Chronic Myeloid Leukemia and BCR-ABL
Chronic myeloid leukemia (CML), also known as chronic myelogenous leukemia, is one of the few cancers that is known to caused by a single, specific genetic mutation in more than 90% of cases.
The transformation to CML is caused by a reciprocal translocation of the BCR gene on chromosome 22 (at 22q11) and the ABL gene on chromosome 9 (at 9q34), resulting in a fused BCR-ABL gene dubbed the “Philadelphia chromosome.” The protein that results from the fused genes promotes transition to the malignant state, increasing proliferation and decreasing apoptosis of the malignant cells (see Images 1 and 2).1,2
The disease is characterized by an overabundance of hematopoietic stem cells and progresses through three phases. In the chronic phase of disease, mature cells proliferate; in the accelerated phase, additional cytogenetic abnormalities occur; in the blast phase, immature cells rapidly proliferate.2 Approximately 85% of patients are diagnosed in chronic phase, and progress to accelerated and blast phases after three to five years.
Clinical Implications of the Genetic Mutation
The tyrosine kinase inhibitors (TKIs) imatinib (Gleevec), dasatinib (Sprycel), and nilotinib (Tasigna) inhibit activity of the BCR-ABL fusion protein, resulting in both hematologic response, ie, normal cell counts in the peripheral blood and normal bone marrow morphology, as well as cytogenetic response, ie, disappearance or reduction of the Philadelphia (Ph) chromosome.3,4,5,6,7,8
Imatinib was the first of the three TKIs to be evaluated in patients with CML. The drug was first evaluated in the second line, following interferon, in 532 patients, 454 of whom had confirmed chronic phase CML. At 18 months, 60% of patients had a major cytogenetic response (MCyR) and 41% had a complete cytogenetic response (CCyR), with no Ph-positive cells in metaphase seen in the bone marrow. Nearly all patients (95%) had a complete hematologic response (CHR).9 At 60 months, 67% had achieved MCyR and 57% had achieved CCyR.10 In the final analysis, at 72 months, the overall survival (OS) rate was 76% and the progression-free survival (PFS) rate was 61%.10
Following on these data, investigators moved imatinib to the first line. In a trial known as IRIS, 1106 patients with treatment-naïve, Ph-positive CML were randomized to imatinib or to interferon alfa + cytarabine. In patients enrolled in the imatinib arm, the CHR rate was 96% at 12 months and reached 98% at 60 months; the MCyR rate was 85% at 12 months and 92% at 60 months; and the CCyR rate was 69% at 12 months and 87% at 60 months. In the final analysis, the 60-month OS rate in the imatinib arm was 89%.3
Based on results from this trial, imatinib was approved as first-line therapy for patients with Ph-positive chronic phase CML.
Dasatinib was the second BCR-ABL TKI to be evaluated in patients with CML, and separate trials were conducted for patients in the three different phases of disease. In the chronic phase, the target population was imatinib failures, or patients who were resistant to or intolerant of imatinib. A total of 387 patients with chronic phase CML, 40% of whom had confirmed BCR-ABL mutations, were treated with dasatinib following imatinib therapy. Prior to imatinib failure, 37% had achieved MCyR and 19% had achieved CCyR. After 24 months of dasatinib therapy, 62% had achieved MCyR and 53% had achieved CCyR; 91% of patients achieved CHR. In the final analysis, the 24-month PFS rate was 80% and the OS rate was 94%.4
Smaller trials of dasatinib were conducted in patients with accelerated and blast phase CML who were resistant to or intolerant of imatinib. One hundred seven patients with accelerated phase CML were treated with dasatinib and followed for 8 months. At study end, 33% had achieved MCyR, 39% of patients achieved CHR, and the PFS rate was 76%.5 Similar results were seen in 116 patients in myeloid or lymphoid blast crisis: at 6 months, 31% and 50% of patients in myeloid and lymphoid blast crisis, respectively, had achieved MCyR, 86% of whom achieved CCyR in both groups.6
Dasatinib is approved for use in patients with Ph-positive chronic phase, accelerated phase, or blast phase CML who are resistant to or intolerant of imatinib.
Finally, nilotinib, the third BCR-ABL TKI, was tested in patients resistant to or intolerant of imatinib with chronic phase and accelerated phase CML. Of the 321 patients in chronic phase treated with nilotinib, 58% had achieved MCyR and 42% had achieved CCyR at 18 months. The PFS rate in the final analysis was 67% and the OS rate was 91%.8 In a far smaller trial of 18 patients in accelerated phase, 32% had achieved MCyR and 19% had achieved CCyR at 6 months; at 12 months, the PFS rate was 56% and the OS rate was 82%.7
Nilotinib is approved for use in patients with Ph-positive chronic phase or accelerated phase CML who are resistant to or intolerant of imatinib.
Given the strong evidence demonstrating benefit with BCR-ABL TKIs in patients with CML, NCCN Clinical Practice Guidelines recommends their use in patients with CML with confirmed BCR-ABL transcripts in bone marrow or evidence of translocation on cytogenetics. Treatment-naive patients with chronic phase CML should be started on imatinib, or dasatinib or nilotinib if resistant to or intolerant of imatinib. Patients in accelerated phase should be started on dasatanib or nilotinib, and patients in blast phase should be started on dasatinib.11
Testing for the Genetic Mutation
Two different methods are used to test for the BCR-ABL mutation. Cytogenetic studies of the BCR-ABL gene fusion use fluorescence in situ hybridization (FISH) and DNA probes for the ABL and BCR genes to quantify nonproliferating neoplastic cells with the BCR-ABL fusion. With this method, response to therapy is calculated based on the percentage of Ph-positive cells in metaphase in the bone marrow.
The second method quantifies BCR-ABL transcripts in the marrow. With this method, response to therapy is calculated based on the volume decrease in transcripts, measured in logs.