François-Xavier Mahon, MD, PhD; Carla Boquimpani, MD; Dong-Wook Kim, MD, PhD; Noam Benyamini, MD; Nelma Cristina D. Clementino, MD; Vasily Shuvaev, MD; Sikander Ailawadhi, MD; Jeffrey Howard Lipton, MD, PhD; Anna G. Turkina, MD; Raquel De Paz, MD, PhD; Beatriz Moiraghi, MD; Franck E. Nicolini, MD, PhD; Jolanta Dengler, MD; Tomasz Sacha, MD, PhD; Naoto Takahashi, MD, PhD; Rafik Fellague-Chebra, MD, MSc; Sandip Acharya, MSc; Stephane Wong, PhD, MSc; Yu Jin, MSc; Timothy P. Hughes, MD
Presented in part at the 2016 American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, 3–7 June 2016; the 21st European Hematology Association Congress, Copenhagen, Denmark, 9–12 June 2016; the 4th Society of Hematologic Oncology Annual Meeting, Houston, Texas, 7–10 September 2016; the 58th American Society of Hematology Annual Meeting, San Diego, California, 3–6 December 2016; and the 22nd European Hematology Association Congress, Madrid, Spain, 22–25 June 2017.
Acknowledgment: The authors thank all study participants and their families, the study investigators, and staff at participating study sites. They also thank Joy Loh, PhD, and Jonathan Morgan, PhD, of ArticulateScience LLC, for medical editorial assistance with this manuscript.
Financial Support: By Novartis Pharmaceuticals Corporation, which also provided financial support for medical editorial assistance.
Disclosures: Dr. Mahon reports honoraria from Bristol-Myers Squibb (BMS), Novartis Pharma, and Pfizer; advisory board membership in BMS, Novartis Pharma, and Ariad/Incyte; and research support from Novartis Pharma. Dr. Ailawadhi reports grants and personal fees from Pharmacyclics and personal fees from Takeda Pharmaceuticals, Novartis, and Amgen outside the submitted work. Dr. Lipton reports grants and personal fees from and advisory board membership in Novartis during the conduct of the study and BMS, Pfizer, and Ariad outside the submitted work. Dr. Moiraghi reports speaking fees from BMS and Novartis outside the submitted work. Dr. Nicolini reports personal fees and nonfinancial support from BMS, grants and personal fees from Novartis, and personal fees from Incyte Biosciences Pharma during the conduct of the study. Dr. Sacha reports personal fees from Novartis, BMS, Angelini, and Pfizer outside the submitted work. Dr. Takahashi reports grants and personal fees from Novartis, Otsuka, and Pfizer and personal fees from BMS outside the submitted work. Dr. Fellague-Chebra and Mr. Acharya were employed by Novartis during the conduct of the study. Dr. Wong is employed by and owns stock in Novartis. Dr. Hughes reports grants and personal fees from and board membership in Novartis, BMS, and Ariad outside the submitted work. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M17-1094.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interest to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Catharine B. Stack, PhD, MS, Deputy Editor for Statistics, reports that she has stock holdings in Pfizer and Johnson & Johnson.
Reproducible Research Statement:Study protocol: See the Supplement. Statistical code: Not applicable. Data set: Not available.
Requests for Single Reprints: Timothy P. Hughes, MD, South Australian Health and Medical Research Institute, North Terrace, Adelaide, South Australia 5000, Australia; e-mail, firstname.lastname@example.org.
Current Author Addresses: Dr. Mahon: CRLCC Institut Bergonié, 229 cours de l'Argonne, 33076 Bordeaux Cedex, France.
Dr. Boquimpani: HEMORIO, Rua Frei Caneca 8, Centro–Rio de Janeiro, Brazil 20211-030.
Dr. Kim: Seoul St. Mary's Hospital, The Catholic University of Korea, #62 Youidodong Youngdeungpogu, Seoul, Korea 150-713.
Dr. Benyamini: Rambam Health Care Campus, Department of Hematology and Bone Marrow Transplantation, Rambam Medical Center, Haifa, Israel 31096.
Dr. Clementino: Hospital Das Clinicas da UFMG, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil 31270-901.
Dr. Shuvaev: Russian Research Institute of Hematology and Transfusiology, Saint-Petersburg Russian Federation 191024.
Dr. Ailawadhi: Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224.
Dr. Lipton: Princess Margaret Cancer Centre, University of Toronto, 610 University Avenue, 5th Floor, Room 106, Toronto, Ontario, M5G 2M9, Canada.
Dr. Turkina: FGBS of Hematology Research Center Health Ministry, 125 127, Novy Zykovsky pr, 4a, Moscow, Russia 125167.
Dr. De Paz: Hospital Universitario La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain.
Dr. Moiraghi: Hospital Jose Maria Ramos Mejia, General Urquiza 609, Buenos Aires, Argentina C1221ADC.
Dr. Nicolini: Hématologie Clinique 1G, Centre Hospitalier Lyon Sud D, 165, Chemin du Grand Revoyet, Bérard, 69495 Pierre Benite, Laënnec Cédex 03, France.
Dr. Dengler: Onkologische Schwerpunktpraxis Heilbronn, Allee 40, 74072 Heilbronn, Germany.
Dr. Sacha: Department of Haematology, Jagiellonian University Medical College, Świe˛tej Anny 12, Kraków, Poland 31-008.
Dr. Takahashi: Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Hondo 1-1-1, Akita City, Japan 010-8543.
Dr. Fellague-Chebra: Novartis Pharma SAS, 2 & 4 rue Lionel Terray, F-92500 Rueil-Malmaison, France.
Mr. Acharya: Salarpuria-Sattva Knowledge City, Raidurg/Hyderabad, Rangareddy 500 081 India.
Dr. Wong: 45 Sidney Street, 2nd Floor 609/2116P, Cambridge, MA 02139.
Ms. Jin: Novartis Pharmaceuticals Corporation, USEH, 337.A7.3A, One Health Plaza, East Hanover, NJ 07936.
Dr. Hughes: South Australian Health and Medical Research Institute, North Terrace, Adelaide, South Australia 5000, Australia.
Author Contributions: Conception and design: F.-X. Mahon, J.H. Lipton, R. Fellague-Chebra, S. Acharya, Y. Jin, T.P. Hughes.
Analysis and interpretation of the data: F.-X. Mahon, N. Benyamini, J.H. Lipton, F.E. Nicolini, N. Takahashi, R. Fellague-Chebra, S. Acharya, S. Wong, Y. Jin, T.P. Hughes.
Drafting of the article: F.-X. Mahon, S. Ailawadhi, F.E. Nicolini, N. Takahashi, R. Fellague-Chebra, S. Wong, Y. Jin, T.P. Hughes.
Critical revision for important intellectual content: F.-X. Mahon, D.-W. Kim, N. Benyamini, N.C.D. Clementino, J.H. Lipton, R. De Paz, B. Moiraghi, J. Dengler, T. Sacha, R. Fellague-Chebra, S. Acharya, S. Wong, Y. Jin, T.P. Hughes.
Final approval of the article: F.-X. Mahon, C. Boquimpani, D.-W. Kim, N. Benyamini, N.C.D. Clementino, V. Shuvaev, S. Ailawadhi, J.H. Lipton, A.G. Turkina, R. De Paz, B. Moiraghi, F.E. Nicolini, J. Dengler, T. Sacha, N. Takahashi, R. Fellague-Chebra, S. Acharya, S. Wong, Y. Jin, T.P. Hughes.
Provision of study materials or patients: F.-X. Mahon, C. Boquimpani, N. Benyamini, N.C.D. Clementino, V. Shuvaev, S. Ailawadhi, J.H. Lipton, A.G. Turkina, F.E. Nicolini, N. Takahashi, R. Fellague-Chebra.
Statistical expertise: R. Fellague-Chebra, S. Acharya.
Obtaining of funding: A.G. Turkina, R. Fellague-Chebra, S. Wong.
Administrative, technical, or logistic support: S. Wong, R. Fellague-Chebra, Y. Jin.
Collection and assembly of data: N. Benyamini, S. Ailawadhi, J.H. Lipton, F.E. Nicolini, T. Sacha, R. Fellague-Chebra, S. Wong, Y. Jin.
Treatment-free remission (TFR)—that is, stopping tyrosine kinase inhibitor (TKI) therapy without loss of response—is an emerging treatment goal in chronic myeloid leukemia (CML).
To evaluate TFR after discontinuation of second-line nilotinib therapy.
Single-group, phase 2, open-label study. (ClinicalTrials.gov: NCT01698905)
63 centers in 18 countries.
Adults with CML in chronic phase who received TKI therapy for at least 3 years (>4 weeks with imatinib, then ≥2 years with nilotinib) and achieved MR4.5 (BCR-ABL1 ≤0.0032% on the International Scale [BCR-ABL1IS]) while receiving nilotinib entered a 1-year consolidation phase. Those with sustained MR4.5 during consolidation were eligible to enter TFR.
Patients received nilotinib during consolidation; those who entered TFR stopped treatment. Patients with loss of major molecular response (MMR) (BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 (BCR-ABL1IS ≤0.01%) during TFR reinitiated nilotinib treatment.
Proportion of patients without loss of MMR, confirmed loss of MR4, or treatment reinitiation within 48 weeks of stopping treatment (primary end point).
163 patients who had switched from imatinib to nilotinib (for reasons including resistance, intolerance, and physician preference) enrolled in the study and entered the consolidation phase. Of these patients, 126 met the criteria for entering the TFR phase, and 73 (58% [95% CI, 49% to 67%]) and 67 (53% [CI, 44% to 62%]) maintained TFR at 48 weeks (primary end point) and 96 weeks, respectively. Of the 56 patients who reinitiated nilotinib therapy, 55 regained MMR or better and 52 regained MR4.5. None had CML progression to accelerated phase or blast crisis. Musculoskeletal pain was more frequent during the first 48 weeks after nilotinib discontinuation.
The study included a heterogeneous patient population and was not designed to compare outcomes between patients continuing and those stopping treatment.
TFR seems achievable in patients with sustained MR4.5 after switching to nilotinib.
Novartis Pharmaceuticals Corporation.
Mahon F, Boquimpani C, Kim D, Benyamini N, Clementino NCD, Shuvaev V, et al. Treatment-Free Remission After Second-Line Nilotinib Treatment in Patients With Chronic Myeloid Leukemia in Chronic Phase: Results From a Single-Group, Phase 2, Open-Label Study. Ann Intern Med. [Epub ahead of print 20 February 2018]168:461–470. doi: 10.7326/M17-1094
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Published: Ann Intern Med. 2018;168(7):461-470.
Published at www.annals.org on 20 February 2018
Hematology/Oncology, Infectious Disease, Leukemia/Lymphoma, Prevention/Screening, Vaccines/Immunization.
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