Chemoimmunotherapy (CIT) with fludarabine, cyclophosphamide, and rituximab (FCR) remains the standard first-line treatment for young, fit patients with chronic lymphocytic leukemia (CLL), particularly for those with mutated (M)-IGHV. Recent studies have shown that ibrutinib + rituximab improved progression-free survival (PFS) and overall survival versus the FCR arm; however, the PFS benefit did not extend to the M-IGHV group. For young, fit patients with CLL with M-IGHV and without del(17p)/mutated TP53, a phase 2 study (NCT02629809) was designed to evaluate a novel CIT regimen consisting of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) to attain higher undetectable minimal residual disease (U-MRD) and lower risk for treatment-related myelodysplastic syndrome/acute myelogenous leukemia.
All patients with M-IGHV CLL and no del(17p) or TP53 mutation, and a 2008 International Workshop on Chronic Lymphocytic Leukemia indication for treatment received first-line iFCG regimen for the first 3 cycles. Patients who achieved complete remission (CR)/CR with incomplete hematologic recovery (CRi) with bone marrow (BM) U-MRD received 9 additional cycles of ibrutinib with 3 additional cycles of obinutuzumab; all other patients received 9 additional cycles of ibrutinib and obinutuzumab. At the end of the planned 12 cycles, all patients who achieved U-MRD stopped therapy.
A total of 45 patients were enrolled and 44 completed 3 cycles of iFCG. The median age of study population was 60 years (range, 25-71), 69% had del(13q) alteration and diploid cytogenetics. In the intent-to-treat population, after 3 cycles of iFCG, CR/CRi was achieved by 69% of patients and BM U-MRD by 98% of patients. Responses improved with continued therapy with ibrutinib and obinutuzumab.
In total, 41 patients completed all planned 12 cycles. Reasons for study discontinuation were due to adverse events (congestive heart failure, pulmonary mycobacterium avium complex [MAC] infection, and grade 3 infusion reaction to obinutuzumab accompanied by grade 4 thrombocytopenia; n = 1 each) and consent withdrawal (n = 1). Grade 3/4 neutropenia was reported in 58% of patients and grade 3/4 thrombocytopenia in 40% of patients. Notable infusion-related reactions (all grades) were reported in 44% of patients, atrial fibrillation (all grades) in 11% of patients, and grade 3/4 transaminitis in 13% of patients. Infectious complications (n = 45) without neutropenia leading to hospitalization included pneumonia (culture negative; n = 2), cellulitis (n = 1), pulmonary MAC infection (n = 1), fever (n = 1), acute cholecystitis (n = 1), and colitis (n = 1). Neutropenic fever occurred in 6 patients; no patient had neutropenic fever after institution of prophylactic granulocyte–colony stimulating factor.
All 41 patients achieved BM U-MRD and discontinued ibrutinib per protocol. With a median follow-up of 22.7 months after discontinuing ibrutinib, no patient had clinical relapse, 1 patient had MRD recurrence, and 1 patient had therapy-related myelodysplastic syndrome.
The study investigators concluded that 3 cycles of the iFCG regimen is an effective CIT for young patients with M-IGHV and without del(17p)/mutated TP53.
Jain N, et al. ASH Abstract 357. Session 642.