Achievement of CR with undetectable minimal residual disease (uMRD) may be associated with a longer survival in CLL, but BCR signaling inhibitors alone seldom allow reaching uMRD. We conducted a multicenter phase II trial aiming at exploring the efficacy of an induction treatment associating obinutuzumab and ibrutinib, followed by immunochemotherapy for patients who do not reach CR with uMRD. Previously untreated fit patients with active Binet stage A and B or stage C CLL, no TP53 mutation/deletion, CIRS score Between November 2015 and May 2017, 135 patients (89 males/46 females) were enrolled; 7% were Binet stage A, 67% stage B and 26% stage C. Median age was 62 years (range, 35-80). Genetic alterations included 26% del(11q), 19% trisomy 12 and 56% del(13q); 15% had a complex karyotype and 56% patients had unmutated IGHV status. Median Beta 2 microglobulin was 3.6 mg/L (1.5-7.5) and median GFR (Cockroft) was 81 mL/min (42-173). At Month 9, 92% patients had received the 8 planned infusions of obinutuzumab. Ibrutinib dosage was reduced in 4 patients and definitively discontinued in 3 of them (3.9%) due to AE (atrial fibrillation, atrial flutter and neutropenia). Fifty seven percent of the patients presented at least a grade (G) 3 toxicity during the first 9 months of treatment (neutropenia 24%, anemia 6% and thrombocytopenia 31%). One hundred and thirty patients were evaluable for response at M9 and 5 not evaluable (2 deaths: one sudden at M7 and one accidental at M8; one acute coronary syndrome; one listeria meningitidis and one acute pulmonary edema at day 1 cycle 1). In intention to treat (ITT), ORR was 100% with 41% of patients reaching CR (42% for evaluable patients) but only 12% had BM MRD At month 16, 115 patients were evaluable for response. In ITT, the CR rate was 69% (78% for evaluable patients) and 79% of patients had BM MRD During the trial second period (M9 to M16), 38% patients presented at least a G3 toxicity: neutropenia 24%, thrombocytopenia 15%, anemia 1.5%, febrile neutropenia 3%, gastrointestinal disorders 9.5% and cardiac events 2.4%. A total of 41 serious AEs were observed throughout the entire treatment duration: 9 cardiac events including 1 atrial flutter and 3 atrial fibrillations, 4 hemorrhagic events, 7 infections, 3 second cancers (2 basocellular carcinoma, 1 renal adenocarcinoma) and 2 deaths. In conclusion, this MRD-driven strategy given for a definite period of time leads to a very high rate of uMRD CR in previously untreated CLL fit patients without TP53 aberration and displays an acceptable security profile. To our knowledge, these results are superior to standard FC + rituximab (FCR) or any chemo-free regimen. We hypothesize that this very high rate of bone marrow undetectable MRD will translate in a prolonged PFS while discontinuing treatment. Disclosures Laribi:Novartis: Other: Grant and personal fees; Takeda: Other: Grant and personal fees; Teva: Other: Grant; Gilead: Other: Personal fees; Sandoz: Other: Grant; Roche: Other: Grant; Amgen: Other: Personal fees; Hospira: Other: Grant. Salles:Novartis: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Acerta: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria; Servier: Honoraria; Takeda: Honoraria. Leblond:Gilead: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sandoz: Honoraria; Amgen: Honoraria. Cartron:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria. Ysebaert:Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cymbalista:Gilead: Honoraria; AbbVie, Inc: Honoraria; Janssen: Honoraria; Sunesis: Research Funding. Feugier:Gilead: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding.