Discontinuation of tyrosine kinase inhibitors and new approaches to target leukemic stem cells: Treatment-free remission as a new goal in chronic myeloid leukemia

Abstract

Only a small fraction of chronic phase chronic myeloid leukemia patients (CP-CML) achieves a very deep reduction of residual disease with imatinib. Second-generation tyrosine kinase inhibitors administered as front-line therapy for CP-CML have improved the rates and degree of deeper molecular responses. Owing to this improvement, new standardized definition of complete molecular remission has been provided, which allowed plan of prospective strategies to definitively discontinue therapy in the long-term. In this review, we report the results of several published discontinuation studies and critically discuss the new approaches and tools to monitor residual disease during treatment and new strategies to target leukemic stem cells to reach a potential “operational” cure and persistent long-term leukemia-free survival.

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).