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Richter's transformation (RT) is defined as the evolution of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma. This complication is rare and aggressive, with poor prognosis and dismal survival. Clonal relationship with the underlying CLL/SLL, observed in ∼80% of cases, represents one of the main factors affecting prognosis. Treatment has been historically based on chemoimmunotherapy, but frequent mutations in genes involved in cell survival and proliferation-such as TP53, NOTCH1, MYC, CDKN2A-confer resistance to standard treatments. During the last years, advances in the knowledge of the biological mechanisms underlying RT allowed to identify genetic and molecular lesions that can potentially be targeted by novel selective agents. Pathway and checkpoint inhibitors, bispecific antibodies and CAR T-cell therapy are currently under investigation and represent promising treatment options. This review summarizes current biological evidence and available data on novel therapeutic agents.

Background: The diffuse large B-cell lymphoma (DLBCL) variant of Richter transformation (DLBCL-RT) is typically chemoresistant with poor prognosis. Aiming to explore a chemotherapy-free treatment combination that triggers anti-tumour immune responses, we conducted a phase 2 study of atezolizumab (a PD-L1 inhibitor) in combination with venetoclax and obinutuzumab in patients with DLBCL-RT., Methods: This was a prospective, open-label, multicentre, single-arm, investigator-initiated, phase 2 study in 15 hospitals in Italy and Switzerland. Eligible patients had a confirmed diagnosis of chronic lymphocytic leukaemia or small lymphocytic lymphoma as per the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria with biopsy-proven transformation to DLBCL; had not previously received treatment for DLBCL-RT, although they could have received chronic lymphocytic leukaemia therapies; were aged 18 years or older; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. No previous treatment with any of the drugs in the triplet combination was allowed. Patients received 35 cycles of 21 days of intravenous obinutuzumab (100 mg on day 1, 900 mg on day 2, 1000 mg on day 8 and day 15 of cycle 1; 1000 mg on day 1 of cycles 2-8) and intravenous atezolizumab (1200 mg on day 2 of cycle 1 and 1200 mg on day 1 of cycles 2-18), and continuous oral venetoclax (ramp-up from 20 mg/day on day 15 of cycle 1 according to chronic lymphocytic leukaemia schedule, then 400 mg/day from day 1 of cycle 3 to day 21 of cycle 35). The primary endpoint was overall response rate at day 21 of cycle 6 in the intention-to-treat population. We considered an overall response rate of 67% or more to be clinically active, rejecting the null hypothesis of a response of 40% or less. The study is registered with ClinicalTrials.gov, NCT04082897, and has been completed., Findings: Between Oct 9, 2019, and Oct 19, 2022, 28 patients were enrolled (12 [43%] male patients and 16 [57%] female patients). Median follow-up was 16·8 months (IQR 7·8-32·0). At cycle 6, 19 of 28 patients showed a response, yielding an overall response rate of 67·9% (95% CI 47·6-84·1). Treatment-emergent adverse events that were grade 3 or worse were reported in 17 (61%; 95% CI 40·6-78·5) of 28 patients, with neutropenia being the most frequent (11 [39%; 21·5-59·4] of 28 patients). Serious treatment-emergent adverse events were reported in eight (29%; 14·2-48·7) patients, which were most commonly infections (five [18%; 6·1-36·9] of 28 patients). There were two (7%) deaths attributable to adverse events during the study: one from sepsis and one from fungal pneumonia, which were not considered as directly treatment-related by the investigators. Six (21·4%) patients had immune-related adverse events, none of which led to discontinuation. No tumour lysis syndrome was observed., Interpretation: The atezolizumab, venetoclax, and obinutuzumab triplet combination was shown to be active and safe, suggesting that this chemotherapy-free regimen could become a new first-line treatment approach in patients with DLBCL-RT., Funding: Roche., Competing Interests: Declaration of interests AT reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Beigene, and Abbvie; support for attending meetings or travel from Abbvie, Janssen, and Beigene; and participation on a data safety monitoring board or advisory board from Janssen, Abbvie, Beigene, Lilly, and AstraZeneca. AMF reports consulting fees from Janssen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Janssen, Beigene, and AstraZeneca; support for attending meetings or travel from Abbvie, Janssen, Beigene, and AstraZeneca; and participation on a data safety monitoring board or advisory board from Janssen, Beigene, and AstraZeneca. ACo reports grants or contracts from Gilead, BMS, Beigene, Abbvie, Janssen-Cilag, and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Abbvie, and Janssen-Cilag; support for attending meetings or travel from Janssen; and participation on a data safety monitoring board or advisory board from BMS. MC reports grants or contracts from Johnson & Johnson and Abbvie; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbvie and AstraZeneca; support for attending meetings or travel from Johnson & Johnson, Abbvie, and AstraZeneca; and participation on a data safety monitoring board or advisory board from Johnson & Johnson, Abbvie, AstraZeneca, Beigene, and GSK. RC reports support for the present manuscript from the US National Institutes of Health and National Cancer Institute (R01CA196703–01). PLZ reports consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Takeda, BMS, MSD, Roche, Gilead, Novartis, Abbvie, Beigene, Kyowa Kirin, and Janssen. MMot reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events; support for attending meetings or travel; and participation on a data safety monitoring board or advisory board from Abbvie, Janssen, and AstraZeneca. GG reports grants from Associazione Italiana per la Ricerca sul Cancro and Piano Nazionale di Ripresa e Resilienza; consulting fees from Abbvie, AstraZeneca, Beiene, Hikma, and Johnson & Johnson; and participation on a data safety monitoring board or advisory board from Abbvie, AstraZeneca, Beigene, Hikma, Johnson & Johnson, and Lilly. LS reports consulting from Abbvie, Beigene, Lilly, AstraZeneca, Janssen, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbvie, Beigene, Lilly, Octapharma, AstraZeneca, Janssen, and Merck; support for attending meetings or travel from AstraZeneca, Janssen, and Beigene; and participation on a data safety monitoring board or advisory board from Merck. RCa reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbvie, Gilead, Gentilipharma, Pierre Fabre, Celgene, and Menarini stemline; support for attending meetings or travel from Pierre Fabre, Beigene, and Servier; and participation on a data safety monitoring board or advisory board from Celgene, Abbvie, Gentilipharma, and Daichi Samkio. TZ report consulting fees and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, Novartis, Gilead, Janssen, AstraZeneca, Lilly, and Abbvie. EZ reports consulting fees from Abbvie, Beigene, BMS, Cures, Elly and Lilly, Incyte, Ipsen, Merck, Miltenyibiomedicine, and Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbvie, AstraZeneca, Beigene, and Gilead; support for attending meetings or travel from Abbvie; and participation on a data safety monitoring board or advisory board from Merck. DR reports support for the present manuscript from Adaptive; grants or contracts, consulting fees, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbvie, AstraZeneca, Beigene, BMS, Janssen, and Lilly. All other authors declare no competing interests. No honoraria or payments were made for authorship., (Copyright © Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

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.)