gms | German Medical Science

Imatinib is a molecularly targeted therapy that inhibits the oncogenic fusion protein BCR-ABL, the tyrosine kinase involved in the pathogenesis of chronic myelogenous leukemia (CML). Selective inhibition of BCR-ABL activity by imatinib has demonstrated efficacy in the treatment of CML, particularly in chronic phase. Some patients, however - primarily those with advanced disease - are either refractory to imatinib or eventually relapse. Relapse with imatinib frequently depends on re-emergence of BCR-ABL kinase activity but may also indicate BCR-ABL–independent disease progression not amenable to imatinib inhibition. Clinical studies have demonstrated responses in chronic phase (CP) patients lasting more than 3 years, whereas most responding patients in blast crisis (BC) relapse early despite continued therapy. Complete hematologic responses to imatinib have been observed in 96% of newly diagnosed patients in CP, 95% of patients in CP CML after failure of interferon alpha, 71% of accelerated phase (AP) patients, and 31% of patients in myeloid BC. Drug resistance, however, has been observed, particularly in advanced phase but also in CP CML. In AP, 24% of patients treated with imatinib (600 mg/day) failed to reach hematologic remission and 60% relapsed after initial response to imatinib monotherapy. In myeloid BC, 66% failed to achieve hematologic remission and of the patients who achieved hematologic remission, 938% relapsed. In contrast, the proportion of CP patients who relapsed within 36 months was 20% in patients after failure of interferon-a and 7% in newly diagnosed CML patients. In about 50% of patients, mutations of the BCR-ABL kinase domain are associated with hematologic resistance. These observations combined with insights provided by an increased understanding of the molecular mechanisms of resistance, have established the rationale for strategies to avoid and overcome imatinib resistance in the management of CML patients. To prevent resistance, early diagnosis and prompt treatment with appropriate initial dosing is essential. Management of resistance may include therapeutic strategies such as dose escalation to achieve individual optimal levels, combination therapy, treatment interruption, or, preferentially, administration of alternative tyrosine kinase inhibitors, like AMN107 or dasatinib. The oncogenicity of BCR-ABL will likely mandate that inhibition of its kinase activity remains as the cornerstone of treatment for CML. Improvements in the technologies used to characterize disease and monitor response, when integrated with results from clinical trials, will facilitate the design of future strategies aimed at optimizing the prognosis for patients with CML.