Efficacy and safety of switching to nilotinib in patients with CML-CP in major molecular response to imatinib: results of a multicenter phase II trial (NILSw trial)
- 462 Downloads
We evaluated the efficacy and safety of switching to nilotinib in CML-CP patients who had achieved MMR with continuous detectable BCR-ABL1 transcript levels after long-term imatinib treatment. Patients who had achieved MMR, but not deep molecular response (DMR), after > 18 months from the initiation of imatinib received nilotinib 400 mg twice daily for up to 24 months. BCR-ABL1 transcript levels were assessed every 3 months. Thirty-eight patients with a median age of 57.5 years (range 22–76 years) were evaluated. Twenty-seven patients completed 24 months of nilotinib treatment; 11 discontinued nilotinib due to retraction of consent (three patients), loss of MMR (1), intolerance (3) or AEs (5). Twenty patients [52.6%, (90% CI 38.2–66.7%)] achieved DMR. The cumulative incidence of achieving DMR by the time of 3, 6, 9, 12, 15, 18, and 21 months was 22.9, 37.7, 47.0, 53.7, 53.7, 53.7, and 53.7%, respectively. Adverse events were consistent with those reported in other nilotinib studies. Patients experienced each of the following cardiovascular complications: atrial fibrillation (G2), chest tightness and dyspnea (G1), myocardial infarction (G2) and heart failure (G3) (n = 1 for each complication). This study indicates nilotinib achieves strong, rapid induction of DMR for patients who achieved MMR after long-term imatinib therapy.
KeywordsChronic myelogeneous leukemia Deep molecular response Major molecular response Imatinib Nilotinib
This study was supported and funded by Novartis Pharmaceutical Corporation. We would like to thank all of the participated patients and their families. We are indebted to the physicians, all other co-medical staff and Independent Data Monitoring Committee (Masahiro Kizaki, Kazuma Ohyashiki and Noriko Usui) who contributed to this study. We also thank the stuffs at the Clinical Research Support Center Kyushu (CReS Kyushu) for their excellent collection and management of data, secretarial assistance, and any other supports.
Compliance with ethical standards
Conflict of interest
I. M. acted as a consultant for Otsuka and received honoraria for Otsuka, Novartis, Bristol-Myers Squibb. J. K. received research funding from Celgene, Bristol-Myers Squibb and Astra Zeneca and honoraria for Celgene, Bristol-Myers Squibb and Janssen. H. N. acted as a consultant and received research funding and honoraria from Novartis. H. S. received research funding and speaker bureau from Novartis. M. H. received research funding and honoraria from Novartis. K. A. acted as a consultant for Sumitomo Dainippon and Kyowa Hakko Kirin and received research funding from Celgene, Kyowa Hakko Kirin, Astellas, Shionogi, Asahi Kasei, Chugai, Bristol-Myers Squibb. Y. K. received research funding from Kyowa Hakko Kirin, Shionogi, Chugai, Pfizer, Eisai, Astellas, Nippon Shinyaku, Alexionpharma, Bristol-Myers Squibb, Toyama Chemical, Fujimotoseiyaku. The remaining authors declare no competing financial interests.
- 6.Branford S, Seymour JF, Grigg A, Arthur C, Rudzki Z, Lynch K, et al. BCR-ABL messenger RNA levels continue to decline in patients with chronic phase chronic myeloid leukemia treated with imatinib for more than 5 years and approximately half of all first-line treated patients have stable undetectable BCR-ABL using strict sensitivity criteria. Clin Cancer Res. 2007;13:7080–5.CrossRefPubMedGoogle Scholar
- 9.Hehlmann R, Müller MC, Lauseker M, Hanfstein B, Fabarius A, Schreiber A, et al. Deep molecular response is reached by the majority of patients treated with imatinib, predicts survival, and is achieved more quickly by optimized high-dose imatinib: results from the randomized CML-study IV. J Clin Oncol. 2014;32:415–23.CrossRefPubMedGoogle Scholar
- 10.Mahon FX, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029–35.CrossRefPubMedGoogle Scholar
- 12.Imagawa J, Tanaka H, Okada M, Nakamae H, Hino M, Murai K, et al. Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial. Lancet Haematol. 2015;2:e528–35.CrossRefPubMedGoogle Scholar
- 14.Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30:1044–54.CrossRefPubMedPubMedCentralGoogle Scholar