eMedicine Specialties > Genomic Medicine > Oncology
Chronic Myeloid Leukemia and BCR-ABL
Updated: Aug 26, 2009
Overview
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
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.
Open table in new window
Table
| Time Point | MCyR | CCyR | OS | |
| Second-Line | 18 months | 60% | 41% | |
| 60 months | 67% | 57% | 76% (72 mos) | |
| First-Line | 12 months | 85% | 69% | |
| 60 months | 92% | 87% | 89% |
| Time Point | MCyR | CCyR | OS | |
| Second-Line | 18 months | 60% | 41% | |
| 60 months | 67% | 57% | 76% (72 mos) | |
| First-Line | 12 months | 85% | 69% | |
| 60 months | 92% | 87% | 89% |
Dasatinib
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.
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Table
| Time Point | MCyR | CCyR | OS | |
| Chronic Phase | 24 months | 62% | 53% | 94% |
| Accelerated Phase | 8 months | 33% | ||
| Myeloid Blast Phase | 6 months | 31% | ||
| Lymphoid Blast Phase | 6 months | 50% |
| Time Point | MCyR | CCyR | OS | |
| Chronic Phase | 24 months | 62% | 53% | 94% |
| Accelerated Phase | 8 months | 33% | ||
| Myeloid Blast Phase | 6 months | 31% | ||
| Lymphoid Blast Phase | 6 months | 50% |
Nilotinib
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.
Open table in new window
Table
| Time Point | MCyR | CCyR | OS | |
| Chronic Phase | 18 months | 58% | 42% | 91% |
| Accelerated Phase | 6 months | 32% | 19% | 82% (12 mos) |
| Time Point | MCyR | CCyR | OS | |
| Chronic Phase | 18 months | 58% | 42% | 91% |
| Accelerated Phase | 6 months | 32% | 19% | 82% (12 mos) |
Recommendations
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
Importantly, if patients are BCR-ABL negative or Ph-negative, the diagnosis of CML should be reconsidered.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.
The following companies currently offer FISH and/or transcript quantification testing for BCR-ABL:
Asuragen (http://www.asuragen.com/)
Dako (http://www.dakousa.com/)
Invitrogen (http://www.invitrogen.com/)
Ipsogen (http://www.ipsogen.com)
Resources
More information about CML, BCR-ABL, and targeted treatments for Ph+ CML can be found in Medscape's CML Resource Center and the Cancer: Biologic Therapies Resource Center as well as in the eMedicine article on Chronic Myelogenous Leukemia.
Multimedia
 | Media file 1: The Philadelphia chromosome, which is a diagnostic karyotypic abnormality for CML, is shown in this picture of the banded chromosomes 9 and 22. Shown is the result of the reciprocal translocation of 22q to the lower arm of 9 and 9q (ABL) to a specific breakpoint cluster region (BCR) of chromosome 22 indicated by the arrows. Courtesy of Peter C. Nowell, MD, Department of Pathology and Clinical Laboratory of the University of Pennsylvania School of Medicine. |
 | Media file 2: Fluorescence in situ hybridization using unique-sequence, double-fusion DNA probes for BCR (22q11.2) in red and ABL (9q34) gene regions in green. The abnormal BCR-ABL fusion present in Philadelphia chromosome–positive cells is in yellow (right panel) compared with a control (left panel). Courtesy of Emmanuel C. Besa, MD. |
Keywords
Chronic myeloid leukemia, chronic myelogenous leukemia, CML, BCR, ABL, Philadelphia chromosome, translocation, imatinib, dasatanib, nilotinib
More on Chronic Myeloid Leukemia and BCR-ABL |
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References
Faderl S, Talpaz M, Estrov Z, O'Brien S, Kurzrock R, Kantarjian HM. The biology of chronic myeloid leukemia. N Engl J Med. Jul 15 1999;341(3):164-72. [Medline].
Sawyers CL. Chronic myeloid leukemia. N Engl J Med. Apr 29 1999;340(17):1330-40. [Medline].
Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. Dec 7 2006;355(23):2408-17. [Medline].
Mauro MJ, Baccarani M, Cervantes F, et al. Dasatinib 2-year efficacy in patients with chronic-phase chronic myelogenous leukemia (CML-CP) with resistance or intolerance to imatinib (START-C). Proc Am Soc Clin Oncol. 2008;26:Abs 7009.
Guilhot F, Apperley J, Kim DW, Bullorsky EO, Baccarani M, Roboz GJ, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood. May 15 2007;109(10):4143-50. [Medline].
Cortes J, Rousselot P, Kim DW, Ritchie E, Hamerschlak N, Coutre S. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. Apr 15 2007;109(8):3207-13. [Medline].
Le Coutre P, Giles FJ, Apperley J, et al. Nilotinib in accelerated phase chronic myelogenous leukemia (CML-AP) patients with imatinib-resistance or -intolerance: update of a phase II study. Proc Am Soc Clin Oncol. 2008;26:Abs 7050.
Kantarjian HM, Giles FJ, Hochhaus A, et al. Nilotinib in patients with imatinib-resistant or -intolerant chronic myelogenous leukemia in chronic phase (CML-CP): updated phase II results. Proc Am Soc Clin Oncol. 2008;26:Abs 7010.
Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. Feb 28 2002;346(9):645-52. [Medline].
Hochhaus A, Druker B, Sawyers C, Guilhot F, Schiffer CA, Cortes J. Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-alpha treatment. Blood. Feb 1 2008;111(3):1039-43. [Medline].
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology, Chronic Myelogenous Leukemia v1.2010. National Comprehensive Cancer Network. Available at http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf. Accessed July 28, 2009.
Further Reading
Keywords
Chronic myeloid leukemia, chronic myelogenous leukemia, CML, BCR, ABL, Philadelphia chromosome, translocation, imatinib, dasatanib, nilotinib
