Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA101) (iFCG) treatment for first-line therapy of patients with CLL with mutated IGHV and without deletion 17p

Context: Chemotherapy has remained the standard treatment for young patients (pts) with CLL. The role of chemotherapy in the era of novel therapies is evolving. Objective: To determine CR rate with minimal rediual disease (MRD) negativity after 3 courses of iFCG regimen in pts with CLL with mutated IGHV, and without deletion 17p. Design: Investigatorinitiated phase II trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809). Setting: Comprehensive Cancer Center Patients or Other Participants: Diagnosis of CLL/SLL requiring first-line treatment, age ≥18, IGHV-M, no del(17p) Interventions: Pts received 3 courses of iFCG. Pts meeting primary endpoint received ibrutinib with obinutuzumab (iG) for C4-6, then ibrutinib C7-12. Pts not achieving the primary endpoint received iG (C4-12). All pts with undetectable MRD at 1 yr stop all therapy, including ibrutinib. Responses per IWCLL 2008 criteria. Main Outcomes Measures: The primary endpoint is CR/CRi with undetectable BM MRD (4-color flow-cytometry, sensitivity 10-4) after 3 courses of iFCG. The historical rate of C3 undetectable BM MRD with FCR in IGHV-M pts was 26% (Strati, Blood 2014). Target undetectable BM MRD after iFCG x3 is 45%; sample size 45. Results: 32 pts initiated treatment. Median follow-up 10.9 months. Baseline characteristics are shown in Table 1. Twenty-eight pts have completed 3 courses of iFCG and had initial response assessment. All 28 pts achieved a response; 24/28 (86%) achieved MRD-negative remission in BM at 3 month (Table 2). Overall, 13/ 28 (46%) achieved CR/CRi with undetectable MRD at 3 months. Responses continue to improve over time (6 months: CR/CRi 74%, MRD neg 91%; 12 months: CR/CRi 75%, MRD neg 100%). Twelve pts reached the 12 month time-point, and all have stopped treatment per protocol; all remain MRD negative at a median follow-up of 3.2 months after stopping therapy. No patient has progressed, and all but 3 continue to receive treatment on protocol. G3-4 neutropenia occurred in 68% pts; G3-4 thrombocytopenia in 48% pts. Atrial fibrillation occurred in 2 pts. G3 ALT elevation occurred in 3 pts. FC was dose-reduced in 55% pts; ibrutinib dosereduced in 19% pts. There has been 1 death on the study. Conclusions: iFCG achieves high rate of undetectable MRD after 3 (Table Presented).