Abstract
Objectives: Acute myeloid leukemia (AML) with complex/monosomal karyotype (CK/MK) is associated with poor response to conventional chemotherapy and clinical outcome. This study examined the clinicopathologic features, mutation spectrum and clinical outcome of young adult patients with CK/MK AML treated with a uniform protocol in Hong Kong.
Methods: Young adult patients (18-60 year old) with CK/MK-AML treated in 7 regional hospitals in Hong Kong from January 2003 to July 2016, were analyzed retrospectively. CK-AML was defined as those with ≥ 3 clonal abnormalities. MK-AML was defined as those with ≥ 2 autosomal monosomies or single autosomal monosomy and at least one structural abnormality. Treatment comprised induction (7+3 regimen or equivalent) and consolidation (high-dose cytarabine). Relapsed or refractory patients received salvage chemotherapy. All patients who achieved complete remission (CR) were referred to allogeneic hematopoietic stem cell transplantation (HSCT) from HLA identical sibling or matched unrelated donors. Mutation spectra of their diagnostic bone marrow samples were analyzed by MiSeq NGS with the TruSight Myeloid sequencing panel targeting 54 genes covering full coding sequence of 15 genes and exonic hot spot for 39 genes. Leukemia-free survival (LFS) and overall survival (OS) were evaluated by Kaplan-Meier curves and compared by log-rank test. Cox proportional hazard model was used in univariate and multivariate analyses.
Results: Seventy-six patients (41 men and 35 women) with CK/MK-AML were analyzed. Their clinicopathologic features as well as mutation spectra of 45 patients whose diagnostic marrow were examined by NGS were shown in Table 1. A total of 116 genetic mutations were found (median 2 mutations, range 1-7 mutations per patient). Five patients died before induction and 2 refused treatment. Of the 69 patients who received induction chemotherapy, CR was achieved in 48 of them (70%) after one (N=33) or two (N=15) courses. After 1, 2 and 5 years, LFS was 41%, 26% and 18% and OS was 49%, 20% and 12% respectively. There was no significant association between CR and clinicopathologic features including age, gender, presenting WCC, percentage of marrow and circulating blasts, specific subtypes and number of cytogenetic abnormalities, number of gene mutations and presence of TP53 mutations. In univariate analysis, HSCT at CR1 was significantly associated with longer LFS with a hazard ratio (HR) of 6.1 (range, 2.4-15.7, p <0.001). Achievement of CR1, absence of -17/17p- and HSCT at CR1 were significantly associated with OS with HRs of 8.3 (range 4.4-15.8, p <0.001), 3.2 (range, 1.7-3.2, p<0.001) and 5.7 (range, 2.4-13.5, p <0.001) respectively. TP53 mutations, number of karyotypic abnormalities and mutations were not predictive of CR, LFS or OS in this cohort. In multivariate analysis, achievement of CR1 (HR 4.3, 2.2-8.2, p <0.001), absence of -17/17p- (HR 3.0, 1.5-5.9, p=0.002) and HSCT at CR1(HR 5.8, 2.4-13.7, p <0.001) were associated with superior OS.
Conclusion: Karyotypic abnormalities particularly the presence of -17/17p-, the achievement of initial remission upon induction and timely HSCT are important factors associated with disease control and survival in CK/MK AML. The role of gene mutations, particularly TP53, RUNX1 and DMNT3A as well as the best maintenance strategies post HSCT would have to be further evaluated.
No relevant conflicts of interest to declare.
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