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3117 A Fixed-Duration Immunochemotherapy Approach Combined with Ibrutinib in CLL Produces Deep and Sustained MRD Responses: 5.5-Year Results from the Icll-07 Filo Trial

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Clinical Practice (Health Services and Quality), Combination therapy, Therapies, therapy sequence, Adverse Events, Minimal Residual Disease
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Anne-Sophie Michallet, MD, PhD1*, Rémi Letestu, MD2*, Magali Le Garff-Tavernier3*, Carmen Aanaei4*, Michel Ticchioni5*, Marie-Sarah Dilhuydy, MD6*, Stephane Morisset, BioStat7*, Valérie Rouille8*, Béatrice Mahé, MD9*, Kamel Laribi, MD10*, Bruno Villemagne, MD11*, Emmanuelle Ferrant, MD12*, Olivier Tournilhac, MD, PhD13*, Alain Delmer14, Christelle Portois15*, Lysiane Molina, MD16*, Véronique Leblond, MD, PhD17, Cécile Tomowiak, MD18*, Sophie de Guibert, MD19*, Frederique Orsini20*, Anne Banos, MD21*, Philippe Carassou22*, Guillaume Cartron, MD, PhD23,24*, Luc Mathieu Fornecker, MD, PhD25*, Loic Ysebaert, MD, PhD26,27,28*, Caroline Dartigeas, MD29,30*, Margot Truchan31*, Jean-Pierre Vilque, MD32*, Therese Aurran Schleinitz33*, Cymbalista Florence34*, Stéphane Leprêtre, MD35,36*, Vincent Lévy37*, Florence Nguyen Khac38* and Pierre Feugier, MD, PhD39*

1Centre Hospitalier Lyon Sud, Hospices Civils, LYON, France
2Hematology Laboratory, Avicenne Hospital, APHP, Bobigny, France
3Hôpital Pité-Salpétrière, Paris, France
4CHU Saint Etienne, Saint- Etienne, France
6CHU Hopitaux de Bordeaux, Pessac, France
7Hematology, Centre Leon Berard, Lyon, France
8CHU Montpellier, Montpellier, France
9Hematology Department, Nantes University Hospital, Nantes, France
10Hématologie clinique, CH Le Mans, Le Mans, France
11Clinical Hematology, Centre Hospitalier Départemental Vendée, La Roche-sur-Yon, France
12Department of Hematology, Hospices Civils de Lyon, Lyon Sud University Hospital, Pierre Benite, France
13Hématologie Clinique Adulte et Thérapie Cellulaire, CHU Hotel Dieu Hématologie, Clermont-Ferrand, France
14Department of Hematology, CHU de Reims, Reims, Cedex, France
15hematology, CHU Saint Etienne, Saint Etienne, France
16Hématologie clinique, CHU de Grenoble, La Tronche, France
17Department of Clinical Hematology, Sorbonne Université, APHP, Hôpital de la Pitié Salpêtriere, Paris, France
18Department of Hematology, CHU Poitiers, Poitiers, France
19Hématologie Clinique, CHU Rennes, Rennes, France
20Service Hématologie, CH Annecy, ANNECY, France
21Hematology department, CH Côte Basque, Bayonne, France
22CH Metz, Metz, FRA
23Département d'Hématologie clinique, CHU de Montpellier, Montpellier, France
24Hematology Department, Montpellier University Hospital, Montpellier, France
25Department of Hematology, Strasbourg University Hospital, Strasbourg, France
26IUCT-Oncopole, Toulouse, France
27Hematology Department, Institut Universitaire du Cancer Toulouse Oncopole, Toulouse, France
28Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France
29Department of Hematology, Tours, FRA
30Department of Hematology and Cellular Therapy, CHRU de Tours, Hôpital Bretonneau, Tours, France
31CHU angers, ANGERS, France
32Institut d'Hématologie de Basse-Normandie, Centre François Baclesse, Caen, France
33hematology, IPC, MARSEILLE, FRA
34Avicenne Hospital, Bobigny Cedex, France
35Inserm U1245 and Department of Hematology, Centre Henri Becquerel and Normandie Univ UNIROUEN, Rouen, France
36CLCC H Becquerel, Rouen, France
37Department of Clinical Research, APHP, Hôpital Avicenne, Bobigny, France
38Sorbonne Université, Pitié-Salpêtrière Hospital, Paris Cedex 13, France
39Hematology Department, University Hospital of Nancy, Vandoeuvre, France


In previously untreated, medically fit patients with chronic lymphocytic leukemia (CLL), the availability of targeted agents has led to research interest in achieving deep, durable remissions and improving survival outcomes. The phase II ICLL-07 (NCT02666898) trial by the French Innovative Leukemia Organization (FILO) evaluated a fixed-duration (15-month) immunochemotherapy approach (no more than 4 fludarabine/cyclophosphamide [FC]-obinutuzumab cycles). Primary analysis showed the approach was safe and 62.2% (84/135) of all patients enrolled achieved complete response (CR) with bone marrow (BM) minimal residual disease (MRD) <0.01% (Michallet et al Lancet Haematol 2019;6:e470-9). Follow-up at median 37 months from treatment start showed a persistent MRD benefit beyond end of treatment, high survival rates, and low long-term toxicity (Michallet et al Blood 2021;137:1019-23). Here we report long-term results at median 64 months from treatment start (data cut-off 20 May 2022).


Between 27 October 2015 and 16 May 2017, 135 previously untreated, medically fit patients with CLL were enrolled from 27 FILO centers. All received obinutuzumab 1000 mg (8 infusions over 6 cycles) plus ibrutinib (420 mg/day for 9 months). Following evaluation at D1 M9 (N=130 evaluable), those in CR with BM MRD <0.01% then continued only ibrutinib 420 mg/day for 6 additional months (I arm; n=10); otherwise, patients received 4 cycles of FC-obinutuzumab 1000 mg alongside continuing ibrutinib 420 mg/day for 6 additional months (I-FCG arm; n=115). Beyond end of treatment, patients were followed for peripheral blood (PB) MRD every 6 months, response every 3 months, progression-free/overall survival (PFS/OS), and safety. MRD was assessed by 8-color flow cytometry, using a highly sensitive (10-6) technique developed by the FILO group that enables subdivision of classical MRD <0.01% into low-level positive MRD <0.01% and undetectable MRD.


At D1 M16, undetectable PB MRD rates were 80.0% (8/10) in the I arm and 92.5% (99/107) in the I-FCG arm. Beyond end of treatment, in the I arm the undetectable PB MRD rate decreased rapidly, and by M40 all patients had PB MRD positivity (0.01% or low-level positive <0.01%). In the I-FCG arm, the undetectable PB MRD rate was 76.3% (61/80) at M40, and of patients currently investigated at M64, 50/62 (80%) still had undetectable PB MRD (Figure 1). Four relapses occurred beyond end of treatment, including 2 CLL progressions (both Richter’s syndrome). Throughout follow-up, no differences in undetectable PB MRD rates were apparent in the I-FCG arm according to the IGHV -mutated versus unmutated status (currently at M64: 20/27 versus 25/35, P=0.26). Overall 4-year PFS and OS rates (95% confidence intervals) were 95.5% (92% to 99 %) and 96.2% (93% to 99.5%), respectively. Of 12 deaths overall, 7 occurred beyond end of treatment, with 5 since last publication due to Richter’s syndrome at M50, COVID at M50, lung cancer at M50, myelodysplastic syndrome at M60, and acute myeloid leukemia at M69. Other serious adverse events since last publication were metastatic prostate adenocarcinoma at M50 and suspicion of cerebrovascular accident at M65.


Long-term results from the ICLL-07 trial in previously untreated, medically fit patients with CLL demonstrated that that our fixed-duration (15-month) immunochemotherapy approach produced deep and sustained undetectable PB MRD responses that were correlated to PFS, without excess toxicity. These long-term MRD results remain the best to date even compared to the new targeted therapy combinations ie ibrutinib +veneteclax or obinutuzumab + venetoclax A randomized trial is needed to compare our approach with a chemotherapy-free strategy.

Disclosures: 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. Tournilhac: Janssen: Honoraria, Other: Travel grant , Research Funding; Gilead: Honoraria, Other: Travel grant , Research Funding; Securabio: Honoraria, Other: Travel grant , Research Funding; IdeoGen: Honoraria, Other: Travel grant , Research Funding; Abbvie: Honoraria, Other: Travel grant , Research Funding; Takeda: Honoraria, Other: Travel grant , Research Funding. Delmer: Novartis: Honoraria; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Abbvie: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Takeda: Honoraria. Leblond: Abbvie, Beigene, Roche, Amgen, Lilly AstraZeneca, Janssen, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. de Guibert: AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Cartron: Gilead, Novartis, Mylteni, Sanofi, Abbvie, Takeda, Roche, Janssen, Celgene, Novartis, Bristol Myers Squibb: Honoraria; MabQi, Ownards Therapeutics, Abbvie, Roche, Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Ysebaert: Abbvie, Astra-Zeneca, Janssen, Roche, Beigene, BMS/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Dartigeas: Janssen, Abbvie, Roche, AstraZeneca: Other: Travel Grant; Abbvie, Roche, Janssen, Beigene, AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Feugier: AstraZeneca, Janssen, Abbvie, Beigene, Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Congress Invitations.

*signifies non-member of ASH