Clonal evolution and lack of cytogenetic response are adverse prognostic factors for hematologic relapse of chronic phase CML patients treated with imatinib mesylate

Abstract

We followed 141 patients treated with imatinib mesylate (> 300 mg) for chronicphase chronic myelogenous leukemia (CML) following failure of treatment with interferon. During 12 months from the start of imatinib mesylate treatment, 96.5% achieved a complete hematologic response, 47.0% achieved a major cytogenetic response, and 32.4% achieved a complete cytogenetic response. The proportion of patients with hematologic relapse was 10.9% at 12 months and 14.6% at 18 months. In a univariate Cox regression analysis, the only pretreatment characteristics that correlated with an increased risk of hematologic relapse were hemoglobin level less than 120 g/L (12 g/dL) (P ‫؍‬ .02), increased bands in the peripheral blood (P ‫؍‬ .01), and clonal evolution (P < .0001). In a multivariate analysis, an elevated platelet count (P ‫؍‬ .03) and clonal evolution (P < .0001) were the only significant factors for hematologic relapse. During treatment, the absence of a major cytogenetic response within the first 6 months also significantly correlated with relapse (P ‫؍‬ .03). Notably, patients failing to achieve a major cytogenetic response by 6 months had a significantly higher rate of hematologic relapse (27%) compared with those who achieved a major cytogenetic response by 6 months (3%), and patients with clonal evolution had a significantly higher risk of hematologic relapse (50%) than those without clonal evolution (9%

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.…”

Identification of genes involved in imatinib resistance in CML: a gene-expression profiling approach

“…A prompt molecular response is also associated with longer progression-free survival. 4,21 The study has identified an expression profile associated with primary resistance. The classes of genes identified and the lack of mutations in the kinase domain of the bcr-abl gene suggest that this type of resistance is essentially BCR-ABL-independent.…”

“…2 Despite the high rate of response to imatinib therapy, the emergence of resistance to this treatment has been recognized as a major problem in the therapy of Phpositive CML patients. 3,4 Some important imatinib resistance mechanisms have been characterized, including mutations in the BCR-ABL domain and overexpression of BCR-ABL oncoprotein, [5][6][7][8] although these two mechanisms are associated with secondary or acquired resistance. Intrinsic resistance to imatinib has been linked to rapid drug efflux from hematopoietic cells and inactivation of imatinib by binding to serum a1-acid glycoprotein, 9 although supporting in vivo data are lacking.…”

Every case of essential thrombocythemia should be tested for the Philadelphia chromosome

“…Acute leukemia, in the absence of leukemogenic chemotherapy, evolves in less than 5% of patients, in direct contrast to CML. In CML, almost all patients develop a fatal acute leukemic phase usually in less than 5 years, but new targeted molecular therapies promise to greatly improve this situation [5,6].…”