Five-year follow-up of a phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL.

"Conflict-of-interest disclosure: I.E.A. reports receiving consulting fees from AstraZeneca and BeiGene. D.M.B. received research funding from Ascentage, Juno/10.13039/100006436Celgene/Bristol Myers Squibb (BMS), 10.13039/100004325AstraZeneca/Acerta, Allucent, Catapult, NeWave, DTRM, 10.13039/100004328Genentech, 10.13039/100017239BeiGene, 10.13039/100016282MEI Pharma, ArQule/Merck, and AbbVie; and consulting fees from Pfizer, Pharmacyclics, Genentech, TG Therapeutics, ArQule/Merck, and AbbVie. J.M. reports receiving consulting fees from Pharmacyclics, AbbVie, and AstraZeneca. A.A. reports receiving consulting fees from Amgen, Kite, Seagen, Epizyme, Janssen, BeiGene, Incyte, TG Therapeutics, Genentech, and Lilly; and research funding from Loxo, 10.13039/100017239BeiGene, and 10.13039/100017655Incyte. C.A.J. reports receiving consulting fees from Kite/Gilead, BMS/Celgene, Novartis, Miltenyi, Abintus Bio, Ipsen, Instil Bio, Daiichi-Sankyo, MorphoSys, Caribou Bio, ImmPACT Bio, and AstraZeneca; and research funding from Kite/10.13039/100005564Gilead, and 10.13039/100004319Pfizer. P.A. reports receiving consulting fees from Merck, BMS, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, MorphoSys, Daiichi-Sankyo, Miltenyi, Tessa, Genmab, C4, Enterome, Regeneron, Epizyme, AstraZeneca, Genentech, and Xencor; research funding from Kite; institutional research funding from 10.13039/100004334Merck, BMS, Affimed, Adaptive, Tensha, 10.13039/100019120Otsuka, 10.13039/100009996Sigma-Tau, 10.13039/100004328Genentech/10.13039/100004337Roche, and IGM; and honoraria from Merck and BMS. J.C. reports receiving consulting fees from Incyte, Karyopharm, Kite, ADC therapeutics, Genmab; and research funding from 10.13039/100004337Roche, 10.13039/100004334Merck, 10.13039/100006483AbbVie, and 10.13039/100004326Bayer. A.S.L. received fees from Research To Practice; and consulting fees from Seagen, and Kite. J.A reports receiving consulting fees from BMS. E.P.H. holds equity at Leuko. J.S.A. reports receiving consulting fees from AbbVie, AstraZeneca, BeiGene, bluebird bio, BMS, Celgene, Epizyme, Incyte, Kymera, Genmab, Genentech, Ono Pharma, Mustang Bio, MorphoSys, Regeneron, Century, Kite Pharma, Lilly, Janssen, Takeda, Caribou Biosciences, Interius, and Cellectar. J.R.B. reports receiving consulting fees from AbbVie, Acerta/AstraZeneca, BeiGene, Genentech/Roche, Grifols Worldwide Operations, Hutchmed, iOnctura, Janssen, Kite, Loxo/Lilly, MEI Pharma, Numab Therapeutics, Pfizer, and Pharmacyclics; and research funding from 10.13039/100017239BeiGene, 10.13039/100005564Gilead, iOnctura, Loxo/Lilly, 10.13039/100016282MEI Pharma, and 10.13039/100013252TG Therapeutics. M.S.D. received research funding from 10.13039/100006483AbbVie, 10.13039/100004325AstraZeneca, 10.13039/100019621Ascentage Pharma, 10.13039/100004328Genentech, 10.13039/100004336Novartis, Surface Oncology; and consulting fees from AbbVie, Adaptive Biosciences, Ascentage Pharma, AstraZeneca, BeiGene, BMS, Eli Lilly, Genentech, Genmab, Janssen, Merck, Mingsight Pharmaceuticals, Nuvalent, Ono Pharmaceuticals, Secura Bio, TG Therapeutics, and Takeda. The remaining authors declare no competing financial interests."

"10.13039/100014491Pharmacyclics, LLC, an 10.13039/100006483AbbVie company, provided research funding and study drug for this study. I.E.A. is supported by an 10.13039/100001422American Society of Hematology Scholar Award and 10.13039/100005189Leukemia and Lymphoma Society Scholar in Clinical Research Award. J.R.B. is supported by National Institutes of Health R01CA25892. M.S.D. is supported by a National Institutes of Health 1R01CA266298-01A1 award and is a Leukemia and Lymphoma Society Scholar in Clinical Research."

"We previously reported high rates of undetectable minimal residual disease <10−4 (uMRD4) with ibrutinib plus fludarabine, cyclophosphamide, and rituximab (iFCR) followed by 2-year ibrutinib maintenance (I-M) in treatment-naïve chronic lymphocytic leukemia (CLL). Here, we report updated data from this phase 2 study with a median follow-up of 63 months. Of 85 patients enrolled, including 5 (6%) with deletion 17p or TP53 mutation, 91% completed iFCR and 2-year I-M. Five-year progression-free survival (PFS) and overall survival were 94% (95% confidence interval [CI], 89%-100%) and 99% (95% CI, 96%-100%), respectively. No additional deaths have occurred with this extended follow-up. No difference in PFS was observed by immunoglobulin heavy-chain variable region gene status or duration of I-M. High rates of peripheral blood (PB) uMRD4 were maintained (72% at the end of iFCR, 66% at the end of 2-year I-M, and 44% at 4.5 years from treatment initiation). Thirteen patients developed MRD conversion without clinical progression, mostly (77%) after stopping ibrutinib. None had Bruton tyrosine kinase (BTK) mutations. One patient had PLCG2 mutation. Six of these patients underwent ibrutinib retreatment per protocol. Median time on ibrutinib retreatment was 34 months. The cumulative incidence of atrial fibrillation was 8%. Second malignancy or nonmalignant hematologic disease occurred in 13%, mostly nonmelanoma skin cancer. Overall, iFCR with 2-year I-M achieved durably deep responses in patients with diverse CLL genetic markers. Re-emergent clones lacked BTK mutation and retained sensitivity to ibrutinib upon retreatment. This trial is registered at www.clinicaltrials.gov as #NCT02251548."