Combined Ibrutinib and Venetoclax in Patients with Treatment-Naïve High-Risk Chronic Lymphocytic Leukemia (CLL)
Authors: Jain Nitin , Keating Michael J , Thompson Philip A. , Ferrajoli Alessandra , Burger Jan A. , Borthakur Gautam , Takahashi Koichi , Estrov Zeev E. , Fowler Nathan H. , Kadia Tapan M. , Konopleva Marina Y. , Alvarado Yesid , Yilmaz Musa , DiNardo Courtney D. , Bose Prithviraj , Ohanian Maro N. , Pemmaraju Naveen , Jabbour Elias J. , Sasaki Koji , Kanagal-Shamanna Rashmi , Patel Keyur , Jorgensen Jeffrey L. , Garg Naveen , Wang Xuemei , Sondermann Katrina , Cruz Nichole , Wei Chongjuan , Ayala Ana , Plunkett William , Kantarjian Hagop M. , Gandhi Varsha , Wierda William G. 
Published: October 2019

Abstract
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 with the combination, 2) non-overlapping toxicity profiles; 3) non-overlapping mechanisms of action; 4) complementary activity in treating disease compartments. We report results of the firstline cohort of an investigator-initiated phase II trial of combined IBR and VEN for pts with CLL (NCT02756897).
Methods: Pts with treatment-naïve CLL meeting 2008 iwCLL treatment indication 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 monotherapy (420 mg daily) for 3 cycles followed by addition of VEN (weekly dose-escalation to a target dose of 400mg daily). Combined therapy was administered for 24 cycles. Pts with bone marrow (BM) undetectable MRD (U-MRD) (assessed by multi-color flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy will stop both VEN and IBR; MRD+ pts could continue IBR. The primary endpoint is CR/CRi. 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 the combination therapy). After completing combined therapy, pts are monitored by physical exam, blood counts and blood flow cytometry every 6 months.
Results: A total of 80 pts were enrolled. The median age was 65 yrs (26-83). Notably, 30% pts were ≥70 yrs. The baseline characteristics are shown in Table 1. Overall, 92% pts had either an unmutated IGHV, or TP53 aberration, or del(11q). Of the 80 pts, 2 were enrolled in the last 3 months (still receiving IBR monotherapy) and 5 pts came off study during IBR monotherapy phase. 73 pts initiated VEN. The median follow-up for all pts is 9.6 months.
After 3 months of IBR monotherapy, the majority pts were in PR. After addition of VEN, increasing proportions of pts achieved CR/CRi and BM U-MRD remission (Figure 1). At 6 months of the combination, 24/34 (71%) pts achieved CR/CRi and 14/34 (41%) achieved BM U-MRD remission. At 12 months of the combination, 23/25 (92%) of the pts were in CR/CRi with 17/25 (68%) achieving BM U-MRD remission.
Older pts responded well to the therapy; 75% achieved CR/CRi and 56% achieved BM U-MRD remission at 6 months of the combination which improved to 92% CR/CRi and 77% BM U-MRD remission at 12 months of the combination (Table 2). Responses were seen independent of IGHV mutation status, FISH category, TP53 mutation, NOTCH1 mutation, SF3B1 mutation.
IBR monotherapy led to downgrading of TLS risk category in 80% of high-risk and 47% of medium-risk pts. Three pts had laboratory evidence of TLS by Cairo-Bishop criteria. No pt had clinical TLS.
PFS and OS are shown in Figure 2. No pt has had CLL progression. One pt with high-risk CLL [unmutated IGHV, NOTCH1 mutation] developed Richter transformation (DLBCL). One pt died. This was a 60-year-old who had been having CNS symptoms for 1 week prior to starting IBR. The pt received 1 day of treatment with IBR, developed worsening symptoms and was found to have CNS cryptococcus and later died of complications of disseminated cryptococcus. This was deemed unrelated to IBR.
A total of 11 (14%) pts have discontinued study treatments. Five pts came off study during IBR monotherapy [skin rash, n=1; hypertension, n=1; prohibited medication, n=1; unrelated infection (cryptococcus), n=1; withdrew consent, n=1]. Six pts came off study during the combination phase [recurrent neutropenia, n=2; DLBCL transformation, n=1; fallopian tube cancer, n=1; allogeneic SCT, n=1; hemolytic anemia, n=1].
Easy bruising, arthralgia and diarrhea were the most common non-hematological adverse events. Grade 3-4 neutropenia occurred in 48% pts; this was similar among the younger (<65 yrs) vs. older (≥65 yrs) pts (46% vs. 49%, respectively). Grade 3 thrombocytopenia occurred in 2% pts. Neutropenic fever occurred in 5% pts. Atrial fibrillation occurred in 14% pts. IBR was dose-reduced in 35% pts; VEN was dose-reduced in 18% pts.
Conclusions: Combined VEN and IBR is an effective, safe, and chemotherapy-free oral regimen for pts with high-risk treatment-naïve CLL. Responses were noted in older adults and across all high-risk subgroups. Adverse event profile was similar to what has been reported individually with IBR and VEN.

Disclosures
Jain: Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; BMS: Research Funding; Infinity: Research Funding; ADC Therapeutics: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; ADC Therapeutics: Research Funding; Incyte: Research Funding; Infinity: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Servier: Research Funding; Verastem: Research Funding; Astra Zeneca: Research Funding; Cellectis: Research Funding; Adaptive Biotechnologioes: Research Funding; Servier: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; ADC Therapeutics: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Thompson:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Adaptive Biotechnologies: Research Funding; Pharmacyclics: 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. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Kadia:Takeda: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Celgene: Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Abbvie: Consultancy; BMS: Research Funding. Konopleva:Stemline Therapeutics: Research Funding. DiNardo:Bayer: Honoraria; Abbvie: Honoraria; Medimmune: Honoraria; Karyopharm: Honoraria; Agios: Consultancy; Celgene: Honoraria. Bose:Celgene Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corporation: Research Funding; Incyte Corporation: Honoraria, Research Funding. Pemmaraju:novartis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; abbvie: Research Funding; daiichi sankyo: Research Funding; plexxikon: Research Funding; samus: Research Funding; Affymetrix: Research Funding; celgene: Consultancy, Honoraria; SagerStrong Foundation: Research Funding. Sasaki:Otsuka Pharmaceutical: Honoraria. Gandhi:Pharmacyclics: Research Funding. Wierda:AbbVie, Inc: Research Funding; Genentech: Research Funding.