Monitoring Chronic Myeloid Leukemia: How Molecular Tools May Drive Therapeutic Approaches

Abstract

More than 15 years ago, imatinib entered into the clinical practice as a “magic bullet”; from that point on, the prognosis of patients affected by chronic myeloid leukemia (CML) became comparable to that of aged-matched healthy subjects. The aims of treatment with tyrosine kinase inhibitors (TKIs) are for complete hematological response after 3 months of treatment, complete cytogenetic response after 6 months, and a reduction of the molecular disease of at least 3 logs after 12 months. Patients who do not reach their goal can switch to another TKI. Thus, the molecular monitoring of response is the main consideration of management of CML patients. Moreover, cases in deep and persistent molecular response can tempt the physician to interrupt treatment, and this “dream” is possible due to the quantitative PCR. After great international effort, today the BCR-ABL1 expression obtained in each laboratory is standardized and expressed as “international scale.” This aim has been reached after the establishment of the EUTOS program (in Europe) and the LabNet network (in Italy), the platforms where biologists meet clinicians. In the field of quantitative PCR, the digital PCR is now a new and promising, sensitive and accurate tool. Some authors reported that digital PCR is able to better classify patients in precise “molecular classes,” which could lead to a better identification of those cases that will benefit from the interruption of therapy. In addition, digital PCR can be used to identify a point mutation in the ABL1 domain, mutations that are often responsible for the TKI resistance. In the field of resistance, a prominent role is played by the NGS that enables identification of any mutation in ABL1 domain, even at sub-clonal levels. This manuscript reviews how the molecular tools can lead the management of CML patients, focusing on the more recent technical advances.

Molecular Testing in CML between Old and New Methods: Are We at a Turning Point?

“…In the last few years, many studies have been conducted in order to overcome the intrinsic limitations of "classical" quantitative PCR (RT-qPCR) [8,9] (such as the limit of detection fixed at three copies of BCR-ABL1 transcript, the need for a standard curve, or the sensitivity to inhibitors), both improving its performance [10,11] and looking at further novel technologies [12]. In this context, digital PCR (dPCR) seems to be one of the most promising tools [13,14].…”

Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives

“…The main teaching of the countless clinical and biological studies conducted over all these years is that the cure of CML can only pass through the abrogation of the Ph+ clone, which can be detected and monitored by cytogenetics (chromosome banding analysis (CBA), or fluorescent in-situ hybridization (FISH)) or by real time quantitative reverse transcription polymerase chain reaction (RT-qPCR) [ 6 , 7 , 8 ].…”

Latest Implications of Next-Gen Sequencing in Diagnosis of Acute and Chronic Myeloid Leukemia

“…Most cases of chronic myeloid leukemia show the Philadelphia chromosome, which appeared after alteration of chromosome 22, produced by a reciprocal translocation t (9;22) q (34; 11), thus forming the BCR-ABL1 fusion gene, which became the main one diagnostic marker in chronic myeloid leukemia [19].…”