The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML

Abstract

In chronic myelogenous leukemia (CML), the development of chromosomal abnormalities in addition to the Philadelphia chromosome (clonal evolution) is considered by many to be a feature of accelerated phase (AP). Imatinib mesylate (STI571), a selective inhibitor of the Bcr-Abl tyrosine kinase, has significant activity in AP CML. As clonal evolution could allow Bcr-Abl independent proliferation, we analyzed its impact on the outcome of 71 AP patients treated with 600 mg of imatinib mesylate. Fifteen patients had clonal evolution alone (AP-CE), 32 had AP features but no evidence of clonal evolution (HEM-AP), and 24 had AP features plus clonal evolution (HEM-AP + CE). Of the AP-CE patients, 73% had a major cytogenetic response, compared with 31% of the HEM-AP patients (P =.043) and 12.5% of the HEM-AP + CE patients (P =.007). Complete cytogenetic responses were seen in 60% of AP-CE patients, compared with 31% of HEM-AP patients (P =.19) and 8% of HEM-AP + CE patients (P <.001). With mean follow-up of 11.2 months, 35% of all patients failed treatment. The lowest estimated rate of treatment failure at 1 year, 0%, was seen in AP-CE patients, compared with rates of 31% for HEM-AP patients and 69% for HEM-AP + CE patients (P =.0004). After 1 year, 100% of AP-CE patients were still alive, compared with 85% of HEM-AP patients and 67.5% of HEM-AP + CE patients (P =.01). In conclusion, in patients with clonal evolution as the sole criterion of disease acceleration, good responses to imatinib are still possible. Once patients have other signs of acceleration, clonal evolution predicts lower response rates and a shorter time to treatment failure.

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

“…The researchers concluded that good prognosis was still possible if cytogenetic clonal evolution was the only criterion of accelerated phase, whereas clonal evolution with other accelerated features predicted for the worst outcome. Our results confirm some of the findings of O'Dwyer et al 41 and provide additional insights with more detailed (multivariate) analysis of a larger number of patients (n ϭ 498 versus 71 patients) with a longer follow-up (median of 30 months versus mean of 11 months), and a comparison to patients with chronic-phase CML. Unlike the results of O'Dwyer et al, 41 our study did not identify clonal evolution to be associated with a significant difference in major or complete cytogenetic response rates within specific CML phases (ie, chronic Ϯ clonal evolution, accelerated Ϯ clonal evolution).…”

“…Our results confirm some of the findings of O'Dwyer et al 41 and provide additional insights with more detailed (multivariate) analysis of a larger number of patients (n ϭ 498 versus 71 patients) with a longer follow-up (median of 30 months versus mean of 11 months), and a comparison to patients with chronic-phase CML. Unlike the results of O'Dwyer et al, 41 our study did not identify clonal evolution to be associated with a significant difference in major or complete cytogenetic response rates within specific CML phases (ie, chronic Ϯ clonal evolution, accelerated Ϯ clonal evolution). However, clonal evolution was still independently associated with worse survival in both chronic and accelerated phase, independent of other prognostic factors.…”

“…By analyzing patients evaluable at 3 months of therapy, it appeared that lack of a cytogenetic response (major cytogenetic response versus other in chronic phase; any cytogenetic response versus other in accelerated phase) was a stronger independent poor prognostic factor for survival than cytogenetic clonal evolution at the start of therapy. O'Dwyer et al 41 analyzed the outcome of 71 patients with Ph-positive CML treated with imatinib mesylate 600 mg orally daily: 15 patients had chronic-phase CML with clonal evolution, 32 had accelerated phase without clonal evolution, 24 patients had accelerated-phase CML and clonal evolution. The major cytogenetic response rates were 73%, 31%, and 12.5%, respectively (P Ͻ .01).…”

Limited clinical value of regular bone marrow cytogenetic analysis in imatinib-treated chronic phase CML patients monitored by RQ-PCR for BCR-ABL

“…20,21 However, in cases where accelerated phase is defined solely by clonal evolution, the outcome is heterogeneous and the rate of response to imatinib (with short follow-up) may to be similar to that of chronic phase. [22][23][24] The development of clonal cytogenetic abnormalities in Ph-negative cells has also been observed during imatinib treatment of CML. In the two largest studies, none of 55 patients with Ph-negative clonal abnormalities had clinical features of myelodysplasia.…”

A novel mechanism for imatinib mesylate–induced cell death of BCR-ABL–positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity

“…5,7 Imatinib counteracts BCR-ABL tyrosine kinase and induces apoptosis in BCR-ABL-positive cells [8][9][10] in a caspase-dependent fashion. 11,12 Recently, however, it has been revealed that responses to imatinib are not necessarily remarkable or durable in some patients with BCR-ABL-positive leukemia, [13][14][15][16][17][18][19][20][21][22] and thus an increasing number of studies have searched for a novel therapy targeting the BCR-ABL-induced signaling pathways. 5 Cell death is generally classified into 2 categories, apoptosis 23,24 and necrosis.…”