Ibrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (GA101) for First-Line Treatment of Patients with CLL with Mutated IGHV and without TP53 Aberrations
The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has been the standard first-line treatment for young patients with chronic lymphocytic leukemia (CLL), with a complete remission (CR) rate after 6 cycles of 40% to 72%, and an undetectable bone marrow (BM) minimal residual disease (MRD) rate after 6 cycles of 43% to 58%.1 However, there is a 5% risk for therapy-related myelodysplastic syndromes/acute myelogenous leukemia in these patients.2 Patients with mutated IGHV (IGHV-M) have favorable long-term outcomes (10-year progression-free survival >60%) after receiving first-line FCR. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, is approved for patients with CLL/small lymphocytic lymphoma, and obinutuzumab, a glycoengineered type II CD20 monoclonal antibody, was shown to be superior to rituximab in older adults when combined with chlorambucil in the CLL11 trial.3 Emerging data (HELIOS trial) indicated that the combination of ibrutinib with chemoimmunotherapy is safe and effective.4
At ASH 2017, the authors reported on an investigator-initiated phase 2 trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for untreated patients with IGHV-M CLL and no TP53 aberrations.5 In this study, patients received 3 courses of iFCG, with a primary end point of CR/CR with incomplete blood count recovery (CRi) with undetectable BM MRD after 3 courses of iFCG. Patients meeting the primary end point received ibrutinib with obinutuzumab (iG) for cycles 4 through 6, then ibrutinib for cycles 7 through 12. Patients not achieving the primary end point received iG for cycles 4 through 12.
A total of 32 patients initiated treatment. After 3 cycles of iFCG, all patients responded and 28 (87%) achieved BM MRD–negative remission. Fourteen (44%) achieved CR/CRi with undetectable MRD at 3 months. Nineteen patients have reached the 12-month time point (all 19 were MRD-negative); 16 (84%) CR/CRi, 3 (16%) partial responses, and all have stopped treatment per protocol design. All remain MRD-negative at a median follow-up of 5.5 months after stopping ibrutinib.
In the first 3 cycles of therapy, grade 3/4 neutropenia occurred in 68% of the patients. Grade 3/4 thrombocytopenia occurred in 42% of the patients. Atrial fibrillation occurred in 4 (11%) patients.
The authors concluded that iFCG achieves a high rate of undetectable MRD after 3 courses. All 19 patients who have reached the 1-year time point are MRD-negative and have stopped all therapy, including ibrutinib.
- Fischer K, et al. Blood. 2016;127:208-215.
- Benjamini O, et al. Leuk Lymphoma. 2015;56:1643-1650.
- Goede V, et al. N Engl J Med. 2014;370:1101-1110.
- Chanan-Khan A, et al. Lancet Oncol. 2016;17:200-211.
- Jain N, et al. ASH 2017. Abstract 495.