Abstract: Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) that has dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological evasion in patients with RT. We hypothesized that combining nivolumab, a PD-1 blocking antibody, with the BTK inhibitor (BTKi) ibrutinib could potentiate tumor-cell killing. We conducted an investigator-initiated phase 2 clinical trial to assess the efficacy of combined nivolumab and ibrutinib in patients with diffuse large B-cell lymphoma (DLBCL) RT and CLL. Patients included were ≥18 years of age with adequate hepatic and renal function. Patients received nivolumab every 2 weeks of a 4-week cycle for a maximum of 24 cycles. A standard dose ibrutinib was initiated from cycle 2 onward and continued daily until progression. For patients who were already on ibrutinib at the time of study entry, the same was continued while nivolumab was initiated. A total of 24 patients with RT with a median age of 64.5 years (range, 47-88) were enrolled. Ten patients (42%) had received prior treatment for RT and 13 patients (54%) had received a prior BTKi. A total of 10 patients (42%) responded with a median duration of response of 15 months. The median overall survival was 13 months. Four of 24 (17%) patients had checkpoint inhibition–related immunological toxicities. In the CLL cohort, 10 patients were enrolled, of whom 3 patients converted from partial to complete remission; 1 patient had a grade 2 immunological toxicity. Combined nivolumab and ibrutinib is an active regimen for patients with DLBCL RT with an overall response rate of 42%. Given the limited treatment options for patients with RT, checkpoint inhibition provides a potential therapeutic option. This trial is registered at www.clinicaltrials.gov as #NCT02420912.

Abstract: Background: Ibrutinib (IBR) and venetoclax (VEN) combination is a highly effective therapy for patients (pts) with CLL. The ideal treatment duration for the combination therapy is not known. Several ongoing trials are evaluating 1 year (yr), 2 yr, or an MRD-guided strategy for the duration of combination therapy. We previously reported results of the first-line cohort of a phase II trial of combined IBR and VEN for pts with CLL (Jain, NEJM 2019). Here we report updated data for these pts with focus on MRD. Methods: Pts with previously untreated CLL meeting IWCLL treatment criteria were enrolled. Pts received IBR 420 mg daily for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily). Combined therapy was given for 24 cycles (28 days/cycle). Pts with bone marrow (BM) undetectable MRD (U-MRD) (flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy discontinued both VEN and IBR; MRD+ pts continued IBR. Response assessments were performed using BM and CT (2008 IWCLL criteria) after cycle 3 of IBR monotherapy, and then after cycles 3, 6, 9, 12, 18, and 24 of the combination. U-MRD was defined as & lt;0.01%; low MRD+ 0.01% to & lt;1%; high MRD+ ≥1%. Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death from any cause. Overall survival (OS) was assessed as the time from the start of study drug to death from any cause. Results: A total of 80 pts were enrolled. The median age was 65 yrs. Baseline characteristics are shown in Table 1. The median follow-up was 33.8 months. Five pts came off study during IBR monotherapy; 75 pts initiated VEN. Serial BM MRD assessments are shown in Figure 1 (this includes all 80 pts as denominator, including the 5 pts who never started VEN in an intent-to-treat analysis). After 12 cycles of the combination, 45/80 (56%) achieved BM U-MRD remission; 24/80 (30%) were BM MRD-positive (low MRD+, n=19; high MRD+, n=5); 11/80 (14%) were off study prior to cycle 12 assessment. After 24 cycles of the combination, 53/80 (66%) achieved BM U-MRD remission; 14/80 (17%) were BM MRD-positive (low MRD+, n=13; high MRD+, n=1); 13/80 (17%) were off study prior to cycle 24 assessment. Overall, 60/80 (75%) achieved BM U-MRD at any time. For the 24 pts who were BM MRD+ at the end of cycle 12, with continued combination treatment, 12/24 (50%) achieved BM U-MRD at the end of cycle 24 [low MRD+, 10/19 (53%); high MRD+, 2/5 (40%)]. None of the pretreatment characteristics (age, gender, ALC, HGB, PLT, FISH abnormalities, IGHV status, CD38, ZAP-70, TP53-m, NOTCH1-m, SF3B1-m) were statistically associated with achieving BM U-MRD at 6 cycles, 12 cycles, 24 cycles, or MRD at any time. PFS and OS are shown in Figure 2. PFS by FISH and IGHV status is shown in Figure 3. No pt had CLL progression. Richter's transformation developed in 2 pts (during VEN dose escalation, n=1; during cycle 24 of combination, n=1); both pts are alive in remission after receiving allo-SCT. Three pts died. Two pts came off study during the cycle 1 of IBR monotherapy and died 6 mos and 27 mos later due to infection issues; 1 pt died in U-MRD remission during cycle 19 of the combination therapy when found unresponsive at home, had CPR, and CT scan done in hospital showed b/l pneumonia. This was deemed possibly ibrutinib related. Of the 53 pts who were BM U-MRD at the end of cycle 24 of the combination, 41 pts had a subsequent blood MRD assessment done in follow-up (others are too early) with a median time off study drugs of 11.6 mos; 5 pts had recurrence of blood MRD (range, 0.01-0.05%) without any clinical disease progression. There were 14 pts who were BM MRD+ at the end of cycle 24 of the combination (low MRD+, n=13; high MRD+, n=1). The only pt with high-MRD+ at end of cycle 24 was noted to have Richter transformation at that time (described above). The remaining 13 pts (all low MRD+ in BM, range 0.01-0.56%) are on IBR monotherapy; 4/9 who had a subsequent blood MRD assessment achieved blood U-MRD. Conclusions: Combined IBR and VEN is an effective time-limited oral regimen for pts with CLL. We report 50% conversion of BM MRD+ to U-MRD from cycle 12 to cycle 24 with ongoing combination therapy. Whether this would translate into improved PFS remains to be determined. Given improved MRD response from cycle 12 to cycle 24, we have amended the trial to allow another 12 cycles of the combination for pts who are BM MRD+ at cycle 24. Ongoing studies will further help define the role and the optimal duration of this combination in CLL. Disclosures Jain: ADC Therapeutics: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Pfizer: Research Funding; BMS: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:Adaptive Biotechnologies: Consultancy, Research Funding; Pharmacyclics: Research Funding; AbbVie: Research Funding; Genentech: Consultancy; Janssen-Cilag: Honoraria. Burger:Pharmacyclics, an AbbVie company: Consultancy, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Research Funding; Beigene: Research Funding, Speakers Bureau; AstraZeneca: Consultancy; TG Therapeutics: Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Speakers Bureau. Borthakur:Incyte: Research Funding; BioLine Rx: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; FTC Therapeutics: Consultancy; BioLine Rx: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding; Abbvie: Research Funding; Jannsen: Research Funding; BioTherix: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; PTC Therapeutics: Research Funding; BMS: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Cyclacel: Research Funding; GSK: Research Funding. Sasaki:Pfizer Japan: Consultancy; Otsuka: Honoraria; Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kadia:Novartis: Honoraria; BMS: Honoraria, Research Funding; Cellenkos: Research Funding; Genentech: Honoraria, Research Funding; Incyte: Research Funding; Pulmotec: Research Funding; Ascentage: Research Funding; Amgen: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Cyclacel: Research Funding; JAZZ: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Astellas: Research Funding; Abbvie: Honoraria, Research Funding. Konopleva:Sanofi: Research Funding; Forty-Seven: Consultancy, Research Funding; Eli Lilly: Research Funding; Amgen: Consultancy; Stemline Therapeutics: Consultancy, Research Funding; Kisoji: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ascentage: Research Funding; Rafael Pharmaceutical: Research Funding; AbbVie: Consultancy, Research Funding; AstraZeneca: Research Funding; Cellectis: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Ablynx: Research Funding; Calithera: Research Funding; Agios: Research Funding. Alvarado:Sun Pharma: Research Funding; BerGenBio ASA: Research Funding; MEI Pharma: Research Funding; Tolero Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding. Yilmaz:Pfizer: Research Funding; Daicho Sankyo: Research Funding; Pint Pharma: Honoraria. DiNardo:Syros: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; ImmuneOnc: Honoraria; Calithera: Research Funding. Bose:Celgene Corporation: Honoraria, Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Promedior, Inc.: Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Astellas Pharmaceuticals: Research Funding; CTI BioPharma: Honoraria, Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Blueprint Medicines Corporation: Honoraria, Research Funding. Pemmaraju:Plexxikon: Research Funding; AbbVie: Honoraria, Research Funding; Blueprint Medicines: Honoraria; Incyte Corporation: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MustangBio: Honoraria; Samus Therapeutics: Research Funding; DAVA Oncology: Honoraria; Cellectis: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Pacylex Pharmaceuticals: Consultancy; Celgene: Honoraria; Daiichi Sankyo: Research Funding; SagerStrong Foundation: Other: Grant Support; LFB Biotechnologies: Honoraria; Roche Diagnostics: Honoraria. Jabbour:BMS: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding. Kantarjian:Jazz Pharma: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Immunogen: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Research Funding; BMS: Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Research Funding. OffLabel Disclosure: Combination of ibrutinib and venetoclax is not FDA approved

Abstract: Background: Ibrutinib (IBR) and venetoclax (VEN) combination is a highly effective therapy for patients (pts) with CLL (Jain, NEJM 2019; Wierda, ASH 2020; Kater, EHA 2021). We previously reported results of the first-line cohort of a phase II trial of combined IBR and VEN for high-risk pts with CLL (Jain, NEJM 2019; Jain, JAMA Oncology 2021). Here we report updated data for these pts with focus on MRD. Methods: Pts with previously untreated CLL meeting IWCLL treatment criteria were enrolled. All pts had at least one high-risk feature: del(17p), mutated TP53, del(11q), unmutated IGHV, or age ≥65 years (yrs). Pts received IBR 420 mg daily for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily). Combined therapy was given for 24 cycles (28 days/cycle). Pts with bone marrow (BM) undetectable MRD (U-MRD) (flow cytometry; sensitivity 10 -4) at 24 cycles of combined therapy discontinued both VEN and IBR; MRD+ pts continued IBR. A trial amendment allowed an additional 12 cycles of combined VEN and ibrutinib for pts who remained BM MRD+ after Cycle 24. Response assessments were performed using BM and CT imaging studies (2008 IWCLL criteria). U-MRD was defined as & lt;0.01%; low MRD+ 0.01% to & lt;1%; high MRD+ ≥1%. Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death from any cause. Blood MRD was monitored every 6 months in pts off treatment or on ibrutinib monotherapy beyond 24 cycles of combined treatment. Results: A total of 80 pts were enrolled. Baseline characteristics are shown in Table 1. The median follow-up was 44.1 months. Five pts came off study during 1 st 3 cycles of IBR monotherapy; 75 pts initiated VEN. We previously reported that after 12 cycles of the combination, 45/80 (56%) achieved BM U-MRD remission; 24/80 (30%) were BM MRD-positive (low MRD+, n=19; high MRD+, n=5). After 24 cycles of the combination, 53/80 (66%) achieved BM U-MRD remission; 14/80 (17%) were BM MRD+ (low MRD+, n=13; high MRD+, n=1). Overall, 60/80 (75%) achieved BM U-MRD as the best response. Updated PFS is provided in Figure 1. Of the 53 pts who were BM U-MRD at the end of cycle 24 of the combination, 52 pts had a subsequent blood MRD assessment done in follow-up (1 missed due to COVID-19); 51/53 discontinued all therapy, 2 pts continued IBR per treatment physician discretion. With a median time of 18.4 months post Cycle 24, 8 pts had recurrence of blood MRD (defined as MRD ≥ 0.01% in 2 consecutive visits) in follow-up with 1 pt with CLL progression. The sole pt with CLL progression had mutated IGHV with del(11q) and NOTCH1 mutation. The pt had delayed achievement of BM U-MRD with the pt achieving U-MRD for the first time at the end of Cycle 24 of combined therapy. She was noted to have disease progression 22 months off therapy; BTK or PLCG2 mutation were not detected and the patient is currently in clinical remission on acalabrutinib. The time to MRD conversion for these 53 pts is shown in Figure 2. There were 14 pts who were BM MRD+ at the end of cycle 24 of the combination (low MRD+, n=13; high MRD+, n=1). The only pt with high-MRD+ at end of cycle 24 was noted to have Richter transformation at that time. The remaining 13 pts (all low MRD+ in BM, range 0.01-0.56%) continued IBR monotherapy. With a recent trial amendment, MRD+ pts after Cycle 24 could get 12 additional cycles of venetoclax; 9/13 pts have resumed VEN. 6/9 pts have achieved U-MRD remission. 2 pts had Richter transformation and 3 pts have died (Jain, JAMA Oncology 2021). Conclusions: We report long term follow-up of combined IBR and VEN in first-line CLL. Remissions were durable with some pts having recurrence of blood MRD in follow-up, which may be an early indicator of relapse. In a small subset of the pts with BM MRD+ disease at 24 cycles of combined therapy, additional VEN appears to lead to U-MRD remission in majority of the pts. Whether this will lead to improved long-term PFS remains to be determined. Figure 1 Figure 1. Disclosures Jain: TG Therapeutics: Honoraria; Beigene: Honoraria; Janssen: Honoraria; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Precision Biosciences: Honoraria, Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. Thompson: AbbVie: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Amgen: Other: Institution: Honoraria, Research Grant/Funding; Genentech: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Adaptive Biotechnologies: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding, Expert Testimony; Pharmacyclics: Other: Institution: Advisory/Consultancy, Honoraria, Research Grant/Funding; Janssen: Consultancy, Honoraria; Gilead: Other: Institution: Advisory/Consultancy, Honoraria. Ferrajoli: BeiGene: Other: Advisory Board, Research Funding; Janssen: Other: Advisory Board ; AstraZeneca: Other: Advisory Board, Research Funding. Burger: Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau; Beigene: Research Funding, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; AstraZeneca: Consultancy. Borthakur: GSK: Consultancy; ArgenX: Membership on an entity's Board of Directors or advisory committees; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Ryvu: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Takahashi: Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Celgene/BMS: Consultancy; GSK: Consultancy. Sasaki: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Kadia: Cellonkos: Other; Aglos: Consultancy; Dalichi Sankyo: Consultancy; AbbVie: Consultancy, Other: Grant/research support; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Cure: Speakers Bureau; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Liberum: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Other; Pulmotech: Other; Sanofi-Aventis: Consultancy; AstraZeneca: Other; Astellas: Other; Genfleet: Other; Ascentage: Other. Konopleva: Sanofi: Other: grant support, Research Funding; Cellectis: Other: grant support; Calithera: Other: grant support, Research Funding; KisoJi: Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Ablynx: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; AstraZeneca: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Forty Seven: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights. Alvarado: BerGenBio: Research Funding; Jazz Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Sun Pharma: Consultancy, Research Funding; MEI Pharma: Research Funding; FibroGen: Research Funding; Daiichi-Sankyo: Research Funding; CytomX Therapeutics: Consultancy. Yilmaz: Pfizer: Research Funding; Daiichi-Sankyo: Research Funding. DiNardo: Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Takeda: Honoraria; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Forma: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Foghorn: Honoraria, Research Funding. Bose: Kartos Therapeutics: Honoraria, Research Funding; Sierra Oncology: Honoraria; Novartis: Honoraria; Constellation Pharmaceuticals: Research Funding; NS Pharma: Research Funding; Celgene Corporation: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Pfizer: Research Funding; Promedior: Research Funding; Astellas: Research Funding; Incyte Corporation: Honoraria, Research Funding; BMS: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding. Pemmaraju: Blueprint Medicines: Consultancy; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Affymetrix: Consultancy, Research Funding; Samus: Other, Research Funding; ImmunoGen, Inc: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Consultancy; Plexxicon: Other, Research Funding; Springer Science + Business Media: Other; Protagonist Therapeutics, Inc.: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Clearview Healthcare Partners: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; CareDx, Inc.: Consultancy; Sager Strong Foundation: Other; Daiichi Sankyo, Inc.: Other, Research Funding; Incyte: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Bristol-Myers Squibb Co.: Consultancy; DAVA Oncology: Consultancy; Pacylex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Cellectis S.A. ADR: Other, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Wang: Stemline Therapeutics: Honoraria. Kantarjian: Taiho Pharmaceutical Canada: Honoraria; Precision Biosciences: Honoraria; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Jazz: Research Funding; BMS: Research Funding; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; NOVA Research: Honoraria; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria; Astra Zeneca: Honoraria; Astellas Health: Honoraria; Aptitude Health: Honoraria; Amgen: Honoraria, Research Funding; Ascentage: Research Funding. Wierda: Juno Therapeutics: Research Funding; AstraZeneca: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Loxo Oncology, Inc.: Research Funding; Cyclacel: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Miragen: Research Funding; KITE Pharma: Research Funding; Sunesis: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Karyopharm: Research Funding; Genentech: Research Funding; GSK/Novartis: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding. OffLabel Disclosure: The combination of ibrutinib and venetoclax is not FDA approved

Abstract: BACKGROUND Combined fludarabine, cyclophosphamide, and rituximab (FCR) was the preferred regimen for young fit patients (pts) with CLL. The CLL10 trial established FCR as the preferred first-line chemoimmunotherapy (CIT). Recently, the E1912 trial compared first-line FCR vs. ibrutinib + rituximab for young fit pts with CLL. The ibrutinib arm showed an improved PFS and OS vs. the FCR arm; however, there was no difference in PFS for mutated IGHV (M-IGHV) group. With the FCR studies, it is already known that the long-term benefit is seen in pts with M-IGHV. In the MD Anderson Cancer Center (MDACC) FCR trial, long-term follow up demonstrated that the PFS at 10 yrs was approximately 55% for M-IGHV pts with a plateau after 8 yrs, suggesting that these pts may be cured of their CLL. Hence, CIT remains an appropriate first-line option for pts with M-IGHV with fixed duration treatment and expectation for long treatment-free interval. We hypothesized that 1) achieving higher U-MRD would improve PFS and OS and 2) reducing the amount of chemotherapy might lower the risk of t-MDS/AML. We thus developed a CIT regimen called iFCG which consists of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (GA101) for young fit CLL patients with mutated IGHV and without del(17p)/mutated TP53. To decrease chemotherapy exposure, we administered only 3 cycles of chemotherapy in the iFCG regimen. METHODS We designed a phase II study for previously untreated pts with CLL with M-IGHV and absence of del(17p)/mutated TP53 (NCT02629809). All pts had a 2008 IWCLL indication for treatment. Pts received ibrutinib, fludarabine, cyclophosphamide, obinutuzumab for the first 3 cycles. Pts who achieved CR/CRi with bone marrow (BM) undetectable minimal residual disease (U-MRD) after the first 3 cycles received 9 additional cycles of ibrutinib with 3 additional cycles of obinutuzumab; all other pts received 9 additional cycles of ibrutinib and obinutuzumab. Pts with U-MRD (CR/CRi or PR) at 12 cycles stop all therapy, including ibrutinib. Responses were assessed by 2008 IWCLL criteria with BM and CT scans every 3 cycles during the first yr. BM MRD was assessed by flow cytometry (sensitivity 10-4). Post-cycle 12, pts have MRD assessed in blood every 6 months. In pts with available BM samples, MRD was also assessed by an NGS assay (sensitivity up to 10-6). RESULTS 45 pts were treated. Pretreatment characteristics are in Table 1. The median follow-up is 30.2 months. After 3 cycles of iFCG, 39% achieved CR/CRi and 89% achieved BM U-MRD. Responses improved with continued therapy with ibrutinib and obinutuzumab (Figure 1); 73% achieved CR/CRi and 100% achieved BM U-MRD after cycle 12. 41/45 pts completed all planned 12 cycles (4 pts came off study, details below). Per trial design, all 41 pts completing 12 cycles of treatment discontinued ibrutinib since all achieved U-MRD. PFS and OS are shown in Figure 2. No pt had MRD recurrence, CLL progression or Richter transformation, with a median follow-up of 18.7 months (range, 0.2-28.8) post discontinuing ibrutinib. In pts with available BM samples, we also assessed MRD by NGS assay. After 3 cycles of iFCG, 68% (n=28) achieved U-MRD at 10-5 sensitivity and 50% (n=22) achieved U-MRD at 10-6 sensitivity. After cycle 6, the corresponding numbers were 83% (n=30) and 58% (n=24), respectively. After cycle 12, the corresponding numbers were 91% (n=22) and 63% (n=16), respectively. Reasons for study discontinuation included 1) death due to CHF (see below), 2) pulmonary MAC infection, 3) infusion reaction to obinutuzumab, and 4) pt decision. One pt died; 26-yr-old man who developed CHF in cycle 9 (receiving ibrutinib and obinutuzumab). He had no known cardiac comorbidities; he started a weight loss supplement (sympathomimetic agent) few days prior to symptom onset. The pt died from worsening heart failure. One pt developed t-MDS. Grade 3-4 neutropenia and thrombocytopenia occurred in 58% and 40% pts, respectively. Neutropenic fever occurred in 6 pts (culture negative 4 pts, PJP pneumonia 1 pt, staphylococcus skin infection 1 pt). Additional infectious complications without neutropenia leading to hospitalization included pneumonia (culture negative) (n=2), cellulitis (n=1), pulmonary MAC infection (n=1), fever (n=1), acute cholecystitis (n=1), and colitis (n=1). CONCLUSIONS The iFCG regimen with only 3 cycles of chemotherapy is an effective time-limited regimen for young pts with M-IGHV and without del(17p)/ mutated TP53. Disclosures Jain: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Thompson:Pharmacyclics: Research Funding; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Pfizer: Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Research Funding. Burger:Pharmacyclics, an AbbVie company: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria; BeiGene: Research Funding; Gilead Sciences: Research Funding; Aptose Biosciences, Inc: Research Funding; AstraZeneca: Honoraria. Takahashi:Symbio Pharmaceuticals: Consultancy. Borthakur:AstraZeneca: Research Funding; Novartis: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Strategia Therapeutics: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; Cyclacel: Research Funding; Tetralogic Pharmaceuticals: Research Funding; NKarta: Consultancy; Cantargia AB: Research Funding; Arvinas: Research Funding; PTC Therapeutics: Consultancy; Oncoceutics, Inc.: Research Funding; BMS: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly and Co.: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Polaris: Research Funding. Bose:Pfizer: Research Funding; Promedior: Research Funding; CTI BioPharma: Research Funding; Constellation: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Research Funding; Blueprint Medicine Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding; NS Pharma: Research Funding; Astellas: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pemmaraju:mustangbio: Consultancy, Research Funding; plexxikon: Research Funding; novartis: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria; samus: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Garg:Garglet LLC: Other: Owner; Enlitic inc.: Other: Advisor. Plunkett:Cyclacel Ltd: Research Funding. Kantarjian:Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Immunogen: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; Amgen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria. Wierda:Xencor: Research Funding; Cyclcel: Research Funding; Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; GSK/Novartis: Research Funding; Sunesis: Research Funding; KITE pharma: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding. OffLabel Disclosure: Combination of ibrutinib with chemotherapy is not FDA approved