Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy

Abstract

Cytogenetic clonal evolution (CE) is a known poor prognostic factor in Philadelphia chromosome-positive chronic myelogenous leukemia (Ph-positive CML). However, its prognostic relevance in the era of imatinib therapy is unknown. We investigated the independent prognostic relevance of CE in 498 patients with Phpositive CML treated with imatinib for chronic or accelerated phases. One hundred twenty-one patients had CE alone (n ‫؍‬ 70) or with other accelerated phase criteria (n ‫؍‬ 51). Patients were compared in 4 categories: chronic phase (n ‫؍‬ 295), CE only (n ‫؍‬ 70), accelerated phase without CE (n ‫؍‬ 82), and accelerated phase with CE (n ‫؍‬ 51). Statistical methods used established methodologies for univariate and multivariate analyses. In chronic and accelerated phases of CML, CE was not associated with significant differences in major or complete cytogenetic response rates, but it was an independent poor prognostic factor for survival by multivariate analyses in both chronic (P ‫؍‬ .005) and accelerated phase (P ‫؍‬ .03). Multivariate analyses conducted at the 3-month landmark (including the 3-month cytogenetic response) identified the lack of cytogenetic response at 3 months to be a stronger independent poor prognostic factor for survival than CE for both chronic (major cytogenetic response versus other) and accelerated phase (any cytogenetic response versus other). We conclude that cytogenetic CE is not an important factor for achieving major or complete cytogenetic response with imatinib mesylate therapy, but it is an independent poor prognostic factor for survival in both chronic and accelerated phases of CML. The 3-month cytogenetic response to imatinib mesylate refined the prognostic relevance of such studies in patients on imatinib mesylate therapy. (Blood. 2003;

Imatinib improves but may not fully reverse the poor prognosis of patients with CML with derivative chromosome 9 deletions

“…A failure to achieve MCR is associated with an increased risk of disease progression on imatinib. 32,33 Although the deletion status of the cohorts in which this progression is described is not known, the data are compatible with the reduced rate of MCR and increased risk of disease progression that we observed in our patients, both in CP and advanced phase CML.…”

Marrow fibrosis and its relevance during imatinib treatment of chronic myeloid leukemia

“…31,33,39,40 Apart from a few patients with complex karyotype abnormal- Figure 2 Relevance of FFI and full-blown MF to the probability of a cytogenetic or molecular response and the risk of acceleration or death of patients. Among the patients with FFI or MF before or within the first 3 months after the start of imatinib treatment, the probability of achieving a complete cytogenetic or major molecular response was markedly reduced compared to the patients with an initial normal fiber content ((a) complete cytogenetics of major molecular response after detection of FFI or MF before the start of imatinib treatment).…”

“…Additional chromosome aberrations besides t(9;22)(q34;q11) indicate clonal evolution of disease [39][40][41] and are usually regarded as an indicator of loss of efficacy of treatment. 31,33,39,40 Apart from a few patients with complex karyotype abnormal- Figure 2 Relevance of FFI and full-blown MF to the probability of a cytogenetic or molecular response and the risk of acceleration or death of patients.…”

Minimal residual disease diagnostics in myeloid malignancies in the post transplant period

“…126 Early kinetics of the BCR-ABL fusion allow prognostic predictions after SCT: a slow reduction of the BCR-ABL transcripts on days þ 28 and þ 56 showed a significant correlation with higher relapse rates, whereas the achievement of PCR negativity after SCT was associated with stable long-term remissions in a study of Lange et al 129 Asnafi et al 130 determined a threshold of 10 À4 of BCR-ABL/ABL on day þ 100 after SCT to predict the probability of relapse, and another study showed higher relapse rates when BCR-ABL fusion transcripts were detected within the first 3-5 months after SCT. 131 Resistance to TKI can be mediated by different mechanisms, for example, point mutations in the ABL gene, [132][133][134] which can be revealed by sequencing after screening by high performance liquid chromatography. The ELN formulated clear indications: screening is indicated in cases where patients fail to achieve major cytogenetic response (reduction of Ph-positive metaphases o35%) at 12 months or show loss of molecular response as defined by an increase in the BCR-ABL/ABL ratio of X1 on a logarithmic scale.…”