Résumé
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 < 7 and ECOG 0 or 1 were eligible. 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/d for 9 months. Assessment of response to induction was performed at month 9, including CT-scan, bone marrow (BM) biopsy, peripheral blood (PB) and BM MRD testing. Patients in CR with BM MRD < 0.01% (by 8-color flow cytometry) received ibrutinib alone for 6 additional months whereas all the other patients received 4 courses of fludarabine (F) + cyclophosphamide (C) and obinutuzumab along with continuous ibrutinib until month 16. Patients with stable or progressive disease were taken off study. Final evaluation of response was performed at D1 Month 16. The primary endpoint of this study was the rate of CR (according to IWCLL 2008 guidelines) with uMRD in BM at month 16 and the assumption that at least 30% of patients would achieve this goal at the end of the overall strategy.
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 < 0.01%. Therefore 88% of the patients were planned to receive FC and obinutuzumab treatment while continuing ibrutinib.
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 < 0.01% (90% of evaluable patients). Overall, 62% patients achieved CR with BM MRD < 0.01% (ITT) and 70% evaluable patients did so. The IGHV mutational status did not impact the quality of response.
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.