ABSTRACT: The development of imatinib mesylate (Gleevec), a tyrosine kinase inhibitor targeted against the causative Bcr-Abl protein in chronic myeloid leukemia (CML), has resulted in hematologic and cytogenetic remissions in all phases of CML. Following imatinib treatment, more than 90% of patients obtain complete hematologic response, and 70% to 80% achieve a complete cytogenetic response. With 5 years of follow-up, the data are very encouraging, exhibiting a major change in the natural history of the disease. The understanding of at least some of the mechanisms of resistance to imatinib has led to a rapid development of new agents that may overcome this resistance. Combination strategies are currently being investigated in preliminary clinical studies and may prove to be useful. Overall, there are an increasing number of treatment options now available for patients with CML.

Chronic myeloid leukemia (CML) is a rare disease. Although its incidence is low, its prevalence is increasing. In the United States, there are approximately 4,500 new cases of CML per year.[1] The annual incidence of CML is 1.6 cases per 100,000 adults.[1] The median age at diagnosis is 55 years. With an estimated survival rate of 90% at 5 years and an annual mortality rate of 2%, the prevalence of CML in 20 years may become 200,000 to 300,000 cases in the United States. CML is characterized by a balanced genetic translocation, involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) on chromosome 22q11.2, t(9;22)(q34;q11.2), the Philadelphia chromosome (Ph). The molecular consequence of this translocation is the generation of a BCR-ABL fusion oncogene, which in turn translates into a Bcr-Abl oncoprotein. This most frequently has a molecular weight of 210 kD (p210^Bcr/Abl) and has increased tyrosine kinase activity, which is essential to its transforming capability.[2,3]

FIGURE 1

Pathways Activated by Bcr-Abl

Numerous signal transduction pathways, including Ras/Raf/mitogen activated protein kinase (MAPK), phosphatidylinositol 3 kinase, STAT5/Janus kinase, and Myc, are activated by the Bcr-Abl tyrosine kinase (Figure 1).[4,5] Perturbation of these pathways results in uncontrolled cell proliferation and reduced apoptosis. Understanding the CML pathophysiology resulted in the development of novel drugs targeting Bcr-Abl tyrosine kinase and its associated pathways.

The treatment of CML has evolved greatly over the past few years. Imatinib mesylate is now well established as the standard therapy. For many years, stem cell transplantation (SCT) and interferon-alpha were the major therapeutic choices. Long-term survival and possibly cure could be achieved with both of these modalities.[6,7] While SCT is still a valid treatment option for some patients, interferon-alpha has been replaced in CML front-line therapy by imatinib.

Imatinib mesylate is a potent and selective tyrosine kinase inhibitor that has become standard therapy for patients with any stage of CML.[3] A complete cytogenetic response can be achieved in 50% to 60% of patients treated in chronic phase after failure to respond to interferon-alpha[8,9] and in over 80% of those receiving imatinib as first-line therapy.[10,11] Responses are durable in most patients treated in early chronic phase, particularly among those who achieve major molecular responses (eg, ≥ 3-log reduction in transcript levels).[12,13]

Here we will review the current information regarding treatment of patients with newly diagnosed chronic phase CML, issues of imatinib dose schedules, imatinib toxicity and management of adverse events, monitoring of minimal residual disease, and the place of the new tyrosine kinase inhibitors in the front-line therapy arsenal of patients with newly diagnosed CML in chronic phase.

Imatinib: Front-Line Standard of Care in CML

Imatinib is an orally bioavailable 2-phenylaminopyrimidine with targeted inhibitory activity against the constitutively active tyrosine kinase of the Bcr-Abl chimeric fusion protein. Imatinib inhibits other kinases, such as c-kit, platelet-derived growth factor receptor (PDGFR)-alpha and -beta, and Abl-related gene.[14,15] Imatinib has become the standard therapy for CML because of its remarkable activity and mild toxicity profile.

Preclinical studies established that imatinib potently inhibits ABL and the related protein-tyrosine kinase ARG as well as the kinase activity of members of the class III family of receptor tyrosine kinases including KIT, PDGFRs and the macrophage colony-stimulating factor receptor CSF-1R (cFMS).[16-20] Inhibition of BCR-ABL protein-tyrosine kinase activity with imatinib blocks intracellular oncogenic signal transduction pathways.[3,21]

IRIS Trial

The efficacy of imatinib was demonstrated in the phase III International Randomized Study of Interferon and STI571 (IRIS) trial, in which treatment with imatinib at 400 mg daily was compared with combined interferon-alpha/cytarabine in patients with newly diagnosed chronic phase CML (N = 1,106).[22] After a median follow-up of 19 months, imatinib was found to be significantly better than interferon-alpha-based treatment, as shown by rates of complete hematologic response (95% vs 56% of patients; P < .001) and major cytogenetic response (≤ 35% Ph-positive cells in metaphase; 85% vs 22% of patients; P < .001). Major molecular response rates (at 12 months, 40% vs 2%) and progression-free survival were also superior with imatinib.[13,22] Adverse events reported in the imatinib group were generally mild to moderate, and included superficial edema, nausea, muscle cramps, and rashes, and grade 3/4 events were uncommon except for neutropenia (14%) and thrombocytopenia (8%).[22] Adverse event rates of all types were higher in the combination-therapy group.

TABLE 1

Best Responses in Patients Remaining on First-Line Imatinib Therapy: 5-yr Update of the Phase III IRIS Trial

A 5-year update of the IRIS study continued to show positive results (Table 1).[23] A total of 382 patients remained on imatinib front-line therapy. The cumulative best complete hematologic response, major cytogenetic response, and complete cytogenetic response rates were 98%, 92%, and 87%, respectively. The estimated 5-year event-free survival was 83%; only 6.3% of patients progressed to accelerated and blastic phases. The overall annual progression rate has declined to 0.9% in the fifth year of therapy, compared with 1.5%, 4.8%, and 7.5% in the previous 3 years, suggesting that disease progression may be diminished in the following years. The estimated 5-year survival rate was 89%; excluding non-CML deaths, it was 95%. The intensity of the cytogenetic response after 12 and 18 months of imatinib therapy has important implications regarding survival without transformation. The estimated 5-year survival rate in patients not achieving a major cytogenetic response at 12 months was significantly lower (81%) than those who achieved major cytogenetic response (complete, 97%; partial, 93%; P < .001).

FIGURE 2

Survival of Chronic Myeloid Leukemia

At 18 months of therapy, the estimated 5-year survival rate for patients not achieving a complete cytogenetic response was significantly less than for those who achieved a complete cytogenetic response (99% vs 90%; P < .001).[23] The investigators found a continuous improvement in the rate of major molecular response, which rose from 53% at 1 year to 80% at 4 years of therapy (P < .001).[23] This study did not document a survival advantage for imatinib because of the crossover design. Studies comparing the survival of imatinib-treated patients with historical cohorts treated with interferon-alpha-based therapy demonstrated the anticipated survival advantage.[9,24,25] Figure 2 shows the survival of patients treated at M. D. Anderson Cancer Center since 1965 by year of therapy.

Safety Data

Most adverse events with imatinib therapy were mild to moderate in severity. Treatment was discontinued for adverse events in 3.1% of newly diagnosed patients, in 4% of patients in chronic phase after failure of interferon therapy, and in 4% to 5% of patients in accelerated-blastic phase.[10,26-28] The most frequently reported adverse events (all grades) were superficial edema (59%-76%), nausea (47%-73%), muscle cramps (28%-62%), vomiting (21%-58%), diarrhea (39%-57%), musculoskeletal pain (40%-49%), and rash (37%-47%). Severe adverse experiences (grade 3/4) included severe fluid retention (eg, pleural effusion, pulmonary edema, and ascites) in 1% to 6%, superficial edema in 1% to 6%, hemorrhage in 1% to 19%, and musculoskeletal pain in 2% to 9%. Severe fluid retention appeared to be dose-related and was more common in the advanced-phase studies with imatinib dosages of 600 mg/d, and in the elderly.

Grade 3/4 laboratory abnormalities included neutropenia (3%-48%), anemia (< 1%-42%), thrombocytopenia (< 1%-42%), and hepatotoxicity (3%-6%). Treatment was discontinued permanently because of liver function abnormalities in less than 0.5% of patients.

Recently, imatinib was reported to be associated with cardiotoxicity and congestive heart failure, although this toxicity is rare.[29] Among 1,276 patients treated at one institution, 22 patients (1.8%), with a median age of 70 years, were identified as having symptoms that could be attributed to congestive heart failure.[30] At the time these events were reported, 8 were considered possibly or probably related to imatinib. Eighteen patients had previous medical conditions predisposing to cardiac disease: congestive heart failure (6 patients, 27%), diabetes mellitus (6 patients, 27%), hypertension (10 patients, 45%), coronary artery disease (8 patients, 36%), arrhythmia (3 patients, 14%) and cardiomyopathy (1 patient, 5%). Of the 22 patients, 11 continued imatinib therapy with dose adjustments and management for congestive heart failure symptoms with no further complications.