Chronic myeloid leukemia (CML) is the paradigm for targeted cancer therapy. RT-qPCR is the gold standard for monitoring response to tyrosine kinase-inhibitor (TKI) therapy based on the reduction of blood or bone marrow BCR-ABL1. Some patients with CML and very low or undetectable levels of BCR-ABL1 transcripts can stop TKI-therapy without CML recurrence. However, about 60 percent of patients discontinuing TKI-therapy have rapid leukaemia recurrence. This has increased the need for more sensitive and specific techniques to measure residual CML cells. The clinical challenge is to determine when it is safe to stop TKI-therapy. In this review we describe and critically evaluate the current state of CML clinical management, different technologies used to monitor measurable residual disease (MRD) focus on comparingRT-qPCR and new methods entering clinical practice. We discuss advantages and disadvantages of new methods.
Keywords: ABL1, Abelson murine leukaemia virus; ALL, acute lymphoblastic leukaemia; AP, accelerated phase; ARQ, armored RNA Quant; ATP, adenosine triphosphate; BC, blast crisis; BCR, breakpoint cluster region; BM, bone marrow; BMT, bone marrow transplantation; Bp, base pair; CAP, College of American Pathology; CES, capillary electrophoresis sequencing; CML; CML, chronic myeloid leukaemia; CMR, complete molecular response/remission; CP, chronic phase; DESTINY, De-Escalation and Stopping Treatment of Imatinib, Nilotinib or sprYcel in Chronic Myeloid Leukaemia; DNA, deoxyribonucleic acid; EAC, Europe Against Cancer; ELN, European Leukaemia Net; EURO-SKI, European Stop Tyrosine Kinase Inhibitor Study; GUSB, glucuronidase beta gene; IC, inhibotory concentration; IRIS, interferon and cytarabine versus STI571; IS, International Scale; InDels, insertions and deletions; KDa, Kilo Dalton; Kbp, Kilo Base Pairs; LPC, leukemic progenitor cells; LSC, leukemic stem cell; LoD, limit of detection; LoQ, limit of quantification; M-bcr, major-breakpoint cluster region; MMR, major molecular response/remission; MR, deep molecular response/remission; MRD; MRD, minimal residual disease; Mbp, mega base pair; Molecular monitoring; NCCN, National Comprehensive Cancer Network; NEQAS, National External Quality Assessement Service; NGS; NGS, next generation sequencing; NTC, No Template Control; PB, Peripheral Blood; PCR, Polymerase Chain Reaction; PFS, Progression Free Survival; Ph, Philadelpia; Q-PCR, quantitative polymerase chain reaction; QC, Quality Control; RT, reverse transcription; RT-dPCR, reverse transcription-digital polymerase chain reaction; RT-qPCR, reverse transcription-quantitative polymerase chain reaction; SCT, stem cell transplant; SMRT, single-molecule real-time sequencing; STIM, stop imatinib; TKD, tyrosine kinase domain; TKI, tyrosine kinase inhibitor; WHO, World Health Organisation; ZMW, zero-mode wave-guided; allo-SCT, Allogeneic Stem Cell Transplantation; cDNA, coding or complimentary DNA; dMIQE, Minimum Information for Publication of Quantitative Digital PCR Experiments; dPCR; dPCR, digital polymerase chain reaction; emPCR, emulsion PCR; gDNA, genomic deoxyribonucleic acid; m-bcr, minor-breakpoint cluster region; mRNA, messenger RNA; nM, manomolar; μ-bcr, micro-breakpoint cluster region; μg, microgram; μl, microliter.