Karyotype instability between diagnosis and relapse in 117 patients with acute myeloid leukemia: implications for resistance against therapy

Abstract

The instability of the karyotype may play a role in the development of refractoriness of acute myeloid leukemia (AML) to antileukemic therapy. Therefore, in the current study cytogenetic analyses were performed in 117 patients with AML both at diagnosis and at relapse. Changes in karyotype were observed in 38% (36% of initially normal karyotypes, 39% of initially aberrant karyotypes). An evolution of karyotype, ie the acquisition of further aberrations in addition to those present at diagnosis, occurred more frequently in patients with unfavorable karyotypes at diagnosis as compared to all others (60% vs 32%, P = 0.0095). The duration from initial diagnosis to relapse was significantly shorter in cases with an evolution of the aberrant karyotype as compared to cases with no changes in the aberrant karyotype between diagnosis and relapse or with solely regression of aberrations at relapse (9.2 ± 4.4 vs 14.0 ± 8.5 months, P = 0.0081). In an additional analysis, another cohort of 120 patients with refractory and relapsed AML who were treated uniformly within the respective trial of the German AML Cooperative Group was analyzed cytogenetically at diagnosis and at relapse to further prove the prognostic impact of karyotype aberrations at relapse. Karyotypes were prognostically favorable, intermediate, unfavorable and not available in 8%, 50%, 17% and 25% at diagnosis and in 8%, 49%, 21% and 22% at relapse, respectively. Karyotype aberrations at diagnosis had no impact on response to therapy (P = 0.32) but influenced survival and event-free survival significantly (P = 0.03 and P = 0.02). In contrast, karyotype aberrations at relapse strongly influenced response to therapy (P = 0.05), survival (P = 0.01), and event-free survival (P = 0.002). These data suggest that the instability of the karyotype between diagnosis and relapse and thus karyotype aberrations at relapse in particular contribute to the refractoriness of AML to anti-leukemic therapy.

Impact of cytogenetics on the prognosis of adults with de novo AML in first relapse

“…At 3 years, the probabilities of OS and DFS were only 24% (CI: 16-32%) and accordingly 18% (CI: 8-28%), which corresponds to data from the literature. 27,29,39,40 In accordance with many previous studies, we confirmed that the duration of first CR is an important prognostic factor for the achievement of second CR, the duration of OS and DFS from second CR. [21][22][23][24] There was a significant relation between the duration of first CR and the parameters of clinical outcome (rate of second CR, OS and DFS).…”

“…Estey et al 41 found that a change in the cytogenetic pattern at first relapse does not influence the prognosis of therapy for first relapse in the great majority of patients. Data observed by Kern et al 29 suggest that cytogenetics at relapse tended to be related to the outcome more strongly than cytogenetics at diagnosis. We have not studied this question among our patient cohort systematically.…”

“…However, in a bivariate analysis the duration of first CR was of greater significance. Most recently, again, Kern et al 29 were able to show that the outcome of patients with relapsed AML was clearly dependent on the karyotype obtained at diagnosis. The likelihood of a second CR was 80, 49 and 30% in the favourable, intermediate and unfavourable cytogenetic risk groups.…”

Altered nucleophosmin transport in acute myeloid leukaemia with mutated NPM1: molecular basis and clinical implications

“…69,70 Discrepancies with other reports may be due to technical reasons or one might speculate that these cases represent treatment-related or even second de-novo AMLs rather than relapses from previous leukaemia. 71 Extensive investigation by FISH and other molecular techniques are warranted to clarify the issue.…”

Clonal evolution and devolution after chemotherapy in adult acute myelogenous leukemia

“…[23][24][25] Similarly, low resolution SNP array analysis of 27 pairs of diagnosis and relapse adult AML specimens showed that 10 of 11 cases with genomic lesions at diagnosis maintained or added to those lesions at relapse, suggesting proximal clonal relatedness. 26 Likewise, whole genome sequencing of 8 AML diagnosis and relapse pairs compared somatic mutation patterns, indicating the resilience of the dominant diagnosis clone or one of its subclones at relapse.…”