International, Prospective Study Comparing Nilotinib Versus Imatinib with Early Switch to Nilotinib to Obtain Sustained Treatment-Free Remission in Patients with Chronic Myeloid Leukemia. a GIMEMA and HOVON Study
Authors: Pane Fabrizio , Luciano Luigia , Pugliese Novella , Steegman Juan Luis , Westerweel Peter E. , Abruzzese Elisabetta , Breccia Massimo , Bocchia Monica , Soverini Simona , Castagnetti Fausto , Monteverde Maria , Rosti Gianantonio , Saglio Giuseppe , Janssen Jeroen J. 
Published: October 2019

Abstract
Background
The best front-line treatment of CML is not yet defined. Indeed, despite the higher activity of the second-generation TKIs respect to Imatinib and the higher rates of deep molecular remission (DMR), no clear superiority in term of long-term overall survival among the first and second TKIs for the initial treatment of CML has been shown in all the available studies. Furthermore, treatment free remission is emerging as one of the most important goal of the treatment of this disease, but no clinical trial has shown so far the best first line treatment to reach this aim.
Methods
Since it is widely accepted that a sustained DMR is the pre-requisite to discontinue the TKI treatment for an extended duration of time, and since in patients who start treatment with imatinib (IM) and fail EMR, it is expected that a switch to NIL may improve the probability of achieving a DMR, we launched in November 2016 an international, prospective, interventional, randomized, two arms, phase IV study to evaluate both the depth of the molecular response and the rate of TFR in newly diagnosed CP-CML patients treated with a second generation TKI (Nilotinib, NIL) or with Imatinib (IM) followed by switch to NIL in absence of optimal response (defined according the ELN 2013 criteria (Clinical Trial number 02602314) The enrolled patients are randomized 1:1 between NIL and IM. Patients are stratified at randomization according to the Sokal risk score (high versus intermediate/low risk) and country (Italy, The Netherlands, Belgium). All the patients who obtain a reduction greater than 4.0 logs of residual disease (MR4.0) within the first three years of treatment, and maintain this level of response in all the subsequent tests up to the end of the fourth years of therapy qualify for the discontinuation phase of the study. The study has two primary end-points: a) the rates of molecular response (MR4.5) at 24 months, and b) the rate of patients who remain in sustained treatment free remission (≥MR3.0) without molecular relapse 12 months after entering the TFR phase. The molecular relapse is defined as loss of MMR, or confirmed loss of MR3.0. Differences in the patient-reported quality of life (QoL) were are investigated by QoL questionnaires (EORTC QLQ-C30 and EORTC CML-24) at baseline (before the randomization) and at 3, 6, 12, 18, 24, 30, 36, 42, 48, 60 months. A total of 165 patients will be enrolled. Enrollment will be concluded in 2019, and final results will be given in 2024.
Results
From November 2016 to the 15 July 15 2018, 165 patients with newly diagnosed CP-CML patients (mean age 54.6 years - range 20.0-85.8) were enrolled and randomized into the two arms of the study. Of those, 137 (83%) were classified as low/intermediate-risk Sokal, and the remaining 28 (17%) as high-risk. Additional chromosome abnormalities in the Philadelphia positive clone were detected in 20 (12.1%) patients, 7 (8.5%) in the IM group and 13 (15.9%) in the NIL group.
Overall, 12 patients of the IM group switched to NIL; for absence of optimal response at 3 months in two cases, at 6 months in 7 patients and at 12 months in one case. The remaining two patients switched to NIL for IM related toxicity. Among NIL treated patients, two patient stopped treatment, in one case at 1 month due to absence of hematological response and the other due to suboptimal response at 15 months. These patients were treated according to the principal investigator of the participating center and censored for final analysis.
At a preliminary evaluation of patient-reported QoL questionnaires completed at baseline, women and elderly had a perception of higher symptom burden.
Conclusion
This is the first and the unique prospective study comparing not only the rate of DMR but, more important, also the rate of TFR according to treatment: a second generation TKI frontline vs Imatinib frontline followed by the same second generation in case of non-optimal response to Imatinib
Acknowledgments
The present study is a non-commercial study sponsored by Fondazione GIMEMA together with the HOVON that are responsible for the database of the study. Novartis Pharma supports the study with an unrestricted grant.

Disclosures
Pane: AMGEN: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Abruzzese:BMS: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; Novartis: Research Funding. Breccia:Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Soverini:Incyte Biosciences: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Castagnetti:Pfizer: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Janssen:Pfizer: Consultancy, Speakers Bureau; Novartis: Research Funding; Incyte: Consultancy, Speakers Bureau; BMS: Research Funding; Abbvie: Consultancy; Jazz pharmaceuticals: Consultancy.