Longer Term Follow-up of a Multicenter, Phase 2 Study of Ibrutinib Plus Fludarabine, Cyclophosphamide, Rituximab (iFCR) As Initial Therapy for Younger Patients with Chronic Lymphocytic Leukemia
Authors: Davids Matthew S. , Brander Danielle M. , Tyekucheva Svitlana , Chen Chinheng , Kaminski James , Montegaard Josie , Alencar Alvaro J. , Shune Leyla , Omaira Mohammad , Jacobson Caron , Armand Philippe , Ng Samuel Y. , Crombie Jennifer L. , LaCasce Ann S. , Arnason Jon E. , Hochberg Ephraim , Takvorian Ronald W. , Abramson Jeremy S. , Fisher David C. , Brown Jennifer R 
Published: November 2021

Abstract
Introduction
FCR remains the only therapy other than allo transplant proven to provide a significant chance of functional cure with very long term follow-up for young, fit patients with mutated IGHV CLL. Given the excellent efficacy and tolerability of ibrutinib in a broad population of young, fit CLL patients, we designed the frontline iFCR study to investigate whether time-limited novel agent plus chemoimmunotherapy could provide durable remission for CLL patients irrespective of IGHV status. We previously reported that with a median follow-up of 16.5 months, the rate of CR with bone marrow undetectable minimal residual disease (BM-uMRD) 2 months post-FCR (primary endpoint) was 33%, and that 84% of patients achieved BM-uMRD as best response (Davids et al., Lancet Haem, 2019). Here, we report updated data with longer follow-up, with all patients having had the opportunity to complete 2 years of ibrutinib maintenance following iFCR.

Methods
This is a multicenter, single arm, phase 2 investigator sponsored trial (NCT02251548) which enrolled CLL patients age ≤65 years without restriction by IGHV mutation status, all of whom met iwCLL treatment criteria. Ibrutinib 420 mg daily was given for 7 days, then combination ibrutinib with FCR for up to 6 cycles. Responders continued on ibrutinib maintenance, and patients with BM-uMRD after 2 years of maintenance discontinued therapy. Response was assessed by 2008 iwCLL criteria, and toxicity by CTCAE v4.03 and iwCLL criteria. The primary objective was to determine the rate of CR/CRi with BM-uMRD 2 months after iFCR combination. Secondary objectives were to assess response rates, PFS/OS, rates of BM-uMRD after 2 years of ibrutinib maintenance, and safety/tolerability.

Results
Between October, 2014, and April, 2018, 85 patients were enrolled at 9 US sites.As previously reported, the median age was 55 years (range 38-65). IGHV was unmutated in 46/79 patients (58.2%). Deletion of 17p and TP53 mutation were present in 4/83 (4.8%) and 3/81 (3.7%) patients, respectively; 2 of these patients had both. The median number of FCR cycles completed was 6 (range 1-6).
Median follow-up is now 40.3 months (range 3.1-76). Median number of ibrutinib maintenance cycles is 24 (range 0-81). By ITT analysis, the rate of CR with BM-uMRD at any point on study is now 55% (47/85 patients), and best rate of BM-uMRD remained 84% (71/85). After 2 years of ibrutinib maintenance, the rates of CR/CRi, BM-uMRD, and PB-uMRD in patients with available data were 77% (44/57), 81% (50/62), and 81% (55/68), respectively, with no differences based on IGHV status. At the median follow-up time of 40 months, PFS and OS for all patients were 97% and 99%, respectively (see Figure, below). Thirteen of 61 patients (21.3%) who completed iFCR and started ibrutinib maintenance in a BM-uMRD state have had recurrent BM-MRD, with median time to MRD recurrence not yet reached. Seven patients underwent retreatment with ibrutinib monotherapy (5 due to clinical progression and 2 due to recurrent BM-MRD without clinical progression), and all 7 achieved PR with re-treatment. Median time on re-treatment is 12.8 months (range 4.2-26.2), and none of these 7 patients have progressed on re-treatment. One patient died 17 months into ibrutinib maintenance due to presumed sudden cardiac death. In the updated safety analysis, the most common treatment-emergent Gr 3/4 adverse events were hematologic, including neutropenia 40% (up from 35%), thrombocytopenia 32% (unchanged), and anemia 11% (unchanged). Ten patients (12%, up from 9%) experienced Gr ≥3 febrile neutropenia, and 20 patients (24%, up from 11%) had Gr ≥3 infection. Any Gr atrial fibrillation was observed in 8%, and ventricular arrhythmia in 1 patient. No major bleeding events occurred. Two patients developed MDS, and both are now in CR for CLL and MDS after undergoing allo transplant. No patients developed Richter's syndrome.

Conclusions
With longer term follow-up (median of 40.3 months), most patients treated with iFCR have continued to maintain deep responses, including patients with unmutated IGHV. The safety profile remains consistent with the individual toxicities of ibrutinib and FCR. Among the few patients with recurrence after this time-limited therapy, all have responded to re-treatment with ibrutinib monotherapy. iFCR is worthy of exploring in comparative studies in younger, fit CLL patients who desire the possibility of functional cure with time-limited therapy.
Figure 1 Figure 1.

Disclosures
Davids: Ascentage Pharma: Consultancy, Research Funding; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; BeiGene: Consultancy; Adaptive Biotechnologies: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy. Brander: NCCN: Other: panel member; Verastem: Consultancy; MEI Pharma: Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; ArQule: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; DTRM: Research Funding; ArQule/Merck: Consultancy; LOXO: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Genentech: Consultancy, Research Funding; Ascentage: Research Funding; BeiGene: Research Funding. Montegaard: AbbVie: Consultancy; AstraZeneca*-: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy. Alencar: Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Incyte: Consultancy; Epizyme: Consultancy; Celgene: Consultancy; BeiGene: Consultancy; Amgen: Consultancy. Jacobson: Humanigen: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Axis: Speakers Bureau; Lonza: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria. Armand: Infinity: Consultancy; Pfizer: Consultancy; Kite: Research Funding; Tensha: Research Funding; IGM: Research Funding; Roche: Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Epizyme: Consultancy; Enterome: Consultancy; Regeneron: Consultancy; C4: Consultancy; GenMab: Consultancy; Tessa Therapeutics: Consultancy; Miltenyi: Consultancy; Morphosys: Consultancy; Daiichi Sankyo: Consultancy; Otsuka: Research Funding; Sigma Tau: Research Funding; Celgene: Consultancy; ADC Therapeutics: Consultancy; Adaptive: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Crombie: Roche: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Bayer: Research Funding; Karyopharm: Consultancy; Incyte: Consultancy. LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Arnason: Juno/BMS: Honoraria. Hochberg: Trapelo Health: Consultancy; Leuko: Consultancy. Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; Kite Pharma: Consultancy; Novartis: Consultancy; Morphosys: Consultancy; C4 Therapeutics: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Brown: Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding; Invectys: Other: Data Safety Monitoring Committee Service; Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy.

OffLabel Disclosure:
Ibrutinib being used to enhance the efficacy of FCR