Incidences of Deep Molecular Responses and Treatment-Free Remission in de Novo CP-CML Patients.

Gabriel Étienne ,Françoise Durrieu,Corinne Dagada,Marius Moldovan,Fanny Robbesyn,Samia Madene,Axelle Lascaux,Laura Versmée,Anna Schmitt,Stéphanie Dulucq,Sandrine Katsahian,Didier Adiko,François Lifermann,Caroline Lenoir,Fontanet Bijou,Frédéric Bauduer ,E Klein ,Béatrice Turcq ,Marie‐Pierre Fort ,C Fabères ,François‐Xavier Mahon

doi:10.3390/cancers12092521

Abstract

Simple SummaryTyrosine kinase inhibitors (TKI) can be safely discontinued in chronic myeloid leukemia patients. Achieving a sustained deep molecular response (DMR) before stop is recommended. Currently, the proportion of patients who achieve a sustained DMR remains to be determined. Based on the follow-up of 398 patients over a ten-years period, we evaluate that 46% of them have achieved a sustained DMR. Gender, BCR-ABL1 transcript type, and disease risk scores were significantly associated with the probability of achieving a DMR. 95/398 (24%) patients stopped TKI with a probability of maintaining molecular reponse without TKI resumption of 47% at 48 months after stop. In this study, TKI duration before stop and second (nilotinib, dasatinib, bosutinib) generation frontline TKI compared to imatinib were significantly associated with a lower risk of molecular relapse after stop in patients who have achieved a sustained DMR.Background: Tyrosine Kinase Inhibitors (TKIs) discontinuation in patients who had achieved a deep molecular response (DMR) offer now the opportunity of prolonged treatment-free remission (TFR). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation. Results: Over a period of 10 years, 398 CP-CML patients treated with first-line TKIs were included. Median age at diagnosis was 61 years, 291 (73%) and 107 (27%) patients were treated with frontline imatinib (IMA) or second- or third-generation TKIs (2–3G TKI), respectively. With a median follow-up of seven years (range, 0.6 to 13.8 years), 182 (46%) patients achieved a sustained DMR at least 24 months. Gender, BCR-ABL1 transcript type, and Sokal and ELTS risk scores were significantly associated with a higher probability of sustained DMR while TKI first-line (IMA vs. 2–3G TKI) was not. We estimate that 28% of CML-CP would have been an optimal candidate for TKI discontinuation according to recent recommendations. Finally, 95 (24%) patients have entered in a TFR program. MRFS rates at 12 and 48 months were 55.1% (95% CI, 44.3% to 65.9%) and 46.9% (95% CI, 34.9% to 58.9%), respectively. In multivariate analyses, first-line 2–3G TKIs compared to IMA and TKI duration were the most significant factors of MRFS. Conclusions: Our results suggest that frontline TKIs have a significant impact on TFR in patients who fulfill the selection criteria for TKI discontinuation.

Highlights

Targeting the deregulated tyrosine kinase activity of the BCR-ABL1 fusion protein with selective agents, namely the tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) patients constitutes one of the most impressive therapeutic progress over the past 20 years
From January 2006 to December 2015, 398 CML patients in CP at diagnosis were recruited in the nine southwest French participating centers and were included in the study
The median age at diagnosis and the proportion of high Sokal risk score significantly differ between patients receiving frontline 2–3G 2nd or 3rd Generation Tyrosine Kinase (TKI) or IMA

Summary

Introduction

Targeting the deregulated tyrosine kinase activity of the BCR-ABL1 fusion protein with selective agents, namely the tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) patients constitutes one of the most impressive therapeutic progress over the past 20 years. Achieving an MR4.5 log reduction in the BCR-ABL1/ABL1 ratio during at least two years or an MR4 log reduction lasting more than three years before stopping together with an M BCR-ABL1 transcript, chronic phase at diagnosis and the absence of suboptimal response or failure during TKI treatments are recommended for TKI discontinuation outside a clinical trial [12–14]. It has been estimated that 28 to 36% of CP-CML patients receiving imatinib frontline or after interferon achieved a sustained DMR defined as BCR-ABL1/ABL1 4 log (MR4). Patients and Methods: Aims of this study were to evaluate the proportion of de novo chronic-phase chronic myeloid leukemia (CP-CML) patients who achieved a sustained DMR and to identify predictive factors of DMR and molecular recurrence-free survival (MRFS) after TKI discontinuation.

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