Venetoclax with intensive chemotherapy in acute myeloid leukemia
Treatment of acute myeloid leukemia (AML) is broadly categorized as intensive chemotherapy (IC) for medically fit patients and less IC for older or unfit patients (1). For several decades, the standard IC approach has been 7 days of cytarabine and 3 days of anthracycline, termed the 7+3 regimen (2). Depending on patient and disease characteristics, the response rate with 7+3 is approximately 40–70% with long-term survival achieved in 30–55% of patients (1). More recently, advancements in less intense therapy have improved outcomes for older patients with AML as well. One of the major breakthroughs was the addition of venetoclax to hypomethylating agents (HMA), setting the standard of care for older patients per the VIALE-A trial (3).
Venetoclax is a B-cell lymphoma-2 (BCL-2) inhibitor, which in turn blocks the BCL-2 protein from preventing cell death. BCL-2 overexpression commonly occurs in leukemia and leads to an abundance of cytochrome C being released from cellular mitochondria, allowing for delay of apoptosis/cell death (4). Given that venetoclax inhibits this process from occurring, it has been used to treat leukemia either as monotherapy or in combination with other chemotherapy agents. In the context of AML, venetoclax was first studied by Konopleva et al. in 2016 as monotherapy for patients unfit for intensive therapy or for patients with relapsed/refractory cases in a phase II clinical trial. Overall, 6 of the 32 patients (19%) exhibited a level of therapeutic response with most patients receiving 4 weeks total of 800 mg venetoclax. The most common adverse effects included nausea (59%), vomiting (56%) and diarrhea (41%), febrile neutropenia (28%) and pneumonia (16%) (5). Subsequently, additional studies utilizing venetoclax in combination with traditional non-IC agents (such as HMAs) were published.
The pivotal trial (VIALE-A) included 431 older patients with newly diagnosed AML randomized to HMA alone vs. HMA plus venetoclax. The study met the primary endpoint of superior survival with HMA plus venetoclax compared to HMA alone (14.7 vs. 9.6 months). The rate of complete remission (CR) in the HMA plus venetoclax group was 36.7% compared to 17.9% in the control group (3). In another randomized phase III trial (VIALE-C) by Wei et al., venetoclax was combined with low dose cytarabine (LDAC) in less-fit patients with multiple comorbidities and/or older age. Compared to the control group (LDAC alone), the rate of CR (including those with incomplete count recovery) was higher in the LDAC plus venetoclax group (48% vs. 13%). The overall survival was 7.2 months in the combination group, compared to 4.1 months in the LDAC group but this was not statistically significant (6). As previously summarized by Amador-Medina et al., there has yet to be a trial directly comparing the efficacy of venetoclax + LDAC vs. venetoclax + azacitidine in newly diagnosed AML patients though there appears to be an overall preference to utilize venetoclax with azacitidine based upon the initial data released from VIALE-A as well as the availability of a plethora of other research studies on this regimen. What is significant to note is that VIALE-A excluded patients with prior exposure to HMAs and primarily focused on patients with newly diagnosed AML while VIALE-C included patients with prior HMAs and an increased number of patients with unfavorable prognostic indicators such as those with secondary AML (41% of the sample population). Both regimens are currently being utilized today for patients who are less likely to tolerate traditional 7+3 regimens though venetoclax + LDAC is primarily utilized in the subset of patients with prior HMA exposure or in resource-limited areas (7).
Given the favorable outcomes observed with venetoclax in combination with lower-intensity therapies, its use was subsequently evaluated in combination with IC regimens in younger patients. Venetoclax was investigated in patients with de novo AML and myelodysplastic syndromes (MDS) when combined with intensive regimens such as cladribine, idarubicin, and cytarabine (CLIA), as well as fludarabine, cytarabine, granulocyte colony-stimulating factor (G-CSF), and idarubicin (FLAG-IDA) (8,9).
With respect to CLIA-based therapy, a study by Kadia et al. evaluated 50 patients with AML or MDS who received venetoclax in combination with CLIA as induction therapy. Venetoclax was administered at a dose of 400 mg once daily on days 2–8 without ramp-up dosing. This regimen resulted in a CR rate of 97%, with 82% of patients achieving measurable residual disease (MRD) negativity. The median overall survival was not reached, and the estimated overall and event-free survival rates were approximately 72%. The most common adverse events included neutropenic fever (n=42), infections (n=6), and elevated liver enzymes (n=6) (9). The combination of venetoclax with FLAG-IDA was evaluated in a multi-phase clinical trial conducted by DiNardo et al. in 2021 (8), which included phase IB, IIA, and IIB cohorts. Venetoclax was administered at doses of 200 mg once daily in select phase IB patients (with subsequent escalation to 400 mg) and 400 mg once daily on days 1–14 in other cohorts. A total of 68 patients were enrolled, including 16 patients with relapsed or refractory (R/R) AML in phase IB, 29 newly diagnosed AML patients in phase IIA, and 23 R/R AML patients in phase IIB. Overall response rates were 75%, 97%, and 70% in phases IB, IIA, and IIB, respectively. Composite CR (CRc) rates were 75% in phase IB, 90% in phase IIA, and 61% in phase IIB. MRD negativity was observed in 96% of newly diagnosed patients and 69% of those with R/R AML. Additionally, 56% of patients proceeded to allogeneic hematopoietic stem cell transplantation, with one-year overall survival rates of 94% in newly diagnosed AML patients and 78% in those with R/R AML (7). Collectively, these outcomes represent a marked improvement over historical results achieved with standard 7+3 induction chemotherapy, which typically yields CR rates of approximately 40–70% after a single treatment cycle (1).
Although the data with CLIA and FLAG-IDA appears promising, 7+3 remains the standard intensive backbone for AML at most centers. Wang et al. first investigated the combination of venetoclax with 7+3. They conducted a multicentre, single-arm, phase II trial to evaluate the safety and efficacy of adding venetoclax to conventional daunorubicin and cytarabine (7+3) chemotherapy as induction therapy for adults aged 18–60 years with newly diagnosed, de novo AML. In this study, 33 patients received induction with 7+3 and escalating doses of venetoclax administered from days 4–11. The CRc rate after one induction cycle was 91%, and 97% of responders achieved undetectable MRD. Although all patients experienced grade 3 or worse cytopenias, and common serious adverse events included febrile neutropenia, pneumonia, and sepsis, no treatment-related deaths occurred. With a median follow-up of 11 months, the estimated one-year overall survival was 97% and one-year event-free survival was 72%. These findings provided support for further investigation of incorporation of venetoclax into intensive induction chemotherapy for newly diagnosed AML (10).
Although the phase II study by Wang et al. provided important proof of concept for incorporating venetoclax into the 7+3 induction regimen, several key limitations necessitated further investigation, which were somewhat addressed by a more recent phase 1b study conducted by Mantzaris et al. (11). The Wang et al. trial was limited by a small, homogeneous cohort composed exclusively of younger Chinese patients and employed a single, fixed eight-day venetoclax schedule selected primarily to mitigate myelosuppression, leaving ambiguity regarding the optimal schedule of venetoclax and the generalizability of the findings to a broader patient populations. Additionally, the short follow-up period restricted conclusions regarding long-term outcomes and durability of response. Mantzaris et al. designed a study to systematically evaluate 7+3 plus multiple venetoclax durations (8, 11, and 14 days) using step-up dosing in a more demographically diverse cohort that included older but fit patients, thereby addressing critical questions related to dosing optimization, safety, and applicability across an ethnically and racially diverse population from the Bronx region of New York. As such, the Mantzaris et al. study served as a much-needed complementary study to the one conducted by Wang et al. to refine treatment parameters and lay the groundwork for future randomized trials comparing venetoclax plus 7+3 regimens with the established standard of care (11).
The study by Mantzaris et al. enrolled 34 patients with a median age of 59 years (range, 27–71 years), and 44% were female. The majority of the patients were non-White (61.8%). Secondary AML was present in 11.7% of patients. Cytogenetic risk was favorable, intermediate and adverse in 14.7%, 58.8% and 26.5% of the patients, respectively. According to European LeukemiaNet (ELN) 2022 risk stratification, 38.2%, 17.7% and 44.1% of the patients had favorable, intermediate and adverse-risk disease, respectively. The most common molecular alterations were nucleophosmin 1 (NPM1) mutations (38.2%), followed by FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) (20.6%) and tumor protein 53 (TP53) mutations (14.7%), with generally similar baseline characteristics across the three venetoclax duration cohorts.
The CRc rate was 85.3% (CR rate of 82.3%), with MRD negativity by multiparameter flow cytometry achieved in 86.2% of responders, highlighting the depth of response with the addition of venetoclax to 7+3. These results compare favorably with historical outcomes of conventional 7+3 therapy, which typically yields lower MRD-negative rates in comparable patient populations (1,12,13). The high proportion of MRD-negative responses is particularly notable, as MRD negativity has been consistently associated with improved long-term outcomes, including relapse-free and overall survival.
Importantly, the study demonstrated no differences in toxicity among venetoclax durations of 8, 11, or 14 days, suggesting a degree of flexibility in the duration of venetoclax. The most often observed toxicities, including pancytopenia and febrile neutropenia, pneumonia, neutropenic enterocolitis, nausea, diarrhea, elevated liver function enzymes, sepsis and skin and soft tissue infection (SSTI) were consistent with prior studies combining venetoclax with IC and did not appear to worsen with prolonged venetoclax exposure (incidence of most adverse events are summarized in Table 1). Although the incidence of neutropenic enterocolitis was relatively high (mean percentage of 23.5% amongst all duration groups), this complication has been variably reported in earlier venetoclax-based regimens and was not clearly associated with venetoclax duration, patient age, or prior cytoreductive therapy. Median hematologic recovery time was less than 30 days for all cohorts, and the recovery pattern was consistent with typical 7+3 regimens. These findings suggest that the addition of venetoclax does not introduce unexpected or prohibitive toxicities beyond those anticipated with intensive induction therapy in an older but fit population. No induction mortality further supports the investigation of this combination.
Table 1
| Study | Sample size | Phase | Induction chemotherapy dosing | Venetoclax dosing | Complete remission rate (%) | Overall survival (1-year) (%) | Event-free survival (1-year) (%) | Grade 3/4 toxicity incidence [%] |
|---|---|---|---|---|---|---|---|---|
| Kadia et al. 2020 | 50 | II | Cladribine (5 mg/m2) and cytarabine (1.5 g/m2 for age <60 years, 1 g/m2 for age ≥60 years) for D1–5. Idarubicin (8 mg/m2) on D1–2 | 400 mg on D2–8 | 94 | 85 (estimated) | 68 (estimated) | Neutropenic fever [84], infection [12], ALT elevation [12], death—aforementioned regimen combined with a FLT3 inhibitor [2] |
| DiNardo et al. 2021 | 29 | IIA (ND-AML) | Fludarabine (30 mg/m2) and cytarabine (1.5–2 g/m2) on D2–6. Idarubicin (8 mg/m2) on D4–6 and filgastrim (5 μg/kg) on D1–7 | 400 mg on D1–14 | 90 | 94 | 85 | Neutropenic fever [48.3], pneumonia [27.6], bacteremia [20.6], SSTI [10.3], sepsis [10.3] |
| 16 | IB (R/R AML) | Fludarabine (30 mg/m2) and cytarabine (1.5–2 g/m2) on D2–6. Idarubicin (6 mg/m2) on D4–5 and filgastrim (5 μg/kg) on D1–7 | 200 mg on D1–21 with cytarabine 2 g/m2 (8 pts), 200 mg on D1–14 with cytarabine 1.5 g/m2 (5 pts), 400 mg on D1–14 with cytarabine 1.5 g/m2 (3 pts) | 75 | 38 | 31 | Neutropenic fever [50], bacteremia [50], pneumonia [25], sepsis [25], SSTI [0] | |
| 23 | IIB (R/R AML) | 400 mg on D1–14 | 61 | 68 | 41 | Neutropenic fever [52.2], bacteremia [34.5], pneumonia [24.1], sepsis [3.4], SSTI [3.4] | ||
| Wang et al. 2022 | 33 | II | Daunorubicin (60 mg/m2) on D1–3, cytarabine (100 mg/m2) on D1–7 | 100 mg on D4, 200 mg on D5, 400 mg on D6–11 | 91 | 97 | 72 | Pancytopenia [100], neutropenic fever [54.5], pneumonia [21.1], sepsis [12.1] |
| Mantzaris et al. 2025 | 14 | IB (8-day Ven) | Daunorubicin (60 mg/m2) on D1–3, cytarabine (100 mg/m2) on D1–7† | 100 mg on D1, 200 mg on D2, 400 mg on D3–8 | 71 | Median overall survival not reached | Median event-free survival not reached | Pancytopenia [100], neutropenic fever [100], neutropenic enterocolitis [21], sepsis [36], pneumonia [14], SSTI [14] |
| 9 | IB (11-day Ven) | 100 mg on D1, 200 mg on D2, 400 mg on D3–11 | 89 | Pancytopenia [100], neutropenic fever [100], neutropenic enterocolitis [11], pneumonia [11], SSTI [11] | ||||
| 11 | IB (14-day Ven) | 100 mg on D1, 200 mg on D2, 400 mg on D3–14 | 91 | Pancytopenia [100], neutropenic fever [100], neutropenic enterocolitis [36], sepsis [45.5], pneumonia [27], no SSTI |
†, all but 3 patients who received daunorubicin (90 mg/m2) on D1–3, cytarabine (100 mg/m2) on D1–7 along with venetoclax (3-day ramp from 100 to 200 to 400 mg) on D1–8. ALT, alanine aminotransferase; AML, acute myeloid leukemia; D, day(s); FLT3, FMS-like tyrosine kinase 3; ND, newly diagnosed; pts, patients; R/R, relapsed/refractory; SSTI, skin and soft tissue infection; Ven, venetoclax.
Despite these encouraging results, several limitations must be clearly acknowledged. Although the sample population is diverse, it is still very small to provide conclusive results. Furthermore, the short median follow-up of 9.6 months limits the ability to draw definitive conclusions regarding long-term overall survival, event-free survival, and relapse risk. While early response and MRD data are compelling, longer follow-up will be essential to determine whether these deep remissions translate into durable clinical benefit. Additionally, although the study addresses venetoclax duration, it was not powered to definitively identify a superior schedule, leaving uncertainty regarding whether shorter or longer venetoclax exposure optimally balances efficacy and toxicity. Collectively, the findings from Mantzaris et al. (11) strengthen the growing body of evidence supporting venetoclax as a valuable addition to intensive induction therapy in newly diagnosed AML. When considered alongside earlier studies using 7+3, CLIA, and FLAG-IDA backbones (Table 1), these results suggest that venetoclax may enhance remission depth without compromising tolerability in fit patients. However, confirmation in larger, randomized trials comparing 7+3 plus venetoclax directly against 7+3 will be necessary before this approach can be widely adopted as a new standard of care.
Building on the promising results of venetoclax combined with IC in newly diagnosed AML, several avenues of ongoing research aim to optimize its clinical application and address mechanisms of resistance. In the United States, the myeloMATCH trial is currently evaluating multiple treatment regimens, including the 7+3 plus venetoclax regimen, in younger patients with newly diagnosed intermediate and adverse-risk AML (NCT05554406, NCT05554393). Patients are assigned to standard-of-care or investigational treatments based on individual biomarker profiles, with disease response monitored through serial bone marrow biopsies and advanced MRD detection techniques.
Concurrently, research is uncovering the mechanisms behind venetoclax resistance, a proposed reason for treatment failure in refractory/relapsed AML patients, offering potential avenues for new therapeutic strategies in patients after initial therapy has failed. We acknowledge that the data for resistance mechanisms to venetoclax is largely in the setting of less-IC. As more trials combine venetoclax with IC, data on venetoclax resistance mechanisms unique to such therapy will emerge. Nonetheless, it is possible that the underlying genetic mutations or non-genetic cellular adaptations conferring resistance to venetoclax may overlap regardless of the intensity of the chemotherapy backbone. Raghuwani et al. [2025] identified the transcription factor forkhead box protein M1 (FOXM1), which is commonly expressed in AML, as a key regulator of B-cell lymphoma-2 related protein A1 (BCL-2A1), a protein associated with reduced venetoclax sensitivity. In AML cell models, silencing BCL-2A1 increased apoptosis in response to venetoclax, and pharmacological inhibition of FOXM1 further amplified venetoclax-induced cell death (14). These results indicate that targeting the FOXM1/BCL-2A1 pathway could help overcome resistance in refractory AML and enhance the effectiveness of venetoclax-based treatments. In AML and other hematologic malignancies, high myeloid cell leukemia-1 (MCL-1) levels can allow cancer cells to survive despite BCL-2 inhibition by venetoclax. Preclinical studies have shown that pharmacologic inhibition of cyclin-dependent kinase-9 (CDK9) rapidly decreases MCL-1 expression, restoring apoptosis in venetoclax-resistant cells. Combining CDK9 inhibitors with venetoclax synergistically enhances cell death and has shown promising activity in refractory AML trials. In a recent phase 2a trial by Zeidner et al., when combining a CDK9 inhibitor with venetoclax + azacitidine in 29 patients with previous venetoclax exposure, 31% of patients demonstrated an overall response and 17% achieved CR across all tested dose ranges of the CDK9 inhibitor (SLS009) (15). Mechanisms of venetoclax resistance and strategies to overcome it are active areas of ongoing research.
In conclusion, the integration of venetoclax into both lower-intensity and IC regimens has significantly advanced the treatment landscape for AML. Single-arm studies with CLIA, FLAG-IDA, and 7+3 regimens demonstrate that venetoclax may lead to high CR rates and depth of response, particularly as measured by MRD negativity, without introducing prohibitive toxicities in a select population. A cautious approach to the interpretation of these results is still required given the failures of phase III trials (magrolimab in AML/MDS and venetoclax in MDS) conducted based on successful single-center phase I/II trials in high-risk myeloid malignancies. While we observe promising results of combining venetoclax with standard 7+3 induction therapy as demonstrated by Wang et al. and Mantzaris et al., large, randomized trials are needed to confirm these findings.
Acknowledgments
None.
Footnote
Provenance and Peer Review: This article was commissioned by the editorial office, Chinese Clinical Oncology. The article has undergone external peer review.
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Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0005/coif). O.J. reports advisory board participation for TERNS, Ascentage and Sellas. The other author has no conflicts of interest to declare.
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