Ibrutinib and Rituximab Provides Superior Clinical Outcome Compared to FCR in Younger Patients with Chronic Lymphocytic Leukemia (CLL): Extended Follow-up from the E1912 Trial
Authors: Shanafelt Tait D. , Wang Victoria , Kay Neil E. , Hanson Curtis A. , O'Brien Susan M. , Barrientos Jacqueline C. , Jelinek Diane F , Braggio Esteban , Leis Jose F. , Zhang Cong Christina , Coutre Steven , Barr Paul M. , Cashen Amanda F , Mato Anthony R. , Singh Avina , Mullane Michael P. , Little Richard F. , Erba Harry P. , Stone Richard M. , Litzow Mark , Tallman Martin S. 
Published: February 2020

BACKGROUND:
Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has been the standard therapy for younger patients with CLL. FCR therapy is particularly effective in patients with immunoglobulin heavy chain variable region (IGHV) mutated CLL. Approximately half of IGHV mutated patients are progression free 8 years after FCR therapy.
At the ASH 2018 meeting, we reported the initial results of the ECOG 1912 (E1912) trial, a phase 3 trial comparing the FCR regimen to the combination of ibrutinib and rituximab (IR) for previously untreated CLL patients age 70 or younger who required therapy. With median follow-up of approximately 34 months, the trial demonstrated both a progression-free survival (PFS) and an overall survival (OS) benefit relative to FCR. On sub-set analysis by IGHV mutation status, the difference in PFS was statistically significant for IGHV unmutated patients but, with current follow-up, not IGHV mutated patients. Here, we present updated results for PFS in the E1912 trial.
METHODS: As previously reported, eligible patients were treatment-naive individuals with CLL age 70 or younger. Patients with deletion 17p- were excluded from participating in the E1912 trial given their known poor response to FCR therapy. Patients were randomly assigned in a two-to-one ratio to receive ibrutinib (420 mg/day until disease progression or unacceptable toxicity) and rituximab (50 mg/m2 on day 1 of cycle 2, 325 mg/m2 on day 2 of cycle 2, and then 500 mg/m2 on day 1 of cycles 3-7) or six courses of intravenous fludarabine (25 mg/m2 days 1-3), cyclophosphamide (250 mg/m2 days 1-3) and rituximab (50 mg/m2 on day 1 of cycle 1, 325 mg/m2 on day 2 of cycle 1, and then 500 mg/m2 on day 1 of cycles 2-6) every 28-days.
Adverse events (AEs) were graded according to the NCI Common Toxicity Criteria (version 4). Dose adjustments for cytopenias were based on the IWCLL CLL Working Group grading scale. The primary endpoint of the trial was PFS with OS a secondary endpoint. Analysis was by intention to treat.
RESULTS: With median follow-up of 45 months, 257 (73%) of 354 patients randomized to IR remain on ibrutinib. With extended follow-up, grade 3 and above treatment-related AEs were observed in 70% of IR and 80% of FCR treated patients (OR=0.56; 95% CI 0.34 - 0.90; p=0.013). Among IR-treated patients, the median time on treatment is currently 43 months (range=0.2-61).
Among the 95 patients who have discontinued ibrutinib, the reason for discontinuation was progression or death in 23 (7% of patients who started IR; 24% of those who discontinued treatment), AE or complication in 48 (14% of patients who started IR; 51% of those who discontinued treatment), and withdrawal of consent or other reasons in 24 (7% of patients who started IR; 25% of those who discontinued treatment). On multivariable Cox regression adjusting for Timed Up and Go test score, Cumulative Illness Rating Scale (CIRS) score, age, gender, ECOG performance status, creatinine clearance, and baseline anemia/thrombocytopenia, only CIRS score (range 0 - 14) predicted discontinuation of ibrutinib for a reason other than progression or death (HR=1.13 per unit increase; 95% CI 1.03 - 1.23; p=0.009). Among the 72 patients who discontinued ibrutinib for a reason other than progression or death, the median time on ibrutinib was 15.1 months (range 0.2-58.2 months). The median time from ibrutinib discontinuation to disease progression or death was 23 months.
With current follow-up, we observed 110 PFS events. The hazard ratio (HR) for PFS favored IR over FCR (HR=0.39; 95% CI 0.26-0.57; p&lt;0.0001). Updated analysis of OS will be presented. On sub-group analysis by IGHV mutation status, IR was superior to FCR for IGHV unmutated patients (HR=0.28; 95% CI 0.17-0.48; p&lt;0.0001). With current follow-up the difference is not significant in IGHV mutated patients (HR=0.42; 95% CI 0.16-1.16; p=0.086). Kaplan-Meier estimates for PFS are shown in Figure 1.
CONCLUSIONS:
Although less than 7% of ibrutinib treated patients progressed while on therapy, roughly 1 in 5 patients have discontinued ibrutinib for a reason other than progression or death. The only parameter significantly associated with discontinuation for a reason other than progression was increased baseline CIRS score. With extended follow-up, the combination of ibrutinib and rituximab continues to provide superior PFS compared to FCR for younger patients with previously untreated CLL.

Disclosures
Shanafelt: Pharmacyclics: Research Funding; Patent: Patents & Royalties: US14/292,075 on green tea extract epigallocatechin gallate in combination with chemotherapy for chronic lymphocytic leukemia; Polyphenon E International: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Glaxo-SmithKline: Research Funding; Hospira: Research Funding; Cephalon: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Astellas: Consultancy; Aptose Biosciences, Inc: Consultancy; Amgen: Consultancy; Alexion: Consultancy; Acerta: Research Funding; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Verastem: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Regeneron: Research Funding; Kite: Research Funding. Barrientos:AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Janssen: Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding. Coutre:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Gilead: Research Funding; BeiGene: Other: Travel, Accommodations, Expenses & Data Safety Monitoring Committee; Genentech: Consultancy. Barr:Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; Gilead: Consultancy; Verastem: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Celgene: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; Astra Zeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Cashen:Celgene: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy. Erba:Amgen: Consultancy; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; Astellas Pharma: Consultancy; Astellas Pharma: Consultancy; Amgen: Consultancy; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Pfizer: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding. Stone:Arog Pharmaceuticals: Consultancy, Honoraria, Research Funding; Otsuka-Astex Pharmaceuticals: Consultancy; Fujifilm: Consultancy; AstraZeneca: Consultancy; Celator Pharmaceuticals: Consultancy; Abbvie: Consultancy, Research Funding; Ono Pharmaceutical-Theradex Oncology: Consultancy; Cornerstone Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Takeda: Other: Fees for serving on a data and safety monitoring board ; Orsenix: Consultancy; MacroGenics: Consultancy; Jazz Pharmaceuticals: Consultancy; Agios: Consultancy, Research Funding; Stemline Therapeutics: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Fees for serving on a steering committee, and fees for serving on a data and safety monitoring board; Novartis: Consultancy, Research Funding; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees; Argenx: Other: Fees for serving on a data and safety monitoring board ; Roche: Consultancy. Tallman:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees.