Medical Policy: 02.04.62 

Original Effective Date: August 2016 

Reviewed: August 2017 

Revised: August 2017 

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

The Philadelphia chromosome (Ph), a derivative chromosome 22 resulting from a translocation between chromosomes 9 and 22 causing the BCR-ABL fusion, is present in approximately 95% of chronic myeloid leukemia (CML) and 25-30% of adult acute lymphoblastic leukemia (ALL) cases. In general, the ratio of the fusion to a reference control can be used for diagnosis, prognosis, and ongoing therapeutic monitoring.

 

BCR-ABL cytogenetic testing detects the presence of the 9;22 translocation and the BCR-ABL fusion gene within somatic cells. This test may also identify an additional copy of Ph in cells or an atypical 9/22 translocation. Cytogenetic testing is indicated as an initial evaluation for patients suspected to have chronic myeloid leukemia (CML) or adult acute lymphoblastic leukemia (ALL) and then for monitoring disease status.

Qualitative BCR-ABL testing is indicated as an initial evaluation for patients known to have a positive FISH cytogenetic test for BCR-ABL. The qualitative BCR-ABL test can determine the specific type (isoform) of the Philadelphia chromosome present which is important for appropriate diagnosis and treatment.

Patients with CML are treated with the drug Imatinib, or a second generation tyrosine kinase inhibitor, at diagnosis. The treatment is highly effective however it is essential that any relapse in the disease is identified as soon as possible to ensure the best clinical outcome for the patient. As such the expression level of the fusion gene is monitored in patients over time.

For CML, inadequate initial response to tyrosine kinase inhibitors (TKIs) is defined as failure to achieve complete hematologic response at 3 months, only minor cytologic response at 6 months, or major (rather than complete) cytogenetic response at 12 months.

Unlike in CML, ALL resistance to TKIs is less well studied. In patients with ALL receiving a TKI, a rise in the BCR-ABL mRNA level while in hematologic complete response or clinical relapse warrants mutational analysis.

Loss of response to TKIs is defined as hematologic relapse, cytogenetic relapse, or 1-log increase in BCR-ABL1 transcript ratio and therefore loss of major molecular response.

The ELN (European LeukemiaNet), European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN) provide recommendations about when BCR-ABL1 KD mutation analysis should be performed in patients treated with TKIs. According to the ELN and the ESMO recommendations, mutation analysis is recommended at diagnosis only in AP-/BP-CML patients, before starting first-line therapy. However, in the absence of prospective studies based on mutation screening up front and the low rate of mutation detection, it is questionable whether this is sensible or cost-effective. The NCCN recommends mutation analysis in TKI-pretreated AP-/BP-CML patients

The ELN and the ESMO recommendations differentiate between first-line and second-line treatment, while the NCCN guidelines do not differentiate across lines of treatment. According to the ELN and the ESMO recommendations, BCR-ABL1 KD mutation analysis should be performed during second-line treatment in case of hematologic or cytogenetic failure, whereas based on the NCCN guidelines, mutation analysis should also be performed in case of loss of response, inadequate response, or increased BCR-ABL1 transcript levels.

Summary of recommendations for BCR-ABL1 mutation analysis.
blank cell At diagnosis During first-line therapy with imatinibDuring second-line therapy with dasatinib or nilotinib
ELN and ESMO recommendations Only in patients with AP-/BP-CML
  • In case of failure
  • In case of an increase in BCR-ABLI transcript levels leading to a loss of MMR
  • In case of suboptimal response
  • Before changing to other TKIs or other therapies

In case of hematologic or cytogenetic failure, including:

  • No CyR at 3 months
  • Minimal CyR at 6 months
  • Less than PCyR at 12 months.
  • Before changing to other TKIs or other therapies
NCCN recommendations In case of disease progression to AP or BP In patients with CP-CML who have inadequate initial response, defined as failure of achieving PCyR or BCR-ABL1/ABL1 ≤10% (on the international scale) at 3 months or CCyR at 12 and 18 months In patients with CP-CML at any sign of loss of response, defined as hematologic or cytogenetic relapse or 1-log increase in BCR-ABL1 transcript level and loss of MMR

ELN, European LeukemiaNet; ESMO, European Society for Medical Oncology; AP, accelerated phase; BP, blast phase; CML, chronic myeloid leukemia; MMR, major molecular response; CyR, cytogenetic response; PCyR, partial cytogenetic response; CP, chronic phase; NCCN, National Comprehensive Cancer Network; CCyR, complete cytogenetic response.

 

National Cancer Institute (NCI): Regarding BCR-ABL mutation analysis in individuals with chronic myelogenous leukemia (CML), the NCI notes “In case of treatment failure or suboptimal response, patients should undergo BCR/ABL kinase domain mutation analysis to help guide therapy with the newer tyrosine kinase inhibitors or with allogeneic transplantation (2016)


The National Comprehensive Cancer Network (NCCN, 2017) recommends bone marrow cytogenetics to confirm a diagnosis of CML. If bone marrow is not available, FISH on a peripheral blood specimen using probes for both BCR and ABL can confirm the diagnosis.  NCCN recommends BCR-ABL transcript levels be obtained by quantitative RT-PCR:

  • At diagnosis.
  • Every three months after initiating treatment. After a patient reaches complete cytogenetic response, every 3 months for two years and every 3-6 months thereafter.
  • If a patient has a rising level of BCR-ABL transcripts (1 log increase), repeat testing in 1 – 3 months.

These recommendations are category 2A: "based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate."

 

Prior Approval:

Not applicable

 

Policy:

BCR/ABL1 qualitative testing for the presence of the fusion gene may be considered medically necessary for diagnosis of chronic myeloid leukemia, lymphoblastic lymphoma, acute myeloid leukemia, acute lymphocytic leukemia.

BCR/ABL1 testing at baseline prior to initiation of treatment and at appropriate intervals during therapy may be considered medically necessary for monitoring treatment response and remission.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • 81206  BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis; major breakpoint, qualitative or quantitative
  • 81207  BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis; minor breakpoint, qualitative or quantitative
  • 81208  BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis; other breakpoint, qualitative or quantitative
  • 0016U Oncology (hematolymphoid neoplasia), RNA, BCR/ABL1 major and minor breakpoint fusion transcripts, quantitative PCR amplification, blood or bone marrow, report of fusion not detected or detected with quantitation
  • 0040U BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis, major breakpoint, quantitative

 

Selected References:

  • A. Hochhaus. Chronic myelogenous leukemia (CML): resistance to tyrosine kinase inhibitors. Ann Oncol, 17 (Suppl. 10) (2006), pp. x274–x279.
  • H. Kantarjian, N.P. Shah, A. Hochhaus, J. Cortes, S. Shah, M. Ayala, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med, 362 (2010), pp. 2260–2270
  • NCCN Clinical Practice Guidelines in Oncology. NCCN Acute Lymphoblastic Leukemia (V.1.2016). Revised April 6, 2016.
  • S. Soverini, A. Hochhaus, F.E. Nicolini, F. Gruber, T. Lange, G. Saglio, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood, 118 (2011), pp. 1208–1215
  • M. Baccarani, S. Pileri, J.L. Steegmann, M. Muller, S. Soverini, M. Dreyling  Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol, 23 (Suppl. 7) (2012), pp. vii72–vii77.
  • S. Soverini, S. Branford, F. Nicolini, et al. Implications of BCR-ABL1 kinase domain mediated resistance in chronic myeloid leukemia. Leuk Research 38(1) 10-20.
  • Elias MH, Baba AA, Azlan H, et al. BCR-ABL kinase domain mutations, including 2 novel mutations in imatinib resistant Malaysian chronic myeloid leukemia patients-Frequency and clinical outcome. Leuk Res. 2014; 38(4):454-459.
  • Hughes T, Branford S. Molecular monitoring of BCR-ABL as a guide to clinical management in chronic myeloid leukaemia. Blood Rev 2006; 20(1):29-41.
  • Maino E, Sancetta R, Viero P,. Current and future management of Ph/BCR-ABL positive ALL. Expert Rev Anticancer Ther. 2014; 14(6):723-740.
  • Radich JP. Measuring response to BCR-ABL inhibitors in chronic myeloid leukemia Cancer 2012; 118(2):300-11.
  • American Cancer Society. Chronic Myeloid (CML). 2014.
  • Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012a; 367(22):2075-2088
  • Agency for Healthcare Research and Quality. Systematic reviews on selected pharmacogenetic tests for cancer treatment: CYP2D6 for Tamoxifen in breast cancer, KRAS for anti-EGFR antibodies in colorectal cancer, and BCR-ABL1 for tyrosine kinase inhibitors in chronic myeloid leukemia. Technology Assessment Report 2010 June. Project ID: GEN0609. .
  • Baccarani M, Deininger MW, Rosti G, et al: European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013;122:872-884
  • Jones D, Kamel-Reid S, Bahler D, et al: Laboratory practice guidelines for detecting and reporting BCR-ABL drug resistance mutations in chronic myelogenous leukemia and acute lymphoblastic leukemia A Report of the Association for Molecular Pathology. J Mol Diagn 2009;11:4-11
  • Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G, Pane F, Muller MC, Ernst T, Rosti G, Porkka K, Baccarani M, Cross NC, Martinelli G (2011) BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood 118: 1208–1215.
  • Association for Clinical Genetic Science (ACGS). Professional guidelines for clinical cytogenetics.  Published July 2011.

  • National Comprehensive Cancer Network (NCCN) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidlines®), Chronic Myeloid Leukemia, Version 1.2018

  • National Comprehensive Cancer Network (NCCN) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidlines®), Acute Lymphoblastic Leukemia, Version 1.2017

  • National Comprehensive Cancer Network (NCCN) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidlines®), Acute Lymphoblastic Leukemia, Version 3.2017

  • Baccarani M, Deininger MW, Rosti G, et al. European LeukemiaNet recommendations for the
    management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872-84.

  • Radich JP. Monitoring response to tyrosine kinase inhibitor therapy, mutational analysis, and new treatment options in chronic myelogenous leukemia. J Natl Compr Canc Netw. 2013;11(5 Suppl):663-6.

 

Policy History:

  • August 2017 - Annual Review, Policy Revised
  • August 2016 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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