The efficacy of the combination of venetoclax and hypomethylating agents versus HAG agents in patients with acute myeloid leukemia: a retrospective study

ABSTRACT

Objectives:

The purpose of this study was to compare the effectiveness of the combination of venetoclax and hypomethylating agents with the HAG regimen.

Methods:

We studied 52 cases of newly diagnosed AML and 26 cases of relapsed refractory AML, (including AML patients with treatment-related and ELN-adverse risk disease (n = 50)). These patients were treated with venetoclax and hypomethylating agents and HAG regimens, respectively.

Results:

Twenty-nine patients newly diagnosed with acute myeloid leukemia were treated with VEN-HMA (venetoclax-hypomethylating agent), while 23 patients were treated with HAG. The median age of the VEN-HMA group was 70 years, while the HAG group had a median age of 69 years. The VEN-HMA group achieved a significantly higher rate of complete remission (82.7%) compared to the cohort treated with the HAG regimen (21.7%) (P < 0.001). At the same time, the VEN-HMA group exhibited a significant survival advantage compared to the HAG treatment group(HR = 0.328, 95%CI: 0.158-0.683, P = 0.003).

In patients with relapsed and refractory acute myeloid leukaemia, 43.8% of patients in the VEN-HMA treatment group achieved complete remission, which was similar to the 50% in the HAG treatment group (P > 0.99). The median overall survival was similar between the VEN-HMA and HAG groups, with 4 and 3.67 months, respectively (P = 0.290).

Conclusions:

In conclusion, our analyses indicated that VEN-HMA resulted in better therapeutic outcomes compared to HAG for newly diagnosed AML patients, with higher rates of complete remission and overall survival. In relapsed/refractory AML patients, there was no significant difference in the efficacy of the two treatments and further studies with larger sample sizes are warranted.

KEYWORDS:

• Acute myeloid leukemia
• venetoclax
• HAG regimen
• complete remission
• overall survival
• newly diagnosed
• relapsed/refractory

1. Introduction

Acute myeloid leukemia (AML) is a malignant tumour that develops from hematopoietic stem cells. Standard chemotherapy is a significant treatment strategy that can enhance treatment outcomes and prognosis for young adults. However, this may unavoidably cause a high rate of harm and result in genetic mutations that can lead to drug resistance and relapse. Meanwhile, individuals with debilitated conditions, including the elderly and those with relapsed/refractory or secondary AML, often have unsatisfactory outcomes following intensive chemotherapy.

In 1995, Yamada first presented CAG(an unconventional low-dose chemotherapy) as the therapy for AML patients, comprising of low-dose cytarabine, aclarubicin coupled with granulocyte colony-stimulating factor (G-CSF), proving to be an effective treatment for refractory and relapsed AML and high-risk myelodysplastic syndromes (MDS) [1]. However, the use of CAG is limited in elderly patients with concomitant heart disease due to the cardiotoxicity of aclarubicin. Homoharringtonine (HHT) is a plant alkaloid extracted from Cephalotaxus in China. It is a chemotherapeutic agent that is specific to the G1 and G2 phases, and increases both S phase cells. When combined with G-CSF, it can clear leukemia cells more effectively than when used alone. Due to its absence of serious cardiotoxicity, it is commonly used as an alternative to aclarubicin in the CAG regimen, also known as the HAG regimen. It is not significantly different from CAG in terms of response rate and is equally effective in the treatment of acute leukemia and MDS [2]. However, the response rates, which range from 10% to 50% and include hematologic improvement, are still unsatisfactory, with a median overall survival of less than one year. Therefore, it is imperative to discover targeted therapies that can elicit a high response rate quickly, with improved tolerability for elderly and unfit patients with AML.

The BCL-2 (B-cell lymphoma-2) gene family encodes related proteins that regulate the intrinsic apoptotic pathway. These proteins mediate either pro-apoptotic or anti-apoptotic activity, with the balance between them determining whether the cell survives or undergoes apoptosis. BCL-2 is overexpressed in AML cells and plays a significant role in the survival and persistence of AML blasts. Venetoclax (VEN) is an oral inhibitor of B-cell leukemia/lymphoma-2 (BCL-2) that has demonstrated a favourable response rate in the treatment of older, naive, or frail patients. Venetoclax in combination with azacitidine or decitabine has demonstrated an inspiring effect of 67% (CR + CRi)rate and median overall survival of 17.5 months [3]. A phase 3 randomized placebo-controlled trial showed that venetoclax plus low-dose cytarabine (LDAC) improved the response rate of 48% CR compared to 13% in LDAC alone [4]. It was approved by FDA as an inhibitor for newly diagnosed AML patients who are elderly and cannot tolerate intensive chemotherapy in November 2018 [5]. In a retrospective study, VEN-HMA (venetoclax-hypomethylating agent) achieved a superior complete rate (88%) and prolonged overall survival (OS) compared to a group of elderly leukemia patients treated with intensive induction therapy (56% complete rate and 0.9 years OS) [6]. However, there is a lack of studies specifically focused on the response to VEN-HMA in AML patients, comparing HMA (hypomethylating agents) or intensive therapy, taking into account the AML setting (de novo versus r/r), the type of gene mutation, and the responses of venetoclax versus HAG in weak patients with AML.

This retrospective analysis compares the efficacy and survival rates of VEN-HMA treatment with the HAG regimen in both treatment-naive and relapsed/refractory AML cohorts. Additionally, we aim to identify factors that impact responses and survival rates, which may help patients benefit more from these treatments.

2. Methods

Fifty-two patients with newly diagnosed acute myeloid leukemia and twenty-six relapsed refractory acute myeloid leukemia patients were retrospectively enrolled for this study who accepted therapy with VEN-HMA (venetoclax hypomethylating agent) and HAG, respectively, between July 2019 and August 2023 in Heping Hospital affiliated to Changzhi Medical College, excluding acute promyelocytic leukaemia, including post-myelodysplastic syndrome (MDS) patients. PCR sequencing, flow cytometry, chromosomal karyotyping and fluorescence in situ hybridization FISH were used for molecular and cytogenetic data to diagnose and identify leukemia relapse. Both leukemia type and risk level were categorized according to the 2016 WHO classification and the 2017 European Leukaemia Net (ELN) risk stratification [7, 8]. Refractory acute leukemia is defined as failure to achieve complete remission(CR) on response markers after 2 courses of intensive induction therapy [9]. Relapsed disease is defined as bone marrow blasts ≥ 5% or reappearance of blasts in the blood in at least 2 peripheral blood samples at least one week apart or development of extramedullary disease after achieving complete remission. Outcomes were assessed as the rate of objective response CR (complete remission), defined as an absolute neutrophil count greater than 1,000 cells/cubic millimetre, a platelet count greater than 100,000 cells/cubic millimetre, no transfusion therapy within 7 days prior to haematological remission assessment, and less than 5% bone marrow primitive cells, and OS (overall survival), identified as the interval from initiation of treatment to death or censored if survival at follow-up.

We used venetoclax at a daily dose of 100 mg for three days, increasing to 400 mg for 28 days in the first cycle. The dose of venetoclax was adjusted according to drug combinations, especially with azole antifungals for prophylaxis. Azacitidine 75 mg/m² days 1–7 or decitabine 20 mg/m² daily for 5 days was used. In another cohort, HAG consisting of cytarabine (7.5 mg/m²/12 h, subcutaneous injection, on days 1-14), homoharringtonine (1.5 mg/m²/day, intravenous, on days 1-14) and G-CSF administered 1 d prior to chemotherapy (150 ug/m²/day, subcutaneous, on days 0-14) was used as a single regimen or in combination with decitabine. Bone marrow assessments were performed 1–2 cycles after initial treatment and all subjects received tumour lysis syndrome (TLS) prophylaxis. The study was approved by the Ethics Committee of Heping Hospital Affilitated to Changzhi Medical College and was conducted in accordance with the Declaration of Helsinki, and the ethics committee's registration number is (2023)024. The requirement of informed consent was waived by the Ethics Committee.

The clinical characteristics of the patients were described by descriptive statistics, using frequencies (percentages) to describe categorical variables and median values to describe continuous variables. Chi-squared or Fisher's exact test was used to assess treatment response in nominal data, and the log-rank test was used to analyse the correlation between these covariates and the AML setting. Median OS curves were constructed using the Kaplan-Meier method, and differences between groups were compared using the log-rank test. The logistic regression model and the Cox proportional hazards model were used for multivariate analysis between predictors of treatment response and survival, respectively. Data processing and analyses were performed using R version 4.3.0 (2023-04-21), along with Storm Statistical Platform (www.medsta.cn/software). Statistically significance was defined when p-value was less than 0.05.

3. Results

3.1. Newly diagnosed AML

3.1.1. Demographic characteristics

Fifty-two patients with newly diagnosed AML were enrolled. 29 were treated with VEN-HMA, with a median age of 70 years (range: 36-86) and 50% (n = 26) were female. 23 patients with a median age of 69 years (range: 24-87) were treated with HAG. Table 1 shows these clinical characteristics of the study patients with newly diagnosed AML. The clinical and molecular characteristics were balanced between the two groups. There was no significant difference between the two groups.

Table 1. Demographic characteristics of Patients with first-treatment acute leukemia treated with the venetoclax and hypomethylating agent (VEN-HMA ) and the HAG regimen.

Variable	Total (n = 52)	VEN-HMA (n = 29)	HAG(n = 23)	P value
Age, M (Q₁, Q₃)	69.00 (63.00–75.25)	70.00 (63.00–76.00)	69.00 (63.50–73.00)	0.573
Sex, n (%)				0.780
male	26 (50)	14 (48.28)	12 (52.17)
female	26 (50)	15 (51.72)	11 (47.83)
DelevolepfromMDS, n (%)				0.314
NO	37 (71.15)	19 (65.52)	18 (78.26)
YES	15 (28.85)	10 (34.48)	5 (21.74)
ELN cytogenetic molecular risk, n (%)				0.860
Favorable	1 (1.92)	1 (3.45)	0 (0.00)
Intermediate	12 (23.08)	6 (20.69)	6 (26.09)
Adverse	39 (75)	22 (75.86)	17 (73.91)
Monomsomal karyotype, n (%)	2 (3.85)	1 (3.45)	1 (4.35)	>0.999
Complecated karyotype, n (%)	8 (15.38)	2 (6.90)	6 (26.09)	0.129
NPM1, n (%)	7 (13.46)	5 (17.24)	2 (8.70)	0.626
FLT3, n (%)	8 (15.38)	7 (24.14)	1 (4.35)	0.115
EVI1, n (%)	3 (5.77)	0 (0.00)	3 (13.04)	0.160
IDH1, n (%)	5 (9.62)	4 (13.79)	1 (4.35)	0.500
DNMT3A, n (%)	9 (17.31)	5 (17.24)	4 (17.39)	>0.999
TP53, n (%)	4 (7.69)	3 (10.34)	1 (4.35)	0.778
ASXL1, n (%)	4 (7.69)	2 (6.90)	2 (8.70)	>0.999
Complete Responses, n (%)	23 (44.23)	24 (82.76)	5 (21.74)	<.001

Abbreviations: CR,complete response;

In the VEN-HMA treatment group, 19 patients younger than 60 years of age were unable to receive intensive chemotherapy due to frailty resulting from invasive fungal infection, secondary AML, or high probability of treatment-related mortality.15 patients had transformed from high-grade myelodysplastic syndrome, and one patient had a secondary tumour. It is worth noting that 82.7% of patients accepted azole antifungal prophylaxis [10]. The dose of venetoclax was adjusted to 100 mg accordingly. In the cohorts treated with ventoclax along with decitabine, the majority of cases (93.1%) received azacitidine as HMA. While in the HAG treatment group, 11 out of 23 patients were female, and five patients had transformed from high-grade myelodysplastic syndrome. Regarding the VEN-HMA treatment group, it was found that 75.9% (n = 22) were at adverse risk according to ELN stratification. Out of these, 24.1% (n = 7) had FLT3 mutation, while 17.2% (n = 5) had NPM1 and DNMT3A mutations, respectively. Only 2 (6.9%) had ASXL1 mutations. In the cytogenetics analysis, two patients had complex karyotypes, and two had monosomy karyotypes. On the other hand, in the HAG treatment group, 17 out of 23 patients had adverse cytogenetics, and 3.57% had secondary AML. The cohort consisted of patients with various mutations, such as FLT3 (n = 1), DNMT3A (n = 4), EVI1 (n = 3), and NPM1 (n = 2).

3.1.2. Response evaluation

In treatment-naive AML, complete remission (CR) was achieved in twenty-four patients (82.7%) who accepted VEN-HMA treatment, while the CR rate within the HAG treatment cohort was 21.7% (n = 5), a statistically significant difference between the two groups (χ² = 19.362, P < 0.001). An encouraging CR rate of 81.8% in the ELN adverse risk group (18 of 22 patients treated with VEN-HMA) was demonstrated, compared to a CR rate of 23.5% in the HAG group (P < 0.001). In the intermediate-risk population, the CR rate tended to be significant in the VEN-treated group versus the HAG-treated group (83.3% vs 16.6%, P = 0.08). Stratified analysis by age showed a statistically significant difference in remission rates between the VEN-treated group (n = 23) and the HAG-treated group (n = 19) in patients older than 60 years (82.6% vs. 15.8%, P < 0.001). However, it is worth noting that in patients under 60 years of age, there was no significant difference in efficacy between the VEN-treated group and the HAG-treated group (83.3% in the VEN-treated group and 50% in the HAG group, P = 0.50), as shown in Table 2.

Table 2. Treatment outcomes in Patients with newly diagnosed acute leukemia.

Treatment group	HMA + VEN, n (%) (n = 29)	HAG, n (%) (n = 23)	P value
Response
CR	24 (82.8)	5 (21.7)	<0.001
Treatment outcomes by age, y
<60	5 (83.3)	2 (50)	0.50
> = 60	19 (82.6)	3 (15.8)	<0.001
Total	24 (82.8)	5 (21.7)	<0.001
Treatment outcomes by ELN cytogenetic-molecular risk
Intermediate	5 (83.3)	1 (16.7)	0.08
Adverse	18 (81.8)	4 (23.5)	<0.001
Favorable	1	-	-
Total	23 (82.8)	5 (21.7)

No differences were found in the genetic alteration subgroups FLT3-ITD (P = 0.247), DNMT3A (P = 0.160), NPM1 (P = 0.378), TP53 (P = 0.43), female (OR = 1.17, 95% CI: 0.39-3.50, P = 0.780), and AML with myelodysplasia-related changes (OR = 1.28, 95% CI: 0.38-4.31, P = 0.696) among the features examined in univariate logistic regression analysis, as shown in Table 3. In the unadjusted model, the VEN-HMA treated group had a higher remission rate (OR = 17.28, 95% CI: 4.34-68.83, P < 0.001) compared to the HAG treated group. This result remained stable after adjusting for age, gender, MDS transformation, and ELN molecular cytogenetic risk, as shown in Table 4.

Table 3. Univariate logistic analysis of response for newly diagnosed AML.

Variable		OR(95%CI)	P_value
group	VEN-HMA	1.00 (Reference)
	HAG	0.06 (0.01∼0.23)	<0.001
sex	male	1.00 (Reference)
	female	1.17 (0.39∼3.5)	0.78
age		1 (0.96∼1.04)	0.991
Delevolep from MDS		1.28 (0.38∼4.31)	0.696
ELN cytogenetic molecular risk	Favorable	1.00 (Reference)
	Intermediate	–	0.991
	Adverse	–	0.992
Monomsomal.karyotype		–	0.992
Complecated.karyotype		0.76 (0.17∼3.44)	0.721
NPM1		2.19 (0.38∼12.48)	0.378
FLT3		2.74 (0.5∼15.09)	0.247
EVI1		–	0.99
IDH1		–	0.992
DNMT3A		3.34 (0.62∼17.95)	0.16
TP53		2.54 (0.25∼26.18)	0.434
ASXL1		0.78 (0.1∼5.99)	0.809

Abbreviations: CR,complete response;OR,odds ratio;CI,confidence interval.

Table 4. Multivariate logistic regression modelling of the complete remission rate of newly diagnosed acute myeloid leukemia treated with venetoclax and hypomethylating agents (VEN-HMA) versus HAG.

Group	Total(n)	Event(n%)	Model I		Model II		ModeIII
			OR(95%CI)	P value	OR(95%CI)	P value	OR(95%CI)	P value
HAG-treatment	23	5 (21.7)	1(Ref)		1(Ref)		1(Ref)
VEN-HMAtreatment	29	24 (82.8)	17.28 (4.34∼68.83)	<0.001	18.05 (4.42∼73.73)	<0.001	17.66 (4.21∼74.11)	<0.001

Abbreviations:OR,odds ratio;CI,confidence interval.

Model I: adjust for none;Model II:adjust for age and sex;ModeIII:adjust for age, sex,Delevolep from MDS and ELN cytogenetic molecular risk.

3.1.3. Survival

The median follow-up for the entire cohort was 6.9 months (range, 0.5 −31.8). In patients with newly diagnosed AML, the VEN-HMA treatment group did not reach median overall survival (OS), while the HAG treatment group had a median overall survival of 3.43 months (95% CI: 1.27, 5.59), as illustrated in Figure 1. The response rate in the HAG cohort was lower compared to that in VEN-HMA patients (HR = 0.328, P = 0.003). Patients who achieved complete remission had a significantly different overall survival compared to those who did not (HR = 4.732, P < 0.001). Please refer to Figure 2. In newly diagnosed patients with acute myeloid leukemia (AML), there was a tendency for a significant difference in overall survival rates between different cytogenetic risk classifications (P = 0.02) . For patients with adverse cytogenetic risk, the overall survival of the VEN treatment group was significantly different from that of the HAG treatment group (HR = 0.239, P = 0.008). However, for patients with intermediate cytogenetic risk, the median overall survival (OS) was 8.1 months in the VEN group and 2.7 months in the HAG group. There was no statistically significant difference between the two groups (HR = 0.912, P = 0.879). In the subgroup of patients aged over 65 years, the median overall survival (OS) of patients treated with VEN-HMA was significantly improved compared to those treated with HAG (HR = 0.286, P = 0.002). However, the difference in overall survival between the VEN-HMA and HAG groups lost significance in patients younger than 60 years of age (HR = 0.651, 95%CI: 0.058-0.633, P = 0.725). Figure 3 displays the survival curves for both treatments among the different subgroups.

Figure 1. Kaplan-Meier estimates of OS by treatment group in treatment-naive patients; OS,overall survival; VEN,venetoclax-hypomethylating agent combination theraby. The dashed line indicates 50% overall survival probability.

Figure 2. Kaplan-Meier Estimates of OS in Complete Remission vs. Not in complete remission in Treatment Groups of treatment-naive acute myelocytic leukemia patients; CR,Complete Remission;NR,Not in complete remission. The dashed line indicates 50% overall survival probability.

Figure 3. Kaplan-Meier estimated the overall survival of diffferent cytogenetic risk classification in newly diagnosed acute myelocytic leukemia patients(A). Kaplan-Meier assessment of VEN-HMA versus HAG in the adverse cytogenetic risk of patients with newly diagnosed acute myeloid leukaemia(B). Kaplan-Meier assessment of VEN-HMA versus HAG in the intermediate cytogenetic risk of patients with newly diagnosed acute myeloid leukaemia(C). Kaplan-Meier estimated the overall survival of the VEN treatment group and the HAG treatment group in newly diagnosed acute myelocytic leukemia patients older than 60 years old(D). Kaplan-Meier estimated the overall survival of the VEN treatment group and the HAG treatment group in newly diagnosed acute myelocytic leukemia patients less than 60 years old(E). The dashed line indicates 50% overall survival probability.

Figure 4 shows a significant difference between the two treatment regimens in terms of overall survival in the age group >60 years(P = 0.002). After adjusting for covariates, the difference in overall survival between the VEN-HMA-treated group and the HAG-treated group remained significant(P = 0.004). Subgroup analyses did not reveal any interaction between the effects of the various subgroups on outcomes.

Figure 4. Subgroup analysis of overall survival in patients with newly diagnosed acute myeloid leukaemia treated with VEN-HMA vs HAG. The hazard ratio for death was estimated with the stratified Cox proportional-hazards model. Adjust for age, sex,Delevolep from MDS and ELN cytogenetic molecular risk.

3.2. Relapsed/refractory AML

3.2.1. Demographic characteristics

A retrospective evaluation was conducted on 26 patients diagnosed with relapsed or refractory acute myeloid leukemia. Of these, 16 patients received venetoclax treatment while the remaining 10 received HAG treatment. The VEN-HMA arm had a median patient age of 58 years (range: 33-66), with 50% being female. Additionally, 25% of patients were converted from MDS. Two patients relapsed after autologous transplantation and one after microtransplantation. Thirty-seven percent of the sample had intermediate-risk cytogenetics, while 50% had poor-risk cytogenetics. Compared to the VEN-HMA group, the HAG group had a median age of 60 years (range: 33-66), with 70% of patients being female. Table 5 displays the demographic and clinical characteristics of patients with relapsed refractory at baseline. The groups had a balanced proportion of clinical features, and the difference was not statistically significant.

Table 5. Demographic characteristics of Patients with relapsed/refractory acute leukemia treated with the venetoclax and hypomethylating agent (VEN-HMA) and the HAG regimen.

Variable	Total (n = 26)	VEN-HMA(n = 16)	HAG(n = 10)	P_value
Age, M (Q₁, Q₃)	60.00 (47.00–64.75)	58.00 (33.75–66.25)	60.00 (55.00–63.00)	>0.99
Sex, n (%)				0.428
male	11 (42.31)	8 (50.00)	3 (30.00)
female	15 (57.69)	8 (50.00)	7 (70.00)
DelevolepfromMDS, n (%)				0.617
NO	21 (80.77)	12 (75.00)	9 (90.00)
YES	5 (19.23)	4 (25.00)	1 (10.00)
ELNcytogeneticmolecularrisk, n (%)				0.443
Favorable	5 (19.23)	2 (12.50)	3 (30.00)
Intermediate	10 (38.46)	6 (37.50)	4 (40.00)
Adverse	11 (42.31)	8 (50.00)	3 (30.00)
Monomsomal karyotype, n (%)	1 (3.85)	1 (6.25)	0 (0.00)	>0.99
Complecated karyotype, n (%)	2 (7.69)	2 (12.50)	0 (0.00)	0.508
NPM1, n (%)	3 (11.54)	2 (12.50)	1 (10.00)	>0.99
FLT3, n (%)	2 (7.69)	0 (0.00)	2 (20.00)	0.138
EVI1, n (%)	2 (7.69)	1 (6.25)	1 (10.00)	>0.99
DNMT3A, n (%)	2 (7.69)	1 (6.25)	1 (10.00)	>0.99
TP53, n (%)	1 (3.85)	1 (6.25)	0 (0.00)	>0.99
Complete Responses, n (%)	12 (46.15)	7 (43.75)	5 (50.00)	>0.99

3.2.2. Response evaluation

There was no significant difference in the complete response (CR) rate between the VEN-HMA treatment group (43.8%) and the HAG treatment group (50%) (RR = 1.143, 95%CI:0.497-2.627, P > 0.99). After stratifying by age, there was no statistically significant difference in remission rates between the VEN-treated group and the HAG-treated group in patients under 60 years old (62.5% vs 60%, respectively, P > 0.99). Similarly, there was no significant difference in complete response (CR) rates between the two groups for patients aged over 60 years (40% vs 25%, respectively, P > 0.99).

3.2.3. Survival

The median follow-up time for patients with relapsed refractory AML was 4 months (range:0.1-19.56). Patients treated with VEN-HMA had a median overall survival of 4.5 months (95% CI: 0-9.36), compared to 3.67 months (95% CI: 0-12.34) for the HAG cohort. There was no statistically significant difference found between the two groups (HR = 1.631, P = 0.290). The 12-month overall survival (OS) was 33% for the VEN-HMA cohort and 37.5% for the HAG group, as shown in Figure 5.

Figure 5. Kaplan-Meier estimates of OS by treatment group in patients patients with relapsed refractory acute myeloid leukemia; OS,overall survival; VEN-HMA,venetoclax-hypomethylating agent combination theraby. The dashed line indicates 50% overall survival probability.

4. Discussion

The combination of venetoclax as a new targeted therapy has led to widespread use in elderly patients who are ineligible for intensive chemotherapy. This report focuses on AML treated with VEN-HMA and presents encouraging results of a complete response rate as high as 82.7% for older treatment-naïve patients (median age 70 years), which is consistent with the report. [11]. The response rate for the HAG regimen in the counterparts is 21.7%, which is consistent with the response rates of low-intensity therapies like decitabine or azacitidine in AML patients, which typically range from 10% to 50% [12], corresponding to a median OS of 6 to 12 months. Venetoclax combinations are more advantageous than the HAG regimen in ND AML, particularly among patients over 60 years old (P < 0.001). The results of a multicenter phase I/II clinical trial of venetoclax in combination with LDAC or HMA for the treatment of newly diagnosed untreated AML patients ineligible for intensive chemotherapy showed that the incidence of CR + CR with incomplete hematologic recovery (CRi) was 54% and 67% in patients treated with venetoclax plus LDAC or HMA, respectively. The median OS was 10.4 and 17.5 months, respectively, which represents a significant improvement over the historical cohort treated with LDAC or HMA monotherapy. [3, 13]. The study confirmed that venetoclax combination therapy is more effective in patients over 75 years old. However, there is no evidence of its effectiveness in patients under 60 years old. The remission rates for patients under 60 years of age in the VEN treatment group did not show a significant difference from those in the HAG treatment group in terms of complete remission rates (P = 0.50). In a randomized controlled trial, 433 newly diagnosed patients with acute myeloid leukemia (AML) were randomly assigned to receive either azacitidine plus venetoclax or a placebo [14]. A subgroup analysis was conducted to evaluate overall survival, which revealed a significant difference in patients over the age of 75, but not in those under 75. These are consistent with our conclusions, but further validation of the therapeutic efficacy of azacitidine-venetoclax versus HAG regimens in patients younger than 60 years of age is needed in studies with larger sample sizes.

The logistic regression analysis of the complete remission rate in newly diagnosed AML patients revealed that FLT3-ITD, DNMT3A, NPM1, monomer karyotype, and complex karyotype did not act as confounding factors in the results. The overall incidence of complete remission significantly improved in AML genetic risk groups treated with VEN-HMA, including patients with adverse cytogenetic risk, secondary AML, and high-risk somatic mutations [6, 15, 16]. It has been confirmed that VEN-HMA provides a significant advantage over HAG in de novo AML patients who are at risk of poor cytogenetics(P < 0.001).

It is not surprising that there was a lower response to VEN-HMA in the relapsed or refractory (r/r) setting compared to newly diagnosed patients. In Ibrahim Aldoss's studies, it was found that the r/r AML setting was an independent predictor of lower complete response in univariate analyses (OR: 0.162; 95% CI: 0.041-0.644, P = 0.010) [11]. Furthermore, there was no superior response rate compared to the HAG group in patients with r/r. A current meta-analysis (n = 224) demonstrated a 34.7% response rate in the r/r AML patients dealed with VEN-HMA [17]. In a retrospective analysis, Dinardo reported that the combination of venetoclax and AZA had limited efficacy in treating r/r AML, with a response rate of only 21% [18]. Response rates were found in other reports, which include post-transplant relapses, to be volatile ranging from 21% to 64% [19, 20]. Considerable inconsistency exists regarding mutative predictors for response and survival, which is likely due to the biological heterogeneity of diseases and previous therapies accepted by relapsed or refractory acute myeloid leukemia (AML) patients. However, the response to VEN-HMA was still significant in the r/r AML setting, even in patients carrying FLT3 mutations. Some of these patients were able to undergo potentially curative allogeneic hematopoietic cell transplantation (HCT) after achieving remission [11].

We enrolled AML patients who had not previously accepted treatment and who were ineligible for intensive chemotherapy due to prior age-related comorbidities, and the combination of venetoclax plus azacitidine showed superior survival compared to the HAG cohort (median overall survival: not reached vs. 3.43 months, P = 0.003). In the VEN-HMA study, the median OS for treatment-naive patients was reported to be 17.5 months. [3]. A randomized phase III study (VIALE-A) showed that the median overall survival of the azacitidine plus venetoclax cohort was 14.7 months compared to 9.6 months with azacitidine alone in upfront AML patients older than 75 years or with comorbidities (hazard ratio for death, 0.66; P < 0.001), favouring the VEN-HMA regimen. [14]. These reports were consistent with our findings. As expected, the achievement of complete remission was the main determinant of survival in our cohort (HR = 4.732, 95%CI: 2.275-9.842, P < 0.001). In the retrospective study by Lachowiez, the VEN-HMA cohort had a superior CR rate (88% vs. 56%) and improved OS (not reached vs. 0.9 years) compared to elderly patients with NPM1 m who were treated with intensive chemotherapy [6]. A functional study showed that mutant NPM1 was associated with prolonged OS and a high response rate [21]. However, we acknowledged the limited sample size of only seven patients carrying NPM1, which is not consistent with the literature. We also found that the use of VEN-HMA in patients with adverse cytogenetic risk or adverse prognostic effects at age >60 years has a significant overall survival benefit compared to HAG, as reported in previous studies. However, the restricted sample size prevented us from determining any difference between the two treatments in patients under 60 years of age. Nevertheless, this study did not find any significant differences. A subgroup analysis of overall survival in newly diagnosed AML patients showed that there was a statistically significant sex difference between the venetoclax and HAG treatment groups. These suggest that we should differentiate the choice of therapeutic drugs according to different conditions, such as sex, age and genetic prognostic stratification. Due to the limited number of cases, we could not determine the effect of gene mutation and chromosome karyotype on survival.

In contrast, the VEN-HMA combination improved outcomes in the ND setting, leading to its prolonged use in r/r AML patients. The report shows that there was no significant difference in overall survival between the VEN-HMA treatment arm and the HAG group (4.5 months vs 3.67 months, P = 0.290). A prospective study enrolled 83 patients with relapsed or refractory acute myeloid leukemia who received venetoclax in combination with decitabine for 10 days. The study showed a median overall survival of 7.8 months (5.4-13.3) [22]. In a study conducted by the Mayo Clinic on 42 patients with relapsed or refractory acute myeloid leukemia, the cohort that received VEN-HMA had a median overall survival of 5 months (95% CI, 3–9 months) [16]. A meta-analysis of venetoclax treatment in the r/r AML setting, based on seven studies with 224 patients, showed that the median OS for patients treated with venetoclax monotherapy ranged from 1.8 to 7.8 months, while for those treated with venetoclax + HMA/LDAC, it ranged from 3.0–6.6 months. Additionally, a literature study indicated that previous exposure to HMA may weaken the response to subsequent VEN treatment [17]. The remission rate and overall survival (OS) of relapsed refractory acute myeloid leukemia (AML) patients treated with venetoclax (VEN) and hypomethylating agents (HAG) in this study were consistent with previous literature reports. However, larger studies are needed to confirm the difference in therapeutic efficacy between the two regimens in relapsed refractory patients. Data reported that the presence of IDH1/2, TET2, and ASXL1 mutations was associated with higher response rates to venetoclax combination treatment [23–26]. The study found that TP53 mutation is an independent predictor of inferior survival in the r/r cohort treated with VEN-HMA therapy [27]. Due to the limited sample size, our report found that these findings were not applicable, which makes the comparison less valid.

Due to the retrospective nature of the study and potential differences in patient subgroups, we cannot definitively conclude whether cytogenetic risk has a causal effect on the prognosis of the cohort treated with venetoclax combination. However, the treatment-naïve cohort demonstrated an association between complete remission and improved survival. Due to the small sample size, we could not determine if there was a difference in treatment efficacy between patients under 60 years old and those with relapsed refractory disease. However, it is probable that with a larger sample size, there will be a significant difference in the results, which were initially insignificant.

5. Conclusion

In conclusion, our analyses indicate that VEN-HMA resulted in better therapeutic outcomes compared to HAG for newly diagnosed AML patients, with higher rates of complete remission and overall survival. However, there was no significant difference in efficacy between the two treatments for relapsed refractory patients. To assess the comparative efficacy of these two treatment regimens in different populations, larger randomized controlled trials are necessary. This will provide a therapeutic basis for future clinical work.

Ethical approval

The study was approved by the Ethics Committee of Heping Hospital Affilitated to Changzhi Medical College and was conducted in accordance with the Declaration of Helsinki, and the ethics committee's registration number is (2023)024.

Disclosure statement

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

Additional information

Funding

This work was supported by the efforts of all members of the Hematology Department in Heping Hospital Affiliated to Changzhi Medical College.