Is Imatinib Still an Acceptable First-Line Treatment for CML in Chronic Phase?

The introduction of the tyrosine kinase inhibitor (TKI) imatinib (Gleevec) into clinical practice resulted in a very dramatic prolongation of survival for most, but not all, patients with chronic myeloid leukemia in chronic phase (CML-CP). A leukemia with a median survival of about 5 years was transformed into one for which the survival in many cases promises to be comparable to that of normal persons of similar age. The more recently available TKIs, namely nilotinib (Tasigna) and dasatinib (Sprycel), produce more rapid responses but have not yet shown any overall survival advantage compared with long-term administration of imatinib. They are, however, useful in treating imatinib intolerance or resistance. There are currently two choices for initial treatment of CML-CP: (1) starting all new patients on imatinib and changing to a second-generation TKI in those who fail or who are predicted to fare badly, or (2) starting all new patients on a second-generation TKI. This choice may be based primarily on considerations of cost or possible side effects.

Introduction

The management of patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CML-CP) has changed very fundamentally over the past 10 years. Until 1998 there was little dispute that a new patient should be offered treatment by allogeneic stem cell transplantation (allo-SCT) if he or she was relatively young and had a suitable human leukocyte antigen (HLA)-matched sibling donor. If there were no sibling donors, then efforts were made to identify an HLA-matched family member or an unrelated volunteer from the general public. Patients not eligible for treatment by allo-SCT usually received interferon alfa or hydroxyurea, but the median expectation of life ranged between 3 and 6 years. In the 1990s, Druker, working in conjunction with Ciba-Geigy (now Novartis) in Switzerland, developed the 2-phenylaminopyrimidine derivative tyrosine kinase inhibitor (TKI) imatinib mesylate (Gleevec), now referred to just as imatinib, which specifically targeted the BCR-ABL1 oncoprotein characteristic of CML and selectively killed CML cells in vitro.[1,2] Imatinib was first used in the clinic in 1998, and it soon became clear that this agent produced impressive cytogenetic responses in patients with interferon-resistant CML.[3] This led rapidly to the initiation in 2000 of the International Randomized Study of Interferon vs STI571 (IRIS study), in which 1,106 CML-CP patients from 15 countries were recruited over a 6-month period and randomly assigned to receive either imatinib or interferon + cytarabine in a 1:1 ratio. The early results of this study were reported first in 2003[4] and have been updated at intervals since then.[5,6] They showed that imatinib produced an extremely high cumulative incidence of complete cytogenetic responses, and the patients who experienced a complete response had a mortality at 8 years of 16%. The crossover or drop-out of patients from the interferon/cytarabine arm was so great that the comparison component of the study rapidly became inevaluable, but the long-term survival of patients treated in the imatinib arm was of course substantially better than would have been expected based on treatment with interferon in an earlier era.

In the past decade, the notion of treating CML by targeting the BCR-ABL1 oncoprotein has been developed further. Four new TKIs, namely dasatinib (Sprycel), nilotinib (Tasigna), bosutinib (Bosulif), and ponatinib, have been introduced; all have demonstrable efficacy in treating patients whose leukemia has proved resistant to imatinib. The first three agents, dasatinib, nilotinib, and bosutinib, have been compared prospectively with imatinib in newly diagnosed patients, and all clearly produced more rapid responses than imatinib at the dose levels employed.[7-9] A phase III study of ponatinib compared with imatinib is just starting, and the same may prove to be true for ponatinib. The newer TKIs are, however, generally more expensive than imatinib, and when the patents on imatinib expire and generic versions become available, the difference in cost may increase still further. The critical question is therefore: Is it reasonable to start all new CML patients on treatment with imatinib alone and continue the drug indefinitely in those who fare well, or should one start treatment with one of the newer agents or possibly with imatinib in combination with another anti-CML agent in order to secure the best possible outcome for an individual patient?

TKIs: Side-Effect Overview

TABLE 1

Comparison of Efficacy, Adverse Events, and Laboratory Abnormalities Associated With the Four TKIs Used as Initial Therapy for Patients With CML-CP

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