5‐YEAR (Y) FOLLOW‐UP OF A PHASE 2 STUDY OF IBRUTINIB PLUS FLUDARABINE, CYCLOPHOSPHAMIDE, RITUXIMAB (IFCR) AS INITIAL THERAPY FOR YOUNGER CLL PATIENTS (PTS)

Abstract

Introduction: This frontline study investigates whether iFCR followed by 2Y ibrutinib (IBR) maintenance (I-M) could provide deep and durable responses in CLL irrespective of IGHV status. We previously reported high rates of bone marrow undetectable minimal residual disease (BM-uMRD) in both IGHV unmutated (U-IGHV, 83%) and mutated (M-IGHV, 82%) pts (Davids et al., Lancet Haematol, 2019). Here, we report updated data at a median follow-up of 63 months. Methods: In this phase 2 investigator-sponsored trial (NCT02251548), eligible pts received up to 6 cycles of iFCR followed by 2Y I-M. Pts with BM-uMRD after 2Y I-M had the option to stop IBR. MRD was assessed with multicolor flow at 10-4. Targeted NGS covering 97 genes was applied to peripheral blood (PB) samples at MRD recurrence. Results: 85 pts with a median age of 55Y (range 38–65) were treated, including 53% with U-IGHV and 6% with del17p and/or TP53MUT. 77 pts (91%) completed 2Y I-M. 20 pts continued IBR beyond 2Y I-M, including 13 with detectable MRD in BM or PB at 2Y. Safety was similar to our previous report; the cumulative incidence of atrial fibrillation was 8%, and second malignancy occurred in 11%, mostly non-melanoma skin cancer. Two pts (2%) had secondary myeloid neoplasms. No new deaths have occurred since the one death reported in the prior publication (sudden cardiac death during I-M). 5Y PFS was 94% (95% CI 89%–100%) and 5Y OS was 99% (95% CI 96%–100%). There was no difference in PFS by IGHV status or duration of I-M (Figure A). Five pts progressed with CLL, all after cessation of IBR. Fourteen pts remained in response on continuous IBR therapy, two of whom had achieved BM-uMRD at 2Y but chose to continue IBR. We longitudinally tracked PB MRD of 69 pts treated with at least 2Y of I-M with available samples and observed high rates of PB-uMRD post-iFCR (75%) and after 2Y I-M (77%). At 4Y after completion of iFCR, 63% of evaluable pts maintained PB-uMRD (Figure B). Thirteen pts (15%) had MRD recurrence without clinical progression, mostly after stopping IBR; 62% of these pts had U-IGHV, 7% del17p, and 15% NOTCH1MUT. BTKMUT was not detected in any of the ten pts analyzed at time of MRD recurrence. One pt had PLCG2MUT at a low allele frequency (2%). Driver gene mutations were commonly detected at MRD recurrence (23% with TP53MUT, 38% with 1–2 other mutations per pt affecting NOTCH1, SF3B1, ATM, XPO1, and/or BRAF). Four of six pts (67%) who received IBR retreatment after MRD recurrence achieved PR. Median duration of IBR retreatment was 34 months. Serial PB MRD data from five pts on IBR retreatment revealed that the MRD growth stabilized but was not eradicated during retreatment. Keywords: chronic lymphocytic leukemia (CLL), minimal residual disease, molecular targeted therapies This study was funded by Pharmacyclics, an AbbVie Company. Conflicts of interests pertinent to the abstract I. E. Ahn Consultant or advisory role: BeiGene D. M. Brander Conflicts of interests pertinent to the abstract Consultant or advisory role: Pfizer, Pharmacyclics, Genentech, TG Therapeutics, ArQule/Merck, AbbVie Research funding: Juno/Celgene/BMS, AstraZeneca/Acerta, CATO/SMS Catapult, NeWave, DTRM, Genentech, BeiGene, MEI Pharma, ArQule/Merck, AbbVie Other remuneration: Ascentage J. Montegaard Consultant or advisory role: Pharmacyclics, Abbvie, AstraZeneca A. Alencar Consultant or advisory role: Amgen, Kite, Seagen, Epizyme, Janssen, BeiGene, Incyte, TG Therapeutics, Genentech, Lilly Research funding: Loxo, BeiGene, Incyte C. A. Jacobson Consultant or advisory role: Kite/Gilead, BMS/Celgene, Novartis, Miltenyi, Abintus Bio, Ipsen, Instil Bio, Daiichi-Sankyo, Morphosys, Caribou Bio, ImmPACT Bio, AztraZeneca Research funding: Kite/Gilead, Pfizer P. Armand Consultant or advisory role: Merck, BMS, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, Morphosys, Daiichi Sankyo, Miltenyi, Tessa, GenMab, C4, Enterome, Regeneron, Epizyme, Astra Zeneca, Genentech, Xencor Honoraria: Merck, BMS Research funding: Kite; Research funding (institutional), Merck, BMS, Affimed, Adaptive, Tensha, Otsuka, Sigma Tau, Genentech/Roche, IGM J. Crombie Consultant or advisory role: Incyte, Karyopharm, Kite, ADC therapeutics, Genmab Research funding: Roche, Merck, Abbvie, Bayer A. S. LaCasce Consultant or advisory role: Seagen, Kite Honoraria: Research to practice J. Arnason Consultant or advisory role: BMS E. P. Hochberg Other remuneration: Leuko (Equity) J. S. Abramson Consultant or advisory role: Abbvie, Astra-Zeneca, 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, Cellectar J. R. Brown Consultant or advisory role: Abbvie, Acerta/Astra-Zeneca, BeiGene, Genentech/Roche, Grifols Worldwide Operations, Hutchmed, iOnctura, Janssen, Kite, Loxo/Lilly, MEI Pharma, Numab Therapeutics, Pfizer, Pharmacyclics Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, TG Therapeutics M. S. Davids Consultant or advisory role: AbbVie, Adaptive Biosciences, Ascentage Pharma, AstraZeneca, BeiGene, BMS, Eli Lilly, Genentech, Janssen, Merck, Mingsight Pharmaceuticals, ONO Pharmaceuticals, Secura Bio, TG Therapeutics, Takeda Research funding: AbbVie, AstraZeneca, Ascentage Pharma, Genentech, MEI Pharma, Novartis, Surface Oncology, TG Therapeutics