Discontinuation of TKI therapy and ‘functional’ cure for CML

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Abstract

Stopping tyrosine kinase inhibitor (TKI) therapy after achieving a sustained deep molecular response is an emerging treatment goal for patients with chronic myeloid leukaemia in chronic phase (CML-CP). Indeed, the feasibility of stopping TKI therapy has been confirmed in various studies. The Stop Imatinib 1 (STIM1) study has shown a consistent follow-up which allowed defining a new criterion of clinical outcome evaluation, the treatment free remission (TFR). However, announcing a definitive cure remains a challenge owing to the discovery that TKIs spare quiescent leukaemic stem cells (LSC). It is definitely known that even a patient in long-term TFR has persistent LSCs. For this reason, a “functional” cure has been defined and proposed.

Introduction

For the patients with chronic myeloid leukaemia in chronic phase (CML-CP), the evaluation of the new treatments is no longer for the overall survival but for the quality of life. Nowadays, most patients with CML-CP have the expectation of a favourable outcome when treated with tyrosine kinase inhibitors (TKIs) [1]. Long-term survival estimates show that life expectancy is increasing to the levels close to those observed in the general population [2]. Thanks to the progress in research and a better understanding of the disease, CML could be a model disease for targeted therapy [3].

The development of BCR-ABL1 TKIs dramatically improved the outcome for patients with CML-CP. With TKI therapy, most of the patients with CML-CP achieve deep molecular responses (DMRs), as measured by real-time quantitative polymerase chain reaction (qRT-PCR) [4], [5], [6], [7]. In addition, there is data suggesting that patients with DMRs have a low risk of progression and a high rate of long-term survival [8], [9]. Several ongoing discontinuation clinical trials have demonstrated that TKI therapy can safely be suspended in patients with sustained DMRs and treatment free remission (TFR) can be achieved [10], [11], [12], [13], [14], [15], [16], [17]. Indeed, we have reported preliminary results of imatinib (IM) discontinuation study entitled STIM1 for “Stop Imatinib”. The analysis showed that nearly 40% of the patients maintained a molecular remission following IM cessation, despite low-level persistence of leukaemic cells in most if not all patients [10], [18], [19]. As yet, no case of progression following IM discontinuation has been reported and rechallenge treatment for molecular recurrence (MR) was associated with the occurrence of a second DMR suggesting that IM discontinuation in selected patients is safe [10]. Similar results have been reported in a comparable cohort of patients with a short follow-up [12]. Although the definition of MR leading to treatment resumption was slightly different, the common feature is that most cases of MR occur during the first months following IM cessation. The feasibility of achieving TFR has been confirmed in subsequent studies, including patients that were treated with second generation TKIs [20]. To date, the occurrence of late MR with a long-term follow-up after cessation of TKI remains the most important issue. Of note, due to the modern criteria for TFR, CML is now also a model for addressing the concept of curability in leukaemia and cancer.

Section snippets

Lessons from the previous treatment before the millennium (allo-HSCT and IFN-α therapy)

For a long time, allogeneic haematopoietic stem cell transplantation (allo-HSCT) has been considered as the sole treatment able to cure CML [21]. This belief was based on the evidence that allo-HSCT can offer long-term freedom from cytogenetic or haematologic recurrence of the disease without the need for a maintenance therapy. Furthermore, CML was the best indication for allo-HSCT due to the graft versus leukaemia effect mediated by donor-derived T lymphocytes was more prominent than in other

Current experience with TKI discontinuation: imatinib is not a lifelong treatment

The proof of concept of stopping IM in good responder patients has been preliminary brought by a pilot study reported on 12 patients and STIM1 trial [10], [11]. In both studies, the criterion for stopping IM was strictly undetectable molecular residual disease (UMRD) during two following years. STIM1 enrolled patients who had received IM therapy de novo (n = 50) and after IFN-α (n = 50) and had maintained undetectable BCR-ABL1 (in five assessments, confirmed at screening with sensitivity of

What do we know about second generation TKI cessation?

The feasibility of TFR following nilotinib or dasatinib has also been demonstrated. The Stop Second-Generation Tyrosine Kinase Inhibitor (STOP 2G-TKI) study enrolled patients who had received 3 years of TKI therapy, were currently receiving either nilotinib or dasatinib as frontline therapy or following IM, and had maintained UMRD (i.e., undetectable MR4.5, as assessed in standardized laboratories) for 2 years [30]. With a median follow-up of 32 months (range, 12–56 months) in STOP 2G-TKI, the

From the largest cohort of patients who stop TKI to the true life

A large trial evaluating TFR in a wider population of patients than those from the previous studies has been proposed by the European Stop Tyrosine Kinase Inhibitor (EURO-SKI) study. Wider criteria were proposed for performing a robust statistical analysis, i.e. patients must have received TKI therapy for 3 years (including frontline therapy, second-line therapy due to toxicity of frontline therapy, and/or TKI combination therapy) and must have maintained MR4.5 for 1 year; MR was defined as

Summary

A consensus and an algorithm will perhaps emerge from the results and the publications of ongoing studies which use TFR as a main criterion of evaluation. It is a criterion of “functional” cure and we look forward to obtaining the results of all the CML studies and continue to lead the way in cancer.

Conflict of interest

None.

References (37)

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