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641 Preliminary Results of the Filo Phase 2 Trial for Untreated Fit Patients with Intermediate Risk Chronic Lymphocytic Leukemia Comparing Ibrutinib Plus Venetoclax (IV) Versus FCR

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological II
Hematology Disease Topics & Pathways:
Clinical Trials, Non-Biological, Clinical Research, Chemotherapy, Therapies
Monday, December 13, 2021: 11:30 AM

Anne-Sophie Michallet1*, Anne Quinquenel, MD, PhD2*, Remi Letestu3*, Magali Le Garff-Tavernier4*, Fabien Subtil5*, Mad-Helenie Elsensohn, Msc6*, Therese Aurran7*, Kamel Laribi, MD8*, Florence Cymbalista9*, Vincent Levy, MD, PhD10*, Laurence Simon, MD11*, Damien Roos-Weil12*, Veronique Leblond, MD, PhD13, Marie-Sarah Dilhuydy, MD14*, Cécile Tomowiak15*, Caroline Dartigeas, MD16*, Romain Guieze17*, Olivier Tournilhac18*, Emmanuelle Ferrant, MD19*, Sophie de Guibert, MD20*, Pierre Feugier, MD, PhD21*, Fatiha Merabet22*, Stéphane Leprêtre, MD23*, Philippe Carassou24*, Julie Gay, MD25*, Bénédicte Hivert, MD26*, Luc Mathieu Fornecker, MD, PhD27*, Jehan Dupuis, MD28*, Lysiane Molina, MD29*, Bruno Villemagne, MD30*, Guillaume Cartron, MD, PhD31*, Bernard Drenou, MD, PhD32*, Béatrice Mahé, MD33*, Omar Benbrahim, MD34*, Xavier Cahu35*, Christelle Portois36*, Loic Ysebaert, MD, PhD37*, Florence Nguyen-Khac, MD, PhD38*, Valérie Rouille39* and Alain Delmer40

1Service d'hématologie, Centre Léon Bérard, Lyon, France
2Hematology department, Robert Debré University Hospital, Reims, France
3Laboratoire d'Hématologie, APHP Hôpital Avicenne, Bobigny, FRA
4APHP, Paris, France
5Department of biostatistics, Hospices Civils de Lyon, LYON, France
6department of biostatistics, Hospices civils de Lyon, Lyon, France
7Institut Paoli Calmettes, Marseille, France
8Department of Hematology, CH Le Mans, Le Mans, France
9Laboratory of Hematology, APHP, Hôpital Avicenne, Bobigny, NULL, France
10Hôpital Avicenne, Bobigny, France
11HôPital Civil, Strasbourg Cedex, FRA
12Department of Hematology, APHP, Hôpital de la Pitié Salpêtriere, Paris, France
13Service d'hématologie, Hopital Pitie-Salpetriere, Sorbonne Université, Paris, FRA
14CHU Hopitaux de Bordeaux, Pessac, France
15Department of Hematology, CHU Poitiers, Poitiers, France
16Department of Hematology, CHU Tours, Tours, France
17Department of Hematology, CHU Clermont Ferrand, Clermont Ferrand, MA, France
18Service d'Hematologie Clinique et de Therapie Cellulaire, CHU Estaing, Universite Clermont Auvergne, EA7453, CIC-1405, CLERMONT FERRAND, France
19Department of Hematology and Oncology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Université Claude Bernard, Pierre-Benite, France
20Centre Hospitalier Pontchaillou, Rennes, FRA
21Département d'Hématologie, CHRU Nancy, Hôpitaux de Brabois, Vandoeuvre-lès-Nancy, France
22Service Hématologie et Oncologie, Hôpital André Mignot, Le Chesnay, France
23Inserm U1245 and Department of Hematology, Centre Henri Becquerel and Normandie Univ UNIROUEN, Rouen, France
24CH Metz, Metz, FRA
25Service d'Hématologie, Centre Hospitalier de la Côte Basque, Bayonne, France
26Centre Hospitalier Schaffner, Lens Cedex 9, Lens, France
27Department of Hematology, Strasbourg University Hospital, Strasbourg, France
28Lymphoid Malignancies Unit, Henri Mondor University Hospital, APHP, Créteil, France
29Hématologie clinique, CHU de Grenoble, La Tronche, France
30Clinical Hematology, Centre Hospitalier Départemental Vendée, La Roche-sur-Yon, France
31Hematology Department, Montpellier University Hospital, Montpellier, France
32HôPital Emile Muller, Mulhouse Cedex 1, FRA
33Clinical Hematology, Nantes University Hospital, Nantes, France
34Hematology Department, Orleans CHR, Orleans, France
35Hopital privé, Cesson sevigne, France
36hematology, CHU Saint Etienne, Saint Etienne, France
37Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
38Hematologie Biologique, APHP Pitié Salpêtrière, Paris, France
39CHU Montpellier, Montpellier, France
40Department of Hematology, CHU Reims, Reims, Cedex, France

With the emergence of targeted therapies, defining the best strategy for the treatment of previously untreated CLL patients remains challenging. The aim of this phase 2 study was to compare the efficacy of an association with ibrutinib and venetoclax (IV) to the standard FCR regimen in fit patients with intermediate risk CLL defined by either unmutated IGHV status, 11q deletion or complex karyotype in the absence of TP53 abnormality.

Patients were randomized 1:1 between two treatment arms, ie FCR 6 cycles or IV. After a lead-in phase of ibrutinib as a single agent from month (M)1 to M3, the total duration of treatment with IV was based on the response achieved at M9; if bone marrow (BM) MRD was < 0.01% using flow cytometry, the treatment was continued for 6 additional months until M15 and then stopped; if BM MRD at M9 was ≥ 0.01%, the treatment with IV was continued for 18 additional months until M27. The primary endpoint was the percentage of patients with BM MRD < 0.01% at M27 in both arms. We present here the preliminary results on the first evaluation done at M9 including CT-scan, BM biopsy and MRD assessment in PB and BM after the inclusion of all the 120 patients as initially planned.

One hundred and twenty patients were enrolled from September 2019 to February 2021. The median age was 59 [34-72] and 61 [34-74] years in the FCR and IV arms, respectively. The characteristics of the patients were well balanced between the 2 arms in terms of gender (male 72% FCR, 74% IV), PS ECOG 0-1 (59% FCR, 68% IV) and Binet stage (A, B and C 15%, 64%, 21% for FCR ; 8.5%, 59% and 32% for IV). No major difference in terms of cytogenetic features was noted, all patients but one had unmutated IGHV.

At the time of data cut-off for this interim analysis, the median follow-up for the all cohort was 11 [2.9 – 19.8] months. The frequency of all grades adverse events (AE) observed so far was 53% (grade 3-4, 24%) in the FCR arm and 47% (grade 3-4, 17%) in the IV arm. The rate of infusion-related reactions (IRR) in the FCR arm was 35% on cycle 1-day 1 (14% grade 3-4) ; for the IV arm, 6% of patients experienced tumor lysis syndrome (TLS) (grade 4 for 4 patients). ibrutinib doses were reduced for 7 patients (4 permanently stopped and 3 resumed at a lower dose because of toxicities (digestive, hepatic or haematological)). Venetoclax was permanently discontinued before M9 in 4 patients (digestive toxicities and grade 4 neutropenia). Forty serious adverse events were reported of which 15 in the IV arm (1 sudden death, 1 ischemic stroke, 2 atrial fibrillations, 2 clinical TLS, 1 hepatitis, 1 neutropenia, 4 COVID pneumonitis and one osteoporotic fracture) and 25 in the FCR arm (2 neutropenias, 1 anemia, 1 thrombocytopenia, 1 autoimmune haemolytic anemia, 3 IRR, 4 TLS, 2 COVID pneumonitis, 4 fever episodes of undetermined origin, 1 community-acquired pneumonia, 1 gastrointestinal toxicity, 1 confusion, 2 chest pains, 1 acute myeloid leukemia, 1 myelodysplasic syndrome). The patients with COVID pneumonitis had a favorable evolution with the need for intensive care and convalescent plasma for 3 of them.

The first 60 patients included in the study have reached M9 and among them, 6 prematurely discontinued the study, 3 in each arm (active hemolysis, ischemic stroke and sudden death in the IV arm; 2 grade 4 hematologic toxicities and 1 early progression in the FCR arm). In the evaluated patients (n=54), 71% of patients in the FCR arm and 48% of patients in the IV arm achieved bone BM MRD < 0.01%. The complete (CR, CRi) and partial response rates were 54% and 46% in the FCR arm and 76% and 24% in the IV arm respectively.

In conclusion, the preliminary results show a lower BM MRD rate in the IV arm compared to the FCR arm at M9, with a toxicity that remains significant and relatively similar between the two arms. However, BM MRD rate should improve after longer exposure to the IV combination and the analysis of the primary endpoint at M27 will be decisive in determining the best therapeutic strategy.

Disclosures: Quinquenel: Abbvie: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria. Laribi: Le Mans Hospital: Research Funding; Novartis: Other: Personal Fees, Research Funding; Takeda: Other: Personal Fees, Research Funding; BeiGene: Other: Personal Fees; IQONE: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; Astellas Phama, Inc.: Other: Personal Fees; AstraZeneca: Other: Personal Fees; Jansen: Research Funding. Cymbalista: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly-LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTRA ZENECA: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leblond: AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Roche: Honoraria; Amgen: Honoraria; Beigene: 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. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Ferrant: Janssen: Other: Travel, Accommodations, Expenses; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses; AstraZeneca: Honoraria. de Guibert: Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Feugier: Astrazeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Ysebaert: Abbvie, AstraZeneca, Janssen, Roche: Other: Advisory Board, Research Funding.

*signifies non-member of ASH