Considerations in the Management of Patients With Philadelphia Chromosome–Positive Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitor Therapy

Abstract

The phenomenal success of therapy with tyrosine kinase inhibitors (TKIs) in Philadelphia chromosome (Ph) –positive chronic myeloid leukemia (CML) has drastically changed the prognosis of this disease. With imatinib mesylate, the estimated 7- to 10-year survival is 80% to 85%, 90% to 93% if only CML-related deaths are considered.1–5 Nilotinib and dasatinib are more potent second generation TKIs with activity in CML after imatinib failure.6–8 In randomized trials of first-line CML therapy, nilotinib and dasatinib, compared with imatinib, demonstrated significantly higher rates of complete cytogenetic response (CCyR) and of major molecular response (MMR) at 12 to 18 months, reductions in the incidence of transformation to accelerated and blastic phases, and, on average, better tolerance.9,10 Both nilotinib (300-mg twice daily) and dasatinib (100-mg once daily) were recently approved for first-line CML therapy. In the accompanying article, Hehlmann et al11 report the results of first-line CML therapy with standard dose imatinib with or without interferon alfa, and with high-dose imatinib. They analyze the incidence of MMR as the study primary end point.11 This emphasis on MMR as a primary end point in CML therapy, and the availability of three TKIs for CML therapy, raise important questions related to the management of chronic phase CML in our daily practice. What are the important early end points of therapy with TKI in CML that predict long-term prognosis (eg, achievement of CCyR, MMR)? How should we monitor response to therapy (cytogenetic, fluorescent in situ hybridization [FISH], molecular studies, mutational analysis)? What are the long-term end points relevant to therapeutic decisions (survival, progression-free survival [PFS], event-free survival [EFS])? Imatinib will become available in generic formulations in the next few years, at a significantly lower cost than second generation TKIs. Oncologists are then faced with important therapeutic questions. Would it be better to use the less expensive TKI, imatinib, as first-line CML therapy and reserve the second generation TKIs for imatinib failure, or should second generation TKIs be used as first-line therapy? What is a clinically relevant definition of poor response to imatinib? If imatinib is selected for first-line therapy, is it better to change to second generation TKIs at the time of suboptimal response to imatinib, or at the time of cytogenetic or hematologic relapse? These questions raise several important issues related to how best to integrate the new generation of TKIs into the management of patients with CML.