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446 Treatment Free Remission after Nilotinib Plus Peg-Interferon Alpha Induction and Peg-Interferon Alpha Maintenance Therapy for Newly Diagnosed Chronic Myeloid Leukemia Patients; The Tiger Trial

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Treatment-Free Remission and Prognostication
Hematology Disease Topics & Pathways:
clinical trials, Research, CML, Clinical Research, Chronic Myeloid Malignancies, Diseases, Therapies, Myeloid Malignancies
Sunday, December 10, 2023: 9:45 AM

Andreas Hochhaus, MD1, Andreas Burchert, MD2, Susanne Saussele, MD 3, Gabriela M Baerlocher, MD4*, Jiří Mayer, MD5, Tim H. Brümmendorf6, Paul La Rosée, MD7*, Dominik Heim, MD8, Stefan W. Krause, MD9*, Philipp le Coutre, MD10*, Jenny Rinke, PhD11*, Thoralf Lange, MD12*, Alice Fabarius, PhD13*, Marcel Lorch3*, Mathias Hanel, MD14, Frank Stegelmann15*, Georg-Nikolaus Franke16*, Markus P. Radsak17*, Volker Kunzmann, MD18*, Daniela Zackova, MD5*, Danny Himsel, MSc11*, Denise Kohn19*, Thomas Lang, MSc19*, Rüdiger Hehlmann, MD 20, Christian Fabisch11*, Thomas Ernst, MD11 and Markus Pfirrmann, PhD19*

1Universitätsklinikum Jena, Jena, Germany
2Department of Hematology, Oncology and Immunology, University Hospital Marburg, Marburg, Germany
3Universitätsmedizin Mannheim, Mannheim, Germany
4Laboratory for Hematopoiesis and Molecular Genetics, University of Bern, Bern, Switzerland
5Masaryk University, Brno, Czech Republic
6Hematology/Oncology, Universitätsklinikum RWTH Aachen, Aachen, Germany
7Schwarzwald-Baar Klinikum, Villingen-Schwenningen, Germany
8Division of Hematology, University Hospital Basel, Basel, Switzerland
9Universitätsklinikum Erlangen, Erlangen, Germany
10Charité Humboldt Universität, Berlin, Germany
11Hematology/Oncology, Universitätsklinikum Jena, Jena, Germany
12Hematology/Oncology, Asklepios Klinikum, Weißenfels, Germany
13Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany
14Hematology/Oncology, Klinikum Chemnitz, Chemnitz, Germany
15Hematology/Oncology, Universitätsklinikum Ulm, Ulm, Germany
16Hematology, Universitätsklinikum Leipzig, Leipzig, Germany
17Hematology/Oncology, Universitätsmedizin Mainz, Mainz, Germany
18Medizinische Klinik II, Universitätsklinikum Wuerzburg, Wuerzburg, Germany
19Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie (IBE), Ludwig-Maximilians-Universität, München, Germany
20ELN-Foundation, Weinheim, Germany

Background: The TIGER-trial (NCT01657604) is a multicenter, randomized phase III study to evaluate efficacy and tolerability of nilotinib (NIL) vs NIL+pegylated interferon alpha2b (IFN) combination therapy with IFN maintenance as first-line treatment for patients (pts) with chronic myeloid leukemia (CML) in chronic phase.

Methods: A total of 717 pts were recruited from 110 sites in Germany, Switzerland, and the Czech Republic. A pilot phase (n=25) validated the feasibility of the combination of NIL 300 mg BID and IFN (30-50µg/week according to tolerability and commenced after ≥6 weeks NIL monotherapy). In the main phase, 692 pts were randomly assigned to NIL (n=353) and NIL/IFN (n=339). Achievement of major molecular remission (MMR, BCR::ABL1 ≤0.1% on the International Scale, IS) after >24 months (mo) of therapy was the trigger to start the maintenance phase; treatment-free remission (TFR) started in pts with ≥12 mo persistence of MR4 (BCR::ABL1 ≤0.01% IS) after >36 mo total therapy. Quality of life (QoL) was evaluated using EORTC QLQ-C30 and CML24 questionnaires.

Results: From 692 randomized pts, 411 were male (59%), median age was 51 years (range, 18-85). In the monotherapy arm, median treatment duration with NIL was 3.1 years (0.02-8.9), median daily dose 600 mg (183-764). In the combination arm, median treatment duration with NIL was 2.3 years (0.02-9.1), median daily dose 600 mg (106-792). Median duration of IFN therapy was 2.4 years (0-9.0). A median of 77 (0-485) IFN injections were administered, the median dose of IFN per injection was 30µg (0-50). Probabilities of MMR and MR4.5 (BCR::ABL1 ≤0.0032% IS, Fig 1) by 24 mo were 89% (95% CI: 85-92%) and 49% (44-55%) vs 93% (89-95%) and 64% (59-69%) with NIL vs NIL/IFN, respectively. In 356 pts (53%) qualifying for the discontinuation phase (NIL, n=197; NIL/IFN, n=159), probabilities of maintained MMR by 24 mo were 53% (45-60%) and 62% (54-70%) after NIL and NIL/IFN, respectively, in an intention-to-treat-analysis (p=0.13). 273 (40%) eligible pts actually discontinued therapy (per-protocol-analysis, NIL, n=163; NIL/IFN, n=110). Probabilities of TFR by 24 mo were 53% (45-61%) vs 59% (49-68%) for NIL and NIL/IFN, respectively (Fig 2).

Fifteen pts (2.2%) with atypical BCR::ABL1 transcripts (e1a2, n=7; e19a2, n=4; e8a2, n=2; e13a3 and e14a3, n=1 each) were randomized to receive NIL (n=7) or NIL/IFN (n=8). After a median treatment period of 37 mo (36-39) 9 pts achieved and maintained a BCR::ABL1 reduction of at least 4 orders of magnitude and were eligible for TFR. 6 pts failed to achieve an individual transcript decline by at least 3 logs. TFR was commenced in 7 and maintained in 6 pts after 32 (range, 20-84) mo.

Adverse events of special interest grades 3-5 were arterio-vascular disorders in 9 vs 8%, fatigue in 2 vs 4%, thrombocytopenia in 8 vs 8%, and alanine aminotransferase elevation in 4 vs 9% of pts in the NIL vs NIL/IFN arms, respectively. QoL analyses revealed the perception of a decreased cognitive function and higher rates of fatigue in pts in the NIL/IFN arm, particularly in pts older than 40 years.

In total, 24 pts (NIL, n=13; NIL/IFN, n=11) progressed to advanced disease. By 8 years, progression-free survival was 94% (95% CI: 90-96%) and 92% (88-95%), overall survival 95% (92-97%) and 94% (91-97%) in the NIL and NIL/IFN arms, respectively. 28 pts (3.9%) received an allogeneic stem cell transplantation, 14 after disease progression. 35 pts died (NIL, n=18; NIL/IFN, n=17), 9 related to CML.

Conclusions: Survival of CML pts has reached probabilities close to normal. The combination of NIL with IFN is associated with a higher rate of molecular responses but also impaired tolerability. IFN maintenance is feasible, and resulted in a trend towards higher rates of long-term TFR.

The study was conducted on behalf of the German CML Study Group in cooperation with the East German Study Group on Hematology and Oncology (OSHO) and the Swiss Group for Clinical Cancer Research (SAKK).

Disclosures: Hochhaus: Bristol Myers Squibb: Consultancy, Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Burchert: MSD: Research Funding; Incyte: Honoraria; Novartis: Honoraria, Research Funding. Saussele: Incyte: Research Funding; BMS: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Roche: Consultancy. Baerlocher: MSD: Research Funding; Novartis: Research Funding; Geron Corporation: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Mayer: MSD: Research Funding; Novartis: Research Funding. Brümmendorf: Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. La Rosée: MSD: Research Funding; Novartis: Research Funding. le Coutre: Incyte: Honoraria; Blueprint: Honoraria; AOP: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Hanel: Novartis: Research Funding. Stegelmann: AOP Pharma: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; GSK: Consultancy, Honoraria. Radsak: Cogent Biosciences: Honoraria; Pfizer: Honoraria; JAZZ: Other: Travel support; Bristol Myers Squibb: Other: Travel support; TEVA: Honoraria; Abbvie: Honoraria; Lilly: Honoraria; Otsuka: Honoraria; Takeda: Honoraria; Novartis: Other: Travel support; Corat: Honoraria; Incyte: Honoraria; Daiichi Sankyo: Other: Travel support; Glaxo Smith Kline: Honoraria; Beigene: Honoraria; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Amgen: Other: Travel support; Abbvie: Other: Travel support; Astellas: Other: Travel support; SOBI: Other: Travel support; AOP: Other: Travel support. Kunzmann: Novartis: Research Funding. Zackova: Pfizer: Honoraria, Other: travel grant, Speakers Bureau; Astra Zeneca: Other: travel grant; Angelini Pharma: Consultancy, Honoraria, Other: travel grant, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel grant, Speakers Bureau. Ernst: Novartis: Research Funding. Pfirrmann: Novartis: Honoraria.

OffLabel Disclosure: Combination of Nilotinib and pegylated Interferon alpha in CML.

*signifies non-member of ASH