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Clinical Trial
. 2025 Feb 11;9(3):617-626.
doi: 10.1182/bloodadvances.2024014405.

Venetoclax plus low-intensity chemotherapy for adults with acute lymphoblastic leukemia

Marlise R Luskin  1 , Shai Shimony  1 , Julia Keating  2 , Eric S Winer  1 , Jacqueline S Garcia  1 , Richard M Stone  1 , Elias Jabbour  3 , Yael Flamand  2 , Kristen Stevenson  2 , Jeremy Ryan  1 , Zhihong Zeng  3 , Anthony Letai  1 , Marina Konopleva  3   4 , Nitin Jain  3 , Daniel J DeAngelo  1
Affiliations
Clinical Trial

Venetoclax plus low-intensity chemotherapy for adults with acute lymphoblastic leukemia

Marlise R Luskin et al. Blood Adv. .

Abstract

In acute lymphoblastic leukemia (ALL), the B-cell lymphoma 2 inhibitor venetoclax may enhance the efficacy of chemotherapy, allowing dose reductions. This phase 1b study of venetoclax plus attenuated chemotherapy enrolled 19 patients with ALL either newly diagnosed (aged ≥60 years, n = 11 [B-cell, n = 8; T-cell, n = 3]) or relapsed/refractory (R/R; aged ≥18 years, n = 8 [B-cell, n = 3; T-cell, n = 5]). Venetoclax was given for 21 days with each cycle of mini-hyper-CVD (mini-HCVD; cyclophosphamide, vincristine, dexamethasone alternating with methotrexate and cytarabine). There were no dose-limiting toxicities at dose level 1 (DL1; n = 3, 400 mg/d) or DL2 (n = 6, 600 mg/d); DL2 was the recommended phase 2 dose and explored further (n = 10). The most common nonhematologic adverse events were grade ≥3 infections. There were no deaths within 60 days. There was no tumor lysis syndrome, hepatotoxicity, prolonged cytopenias, or early discontinuation for toxicity. Among patients with newly diagnosed ALL, 10 of 11 (90.9%) achieved a measurable residual disease-negative (<0.01% sensitivity) complete remission (CR) including 6 patients with hypodiploid TP53-mutated ALL. All patients in CR bridged to hematopoietic stem cell transplant (n = 9) or completed protocol (n = 1). With a median follow-up of 60 months, median disease-free survival (DFS) for patients with newly diagnosed ALL was 54.6 months (95% confidence interval [CI], 35.5 to not available), with a 2-year DFS rate of 90% (95% CI, 71-100). Among patients with R/R ALL, 3 of 8 (37.5%) achieved CR. In summary, for patients with newly diagnosed ALL, venetoclax plus mini-HCVD is well tolerated with promising efficacy. This trial was registered at www.clinicaltrials.gov as #NCT03319901.

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Conflict of interest statement

Conflict-of-interest disclosure: M.R.L. reports institutional research support from Novartis and AbbVie, and consulting/advisory roles with Novartis, Pfizer, Kite, and Jazz. E.S.W. reports a consulting/advisory role with and institutional research support from Curis. J.S.G. reports consulting/advisory roles with AbbVie, Astellas, Bristol Myers Squibb, Gilead, and Servier, and institutional research support from AbbVie, Genentech, New Wave, Prelude, Pfizer, and AstraZeneca. R.M.S. reports institutional research support from AbbVie, Syndax, and Janssen; reports consulting/advisory roles with AbbVie, Amgen, AvenCell, BerGen Bio, Bristol Myers Squibb, Cellarity, CTI BioPharma, Curis Oncology, Daiichi Sankyo, Epizyme, GlaxoSmithKline, Hermavant, Jazz, Kura Oncology, Lava Therapeutics, Ligand Pharma, Redona Therapeutics, and Rigel; and serves on the data and safety monitoring boards of Aptevo, Epizyme, Syntrix, and Takeda. E.J. reports research grants from, and consultancies with, AbbVie, Amgen, Pfizer, Takeda, Autolus, and Kite. J.R. reports a consulting role with Zentalis. A.L. reports serving on the advisory boards of Zentalis Pharmaceuticals and Flash Therapeutics, and his employer, the Dana-Farber Cancer Institute, owns a patent portfolio around BH3 profiling. M.K. reports research funding from AbbVie, Allogene, AstraZeneca, Genentech, Gilead, ImmunoGen, MEI Pharma, Precision, Rafael, Sanofi, and Stemline; reports advisory/consulting roles with AbbVie, AstraZeneca, Auxenion, Bakx, Boehringer, Dark Blue Therapeutics, F. Hoffman La-Roche, Genentech, Gilead, Janssen, Legend, MEI Pharma, Redona, Sanofi, Sellas, Stemline, and Vincerx; holds stock options in/receives royalties from Reata Pharmaceuticals (intellectual property); and reports a patent with Novartis, Eli Lilly, and Reata Pharmaceuticals. N.J. reports research funding from Pharmacyclics, AbbVie, Genentech, AstraZeneca, Bristol Myers Squibb, Pfizer, ADC Therapeutics, Cellectis, Adaptive Biotechnologies, Precision Biosciences, Fate Therapeutics, Kite/Gilead, MingSight, Takeda, Medisix, Loxo Oncology, Novalgen, Dialectic Therapeutics, Newave, Novartis, Carna Biosciences, Sana Biotechnology, and Kisoji Biotechnology, and advisory board membership/honoraria from Pharmacyclics, Janssen, AbbVie, Genentech, AstraZeneca, Bristol Myers Squibb, Adaptive Biotechnologies, Kite/Gilead, Precision Biosciences, Loxo Oncology, BeiGene, Cellectis, MEI Pharma, Ipsen, CareDx, MingSight, Autolus, and Novalgen. D.J.D. reports consulting roles with Amgen, Autolus, Blueprint, Gilead, Jazz, Novartis, Pfizer, Servier, and Takeda, and grant/research funding from AbbVie, Novartis, Blueprint, and GlycoMimetics. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Patient response and outcomes in newly diagnosed and R/R patients. MRD with sensitivity of <0.01%.
Figure 2.
Figure 2.
Survival of newly diagnosed patients. DFS and OS in newly diagnosed patients. Median DFS is 54.6 months (95% CI, 35.5 to NA). DFS at 1 and 2 years is 100% and 90% (95% CI, 71-100), respectively. 5-year DFS is NA. Median OS is NA. OS at 1, 2, and 5 years is 91% (95% CI, 74-100), 82% (95% CI, 59-100), and 55% (95% CI, 25-84), respectively.
Figure 3.
Figure 3.
BH3 profiling of pretreatment samples from patients with ALL. (A) Mitochondrial response to BAD BH3 (P = .27; 1-tailed t test) or venetoclax (P = .16) are not significant predictors of relapse. (B) Mitochondrial response to the MS1 peptide is the best BH3 profiling predictor of relapse (P = .11). (C) Receiver operator curve (ROC) for 10 μM MS1 as a binary predictor of relapse on venetoclax-based therapy (P = .18; AUC = 0.76). Black line indicates median. Each dot represents an individual patient. AUC, area under the curve.
Figure 4.
Figure 4.
High-dimensional CyTOF analysis of serial bone marrow samples in nonresponder patient 18. (A) Uniform manifold approximation and projection plots display the expression of CD45, CD34, BCL-2, BCL-XL, MCL-1, and clustering. (B) The percentages of persistent blast subpopulation (Pop4) and the expression of BCL-2, BCL-XL, and MCL-1 at the indicated time points. (C) Heat map displays the expression level of BCL-2, BCL-XL, and MCL-1 in Pop4 and in total population (Total Pop). (D) Expression ratio of EOC1 and EOC2 to baseline (BL) in Pop4.
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