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Chronic lymphocytic leukemia

Ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) regimen for chronic lymphocytic leukemia (CLL) with mutated IGHV and without TP53 aberrations

Abstract

Chemoimmunotherapy with combined fludarabine, cyclophosphamide and rituximab (FCR) has been an effective treatment for patients with chronic lymphocytic leukemia (CLL). We initiated a phase II trial for previously untreated patients with CLL with mutated IGHV and absence of del(17p)/TP53 mutation. Patients received ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for three cycles. Patients who achieved complete remission (CR)/CR with incomplete count recvoery (CRi) with marrow undetectable measurable residual disease (U-MRD) received additional nine cycles of ibrutinib with three cycles of obinutuzumab; all others received nine additional cycles of ibrutinib and obinutuzumab. Patients in marrow U-MRD remission after cycle 12 discontinued all treatment, including ibrutinib. Forty-five patients were treated. The median follow-up is 41.3 months. Among the total 45 treated patients, after three cycles, 38% achieved CR/CRi and 87% achieved marrow U-MRD. After cycle 12, the corresponding numbers were 67% and 91%, respectively. Overall, 44/45 (98%) patients achieved marrow U-MRD as best response. No patient had CLL progression. The 3-year progression-free survival (PFS) and overall survival (OS) were 98% and 98%, respectively. Per trial design, all patients who completed cycle 12 discontinued ibrutinib, providing for a time-limited therapy. Grade 3–4 neutropenia and thrombocytopenia occurred in 58% and 40% patients, respectively. The iFCG regimen with only 3 cycles of chemotherapy is an effective, time-limited regimen for patients with CLL with mutated IGHV and without del(17p)/TP53 mutation.

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Fig. 1: Trial profile.
Fig. 2: Response to treatment.
Fig. 3: MRD response by NGS MRD assay.
Fig. 4: Progression-free survival and overall survival for all patients (N = 45).

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Acknowledgements

Supported by Pharmacyclics LLC, an AbbVie Company and Genentech. This research is supported in part by the MD Anderson Cancer Center CLL Moon Shot program and MD Anderson Cancer Center Support Grant P30 CA016672. We thank the patients who participated in this trial and their families, the MDACC IND office for their oversight of the study, and the referring physicians. We thank the entire clinical and research staff at the Department of Leukemia, MDACC.

Funding

The study was supported in part with funding and drug supply (ibrutinib, obinutuzumab) by Pharmacyclics and Genentech. The pharmaceutical sponsors approved the study design and reviewed the paper, but had no role in the collection or analyses of the data.

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NJ, PT, JB, AF, ZE, HK, SOB, MK, and WW designed the study. NJ, PT, JB, AF, KT, ZE, GB, PB, TK, NP, KS, MK, EJ, HK, SOB, MK, and WW enrolled and managed patients on the trial. NG read the radiology reports for the trial. XW was the trial statistician. RKS and KP performed genomic sequencing. WW, JJ, and SW performed flow cytometry for MRD. WL and AA were study managers. WP and VG provided clinical and scientific input. All authors read and approved the final paper.

Corresponding author

Correspondence to William G. Wierda.

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Conflict of interest

NJ has received research funding from Pharmacyclics, Genentech, AbbVie, ADC Therapeutics, Pfizer, BMS, Verastem, AstraZeneca, Seattle Genetics, Incyte, Celgene, Servier, Cellectis, Adaptive Biotechnologies, Fate Therapeutics, Aprea Therapeutics, and Precision Biosciences. NJ has served on the advisory boards and has received honoraria from Pharmacyclics, Genentech, AbbVie, Adaptive Biotechnologies, TG Therapeutics, Pfizer, Janssen, AstraZeneca, Verastem, Servier, BMS, Beigene, Cellectis, ADC Therapeutics, and Precision Biosciences. VG received research funding from Pharmacyclics, AbbVie, Verastem, Dava Oncology, AstraZeneca, Gilead, Sunesis, and Loxo Oncology. WW has received research support from AbbVie, Pharmacyclics, and Genentech and has received honoraria from Pharmacyclics, AbbVie, Roche, and Genentech. All other authors declare no competing interests.

Ethical approval

The MDACC IRB approved this study and the study was conducted in accordance with the Declaration of Helsinki. This trial was registered on Clinicaltrials.gov (NCT02629809).

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All patients provided written informed consent.

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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 35, 3421–3429 (2021). https://doi.org/10.1038/s41375-021-01280-8

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