Mini-reviewDiscontinuation of tyrosine kinase inhibitors and new approaches to target leukemic stem cells: Treatment-free remission as a new goal in chronic myeloid leukemia
Introduction
Imatinib has dramatically changed the treatment of chronic myeloid leukemia (CML) by inducing more than 80% of complete cytogenetic response (CCyR) and long-term overall survival (OS) of more than 85% [1]. However, deep molecular responses, as measured by reductions in BCR-ABL transcript levels below the threshold of major molecular response (MMR, ratio BCR-ABL/ABL <0.1% according to International Scale), are achieved only by a small proportion of patients [2]. Second-generation tyrosine kinase inhibitors (TKIs), such as nilotinib and dasatinib for the treatment of newly diagnosed CML-CP have increased the proportion of patients who achieve profound molecular responses [3], [4]. New cut-offs were created after the use of the more potent drugs to identify patients with deeper molecular responses: MR4, corresponding to a BCR–ABL ratio <0.01%, MR4.5, corresponding to a ratio <0.0032% and UMRD or undetectable molecular disease, corresponding to 5-log reduction or <0.001% [5]. With these new drugs, the potential for patient eligibility in TKIs cessation studies is becoming a more widely discussed topic and area for research, even if current guidelines, such as the National Comprehensive Cancer Network (NCCN) or European LeukemiaNet (ELN), recommend continuing imatinib indefinitely in all responding patients, even in those with UMRD [6], [7]. Several groups reported studies aiming to explore the option of discontinuation in patients who achieved a sustained complete molecular remission (CMR) [8].
Purpose of this review is to refer on results of different published studies upon discontinuation and new approaches to target stem cells, to discuss the new endpoint in the treatment of CML, which is the treatment-free remission (TFR).
Section snippets
Imatinib discontinuation: first evidences
At first, several small series of patients were described that showed how discontinuation was possible but was unfortunately followed by molecular relapse, probably due to the absence of deep and sustained molecular response at the time of discontinuation. Cortes et al. [9] described 3 patients: the first one had achieved a CMR with a total duration of 12 months, discontinued therapy due to pregnancy but relapsed after 3 months and regained CMR after restarting imatinib. The second patient
Discontinuation of second generation TKIs
Only few reports referred on discontinuation of second-generation inhibitors. In particular, Ross and colleagues described 3 patients treated with dasatinib after imatinib failure. The first patient received dasatinib while in AP after failing IFN plus standard and escalated dose of imatinib: this patient achieved a CMR after only two months and discontinued the drug for recurrent pleural effusions after 35 months of stable CMR. The patient remained in stable CMR for 27 months with the evidence
Interferon-alpha as maintenance after imatinib discontinuation
The use of IFN as maintenance therapy after discontinuation of imatinib was explored. Burchert and colleagues reported 20 patients who discontinued imatinib after a concomitant treatment of this drug with IFN, lasting a median time of 2.4 years. Longitudinal monitoring with RQ-PCR for BCR-ABL transcript was performed with also measurement of proteinase-3 and proteinase-3 specific cytotoxic T cells. After a median follow-up of up to 2 years, 15 out of 20 patients remained in CMR. Relapses occurred
New technologies for monitoring patients and mathematical models to predicts molecular relapse after discontinuation
New technologies will be probably available in order to identify patients eligible for future discontinuation of treatment. However, although the efforts for standardization of molecular methods for measurement of BCR-ABL transcript, there are still some inconsistencies. A possible new technology could be the automated BCR-ABL assay contained in single-use microfluidic cartridge. An instrument, the GeneXpert, is required, but it still needs the introduction of International Scale, to control
New pathways to target LSC
Even if in the era of second-generation TKIs in first line we can reach a faster and deeper molecular response, the risk of progression is substantially a still open question, due to the persistence of Ph + LSC. Indirect evidences of LSC existence showed that CML progenitors probably have the stem cell-like capacity of self-renewal, not conferred by BCR-ABL1: Ph + LSC have the same immunophenotype of normal human SC (CD34+ CD38− CD90+) with low capacity of engraftment. Several experiences have
Conclusions
Treatment-free remission endpoint in CML is based on the hypothesis that it is possible to discontinue TKIs in some patients after the achievement of a deep molecular response. Maintenance therapy with IFN after imatinib discontinuation has been also proven as a possible therapeutic strategy. In several trials it has been demonstrated that degree of molecular response and time-length of imatinib therapy should improve the percentage of treatment-free remission. Second-generation TKIs in first
Conflict of Interest
MB received honoraria from Novartis, Bristol Myers-Squibb.
All other authors have no conflict of interest to report.
Acknowledgement
MB wrote the review, analysed all the literature; GA critically revised and approved the final version of the paper.
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