Medical Policy

 

Subject: BCR-ABL Mutation Analysis
Document #: GENE.00005 Publish Date:    06/06/2018
Status: Reviewed Last Review Date:    05/03/2018

Description/Scope

This document addresses BCR-ABL mutation analysis.

Position Statement

Medically Necessary:

BCR-ABL kinase domain point mutation analysis is medically necessary in the evaluation of individuals with chronic myelogenous leukemia or BCR-ABL positive acute lymphoblastic leukemia to evaluate treated individuals who manifest suboptimal response to initial tyrosine kinase inhibitor therapy or loss of response to tyrosine kinase inhibitor therapy.

Investigational and Not Medically Necessary:

All other indications of BCR-ABL mutation analysis are considered investigational and not medically necessary in the management of chronic myelogenous leukemia and acute lymphoblastic leukemia when the above criteria are not met.

Rationale

BCR-ABL mutation analysis has been proposed as a diagnostic test to detect secondary mutations in the ABL portion of the BCR-ABL oncogene associated with chronic myelogenous leukemia (CML) and a cytogenetic subtype of acute lymphoblastic leukemia (Philadelphia chromosome positive [Ph+] ALL). Standard treatment of newly diagnosed Philadelphia chromosome positive (Ph+) CML is typically an agent from the class of drugs called protein tyrosine kinase inhibitors (TKIs). TKIs are also used in the management of ALL. Most individuals have a good response to this first-line of therapy. However, some individuals develop secondary (acquired) resistance to the first-line therapeutic agent, which may be due to secondary mutations of the BCR-ABL gene.

There is a commercially available BCR-ABL Mutation test (Genzyme Genetics, Westborough, MA) which is designed to detect the presence of BCR-ABL kinase domain mutations. The test is a molecular diagnostic procedure which uses polymerase chain reaction (PCR) amplification and gene sequencing of exons 18-21 of the tyrosine kinase domain of the BCR-ABL fusion gene. The test examines both peripheral blood and bone marrow specimens. Documentation from the manufacturer does not define which specific mutations are included in this test.

CML
Identification of BCR-ABL mutations as a source of protein TKI resistance may be a useful research tool in understanding the natural history of CML and its transition to more aggressive phenotypes for example, accelerated phase and blast crisis. Although certain BCR-ABL mutations may be associated with protein TKI resistance, the significance of many other mutations is unknown. In addition, the presence of a mutation does not invariably lead to protein TKI resistance (Khorashad, 2006; Willis, 2005).

Primary resistance to protein TKIs is defined as failure to obtain a complete hematologic response, and occurs in roughly 5% of individuals with newly diagnosed CML. While the mechanisms for primary resistance are poorly understood, it is felt to be independent of the BCR-ABL gene. Approximately 20% to 30% of individuals with CML fail to respond to imatinib or have disease relapse after an initial response (Jabbour, 2013). Secondary resistance is defined as loss of a previously established response. Acquired or secondary resistance to protein TKIs may be the result of gene amplification, where increased tyrosine kinase production occurs, or specific point mutations in the BCR-ABL gene. Increasing the dosage of protein TKIs can often overcome the resistance due to gene amplification. Resistance due to BCR-ABL gene mutation is more difficult to treat. BCR-ABL mutations may confer resistance by a variety of mechanisms, but commonly affect conformation of the protein TKI binding site on the tyrosine kinase phosphate binding loop (“P-loop”) or adenosine triphosphate (ATP) binding site such that protein TKI inactivation of tyrosine kinase is blocked. More than 40 different mutations have been associated with resistance to protein TKIs.

Desatinib, a second-generation TKI (ABCR-ABL) , has a 325-times higher potency than imatinib against unmutated BCR-ABL in vitro (O’Hare, 2005). Since imatinib failure is commonly caused by BCR-ABL mutations, Muller and colleagues (2009) analyzed data from three phase II/III clinical trials which studied the response to desatinib of individuals with chronic phase CML with or without BCR-ABL mutations after prior therapy with imatinib. Of 1043 individuals who underwent mutational assessment, 39% had a BCR-ABL mutation prior to dasatinib and 48% of 805 individuals with either imatinib resistance or a poor response to imatinib had a BCR-ABL gene mutation. A total of 63 different BCR-ABL mutations were detected, with G250, M351, M244, and F359 most frequently found. After 2 years of follow-up, desatinib treatment of imatinib-resistant individuals resulted in a complete cytogenetic response in 43% of individuals with a BCR-ABL mutation and 47% of those without mutation. Progression-free survival was 70% in individuals with BCR-ABL mutation and 80% in those without a mutation. The authors concluded that overall, dasatinib has a durable efficacy in individuals with or without BCR-ABL mutations.

Second-generation TKIs have been approved (desatinib/nilotinib) and shown to be effective against imatinib-resistant CML, with the exception of the BCR-ABL mutant T315-I. Soverini (2007) studied 45 individuals who were resistant or intolerant to imatinib and were treated with the second-generation TKI, dasatinib. With a median follow-up of 12 months, 21 individuals showed either primary or secondary resistance to dasatinib or loss of hematologic response during treatment. Eight individuals had primary resistance to dasatinib, and 13 individuals had secondary resistance to dasatinib. The T315-I mutation accounted for dasatinib treatment failure in 13 of the 21 cases confirming that the T315-I mutation is highly resistant to dasatinib. Additional studies have also confirmed that the mutant T315-I is resistant to TKIs currently available (Branford, 2009; Muller, 2009).

Cortes et al (2012a) reported on a phase I trial of 81 participants with resistant hematologic cancer that had either relapsed, were resistant to standard care or for which no standard care was available or acceptable and received daily ponatinib. Sixty-five of the total participants had CML. At the beginning of the study, 42 of the 65 participants with CML carried at least one BCR-ABL mutation; T315-I was the most frequent mutation (n=19). All participants received ponatinib daily. Twelve of the participants had chronic-phase CML and a T315-I mutation. Eleven out of 12 had a major cytogenetic response, 9 had a complete cytogenetic response, and 8 had a major molecular response. Of the 7 participants with advanced disease who had the T315-I mutation, 2 had a major hematologic response, 2 had a major cytogenetic response, and 2 had a major molecular response.

Cortes and colleagues (2012b) reported on a phase 2 prospective, single-arm, multicenter, open-label study of 62 participants with chronic-phase CML who harbored the T315-I mutation and who received omacetaxine mepesuccinate. Forty-eight participants achieved complete hematologic response and 14 participants achieved major cytogenetic response. All participants had received prior TKIs and 46 participants had failed therapy with at least two TKIs.

In a 2014 study by Elias and colleagues, 125 individuals with CML who were on imatinib therapy with either TKI refractory or resistance to imatinib were screened for the frequency and pattern of BCR-ABL kinase domain mutations. Mutations were detected in 28 individuals. There were 15 different types of mutations found, including 2 new ones. However, the T315-I mutation was the predominant mutation found. The monitoring of BCR-ABL in individuals with CML ensures that the appropriate selection of individuals for BCR-ABL1 kinase domain mutation analysis associated with acquired TKI resistance.

In 2010, the Agency for Healthcare Research and Quality (AHRQ) posted their Technology Assessment and concluded that:

The presence of any BCR-ABL1 mutation (that is when considering all mutations together) does not appear to predict differential response to tyrosine kinase inhibitor (TKI) treatments (defined as imatinib-, dasatinib-, and nilotinib-based regimens). There is consistent evidence that presence of the relatively rare T315I mutation can predict TKI treatment failure, mainly in terms of hematologic and cytogenetic response.

ALL
Philadelphia chromosome-positive ALL (Ph+ ALL) is a subtype of ALL. The incidence of Ph+ ALL increases to 20%-40% in adults. Resistance to one or more TKIs during treatment or resistance to induction therapy can lead to a poor prognosis. Individuals with Ph+ALL frequently relapse on imatinib with the acquisition of BCR-ABL kinase domain mutations. In 2014, Soverini and colleagues looked at laboratory data and analyzed the changes that second-generation TKIs brought in mutation frequency and type. Data were analyzed for 272 individuals. A total of 189 individuals were reported to be resistant to imatinib, 131 were found to be positive for the BCR-ABL kinase domain mutation. Ninety-eight individuals had developed resistance to secondary TKIs and 76 of those individuals were found to be positive for BCR-ABL kinase domain mutations. Of these 98 individuals, 93 were resistant to dasatinib as second-line therapy. Of the 93 who relapsed while on second-line dasatinib, 74 showed BCR-ABL kinase domain mutations. Of the mutations found, T315-I was the most frequent and accounted for 70% of the mutations.

For individuals with less than a complete response to induction or who have relapsed disease not participating in a clinical trial, the National Comprehensive Cancer Network® NCCN Clinical Practice Guidelines in Oncology for Acute Lymphoblastic Leukemia recommends treatment with multiagent chemotherapy combined with an alternative TKI (that is, different from the TKI used as part of induction therapy). The choice of TKI would be directed by BCR-ABL kinase domain mutations. NCCN adopted recommendations for treatment options based on ABL mutation status for CML developed by the European Leukemia Network. Based on these recommendations, dasatinib (if not used for induction) could be considered for individuals with relapsed/refractory Ph+ disease with mutations Y253H, E255K/V, or F359V/C/I. For individuals with relapsed/refractory disease with BCR-ABL mutations V299L, T315A, or F317L/V/I/C, nilotinib could be considered. Bosutinib has shown activity against several of the BCR-ABL mutations (E255K/V, F317L/V/I/C, F359V/C/I, T315A, Y253H), but not T315-I. More recently, additional TKI agents have been developed which have shown promising results in the management of those individuals with T315-I mutation. Ponatinib has been shown to be active against several of the BCR-ABL mutations in addition to T315-I (NCCN, 2018).

Background/Overview

 

Leukemia is a type of cancer that affects the blood and bone marrow. The disease occurs when blood cells produced in the bone marrow grow out of control. There are several types of leukemias. CML is a condition in which the bone marrow makes too many myeloid cells. These blood cells are abnormal and can build up in the blood and bone marrow so there is less room for the healthy white blood cells. CML is a relatively uncommon disease, primarily affecting older adults at an average age of 64 years. ALL is a disease characterized by the production of immature lymphoid cells in the bone marrow and blood. ALL progresses rapidly without treatment. According to the American Cancer Society (2018), approximately 8430 new cases of CML and approximately 5960 new cases of ALL will be diagnosed in 2018. The risk of developing ALL is highest in children under the age of 5. Overall, about one third of ALL cases are in adults.

 

Prior to the availability of protein TKIs, the only curative option for CML was high-dose chemotherapy with allogeneic stem cell support. Protein TKIs are typically utilized in the treatment of CML. The standard of care for ALL has been hematopoietic stem cell transplantation (HSCT), but with the emergence of BCR-ABL-targeted TKIs, the role of HSCT has become less clear. Several drugs in the protein TKI class have now been approved by the United States Food and Drug Administration for the treatment of CML and ALL.

 

The protein TKIs act to bind the inactive forms of the ABL kinase and function as a competitive inhibitor at the ATP binding site (P-loop) of the BCR-ABL protein. The primary effect is to block the auto-phosphorylation of the kinase, a requirement for kinase activation and signal transduction. The bound BCR-ABL tyrosine kinase is acted upon by phosphatases and remains in an enzymatically inert state. Clinical trials are in progress to research the use of additional medications in conjunction with other treatments such as chemotherapy and stem-cell transplants.

 

This document addresses gene mutation testing and does not involve gene translocation analysis, such as GenoTRACE® assay.

 

Definitions

 

Apoptosis: A series of molecular steps resulting in a type of cell death. A normal way for the body to get rid of unneeded or abnormal cells. A form of programmed cell death.

 

First-line of therapy: The first or primary treatment for the diagnosis, may include surgery, chemotherapy, radiation therapy or a combination of these therapies.

 

Leukemia: A type of cancer that affects the blood and bone marrow.

 

Mutation: A permanent transmissible change in DNA sequence. It can be an insertion or deletion of genetic information, or an alteration in the original genetic information.

 

Oncogene: A gene having the potential to cause a normal cell to become cancerous.

 

Translocation: The transfer of part of a chromosome (gene fragment) from one chromosomal location to another.

 

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

CPT

 

81170

ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) (eg, acquired imatinib tyrosine kinase inhibitor resistance), gene analysis, variants in the kinase domain

81401

Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat)
[when specified as the following]:

  • ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) (eg, acquired imatinib resistance), T315I variant

 

 

ICD-10 Diagnosis

 

C91.00-C91.02

Acute lymphoblastic leukemia [ALL]

C92.10-C92.12

Chronic myeloid leukemia, BCR/ABL-positive

C92.20-C92.22

Atypical chronic myeloid leukemia, BCR/ABL-negative

C92.Z0-C92.Z2

Other myeloid leukemia

C92.90-C92.92

Myeloid leukemia, unspecified

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Note:  CPT codes for BCR/ABL translocation analysis are not addressed in this document and are not included.

References

Peer Reviewed Publications:

  1. Branford S, Melo JV, Hughes TP. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood. 2009; 114(27):5426-5435.
  2. Cortes J, Lipton JH, Rea D, et al. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation. Blood. 2012(b) ;120(13):2573-2580.
  3. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012a; 367(22):2075-2088.
  4. 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.
  5. Fielding AK, Zakout GA. Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Curr Hematol Malig Rep. 2013; 8(2):98-108.
  6. Jabbour E, Kantarjian H, Jones D, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia. 2006; 20(10):1767-1773.
  7. Jabbour EJ, Cortes JE, Kantarjian HM. Resistance to tyrosine kinase inhibition therapy for chronic myelogenous leukemia: a clinical perspective and emerging treatment options. Clin Lymphoma Myeloma Leuk. 2013; 13(5):515-529.
  8. Khorashad JS, Anand M, Marin D, et al. The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib. Leukemia. 2006; 20(4):658-663.
  9. Kolibaba KS. Molecular monitoring of response in patients with chronic myeloid leukemia. Manag Care. 2013; 22(7):40, 50-61.
  10. 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.
  11. Marin D, Milojkovic D, Olavarria E, et al. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood. 2008; 112(12):4437-4444.
  12. Müller MC, Cortes JE, Kim DW, et al. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. Blood. 2009; 114(24):4944-4953.
  13. O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res.2005; 65(11)4500-4505.
  14. Soverini S, Colarossi S, Gnani A, et al. Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selection of mutations at residues 315 and 317 in the BCR-ABL kinase domain. Haematologica. 2007; 92(3):401-404.
  15. Soverini S, De Benedittis C, Papayannidis C, et al. Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era: The main changes are in the type of mutations, but not in the frequency of mutation involvement. Cancer. 2014; 120(7):1002-1009.
  16. Soverini S, Hochhaus A, Nicolini FE, 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. 2011 Aug; 118(5):1208-1215.
  17. Willis SG, Lange T, Demehri S, et al. High-sensitivity detection of BCR-ABL kinase domain mutations in imatinib-naïve patients: correlation with clonal cytogenetic evolution but not response to therapy. Blood. 2005; 106(6):2128-2137.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Cancer Society. Acute Lymphocytic Leukemia (ALL). 2018. Available at: http://www.cancer.org/cancer/leukemia-acutelymphocyticallinadults/index. Accessed on April 09, 2018.
  2. American Cancer Society. Chronic Myeloid (CML). 2018. Available at: https://www.cancer.org/cancer/chronic-myeloid-leukemia.html. Accessed on April 09, 2018.
  3. Baccarani M, Castagnetti F, Gugliotta G, Rosti G. A review of the European LeukemiaNet recommendations for the management of CML. Ann Hematol. 2015; 94(Supplement 2):141-147.
  4. National Cancer Institute. Acute Lymphoblastic Leukemia. Available at: http://www.cancer.gov/cancertopics/types/leukemia. Accessed on April 09, 2018.
  5. National Cancer Institute. Chronic Myelogenous Leukemia (PDQ®). Last Modified on March 15, 2018. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/CML/HealthProfessional. Accessed on April 09, 2018.
  6. NCCN Clinical Practice Guidelines in Oncology. © 2018 National Comprehensive Cancer Network, Inc. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on April 09, 2018.
    • Acute Lymphoblastic Leukemia (V.1.2018). Revised March 12, 2018.
    • Chronic Myeloid Leukemia (V.4.2018). Revised January 24, 2018.
  7. Shah NP. Loss of response to imatinib: mechanisms and management. Hematology Am Soc Hematol Educ Program. 2005; 183-187.
Websites for Additional Information
  1. The Leukemia and Lymphoma Society. Available at: http://www.lls.org/#/diseaseinformation/leukemia/. Accessed on April 09, 2018.
Index

 

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
BCR-ABL Mutation Analysis
Chronic Myelogenous Leukemia

 

Document History

Status

Date

Action

Reviewed

05/03/2018

Medical Policy & Technology Assessment Committee (MPTAC) review.

Reviewed

05/02/2018

Hematology/Oncology Subcommittee review. The document header wording updated from “Current Effective Date” to “Publish Date.” Updated Rationale, Background/Overview and References sections.

Reviewed

05/04/2017

MPTAC review.

Reviewed

05/03/2017

Hematology/Oncology Subcommittee review. Updated Rationale, Background/Overview, and References sections.

Reviewed

05/05/2016

MPTAC review.

Reviewed

05/04/2016

Hematology/Oncology Subcommittee review. Updated Description/Scope, Rationale, and References sections.

 

01/01/2016

Updated Coding section with 01/01/2016 CPT changes, removed 81403 (no longer applicable); also removed ICD-9 codes.

Reviewed

05/07/2015

MPTAC review.

Reviewed

05/06/2015

Hematology/Oncology Subcommittee review. Updated Rationale, Background/Overview and References.

Revised

05/15/2014

MPTAC review.

Revised

05/14/2014

Hematology/Oncology Subcommittee review. Added ALL to the Position Statement and scope of document. Updated Description/Scope, Rationale, Background/Overview, Definitions, References, and Index.

Reviewed

05/09/2013

MPTAC review.

Reviewed

05/08/2013

Hematology/Oncology Subcommittee review. Updated Rationale, Background/Overview, and References.

Reviewed

05/10/2012

MPTAC review.

Reviewed

05/09/2012

Hematology/Oncology Subcommittee review. Updated Rationale, Background/Overview and References.

Reviewed

11/17/2011

MPTAC review.

Reviewed

11/16/2011

Hematology/Oncology Subcommittee review. Discussed new genetic testing codes with no revision to the Position Statements. Updated Coding section with 01/01/2012 CPT changes.

Reviewed

05/19/2011

MPTAC review.

Reviewed

05/18/2011

Hematology/Oncology Subcommittee review. Updated Rationale, Background/Overview and References.

Revised

05/13/2010

MPTAC review.

Revised

05/12/2010

Hematology/Oncology Subcommittee review. Addition of medically necessary statement regarding T315-I mutation analysis. Clarified investigational and not medically necessary statement. Updated Rationale, Background/Overview, References.

Reviewed

11/19/2009

MPTAC review.

Reviewed

11/18/2009

Hematology/Oncology Subcommittee review. Updated Rationale, Background/Overview and References.

Reviewed

11/20/2008

MPTAC review.

Reviewed

11/19/2008

Hematology/Oncology Subcommittee review. Updated References, Web Sites, Coding, Description, Rationale and Background/Overview sections.

 

10/01/2008

Updated Coding section with 10/01/2008 ICD-9 changes.

Reviewed

11/29/2007

MPTAC review. References updated.

Reviewed

11/28/2007

Hematology/Oncology Subcommittee review. Updated References, Coding section and Web Sites. No change to position. The phrase “investigational/not medically necessary” was clarified to read “investigational and not medically necessary.”

Reviewed

12/07/2006

MPTAC review.

Reviewed

12/06/2006

Hematology/Oncology Subcommittee review. 

New

09/14/2006

MPTAC initial document development.