Combining ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab/GA101 (iFCG) with only 3 cycles of chemotherapy may be an effective, time-limited regimen for patients with chronic lymphocytic leukemia (CLL) with mutated immunoglobulin heavy-chain variable (IGHV) gene and without del(17p)/TP53 mutation, according to phase 2 research published in Leukemia.
The combination of fludarabine, cyclophosphamide, and rituximab (FCR) previously demonstrated long-term benefit in CLL patients. However, the FCR combination is associated with a 2% to 5% risk of treatment-related myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML).
Researchers from the University of Texas MD Anderson Cancer Center and the University of California Irvine Medical Center designed an investigator-initiated phase 2 study (ClinicalTrials.gov Identifier: NCT02629809) with iFCG for previously untreated CLL patients with mutated IGHV and absence of del(17p)/TP53 mutation. The study intended to develop a chemoimmunotherapy-based regimen with reduced chemotherapy exposure that could lower the risk of MDS/AML.
The study enrolled a total of 45 patients who received iFCG for 3 cycles. The median follow-up of the study was 41.3 months. After completing 3 cycles, 38% of the patients achieved complete remission (CR) or complete remission with incomplete count recovery (CRi), and 87% achieved bone marrow undetectable measurable residual disease (U-MRD).
After completing 12 cycles, 67% of the patients achieved CR/CRi and 91% achieved U-MRD. Of the total study population, 44 (98%) patients achieved marrow U-MRD as the best response. Seventeen patients who achieved CR/CRi received an additional 9 cycles of ibrutinib with 3 cycles of obinutuzumab and all other patients received 9 additional cycles of ibrutinib and 9 cycles of obinutuzumab. Per protocol, after completing 12 cycles, patients with marrow U-MRD remission discontinued all treatment, including ibrutinib.
There were no patients with progressive disease. The 3-year PFS and OS were similar (98%).
Grade 3 to 4 hematologic adverse events (AEs) included neutropenia, which occurred in 27 patients, and thrombocytopenia, which occurred in 18 patients. Grade 3 to 4 non-hematologic AEs included an increase in transaminase level which was noted in 6 patients and atrial fibrillation occurred in 5 patients.
“The results of the targeted therapy combination regimens are very encouraging and may provide chemotherapy-free options for the majority of patients with CLL,” the authors wrote. “However, long-term data are not yet available with these time-limited targeted therapy combinations and it remains to be seen whether they produce very long-term, treatment-free remissions similar to those seen after FCR.”
Disclosure: This research was supported by Pharmacyclics and Genentech. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Jain N, Thompson P, Burger J, et al. Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) regimen for chronic lymphocytic leukemia (CLL) with mutated IGHV and without TP53 aberrations. Leukemia. Published online May 18, 2021. doi:10.1038/s41375-021-01280-8