The combination therapy with venetoclax in therapeutic strategy of acute lymphoblastic leukemia.

Background

ALL is an aggressive hematologic malignancy characterized by the malignant transformation and proliferation of lymphoid progenitor cells in the bone marrow, peripheral blood, and extramedullary sites [ 1 ]. Based on immunophenotyping, ALL is broadly classified into B-cell ALL (B-ALL) and T-cell ALL (T-ALL), with B-ALL accounting for approximately 85% of cases, although this proportion varies according to age, race, and ethnicity [ 2 ]. The incidence of ALL follows a bimodal distribution, with a peak in early childhood and a second, smaller peak in older adults [ 3 ]. Despite substantial advances in risk-adapted chemotherapy, supportive care, and hematopoietic stem cell transplantation (HSCT), clinical outcomes in adult ALL remain unsatisfactory [ 1 ]. Although induction chemotherapy can achieve high initial remission rates, only 30–40% of adult patients ultimately achieve durable remission [ 4 ], in contrast to pediatric survival rates exceeding 90% in high-income countries [ 5 – 7 ]. Overall survival has improved significantly over recent decades, increasing from less than 50% in the 1970 s to approximately 85% today; however, this progress has been driven largely by improvements in pediatric treatment, underscoring persistent unmet needs in adult and high-risk ALL [ 8 ].

ALL is a biologically heterogeneous disease encompassing multiple immunophenotypic and molecular subtypes, including B-ALL, T-ALL, early T-cell precursor (ETP) ALL, and genetically high-risk entities such as TCF3-HLF and MLL-AF4 ALL. This heterogeneity contributes to marked variability in treatment response and clinical outcomes. Increasing evidence indicates that dysregulation of apoptotic signaling pathways plays a central role in leukemic cell survival and treatment resistance across ALL subtypes. In particular, overexpression of anti-apoptotic BCL-2 family proteins, including BCL-2 and BCL-XL, has been documented in several ALL subtypes, suggesting a critical dependence on these pathways for leukemic cell survival [ 14 ].

Venetoclax, an orally bioavailable BH3 mimetic and selective small-molecule inhibitor of BCL-2, has been approved by the US Food and Drug Administration (FDA) for use either alone or in combination with other agents [ 9 , 10 ]. It is reported that venetoclax inhibits the anti-apoptotic protein BCL-2, highlighting the therapeutic potential of targeting anti-apoptotic pathways in hematologic malignancies including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL) [ 11 – 13 ] ( Fig. 1 ).

Several recent retrospective studies have reported the increasing use of Venetoclax in ALL patients, demonstrating encouraging outcomes when combined with chemotherapy. For example, the addition of Venetoclax to mini-hyper-CVD has yielded high response rates and frequent conversion to measurable residual disease (MRD)-negative status in frontline treatment settings [ 14 , 15 ]. Venetoclax has also been investigated in Philadelphia chromosome-positive (Ph+) ALL, showing synergistic inhibition of leukemic cell growth and enhanced apoptosis in vitro, particularly when combined with tyrosine kinase inhibitors such as dasatinib or ponatinib [ 16 , 17 ]. In one study, 34% of patients achieved MRD negativity, and 60% achieved complete remission (CR) when Venetoclax was combined with Navitoclax and chemotherapy [ 18 ]. Additional research has explored combination strategies to further enhance Venetoclax efficacy, including monoclonal antibodies (blinatumomab, daratumumab, inotuzumab), pyrimidine analogs (azacitidine, decitabine), proteasome inhibitors (bortezomib), cyclin-dependent kinase (CDK) inhibitors (dinaciclib), signal transduction inhibitors (ibrutinib, ponatinib), microtubule agents (vincristine), and anti-inflammatory drugs (prednisone, dexamethasone).

Given the rapidly expanding yet heterogeneous nature of the available evidence—derived largely from preclinical studies, retrospective analyses, early-phase clinical trials, and case reports a focused narrative synthesis is warranted. Therefore, this review aims to critically summarize and integrate current preclinical and clinical findings on Venetoclax-based combination therapies in ALL, categorize combination strategies according to their mechanistic and therapeutic rationale, and highlight key challenges and future directions for the incorporation of Venetoclax into ALL treatment paradigms (see Fig. 2 ).

Methods

This narrative review was conducted using a comprehensive but non-systematic literature search strategy, consistent with the methodological framework of narrative reviews.

Relevant studies published in English were identified through searches of major biomedical databases, including PubMed, Scopus, and Web of Science. The search focused on publications evaluating Venetoclax in combination with other therapeutic agents in ALL, using keywords such as “Venetoclax,” “acute lymphoblastic leukemia,” “ALL,” “combination therapy,” and related terms. Additional articles were identified by manually screening the reference lists of key publications.

Both preclinical studies (in vitro and in vivo models) and clinical evidence, including retrospective analyses, early-phase clinical trials, and case reports, were considered for inclusion (see Table 1 ).

Results

The combination of venetoclax with azacitidine

Venetoclax combined with azacitidine has been primarily investigated in patients with relapsed or refractory (R/R) ALL, including T-ALL, ETP-ALL, and B-ALL. The combination is based on the rationale that hypomethylating agents can restore chemosensitivity and enhance BCL-2 inhibition [ 19 , 20 ].

Clinical evidence, though limited in sample size, has demonstrated encouraging efficacy. In patients with aggressive T-lineage disease, overall response rates (ORR) reached 88.9%, including CR and CR with incomplete hematological recovery (CRi), with grade ≥ 3 neutropenia as the most common adverse event [ 21 ].

Smaller cohorts, including R/R T-ALL and angioimmunoblastic T-cell lymphoma, also showed responses ranging from 60% to 100%, often accompanied by deep MRD negativity [ 22 , 23 ]. In R/R B-ALL, 62.5% of patients achieved remission, with several attaining substantial MRD reduction [ 24 , 25 ], and post-transplant maintenance studies reported sustained MRD-negative remission in all treated individuals [ 26 ].

Overall, these findings suggest that the Venetoclax–azacitidine combination is effective across multiple ALL subtypes, particularly in relapsed or post-transplant settings, with manageable hematologic toxicity (see Fig. 3 ).

The combination of venetoclax with blinatumomab

Venetoclax combined with blinatumomab has been explored in CD19-positive leukemias, leveraging complementary mechanisms: Venetoclax induces apoptosis, while blinatumomab redirects cytotoxic T cells toward CD19-expressing blasts. This strategy has primarily been evaluated in small cohorts and early clinical observations, demonstrating promising molecular and hematologic activity [ 27 , 28 ].

Clinical evidence, although limited in size, suggests encouraging efficacy. In a case report of a patient with molecular relapse, the combination achieved complete MRD clearance without significant toxicity [ 29 ]. Small cohorts, including patients with mixed-phenotype acute leukemia (MPAL) and relapsed/refractory or MRD-positive Ph-negative B-cell precursor ALL, reported high rates of hematologic recovery and MRD negativity, despite some occurrences of grade 3–4 cytopenias [ 30 , 31 ].

Overall, these findings indicate that the Venetoclax–blinatumomab combination may be particularly effective in achieving deep molecular remissions in CD19-positive ALL, with a generally manageable safety profile.

The combination of venetoclax with decitabine

Decitabine, a hypomethylating agent, can reactivate silenced tumor suppressor genes and is primarily used in AML, but has also been applied in ALL. Combining decitabine with Venetoclax has been investigated for potential synergistic effects, including enhanced apoptosis and overcoming drug resistance in relapsed or refractory T-ALL and MPAL.

Clinical evidence, although limited to small cohorts and case reports, indicates robust antileukemic activity. For example, a six-year-old girl with relapsed T-ALL and high-risk features, including TP53 mutation and MRD positivity, achieved morphologic remission and MRD negativity after post-transplant therapy with Venetoclax and decitabine [ 35 ]. Similar deep molecular responses were observed in relapsed T-ALL patients following allogeneic HCT [ 36 ] and in adults with relapsed T/myeloid MPAL [ 37 , 39 ]. Clinical trials have further suggested that Venetoclax combined with decitabine or other epigenetic modulators can overcome resistance to ABT-199, supporting broader applicability across leukemia subtypes [ 38 ].

Overall, these findings suggest that the Venetoclax–decitabine combination may be particularly effective in inducing MRD-negative remissions in high-risk and post-transplant ALL/MPAL patients, with manageable but notable hematologic toxicities.

The combination of venetoclax with dinaciclib

Dinaciclib, a CDK inhibitor targeting CDK1, CDK2, CDK5, and CDK9, induces apoptosis and arrests the cell cycle at the G2/M phase. Its combination with Venetoclax has been explored in ALL, particularly hypodiploid ALL, leveraging complementary mechanisms to promote apoptosis and disrupt cell-cycle progression. Preclinical studies provide strong evidence of synergy. In a study by Holly Pariury et al., primary human hypodiploid ALL samples implanted into immunodeficient NSG mice were screened against multiple CDK inhibitors, identifying dinaciclib as a potent partner for Venetoclax. Treatment with the combination enhanced apoptosis and produced a greater reduction in leukemic burden compared to either agent alone, with Bliss synergy scoring confirming dinaciclib as the optimal combination partner [ 40 , 41 ].

These findings establish a strong preclinical rationale for clinical investigation of Venetoclax combined with CDK inhibitors in high-risk hypodiploid ALL, highlighting the potential of simultaneously targeting apoptotic and cell-cycle pathways to overcome resistance in aggressive ALL subtypes.

The combination of venetoclax with ibrutinib

Ibrutinib, a selective Bruton’s tyrosine kinase (BTK) inhibitor, has demonstrated potent activity against several B-cell malignancies, including CLL, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, and multiple myeloma. It binds covalently to the BTK kinase domain, providing high selectivity and efficacy, while generally avoiding clinically significant myelosuppression [ 42 ].

The combination of Ibrutinib and Venetoclax (IBR + VEN) has been investigated in preclinical studies to assess potential synergistic anti-leukemic effects in ALL. Christopher A. Eide et al. evaluated 808 patient-derived hematologic malignancy samples, including 100 unique ALL samples. The combination demonstrated significantly greater efficacy than either agent alone, with pronounced synergy in precursor B-ALL cells. T-ALL samples were generally less sensitive, and samples harboring BCR-ABL1 fusion or NOTCH1 mutations showed trends toward reduced responsiveness, although these differences were not consistently statistically significant. Importantly, primary cells from healthy donors showed no appreciable response, indicating selectivity. Testing across multiple ALL cell lines confirmed variable but overall consistent synergistic activity, and in RCH-ACV B-ALL cells, synergy was pronounced according to the highest single agent (HSA) model [ 43 ].

These findings underscore the rationale for simultaneously targeting kinase signaling and apoptotic pathways in ALL, highlight the influence of genetic context on treatment response, and provide a strong preclinical foundation for potential clinical translation of the IBR + VEN combination.

The combination of venetoclax with bendamustine

Bendamustine is an alkylating agent with structural features resembling both purine analogues and nitrogen mustards, approved for B-cell malignancies, including CLL and non-Hodgkin lymphoma. Its cytotoxic effect primarily results from DNA alkylation, and its unique pharmacological properties have prompted investigation of combination therapies in ALL [ 44 ].

The combination of Venetoclax and Bendamustine has been evaluated in primary T-cell progenitor cells, including early T-cell precursor ALL (ETP-ALL) samples. Venetoclax showed additive effects with bendamustine, azacitidine, and cytarabine; however, the strongest synergistic interactions were observed with bendamustine and azacitidine. Among these, Venetoclax plus Bendamustine exhibited the highest degree of synergy according to Bliss/Loewe scoring, significantly inhibiting proliferation of ETP-ALL cells [ 45 ].

These findings suggest that simultaneously targeting the BCL-2–mediated apoptosis pathway and the DNA damage pathway may enhance anti-leukemic effects, particularly in aggressive or treatment-resistant ALL subtypes, highlighting the potential of this combination as a therapeutic strategy in high-risk patients.

The combination of venetoclax with inotuzumab ozogamicin

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate that combines a humanized anti-CD22 monoclonal antibody with ozogamicin, a cytotoxic agent derived from calicheamicin. The antibody selectively binds CD22 on B cells, and upon internalization, ozogamicin induces DNA double-strand breaks, triggering apoptosis. InO is primarily indicated for relapsed or refractory B-cell precursor ALL and can be combined with other agents, such as Venetoclax, to enhance efficacy while potentially reducing systemic toxicity [ 46 – 48 ].

Clinical studies in pediatric patients demonstrate promising efficacy and safety. Bhojwani et al. reported that 67% of pediatric patients with overt marrow disease achieved CR, with 71% of responders attaining MRD negativity [ 49 ]. Adverse events were generally manageable, with grade 3–4 infections in 22% and grade 3 hepatic transaminitis or hyperbilirubinemia in 12% of patients. No patients developed sinusoidal obstruction syndrome (SOS) during InO therapy, though among those who underwent subsequent HSCT, 52% experienced SOS, highlighting the need for careful post-transplant monitoring [ 49 ]. O’Brien et al. evaluated 48 patients and found a combined CR/CRi rate of 58.3% after the first treatment cycle, with 27 of 28 evaluable patients achieving MRD negativity [ 50 ]. Delayed count recovery beyond day 42 occurred in 25% of patients, and grade 3 SOS developed in 28.6% of those undergoing HSCT. Reduced response was linked to lower CD22 site density or incomplete expression [ 50 ].

In pediatric patients with relapsed or refractory ALL, Venetoclax combined with InO appears both safe and effective, selectively targeting CD22-expressing B cells while mitigating systemic toxicity. Since most de novo ALL patients do not require HSCT, InO represents an attractive option for combination therapy with Venetoclax, offering immune-targeted benefits while addressing the primary concern of SOS [ 49 – 50 ].

The combination of venetoclax with navitoclax

Navitoclax (ABT-263) is an oral BCL-2 family inhibitor targeting BCL-2, BCL-XL, and BCL-w. Its clinical application is limited by BCL-XL inhibition, which can reduce platelet lifespan and cause thrombocytopenia [ 51 – 53 ]. In combination with Venetoclax, Navitoclax has been investigated in R/R ALL to enhance apoptosis and overcome treatment resistance (see Fig. 4 ).

Lacayo et al. evaluated 36 patients with B- and T-cell ALL, including seven pediatric patients with multiple prior therapies, such as stem cell transplantation (SCT) or CAR-T therapy. The combination achieved an ORR of 56% for CR, CRi, or CRp; pediatric patients demonstrated an ORR of 86%, with 10 of 18 achieving undetectable MRD. Adverse events were manageable and included nausea, vomiting, diarrhea, hypokalemia, febrile neutropenia, and transaminase elevations [ 54 ].

Rubnitz et al. studied 18 pediatric patients (median age 10 years) and reported febrile neutropenia (50%), vomiting (44%), hyperglycemia (39%), and hypokalemia (39%) as the most common adverse events. Seven patients (39%) achieved CR/CRi/CRp, and 10 patients (56%) attained undetectable MRD; eight patients (44%) subsequently underwent SCT or CAR-T therapy [ 55 ]. Pullarkat et al. reported a CR rate of 59.6% in 47 patients, including heavily pretreated individuals. Pediatric patients ( n = 12) had a CR rate of 75%, with 50% achieving undetectable MRD. MRD negativity was observed in 67% of pediatric and 57% of all patients achieving CR/CRi/CRp [ 18 ].

Alexander et al. evaluated nine adult patients (four T-ALL, five B-ALL); despite intensive prior therapy, five patients achieved CR/CRi/CRp, including two with undetectable MRD. Adverse events included febrile neutropenia, pancreatitis, vomiting, septic shock, and pulmonary embolism, though only febrile neutropenia was possibly related to the combination. No dose-limiting toxicities were observed [ 56 ].

Overall, Venetoclax plus Navitoclax demonstrates substantial anti-leukemic activity, inducing high rates of CR and MRD negativity in both pediatric and adult R/R ALL, including patients with prior SCT or CAR-T therapy. The combination is generally well tolerated with manageable adverse events, supporting its potential as a therapeutic option for advanced ALL [ 56 ].

The combination of venetoclax with ponatinib

Ponatinib (Iclusig) is a multi-target tyrosine kinase inhibitor primarily used in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph + ALL). It inhibits the abnormal BCR-ABL protein that drives leukaemia cell proliferation, thereby suppressing disease progression [ 57 ]. The rationale for combining ponatinib with venetoclax is based on their complementary mechanisms: ponatinib targets BCR-ABL-driven signalling, while venetoclax induces apoptosis through Bcl-2 inhibition. This combination may enhance treatment efficacy in patients with R/R Ph + ALL. Dexamethasone is added to provide additional cytotoxic and anti-inflammatory effects. In the Short NJ trial, patients with R/R Ph + ALL received a regimen of ponatinib, venetoclax, and dexamethasone without concurrent chemotherapy [ 58 ].

Among the evaluable patients, three individuals (50%) achieved CR. Notably, all patients who attained CR received the higher venetoclax dose (800 mg daily). One patient on a lower venetoclax dose exhibited a substantial reduction in bone marrow blasts, from 94% to 6%, along with complete neutrophil recovery and near-complete platelet recovery; however, this did not formally meet the criteria for partial remission. At the most recent follow-up, responders maintained continuous molecular remission (MR) for 1, 5, and 8 months, respectively. The projected 9-month overall survival (OS) rate was 60%, with the median OS not yet reached after a median follow-up of 8.6 months. The regimen was generally well tolerated, with no unexpected toxicities observed. These findings suggest that the oral combination of ponatinib, venetoclax, and dexamethasone could serve as a safe and effective alternative for patients with relapsed/refractory Ph + ALL who have undergone multiple prior therapies. This study underscores the potential of chemotherapy-free regimens in high-risk populations, although larger trials are required to fully evaluate efficacy, durability of responses, and long-term safety [ 56 ].

The combination of venetoclax with vincristine

Vincristine, also known as leurocristine, is a widely used chemotherapeutic agent for ALL and other malignancies [ 59 ]. Its primary mechanism involves inhibition of microtubule polymerization, leading to metaphase arrest and induction of apoptosis [ 61 , 62 ]. While effective against leukemic cells, vincristine also affects all rapidly dividing cells, which can result in common toxicities such as leukopenia and increased infection risk [ 60 , 63 ]. It is frequently incorporated into multi-agent ALL regimens, including Stanford V, often combined with prednisone, dexamethasone, or L-asparaginase [ 64 ].

The combination of Venetoclax with vincristine has been evaluated in patients with R/R ALL. Johnson et al. reported a favorable safety profile, with most adverse events being hematologic [ 65 ]. Although high doses of Venetoclax have been associated with cardiotoxicity, no unexpected safety issues were observed when used in combination with vincristine.

Efficacy data indicate that response rates in newly diagnosed patients may approach 100%, whereas in R/R cases, response rates range from 38% to 65% [ 66 , 67 ]. These results suggest that the Venetoclax–vincristine combination is effective across diverse patient populations and may serve as a viable option in both frontline and salvage settings. Overall, this regimen demonstrates promising anti-leukemic activity while maintaining manageable toxicity, particularly in heavily pretreated R/R patients [ 66 , 67 ].

Discussion (c ritical review)

This narrative review highlights the expanding therapeutic role of Venetoclax-based combination regimens in ALL and emphasizes how different partner agents may provide distinct clinical benefits across biological subgroups. While various combinations have shown substantial promise, their efficacy appears to depend heavily on disease subtype, molecular characteristics, and prior treatment history.

In Philadelphia chromosome–positive (Ph⁺) ALL, combinations such as Venetoclax with ponatinib and dexamethasone have produced notable clinical outcomes, inducing deep molecular remissions even in heavily pretreated patients, including those with T315I or compound BCR-ABL1 mutations. The observed synergy between BCL-2 inhibition and tyrosine kinase blockade supports the development of chemotherapy-free strategies in this population.

In T-ALL and ETP ALL—subtypes often associated with poor responses to conventional chemotherapy—Venetoclax combined with hypomethylating agents such as azacitidine or decitabine has shown encouraging activity, including high response rates and achievement of MRD-negative remissions in relapsed or post-transplant settings. Preclinical and early clinical data suggest that T-lineage leukemias frequently rely on BCL-2 or BCL-XL–mediated survival pathways, providing a mechanistic rationale for these combinations.

In B-ALL and MPAL, immune-directed combinations such as Venetoclax with blinatumomab or inotuzumab ozogamicin appear particularly advantageous. Venetoclax may enhance immune-mediated cytotoxicity, leading to high remission rates and frequent MRD negativity while maintaining an acceptable toxicity profile. These regimens are especially valuable for older or medically unfit patients, offering effective bridging to transplantation or opportunities for sustained remission.

Despite these promising results, current evidence is limited by small, heterogeneous, and predominantly non-randomized studies. Much of the data derives from retrospective analyses, early-phase trials, or isolated case reports, which restricts generalizability and prevents robust comparisons among different Venetoclax-based combinations. Therefore, there is a critical need for large-scale, prospective, multicenter trials to comprehensively assess the efficacy, safety, and optimal integration of Venetoclax into ALL treatment. Such studies should include standardized dosing, harmonized MRD assessment, molecularly informed stratification, and long-term follow-up to clarify response durability and define the role of Venetoclax in both frontline and relapsed/refractory settings.

Overall, Venetoclax-based strategies represent a mechanistically compelling and potentially transformative approach across ALL subtypes; however, rigorous prospective evidence is required before these regimens can be fully integrated into standard clinical practice.

Safety and adverse events

Venetoclax-based combinations are generally well tolerated, although adverse events vary depending on the specific regimen and patient population. Hematologic toxicities, including neutropenia, thrombocytopenia, and febrile neutropenia, are the most frequently reported [ 22 , 23 , 30 , 52 – 54 ]. Non-hematologic adverse events, such as nausea, vomiting, diarrhea, elevated liver enzymes, and electrolyte disturbances, have also been observed [ 52 , 53 ]. Special attention should be given to SOS following HSCT, particularly when venetoclax is combined with inotuzumab ozogamicin [ 47 , 48 ]. Overall, toxicities are manageable with supportive care, dose adjustments, and close monitoring. However, standardized reporting in future studies is essential to better define safety profiles across different ALL subtypes.

Challenges and limitations

Despite growing interest in Venetoclax-based therapeutic strategies for ALL, interpretation and generalization of current findings remain limited by several important factors. First, the available evidence is predominantly derived from small, single-center, non-randomized studies, including retrospective analyses, early-phase trials, and isolated case reports [ 21 – 23 , 29 – 31 , 34 – 39 , 49 , 50 , 52 – 55 ]. These study designs inherently introduce selection bias, inconsistent patient recruitment, and heterogeneous treatment protocols, collectively reducing the robustness and comparability of reported outcomes.

A second major challenge is the lack of standardized treatment schedules. Significant variability exists in Venetoclax dosing strategies (ramp-up versus fixed dosing), cycle duration, and the choice of combination therapies [ 21 – 26 , 29 – 31 , 34 – 39 ]. This heterogeneity complicates efforts to identify optimal dosing frameworks and raises safety concerns, particularly for heavily pretreated patients who are more susceptible to hematologic toxicities such as neutropenia and thrombocytopenia [ 22 , 23 , 30 , 52 – 54 ].

Additionally, differences in MRD assessment methodologies pose another limitation. While some studies employ multiparametric flow cytometry, others utilize PCR- or NGS-based assays, each with distinct sensitivity thresholds. These inconsistencies impede direct comparison across studies and may result in over- or underestimation of treatment efficacy [ 29 – 31 , 49 , 50 ].

The absence of long-term follow-up data further restricts assessment of remission durability, late toxicities, relapse patterns, and post-transplant outcomes after Venetoclax-based therapies [ 21 , 22 , 34 – 39 ]. Combinations involving inotuzumab ozogamicin are of particular concern, as extended monitoring is needed due to the risk of SOS following hematopoietic stem cell transplantation [ 47 , 48 ].

Finally, the literature is likely influenced by publication bias, with studies reporting favorable outcomes being more frequently published than those with negative or inconclusive results. Collectively, these limitations underscore the need for rigorously designed, multicenter, prospective trials with standardized dosing protocols, harmonized MRD evaluation, and long-term follow-up before Venetoclax combinations can be fully integrated into standard therapeutic algorithms for ALL.

Future directions

Future research should focus on:

Conducting large-scale, prospective, multicenter RCTs to validate efficacy and safety.

Systematic comparison of different Venetoclax-based combinations to identify optimal regimens.

Molecular profiling to guide personalized therapy and identify patients most likely to benefit.

Long-term follow-up to assess durability of response, late toxicity, and overall survival.

Real-world studies evaluating cost-effectiveness, quality of life, and accessibility of Venetoclax combinations.

Exploring mechanisms of resistance and potential synergistic interactions with other targeted agents or chemotherapies.

Conclusion

Venetoclax-based combination regimens exhibit substantial therapeutic potential in ALL, particularly in patients with relapsed or refractory disease and those with high-risk cytogenetic features. Combinations with hypomethylating agents have produced high complete remission rates and deep MRD negativity, while the addition of targeted immunotherapies, such as blinatumomab or inotuzumab ozogamicin, provides effective and generally well-tolerated options, especially in B-lineage disease. Emerging evidence suggests that dual BCL-2 inhibition or integration with kinase inhibitors may further enhance efficacy in specific molecular subgroups, including Philadelphia chromosome–positive (Ph⁺) ALL. Collectively, these data support Venetoclax-based strategies as a flexible and potent therapeutic platform across ALL subtypes, while highlighting the critical need for large, randomized trials to optimize dosing, refine patient selection, and clarify their definitive role in clinical practice.

Acknowledgements

We would like to thank all of our colleagues at Birjand and Zahedan University of Medical Sciences who have supported us throughout this study. Additionally, we acknowledge that artificial intelligence was used exclusively to assist in conceptualizing the figures and was not involved in the content creation or data analysis.

Author contributions

Mobina Nakhaei Shamahmood and Mohammad Javad Yousefi and Abolfazl Miri conceived the study, performed the literature search, curated the data, and wrote the original draft and contributed to proofreading and validation. Fatemeh Mezginejad developed the methodology, carried out the analysis, reviewed and edited the manuscript, and supervised the work.

Funding

Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.