Abstract
Tyrosine kinases inhibitors (TKIs) revolutionized chronic myeloid leukemia (CML) treatment for many years, prolonging patients’ life expectancy to be comparable to age-matched healthy individuals. According to the latest the European LeukemiaNet (ELN) recommendations, CML treatment aims to achieve long-term remission without treatment (TFR), which is feasible in more than 40% of patients. Nearly all molecular relapses occur during the first 6 months after TKI withdrawal and do not progress to clinical relapse. The mechanisms that are responsible for CML relapses remain unexplained. It is suggested that maintaining TFR is not directly related to the total disposing of the gene transcript BCR-ABL1, but it might be a result of the restoration of the immune surveillance in CML. The importance of the involvement of immunocompetent cells in the period of TKI withdrawal is also emphasized by the presence of specific symptoms in some patients with “withdrawal syndrome”. The goal of this review is to analyze data from studies regarding TFRs in order to characterize the elements of the immune system of patients that might prevent CML molecular relapse. The role of modern droplet digital polymerase chain reaction (ddPCR) and next-generation sequencing (NGS) in better identification of low levels of BCR-ABL1 transcripts was also taken into consideration for refining the eligibility criteria to stop TKI therapy.
Highlights
Chronic myeloid leukemia (CML) is the first malignant monoclonal disease of hematopoietic stem cells (HSCs) with identification of an acquired chromosomal abnormality: the Philadelphia chromosome (Ph) [1]
Important observations were made by Alves et al [113], who proved that chronic myeloid leukemia (CML) patients treated with 2G Tyrosine kinases inhibitors (TKIs) had a lower percentage of CD4+ Treg and granulocytic myeloid-derived suppressor cells (Gr-MDSC) compared to patients receiving imatinib, but higher levels of programmed death-1 (PD-1)-co-expressing CD4+ cells (1.92 vs. 1.0%; p = 0.001)
Schütz [134] suggested that low levels of CD86+ on Plasmacytoid dendritic cells (pDCs) may be a predictor of treatment-free remission (TFR) as it increases RFS for patients with 95 CD86+ pDC per 105 lymphocytes (70 vs. 30.1%; p < 0.0001)
Summary
Chronic myeloid leukemia (CML) is the first malignant monoclonal disease of hematopoietic stem cells (HSCs) with identification of an acquired chromosomal abnormality: the Philadelphia chromosome (Ph) [1] This chromosome 22 is the result of a balanced exchange of genetic material between the long arms of chromosome 9 and 22 (translocation, t(9;22)(q34;q11)), generating juxtaposition of the BCR gene in 9q to the ABL1 proto-oncogene in 22q [2,3]. The natural evolution of CML consists of three phases: a chronic phase (CP-CML) that without tyrosine kinases inhibitor (TKI) therapy could last 3–4 years with harmonic malignant HSC differentiation; an accelerated phase (AP-CML) with HSC maturation hiatus and a blastic phase (BP-CML) in acute leukemia—myeloblastic or lymphoblastic—with a fatal outcome within a few months This three-phase evolution has been modified by the clinical results of TKIs, and since CML is no longer a fatal disease but rather a chronic condition with age-related diseases. The ability to discontinue TKI treatment and achieve long-term remission without treatment (treatment-free remission— TFR) has become a new goal in CML, and the selection of appropriate therapy is a key element in the depth and speed of achieving a very deep molecular response
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