Abstract
Acute myeloid leukemia (AML) encompasses heterogeneous entities with dismal outcomes. Intermediate and unfavorable-risk AML represent the most difficult-to-treat entities. We recently reported the benefit of the clofarabine-based consolidation (CLARA) regimen compared to the standard high-dose cytarabine (HDAC) regimen in younger AML patients. Here, we aimed at assessing the clinical significance of single-nucleotide polymorphism (SNP)-array alterations and their interactions with chemotherapy regimens. A SNP-array was successfully performed in 187 out of the 221 intent-to-treat patients (CLARA arm: n = 92 patients, HDAC arm: n = 95 patients). The CLARA regimen did not significantly improve relapse-free survival (RFS) among patients who displayed a complex karyotype when compared to the HDAC regimen (4-year RFS (4y-RFS): 36.4% vs. 18.8%, respectively; p = 0.134). Defining micro-complex karyotypes from at least four SNP-array lesions enabled us to refine and enlarge the subset of adverse patients. In such patients, the CLARA regimen significantly improved RFS compared to the HDAC regimen (4y-RFS: 44.4% vs. 13.8%, respectively; p = 0.004). From our study cohort, 8% of patients displayed TP53 mutations, which were associated with an impaired RFS (4y-RFS: 20.0% vs 43.7%; p = 0.029). In a multivariate analysis, micro-complex karyotypes remained the sole poor prognostic factor in the HDAC arm (hazard ratio (HR) = 2.324 (95% confidence interval (CI) = 1.337–4.041), p = 0.003). The SNP array represents a powerful and reproductive approach to refine adverse AML patients that may benefit from alternative consolidation regimens.
Highlights
Acute myeloid leukemia (AML) encompasses heterogeneous entities, but its global outcome remains of concern
The single-nucleotide polymorphism (SNP)-array was performed in 187 randomized patients (CLARA arm, n = 92; HDAC arm, n = 95)
A previous by Bullinger et al [4]AML; showed that contrast to cohort, which was number enriched with patients who harbored abnormal cytogenetics. Another neither theour presence nor the of copy number alterations (CNAs) predict outcome, but this study focused on study by Parkinnormal et al [5]AML; foundthis thatistwo or more SNP-array alterations impacted overall cytogenetically in contrast to our cohort, which negatively was enriched with patients survival, including when cytogenetics
Summary
Acute myeloid leukemia (AML) encompasses heterogeneous entities, but its global outcome remains of concern. Nearly 50% of AML patients show a normal karyotype in conventional cytogenetics, and about 25% have uncommon aberrations [2]. In this context, high resolution approaches such as single-nucleotide polymorphism (SNP)-array karyotyping are attractive to better characterize unrecognized or cryptic copy number alterations (CNAs) and copy-neutral-loss of heterozygosity (CN-LOH), and these approaches may provide new information in AML diagnosis and prognostication [3]. Some studies have shown the feasibility of interrogating AML genomes with such technologies [4,5] They have led to the discovery of novel recurrent gene deletion, amplification, and CN-LOH encompassing important targets including TET2, CBL, EZH2 or FLT3 (reviewed in [6])
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