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3268 Minimal Residual Disease-Guided Combination of Ibrutinib and Venetoclax Compared to FCR in Untreated Patients with CLL of Intermediate Risk : Interim Results of MRD Kinetics in the Eradic Trial from the Filo Group

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Combination therapy, Therapies, therapy sequence, Minimal Residual Disease
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Anne-Sophie Michallet, MD, PhD1*, Anne Quinquenel, MD, PhD2*, Remi Letestu3*, Tavernier Magali4*, Stéphane Morisset5*, Therese Aurran6*, Kamel Laribi7*, Florence Cymbalista, MD, PhD8*, Vincent Levy, MD, PhD9*, Laurence Simon10*, Damien Roos Weil, MD, PhD11*, Veronique Leblond, MD12*, Marie Sarah Dilhuydy, MD13*, Cecile Tomowiak14*, Caroline Dartigeas15*, Romain Guieze, MD, PhD16*, Olivier Tournilhac17*, Emmanuelle Ferrant, MD18*, Sophie De Guibert19*, Pierre Feugier20*, Fatiha Merabet21*, Stéphane Lepretre22*, Philippe Carassou23*, Julie Gay24*, Benedicte Hivert25*, Luc Matthieu Fornecker, MD, PhD26*, Jehan Dupuis27*, Lysiane Molina, MD28*, Bruno Villemagne29*, Guillaume Cartron, MD, Ph-D30*, Bernard Drenou, MD31*, Béatrice Mahé32*, Omar Benbrahim33*, Xavier Cahu34*, Christelle Portois35*, Loic Ysebaert, MD, PhD36*, Florence Nguyen Khac37*, Valerie Rouillé38* and Alain Jacques Delmer, MD39*

1Centre Leon Berard, Lyon, France
2Hematology department, Robert Debré University Hospital, Reims, France
3APHP, Avicennes Hospital, Bobigny, FM, FRA
4APHP, la pitié salpetriere, Paris, FRANCE, FRA
5Hospices Civils De Lyon, Chazey-sur-Ain, FRA
6Institut Paoli-Calmettes, Marseille, FRA
7Hematology Department, Le Mans Hospital, Le Mans, France
8Hopital Avicenne, Bobigny, FRA
9Hôpital Avicenne, AP-HP, BOBIGNY, France
10hospital Corbeil essonnes, Corbeil-Essonnes, FRA
11Clinical Hematology, APHP, La Pitié Salpétriere, Sorbonne Universite, Paris, FRA
12APHP, La pitié salpétriere, Paris, FRA
13CHU Bordeaux, PESSAC, FRA
14Centre Hospitalier Universitaire de Poitiers, Poitiers, France
15CHU Bretonneau, Tours, FRA
16CHU Estaing, Clermont Ferrand, FRA
17CHU clermont ferrand, Clermont ferrand, France
18CHU Lyon Sud, Pierre Benite, FRA
19Centre Hospitalier Pontchaillou, Rennes, FRA
20Henri Poincaré University, Vandoeuvre Les Nancy, FRA
21andre mignot hospital, LE CHESNAY, FRA
22centre henri becquerel, Rouen, FRA
23chu metz thionville, Ars Laquenexy, FRA
24Hospital St Antoine, Paris, FRA
25GHICL, Lille, FRA
26Institut de cancérologie Strasbourg Europe, Strasbourg, France
27APHP, Creteil, Creteil, FRA
28CHU grenoble, grenoble, France
29CH la roche sur yon, La Roche Sur Yon, FRA
30Dept. Biological Hematology, Montpellier University Hospital Center, Montpellier, FRA
31HôPital Emile Muller, Mulhouse Cedex 1, FRA
32CHU nantes, Nantes, FRA
34hospital cesson sevigne, cesson sevigne, France
36Hematology Department, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
37Hôpital Pitié-Salpêtrière, Service d'Hématologie, Paris Cedex 13, France
38CHU montpellier, montpellier, France
39Hôpital Robert Debré CHU de Reims, Reims Cedex, -, FRA

With the emergence of targeted therapies, defining the best strategy for first-line treatment in chronic lymphocytic leukemia (CLL) patients has become challenging. The aim of the ERADIC phase 2 study was to compare the efficacy of a standard FCR regimen to that of an MRD-guided combination of ibrutinib and venetoclax (IV), 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. MRD was assessed in bone marrow (BM) or peripheral blood (PB) by flow cytometry. 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 combination was based on BM M9 MRD. If it was <0.01% (uMRD) at that time, treatment was continued for 6 additional months (M15) then stopped. If M9 BM-MRD was ≥0.01%, IV treatment was continued for 18 additional months (M27). BM-MRD was reassessed at that time-point in both arms. Additionally, PB-MRD evaluation was performed every 6 months.The primary endpoint will be the percentage of patients with BM uMRD at M27. Here, intermediate safety data and MRD kinetics (M9 to M21) are presented.

Between September 2019 and February 2021, 120 patients were randomized 1:1 between the two treatment arms. The median age was 59 [34-72] and 61 [34-74] year-old in the FCR and IV arms, respectively. Patient characteristics 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). An11q deletion was found in 20% and 24% of the 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 analysis, the median follow-up was 29.7 months [range: 25.3– 32.8]. Sixty-three serious adverse events (SAE) have been reported so far, 32 in the FCR arm and 31 in the IV arm. In the FCR arm, the most frequent SAE were infections (N=12 including 4 COVID-19), febrile neutropenia (N=5) biological tumour lysis syndrome (N=3), and secondary malignancies (N=2, including 1 myelodysplastic syndrome and 1 acute myeloid leukemia). In the IV arm, the most frequently reported SAE were infections (N=8 including 4 COVID-19), cardiovascular events (N=7), biological tumour lysis syndrome (N=5), acute renal failure (N=2) and secondary malignancies (N=2, including 1 colorectal cancer and 1 skin basal cell carcinoma). Four grade 5 adverse events were reported, respectively 2 in the FCR arm (1 septic shock and 1 AML) and 3 in the IV arm (2 sudden deaths and one death COVID-19-related).

In the FCR arm (intention to treat [ITT] n=57), 59.6% of the patients had BM-uMRD at M9. The kinetics of PB-uMRD was 68% at M9, 65% at M15 and 52% at M21. In the IV arm (ITT n=54), the rate of BM-uMRD at M9 was much lower at 33%. PB-MRD kinetics showed levels of uMRD of 52%,70% and 67% at M9, M15 and M21 respectively.

In terms of response, CR/CRi rates were 56% for the FCR arm and 66% for the IV arm. Three patients progressed in the FCR arm (1 at M9 and 2 at M15) and 2 in the IV arm, at respectively M13 and M39. Among the 13 patients who achieved BM-uMRD at M9 in the IV arm, 10 have indeed stopped according to the protocol and only 1 has progressed at M39.

In conclusion, monitoring MRD kinetics in this trial showed a stable level of PB-uMRD in the FCR arm yet a clear increase in the IV arm between M9 and M15. Toxicity remains an important parameter in both treatment arms that will have to be taken into account when determining whether treatment should be continued because of detectable BM-MRD at M9 (IV arm). Upcoming data of the primary enpoint analysis at M27 will be of great interest to try to determine the best strategy.

Disclosures: Quinquenel: Janssen Cilag: Honoraria; Abbvie: Honoraria; Beigene: Honoraria, Research Funding; AstraZeneca: Honoraria. Cymbalista: AstraZeneca: Honoraria; Abbvie: Honoraria; Lilly: Honoraria. Levy: Amgen, Abbvie, AZ, Beigene, BMS, Dova/Sobi, Glead, Morphosys/Incyte, Seagen, Takeda, Karyoparms, pharmaEssentia, Genmab, Janssen, Sanofi: Consultancy, Honoraria, Speakers Bureau. Dartigeas: Janssen, AbbVie, BeiGene, astrazeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grant. De Guibert: ABBVIE: Honoraria; Astra Zeneca: Honoraria; JANSSEN: Honoraria; Beigene: Honoraria. Cartron: Roche: Consultancy, Honoraria; Ownards Therapeutics: Consultancy; Novartis: Honoraria; MabQi: Consultancy; MedxCell: Consultancy; Janssen: Honoraria; Gilead: Honoraria; Emercell: Consultancy; BMS: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; MabQi, Ownards Therapeutics, Abbvie, Roche, Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; MedxCell, Ownards Therapeutics, MabQi, Emercell, F. Hoffmann-La Roche Ltd, BMS, Abbvie: Consultancy; Jansen, Gilead, Novartis, F. Hoffmann-La Roche Ltd, BMS, Abbvie: Honoraria. Drenou: Alexion Pharma France: Honoraria; Abbvie, Gilead, Janssen: Membership on an entity's Board of Directors or advisory committees. Ysebaert: Beigene: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead/Kite: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria; Abbvie: Honoraria, Research Funding, Speakers Bureau.

*signifies non-member of ASH