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458 Outcome of 472 Chronic Myeloid Leukemia Patients Treated with Frontline Nilotinib: A Gimema CML WP Analysis

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Therapy: First Line Trials and Prognostic Factors of Treatment-Free Remission
Hematology Disease Topics & Pathways:
Adult, Biological, Diseases, CML, Therapies, Study Population, Clinically relevant, Myeloid Malignancies, TKI
Sunday, December 2, 2018: 4:45 PM
Room 6E (San Diego Convention Center)

Gabriele Gugliotta, MD, PhD1, Fausto Castagnetti, MD, PhD2, Massimo Breccia, MD3*, Alessandra Iurlo4*, Mariella D'Adda5*, Fabio Stagno, MD, PhD6, Luciano Levato7*, Bruno Martino, MD8*, Francesca Lunghi9*, Mario Tiribelli10*, Giovanna Rege Cambrin, MD11*, Elisabetta Abruzzese, MD12, Serena Rupoli, MD13*, Antonella Gozzini14*, Patrizia Pregno15*, Marzia Salvucci, MD16*, Elena Trabacchi, MD17*, Giovanni Caocci, MD18*, Anna Rita Scortechini, MD19*, Luigia Luciano, MD20, Giuseppe Tagariello21*, Massimiliano Bonifacio22*, Simona Soverini, PhD23, Robin Foà, MD24, Giovanni Martinelli, MD25, Michele Cavo, MD2*, Fabrizio Pane26, Giuseppe Saglio27, Michele Baccarani, MD1 and Gianantonio Rosti1*

1Institute of Hematology "L. and A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine, Bologna, Italy
2Institute of Hematology "L. and A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, "S. Orsola-Malpighi" Hospital, Bologna, Italy
3Division of Cellular Biotechnologies and Hematology, University "Sapienza", Roma, Italy
4Hematology Division, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
5Department of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy
6Hematology Unit, Hematology Section, Biomedical Sciences, Trecastagni, Catania, Italy
7Department Hematology-Oncology, Azienda Ospedaliera Pugliese-Ciaccio, Catanzaro, Italy
8Hematology Department, Grande Ospedale Metropolitano-G.O.M. Bianchi-Melacrino-Morelli, Reggio Calabria, Italy
9Haematology and Bone Marrow Transplant Unit, San Raffaele Scientific Institute IRCCS, Milano, Italy
10Division of Hematology and BMT, Department of Medical Area, University of Udine, Udine, Italy
11University of Turin, ORBASSANO TORINO, ITA
12Haematology Unit, S. Eugenio Hospital, Rome, Italy
13Hematology Unit, AOU- Ospedali Riuniti Umberto I, Ancona, Italy
14Divisione di Ematologia-Policlinico Careggi di Firenze, Firenze, ITA
15Hematology Unit, Az Ospedaliero Universitaria Città' della Salute e della Scienza, Torino, Italy
16Hematology Unit, S. Maria delle Croci Hospital, Ravenna, Italy
17Hematology and BMT Unit, Department of Hematology and Oncology, Guglielmo da Saliceto Hospital, Piacenza, Italy
18Department of Medical Sciences and Public Health, University of Cagliari, "A.Businco" Hospital, Cagliari, Italy
19Hematology Unit, Ospedali Riuniti University Hospital, Ancona, Italy
20Hematology Unit, Federico II University of Naples, Napoli, ITA
21Regional General Hospital, Castelfranco Veneto, ITA
22Department of Medicine, Section of Haematology, University of Verona, Verona, Italy
23Institute of Hematology "L. and A. Seràgnoli", Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, "S. Orsola-Malpighi" Hospital, Castel Maggiore, Bologna, Italy
24Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Policlinico Umberto I, Rome, Italy
25Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRST IRCCS, Meldola, Italy
26Hematology Unit, Federico II University of Naples, Napoli, Italy
27Hematology Division, Ospedale Mauriziano, University of Turin, Torino, Italy

BACKGROUND: In chronic phase (CP) chronic myeloid leukemia (CML) nilotinib showed better efficacy compared to imatinib. The higher rates of deep molecular response with nilotinib may translate in more patients (pts) eligible for treatment discontinuation. On the other hand, cardiovascular toxicity may limit nilotinib use in selected groups of pts (e.g. elderly pts).

AIM: To investigate the efficacy and safety, overall and according to age, of first-line treatment with nilotinib in CML pts.

METHODS: We analyzed response rates, events and outcome of 472 pts ≥ 18 y of age with CP CML, enrolled in clinical trials of the GIMEMA CML WP with nilotinib frontline. Pts were treated with: nilotinib 300 mg BID (n=276); nilotinib 400 mg BID (n=73); rotation of nilotinib 400 mg BID / imatinib 400 mg OD (3-month periods for each drug)(n=123). The median follow-up was 36 (3-82) months. Pts were further analyzed considering 3 age groups: 18-39 y (98 pts); 40-59 y (217 pts); and ≥ 60 y (157 pts). Definitions: Major molecular response (MR3): BCR-ABL≤0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies. Events: permanent discontinuation of nilotinib for any reason, including adverse events, progression to accelerated/blast phase (AP/BP), or deaths. Arterial thrombotic events (ATEs): peripheral arterial obstructive disease, acute coronary syndrome, chronic ischemic heart disease, significant carotid stenosis and ischemic stroke, or other significant ischemic events.

RESULTS: Overall, the cumulative incidences of MR3 by 12, 24, and 36 months were 75, 88, and 93%, respectively. The cumulative incidences of MR4 by 12, 24, and 36 months were 38, 63, and 76%, respectively. Events leading to permanent nilotinib discontinuation occurred in 132 (27.9%) pts. ATEs occurred in 33 (7% of pts) ATEs, corresponding to 19.7 ATEs/1000 pt-y. Fifteen (3.1%) pts progressed to AP/BP. Overall, 23 (4.9%) pts died, 11 of them after progression to AP/BP. The estimated 5-year OS was 93%.

The sub-analysis according to age showed that: MR3 and MR4 rates were similar across the 3 age groups (cumulative incidences of MR4 by 24 months were 55, 62, and 70% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively; p=0.25). Progressions to AP/BP were: 6.1% in pts 18-39 y, 2.8% in pts 40-59 y, and 1.9% in pts ≥ 60 y. ATEs were: 0 in pts 18-39y, 4.1% (11.7/1000 pt-years) in pts 40-59 y, and 15.3% (41.3/1000 pt-years) in pts ≥ 60 y (no difference in ATEs was found between pts 60-69 y and those ≥ 70 y). The 5-y OS was 91, 97, and 89% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively (p=0.065). Death was always leukemia-related in pts 18-39 y (100%), while it was mainly leukemia-unrelated (75%) in pts ≥ 60 y.

SUMMARY/CONCLUSION: Nilotinib as first-line treatment of newly diagnosed CP CML pts showed high rates of deep molecular responses, few progressions to AP/BP, and a high OS. Deep molecular response were similar in all age groups; as expected, ATEs were more frequent in pts > 60 y. These data suggest that: in pts > 60 y, the high efficacy of nilotinib should be weighed against its potential toxicity; in pts < 60 years, nilotinib may be a very good choice, with high efficacy and low toxicity.

Disclosures: Gugliotta: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria. Castagnetti: Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria. Levato: Novartis: Other: Advisory board. Abruzzese: Pfizer: Consultancy; Ariad: Consultancy; Novartis: Research Funding; BMS: Consultancy. Soverini: Bristol Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy. Foà: NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; AMGEN: Other: ADVISORY BOARD. Martinelli: Astellas Pharma: Research Funding; Amgen: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cavo: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pane: Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; AMGEN: Speakers Bureau.

*signifies non-member of ASH