Targeted chronic myeloid leukemia therapy: seeking a cure.

BACKGROUND

Chronic myeloid leukemia (CML) is a hematopoietic stem cell cancer driven by the BCR-ABL fusion protein that arises from the translocation of chromosomes 9 and 22. The disease begins with an indolent chronic phase (CP) that can last for 3 to 5 years. If untreated, it progresses into accelerated phase (AP) and within a year, blast phase (BP). Survival at this point is less than 1 year. during disease progression, mutations and the Philadelphia chromosome (Ph) appear (a process called clonal evolution). The only known curative therapy for CML is allogeneic bone marrow transplant (BMT). However, toxicity is formidable, with treatment- related mortality reported in the 30% range. Thus, effective therapy that maintains the patient with CML in CP with minimal toxicity is the goal for treatment of modern therapies. Because the preeminent mutation driving CML is BCr-ABL, therapies targeting BCR-ABL are the logical choice for disease-specific therapy. BCR-ABL inhibitors, such as imatinib, are proof that targeting specific genetic mutations associated with cancer yields a high degree of efficacy with minimal toxicity.

OBJECTIVE

This review will outline the evolution of therapy in CML. Preimatinib and imatinib-based treatment strategies, clinical efficacy, and the mechanism of imatinib resistance will be discussed.

CONCLUSIONS

The discovery of the Ph and, subsequently, the identification of BCr-ABL revolutionized the treatment of CML. Cytoreductive chemotherapy, such as busulfan and hydroxyurea, was a mainstay of therapy to control white blood cell (WBC) counts; however, it did not modify the progression of the disease to AP and BP. The overall survival with CML ranges from 45 to 58 months in patients treated with cytoreductive therapy only. Treatment was advanced with the introduction of interferon (IFn ) immunotherapy in the 1980s. In some studies, IFn produced a complete hematologic response (CHR) in more than 50% of patients; however, its nonspecific immunostimulatory mechanism also produced severe flulike symptoms that limited tolerability. despite the significant toxicity, cost, and inconvenience of injecting IFN thrice weekly, median survival ranged from 60 to 89 months. Allogeneic BMT is the only known curative therapy for CML; however, treatment-related mortality from infection, bleeding, and graft versus host disease, age, and the availability of suitable donors limits its widespread use. Imatinib functions by competing with adenosine triphosphate (ATP) for binding to the BCr-ABL tyrosine kinase. In the absence of ATP, BCR-ABL is not able to activate downstream effector tyrosine kinase molecules that drive wBC proliferation. The International randomized Interferon versus STI571 clinical trial was the first to document the efficacy of imatinib as a first-line therapy for patients in CP. More than 90% of these patients had a CHr. Toxicities associated with this therapy are low. response in patients with advanced CML is less pronounced than in CP and is shorter lived, with less than 30% of patients achieving a CHR. For patients with CML in BP, the only viable therapy is to attempt a temporary reduction in disease burden with a salvage chemotherapy regimen, such as VAC (etoposide, cytarabine, and carboplatin). The goal of this induction chemotherapy is to induce a second remission; then the patient may be considered for allogeneic BMT. The main toxicities seen with imatinib therapy are myelosuppression, edema, and myalgia/arthralgia. In many cases, imatinib dosage can be briefly halted or lowered while the toxicity is managed. Imatinib resistance may develop at any time and inevitably leads to disease progression. resistance is usually caused by mutations within BCr-ABL, decreasing the affinity of imatinib binding. next-generation kinase inhibitors are focused on the ability to inhibit these mutated forms of BCR-ABL.

CONCLUSIONS

For the majority of patients with CML in CP, the standard of care is to maintain the patient in CP with imatinib therapy. Clinical trials have been extraordinarily successful, with 5-year survival rates greater than 90%. Allogeneic BMT continues to be an option for those who cannot tolerate imatinib or when CML progresses on imatinib therapy.