Real-world results of venetoclax combined with hypomethylating agents in young adults with relapsed/refractory acute myeloid leukemia

ABSTRACT

Objectives

Young adults with acute myeloid leukemia (AML) often fail to achieve permanent complete remission (CR) and frequently relapse, indicating an urgent need to explore effective salvage therapies. Recent advances in AML treatment have been attributed to the combination of the B-cell lymphoma 2 (Bcl-2) inhibitor venetoclax (VEN) with hypomethylating agents (HMAs); however, the use of this combination in young adults with relapsed or refractory (R/R) AML has not been reported.

Methods

We retrospectively examined 31 young patients with R/R AML treated with VEN plus an HMA. We evaluated the demographic data, cytogenetic characteristics, AML types, response rates, and transplantation-related data for the patients in our cohort.

Results

The combination of VEN + HMA yielded a CR rate of 48.4%. The most prominent hematologic adverse event was neutropenia, which occurred in all patients, with 90.3% of cases being grade ≥3. Non-hematologic toxicities were relatively mild and infrequent, with an incidence of 45.2%. More than half of the patients with sustained CR had received an allogeneic hematopoietic stem cell transplantation (allo-HSCT), of whom two died of transplant-related complications.

Conclusion

Our results showed that the combination of VEN + HMA appeared to be a highly effective and well-tolerated salvage therapy option for young patients with R/R AML, enabling more young patients to proceed to potentially curative allo-HSCT. However, additional, well-designed studies with larger numbers of patients are required to confirm the advantages of VEN + HMA in this population.

KEYWORDS:

• Acute myeloid leukemia
• venetoclax
• hypomethylating agents
• azacytidine
• refractory
• relapsed
• young patients
• allogeneic hematopoietic stem cell transplantation

1. Introduction

The treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) poses a formidable challenge for experienced clinicians. Chemotherapy regimens, including combinations of high dose cytarabine, clofarabine, etoposide, mitoxantrone, and fludarabine, are commonly recommended for eligible young patients, with the aim of achieving second complete remission (CR) for further allogeneic hematopoietic stem cell transplantation (allo-HSCT) [1–3]; however, these salvage reinduction therapies only result in CR in about one-third of patients [4–6], and treatment-related complications, such as severe organ toxicity and increased risks of serious infections, may make candidates ineligible for HSCT.

Moreover, the cumulative effects of previous treatments have also been shown to have a negative impact on the recovery capacity of bone marrow [7,8]. R/R AML patients are thus more likely to experience longer periods of bone marrow suppression. In addition, the demand for blood products is increasing. There were worldwide blood-supply shortages during the COVID-19 pandemic, with many blood-donation drives canceled due to the closure of schools and workplaces, resulting in thousands of fewer blood donations than normal [9]. A shortage of blood products poses a threat for patients undergoing routine intensive chemotherapy [10]. The efficacy and tolerability of salvage therapies is thus critical for the successful management of R/R AML.

Venetoclax (VEN), a selective BH3 analog, specifically inhibits B-cell lymphoma 2 (Bcl-2) leading to programed tumor cell death. Preclinical studies [11] showed that hypomethylating agents (HMAs), such as azacytidine (AZA), could enhance the sensitivity of tumor cells to VEN, and several clinical trials have confirmed that VEN in combination with HMAs could be an effective treatment for patients with newly diagnosed AML [12]. In addition, VEN + HMA has demonstrated encouraging remission rates in R/R patients. Notably, CR rates for VEN + HMA do not appear to be significantly affected by high risk biological characteristics, such as TP53 mutation status, which are associated with poor responses to conventional chemotherapies [13]. Meanwhile, the combination treatment is well tolerated, with low toxicity and low treatment-related mortality, and has been widely used in elderly or frail patients [14–19]. This lower intensity therapy might therefore alleviate the need for blood transfusions and reduce the risk of therapy-related neutropenia compared with intensive chemotherapy [20].

Combination therapy with VEN + HMA has become increasingly common for R/R AML, but most patients included in VEN + AZA studies were elderly patients and the results were not expressed by age subgroups [21–23]. The effects of this treatment in young patients with R/R AML thus remain unclear. We therefore conducted a comprehensive retrospective analysis of 31 young adult patients diagnosed with R/R AML who were treated with VEN + AZA in our center.

2. Patients and methods

2.1. Patients

We included 31 young adult patients diagnosed with R/R AML who were treated at the Department of Hematology, the Second Affiliated Hospital of Xi’an Jiaotong University, from April 1, 2021 to May 31, 2023.

Information including demographic data, disease characteristics, laboratory results, details of prior therapies, and molecular and cytogenetic abnormalities at the time of R/R AML diagnosis was collected. FAB types and risk stratification were classified according to the WHO 2016 classification and 2017 European Leukemia Net (ELN) risk stratification [24,25], respectively. We also obtained information on patients’ responses to VEN + HMA combination therapy, adverse events (AEs) of combination therapy, and survival and transplantation data, including donor type, graft-versus-host disease (GVHD) prophylaxis, and graft source. The Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) was recorded, as described previously [26].

This study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the Second Affiliated Hospital of Xi'an Jiaotong University.

The inclusion criteria were as follows: (1) the diagnosis of R/R AML based on [25] criteria; (2) aged 18–60 years; (3) treatment with at least one cycle of VEN plus HMAs; and (4) at least one bone marrow follow-up.

2.2. Treatment

All patients received treatment with VEN in combination with AZA (75 mg/m² × 7 days). During the first course of treatment, VEN was initially administered at 100 mg/day, gradually increasing to 400 mg/day over 3 days, with administration for 28 days. In the second course, VEN was administered orally at 400 mg/day. VEN exposure was reduced to 21 days if the patient had excessive treatment-related myelosuppression, and the dosage was adjusted accordingly [27]. For example, VEN was reduced to 100 mg/day in patients taking CYP3A inhibitors (such as voriconazole). Routine blood tests, liver and kidney function tests, electrocardiogram, and myocardial enzymes were monitored regularly. Blood transfusion was administered if the hemoglobin level fell to <70 g/L or the platelet count was <20 × 10⁹/L. Patients showing a clinical response continued to receive VEN + AZA until disease progression, life-threatening adverse reactions, or allo-HSCT.

2.3. Treatment response and prognosis

Treatment response was defined according to the 2017 ELN response criteria [25] at the beginning of each cycle. At the same time, minimal residual disease (MRD) was evaluated by flow cytometry (Beckman, USA) with a sensitivity ≥0.01%. Toxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Event (CTCAE) version 5.0 [28].

2.4. Statistical analysis

Statistical analysis was performed using SPSS 24.0 software. Categorical variables were presented as numbers and percentages and analyzed using χ² test. Continuous variables were described as median and range and analyzed using Student’s t-tests. A P value <0.05 was considered statistically significant.

3. Results

3.1. Patient characteristics

This study included 31 young patients with R/R AML who received VEN + HMA (mainly AZA) treatment between April 1, 2021 and May 31, 2023 (Table 1). In our cohort, 54.8% of patients were male and the median age was 53 years (range, 18–60 years). Twenty-six patients (83.9%) had de novo AML and five had secondary or therapy-related AML, including myelodysplastic syndrome (3/31), solid tumor (1/31), and lymphoma (1/31). Notably, > 80% of cases (26/31) were treated with cytarabine + anthracycline (3 + 7) protocol as standard intensive induction when they were first diagnosed with AML. Thirteen refractory patients (41.9%) had a minor or no response to the first or second induction therapy. Nine patients (29%) had experienced at least one prior relapse at the time of VEN initiation. The median number of prior salvage therapies was one (range, 0–3), including intensive chemotherapy protocols, such as high-dose cytarabine and FLAG protocol (fludarabine, cytarabine, granulocyte colony-stimulating factor). Twenty-four patients had received previous HMA treatment and four had undergone allo-HSCT prior to VEN therapy. In our cohort, most patients were M2 (15/31, 48.4%), followed by M4 (8/31, 25.8%) and M5 (5/31, 16.1%). The most frequent mutations were FLT3 (8/31, 25.8%; FLT3-ITD 6/8) and K/NRAS mutations (6/31, 19, 4%), followed by IDH1/IDH2 (5/31, 16.1%), KIT (5/31, 16.1%), TP53 (5/31, 16.1%), and NPM1 (4/31, 12.9%) mutations.

Table 1. Patients’ characteristics and CR rates.

Characteristics	Number,n (%)	CR/CRi, n (%)	P-value
Sex, n (%)			1.000
Female	14(45.2)	7(50.0)
Male	17(54.8)	8(47.1)
Disease status, n (%)			0.722
Refractory	13(41.9)	7(53.8)
Relapsed	18(58.1)	8(44.4)
1	9(29.0)	4(44.4)
2	5(16.1)	3(60.0)
≥3	4(12.9)	1(25.0)
ECOG score, n (%)			0.658
0	6(19.4)	3(50.0)
1	19(61.3)	10(52.6)
2	5(16.1)	2(40.0)
3	1(3.2)	0(0.0)
AML Status			0.330
De novo AML	26(83.9)	14(53.8)
Secondary AML	5(16.1)	1(20.0)
Prior Treatment Exposure, n (%)
HMA	24(77.4)	11(45.8)	1.000
Allogeneic HSCT	4(12.9)	2(50.0)	0.228
Frontline ‘3 + 7’	26(83.9)	13(50.0)	1.000
High-dose cytarabine	10(32.3)	6(60.0)	0.458
Low-dose cytarabine	17(54.8)	9(52.9)	0.722
Other intensive chemotherapy (e.g. FLAG, MEC)	4(12.9)	1(25.0)	0.600
Prior Allogeneic HCT, n (%)			0.228
Yes	4(12.9)	2(50.0)
No	27(87.1)	13(48.1)
FAB types, n (%)			0.712
M1	2(6.5)	1(50.0)
M2	15(48.4)	8(53.3)
M4	8(25.8)	3(37.5)
M5	5(16.1)	2(40.0)
M7	1(3.2)	1(100.0)
2017 ELN risk stratification, n (%)			0.673
Favorable	5(16.1)	2(40.0)
Intermediate	14(45.2)	6(42.9)
Adverse	12(38.7)	7(58.3)
Molecular mutation, n (%)
FLT3	8(25.8)	4(50.0)	1.000
K/NRAS	6(19.4)	3(50.0)	1.000
TP53	5(16.1)	3(60.0)	0.654
IDH1/IDH2	5(16.1)	2(40.0)	1.000
KIT	5(16.1)	1(20.0)	0.333
NPM1	4(12.9)	2(50.0)	1.000
ASXL1	4(12.9)	2(50.0)	1.000
CEBPA	4(12.9)	2(50.0)	1.000
AML1/ETO	3(9.7)	1(33.3)	1.000
BCOR	2(6.5)	1(50.0)	1.000
WT1	2(6.5)	1(50.0)	1.000
PHF6	2(6.5)	0(0.0)	0.484
RUNX1	2(6.5)	2(100.0)	1.000

AML: acute myeloid leukemia; ASXL1: additional sex combs-like 1; BCOR: BCL6 corepressor; CEBPA: CCAAT/enhancer-binding protein α; CRi: Complete remission with incomplete count recovery; ECOG: Eastern Cooperative Oncology Group; FLT3: Fms-like tyrosine kinase 3; FLAG: fludarabine + cytarabine + granulocyte colony-stimulating factor; HMA: hypomethylating agent; HSCT: hematopoietic stem cell transplantation; IDH: isocitrate dehydrogenase; KIT: proto-oncogene receptor tyrosine kinase; MEC: etoposide + cytarabine; NPM1: nucleophosmin 1; PHF6: plant homeodomain finger 6.

3.2. Response to the combination treatment

The overall response rate was 67.7% (21/31), with 15 patients (48.4%) achieving CR/Complete remission with incomplete count recovery (CRi) and six patients (19.4%) achieving partial remission. Among the responders, almost half of the patients (46.7%, 7/15) who achieved CR/CRi had unfavorable cytogenetics (Table 1): four patients with FLT3 mutations, two with IDH1/2 mutations, three with K/NRAS mutations, and three with TP53 mutations had CR/CRi. Eight of 15 patients who achieved CR/CRi were MRD-negative (Table 2). The median number of VEN + AZA cycles was three (range, 1–13). Twelve (38.7%) patients achieved CR/CRi and five (16.1%) achieved MRD-negativity within one cycle. The early mortality (first 8 weeks) was 6.5% (2/31).

Table 2. MRD in responders.

	CR/Cri, n (%)		P-value
	MRD+	MRD−
All (N = 15)	7(46.7)	8(53.3)
Sex, n (%)			1.000
Female	3(42.8)	4(50.0)
Male	4(57.2)	4(50.0)
AML type, n (%)			0.467
Primary	6(85.7)	8(100.0)
Secondary	1(14.3)	0(0.0)
Disease status, n (%)			0.619
Refractory	4(57.2)	3(37.5)
Relapsed	3(42.8)	5(62.5)
1	1(14.3)	3(37.5)
2	1(14.3)	2(25.0)
≥3	1(14.3)	0
ECOG score, n (%)			0.262
0	1(14.3)	2(25.0)
1	4(57.1)	6(75.0)
2	2(28.6)	0
3	0	0
Prior Treatment Exposure, n (%)
HMA	6(85.7)	5(62.5)	0.569
Allogeneic HCT	5(71.4)	6(75.0)	1.000
Frontline ‘3 + 7’	6(85.7)	7(87.5)	1.000
High-dose cytarabine	2(28.6)	4(50.0)	0.608
Low-dose cytarabine	6(86.7)	3(37.5)	0.119
Other intensive chemotherapy (e.g. FLAG, MEC)	1(14.3)	0(0)	0.467
Prior Allogeneic HCT, n (%)			1.000
Yes	5(71.4)	6(75.0)
No	2(28.6)	2(25.0)
FAB types, n (%)			0.310
M1	1(14.3)	0
M2	5(71.4)	3(37.5)
M4	1(14.3)	2(25.0)
M5	0	2(25.0)
M7	0	1(12.5)
Risk stratification, n (%)			0.352
Favorable	0	2(25.0)
Intermediate	3(42.8)	3(37.5)
Adverse	4(57.1)	3(37.5)

3.3. Safety and toxicities

Among all AEs (Table 3), hematologic AEs were the most common (100%), while non-hematologic toxicities were relatively mild and infrequent (45.2%). All patients experienced AEs during the first cycle, but no tumor lysis syndrome occurred. Twenty-nine patients had AEs grade ≥3. The most frequent hematologic AE was neutropenia, which occurred in all patients and was grade ≥3 in 90.3% of cases. The median neutrophil nadir count was 0.145 × 10⁹/L (0–2.3). Ten patients (32.3%) had agranulocytosis with fever, all grade ≥3. Twenty-eight patients had thrombocytopenia, with a median platelet nadir count of 10 × 10⁹/L (1–53). Among patients who achieved CR/CRi, the median times to neutrophil recovery (1 × 10⁹/L) and platelet recovery (50 × 10⁹/L) were 22 days (range, 15–39) and 23 days (range, 15–35), respectively.

Table 3. AEs during therapy.

Hematologic AE
Neutropenia
Grade ≥3, n (%)	28 (90.3%)
Agranulocytosis with fever, n (%)	10 (32.3%)
Median ANC nadir, × 10^3/µL (range)	0.145 (0–2.3)
Median time post-VEN initiation of ANC nadir, days (range)	12 (4–67)
Cycle of therapy during which neutropenia occurred, n (%)
1	31 (100%)
2	16 (51.6%)
3	12 (38.7%)
Anemia
Grade ≥3,n (%)	27 (87.1%)
Median hemoglobin nadir, g/dL (range)	6.7 (5.8–10.5)
Median time post-VEN initiation of hemoglobin nadir, days (range)	12 (2–57)
Cycle of therapy during which anemia occurred, n (%)
1	30 (96.8%)
2	16 (51.6%)
3	11 (35.5%)
Thrombocytopenia
Grade ≥3, n (%)	26 (83.9%)
Median platelet nadir, x 10^3/uL (range)	10 (1–53)
Median time post-VEN initiation of platelet nadir, days (range)	14 (1–65)
Cycle of therapy during which thrombocytopenia occurred, n (%)
1	28 (90.3%)
2	15 (48.4%)
3	10 (32.3%)
Non-hematologic AE
Infection, n (%)	14 (45.2%)
Pulmonary infection, n (%)	10 (32.3%)
Grade ≥3, n (%)	7 (22.6%)
Perlanal infection, n (%)	1 (3.2%)
Skin and soft tissue infection, n (%)	2 (6.5%)
Urinary system infection, n (%)	1 (3.2%)
Skin rash, n (%)	1 (3.2%)
Gastrointestinal side effects, n (%)	3 (9.7%)
Nausea, n (%)	1 (3.2%)
Vomiting, n (%)	1 (3.2%)
Constipatlon, n (%)	1 (3.2%)
Abnormal liver function, n (%)	2 (6.5%)

ANC: absolute neutrophil count.

The most frequent non-hematologic AE was infection, with pulmonary infections grade ≥3 in 22.6% of patients. Gastrointestinal AEs occurred in three patients (9.7%). No neurotoxicity or nephrotoxicity was observed in our cohort. There was no significant difference in toxicity between patients who did and did not achieve CR.

Fourteen patients were able to tolerate the dose of VEN continuously, while 17/31 of patients (54.8%) required a decreased dosage due to severe bone marrow suppression. The total duration of VEN was thus reduced to 21 days for the first two cycles in 10 patients, and VEN treatment was interrupted due to myelosuppression in a further seven patients. All patients were hospitalized for the first cycle of treatment, and nine were subsequently followed daily as outpatients after the VEN dose ramp-up phase. Four (12.9%) patients were hospitalized throughout the entire treatment period. The median hospital stay was 23 days (range, 7–42) during the first treatment cycle. The two deaths reported within the 8 weeks after treatment were attributed to disease progression and intracranial hemorrhage, respectively.

3.4. Post-induction therapy

Among patients with sustained CR (N = 15), nine (60.0%) responders eventually underwent successful allo-HSCT, while the other six patients were unable to receive allo-HSCT due to their general condition, patient willingness, or economic reasons. These patients received routine consolidation and maintenance therapy, including VEN + HMA (2, 33.3%), enasidenib (2, 33.3%), cytarabine + HMA (1, 16.7%), and other regimens (1, 16.7%).

3.5. Allo-HSCT recipient outcomes

The median age of the allo-HCT recipients was 39 years (range, 18−54), and three patients had an HCT-CI of >1. The sources of the transplant were a matched related donor in five cases (44.4%), a matched unrelated donor in three (22.2%), and a haploidentical donor in one (11.1%). Seven patients (77.8%) underwent peripheral blood stem cell grafts and six patients (66.7%) received busulfan and cyclophosphamide myeloablative conditioning. Tacrolimus was used as GVHD prophylaxis in eight patients (88.9%). The characteristics of the allo-HSCT recipients are summarized in Supplementary Table 1. The 100-day survival and non-relapse mortality rates for these nine patients were 88.9% and 0%, respectively, and only two patients relapsed within 100 days after HSCT. To date, two patients had died of transplant-related complications and one died of disease relapse, and the remaining patients were alive and treated with regular follow-up.

4. Discussion

AML is one of the most common hematological malignancies characterized by rapid progression, high heterogeneity, and a poor prognosis [29], with an OS of around 8.5 months and a 5-year survival rate of only 28.7% [30,31]. For young patients, the goal of induction treatment is to provide a bridge therapy for allo-HSCT. Current practice and National Comprehensive Cancer Network (NCCN) guidelines [29] also indicate that allo-HSCT should be offered to patients who achieve CR, and allo-HSCT in CR following salvage chemotherapy resulted in significantly better survival outcomes than allo-HSCT after failed rescue chemotherapy [32]. AML patients should thus aim to achieve CR where possible before proceeding to allo-HSCT.

VEN + HMA has demonstrated good efficacy in elderly and newly diagnosed unfit AML patients, with good tolerability, mild toxicity, and low treatment-related mortality. Moreover, VEN + AZA therapy has changed the treatment landscape for R/R AML, with a favorable overall response rate of 64% and CR/CRi of 51% [33]. However, most patients enrolled in clinical trials of VEN + HMA were >60 years old, with little information for young patients (< 60 years), and only one clinical trial evaluating VEN + AZA in young adults with newly diagnosed AML is currently underway (NCT03573024).

We retrospectively analyzed the efficacy of VEN + AZA for the treatment of young adults with R/R AML and observed a high CR rate of 48.4%. We compared several salvage regimens for relapsed or refractory AML in younger adults, which had CR/CRi rates of 32%–48% [34,35]. The efficacy of VEN + HMA in younger patients with R/R AML was therefore not inferior to other rescue schemes. Notably, this combination has consistently shown high response rates in most biological subtypes of AML, including RUNX1-, TP53-, and FLT3-mutated disease, which are normally associated with dismal prognostic outcomes. However, the retrospective, observational and non-controlled nature of the study meant that the current results should be interpreted with caution.

The MRD-negativity rate of 53.3% in this study was generally comparable to previous trials in which around two-thirds of evaluable responders attained MRD-negativity [14]. A relatively high proportion of patients thus achieved MRD-negativity after VEN + HMA, demonstrating deep complete responses with this combination [33].

Importantly, VEN is administered orally and AZA is injected subcutaneously, both of which are less traumatic and easier to deliver than intravenous infusion. Moreover, direct comparisons of VEN + AZA with other commonly used chemotherapy protocols, such as MEC (mitoxantrone, etoposide, cytarabine) and FLAG, showed clear advantages of the combination strategy with regard to marrow recovery, mean hospital stay, and transfusion needs, thus confirming HMA + VEN as a promising treatment option in a real-world setting. Previous retrospective studies showed median durations until neutrophil (≥0.5 × 10⁹/L) and platelet recovery (≥50 × 10⁹/L) following these induction chemotherapies of about 24 and 25 days, respectively [36,37], which were comparable with those for VEN + AZA. The median length of hospital stay for traditional induction chemotherapy is 30–36 days, and up to 92% of the cost of AML treatment has been attributed to inpatient costs [38]. In this study, the median length of hospital stay was 23 days, which was much shorter than that for conventional intensive chemotherapy, potentially reducing treatment costs and improving overall patient satisfaction. In addition, the time to best response for ZEN + AZA was relatively short, with a median time of only around 2 months/cycles and as early as one cycle [39]. This would allow patients to undergo allo-HCT in a timely manner, thereby potentially improving outcomes. The early and high remission rate achieved by this combination therapy could also effectively reduce the cost of supportive care for AML (blood transfusions, antibiotics, etc.), helping to make treatment more accessible and contributing to overcoming the shortage of blood products. However, more research is needed to verify the advantages of this combination due to the intrinsic limitations of the current analysis.

Given that allo-HSCT is the ultimate goal for appropriate patients (especially young patients), avoiding additional toxicity is a critical consideration for AML salvage treatment [40]. Nine responders in the current study were successfully bridged to allo-HSCT. One advantage of the VEN + HMA regimen for R/R AML patients, especially for HSCT candidates, is that this salvage therapy may cause fewer toxicities than cytotoxin-based regimens, such as anthracyclines, which are commonly used in induction therapy for AML but can lead to cardiotoxicity and impaired cardiac function, which can negatively affect the outcome of HSCT in AML patients [41]. Previous research also demonstrated that allo-HSCT after HMA + VEN was associated with favorable allo-HSCT outcomes in older R/R patients with AML [42]. The VEN + HMA regimen is thus a better choice for allo-HSCT candidates with R/R AML.

VEN + AZA is effective in young AML patients; however, its toxicity is an issue should be paid attention to. The most common grade ≥3 AEs were hematologic AEs, which were also a common cause of dose reduction and/or interruption [43]. Non-hematologic toxicity was minimal and most non-hematologic AEs resulting from VEN-based combinations were mild and easily managed. In this study, hematologic AEs occurred in all patients, with grade ≥3 in 96.4% (54/56) of cases. One patient died of cerebral hemorrhage within 30 days after VEN treatment, due to a severe hematologic AE, 26 patients (46.4%) developed infections during treatment, and 66.1% patients required a reduced VEN dosage. Notably, myelosuppression can be alleviated by routine leukogenic treatment, blood transfusion, and anti-infection and other supportive treatments. In addition, it is suggested that patients should have a delayed treatment cycle, an adjusted dosage of VEN, or a shortened duration of VEN administration to reduce the risk of hematological AEs [44]. Monitoring the optimal response time can guide the early discontinuation of VEN therapy, which might help to mitigate the risks of infection, bleeding, and other AEs in VEN combination therapy.

There were some limitations in this study. First, it was a retrospective study with a limited number of patients from a single institution, and the patients included were not consecutive patients. In addition, the sample sizes for subset analyses were small and the duration of HSCT patient follow-up was relatively short. These limitations prevented formal efficacy analyses. Further randomized, prospective, multicenter studies with larger samples are required to verify the efficacy of this combination.

5. Conclusion

We concluded that the VEN + AZA regimen was highly effective and well-tolerated in young patients with R/R AML. This regimen may allow eligible patients to undergo curative allo-HSCT, by virtue of its low toxicity and high response rate. However, the inherent limitations of this retrospective analysis of a small single-institution cohort meant that further studies and well-designed systematic testing of VEN-based regimens are needed to confirm their effectiveness in larger cohorts of patients with R/R AML.

Author contribution

XX and FW designed the study, performed the research and wrote the manuscript; XX, FW and AH collected and analyzed the data; RL edited the paper; AH reviewed and revised the paper.

Ethics approval

The studies involving human participants were reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Xi'an Jiaotong University.

Disclosure statement

No potential conflict of interest was reported by the author(s).