Combined Ibrutinib and Venetoclax for First-Line Treatment for Patients with Chronic Lymphocytic Leukemia (CLL): Focus on MRD Results
Authors: Jain Nitin , Keating Michael J. , Thompson Philip A. , Ferrajoli Alessandra , Burger Jan A. , Borthakur Gautam , Takahashi Koichi , Estrov Zeev E. , Sasaki Koji , Fowler Nathan H , Kadia Tapan M. , Konopleva Marina , Alvarado Yesid , Yilmaz Musa , DiNardo Courtney D. , Bose Prithviraj , Ohanian Maro , Pemmaraju Naveen , Jabbour Elias , Kanagal-Shamanna Rashmi , Patel Keyur , Wang Wei , Jorgensen Jeffrey L. , Wang Sa A , Garg Naveen , Wang Xuemei , Wei Chongjuan , Cruz Nichole , Ayala Ana , Plunkett William , Kantarjian Hagop M. , Gandhi Varsha , Wierda William G. 
Published: November 2020

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