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

Background: Ibrutinib (IBR), a BTK inhibitor, and venetoclax (VEN), a BCL-2 inhibitor are approved for patients (pts) with CLL. The rationale for combining IBR and VEN includes: 1) preclinical models showing synergism, 2) non-overlapping toxicities; 3) non-overlapping mechanisms of action. We recently reported results of the first-line cohort of an investigator-initiated phase II trial of combined IBR and VEN for pts with CLL (Jain N et al. NEJM 2019). Here we report results of the 80 pts from the R/R CLL cohort of the trial (NCT02756897).
Methods: Pts with R/R CLL meeting 2008 IWCLL treatment criteria were enrolled. Pts received IBR monotherapy (420 mg daily) for 3 cycles followed by addition of VEN (weekly dose-escalation to the 400mg daily target dose). Combined therapy was administered for 24 cycles. Pts with bone marrow (BM) undetectable MRD (U-MRD) (multi-color flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy stopped both VEN and IBR; MRD+ pts could continue IBR. Response assessments were performed using blood, BM and CT imaging (2008 IWCLL criteria) at the following time-points (after cycle 3 of IBR monotherapy, and then after cycles 3, 6, 9, 12, 18, and 24 of combined therapy). Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death. Overall survival (OS) was assessed as the time from the start of study drug to death.
Results: A total of 80 pts were enrolled. The median age was 61.5 yrs (32-79). The baseline characteristics are shown in Table 1. Overall, 30 (38%) pts had a TP53 aberration. The median follow-up for all pts is 22.3 months. Of the 80 pts, 1 pt was later reclassified as splenic marginal zone lymphoma and is excluded from further analyses. Five pts came off study during IBR monotherapy phase (reasons listed below). 74 pts initiated VEN.
Serial BM MRD responses are shown in Figure 1. One pt with a prior allo-SCT had no marrow disease at screening and is therefore excluded from serial MRD analyses. After 3 cycles of IBR monotherapy, none of the 73 pts achieved BM U-MRD. After addition of VEN, increasing proportions of pts achieved BM U-MRD remission. After 3 cycles of the combination, 7/68 (10%) achieved BM U-MRD remission. After 6 cycles of the combination, 15/67 (22%) achieved BM U-MRD remission. After 12 cycles of the combination, 29/60 (48%) achieved BM U-MRD remission. After 24 cycles of the combination, 16/24 (67%) achieved BM U-MRD remission. To assess the incremental benefit of the combined IBR and VEN beyond the first 12 cycles, we analyzed the MRD for pts who had received 24 cycles of combined therapy (n=24). Among these 24 pts, 13 were MRD+ at end of 12 cycles; 4/13 (31%) became U-MRD at end of 18 cycles of combination. Similarly, among these 24 pts, 9 were MRD+ at end of 18 cycles of combination; only 1/9 (11%) achieved U-MRD after 24 cycles of combination.
PFS and OS are shown in Figure 2. Two pts had CLL progression after completing 24 cycles of combined therapy. 1 pt was in U-MRD remission at 24 cycles and stopped both IBR and VEN per study design; he relapsed 3 months later and responded to IBR monotherapy. The second pt was MRD+ at 24 cycles of combined therapy and continued IBR monotherapy after 2 yrs per study design; he relapsed few months later and is now in remission post CD19 CAR-T. One pt developed Hodgkin's transformation. Two pts died; both due to infectious complications during the IBR monotherapy. One pt developed severe cytopenias during the VEN dose escalation, was non responsive to multiple therapies for worsening cytopenias, then underwent an allogeneic stem cell transplant. One pt, with prior FCR therapy developed MDS.
A total of 15 (19%) pts have come off trial; 5 pts came off study during IBR monotherapy (death from infection, n=2; skin rash, n=1; insurance issue, n=1; pt decision, n=1). Three pts came off trial during VEN ramp up (cytopenias, n=2; noncompliance, n=1). Four pts came off trial during the combination phase of IBR and VEN (arthralgia, n=1; Hodgkin's transformation, n=1; renal cancer, n=1; MDS, n=1). Three pts came off trial after completing 24 cycles of combined therapy (CLL progression, n=2; pt decision to continue VEN beyond 24 cycles, n=1).
Grade 3-4 neutropenia occurred in 29% pts. Grade 3-4 thrombocytopenia occurred in 3% pts. Atrial fibrillation occurred in 7 (9%) pts.
Conclusions: Combined VEN and IBR is an effective well-tolerated chemotherapy-free oral regimen for pts with R/R CLL.

Disclosures
Jain: Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Pfizer: 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; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: 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; Incyte: Research Funding; ADC Therapeutics: 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; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding. Thompson:Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Pharmacyclics: Research Funding; Pfizer: Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Research Funding. Burger:Gilead Sciences: Research Funding; Pharmacyclics, an AbbVie company: Research Funding; Janssen Pharmaceuticals: Consultancy, Honoraria; Aptose Biosciences, Inc: Research Funding; BeiGene: Research Funding; AstraZeneca: Honoraria. Borthakur:Cyclacel: Research Funding; Eli Lilly and Co.: Research Funding; PTC Therapeutics: Consultancy; AbbVie: Research Funding; Xbiotech USA: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Research Funding; Agensys: Research Funding; Bayer Healthcare AG: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; Oncoceutics, Inc.: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; Strategia Therapeutics: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Eisai: Research Funding; Janssen: Research Funding; GSK: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Bose:Constellation: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; CTI BioPharma: Research Funding; Incyte Corporation: Consultancy, Research Funding, Speakers Bureau; Blueprint Medicine Corporation: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Kartos: Consultancy, Research Funding. Fowler:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: 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; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bioline RX: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; AbbVie: Consultancy, Research Funding. Konopleva:Ablynx: Research Funding; Eli Lilly: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Agios: Research Funding; Astra Zeneca: Research Funding; Forty-Seven: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. DiNardo:medimmune: Honoraria; agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; syros: Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria; jazz: Honoraria. Pemmaraju:samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; cellectis: Research Funding; celgene: Consultancy, Honoraria. Jabbour:Cyclacel LTD: Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Garg:Garglet LLC: Other: Owner; Enlitic inc.: Other: Advisor. Plunkett:Cyclacel Ltd: Research Funding. Kantarjian:Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; Cyclacel: Research Funding; Novartis: Research Funding; Jazz Pharma: Research Funding; Pfizer: Honoraria, Research Funding; Agios: Honoraria, Research Funding; BMS: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:Oncternal Therapeutics Inc.: Research Funding; Miragen: Research Funding; Genentech: Research Funding; Sunesis: Research Funding; Pharmacyclics LLC: Research Funding; KITE pharma: Research Funding; Acerta Pharma Inc: Research Funding; Juno Therapeutics: Research Funding; Gilead Sciences: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Loxo Oncology Inc.: Research Funding; Cyclcel: Research Funding; AbbVie: Research Funding; GSK/Novartis: Research Funding.

OffLabel Disclosure:
Combination of ibrutinib and venetoclax is not FDA approved