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3115 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: Results of the Month 15 MRD Evaluation

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
clinical trials, Lymphoid Leukemias, Research, CLL, Combination therapy, Clinical Research, Diseases, Therapies, Lymphoid Malignancies, Minimal Residual Disease
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Anne Quinquenel, MD, PhD1,2*, Rémi Letestu, MD3*, Magali Le Garff-Tavernier4*, Fabien Subtil5*, Therese Aurran-Schleinitz6*, Kamel Laribi, MD7*, Florence Cymbalista, MD PhD8*, Vincent Levy, MD, PhD9*, Laurence Simon10*, Damien Roos-Weil, MD, PhD11*, Véronique Leblond, MD, PhD12*, Marie-Sarah Dilhuydy, MD13,14*, Caroline Dartigeas, MD15*, Cecile Tomowiak, MD16*, Romain Guieze, MD, PhD17*, Olivier Tournilhac, MD, PhD18*, Emmanuelle Ferrant, MD19*, Sophie de Guibert, MD20*, Pierre Feugier, MD, PhD21*, Fatiha Merabet, MD22*, Stephane Lepretre, 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 Drenou32*, Béatrice Mahé, MD33*, Omar Benbrahim, MD34*, Xavier Cahu35*, Christelle Portois36*, Loic Ysebaert, MD, PhD37*, Florence Nguyen Khac38*, Valérie Rouille39*, Alain Delmer40 and Anne-Sophie Michallet, MD, PhD41*

1Hematology department, Robert Debré University Hospital, Reims, France
2UFR Médecine, Université Reims Champagne-Ardenne, Reims, France
3Hematology Laboratory, Avicenne Hospital, APHP, Bobigny, France
4Sorbonne Université-INSERM UMRS 1138, AP-HP, Hopital Pitie-Salpetriere, Service d’Hématologie Biologique, Paris, France
5Department of biostatistics, Hospices Civils de Lyon, LYON, France
6Institut Paoli Calmettes, Marseille, France
7Hématologie clinique, CH Le Mans, Le Mans, France
8Laboratory of Hematology, APHP, Hôpital Avicenne, Bobigny, France
9URC/CRC, Hopital Avicenne, AP-HP, Bobigny, France
10Centre Hospitalier Sud Francilien, Corbeil-Essonnes, FRA
11Hematology Department,Sorbonne Universités, UPMC Univ Paris 06, GRC-11, Service d’Hématologie, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris., Paris, France
12Département d’ Hématologie Hôpital Pitié-Salpêtrière APHP, UPMC Université Paris, Paris, France
13Department of hematology, Bordeaux, France
14CHU Hopitaux de Bordeaux, Pessac, France
15Department of Hematology and Cellular Therapy, CHRU de Tours, Hôpital Bretonneau, Tours, France
16Hematology, Poitiers University Hospital / INSERM CIC 1402, Poitiers, France
17Department of Hematology, CHU Clermont Ferrand, Clermont Ferrand, MA, France
18Hématologie Clinique Adulte et Thérapie Cellulaire, CHU Hotel Dieu Hématologie, Clermont-Ferrand, France
19Department of Hematology, Hospices Civils de Lyon, Lyon Sud University Hospital, Pierre Benite, France
20Hématologie Clinique, CHU Rennes, Rennes, France
21Hematology Department, University Hospital of Nancy, Vandoeuvre, France
22Service Hématologie et Oncologie, Hôpital André Mignot, Le Chesnay, France
23Centre Henri Becquerel, Rouen, Rouen, FRA
24CH Metz, Metz, FRA
25Service d'Hématologie, Centre Hospitalier de la Côte Basque, Bayonne, France
26GHICL, Lille, FRA
27Department of Hematology, Strasbourg University Hospital, Strasbourg, France
28Lymphoid Malignancies Department, Henri Mondor University Hospital, Créteil, France
29Hématologie clinique, CHU de Grenoble, La Tronche, France
30Clinical Hematology, Hospital of Vendée, La Roche-sur-Yon, France
31Hematology Department, Montpellier University Hospital, Montpellier, France
32Department of Hematology, CH Mulhouse, Mulhouse, France
33Hematology Department, Nantes University Hospital, Nantes, France
34Hematology Department, CHR Orléans, Orleans, France
35Hopital privé, Cesson sevigne, France
36hematology, CHU Saint Etienne, Saint Etienne, France
37Hematology Department, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
38Sorbonne Université, Pitié-Salpêtrière Hospital, Paris Cedex 13, France
39CHU Montpellier, Montpellier, France
40Department of Hematology, CHU de Reims, Reims, Cedex, France
41Centre Hospitalier Lyon Sud, Hospices Civils, LYON, 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 in first line of combined ibrutinib and venetoclax (IV) to the standard FCR regimen in fit patients with CLL of intermediate risk defined by either unmutated IGHV status, 11q deletion or complex karyotype in the absence of TP53 alteration.

As previously reported (Michallet et al., Blood 2021; 138 (suppl 1):641), 120 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 the IV combined treatment 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. PB MRD evaluation was performed every 6 months, whereas BM MRD was performed at M9 and M27.The primary endpoint was the percentage of patients with BM MRD < 0.01% at M27 in both arms. We present herein safety data and the preliminary results of the PB MRD evaluation at M15 .

These 120 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 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). 11q deletion was found in 20% and 24% of cases in the FCR and IV arms, respectively and all patients but one had unmutated IGHV.

At the time of data cut-off for this interim analysis, the median follow-up was 24.8 [16.7 – 33.6] months. Sixty-three serious adverse events (SAE) were reported so far, 33 in the FCR arm and 30 in the IV arm. In the FCR arm, the most frequent SAE were tumour lysis syndrome (N=3), infections (N=12 including 4 COVID19 infections), febrile neutropenia (N=5) and secondary malignancies (N=2, including 1 myelodysplastic syndrome and 1 acute myeloid leukemia). In the IV arm, the most frequently reported SAE were tumour lysis syndrome (N=5), infections (N=8 including 4 COVID19 infections), cardiovascular events (N=7), acute renal failure (N=2) and secondary malignancies (N=2, including 1 colorectal cancer and 1 skin basal cell carcinoma). Three grade 5 adverse events were reported consisting in 1 acute myeloid leukemia in the FCR arm and 2 sudden death in the IV arm. No patient died because of COVID19 in the study.

At M15, in intention to treat, in the FCR arm, 61.3 % of patients had peripherical blood MRD <0.01%, whereas MRD was ≥ 0.01% without clinical progression in 19.4% of patients and 6.5% of patients had experienced clinical progression. In the IV arm, PB MRD < 0.01% was reached in 63.8% of cases, MRD was ≥ 0.01% in 29.4% of patients and clinical progression was reported in 1.7% of patients (figure 1). In the FCR arm, 1 patient with MRD ≥ 0.01% at M9 converted to MRD < 0.01% at M15 while 2 patients had a signigicant increase of their PB MRD level from <0.01 to ≥ 0.01%. Conversely, in the IV arm, 12 patients converted from MRD ≥ 0.01% at M9 to MRD < 0.01% at M15 while 2 patients increased their PB MRD level from <0.01 to ≥ 0.01%. The two later patients had prematurely discontinued treatment before M15 evaluation.

In conclusion, these preliminary results show an increase in PB MRD < 0.01% rates between M9 and M15 in the IV arm, with rates similar to those of the FCR arm at M15. However, toxicity remains significant. The primary enpoint analysis at M27 will be of great interest to try to determine the best strategy.

Disclosures: Quinquenel: Janssen: Honoraria; Abbvie: Honoraria; Beigene: Honoraria; AstraZeneca: Honoraria. Letestu: Abbvie: Consultancy, Other: Funding for congress expenses, Speakers Bureau; AstraZeneca: Speakers Bureau. Le Garff-Tavernier: Abbvie: Consultancy, Honoraria; Janssen: Honoraria. Laribi: AbbVie, AstraZeneca, Beigene, Iqone, Janssen, Novartis, Takeda: Honoraria. Leblond: Abbvie, Beigene, Roche, Amgen, Lilly AstraZeneca, Janssen, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dartigeas: Janssen, Abbvie, Roche, AstraZeneca: Other: Travel Grant; Abbvie, Roche, Janssen, Beigene, AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Guieze: Astrazeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Roche: 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; Abbvie, Beigene, Janssen, Gilead, Roche, AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees. Tournilhac: IdeoGen: Honoraria, Other: Travel grant , Research Funding; Abbvie: Honoraria, Other: Travel grant , Research Funding; Takeda: Honoraria, Other: Travel grant , Research Funding; Securabio: Honoraria, Other: Travel grant , Research Funding; Gilead: Honoraria, Other: Travel grant , Research Funding; Janssen: Honoraria, Other: Travel grant , Research Funding. de Guibert: Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Feugier: AstraZeneca, Janssen, Abbvie, Beigene, Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Congress Invitations. Lepretre: AbbVie, Roche, Amgen, AstraZeneca, Janssen, Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dupuis: abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cartron: MabQi, Ownards Therapeutics, Abbvie, Roche, Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead, Novartis, Mylteni, Sanofi, Abbvie, Takeda, Roche, Janssen, Celgene, Novartis, Bristol Myers Squibb: Honoraria. Ysebaert: Abbvie, Astra-Zeneca, Janssen, Roche, Beigene, BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Delmer: AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Novartis: Honoraria; Takeda: Honoraria; Abbvie: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support.

*signifies non-member of ASH