Abstract: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the BCR-ABL1 fusion gene generation as a consequence of the t(9;22)(q34;q11) rearrangement. The identification of the BCR-ABL1 transcript was of critical importance for both CML diagnosis and minimal residual disease (MRD) monitoring. In this review, we report the recent advances in the CML MRD monitoring based on RNA, DNA and protein analysis. The detection of the BCR-ABL1 transcript by the quantitative reverse-transcriptase polymerase chain reaction is the gold standard method, but other systems based on digital PCR or on GeneXpert technology have been developed. In the last years, DNA-based assays showed high sensitivity and specificity, and flow cytometric approaches for the detection of the BCR–ABL1 fusion protein have also been tested. Recently, new MRD monitoring systems based on the detection of molecular markers other than the BCR-ABL1 fusion were proposed. These approaches, such as the identification of CD26+ leukemic stem cells, microRNAs and mitochondrial DNA mutations, just remain preliminary and need to be implemented. In the precision medicine era, the constant improvement of the CML MRD monitoring practice could allow clinicians to choose the best therapeutic algorithm and a more accurate selection of CML patients eligible for the tyrosine kinase inhibitors discontinuation.

Keywords: chronic myeloid leukemia, minimal residual disease, MRD monitoring


Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder driven by the chimeric BCR-ABL1 oncoprotein, resulting from a t(9;22)(q34;q11) balanced reciprocal translocation. The rearrangement produces the Philadelphia (Ph) chromosome where the BCR-ABL1 oncogene is generated; its chimeric transcript is the marker of the disease.1,2 Tyrosine kinase inhibitors (TKIs) therapy targets BCR‑ABL1 positive cells and induces hematologic and molecular remission in 80–90% of CML patients, with a survival rate comparable to that of age-matched healthy individuals.3–5 Response to TKI treatment is assessed by hematologic, cytogenetic, and molecular testing performed at specific time-points during follow-up. Detection of the BCR-ABL1 transcript level by quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) is the gold standard method for monitoring CML minimal residual disease (MRD) and the optimal CML patient management.6 In fact, standardized and regular MRD monitoring in CML patients is essential for defining the response to treatment and choosing the best therapeutic strategy (as well as providing prognostic information) and also for selecting patients in sustained deep molecular response who are eligible for TKI discontinuation.7 This gains relevance in the era of targeted therapy, where the introduction of MRD monitoring has profoundly transformed patients management.8 Efficient methods for disease monitoring should guarantee fast, inexpensive and sensitive disease detection. In fact, even if in the last two decades the standardization of CML monitoring has remained one of the most laborious procedures, the efficacy of different new approaches has recently been tested. The main strategies developed in the last years, are based on BCR-ABL1 chimeric gene or transcript or protein detection, although some alternative strategies have been made (Figure 1). In this review we summarize the recent advances in the CML MRD monitoring, considering the advantages and disadvantages of each approach and focusing on future perspectives.

Figure 1

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