Safety and Efficacy of a Switch to Nilotinib in Patients with CML-CP Showing MMR to Imatinib: Results of a Multicenter Phase II Trial (NILSw Trial)
Authors: Shibayama Hirohiko , Kawaguchi Tatsuya , Kuroda Junya , Nakamae Hirohisa , Matsumura Itaru , Miyamoto Toshihiro , Ishikawa Jun , Kamimura Tomohiko , Fukushima Kentaro , Imamura Yutaka , Eto Tetsuya , Sunami Kazutaka , Shimokawa Mototsugu , Akashi Koichi , Kanakura Yuzuru 
Published: October 2019

Abstract
Introduction:
Tyrosine-kinase inhibitor (TKI) treatment generally induces a good response and shows long-term efficacy in patients with chronic myeloid leukemia in chronic phase (CML-CP). The ENESTnd trial demonstrated that nilotinib was superior to imatinib in terms of inducing rapid and deep responses and preventing transformation to acute phase/blast crisis in patients with untreated CML-CP. The optimal goal of CML-CP treatment is to cure the patient, such that they remain tumor free without continuing TKI treatment. The STIM trial showed that continuous complete molecular response (CMR) is essential for discontinuing TKI, while a major molecular response (MMR) is insufficient.
Aim:
Here we evaluated the efficacy and safety of a change to nilotinib in Japanese patients who achieved MMR with continuous detectable BCR-ABL1 transcript levels after imatinib treatment.
Patients and methods:
Patients with CML-CP who had achieved MMR but not CMR (MR4.5) after over 18 months of imatinib therapy were switched to treatment with nilotinib 400 mg twice daily for up to 24 months. BCR-ABL1 transcript levels were assessed every three months. The primary endpoint was the accumulative rate of CMR (MR4.5) up to 24 months after initiating nilotinib.
Results:
Between Feb. 2012 and Jan 2014, 53 patients were enrolled, of whom 39 met the eligibility criteria. We evaluated a total of 38 patients with a median age of 57.5 years (range, 22-76 years). Of these 38 patients, 27 completed 24 months of nilotinib treatment. The remaining 11 discontinued nilotinib due to retraction of consent (3 patients), MMR loss (1 patient), intolerance (3 patients), or adverse events (5 patients). Twenty patients (52.6%, 90% CI: 33.3-61.8%) achieved CMR (MR4.5). The accumulative incidences of achieving CMR (MR4.5) by 3, 6, 9, 12, 15, 18, 21, and 24 months were 21.1%, 34.2%, 42.1%, 47.4%, 47.4%, 47.4%, 47.4%, and 52.6%, respectively. None of the patients transformed to acute phase/blast crisis. Neither the periods of achieving CCyR nor MMR correlated to the incidence of achieving CMR (MR4.5) after switching from imatinib to nilotinib. The adverse events were consistent with those found in other nilotinib studies: grade 3/4 adverse events included anemia (5.3%), neutropenia (2.6%), thrombocytopenia (2.6%), lipase increase (5.3%), hypoglycemia (5.3%), hypophosphatemia (39.5%), ascites (2.6%), AST, ALT increase (2.6%), pulmonary edema (2.6%), muscle pain (2.6%), nausea (2.6%), skin rash (2.6%), dyspnea (2.6%), and hyponatremia (2.6%). Cardiovascular events included atrial fibrillation (G2), chest tightness and dyspnea (G1), myocardial infarction (G2), and heart failure (G3), which occurred in one patient each and the latter three complications led to nilotinib discontinuation.
Discussion and Conclusion:
This NILSw trial showed that nilotinib rapidly induced CMR in 52.6% of patients who had achieved MMR with continuous detectable BCR-ABL1 levels after long-term imatinib therapy. The safety concerns associated with nilotinib were close to those expected. Cardiovascular events during nilotinib treatment must be managed. Switching to nilotinib 400 mg twice daily may represent an alternative treatment strategy for inducing a deeper response (CMR) in relatively imatinib-resistant CML-CP patients.

Disclosures
Shibayama: Novartis Pharma: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau. Kawaguchi:Novartis: Honoraria. Kuroda:Janssen: Honoraria; Astra Zeneca: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Nakamae:Mochida Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis Pharma KK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel/accommodation/meeting expenses, Research Funding. Matsumura:Bristol-Myers Squibb Company: Honoraria; Novartis Pharma K.K: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria; Pfizer Japan Inc.: Honoraria. Sunami:Takeda: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Research Funding; Bristol-Myers Squibb K.K.: Research Funding; Daiichi Sankyo: Research Funding; Sanofi: Research Funding; Janssen Pharmaceutical: Research Funding; Ono Pharmaceutical: Research Funding. Akashi:Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Hakko Kirin: Consultancy, Research Funding; Shionogi & Co., Ltd: Research Funding; Asahi Kasei Pharma Corporation: Research Funding; Astellas Pharma: Research Funding; Bristol Meyers Squibb: Research Funding; Sunitomo Dainippon Pharma: Consultancy; Celgene: Research Funding. Kanakura:Bristol Myers: Research Funding; Alexionpharma: Research Funding; Nippon Shinyaku: Research Funding; Astellas: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Chugai Pharmaceutical: Research Funding; Shionogi: Research Funding; Kyowa Hakko Kirin: Research Funding; Toyama Chemical: Research Funding; Fujimotoseiyaku: Research Funding.