{"doi":"10.1111/bjh.70234","title":"Enitociclib ( <scp>VIP152</scp> ), venetoclax and prednisone in relapsed or refractory aggressive non‐Hodgkin lymphoma","abstract":"To the Editor, Dysregulated proliferation and survival are fundamental hallmarks of cancer. In aggressive lymphomas, alterations in the MYC oncogene and anti-apoptotic regulators such as MCL1 and BCL2 are frequent promoters of this phenotype.1-3 MYC is essential for cell growth and proliferation whereas BCL2 and MCL1 regulate cell death and are potentially important therapeutic targets.4 Unfortunately, directly targeting MYC or MCL1 has been challenging due to poor clinical activity and excess toxicity.5, 6 While the BCL2 inhibitor venetoclax has shown modest single-agent activity in aggressive lymphomas, including diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma (PTCL), durable remissions are rarely observed.7, 8 Cyclin-dependent kinase 9 (CDK9) regulates the activity of RNA polymerase II (RNAPII) and CDK9 inhibition has been identified as a mechanism to indirectly target MYC and MCL1, among other short-lived proteins, through inhibition of RNAPII transcription.9, 10 CDK9 inhibitors have shown activity in relapsed or refractory (R/R) lymphomas; however, durable remissions are observed in a minority of patients. In a study of single-agent enitociclib (VIP152), a CDK9 inhibitor, two of seven patients with high-grade B-cell lymphoma double-hit with MYC and BCL2 rearrangements (HGBCL-DH-BCL2) achieved complete response (CR), both ongoing after 2.3 and 3.7 years of follow-up.11, 12 Increased BCL2 and MCL1 have been identified as mechanisms of resistance to CDK9 and apoptosis, respectively, suggesting a therapeutic benefit to combining venetoclax and enitociclib.1, 13 Additionally, we have shown that prednisone inhibits B-cell receptor signalling and is synergistic with venetoclax in aggressive B-cell lymphoma cell lines.14, 15,16 We hypothesized that the combination of enitociclib, venetoclax and prednisone (VVIP) would be active in R/R aggressive lymphomas, many of which express increased MYC, BCL2 and MCL1. We conducted a single-centre phase 1/2 trial of VVIP in patients with R/R PTCL, MYC-rearranged DLBCL/HGBCL and non-germinal centre B-cell (GCB) DLBCL. Patients ≥18 years with adequate organ function were eligible. Two or more prior lines of therapy were required, including prior anthracycline in all patients, brentuximab vedotin in anaplastic large cell lymphoma patients and anti-CD20 therapy in aggressive B-cell lymphoma patients. Exclusions included prior allogeneic stem cell transplantation (allo-SCT) within 6 months of study enrolment, human immunodeficiency virus (HIV) infection, malabsorptive syndrome or significant cardiovascular disease (Supporting Information S1). A ‘3 + 3’ design was used to determine the recommended phase 2 dose (RP2D) of dose-escalated enitociclib and venetoclax with fixed-dose prednisone. Primary objectives included determination of the RP2D in the phase 1 cohort and CR rate in the phase 2 cohort with secondary objectives including response rate, response durability, event-free survival, progression-free survival (PFS) and overall survival (OS). Phase 2 expansion cohorts of up to 29 patients each were planned for each eligible subtype with a total accrual ceiling of 130 patients. Four dose levels (DLs) of enitociclib administered intravenously on days 2 and 9 (DL1 = 15 mg, DL2 = 22.5 mg and DLs 3–4 = 30 mg) and venetoclax orally on days 1–10 (DLs 1–3 = 600 mg and DL4 = 800 mg) were given along with fixed-dose prednisone 100 mg orally on days 1–10 to maximize drug synergy with combination therapy.15,16 Patients received treatment in 21-day cycles for up to 24 total cycles of therapy. Patients who achieved CR could discontinue treatment after 12 cycles. Pegfilgrastim 6 mg was administered subcutaneously on day 11 (Figure S1). All patients received prophylaxis against Pneumocystis jiroveccii throughout treatment in addition to tumour lysis syndrome (TLS) prophylaxis during the first cycle of therapy. Adverse events (AEs) were assessed using Common Terminology Criteria for Adverse","journal":"British Journal of Haematology","year":2025,"id":537025,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9547,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":716922,"name":"Rahul Lakhotia","orcid":"0000-0003-3123-6844","position":1,"is_corresponding":false},{"id":225661,"name":"Stefania Pittaluga","orcid":"0000-0001-7688-1439","position":2,"is_corresponding":false},{"id":250439,"name":"Svetlana Pack","orcid":"0000-0003-3256-6626","position":3,"is_corresponding":false},{"id":1144816,"name":"Anna Marie Juanitez","orcid":null,"position":4,"is_corresponding":false},{"id":1422375,"name":"Ahmed Hamdy","orcid":"0000-0002-3646-9594","position":5,"is_corresponding":false},{"id":395711,"name":"Amy J. Johnson","orcid":"0000-0002-0306-4646","position":6,"is_corresponding":false},{"id":298603,"name":"Melanie M. Frigault","orcid":"0009-0002-8525-4239","position":7,"is_corresponding":false},{"id":278262,"name":"Raquel Izumi","orcid":"0000-0002-0895-2597","position":8,"is_corresponding":false},{"id":232025,"name":"Mark Raffeld","orcid":"0000-0002-4039-6957","position":9,"is_corresponding":false},{"id":233601,"name":"Mark Roschewski","orcid":"0000-0003-0278-2635","position":10,"is_corresponding":false},{"id":35694,"name":"Wyndham H. Wilson","orcid":"0000-0002-2862-9711","position":11,"is_corresponding":false},{"id":258330,"name":"Christopher Melani","orcid":"0000-0002-9661-4570","position":12,"is_corresponding":false},{"id":682155,"name":"Max J. Gordon","orcid":"0000-0003-3940-4451","position":0,"is_corresponding":true}],"reference_count":15,"raw_metadata":null,"created_at":"2026-07-19T02:52:09.056872Z","pmid":"41169010","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}