Background

While the MURANO venetoclax (V) + rituximab regimen is highly effective, it spans 2 years and includes 6 months of infusional therapy. Duvelisib (D) is an oral PI3K-δ/γ inhibitor (PI3Ki) FDA-approved for R/R CLL after 2 prior therapies. Preclinical data support V + D in CLL and RS (Patel 2017; Iannello 2019), and we previously demonstrated that V + D was well-tolerated at the FDA-approved doses of each drug (Crombie, ASH 2020). Here, we report the phase 2 results of our investigator-sponsored trial (NCT03534323) in patients (pts) with R/R CLL and RS.

Methods

Key eligibility criteria for CLL pts: requiring treatment by iwCLL criteria, ≥ 1 prior therapy with no prior V or D, ECOG PS ≤ 2, and for RS pts: no V within 1 year. Treatment began with a 7-day lead-in of D 25mg BID, and V starting on day 8. V was initiated at 10mg (outpt) or 20mg (inpt), with weekly ramp-up to 400mg daily. Pts with RS could accelerate V ramp-up to 400mg over 5 days (inpt). After 12 cycles, pts with bone marrow (BM)- undetectable minimal residual disease (uMRD) could discontinue treatment and reinitiate V at time of progression, and pts with detectable MRD continued V alone, with an option to discontinue later if they achieved BM-uMRD. Assessments of toxicities were by CTCAE v5, efficacy by 2008 iwCLL criteria, and MRD by central 8-color flow (10-4 sensitivity).

Results

As of May 2, 2024, enrollment was complete for 38 pts (n=29 CLL and n=9 RS). Baseline characteristics included: median age: 69 years (range 50-79); 70% male; 66% unmutated IGHV; 11% del(11q); 26% complex karyotype (≥3 abnormalities); 48% TP53-aberrant; 18% NOTCH1 mutant; median prior treatments: 2 (range 1-5); 45% with prior BTKi.

In the total population of 38 pts, the median number of cycles was 13 (range 1-50), and all-grade heme tox included: neutropenia (86%; 79% Gr3/4) and thrombocytopenia (58%; 21% Gr3/4). Notable non-heme tox ≥ 20% included: diarrhea (63%; 13% Gr 3/4), nausea (55%, 3% Gr3), increased alkaline phosphatase (45%, all Gr1), increased AST (42%; 8% Gr3/4), hypertension (42%, 8% Gr3), and headache (34%, all Gr1). Other notable SAEs included: colitis (11%, 3% Gr3), tumor lysis syndrome (5% Gr3/4, n=1 lab and 1 clinical), febrile neutropenia (5% Gr3), and infection (5% Gr3). One pt developed a gastric perforation requiring surgical repair while on high-dose steroids to manage diarrhea and discontinued treatment. Gr5 events included n=1 hepatic failure attributed to progressive RS and n=1 COVID-19 pneumonia.

In pts with CLL, the best ORR and CR/CRi (primary endpoint) rates were 97% and 62%, respectively. After 12 cycles, the ORR was 72% (44% CR/CRi). CR/CRi was 64% and 46% for TP53-aberrant (n=14) and post-BTKi (n=13) pts, respectively. At this time point, PB and BM-uMRD were 45% and 41%, respectively. 11 pts of 29 achieved BM-uMRD after 12 cycles and electively discontinued therapy, 3 of whom later restarted V once MRD re-detected (median yrs off treatment=1.2 [range: 0.97-3.7]). In the 9 pts with RS, 3 achieved CR, including one pt who proceeded to alloSCT and remains in remission 2.3 yrs later.

Reasons for discontinuation included: achievement of BM-uMRD (n=11 CLL), alloSCT (n=1 RS), PD (n=3 CLL, n=6 RS), unacceptable tox (n=4 CLL, n=1 RS), and fatal COVID-19 pneumonia (n=1 CLL). For pts with CLL, the 3-year PFS and OS were 68% and 89%, respectively. 3-year PFS in TP53-aberrant and post-BTKi pts were 47% and 46%, respectively.

Conclusions

The all-oral, MRD-driven, time-limited regimen V + D is active in R/R CLL and RS, including in high-risk pts with TP53-aberrant disease and post-BTKi. Toxicities were observed, but were manageable for most patients. Our data support exploration of V + D in larger studies of pts with R/R CLL and RS.

Disclosures

Crombie:Genmab/Abbvie: Consultancy; Genentech: Consultancy; Genentech/Roche: Research Funding; Bayer: Research Funding; Abbvie: Research Funding; Merck: Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy; Seagen: Consultancy; ADCT: Consultancy. Ryan:AstraZeneca Brazil: Honoraria; Genentech: Other: Research Funding to institution. Montegaard:AbbVie: Consultancy; Bristol Myers Squibb: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy. Soumerai:TG Therapeutics: Research Funding; Bristol Myers Squibb: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Research Funding; BostonGene: Research Funding; Takeda: Research Funding; LOXO@Lilly: Consultancy; Beigene: Consultancy, Research Funding; Adaptive Biotechnologies: Research Funding; Moderna: Research Funding; Roche/Genentech: Consultancy, Research Funding. Arnason:BMS: Other: Speaker fees; Regeneron Pharmaceuticals, Inc.: Other: Speaker fees. Alencar:Amgen: Consultancy; Kite: Consultancy; SeaGen: Consultancy; Epizyme: Consultancy; Janssen: Consultancy; Beigene: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Loxo/Lilly: Consultancy, Research Funding; TG therapeutics: Consultancy; Abbvie: Consultancy. Armand:Merck: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Genmab: Consultancy; Enterome: Consultancy; Genentech/Roche: Consultancy, Research Funding; ATB Therapeutics: Consultancy; Foresight: Consultancy; Regeneron: Consultancy; Kite: Research Funding; Adaptive: Research Funding; IGM: Research Funding; AstraZeneca: Research Funding. Brown:Grifols Therapeutics: Other: Data Safety Monitoring Board Member; UpToDate: Patents & Royalties: Author Royalties; TG Therapeutics: Research Funding; MEI Pharma: Research Funding; Gilead: Research Funding; Pfizer: Consultancy; Pharmacyclics: Consultancy; Numab Therapeutics: Consultancy; Merck: Consultancy; Loxo/Lilly: Consultancy, Research Funding; Kite: Consultancy; iOnctura: Consultancy, Research Funding; InnoCare Pharma Inc: Consultancy; Grifols Worldwide Operations: Consultancy; Genentech/Roche: Consultancy; Bristol-Myers Squibb: Consultancy; BeiGene: Consultancy, Research Funding; Alloplex Biotherapeutics: Consultancy; Acerta/AstraZeneca: Consultancy; AbbVie: Consultancy. Davids:BMS: Consultancy; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Research Funding; BeiGene: Consultancy; Surface Technology: Research Funding; AbbVie: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; MEI Pharma: Research Funding; Adaptive Biosciences: Consultancy; Genmab: Consultancy; Eli Lilly: Consultancy; Genentech: Consultancy, Research Funding; Merck: Consultancy.

Off Label Disclosure:

While both venetoclax and duvelisib are approved by the US FDA for the treatment of chronic lymphocytic leukemia (CLL), they are not approved in combination, as studied in this clinical trial

This content is only available as a PDF.
2024
Sign in via your Institution