CurrentCapital BluecrossPolicy MP 2.317

BCR-ABL1 testing and ABL kinase domain mutation testing in CML and Ph+ ALL

Clinical policy governing when BCR-ABL1 qualitative and quantitative testing and ABL kinase-domain (KD) point mutation testing are considered medically necessary versus investigational for members of Capital BlueCross products (subject to plan benefit variations).

Policy Summary

PayerCapital Bluecross

PolicyBCR-ABL1 testing and ABL kinase domain mutation testing in CML and Ph+ ALL

Policy CodePolicy MP 2.317

Change TypeNo material changes

Effective DateFeb 1, 2025

Next Review Date

Key ActionVerify member benefit coverage and obtain any required preauthorization before ordering BCR-ABL1 or ABL KD mutation testing.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

2Definitions provided (e.g., MMR, TFR)

2Relevant coding groups listed

2024-11-12Last review date

When Testing Is Medically Necessary

BCR-ABL1 qualitative testing — Diagnosis of CML

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BCR-ABL1 quantitative RT-PCR testing — Monitoring CML and Ph+ ALL

Quantitative BCR-ABL1 testing by standardized qRT-PCR on the International Scale (IS) may be considered medically necessary at baseline and at specified intervals for monitoring treatment response and remission:

ALL of the following

Baseline quantitative BCR-ABL1 transcript level prior to initiation of TKI therapy
Repeated quantitative monitoring at appropriate intervals during therapy as per guidance
CML-specific monitoring intervals (examples provided in policy)
- For CML: testing at baseline, then every 3 months for 2 years once cytogenetic response is achieved, then every 3 to 6 months thereafter
- If complete cytogenetic response is not achieved: continue monitoring at 3-month intervals
- More frequent monitoring for patients in complete molecular remission who are not undergoing TKI therapy (e.g., monitoring during attempts at treatment discontinuation/TFR)
For Philadelphia chromosome–positive ALL: baseline and monitoring at appropriate intervals (optimal timing depends on chemotherapy regimen)
Reported results should be standardized to the International Scale (IS) and use recommended reference genes for normalization

ABL kinase domain (KD) point mutation testing — Evaluation for TKI resistance

Evaluation of ABL KD point mutations may be considered medically necessary to assess TKI resistance when clinical criteria indicate treatment failure or loss of response; testing is investigational for routine monitoring before signs of failure:

ANY of the following

Indicated (medically necessary) when: there is inadequate initial response to TKI (see definition) OR any sign of loss of response OR progression to accelerated or blast phase
Investigational / not medically necessary when used for routine monitoring in advance of signs of treatment failure or disease progression (insufficient evidence)

Definitions of inadequate initial response (CML)

Failure to achieve a complete hematologic response at 3 months
Only minor cytogenetic response at 6 months
Major (rather than complete) cytogenetic response at 12 months

Loss of response

Hematologic relapse
Cytogenetic relapse
1-log (10-fold) increase in BCR-ABL1 transcript ratio (loss of major molecular response)

Relevant Procedure and Diagnosis Codes

Molecular and mutation testing CPT/HCPCS/Laboratory codes listed in policymixed

81170	Molecular pathology procedure level (listed repeatedly in policy coding section)
81206	BCR-ABL1 (e13a2 and e14a2) detection — listed in coding section
81207	BCR-ABL1 detection/quantitation (other variants) — listed in coding section
81208	ABL1 (ABL) gene rearrangement/mutation testing — listed in coding section
81401	Molecular pathology procedure, tier 1 — included in coding list
0016U	FDA-cleared/authorized BCR-ABL test (category I) — added previously per history

Relevant ICD-10 diagnosis codes mentionedICD-10

C91.01	Acute lymphoblastic leukemia not having achieved remission
C91.02	Acute lymphoblastic leukemia, in remission
C92.10	Chronic myeloid leukemia, BCR-ABL1-positive, not having achieved remission
C92.11	Chronic myeloid leukemia, BCR-ABL1-positive, in remission
C92.12	Chronic myeloid leukemia, BCR-ABL1-positive, in relapse

Prior Authorization and Documentation Requirements

Prior Authorization

Benefit / preauthorization check required

Providers must verify whether BCR-ABL1 testing and ABL KD mutation testing are covered benefits under the member's specific health benefit plan; the medical policy does not guarantee coverage and preauthorization/benefit determination may be required.

Documentation Required

Document indication for mutation testing

When ordering ABL KD mutation testing, document the clinical indication to support medical necessity — examples include inadequate initial response per the defined timepoints, hematologic or cytogenetic relapse, or a 1-log (10-fold) increase in BCR-ABL1 transcript ratio (loss of major molecular response).

Documentation Required

Standardization requirement for quantitative tests

Ensure quantitative BCR-ABL1 qRT-PCR results are reported on the International Scale (IS) and normalized to recommended reference genes (e.g., ABL) as specified for standardized reporting.

Clinical Rationale and Context

Chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (Philadelphia chromosome–positive ALL) share the pathogenetic lesion of the Philadelphia chromosome resulting from t(9;22), which creates the BCR-ABL1 fusion that encodes a constitutively active tyrosine kinase. This abnormal kinase drives uncontrolled cell proliferation and is the principal therapeutic target for tyrosine kinase inhibitors (TKIs). (See description of disease genetics and clinical significance.)

Quantitative measurement of BCR-ABL1 transcript levels by standardized qRT-PCR on the International Scale (IS) is used to establish baseline burden before therapy and to monitor molecular response during TKI treatment. The IS defines 100% as the median pretreatment baseline and major molecular response (MMR) as a 3-log reduction (≤ 0.1% on the IS); serial molecular response correlates with risk of disease progression and long-term outcomes, and rising transcript levels predict treatment failure. Laboratories should report results standardized to the IS and use recommended reference genes for normalization.

Resistance to TKIs is frequently explained by point mutations in the ABL kinase domain (KD). These single-nucleotide variants account for a substantial portion of secondary resistance and the degree of resistance depends on variant position within the KD. Detection of ABL KD mutations when there is an inadequate initial response, loss of response, or progression can guide selection of alternative TKIs or dose changes. For example, the T315I variant confers resistance to imatinib, dasatinib, and nilotinib, whereas ponatinib is active against T315I-positive disease and is indicated for patients with the T315I mutation.

Defined Terms

Definitions

International Scale (IS)A standardized reporting scale for BCR-ABL1 transcript levels where 100% represents median pretreatment baseline; MMR is 0.1% on IS (3-log reduction).

Major molecular response (MMR)A 3-log reduction in BCR-ABL1 transcript level relative to standardized baseline (≤0.1% on IS).

Treatment-free remission (TFR)Sustained deep molecular response allowing discontinuation of TKI therapy under monitoring.

Policy Summary

PayerCapital Bluecross

PolicyBCR-ABL1 testing and ABL kinase domain mutation testing in CML and Ph+ ALL

Policy CodePolicy MP 2.317

Change TypeNo material changes

Effective DateFeb 1, 2025

Next Review Date

Key ActionVerify member benefit coverage and obtain any required preauthorization before ordering BCR-ABL1 or ABL KD mutation testing.

SourceLink

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