Risk Factors for Early Relapse after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia

Abstract

BackgroundWhile allogeneic hematopoietic cell transplantation (alloHCT) can be curative for patients with acute myeloid leukemia (AML), relapse remains a significant challenge. Previous work has suggested that disease status at time of transplant and cytogenetics are important predictors of relapse. However, it is unclear if common somatic mutations or dimorphisms of MHC class I chain-related gene A (MICA), a ligand of the natural killer (NKG2D) receptor on immune effector cells that helps mediate NK cell alloreactivity, also contribute. Moreover, the mechanisms of early relapse are an area of ongoing investigation. We assessed risk factors for relapse within 6 and 12 months after alloHCT.MethodsWe conducted a single center, retrospective analysis of adults with AML who underwent a first alloHCT. Analysis was restricted to patients with T-cell replete HLA-8/8 matched related or unrelated donor. In addition to cytogenetic risk group stratification by European LeukemiaNet criteria (Döhner H, et al, Blood 2016), a subset of patients had a 36-gene somatic mutation panel assessed prior to alloHCT by next-generation sequencing. Dimorphisms at the MICA-129 position have previously been categorized as weaker (valine/valine: V/V), heterozygous (methionine/valine: M/V), or stronger (methionine/methionine: M/M) receptor binding affinity. Risk factors for early relapse were assessed with Fine and Gray competing risk regression with results as hazard ratios (HR) and 95% confidence intervals (CI).ResultsFrom 2000 - 2017, 319 adult AML patients were identified meeting inclusion criteria. Median age at transplant was 51 years (range, 18-74), with 95% Caucasian. The distribution of low, intermediate, and high HCT-CI scores was 28%, 28%, and 44%, respectively. 75% of patients were transplanted ≤12 months from diagnosis. Disease status at transplant included 48% in first complete remission (CR1), 19% in second CR (CR2), 33% in third CR or relapsed/refractory or untreated (collectively, <0.001), while patients in CR2 also had higher risk of relapse within 12 months relative to CR1 (HR 2.02, CI 1.10-3.70, P=0.024) (Figures 1A, 1B). In addition, adverse-risk cytogenetics were a risk factor for relapse within 6 months (HR 3.96, CI 1.33-11.8, P=0.013) and 12 months (HR 3.58, CI 1.67-7.68 P=0.001) (Figures 2A, 2B). Relapse incidence estimates (CI) at 6 months were 16% (11-22) CR1, 15% (7-25) CR2, and 33% (24-42)