A Standardized BCR-ABL Monitoring Test: Assessment of Potential Adoption Impacts In Healthcare In the United States

BCR-ABL transcript monitoring is a guideline recommended component of Chronic Myeloid Leukemia (CML) management. BCR-ABL monitoring in the U.S. is mainly done using laboratory developed tests (LDTs). Studies found accuracy and reliability problems with LDTs which may lead to undesirable health and economic impacts (Gabert et al, Leukemia, 2003, Zhang et al, J Mol Diagn 2007, Muller et al, Leukemia 2008). There are ongoing efforts to standardize BCR-ABL LDTs in the U.S. and globally (Hughes et al, Blood 2006, Branford et al Blood 2006). A standardized BCR-ABL monitoring test (SBAT) may be an effective method to propagate standardization and improve quality of BCR-ABL testing. A standardized BCR-ABL monitoring test is one which minimizes operator error, and is stringently reviewed and shown to be validated under health authorities’ quality systems regulations (principally Food and Drug Administration's Quality Systems Regulations and European Union's In-Vitro Diagnostics Directive), ensuring the safety and effectiveness of the test, as well as its reliable performance across multiple operators and labs through a thorough examination of its initial design, manufacturing, and associated processes. Our study qualitatively assessed potential benefits and drawbacks of adopting a SBAT, compared to current LDTs.

We conducted peer-reviewed and grey literature review to answer questions: (1) How may the shortcomings of current BCR-ABL LDTs be impacting patient care, outcomes and quality of life? (2) How may adoption of a SBAT address the LDT shortcomings and propagate standardization? (3) What are potential health, economic and care process benefits and drawbacks of SBAT adoption for healthcare stakeholders?

We identified BCR-ABL LDT shortcomings: (a) methodologic shortcomings resulting in suboptimal test accuracy; (b) process shortcomings (e.g. operator error; batch to batch variation in materials) leading to suboptimal reproducibility and (c) variability in methods across labs leading to incomparability of results. Three key results are: (1) Inaccurate over-quantitation of BCR-ABL results may lead to unnecessary further testing (e.g. mutation testing; bone marrow cytogenetic testing) and misinformed therapy decisions, e.g. drug dose escalation. False under-quantitation may lead to missed indications of relapse, resistance to therapy, or problems with therapy compliance. Due to result incomparability, patients often cannot change providers without losing testing history which may impact life decisions such as relocation. (2) A SBAT may address most LDT process shortcomings and important methodologic shortcomings. Consequently, if a SBAT is adopted broadly it may reduce inter- and intra-lab variability. It may also address limitations of standardization efforts, such as minimizing operator error and increasing compliance with harmonization guidelines. (3) SBAT adoption is likely to provide substantial benefits in health outcomes and quality of life to patients who may otherwise receive inaccurate results. Benefits in care process are anticipated to outweigh drawbacks. Benefits include faster results, increased confidence in results, ability to get a second opinion or transition patient care to different providers. Drawbacks may include implementation efforts, and getting used to new report formats by patients and physicians. BCR-ABL testing history may potentially be incomparable for some existing patients if laboratories do not implement effective data transition. We anticipate that the economic impact of SBAT adoption on the healthcare system will be limited due to the relatively small CML patient population. A significant financial impact may be on labs. Some labs may benefit by bringing BCR-ABL test in-house, but this may reduce test volume for labs that provide this as a centralized service.

Implementing a standardized BCR-ABL monitoring test (SBAT) is likely to significantly benefit CML patients’ health and quality of life and provide better utility to providers than LDTs. A SBAT will contribute to addressing the broader quality of diagnostics challenge recognized by payers, providers, guideline bodies and government authorities. A SBAT represents an incremental improvement in a field that has relatively few patients, but potentially paves the way to similar developments in other blood cancers and beyond.

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