Second‐generation tyrosine kinase inhibitors in chronic myelogenous leukemia

Chronic-phase (CP) chronic myelogenous leukemia (CML) once was a terminal cancer with a median survival of about 20 months if left untreated. The use of nonspecific cytoreductive agents, such as hydroxyurea or busulfan, was associated temporally with an improved median survival of approximately 4 years, but the 8-year survival rate remained <15%. Allogenic stem cell transplantation (allo-SCT) was the first treatment modality in CP-CML that was capable of inducing cytogenetic and molecular remissions and resulted in superior long-term, leukemia-free survival in approximately 50% of patients. Consequently, for a time, allo-SCT was considered the first-line treatment of choice for patients with CP-CML despite its association with a >50% incidence of transplantation-related mortality or morbidity from chronic graft-versus-host disease. In the early 1980s, it was demonstrated that interferon-a (IFN-a) induced complete cytogenetic remission (CCyR) or partial cytogenetic remission (PCyR) in approximately 20% of patients with CP-CML, and the 10-year survival rate in such patients was >50% versus <30% for all patients who received IFN-a. The long-term disease progression rate in patients who achieved an IFN-a–induced CCyR was <15%. Therefore, some investigators appropriately argued at the time that patients with CP-CML could undergo a treatment trial with IFN-a first and could consider transplantation only if they failed to achieve CCyR. Such an approach enabled some patients to bypass the ill effects of allo-SCT without compromising its value as salvage therapy. Today, imatinib has replaced both allo-SCT and IFN-a as first-line treatment for CP-CML. Imatinib is a firstgeneration tyrosine kinase inhibitor (TKI) of c-abl oncogene 1 receptor tyrosine kinase (ABL1), arginase (ARG), plateletderived growth factor receptor (PDGFR), and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT). Imatinib targets the adenine triphosphate (ATP) binding site within the breakpoint cluster region (BCR)-ABL1 fusion protein, which is the disease-causing mutant kinase in CML, and disrupts oncogenic signal by forcing an enzymatically inactive conformation. In 2003, results from the International Randomized Study of Interferon Versus STI571 (IRIS) trial were reported; 1106 patients with CP-CML were randomized to receive either imatinib or IFN-a plus cytarabine. At a median follow-up of 19 months, treatment with imatinib was superior in terms of both the CCyR rate (76.2% vs 14.5%) and the progression-free survival (PFS) rate (96.7% vs 91.5%). Those results led to the December 2002 US Food and Drug Administration approval of imatinib for first-line treatment of adult patients with BCR-ABL1– positive CP-CML; the drug previously had received approval for the treatment of advanced-phase CML (AP-CML) or IFN-a–refractory CP-CML inMay, 2001. The 6-year follow-up of patients who were randomized to the imatinib arm (n 1⁄4 553) of the IRIS study was published in 2009. The overall survival rate at 6 years was 88%, and the PFS and event-free survival (EFS) rates were 93% and 83%, respectively. In patients who achieved CCyR or PCyR at 6 months of therapy, the PFS rate was 97% or 94%, respectively. The annual rates of progression to AP-CML in the first 6 years were 1.5%, 2.8%, 1.6%, 0.9%, 0.5%, and 0%, respectively. Approximately 83% of patients achieved CCyR at some point during their treatment; of these, only