Targeted chronic myeloid leukemia therapy: Seeking a cure

Abstract

Purpose: This article focuses on imatinib, how it has altered CML therapy, clinical trials that are the basis for its efficacy, and adverse effects associated with its current clinical use.

Summary: Maintaining patients with CML in chronic phase (CP) yields the prospect of improved long-term survival. As recently as 1993, CML was limited to treatment with standard cytoreductive therapies. These therapies provide temporary disease control but do not alter progression to advanced disease with a median survival ranging 45 to 55 months from diagnosis. In the 1990s, immunologically based therapy with interferon alpha (IFNalpha) therapy was shown to be superior to cytoreductive therapies with a median survival of 60 to 90 months. Allogeneic hematopoietic stem cell transplant (HSCT) has offered curative potential for patients with CML; however, the median age of diagnosis of 55 years, the lack of suitable donors, and the morbidity of the procedure precludes widespread applicability of this treatment. Imatinib, the first approved tyrosine kinase inhibitor, functions by blocking the ATP binding site on the BCR-ABL kinase. It was first shown to be efficacious in patients who failed IFNalpha and then tested as a front line therapy (the International Randomized Study of Interferon [IRIS] trial). The five year follow up on the IRIS trial found that the responses were durable with progression free survival estimated at 93%. Imatinib has been found to have a lower rate of hematologic response and shorter duration of response in patients with advanced disease. Currently patients in blast crisis (BC) have the option to undergo a number of induction chemotherapies, such as etoposide, cytarabine, carboplatin (VAC) with the hope of temporarily restoring the patient to CP in preparation for HSCT. Imatinib, when administered at the standard dose of 400 mg/day is relatively well tolerated with major toxicities limited to myelo-suppression, edema, GI upset, rash, and muscle pain. Many of these toxicities are managed by decreasing the dose until the toxicity resolves. Imatinib is an inhibitor of cytochrome P450 enzymes necessitating careful monitoring of concomitant medications metabolized by these enzymes. Resistance may develop to imatinib most often caused by the evolution of mutations blocking imatinib interactions with the BCR-ABL adenosine triphosphate (ATP) binding site. The second generation BCR-ABL inhibitor, dasatinib, can block the activity of many of these mutations; however, the T315I mutation, at present, is resistant to all available kinase inhibitors. Experimental drugs that block this mutation are just entering phase two clinical trials.

Conclusion: The development of therapeutic agents targeting BCR-ABL has revolutionized the treatment of chronic myeloid leukemia (CML). Imatinib has successfully allowed CML patients to remain in CP for at least five years in 90% of patients. Dasatinib has activity against a number of Imatinib-resistant mutants providing an additional therapeutic option for these patients.