{"doi":"10.1002/ajh.70082","title":"Venetoclax in Combination With Pediatric‐Inspired Chemotherapy in Adults With Newly Diagnosed Acute Lymphoblastic Leukemia: Results of a Phase I Trial","abstract":"While the outcomes of acute lymphoblastic leukemia (ALL) treatment in young children are excellent with > 90% long-term event-free survival (EFS) [1], outcomes among adults have continued to lag behind. Even with the utilization of pediatric-inspired chemotherapy (PIC) regimens, there remains a significant unmet need for 25%–40% of adult ALL patients who are not cured with upfront chemotherapy [2, 3]. Venetoclax is a B-cell lymphoma 2 (BCL-2) inhibitor approved for the treatment of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) in combination with other agents. Preclinical data has long indicated that ALL blasts express high levels of BCL-2 and are sensitive to its inhibition [4]. Based on this data, several clinical trials have incorporated venetoclax in combination with different chemotherapy regimens for relapsed/refractory (R/R) ALL [5-7] as well as in upfront treatment [8] with encouraging results. These reports prompted the question of whether venetoclax can be safely added to a PIC regimen and whether that approach can improve rates of measurable residual disease-negative complete remission (MRD-CR) rates compared to historical treatments. We conducted a phase I clinical trial of oral venetoclax in combination with asparaginase-containing PIC in adult patients with newly diagnosed ALL (NCT05386576). The study was approved by the MSKCC Institutional Review Board and conducted in accordance with the Declaration of Helsinki. The study design was a 3 + 3 dose de-escalation design with 2 dose levels. The total study accrual goal was 12 patients. Inclusion criteria included age 18–60 at the time of registration, ECOG performance status 0–2, and adequate organ function. Further details on the study design, definitions of dose limiting toxicities, and treatment plan are provided in the accompanying appendix. The chemotherapy backbone regimen used in this trial is identical to the one utilized in the published MSKCC PIC protocol (Figure S1) [3]. Venetoclax was administered in the following fashion in the initial protocol: During Induction 1, 100 mg on day 5, 200 mg on day 6, and 400 mg on days 7–28. In patients with Grade 4 neutropenia (Absolute Neutrophil Count (ANC) < 500/μL) with fever or Grade 4 thrombocytopenia (platelet count < 25 000/μL) after day 14, venetoclax was held until ANC recovered to ≥ 1000/μL and platelets recovered to ≥ 50 000/μL. Patients proceeded from Induction I to Induction II on day 35–43 regardless of count recovery, unless the patient demonstrated marrow aplasia in two subsequent biopsies, in which case they were removed from the study (this did not occur to any patient). During Induction II, venetoclax was given at 400 mg during days 1–14 and 29–42. In patients with ANC < 500/μL with fever, ANC < 100/μL irrespective of fever, or platelet < 25 000/μL after day 29, venetoclax was held until ANC recovered to ≥ 1000/μL and platelets recovered to ≥ 50 000/μL. Due to observed prolonged cytopenias, the protocol was amended twice to change the duration of venetoclax dosing (Figure S1). The first amendment, which was applied beginning with the 4th patient, shortened the duration of venetoclax during Induction II to 400 mg on days 1–7 and 29–35. The second amendment, which was applied beginning with the 9th patient, additionally shortened the duration of venetoclax during Induction I to 14 days if the day 14 bone marrow aspirate showed MRD- CR/CRi and a hypocellular marrow. The use of venetoclax beyond induction is also shown in Figure S1. We utilized a historical cohort of patients treated on MSK protocol 12-266 as a comparator cohort [3]. This consisted of 22 patients treated at our institution with the same PIC backbone. A total of 12 patients were enrolled in this trial, as specified in the protocol (Table 1). Their median age at diagnosis was 39 years (IQR: 31–53). Half of the patients (n = 6, 50%) had B-cell ALL, while 6 (50%) had T-cell ALL/LBL, and two patients had early T-cell prec","journal":"American Journal of Hematology","year":2025,"id":547209,"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":0.9484,"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":1012588,"name":"David Nemirovsky","orcid":"0009-0007-6971-1408","position":1,"is_corresponding":false},{"id":348015,"name":"Andriy Derkach","orcid":"0000-0003-2178-8493","position":2,"is_corresponding":false},{"id":1440056,"name":"I. Cacace","orcid":null,"position":3,"is_corresponding":false},{"id":1440057,"name":"Martina Torres","orcid":null,"position":4,"is_corresponding":false},{"id":1440058,"name":"Colleen Finneran","orcid":null,"position":5,"is_corresponding":false},{"id":1440059,"name":"Madhulika Shukla","orcid":null,"position":6,"is_corresponding":false},{"id":284255,"name":"Aaron D. Goldberg","orcid":"0000-0002-2892-2643","position":7,"is_corresponding":false},{"id":284249,"name":"Eytan M. Stein","orcid":"0000-0001-8992-9390","position":8,"is_corresponding":false},{"id":233549,"name":"Mark B. Geyer","orcid":"0000-0001-5248-9117","position":9,"is_corresponding":false},{"id":292601,"name":"Jae H. Park","orcid":"0000-0002-2903-5130","position":10,"is_corresponding":false},{"id":1240644,"name":"Yannis K. Valtis","orcid":"0000-0001-8927-8006","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T02:53:41.314800Z","pmid":"41014203","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":[]}