Clofarabine Improves Relapse-Free Survival of Acute Myeloid Leukemia in Younger Adults with Micro-Complex Karyotype

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.

[1]  J. Welch,et al.  Acute Myeloid Leukemia: The Good, the Bad, and the Ugly. , 2018, American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting.

[2]  H. Dombret,et al.  SNP-array lesions in core binding factor acute myeloid leukemia , 2018, Oncotarget.

[3]  H. Dombret,et al.  Randomized Phase II Study of Clofarabine-Based Consolidation for Younger Adults With Acute Myeloid Leukemia in First Remission. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  Bob Löwenberg,et al.  Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. , 2017, Blood.

[5]  J. Cayuela,et al.  Postinduction Minimal Residual Disease Predicts Outcome and Benefit From Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia With NPM1 Mutation: A Study by the Acute Leukemia French Association Group. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  Sylvie Chevret,et al.  Clinical impact of gene mutations and lesions detected by SNP-array karyotyping in acute myeloid leukemia patients in the context of gemtuzumab ozogamicin treatment: Results of the ALFA-0701 trial , 2014, Oncotarget.

[7]  M. Walter,et al.  Detection of copy number alterations in acute myeloid leukemia and myelodysplastic syndromes , 2012, Expert review of molecular diagnostics.

[8]  Kerby Shedden,et al.  Acquired genomic copy number aberrations and survival in adult acute myelogenous leukemia. , 2010, Blood.

[9]  R. Hills,et al.  Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. , 2010, Blood.

[10]  K Holzmann,et al.  Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis , 2010, Leukemia.