Back to the future: “7+3” joins the venetoclax plus intensive chemotherapy movement

To the Editor,

Since 1973, the “7+3” regimen, with 7 days of cytarabine plus 3 days of an anthracycline (most commonly daunorubicin), has been the backbone of induction treatment for patients with acute myeloid leukemia (AML) eligible for intensive chemotherapy (IC) (1). Permutations to this regimen have emerged since 2017, with Food and Drug Administration (FDA) approvals for CPX-351 (liposomal cytarabine/daunorubicin) for therapy- and myelodysplastic syndromes (MDS)-related AML, gemtuzumab ozogamicin for CD33+ AML, and FMS-like tyrosine kinase 3 (FLT3) inhibitor-based combinations for FLT3-mutated AML (2-5). Following the publication of the pivotal VIALE-A trial, B-cell lymphoma 2 (BCL2)-inhibitor venetoclax (VEN) in addition to a hypomethylating agent (HMA) has become the standard of care for older (≥75 years) or unfit patients with AML (6,7). VEN has since been combined with various IC backbones in an attempt to leverage synergistic activity and to improve response rates, depth of response, and survival in IC-eligible adults with AML. Specifically, VEN has been tested in combination with fludarabine, cytarabine (Ara-c), granulocyte colony-stimulating factor (G-CSF), and idarubicin (FLAG-Ida), cladribine, idarubicin, and Ara-C (CLIA), and now “7+3”, with promising results (8-11).

In a recent issue of Blood, Mantzaris et al. report the results of a phase 1b study evaluating VEN in combination with standard “7+3” (“7+3” + VEN) for newly diagnosed IC-eligible patients with AML (10). While VEN has been studied in combination with alternative IC regimens such as FLAG-IDA and CLIA (8,9), its use in combination with “7+3” has only been reported in a previous single-center study in a Chinese population (12). That prior study, however, enrolled a younger cohort (median age 42 years) with a distinct European LeukemiaNet (ELN) risk distribution, underscoring the need for data generalizable to the broader IC-eligible US population. Although FLAG-IDA-VEN and CLIA-VEN delivered promising results, these regimens can require specialized expertise; as such, their adoption may be limited outside of select academic centers. On the other hand, “7+3” is the most widely used IC regimen for induction in AML worldwide. Mantzaris et al. provide the first US-based experience of VEN’s use in combination with the familiar “7+3” regimen.

In this phase 1b trial (n=34), authors investigated three escalating durations of VEN (8, 11, and 14 days per cycle) with standard “7+3”. Among the most salient findings in this study is the safety profile of “7+3” + VEN. It is reassuring to note that there were no induction-related deaths in this study. Furthermore, the addition of VEN did not appear to prolong time to absolute neutrophil count (ANC) and platelet count recovery post-induction: encouragingly, the respective median times to ANC and platelet recovery of 27 and 28 days are similar to what would be expected with standard “7+3”. No dose-limiting toxicities were seen in any dose cohort, irrespective of VEN duration. However, there was an increased incidence of neutropenic enterocolitis in this cohort (23.5%) compared to what would be expected based on historical IC experiences in AML (13). This observation should be interpreted with caution, however, given the small sample size (n=34), single-center design, and absence of a formal statistical comparison with historical “7+3” controls.

This phase 1b trial demonstrates encouraging efficacy of the “7+3” + VEN regimen, particularly considering the fact that 44% of study patients had adverse risk AML by ELN 2022 (14). The composite complete remission (CRc) of 85.3% generally compares favorably to “7+3”, where CRc rates range 60–70% (14,15). Moreover, 86.2% of responders achieved measurable residual disease (MRD)-negative status, defined per established consensus criteria (16), independent of VEN duration. Of note, this study enrolled 62% non-White patients, a population typically underrepresented in AML trials. The community in which the study was conducted provided an ethnically and racially diverse cohort, strengthening the generalizability of the study findings. The response rates observed by Mantzaris et al. also parallel the results of other IC-VEN combination trials (Table 1).

There are, no doubt, several limitations to this study. Its small sample of 34 patients limits our ability to recognize any significant difference in safety profile and response rates among varying durations of VEN therapy. The median follow-up of 9.6 months is insufficient for optimal characterization of long-term outcomes. Without a control arm, it is not possible to attribute response rates solely to the induction regimen versus institutional expertise or patient selection, and while this study population was notably diverse, it was nevertheless taken from a single urban tertiary care center. Furthermore, efficacy comparisons with other IC-VEN combinations (Table 1) should be interpreted with due caution, given differences in patient populations, risk stratification, response definitions, and assessment methods across trials. Multicenter, randomized validation of “7+3” + VEN is therefore warranted before broad adoption into clinical practice. Taken altogether, these results suggest the addition of VEN to IC may induce higher response rates and deeper remissions, without significant, additional new safety concerns.

The BCL2 inhibitor VEN is thought to synergize with cytotoxic agents by decreasing the apoptotic threshold in leukemic blasts. Under normal conditions, BCL2 sequesters pro-apoptotic Bcl-2 homology 3 (BH3) proteins, preventing downstream activation of apoptosis. VEN displaces BH3 proteins from their binding groove on BCL2, restoring the ability of leukemic cells to undergo apoptosis (19). Simultaneously, chemotherapy upregulates the same pro-apoptotic BH3 proteins, making leukemic cells especially vulnerable to VEN (20). Critically, VEN-based regimens have been shown to selectively target leukemia stem cells (LSCs), the chemotherapy-resistant population responsible for relapse, by disrupting oxidative phosphorylation and amino acid metabolism (21,22). This mechanism is supported clinically in the various aforementioned studies, with consistently high MRD-negative remission rates, rarely achieved with IC alone.

Finally, these data arrive in conjunction with preliminary results of the PARADIGM study presented at the 2025 American Society of Hematology Annual Meeting (23). These findings derive from a congress abstract and have not yet undergone peer review or full publication. In PARADIGM, Fathi et al. compare azacitidine-VEN (AZA-VEN) to conventional IC (“7+3” or CPX351) in younger, fit patients with new AML. The trial met its primary endpoint: the AZA-VEN arm had higher event-free survival (EFS) than the IC arm (53% versus 39%). Plus, 30- and 60-day mortality rates favored the AZA-VEN cohort as well. Notably, the AZA-VEN patients also had higher CRc rates (81% versus 55%).

The findings of the PARADIGM study ultimately raise the question: if lower-intensity therapy outperforms conventional therapies, what role remains for IC? Very likely, this answer hinges on the individual patient’s genomic risk profile. PARADIGM excluded patients with favorable-risk cytogenetics and FLT3 internal tandem duplication (FLT3-ITD) mutations. Patients with NPM1-mutated AML under the age of 60 years were also excluded. Overall, 72% of PARADIGM’s enrolled patients had adverse-risk disease, according to ELN criteria. However, which specific patients with high-risk AML will derive benefit from intensive versus lower-intensity VEN-based regimens remains unclear. On the other hand, IC combined with VEN may potentiate greatest benefit in younger patients with specific cytomolecular subgroups known to be potentially curable by IC by inducing deeper remission with a time-limited therapy, when compared to indefinite treatment with low-intensity VEN combinations. Patients’ goals and transplant eligibility could also guide clinicians in shared decision making around optimal induction regimens for IC-eligible patients with AML. From a resource-utilization standpoint, these approaches also differ meaningfully: IC-VEN is inpatient-delivered and time-limited, typically bridging eligible patients to allogeneic transplant, whereas AZA-VEN is delivered indefinitely in the outpatient setting. Preliminary cost-of-care data presented from PARADIGM study suggest lower resource utilization with AZA-VEN; however, these observations await confirmation in peer-reviewed publication, and formal cost-effectiveness analyses accounting for downstream transplant, relapse, and quality-of-life outcomes will be needed to inform individualized treatment decisions.

Many other questions remain. First, even with VEN-IC combinations, TP53-mutated AML remains remarkably difficult to treat. In this study, 2 of 5 TP53-mutated patients experienced complete remission (CR), including one with MRD-negativity. However, the duration of response is limited in this population. The FLAG-IDA-VEN trial from DiNardo et al. showed similarly poor long-term outcomes in TP53-mutated disease. Second, the optimal duration of VEN therapy remains unclear, though Mantzaris et al.’s study may provide some clarity. Patients responded similarly well to 8, 11, and 14 days of VEN. Toxicity did not appear to increase with longer duration, although 7 days of VEN offers optimal balance of safety and efficacy with FLAG-IDA-VEN (8,24).

In conclusion, Mantzaris et al.’s phase 1b study demonstrates that the historic backbone of AML induction therapy, “7+3”, combined with VEN achieves deep responses with acceptable toxicity profile. Along with other recent studies combining VEN with IC regimens, there is an emerging body of evidence supporting the thesis that use of VEN may safely augment responses to IC. Simultaneously, the recent PARADIGM study results provide a timely reminder that bigger is not always better, and high-intensity versus low-intensity induction choices should be based on the individual patient’s disease characteristics and treatment goals.

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.

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0021/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-2026-1-0021/coif). S.B. reports research funding to institution from Crossbow Therapeutics and Solu Therapeutics. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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