Venetoclax plus Idarubicin and cytarabine as frontline induction for newly diagnosed acute myeloid leukemia in young, fit adults: a real-world study

To the Editors:

Venetoclax (VEN), a selective BCL-2 inhibitor, has become a cornerstone of frontline therapy for older or unfit patients with newly diagnosed acute myeloid leukemia (AML) when combined with hypomethylating agents or low-dose cytarabine, leading to improved remission rates and survival outcomes [1, 2]. However, the role of VEN added to intensive induction chemotherapy in younger, fit patients remains incompletely defined. Although early-phase trials and real-world reports suggest that VEN combined with intensive cytarabine-anthracycline backbones may deepen responses, concerns regarding limited patient numbers, heterogeneity of regimens, and treatment-related toxicity have constrained broader interpretation [3–5]. Additional real-world data are therefore needed to clarify the potential benefit of this approach in routine practice.

We retrospectively analyzed young, fit adults (18–60 years) with newly diagnosed AML treated at a single tertiary center between February 2023 and May 2024. Patients received either conventional IA induction with idarubicin 10–12 mg/m²/day on days 1–3 plus cytarabine 100–200 mg/m²/day by continuous intravenous infusion on days 1–7, or VEN combined with a modified IA backbone consisting of idarubicin 10–12 mg/m²/day on days 1–2 and cytarabine 100–200 mg/m²/day by continuous intravenous infusion on days 1–5, according to physician discretion. Venetoclax was administered orally with dose ramp-up during induction, commonly 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3–7, for a total of 7 days, with dose adjustment when concomitant moderate or strong CYP3A inhibitors were used. For patients achieving remission, the post-remission treatment strategy was consistent between groups and consisted of intermediate- to high-dose cytarabine-based consolidation for 3–4 cycles, followed by maintenance therapy in repeating 2-month cycles: venetoclax 200 mg orally once daily on days 1–14 in both months, with azacitidine 75 mg/m² on days 1–7 added in the second month of each cycle. Treatment was continued until disease progression or last follow-up, as clinically appropriate. A total of 28 patients were included, with 14 patients in each group. Baseline demographic, clinical, cytogenetic, and molecular characteristics were generally balanced between groups. Treatment response was assessed after one induction cycle by bone marrow examination at hematologic recovery, typically around days 28–35 after intensive induction. Post-induction MRD was assessed in all evaluable patients after one induction cycle, irrespective of morphologic CR status, on bone marrow samples by multiparameter flow cytometry using both leukemia-associated immunophenotype (LAIP) and different-from-normal (DfN) approaches. MRD levels were reported quantitatively as the proportion of residual leukemic cells among total nucleated cells, and MRD negativity was defined as < 0.1% only when both LAIP- and DfN-based assessments were negative. No MRD-negative cases were observed among patients who did not achieve morphologic CR.

After induction, complete remission (CR) was achieved in 78.57% of patients in the V + IA group and 57.14% in the IA group, a difference that did not reach statistical significance. In contrast, post-induction MRD negativity was significantly more frequent in patients receiving V + IA than in those treated with IA alone (78.57% vs. 28.6%, Table 1). Among patients who achieved CR, the median duration of CR was not reached in the V + IA group and was 11.0 months in the IA group (95% CI, 6.84–15.16). No patient in either group underwent allogeneic hematopoietic stem cell transplantation during follow-up. With a median follow-up of 13 months, unadjusted exploratory Kaplan-Meier analyses demonstrated that PFS was significantly longer in the V + IA group than in the IA group (HR 0.335, 95% CI 0.121–0.924; P = 0.035). Similarly, a statistically significant improvement in OS was also observed in favor of the V + IA group (HR 0.166, 95% CI 0.029–0.945; P = 0.043) (Fig. 1). However, given the small sample size and limited number of survival events, the survival findings should be interpreted cautiously as hypothesis-generating. Taken together, these findings suggest that the addition of VEN to IA induction may primarily deepen early response rather than substantially increase morphologic CR rates. Early safety outcomes were also assessed. No deaths occurred within 30 days of induction in either group. Common grade ≥ 3 adverse events in the V + IA group included pneumonia (5/14), febrile neutropenia (6/14), and sepsis (1/14), compared with 4/14, 5/14, and 1/14, respectively, in the IA group. Grade ≥ 3 hematologic toxicities in the V + IA group included neutropenia (11/14), thrombocytopenia (10/14), and anemia (10/14), compared with 10/14, 11/14, and 9/14, respectively, in the IA group. The median time to hematologic recovery was 29 days (IQR, 20.75–37.5) in the V + IA group and 28 days (IQR, 18.75–36.5) in the IA group. The median time to neutrophil recovery was 25 days in both groups, whereas the median time to platelet recovery was 21 days in the V + IA group and 20 days in the IA group. No tumor lysis syndrome was observed in either group. Overall, early safety outcomes appeared broadly comparable between groups, with no statistically significant between-group differences observed in this small cohort (Table 1).

Table 1.

Baseline characteristics and early treatment response

Variables	IA (n = 14)	V + IA (n = 14)	P
Age, mean ± SD, years	42.64 ± 9.44	41.79 ± 13.37	0.846
BM blasts, median (IQR), %	55.00 (33.00, 72.12)	60.00 (42.75, 78.75)	0.395
WBC, median (IQR), x109/L	28.40 (6.82, 61.83)	13.71 (1.82, 27.13)	0.306
Sex, n (%)			-
Male	6 (42.86)	6 (42.86)
Female	8 (57.14)	8 (57.14)
Diagnoses, n(%)			0.757*
M1	2 (14.29)	1 (7.14)
M2	6 (42.86)	4 (28.57)
M4	3 (21.43)	4 (28.57)
M5	3 (21.43)	5 (35.71)
a Risk stratification, n(%)			0.121*
Favorable	4 (28.57)	1 (7.14)
Intermediate	2 (14.29)	7 (50.00)
Adverse	8 (57.14)	6 (42.86)
b Cytogenetic category, n(%)			0.420*
Normal karyotype	8 (57.14)	11 (78.57)
Abnormal karyotype	6 (42.86)	3 (21.43)
Extramedullary involvement, n(%)			1.000*
No	10 (71.43)	9 (64.29)
Yes	4 (28.57)	5 (35.71)
CR, n(%)			0.225*
No	6 (42.86)	3 (21.43)
Yes	8 (57.14)	11 (78.57)
MRD			0.008*
Negative	4 (28.57)	11 (78.57)
Positive	10 (71.43)	3 (21.43)
c Molecular abnormalities, n (%)
NPM1 mutation	1 (7.14)	4 (28.57)	0.326*
CEBPA bZIP mutation	6 (42.86)	1 (7.14)	0.077*
FLT3-ITD mutation	4 (28.57)	5 (35.71)	1.000*
IDH1 mutation	0 (0.00)	0 (0.00)	-
IDH2 mutation	1 (7.14)	2 (14.29)	1.000*
TP53 mutation	0 (0.00)	0 (0.00)	-
Grade ≥ 3 non-hematologic toxicities
Pneumonia, n(%)	4 (28.57)	5 (35.71)	1.000*
Febrile neutropenia, n(%)	5 (35.71)	6 (42.86)	1.000*
Sepsis, n(%)	1 (7.14)	1 (7.14)	-
Grade ≥ 3 hematologic toxicities
Neutropenia, n(%)	10 (71.43)	11 (78.57)	1.000*
Thrombocytopenia, n(%)	11 (78.57)	10 (71.43)	1.000*
Anemia, n(%)	9 (64.29)	10 (71.43)	1.000*
d Recovery kinetics
Time to hematologic recovery, median (IQR), days	28 (18.75, 36.5)	29 (20.75, 37.5)	0.646
Time to neutrophil recovery, median (IQR), days	25 (14.75, 33.5)	25 (14, 36)	0.982
Time to platelet recovery, median (IQR), days	20 (13.75, 29.5)	21 (16.75, 28.5)	0.730
CR duration, median (95% CI), months	11 (6.84, 15.16)	not reached	0.026
Tumor lysis syndrome, n(%)	0	0	-
30-day mortality, n (%)	0	0

^* Fisher’s exact test

^a Risk stratification was assigned according to the 2022 European LeukemiaNet (ELN) genetic risk classification

^b Specific cytogenetic abnormalities are provided in Supplementary Table 1

^c Additional somatic mutation and fusion gene profiles are provided in Supplementary Table 2

^d Neutrophil recovery was defined as ANC ≥ 1.0 × 10⁹/L, platelet recovery as platelet count ≥ 100 × 10⁹/L without transfusion support, and hematologic recovery as achievement of both criteria, with recovery times calculated from initiation of induction therapy. Duration of CR was estimated by the Kaplan-Meier method among patients who achieved CR, from first documented CR to relapse or death; patients remaining in CR were censored at last follow-up

BM bone marrow, WBC white blood cell, FAB French-American-British classification, V + IA venetoclax plus idarubicin and cytarabine, IA idarubicin plus cytarabine, CR complete remission, MRD minimal residual disease

Fig. 1.

Progression-free survival and overall survival according to treatment group. Kaplan-Meier analysis of (A) progression-free survival (PFS) and (B) overall survival (OS) in patients treated with V + IA versus IA. Survival curves were compared using the log-rank test. HRs (95% CIs) are shown for V + IA versus IA. For PFS, 12 events occurred in the IA group and 4 events in the V + IA group. For OS, 5 events occurred in the IA group and 1 event in the V + IA group. Abbreviations: V + IA, venetoclax plus idarubicin and cytarabine; IA, idarubicin plus cytarabine

The observed improvement in MRD clearance is clinically relevant, as MRD negativity after induction or before post-remission therapy has consistently been associated with reduced relapse risk and improved survival in AML [6]. From a biological perspective, this finding is plausible given VEN’s ability to restore mitochondrial apoptosis and potentially eradicate chemotherapy-resistant leukemic subclones [7]. In this context, VEN-augmented intensive induction may serve as an effective strategy to achieve deeper cytoreduction before consolidation or allogeneic hematopoietic stem cell transplantation, particularly in patients with intermediate- or high-risk disease. Importantly, in this small cohort, the addition of venetoclax to a modified IA backbone did not appear to substantially worsen early safety, as grade ≥ 3 infections, major hematologic toxicities, and hematologic recovery times were broadly comparable between groups. These preliminary findings suggest that short-course venetoclax may deepen response without a clear early safety penalty, although this observation requires confirmation in larger prospective studies with standardized toxicity monitoring.

Several limitations merit consideration. This was a retrospective, single-center study with a small sample size, which increases susceptibility to selection bias and limits statistical power. In addition, although the post-remission treatment strategy was broadly consistent between groups, the retrospective design, physician-discretion treatment allocation, small sample size, and subtle baseline ELN-risk imbalance may still have affected outcome comparisons. Follow-up was relatively short and the number of survival events was limited; therefore, the survival findings should be interpreted as exploratory and hypothesis-generating. Finally, although we incorporated some early safety data, including grade ≥ 3 infections, hematologic toxicities, and recovery kinetics, more granular comparative safety endpoints and longer-term adverse-event data were not systematically captured in this retrospective cohort.

In summary, in this real-world cohort of young, fit patients with newly diagnosed AML, the addition of venetoclax to idarubicin and cytarabine induction was associated with substantially deeper post-induction MRD clearance despite no significant difference in morphologic CR rate. Any apparent survival differences should be interpreted cautiously as exploratory observations. These findings support further prospective evaluation of VEN-intensified induction strategies and optimization of VEN scheduling to balance efficacy and toxicity in this patient population.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Chengcheng Ma and Ningning Yue: Writing-original draft, Data curation, Investigation, Funding acquisition. Chongyang Wu, Yutong Yang, Lingling Yue and Wanli Hu: Resources and Data analysis. HuiLing Chen and Pengyun Zeng: Writing - review & editing, Supervision, Project administration, and Conceptualization.

Funding

This work was supported by grants from the Gansu Provincial Science and Technology Plan Project (25JRRA1035) and Cuiying Science and Technology Innovation Program of the Second Hospital of Lanzhou University (CY2024-QN-B03).

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study was approved by the Institutional Ethics Committee of Lanzhou University second hospital (2025 A-1374) in accordance with the Declaration of Helsinki and local regulations. Informed consent to participate was obtained from all subjects and/or their legal guardian(s).

Consent for publication

Written informed consent was obtained from all subjects and/or their legal guardian(s) for publication of this case report and any accompanying images.

Competing interests

The authors declare no competing interests.