Best Practices in Chronic Myeloid Leukemia Monitoring and Management

Abstract

: Optimal use of current therapeutic opportunities for chronic myeloid leukemia patients requires integration of clinical and laboratory monitoring. Assessment of molecular response (MR) by real-time quantitative polymerase chain reaction is the most sensitive way to monitor tyrosine kinase inhibitor (TKI) treatment efficacy. Besides major molecular response, which has emerged as a safe haven for survival since the initial studies of first-line imatinib treatment, two additional MR milestones have recently been defined: early molecular response and deep molecular response. The achievement of such MR milestones within defined time points during therapy is thought to draw the ideal trajectory toward optimal long-term outcome and, possibly, successful treatment discontinuation. Sensitive and reproducible MR measurement and proper interpretation of MR results are therefore critical to correctly inform therapeutic decisions. In patients who do not achieve an optimal response to TKI therapy, BCR-ABL1 mutation screening should also be performed, because it may deliver useful information for TKI choice. This review aims to help clinicians apply and translate the latest response definitions and clinical recommendations into practice. We provide a critical update on how these recommendations have incorporated MR levels in the clinical decision algorithms and how detection of BCR-ABL1 mutations should be interpreted. We also include a practical guide for pathologists and molecular biologists to best perform molecular testing and for hematologists and oncologists to best integrate it into routine practice.

Implications for practice: Ever-more-potent therapeutic strategies have been developed for chronic myeloid leukemia (CML) in parallel with the evolution of therapeutic goals and the refinement of response definitions and monitoring schemes and procedures. Terminology and methodology continue to evolve rapidly, making it difficult for busy hematology/oncology professionals to keep abreast of the newest developments. Optimal CML patient management results from the timely and rational use of molecular testing, the critical assessment of the power and pitfalls of current technology, and the appropriate interpretation and contextualization of results.

Keywords: BCR-ABL1; Leukemia, chronic myeloid; Minimal residual disease; Molecular testing; Tyrosine kinase inhibitor.

Figure 1.

Levels of hematologic, cytogenetic, and molecular response in CML and the novel concepts of early molecular response and deep molecular response. The gray area indicates that RQ-PCR cannot measure MRD below MR⁵ (BCR-ABL1 <0.001%); nevertheless, residual leukemia cells may still be present. Novel technologies (such as digital PCR) and approaches (such as assessing genomic DNA rather than RNA), might, in the future, extend the dynamic range of MR detection below MR⁵. Abbreviations: CCyR, complete cytogenetic response; CHR; complete hematologic response; CML, chronic myeloid leukemia; IS, International Scale; MMR, major molecular response; MR, molecular response; MRD, minimal residual disease; RQ-PCR, real-time quantitative reverse-transcription polymerase chain reaction.