Chronic Myeloid Leukemia—Second-generation ABL Kinase Inhibitors and Newly Diagnosed Patients
Jorge E Cortes
Oncology & Hematology Review (US)
Chronic myeloid leukemia (CML) is characterized by the uncontrolled proliferation of hematopoietic cells carrying the Philadelphia chromosome (Ph), the product of reciprocal translocation between chromosomes 9 and 22, t(9;22)(q34.1;q11.2). Its molecular counterpart, the resultant BCR-ABL fusion gene, encodes a constitutively active form of the ABL tyrosine kinase (TK) that induces malignancy through the activation of multiple signal transduction pathways involved in hematopoietic cell growth
... survival. Understanding of the disease pathogenesis made it possible to develop molecularly targeted therapies. One such targeted therapy, imatinib mesylate (Gleevec ® , Novartis), was found to be a relatively specific inhibitor of the BCR-ABL TK and effective in blocking the molecular signals contributing to the CML phenotype. Imatinib binds the ABL domain at the ATP-binding site and traps the protein in an inactive conformation to inhibit the kinase activity. Its favorable pharmacokinetic and toxicity profile, paired with its excellent clinical results, rapidly made imatinib the standard frontline therapy for all chronic-phase CML patients. Evolution of Treatment Regimens For many years, patients with CML relied on agents such as hydroxyurea and busulfan to improve their quality of life. Later, survival prolongation was achieved through recombinant interferon-alpha alone or in combination with cytarabine and, in some patients, allogeneic stem cell transplants. 1,2 In the International Randomized Study of Interferon and STI571 (IRIS), imatinib was found to be superior to interferon-alpha as initial therapy for patients in the early chronic phase. After five years of follow-up, imatinib has resulted in a complete cytogenetic response (CCyR) rate of 82% and a projected rate of death or progression to accelerated-or blastic-phase CML of 7%. 2,3 Six-year follow-up data for imatinib use in the IRIS study continue to provide clear evidence of durable responses, with a 0% rate of transformation to accelerated-phase CML or blast crisis between years five and six, and an overall estimated six-year survival rate of 88%. 4 Imatinib (400mg/day) is now considered by both the US National Comprehensive Cancer Network (NCCN) and the European LeukemiaNet to be the standard approach for the initial treatment of chronic-phase CML. 5, 6 However, the development of imatinib resistance has been reported in some patients, with both primary resistance (failure to achieve a desired response at specific times) and secondary resistance (loss of response) reported in a subset of patients. Primary hematological resistance occurs rarely, affecting 2-4% of cases, whereas 15-25% of patients may experience primary cytogenetic resistance. 7 Secondary resistance to imatinib is thought to involve acquired evasion of BCR-ABL inhibition by various mechanisms such as mutations in the kinase domain that prevent imatinib binding, or genomic amplification and overexpression of BCR-ABL. 8, 9 Knowledge of the molecular mechanisms behind imatinib resistance has led to the development of second-generation ABL kinase inhibitors. These second-generation agents have significantly higher potency compared with imatinib and activity against most imatinib-resistant BCR-ABL kinase domain mutants. A number of these kinase inhibitors have entered clinical trials, and two products-dasatinib (Sprycel ® , Bristol-Myers Squibb) and nilotinib (Tasigna ® , Novartis)-have recently been approved by health authorities in the US and Europe for use in patients with CML experiencing imatinib resistance or intolerance. Intolerance of imatinib is rare, occurring in <1% of patients. 2 Second-generation ABL Kinase Inhibitors in Imatinib Failure Dasatinib in Imatinib Failure Dasatinib is a highly potent multitarget inhibitor of the BCR-ABL kinase and Src family kinases. Dasatinib binds to the ABL kinase in both the active and inactive conformations, 10 and in vitro studies have shown that dasatinib has 325-fold increased potency compared with imatinib in cells with wild-type BCR-ABL. 11 Successful anti-CML activity in phase I studies led to the phase II START (SRC/ABL Tyrosine kinase inhibition Activity: Research Trials of dasatinib) program. This included a series of trials using oral dosages of 70mg dasatinib twice daily (BID) for CML patients in chronic, accelerated, and blastic phases following imatinib resistance or intolerance. 4,12-15 These studies demonstrated the efficacy of dasatinib after imatinib failure. Data from a two-year follow-up of the multinational and multicenter studies are summarized in Table 1 . The proportion of patients remaining progressionfree at two years when treated with dasatinib after resistance or intolerance to imatinib was reported at 80%, with 94% overall survival. The trial data show that dasatinib is generally well-tolerated, with thrombocytopenia and neutropenia as the most common grade 3-4 adverse effects. 16 While the incidence of grade 3-4 neutropenia and thrombocytopenia are 49 and 48%, respectively, in chronic-phase CML, 17 the rates increase as the leukemia progresses, reaching 76 and 82% in accelerated phase 12 and ranges of 79-82% and 84-88% in blast crisis. Dasatinib is currently US Food and Drug Administration (FDA)-approved for treating all phases of Ph+ CML following imatinib resistance or toxicity, as well as for Ph+ acute lymphoblastic leukemia (ALL) with resistance or intolerance to prior therapy. Subsequent studies have shown that in the chronic phase, a dose of 100mg once daily is as effective as the initially used dose of 70mg BID, but is associated with significantly fewer grade 3-4 adverse events, particularly myelosuppression and pleural effusion, compared with combined adverse events for 50mg BID, 70mg BID, and 140mg once daily. 18 Thus, 100mg once daily has become the standard dose in chronic-phase CML.