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Background: Most patients with chronic lymphocytic leukaemia progress after treatment or retreatment with targeted therapy or chemoimmunotherapy and have limited subsequent treatment options. Response levels to the single-agent venetoclax in the relapsed setting is unknown. We aimed to assess venetoclax activity in patients with or without previous B-cell receptor-associated kinase inhibitor (BCRi) treatment., Methods: This multicentre, open-label, single-arm, phase 3b trial (VENICE-1) assessed activity and safety of venetoclax monotherapy in adults with relapsed or refractory chronic lymphocytic leukaemia, stratified by previous exposure to a BCRi. Eligible participants were aged 18 years or older with previously treated relapsed or refractory chronic lymphocytic leukaemia. Presence of del(17p) or TP53 aberrations and previous BCRi treatment were permitted. Patients received 5-week ramp-up to 400 mg of oral venetoclax once daily and were treated for up to 108 weeks, with 2 years follow-up after discontinuation, or optional extended access. The primary activity endpoint was complete remission rate (complete remission or complete remission with incomplete marrow recovery) in BCRi-naive patients. Analyses used the intent-to-treat (ie, all enrolled patients, which coincided with those who received at least one dose of venetoclax). This study was registered with ClinicalTrials.gov, NCT02756611, and is complete., Findings: Between June 22, 2016, and March 11, 2022, we enrolled 258 patients with relapsed or refractory chronic lymphocytic leukaemia (180 [70%] were male; 252 [98%] were White; 191 were BCRi-naive and 67 were BCRi-pretreated). Median follow-up in the overall cohort was 49·5 months (IQR 47·2-54·1), 49·2 months (47·2-53·2) in the BCRi-naive group, and 49·7 months (47·4-54·3) in the BCRi-pretreated group. Of 191 BCRi-naive patients, 66 (35%; 95% CI 27·8-41·8) had complete remission or complete remission with incomplete marrow recovery. 18 (27%; 95% CI 16·8-39·1) of 67 patients in the BCRi-pretreated group had complete remission or complete remission with incomplete marrow recovery. Grade 3 or worse treatment-emergent adverse events were reported in 203 (79%) and serious adverse events were reported in 136 (53%) of 258 patients in the overall cohort. The most common treatment-emergent adverse event was neutropenia (96 [37%]) and the most common and serious adverse event was pneumonia (21 [8%]). There were 13 (5%) deaths reported due to adverse events; one of these deaths (autoimmune haemolytic anaemia) was possibly related to venetoclax. No new safety signals were identified., Interpretation: These data demonstrate deep and durable responses with venetoclax monotherapy in patients with relapsed or refractory chronic lymphocytic leukaemia, including BCRi-pretreated patients, suggesting that venetoclax monotherapy is an effective strategy for treating BCRi-naive and BCRi-pretreated patients., Funding: AbbVie., Competing Interests: Declaration of interests APK is an advisory board member of and received research funding from Astra Zeneca, Janssen, Roche (Genentech), AbbVie, Bristol Myers Squibb, and LAVA. ÖA is an AbbVie speaker and advisory board member. YH declares honoraria from AbbVie, Janssen, AstraZeneca, Roche, and Medison; is an advisory board member for AbbVie, Jansen, AstraZeneca, Medison, and Eli Lilly; and declares a research grant from Janssen. BF is an advisory board member for Takeda Pharmaceuticals, Janssen, and Pfizer and declares speaker fees from AbbVie. MGD declares speaker fees from AbbVie. BL declares speakers bureau or honoraria from AbbVie, Alexion, AMGEN, Astellas, Astex, Bristol Myers Squibb (Celgene), Jazz, Janssen Novartis, Otsuka, Paladin, Pfizer, Roche, and Treadwell, and consulting fees from AbbVie, Novartis, and Pfizer. MM declares speaker bureau from AbbVie and honoraria from Janssen. PP declares a research support grant from AbbVie and honoraria or speaker's bureau from AbbVie, AstraZeneca, and Roche. AS declares consultancy or speaker fees from Alexion, AbbVie, AstraZeneca, ADC Therapeutics, Beigene, Bristol Myers Squibb, Celgene, Epizyme, Genentech, Janssen, Jazz Therapeutics, Kite Pharma, Eli Lilly, MorphoSys, Novartis, Pharmacyclics, SeaGen, GenMab, and TG Therapeutics; payments for presentations or lectures from AstraZeneca, ADC Therapeutics, AbbVie, Beigene, Genentech, GenMab, Jazz Therapeutics, Janssen, Kite Pharma, Eli Lilly, Pharmacyclics, SeaGen, and TG Therapeutics; and participation on the data safety monitoring board for Alexion. CM declares funding from AbbVie for microarray analysis. A-MvdK-K declares funding from AbbVie for funded microarray analysis. RP, BJC, XW, TB, KS, GEP, and TV are AbbVie employees and may hold stock or options. VK was an AbbVie employee at time of study and may hold stock or options. Francesco Forconi is an advisory board member for BeiGene; declares honoraria from AbbVie, Janssen-Cilag, Beigene, and AstraZeneca; speakers bureau from AbbVie, Janssen-Cilag, and AstraZeneca; and travel and accommodation from AbbVie, Janssen-Cilag, and Beigene. FD, DR, AT, MT, SL, BS, and LDR declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

The first-in-class inhibitor of exportin-1 (XPO1) selinexor is currently under clinical investigation in combination with the BTK inhibitor ibrutinib for patients with chronic lymphocytic leukaemia (CLL) or non-Hodgkin lymphoma. Selinexor induces apoptosis of tumour cells through nuclear retention of tumour suppressor proteins and has also recently been described to modulate natural killer (NK) cell and T cell cytotoxicity against lymphoma cells. Here, we demonstrate that XPO1 inhibition enhances NK cell effector function against primary CLL cells via downregulation of HLA-E and upregulation of TRAIL death receptors DR4 and DR5. Furthermore, selinexor potentiates NK cell activation against CLL cells in combination with several approved treatments; acalabrutinib, rituximab and obinutuzumab. We further demonstrate that lymph node associated signals (IL-4 + CD40L) inhibit NK cell activation against CLL cells via upregulation of HLA-E, and that inhibition of XPO1 can overcome this protective effect. These findings allow for the design of more efficacious combination strategies to harness NK cell effector functions against CLL., (© 2023. The Author(s).)