Molecular Monitoring of BCR-ABL Transcripts—Standardization Needed to Properly Use, and Further Investigate the Value of, a Critical Surrogate Marker for Success in Therapy of Chronic Myeloid Leukemia

Francis J Giles
US Oncology & Hematology, 2011;7(2):138-42
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Abstract

Targeted inhibition of the oncogenic function of the constitutively active BCR-ABL kinase with tyrosine kinase inhibitors is a highly effective and now standard therapeutic approach for patients with chronic myeloid leukemia. The early evaluation of response during the course of therapy is important for determining whether therapy is progressing according to expectations that correlate with optimal outcome. Therefore, frequent disease monitoring to assess treatment and to detect failure or suboptimal response is recommended. Current monitoring strategies incorporate hematological, cytogenetic, and molecular analysis, the latter involving the quantification of BCR-ABL transcripts in the blood. Molecular monitoring has been shown to be the most sensitive method available and has shown prognostic impact with regard to progression-free survival, but the use of diverse methods to quantify BCR-ABL levels has made it difficult to compare results between (and sometimes within) laboratories, with resulting implications for patient care. This article discusses the current approaches and challenges to BCR-ABL monitoring, summarizes some of the international efforts under way to standardize BCR-ABL analysis, and suggests potential alternative approaches to facilitating reproducible BCR-ABL monitoring results, such as a standardized US Food and Drug Administration-approved BCR-ABL testing kit.
Keywords
Chronic myeloid leukemia, Philadelphia chromosome, BCR-ABL, imatinib mesylate, nilotinib, dasatinib, cytogenetic response, molecular response, realtime quantitative polymerase chain reaction
Disclosure The author has received research funding from Novartis.
Received: April 12, 2011 Accepted May 31, 2011
Correspondence: Francis J Giles, MB, MD, FRCPI, FRCPath, Director, HRB Clinical Research Facility Galway, National University of Ireland, Galway, Geata an Eolais, University Road, Galway, Ireland. E: frankgiles@aol.com

Chronic myeloid leukemia (CML) is a progressive and potentially fatal myeloproliferative disorder with over 5,000 new cases in the US each year, accounting for approximately 20 % of all leukemias diagnosed in adults.1 The natural history of CML consists of three distinct stages: chronic, accelerated, and blast phase.2 Most patients (90 %) are diagnosed in the chronic phase, a relatively slowly progressing stage that is primarily asymptomatic.3 However, unless the disease is controlled or eliminated, patients eventually progress to an intermediate accelerated phase characterized by poor control of white blood cell counts and increasing numbers of immature blasts in the peripheral blood. After one to two years, the disease transitions into the terminal blast phase,4 which resembles acute leukemia, leading to metastasis, organ failure, and death.2 The disease is characterized by the expansion of a clone of hematopoietic cells that carries the Philadelphia (Ph) chromosome. The Ph chromosome results from a balanced translocation between chromosomes 9 and 22,2 the molecular consequence of which is the constitutive overexpression of a novel fusion gene, BCR-ABL. The BCR-ABL fusion protein contains a constitutively active tyrosine kinase region that deregulates cell growth, motility, angiogenesis, and apoptosis, leading to the development of leukemia.3

Targeted inhibition of the oncogenic function of this constitutively active kinase is a highly effective and now standard therapeutic approach for patients with CML. Standard front-line therapy for CML patients is imatinib mesylate (Gleevec®, Novartis Pharmaceuticals, Basel, Switzerland), the first tyrosine kinase inhibitor (TKI) to be approved by the US Food and Drug Administration (FDA) for the treatment of CML.5 The rates of complete cytogenetic response among patients receiving imatinib were 68 % at 12 months and 87 % at 60 months.6,7 The estimated overall survival of patients who received imatinib as initial therapy was 89 % at 60 months, in marked contrast to survival rates prior to imatinib availability.7 However, patients with CML can exhibit varying responses to first-line treatment with imatinib owing to primary (intrinsic) or secondary (acquired) resistance and these patients have a higher risk of disease progression.8 The currently approved secondgeneration tyrosine kinase inhibitors (TKIs), nilotinib (Tasigna®, Novartis Pharmaceuticals, Basel, Switzerland) and dasatinib (Sprycel®, Bristol- Myers Squibb, New York, USA), are effective for the treatment of patients with imatinib-resistant and imatinib-intolerant disease and are also indicated as first-line treatments for CML in the US.9–12 The early evaluation of response during the course of therapy is important for ascertaining whether therapy is progressing according to expectations that correlate with optimal outcome. Therefore, frequent disease monitoring to assess treatment and to detect failure or suboptimal response is recommended and is one of the key management strategies of CML.13–15

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Molecular Monitoring of BCR-ABL Transcripts—Standardization Needed to Properly Use, and Further Investigate the Value of, a Critical Surrogate Marker for Success in Therapy of Chronic Myeloid Leukemia

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