Journal of Hematology, ISSN 1927-1212 print, 1927-1220 online, Open Access
Article copyright, the authors; Journal compilation copyright, J Hematol and Elmer Press Inc
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Review

Volume 14, Number 4, August 2025, pages 193-201

B-Cell Lymphoma 2 Inhibition in Acute Lymphoblastic Leukemia: Mechanisms, Resistance, and Emerging Combinations With Venetoclax

Figure

Figure 1.
Figure 1. Mechanism of venetoclax-induced apoptosis in ALL. (a) ALL cells express elevated levels of anti-apoptotic BCL-2 family proteins (BCL-2, MCL-1, and BCL-XL) which prevent mitochondrial outer membrane permeabilization (MOMP) and trap pro-apoptotic proteins (BAX and BAK) to stop caspase activation and apoptosis. (b) Venetoclax specifically targets BCL-2 to enable apoptotic signaling through MOMP and caspase activation. The compensatory increase of MCL-1 and BCL-XL proteins helps to preserve anti-apoptotic signaling which leads to venetoclax resistance. ALL: acute lymphoblastic leukemia; BCL-2: B-cell lymphoma 2; MCL-1: myeloid cell leukemia-1; XL: extra large.

Tables

Table 1. Published Experiences of Venetoclax in ALL
 
PopulationInterventionPrimary outcome
ALL: acute lymphoblastic leukemia; allo-HCT: allogeneic hematopoietic cell transplantation; AYA: adolescent/young adult; BM: bone marrow; CAR-T: chimeric antigen receptor T-cell; CR/CRp: complete remission or complete remission with incomplete platelet recovery; ETP: early T-cell precursor; hyper-CVAD: a hyperfractionated chemotherapy regimen alternating cyclophosphamide, vincristine, doxorubicin, and dexamethasone with high-dose methotrexate and cytarabine; LBL: lymphoblastic lymphoma; mini-hyper-CVD: dose-reduced hyperfractionated cyclophosphamide, vincristine, dexamethasone, alternating with methotrexate and cytarabine; anthracycline omitted; MRD: minimal residual disease; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; Ph: Philadelphia chromosome; R/R: relapsed or refractory; VXL: venetoclax with dexamethasone vincristine and/or pegasparaginase.
Older adults with untreated or R/R Ph-negative ALL [17]Venetoclax + mini-hyper-CVD (phase I)ORR 100% (untreated), CR/CRp 37.5% (R/R)
Newly diagnosed or R/R Ph-negative ALL or LBL [18]Venetoclax + mini-hyper-CVD (phase II)CR 75% (frontline), 65% response (R/R)
R/R T-ALL (n = 13) [19]Venetoclax + various chemo regimens60% BM remission, OS 7.7 months
Pediatric and AYA with R/R ALL/LBL (n = 18) [20]Venetoclax + various chemoCR 61%, OS 9.14 months
Adults with R/R ALL/LBL (n = 18) [21]Venetoclax + liposomal vincristine (phase I)CR 22%, MRD-neg in two patients
Pediatric and adult with R/R ALL or LBL (n = 47) [22]Venetoclax + low-dose navitoclax + chemo (phase I)CR 60%, 28% bridged to allo-HCT/CAR-T
Adults with R/R ALL [23]Venetoclax + mini-hyper-CVD (phase 1/2)CR/CRi 57%, MRD-neg 45%
R/R T-ALL or T-LBL (n = 18) [24]Venetoclax + azacitidine (phase II)ORR 88.9%, OS 24.1 months
R/R ETP-ALL (n = 5) [25]Venetoclax + azacitidine/decitabine (case series)CR 60%, MRD-neg 100%
Pediatric/AYA with R/R ALL (n = 31) [26]Venetoclax + VXL/cytarabine regimens (phase I)ORR 42%, all CR/CRi
Frontline T-ALL or T-LBL [27]Venetoclax + hyper-CVAD, nelarabine, and pegylated asparaginasePFS 87.9%, OS 87.8%
Ph-neg B-ALL, 50% Ph-like (n = 24) [28]Venetoclax + CALGB 10403 (prospective)CR/CRi 96%, MRD-neg 91%

 

Table 2. Ongoing Phase I Venetoclax-Based Trials in ALL
 
Study numberPopulationInterventionPrimary outcome
ALL: acute lymphoblastic leukemia; AML: acute myelocytic leukemia; Mini-hyper-CVD: dose-reduced hyperfractionated cyclophosphamide, vincristine, dexamethasone, alternating with methotrexate and cytarabine; anthracycline omitted; Ph: Philadelphia chromosome; R/R: relapsed or refractory.
NCT06082934Newly diagnosed Ph+ ALLOlverembatinib plus venetoclax and dexamethasone (OVD)Efficacy and safety of the OVD chemotherapy-free regimen in Ph+ ALL
NCT03319901ALL (newly diagnosed or R/RMini-hyper-CVD plus venetoclaxEfficacy and safety of the combination in ALL
NCT05182385R/R B-ALLBlinatumomab + venetoclaxFeasibility, safety, tolerability and maximum tolerated dose of venetoclax
NCT05016947R/R B-ALL (Ph- and Ph+)Venetoclax + dexamethasone + inotuzumab ozogamicinSafety and efficacy and maximum tolerated dose of venetoclax
NCT04988555ALL/AML (R/R)Enzomenib, azoles, venetoclax, gilteritinib, azacitidineA phase 1/2 dose escalation/dose expansion study of enzomenib
NCT04872790Ph+ ALL (newly diagnosed or R/R)Dasatinib, venetoclaxThis phase Ib trial studies the effects of venetoclax

 

Table 3. Ongoing Phase II Venetoclax-Based Clinical Trials
 
Study numberPopulationPrimary outcome
ALL: acute lymphoblastic leukemia; AYA: adolescent/young adult; HSCT: hematopoietic stem cell transplantation; Ph: Philadelphia chromosome.
NCT06578546Newly diagnosed Ph+ ALLChemotherapy-free regimen of venetoclax, azacitidine plus orebatinib (VAO regimen)
NCT05376111Newly diagnosed T-ALLStudy of venetoclax combined with azacitidine regimen
NCT06393985Ph-negative B-ALLDecitabine, venetoclax, and blinatumomab for maintenance following HSCT
NCT06754267Ph+ B-ALLVenetoclax combined with olverembatinib and prednisone
NCT06082934Ph+ ALL (newly diagnosed)Olverembatinib plus venetoclax and dexamethasone
NCT05660473ALL (AYA, newly diagnosed)Pediatric-inspired regimen combined with venetoclax
NCT05594784Ph+ ALL (newly diagnosed)Olverembatinib combined with reduced-intensity chemotherapy and venetoclax
NCT03319901R/R ALL (older patients)Venetoclax and chemotherapy as frontline therapy
NCT05182385R/R ALLVenetoclax in addition to blinatumomab
NCT06554626B-ALLBlinatumomab plus venetoclax sequenced with inotuzumab ozogamicin
NCT06742515B-ALLBlinatumomab plus reduced-dose chemotherapy
NCT05576532R/R T-ALLVenetoclax plus IM2