Résumé
Achievement of CR with undetectable residual disease (uMRD) may be associated with a longer survival in CLL. New therapeutic agents have recently emerged, including new anti-CD20 antibodies and agents targeting BCR signaling. We conducted a multicenter phase II trial aimed to explore the efficacy of an induction treatment associating obinutuzumab and ibrutinib, followed by immunochemotherapy only in case of PR or detectable MRD. FIT treatment-naïve patients with active Binet stage A to C CLL and no TP53 mutation/deletion were eligible if CIRS score was < 7 and ECOG 0 or 1. Induction treatment consisted of 6 courses of obinutuzumab (1000 mg D1, D8, D15 for cycle 1 and D1 for cycles 2 to 6) along with ibrutinib 420 mg daily for 9 months. A first assessment of response was performed at month 9, including CT-scan, bone marrow (BM) biopsy and peripheral blood (PB) and BM MRD testing. Patients in CR with uMRD (<10-4, by 8-color cytometry) received ibrutinib alone for 6 additional months whereas the others received 4 courses of fludarabine + cyclophosphamide and obinutuzumab while continuing ibrutinib. Patients with stable or progressive disease were taken off study. Final evaluation of response was performed at Day 1 Month 16. The primary objective of this study was to obtain 30% of CR (according to IWCLL 2008 guidelines) with uMRD in BM at month 16. We report the preliminary results of the induction phase of this trial, including toxicities and response rates.
Between November 2015 and May 2017, 135 planned patients were enrolled (Table 1) including 89 males and 46 females; 8.2% were Binet stage A, 67.2% stage B and 24.6% stage C. The median age was 62.5 years (range, 35-80 years). Patients with del11q, del13q and trisomy 12 were 20.8% (25/120), 52% (51/98) and 21.6% (21/97) respectively; 9% (10/109) 12.5 % had a complex karyotype (>3 abnormalities). The median concentration of Beta 2 microglobulin was 3.6 mg/L (1.5-7). The median of creatinine clearance (Cockroft) was 81 ml/min (42-155).
A total of 37 serious AEs were observed with 24 related to the treatment, including 3 tumor lysis syndrome (grade 3), 5 cardiac events (1 hypertension (grade 3) and 2 atrial flutter (grade 2 and 3) and 2 atrial fibrillation (grade 3)), 1 diabetes mellitus (grade 2), 3 febrile neutropenia (grade 4), 2 neutropenia (grade 3), 1 pneumonia (grade 4), 1 hepatocellular injury (grade 3), 1 severe pain (grade 3), 1 hemoptysis (grade 3), 1 infection of listeria meningitidis complicated with disseminated intravascular coagulation (grade 3), 1 thrombocytopenia (grade 4), 1 hemorragic renal cyst (grade 3), 1 brain hemorrhage (grade 4), 1 diarrhea (grade 3) and 1 vomiting (grade 3). Two patients died during the study at the cut-off date, one of unknown cause and one of brain hemorrhage due to fall on the stairs not reliable to therapy.
Among the other AE, Infusion Related Reaction (IRR) only occurred during cycle 1 at day 1 for 69,5% of the patients (34.8% grade 1, 57.6% grade 2 and 7.6% grade 3), 14.5% at day 2 (only grade 1 and 2) and none at day 8 and 15, respectively. Grade 3-4 neutropenia were observed in 24.3%, 7.7%, 10.2%, 12.2%, 11.8%, 11,1%, 13.6%, 16.7% and 2.7% of cases during cycles 1 to 9, respectively. Grade 3-4 thrombocytopenia and anemia were mainly observed during cycle 1 (30.8% and 6%, respectively). Other significant toxicity was digestive (nausea, vomiting and diarrhea) occurring in 33,6% of the patients (grade 1 and 2) but only during cycle 1.
At Month 9, 92% of the patients had received the 8 planned infusions of obinutuzumab; Ibrutinib dosage was reduced for 5 patients (5/77; 6,8%) and definitively stopped in 3 out of them (3,9%) due to AE (atrial fibrillation, atrial flutter and neutropenia).
Seventy-three patients are evaluable so far for the response at M9. The ORR was 100% with 37% in CR (IWCLL criteria) and 63% in PR. Among the 63 (86%) patients with positive BM MRD, 22 were in CR and 41 in PR; 8 patients had uMRD in PB and BM including 4 patients in CR.
These preliminary results indicated that this 9 month « chemo-free » induction is associated with a high CR rate (37%) without excess of toxicity. However, the majority of the patients required subsequent immuno-chemotherapy because of detectable BM MRD.
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Dilhuydy:Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Laribi:MUNDIPHARMA: Research Funding; NOVARTIS: Honoraria, Research Funding; ROCHE: Research Funding; TEVA: Research Funding; HOSPIRA: Research Funding; AMGEN: Honoraria; TAKEDA: Honoraria, Research Funding. Salles:morphosys: Consultancy, Honoraria; BMS: Consultancy; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding. Tournilhac:AMGEN: Other: Travel funding, Research Funding; ROCHE: Honoraria, Other: Travel funding, Research Funding; GILEAD: Honoraria, Other: Travel Funding, Research Funding; Janssen: Honoraria, Other: travel funding; Abbvie: Honoraria, Other: Travel funding. Delmer:Abbvie: Consultancy, Honoraria; Janssen: Honoraria; Gilead: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Pegourie:Takeda, Novartis, Janssen, BMS: Consultancy. Leblond:SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees; GILEAD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria; ABBVIE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cartron:Sanofi, BMS, Jansen, celgene, Roche, Gilead: Equity Ownership; Celgene: Consultancy, Employment; Roche: Consultancy, Equity Ownership, Honoraria, Research Funding. Fornecker:Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Ysebaert:Janssen: Consultancy, Research Funding, Speakers Bureau. Dartigeas:Gilead: Other: travel grant; Mundipharma: Other: travel grant; Janssen: Consultancy; Roche: Consultancy. Cymbalista:Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Mundipharma: Honoraria; AbbVie: Consultancy, Honoraria; Roche: Other: Travel, Accommodations, Expenses. Letestu:Alexion: Consultancy, Honoraria. Feugier:Roche: Consultancy, Honoraria, Research Funding.