Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study

David M Ross,Eibhlin Conneally,Andreas Hochhaus,Francis J Giles,Nancy Krunic,Bruno Martino,Jesper Stentoft,Weiping Deng,Tamas Masszi,Philipp D Le Coutre,Giuseppe Saglio,Véronique Bédoucha,Andrzej Hellmann,Valentin Garcia-Gutierrez,María Teresa Gómez Casares,Jerald P Radich,Susanne Saussele,Norbert Gattermann,Prashanth Gopalakrishna

doi:10.1007/s00432-018-2604-x

Abstract

PurposeENESTfreedom is evaluating treatment-free remission (TFR) following frontline nilotinib in patients with chronic myeloid leukemia (CML) in chronic phase. Following our primary analysis at 48 weeks, we here provide an updated 96-week analysis.MethodsAttempting TFR required ≥ 3 years of nilotinib, a molecular response of MR4.5 [BCR-ABL1 ≤ 0.0032% on the International Scale (BCR-ABL1IS)], and sustained deep molecular response (DMR) during a 1-year consolidation phase. Patients restarted nilotinib following loss of major molecular response (MMR; BCR-ABL1IS ≤ 0.1%).ResultsNinety-six weeks after stopping treatment (3.6-year median prior nilotinib duration), 93 of 190 patients (48.9%) remained in TFR. Of 88 patients who restarted nilotinib following loss of MMR, 87 regained MMR and 81 regained MR4.5 by the data cut-off. Ninety-six-week TFR rates were 61.3, 50.0, and 28.6% in patients with low, intermediate, and high Sokal risk scores at diagnosis, respectively. Patients consistently in MR4.5 during consolidation had higher TFR rates (50.6%) than patients with ≥ 1 assessment without MR4.5 during consolidation (35.0%). In a landmark analysis, 96-week TFR rates for patients with MR4.5, MR4 (BCR-ABL1IS ≤ 0.01%) but not MR4.5, and MMR but not MR4 at TFR week 12 were 82.6, 23.1, and 0%, respectively. There were no reports of disease progression or death due to CML; overall adverse event frequency decreased following TFR. Within the follow-up period, TFR did not adversely affect disease outcomes.ConclusionsThese results demonstrate the feasibility and durability of TFR following frontline nilotinib and emphasize the importance of sustained DMR for TFR.

Highlights

The treatment-free remission (TFR) rate was 48.9% at 96 weeks and 51.6% at 48 weeks (Hochhaus et al 2017a), suggesting a very low risk of relapse in patients remaining in TFR for > 48 weeks
Of the 98 patients in the TFR phase at 48 weeks, only 3 exited this phase due to loss of major molecular response (MMR) during the second 48 weeks, and 2 others discontinued the study despite remaining in MMR
Patients reinitiating nilotinib following loss of MMR promptly regained molecular responses; 98.9% regained MMR and 92.0% regained MR4.5 by the data cut-off, demonstrating that temporary treatment cessation is safe in patients who experience molecular relapse

Summary

Introduction

For patients with chronic myeloid leukemia in chronic phase (CML-CP) who have achieved a stable deep molecular response (DMR) using BCR-ABL1 tyrosine kinase inhibitors (TKIs), treatment-free remission (TFR) following TKI cessation is an emerging goal (Hughes and Ross 2016; Mahon et al 2010; Etienne et al 2017; Rousselot et al 2014; Ross et al 2013; Lee et al 2016; Mori et al 2015; Hochhaus et al 2017a; Hughes et al 2016; Imagawa et al 2015; Nakamae et al 2017; Saussele et al 2017; Rea et al 2017; Boquimpani et al 2014; Villemagne Sanchez et al 2018). In light of the success of TFR studies and the possible advantages that TFR might confer, the US National Comprehensive Cancer Network and the European Society for Medical Oncology have published guidelines that include criteria for attempting TFR outside of clinical trials (National Comprehensive Cancer Network 2017; Hochhaus et al 2017b)

Methods

Results

Conclusion