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460 Nilotinib Vs Nilotinib Plus Pegylated Interferon-alpha2b Induction and Nilotinib or Pegylated Interferon-alpha2b Maintenance Therapy for Newly Diagnosed BCR-ABL+ Chronic Myeloid Leukemia Patients in Chronic Phase: Interim Analysis of the Tiger (CML V)-Study

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:
Diseases, Biological, Adult, CML, Therapies, Biological Processes, Technology and Procedures, immunotherapy, Study Population, Clinically relevant, Myeloid Malignancies, Quality Improvement , immune mechanism, TKI, molecular testing, signal transduction
Sunday, December 2, 2018: 5:15 PM
Room 6E (San Diego Convention Center)

Andreas Hochhaus, MD1, Susanne Saussele, MD2*, Gabriela M Baerlocher3, Tim H Brümmendorf, MD4, Andreas Burchert, MD5, Paul La Rosée, MD6*, Joerg Hasford, MD7*, Rüdiger Hehlmann, MD8, Dominik Heim, MD9, Stefan W Krause, MD10*, Philipp le Coutre, MD11, Dietger Niederwieser, MD12, Jiří Mayer13, Thoralf Lange, MD14*, Mathias Haenel, MD15*, Frank Stegelmann, MD16*, Arthur Gil, MPH7*, Thomas Ernst17, Christian Fabisch, PhD1* and Markus Pfirrmann, PhD7*

1Klinik für Innere Medizin II, Universitätsklinikum Jena, Jena, Germany
2Universitätsmedizin Mannheim, Mannheim, Germany
3Department of Hematology, Inselspital Bern, University Hospital, University of Bern, Bern, Switzerland
4Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, University Hospital RWTH Aachen University, Aachen, Germany
5Dep. of Internal Medicine, Hematologgy, Oncology and Immunology, Philips Univ. Marburg, Marburg, Hessen, Germany
6Schwarzwald-Baar-Klinikum, Villingen-Schwenningen, Germany
7IBE, Ludwig-Maximilians-Universität, München, Germany
8ELN Foundation, Weinheim, Germany
9Hematology, University Hospital Basel, Basel, Switzerland
10Medizinische Klinik V, Universitätsklinikum Erlangen, Erlangen, Germany
11Hematology and Oncology, Charite Humboldt Universität, Berlin, Berlin, Germany
12Department of Hematology and Oncology, University Hospital Leipzig, Leipzig, Germany
13Department of Internal Medicine, Hematology and Oncology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
14Asklepios Klinikum Weissenfels, Weissenfels, Germany
15Department of Hematology, Oncology and Stem Cell Transplantation, Klinikum Chemnitz GmbH, Chemnitz, Germany
16Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
17Klinik für Innere Medizin II, Abt. Hämatologie und Internistische Onkologie, Universitätsklinikum Jena, Jena, Germany

Introduction: The TIGER (CML V)-study (NCT01657604) is a multicenter, randomized phase III trial to evaluate efficacy and tolerability of nilotinib (NIL) 2*300mg/d monotherapy vs NIL 2*300mg/d + pegylated interferon alpha2b (Peg-IFN) and the option to discontinue therapy after Peg-IFN maintenance as first line therapy for chronic myeloid leukemia (CML) patients in chronic phase.
Methods: Recruitment started in August 2012 with a pilot phase, aiming to validate the recommended dose of PEG-IFN. 25 pilot phase patients (pts) were treated with the combination of NIL 2*300 mg daily and PEG-IFN (30-50μg/week according to tolerability and commenced after >6 weeks NIL monotherapy). During the main phase of the study, newly diagnosed pts were randomized between NIL 2*300 mg/d and NIL/PEG-IFN combination in accordance with the approach which was confirmed to be feasible during the pilot phase. After at least 2 years NIL based induction therapy and achievement of major molecular remission (MMR, BCR-ABL transcript level ≤0.1% according to the international scale, IS), maintenance therapy (NIL vs PEG-IFN) started. Requirements for treatment discontinuation were treatment duration of at least 3 years with stable MR4 (BCR-ABL ≤0.01%) for at least one year. NIL therapy was reinitiated in case of molecular recurrence, defined as loss of MMR. The major co-endpoints of the study are (i) rate of MMR at 18 months (NIL vs NIL+PEG-IFN), and (ii) rate of continuous MMR 12 and 24 months after discontinuation of NIL vs PEG-IFN. Efficacy and safety data are presented without specification of the randomized therapy during the ongoing study.
Results: Within 5 years, a total of 717 pts (429 male; median age 51, range 18-85 years; 13.3% EUTOS high risk) were recruited from 111 sites in Germany, Switzerland, and the Czech Republic. Median observation time since recruitment was 30.3 months. 396 pts concluded the induction phase and reached the maintenance phase of the study. 138 pts achieved and maintained MR4 (BCR-ABL ≤0.01% IS) for at least one year during the maintenance phase and discontinued all therapy. With regard to efficacy in the two treatment arms, 79.5% reached MMR at 12 mo. (95% confidence interval (CI): [76.1-82.7%]), 84.9% at 18 mo. (95% CI: [81.4-88.0%]), and 89.4% at 24 mo. (95% CI: [86.0-92.2%]) after randomization. Probabilities of adverse events of grade 1-5 after 12 mo. of therapy were 83.7 (95% CI: [79.2-87.3%]) and 90.0% (95% CI: [85.8-93.0%]), and of grade 3-5 after 3 years 39.6 (95% CI: [33.4-45.7%]) and 49.5% (95% CI: [42.7-56.0%]) for the two treatment arms. Twelve pts progressed to accelerated phase or blast crisis; four of them died from blast crisis. A total of 13 patients received 14 allogeneic stem cell transplantations in chronic phase (n=7) or blast crisis (n=7). In total, 19 pts died, five related to CML, three from vascular complications.
Conclusions: This interim analysis demonstrates feasibility of 1st-line treatment with NIL 2*300 mg/d combined with PEG-IFN 30-50 μg/week. Molecular response during the first 24 mo. favourably compares with data from recent NIL based studies (ENESTnd, NCT00471497; ENEST1st, NCT01061177) and permits access to the maintenance phase (NIL vs PEG-IFN monotherapies) for the majority of patients – with the potential of treatment-free remission.
The study was conducted by the German CML Study Group in cooperation with the Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) and the Ostdeutsche Studiengruppe Hämatologie und Onkologie (OSHO).

Disclosures: Hochhaus: Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Saussele: Novartis: Research Funding; BMS: Research Funding; MSD: Research Funding. Baerlocher: Novartis: Research Funding. Brümmendorf: Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Consultancy; Merck: Consultancy; Janssen: Consultancy. Burchert: AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Research Funding. La Rosée: Novartis: Research Funding. Hasford: Novartis: Research Funding. Krause: Novartis: Research Funding. le Coutre: Incyte: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Niederwieser: Miltenyi: Speakers Bureau; Novartis: Research Funding. Mayer: Novartis: Research Funding; Amgen: Research Funding. Lange: Novartis: Research Funding. Haenel: Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Stegelmann: Novartis: Consultancy, Honoraria. Gil: Novartis: Research Funding. Ernst: Novartis: Research Funding. Fabisch: Novartis: Research Funding. Pfirrmann: Novartis: Research Funding.

*signifies non-member of ASH