clinical outcomes. The uniform conditioning regimens consisted of fludarabine with pharmacokinetic (PK)-guided intravenous busulfan (Bu). The RIC and MAC regimens were dosed at the average daily area under the concentration-vs-time curve (AUC) of 4000 µMol min and 5000-6000 µMol min, or total course AUC of 16,000 µMol min and 20,000-24,000 µMol min, respectively; PK-guided dosing removes overlap in systemic Bu exposure. When patients' data were propensity-matched, there was a trend toward significantly increased full donor chimerism and decreased chronic graft vs. host disease in RIC, and no significant differences in progression free survival and overall survival between RIC and MAC. Our results also elucidate the efficacy of PK-guided-dosing in the setting of allo-SCT for AML and MDS.

The Art of Transplantation: Conditioning Intensity for Allogeneic Hematopoietic Stem Cell Transplantation

“…Several recent studies exploring high-risk populations support those findings [8,10], including a recent analysis by Veltri et al [13] evaluating HCT in high-risk AML patients age 65 years. A recent analysis by Gilleece et al [14] confirmed no difference between MAC and nonmyeloablative (NMA) conditioning/RIC, except in AML patients age <50 years with positive minimal residual disease (MRD), a population that benefited from MAC over RIC/NMA.…”

“…In this issue, Solh et al [3] present an original analysis evaluating the impact of conditioning intensity on different disease risk index (DRI) groups of patients with AML and MDS. Although this is the first retrospective analysis to evaluate outcomes based on the DRI, numerous other investigations have addressed how best to use MAC versus less intensive conditioning strategies, with somewhat conflicting results [2,[4][5][6][7][8][9][10]. Solh et al sought to determine whether the conditioning regimen intensity impacted outcomes in patients when stratified by the DRI.…”

Immune Reconstitution Disorders: Spotlight on Interferons

“…The reduced-intensity conditioning (RIC) was offered to older patients and to those with increased comorbidities [ 77 ]. Subsequent clinical studies comparing MAC and RIC showed no significant difference in overall survival (OS) between MAC and RIC groups [ 78 , 79 ].…”

“…The leukemia-free survival and non-relapse mortality also did not differ significantly between the compared groups. Moreover, the cumulative incidence of chronic GVHD and all types of infectious complications were less frequent with RIC than with MAC [ 78 , 79 ]. Avetisyan et.…”