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BCR-ABL Testing for Monitoring of Individuals with Chronic Myelogenous Leukemia or Acute Myelogenous Leukemia, who are Receiving Imatinib Mesylate (Gleevec®) Therapy
Pharmacogenetic Testing to Determine Drug Sensitivity (Independence Administrators)
Title: BCR-ABL Testing for Monitoring of Individuals with Chronic Myelogenous Leukemia or Acute Myelogenous Leukemia, who are Receiving Imatinib Mesylate (Gleevec
BCR-ABL1 variants are the focus of study investigating their dynamics and relationship to chronic myelogenous leukemia (CML) disease phenotype, progression, development of imatinib resistance, and response to targeted therapy with second-generation (SG) tyrosine kinase inhibitors (TKIs). The current body of peer-reviewed research exploring these relationships consists of animal studies, basic research studies, review articles, and cohort studies, including phase I/II/III clinical trials. The focus of this analysis is on the relationship between BCR-ABL1 variants and imatinib resistance, as well as response to second-generation tyrosine kinase inhibitor (TKI) (SGI) therapy in individuals with CML.
None of the retrieved studies thoroughly evaluated commercially available testing methods for BCR-ABL1 variants. An early study by Branford and colleagues reported that direct sequencing was capable of detecting variants at 20% dilution ratio (Branford et al., 2003). While other experimental methodologies may detect variants when they are present at lower frequencies in affected cells, the clinical significance of low concentrations of BCR-ABL1 variant cells is not clear, and many researchers consider sequencing to be adequately sensitive (Branford et al., 2003; Hughes et al., 2006; Soverini et al., 2006; Jones et al., 2009; Ernst et al., 2011; Alikian et al., 2012). The same early study by Branford and colleagues provided information pertinent to the clinical validity of BCR-ABL1 testing, reporting that the presence of BCR-ABL1 variants was strongly associated with the development of imatinib resistance in a cohort of CML patients receiving imatinib therapy. This association was stronger in patients with more advanced disease (Branford et al., 2003). Studies describing the overall frequency of BCR-ABL1 variants in CML patients who had developed imatinib resistance had variable inclusion criteria and definitions of imatinib resistance. The most common methodologies used to test for BCR-ABL1 variants were PCR and direct sequencing. The reported frequencies across imatinib-resistant patient populations were 23.3% to 56.4% (Soverini et al., 2006; Hochhaus et al., 2007; Kantarjian et al., 2007; Jabbour et al., 2008a; Ernst et al., 2008c; Apperley et al., 2009; Jabbour et al., 2009; Schnittger et al., 2010; Bengió et al., 2011; Quintás-Cardama et al., 2011). In studies that described BCR-ABL1 variant frequencies according to CML phase, variants were generally more common in advanced disease phases (Soverini et al., 2006; Hochhaus et al., 2007; Kantarjian et al., 2007; Apperley et al., 2009; Bengió et al., 2011; Quintás-Cardama et al., 2011), although one study did report a comparatively reduced frequency in BC-CML patients (Quintás-Cardama et al., 2011). Compound variants were reported in 6.3% to 16.5% of patients with variants. Frequency of the BCR-ABL1 p.Thr315Ile variant ranged from 4.1% to 26.3% (Soverini et al., 2006; Hochhaus et al., 2007; Kantarjian et al., 2007; Jabbour et al., 2008a; Apperley et al., 2009; Jabbour et al., 2009; Schnittger et al., 2010; Bengió et al., 2011; Quintás-Cardama et al., 2011). All studies that investigated response to TKI therapy reported a lack of response to SGI therapy in p.Thr315Ile carriers (Hochhaus et al., 2007; Kantarjian et al., 2007; Jabbour et al., 2008a; Apperley et al., 2009; Jabbour et al., 2009).
The body of literature regarding BCR-ABL1 variants in CML suggests that the issues surrounding the use of BCR-ABL1 variant testing for guidance in clinical decision making following imatinib resistance are complex and multifaceted. The published evidence supports the use of testing for the p.Thr315Ile variant, as patients with p.Thr315Ile do not respond to imatinib, dasatinib, or nilotinib, and should be offered allogeneic stem cell transplantation, omacetaxine, or experimental treatments (Gibbons et al., 2012). Regarding other BCR-ABL1 variants, the evidence suggests that certain common variants confer less sensitivity to SGI. These include p.Phe317Leu and p.Val299Leu, which are less sensitive to dasatinib; and p.Tyr253His, p.Glu255Lys/p.Glu255Val, and p.Phe359Val/p.Phe359Cys, which are less sensitive to nilotinib (Hughes et al., 2009; Jabbour et al., 2009; Müller et al., 2009). There have been > 100 reported BCR-ABL1 variants to date; however, the clinical significance of most of these is unknown, complicating the interpretation of results of BCR-ABL1 variant testing (Jones et al., 2009). Larger studies investigating the clinical response to SGI after imatinib resistance with respect to BCR-ABL1 variant status are needed to definitively ascertain the effects certain variants have on treatment outcomes. It is important that these studies share consistent inclusion criteria, definitions of imatinib resistance, and testing methodologies, in order to robustly compare results (Jones et al., 2009). In addition to single BCR-ABL1 variants, compound variants frequently occur in imatinib-resistant patients, and their clinical significance is not entirely clear; their presence may indicate progressing disease and it is not clear how differing SGI sensitivities of co-occurring variants interact (Branford et al., 2009; Jones et al., 2009; Jabbour et al., 2011; Ernst and Hochhaus, 2012; Soverini et al., 2012).
In reviewing the studies included in this assessment, a number of limitations are noted. Inclusion criteria such as CML stage and prior treatment varied between studies, as did patient response criteria and definitions of imatinib resistance, intolerance, and/or failure. BCR-ABL1 variant detection methods also varied between studies, although PCR amplification followed by direct sequencing was the most common testing methodology. In addition, criteria used to define the sensitivity of BCR-ABL1 variants to TKIs vary from study to study; this considerably limits the current use of BCR-ABL1 variant status other than p.Thr315Ile in informing therapy following imatinib resistance.
Coverage is subject to the terms, conditions, and limitations of the member's contract
BCR-ABL testing for monitoring of individuals with chronic myelogenous leukemia or acute myelogenous leukemia, who are receiving imatinib mesylate (Gleevec®) therapy, is considered medically necessary and, therefore, covered.
The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.
The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.
Subject to the terms and conditions of the applicable benefit contract, BCR-ABL Testing for Monitoring of Individuals with Chronic Myelogenous Leukemia or Acute Myelogenous Leukemia, who are Receiving Imatinib Mesylate (Gleevec®) Therapy is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.
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