Patients with mutated IGHV (IGHV-M) have promising long-term outcomes after chemotherapy with fludarabine, cyclophosphamide, and rituximab. Based on this knowledge, investigators conducted a phase 2 trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated patients with IGHV-M chronic lymphocytic leukemia. The objective of the study was to limit fludarabine and cyclophosphamide to 3 courses, potentially reducing toxicity, while maintaining efficacy through the addition of ibrutinib and obinutuzumab. To be eligible, patients had to be ≥18 years of age with IGHV-M and no del17p. Patients received 3 courses of iFCG. The primary end point was complete response/complete response with incomplete blood count recovery (CR/Cri) with bone marrow (BM) minimal residual disease (MRD)-negativity (4-color flow cytometry) after 3 courses of iFCG.
A total of 23 patients started treatment. The median age of patients was 59 years (range, 25-71 years), and prognostic markers included del13q (n = 17), del13q-negative (n = 3), and trisomy 12 (n = 3). Of the 23 patients who started treatment, 18 completed 3 courses of iFCG and had response at initial assessment. MRD-negativity in BM at 3 months was achieved in 14 of the 18 patients (78%), whereas CR/CRi (all MRD-negative) was achieved in 7 of the 18 patients. No patient has progressed, and all except 1 continue to receive treatment. Patients who received ibrutinib with obinutuzumab for cycles 3 to 6, then ibrutinib for cycles 7 to 12, achieved the primary end point, whereas patients who received ibrutinib with obinutuzumab (cycles 4-12) did not achieve the primary end point. The target BM MRD-negativity after 3 courses of iFCG was 45%. All patients who are MRD-negative at 1 year will stop therapy, including ibrutinib; patients who are MRD-positive at 1 year may continue ibrutinib.
Of the 23 patients, 11 patients had grade 3/4 neutropenia, 5 patients had grade 3/4 thrombocytopenia, 4 patients had neutropenic fever, and 1 patient who achieved MRD-negative CR developed pulmonary Mycobacterium avium complex infection and declined further therapy. Moreover, 1 patient had atrial fibrillation, and grade 3 ALT elevation developed in 3 patients. Consequently, the dose of fludarabine and cyclophosphamide was reduced in 10 patients, and the dose of ibrutinib was reduced in 2 patients.
The results of this study indicate that iFCG achieves a high rate of MRD-negative remission after 3 courses. Patient enrollment is ongoing.
Jain N, et al. ASCO Abstract 7522.