Abstract
Background
Venetoclax (VEN) and azacitidine (AZA) are used to treat patients with newly diagnosed acute myeloid leukaemia (AML) who are unfit for intensive chemotherapy and those with relapsed or refractory AML. Understanding the real-world usage patterns and outcomes after VEN-AZA therapy failure is crucial, yet poorly studied.
Methods
This single-centre retrospective cohort study included 50 patients with AML (29 newly diagnosed and 21 relapsed or refractory cases) who were treated between January 2020 and November 2023. The primary endpoint was overall survival (OS), and secondary endpoints included composite complete remission (CR), partial remission (PR), overall response rate (ORR), event-free survival (EFS), minimal residual disease (MRD), adverse events (AEs), and post-VEN-AZA failure.
Results
Among the newly diagnosed patients (median age, 74 years; follow-up 10.1 months), the median EFS was 9.87 months (95% CI, 6.54–13.2 months) and OS was 11.93 months (95% CI, 7.6–16.29 months). The ORR was 85.7%, CR/CR with incomplete haematologic recovery (CRi) was achieved in 67.9% of patients, and MRD negativity was observed in 26.3% of the cohort. Post-treatment failure included VEN-AZA combined with gilteritinib, chidamide, or selinexor, which resulted in PR or CRi. The median OS after post-failure was 1.6 months. Among relapsed or refractory cases (median age 65 years; follow-up 8.53 months), median EFS was 5.2 months (95% CI, 1.8–8.6 months), and OS was 9.1 months (95% CI, 3.01–15.19 months). The ORR was 52.4%, CR/CRi was achieved in 42.9% of patients, and MRD negativity was observed in 11.11% of the cohort. Post-failure treatments include induction chemotherapy, VEN-AZA combined with enasidenib or gilteritinib, and participation in clinical trials, which yielded varying responses. The median OS after failure was 0.67 months, and the most common AEs were haematological and infectious complications.
Conclusions
VEN-AZA demonstrated high efficacy and manageable toxicity in patients with AML. Following VEN-AZA failure, the combination of VEN-AZA with targeted therapies has shown better efficacy than other VEN-AZA alone, whereas induction chemotherapy or clinical trials were preferred after second-line failure. Larger multicentre studies are warranted to validate these findings.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12885-025-14167-z.
Keywords: Acute myeloid leukemia, Hypomethylating agents, Venetoclax, Relapse, Refractory
Background
Acute myeloid leukaemia (AML) is the most common type of leukaemia in adults, with a median age at diagnosis of 68 years [1]. Although young patients with newly diagnosed (ND) AML can achieve complete remission (CR) rates of 49–86% with intensive therapy [2], approximately half of those who achieve remission are at risk of relapse [3], and the 5-year survival rate is only 10% [4, 5]. There is an urgent need for effective treatment options for patients with relapsed or refractory (R/R) AML following standard induction chemotherapy, and for those with ND AML who are unfit for intensive chemotherapy due to age or comorbidities. The complex interplay of genetic and environmental factors in leukemogenesis highlights the importance of understanding cancer initiation and progression pathways to better inform treatment strategies [6]. Venetoclax (VEN) is a BCL-2 protein inhibitor that induces apoptosis in AML cells [7]. Both the Chinese Society of Hematology and the National Comprehensive Cancer Network (NCCN) guidelines recommend VEN combined with azacitidine (AZA) as the preferred approved treatment option for adult patients with AML who are unfit for intensive chemotherapy due to comorbidities or who are ≥ 75 years of age [8, 9]. Additionally, VEN combined with AZA is administered “off-label” to patients with R/R AML and has demonstrated favourable efficacy and improved survival in clinical practice [10–13], which requires further investigation to establish its full clinical benefit. However, the real-world usage patterns of VEN-AZA in adult patients with AML, particularly the outcomes following VEN-AZA therapy, remain poorly understood.
This study retrospectively analysed the efficacy and safety of the VEN-AZA regimen in patients with ND AML who were unfit for standard induction chemotherapy and in those with R/R AML. The outcomes of patients following VEN-AZA therapy failure were also evaluated to provide real-world evidence for clinical practice, addressing specific gaps left by previous studies [14–16].
Methods
Study design and patients
This single-centre, retrospective, cohort study included patients with AML who received VEN-AZA therapy at the Department of Hematology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, between 3 January 2020 and 14 November 2023. This study was approved by the Ethics Committee of Beijing Hospital and conducted in accordance with the Declaration of Helsinki. The clinical trial was registered under number ChiCTR2400084836.
Fifty patients with AML were enrolled: 29 with ND AML and 21 with R/R AML. Key eligibility criteria were age ≥ 18 years, confirmed diagnosis of AML according to the World Health Organization criteria [17], and receipt of at least one course of VEN-AZA as first-line treatment. Patients with acute promyelocytic leukaemia or uncontrolled infections were excluded from the study. Disease assessments and adverse events (AEs) were evaluated at the end of every therapy cycle and every three cycles thereafter until two consecutive samples confirmed complete composite remission (CRc). Molecular mutations in the bone marrow were assessed at a central laboratory.
Treatment regimens
Patients received a VEN-AZA regimen with VEN dose escalation in cycle 1 as follows: 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3–28. AZA was administered at 75 mg/m2 via subcutaneous injection on days 1–7 of the 28-day cycle. In subsequent treatment courses, the VEN dose was 400 mg daily. Treatment was discontinued or the VEN dose was reduced to 100–200 mg/day in patients with clinically significant uncontrolled systemic infection, severe organ dysfunction, or persistent granulocyte deficiency. Red blood cell transfusion was administered when the haemoglobin level was < 60 g/L or when significant anaemia symptoms were present. Platelet transfusions were administered when the platelet count (PLT) was < 20 × 109/L or when a significant bleeding tendency was observed. When combined with a CYP3A inhibitor, VEN dose were reduced by 50% and 75% for moderate and strong inhibitors, respectively. For patients receiving voriconazole or posaconazole, the VEN dose was adjusted to 100 mg daily, whereas for those receiving fluconazole, the dose was adjusted to 200 mg orally daily [18]. The treatment was continued until disease progression or unacceptable toxicity was observed. Targeted therapies (e.g. chidamide, enasidenib, and gilteritinib) used after VEN-AZA were administered based on clinical factors and, in some cases, molecular profiles (IDH mutations for enasidenib and FLT3 mutations for gilteritinib).
Endpoints and assessments
The primary endpoint was overall survival (OS). The secondary endpoints included CRc, partial remission (PR), overall response rate (ORR), event-free survival (EFS), duration of response (DOR), minimal residual disease (MRD) rate, and AE rate.
Response definitions
CR: Bone marrow blasts < 5%; absence of circulating blasts and extramedullary disease; ANC ≥ 1.0 × 109/L; PLT ≥ 100 × 109/L.
CR with incomplete haematologic recovery (CRi): All CR criteria except for residual neutropenia < 1.0 × 109/L or thrombocytopenia < 100 × 109/L.
CRc: CR with incomplete haematological recovery.
PR: All haematologic criteria of CR, with bone marrow blast percentage reduced to 5–25% and decrease in pretreatment bone marrow blast percentage by at least 50%.
Measurable residual disease (MRD): MRD was assessed by flow cytometry, with MRD positive defined as ≥ 0.1% of bone marrow blast.
OS: the time from the date of diagnosis in patients with ND AML or from the date of receiving VEN-AZA in patients with R/R AML to the date of death from any cause or last follow-up.
EFS: time from the date of receiving VEN-AZA to the date of treatment failure, haematologic relapse from CRc, death from any cause, or the last follow-up.
DOR: Time from achieving CR, CRi, or PR to the date of disease progression, death, or last follow-up [19].
The severity of AEs was graded based on the National Cancer Institute Common Terminology Criteria for AEs, version 5.0 [20]. Follow-ups were performed via telephone or electronic medical records, with a follow-up deadline of 2 March 2024.
Statistical analysis
Statistical analyses were conducted using SPSS version 27.0 and R environment version 4.3.0. Categorical data are presented as numbers (percentages), and continuous data are expressed as medians with interquartile ranges (IQR) or minimum and maximum values. OS and EFS were analysed using the Kaplan–Meier method, and intergroup comparisons were conducted using the log-rank test. Univariate and multivariate Cox regression analyses were used to evaluate hazard ratios (HR) and 95% confidence intervals (CI) for factors influencing OS and EFS. Statistical significance was set at P < 0.05.
Results
Clinical characteristics
This study included 50 patients with AML who completed at least one cycle of VEN-AZA therapy. Among these, 29 (58%) had ND AML and deemed unfit for standard induction chemotherapy, whereas 21 (42%) had R/R AML. The median patient age was 69.5 years (range, 31–89 years), with patients with R/R AML being younger than patients with ND AML (median age, 65 vs. 74 years). The cohort was predominantly men (62%), and the most common subtype was FAB-M2, observed in 62% of patient. Among patients with ND AML, the reasons for being unfit for intensive therapy included age ≥ 75 years (41.38%), an Eastern Cooperative Oncology Group (ECOG) score of 3 (34.5%) or 4 (13.8%), and organ dysfunction, such as renal and hepatic insufficiency and heart failure (37.9%). Additionally, 24.1% of patients with ND AML had prior myelodysplastic syndrome (MDS), and 13.79% had prior exposure to hypomethylating agent (HMA). At disease onset, 48.3% (14/29) had agranulocytosis, and 10.3% (3/29) had granulocyte counts of 0.5–1 × 109/L. According to the 2022 European Leukemia Network (ELN) risk stratification system, patients were categorised as favourable (2 patients, double CEBPA mutations), intermediate (14 patients), or adverse (13 patients) (Table 1). 26 new diagnosed AML patients were sequenced and WT1, IDH1/IDH2, and MLL were the most frequently mutated genes (Fig. 1). In the R/R group, 14 (66.7%) patients were primarily refractory, six (28.5%) had early relapse (relapse within 12 months after remission), and one (4.8%) had late relapse (relapse more than 12 months after remission). An ECOG performance status of 3–4 was observed in 42.9% of patients at the time of R/R, and four (19%) patients had a prior history of MDS. Approximately 17 (81%) patients received first-line intensive chemotherapy, whereas four (19%) received HMA (Table 1). At the time of R/R, 23.8% (5/21) had agranulocytosis, and 38.1% (8/21) had a granulocyte count of 0.5–1 × 109/L. 19 relapse/refractory AML patients were sequenced, genetic mutations in DNMT3A, FLT3-ITD, and RUNX1 were detected in 32%, 26%, and 26% of the patients, respectively (Fig. 1).
Table 1.
Baseline demographic and clinical characteristics of newly diagnosed or refractory/relapse AML patients treated with VEN-AZA
| Clinical characteristics | Total N = 50 |
Newly diagnosed N = 29 |
Relapse/Refractory N = 21 |
|---|---|---|---|
| age, median (min, max) | 69.5(31–89) | 74(46–89) | 65(31–73) |
| <65y, no. (%) | 9(18.00%) | 4(13.79%) | 10(47.62%) |
| ≥65y, no. (%) | 41(82.00%) | 25(86.21%) | 11(52.38%) |
| ≥75y, no. (%) | 12(24.00%) | 12(41.38%) | 0 |
| Sex, no. (%) | |||
| Male | 31(62.00%) | 22(75.90%) | 9(42.90%) |
| Female | 19(38.00%) | 7(24.10%) | 12(57.10%) |
| FAB subtype, no. (%) | |||
| M1 | 8(16.00%) | 4(13.80%) | 4(19.00%) |
| M2 | 31(62.00%) | 20(69.00%) | 11(52.40%) |
| M4 | 6(12.00%) | 2(6.90%) | 4(19.00%) |
| M5 | 4(8.00%) | 2(6.90%) | 2(9.50%) |
| M6 | 1(2.00%) | 1(3.40%) | 0 |
| WBC, median (IQR) | 3.37(1.33–7.02) | 2.00(1.17–6.95) | 4.17(1.59–9.72) |
| Hb, median (IQR) | 70.50(64.00-77.25) | 70.00(63.00–77.00) | 71.00(66.50–80.00) |
| PLT, median (IQR) | 45.50(26.00-90.25) | 61.00(33.00-101.00) | 39.00(24.50–62.00) |
| NEUT, median (IQR) | 0.72(0.28–2.77) | 0.49(0.13–1.98) | 0.92(0.45–3.34) |
| LDH, median (IQR) | 199.0(159.5-302.8) | 213.0(148.0-308.5) | 199.0(163.0-296.0) |
| Bone marrow blast count (%), median (IQR) | 37.3(30.5–69.4) | 44.5(31.0–66.0) | 33.0(18.0–71.0) |
| peripheral blood blast count (%), median (IQR) | 10.50(2.75–51.75) | 10.00(3.00-66.80) | 13.00(1.25–50.50) |
| ELN risk group, no. (%) | |||
| Favorable | 2 (4.00%) | 2 (6.90%) | 0 |
| Intermediate | 18 (36.00%) | 14 (48.30%) | 4 (19.00%) |
| Adverse | 30 (60.00%) | 13 (44.80%) | 17 (81.00%) |
| Cytogenetic risk category, no. (%) | |||
| Normal | 23/45(51.10%) | 15/27(55.60%) | 8/18(44.40%) |
| Trisomy 8 | 4/45(8.90%) | 3/27(11.10%) | 1/18(5.60%) |
| 7 or 7q deletion | 2/45(4.40%) | 1/27(3.70%) | 1/18(5.60%) |
| 5 or 5q deletion | 1/45(2.20%) | 1/27(3.70%) | 0 |
| Complex,≥3 clonal abnormalities | 5/45(11.10%) | 4/27(14.80%) | 1/18(5.60%) |
| Monosomal karyotype | 4/45(8.90%) | 1/27(3.70%) | 3/18(16.70%) |
| HMA history, no. (%) | |||
| Yes | 8(16.00%) | 4(13.80%) | 4(19.00%) |
| No | 42(84.00%) | 25(86.20%) | 17(81.00%) |
| MDS history, no. (%) | |||
| Yes | 11(22.00%) | 7(24.10%) | 4(19.00%) |
| No | 39(78.00%) | 22(75.90%) | 17(81.00%) |
| ECOG, no. (%) | |||
| 0–2 | 27(54.00%) | 15(51.70%) | 12(57.10%) |
| 3 | 19(38.00%) | 10(34.50%) | 9(42.90%) |
| 4 | 4(8.00%) | 4(13.80%) | 0 |
| Dose of therapy, no. (%) | |||
| Full-dose | 16(32.00%) | 12(41.40%) | 4(19.00%) |
| attenuated-dose | 34(68.00%) | 17(58.60%) | 17(81.00%) |
| Cycle of therapy, median (min, max) | 3(1–17) | 6(1–17) | 2(1–10) |
| Reason of unfit full-dose therapy, no. (%) | |||
| age ≥ 75y | NA | 12(41.40%) | NA |
| ECOG > 2分 | NA | 14(48.30%) | NA |
| Organ dysfunction | NA | 11(37.93%) | NA |
Abbreviations: FAB, The French-American-British; WBC, white blood cell; Hb, hemoglobin; PLT, platelet; LDH, lactate dehydrogenase; IQR, interquartile range; ELN, European Leukemia Net; HMA, hypomethylating agent; MDS, myelodysplastic syndromes; ECOG, Eastern Cooperative Oncology Group performance-status scores
Fig. 1.
Waterfall plot of gene mutation or indel in AML patients. The waterfall plot illustrating gene mutations or indel in 26 new diagnosed AML patients (A) and in 19 relapse/refractory AML patients (B). The horizontal axis represents individual patients, while the vertical axis displays the mutated genes. Different types of squares signify various mutation types, with gray squares indicating that the genes are wild-type. The bar graph at the top shows the total number of mutations per gene across all patients. The numbers on the left represent the proportion of mutations relative to the total patient sample, and the bar graph illustrates the proportion of different mutation types within each gene. The plot identifies WT1, IDH1/IDH2 and MLL as the top three genes with the highest mutation/indel frequencies in new diagnosed AML patients (A) and DNMT3A, FLT3 and RUNX1 as predominant in relapse/refractory AML patients (B)
The median number of treatment cycles was six (range, 1–17) for ND AML and two (range, 1–10) for R/R AML. The median follow-up time was 10.1 months (range, 4.23–15.17) for patients with ND AML and 8.53 months (range: 3.8–14.8) for patients with R/R AML. Sixteen (32%) patients received a target dose of 400 mg of Venetoclax, while 34 (68%) underwent dose reduction due to grade 4 haematologic toxicity, renal and hepatic insufficiency, or systemic infections. Voriconazole was administered to nine patients in the ND group and five patients in the R/R group, and fluconazole was administered to 11 patients in the ND group and four patients in the R/R group. The clinical characteristics of the 50 patients included in this study are summarised in Table 1.
Efficacy
For patients with ND AML, the CR rate was 53.6%, CRc rate was 67.9%, and ORR was 85.7%. Five (26.3%) patients with CRc achieved MRD negativity after two treatment cycles. One patient underwent allogeneic stem cell transplantation and remained in CR. In the R/R AML cohort of 21 patients, the CR rate was 19%, the CRc rate was 42.9%, the ORR was 52.4%, and one patient was negative for MRD. Of the three patients underwent allogeneic stem cell transplantation, two remained in CR and one died of sepsis. Eleven patients with complete responses were followed-up and maintained a complete response (Table 2, Figure S1).
Table 2.
Clinical response and survival following VEN-AZA treatment in newly diagnosed or refractory/relapse AML patients
| Variables | Total N = 50 |
Newly diagnosed N = 29 |
refractory/relapse N = 21 |
|---|---|---|---|
| Cycle of therapy, no. (%) | |||
| 1–3 | 26(52.00%) | 11(37.90%) | 15(71.40%) |
| 4–6 | 8(16.00%) | 5(17.25%) | 3(14.30%) |
| 7–9 | 7(14.00%) | 5(17.25%) | 2(9.50%) |
| ≥ 10 | 9(18.00%) | 8(27.60%) | 1(4.80%) |
| ≥ 1 year, no.(%) | 14(28.00%) | 10(34.50%) | 4(19.00%) |
| ORR, no.(%) | 35(70.00%) | 24(85.70%) | 11(52.40%) |
| CRc, no. (%) | 28(56.00%) | 19(67.90%) | 9(42.90%) |
| CR, no. (%) | 19(38.00%) | 15(53.60%) | 4(19.00%) |
| CRi, no. (%) | 9(18.00%) | 4(14.30%) | 5(23.80%) |
| PR, no. (%) | 7(14.00%) | 5(17.80%) | 2(9.52%) |
| NR, no. (%) | 14(28.00%) | 4(14.30%) | 10(47.68%) |
| Not evaluable, no. (%) | 1(2.00%) | 1(3.40%) | 0 |
| MRD negative, no. (%) | 6(21.40%) | 5(26.30%) | 1(11.11%) |
| DOR(months), median(IQR) | 10.13(4.52–14.12) | 9.18(4.23–14.78) | 12.83(5.52–13.83) |
| Relapse rate after remission, no. (%) | 19(54.29%) | 11(45.80%) | 8(72.73%) |
| Rate of death | 36(72.00%) | 19(65.50%) | 17(80.95%) |
| 60-day mortality rate, no. (%) | 3(6.00%) | 2(6.80%) | 1(4.80%) |
| follow-up time(months), median (IQR) | 9.64(3.84–15.08) | 10.1(4.23–15.17) | 8.53(3.8–14.8) |
| Survival | |||
| Overall survival(months), median (95%CI) | 10.1(6.87–13.33) | 11.93(7.6-16.29) | 9.1(3.01–15.19) |
| 1-year OS rate | 45.00% | 47.60% | 41.00% |
| 2-year OS rate | 23.70% | 30.30% | 15.00% |
| Event-free survival (months), median(95%CI) | 8.23(5.20-11.27) | 9.87 (6.54–13.2) | 5.2(1.80–8.6) |
| 1-year EFS rate | 32.70% | 35.20% | 28.60% |
| 2-year EFS rate | 14.40% | 22.00% | 6.30% |
| The reason of death, no.(%) | 36 | 19 | 17 |
| Disease progression | 28(77.78%) | 14(73.70%) | 14(82.35%) |
| Sepsis | 4(11.10%) | 2(10.50%) | 2(11.76%) |
| Covid-19 and severe pulmonary inflammation | 2(5.56%) | 2(10.50%) | 0 |
| Others | 2(5.56%) | 1(5.30%) | 1(5.89%) |
Abbreviations: ORR, overall response rate; CRc, composite complete remission; CR, complete remission; CRi, complete remission with incomplete hematologic recovery; PR, partial remission; NR, not response; MRD, measurable residual disease; DOR, duration of response; EFS, event free survival; OS, overall survival; CI: confidence interval
Table S1 shows the clinical responses to different genetic mutations in patients with AML receiving VEN-AZA therapy. Among patients with IDH1/IDH2 mutations, the incidence of composite remission was 83% in ND patients and 50% in R/R patients. In patients with RUNX1 mutations, the incidence was 100% and 40%, respectively. In those with DNMT3A mutations, the incidence was 100% and 50%, respectively.
Survival
In the ND AML cohort (n = 29), the median OS was 11.93 months (95% CI, 7.6–16.29 months), with 1-year and 2-year OS rates of 47.6% and 30.3%, respectively. The median EFS was 9.87 months (95% CI, 6.54–13.2 months), with 1-year and 2-year EFS rates of 35.2% and 22%, respectively. Among patients with R/R AML, the median OS was 9.1 months (95% CI, 3.01–15.19 months), with 1-year and 2-year OS rates of 41% and 15%, respectively. Furthermore, the median EFS was 5.2 months (95% CI, 1.8–8.6 months), with 1-year and 2-year EFS rates of 28.6% and 6.3%, respectively (Fig. 2). Thirty-six (72%) patients died during the follow-up period (19 in the ND group and 17 in the R/R group). Disease progression was the most common cause of death (77.78%), followed by sepsis (11.1%), COVID-19 and severe pulmonary inflammation (5.56%), intracranial haemorrhage (2%), and suicide due to depression (2%). The 30-day mortality rate was 0, and the 60-day mortality rate was 6% (3/50) (Table 2).
Fig. 2.
Event-free survival and overall survival of patients with new diagnosed AML patients treated with venetoclax-azacitidine. (A) Event-free survival curves for patients with new diagnosed AML treated with VEN -AZA. (B) Overall survival curves for patients with new diagnosed AML treated with VEN-AZA. (C) Event‐free survival curves for patients with relapse/refractory AML treated with VEN-AZA. (D) Overall survival curves for patients with relapse/refractory AML treated with VEN-AZA. Abbreviations: EFS: event‐free survival; OS, overall survival; AZA, azacitidine; VEN, venetoclax
In univariate survival analysis of patients with ND AML, PLT < 40 × 109/L, secondary MDS and prior HMA exposure predicted inferior EFS and OS following VEN-AZA therapy. Conversely, six or more therapy cycles and achieving CR/CRi were associated with superior EFS and OS (Fig. 3A and B). In the subsequent multivariable analysis, both having six or more therapy cycle (OS: HR = 0.09, 95% CI: 0.01–0.63, P = 0.015; EFS: HR = 0.13, 95% CI: 0.022–0.755, P = 0.023) and achieving CR/CRi (OS: HR = 0.053; 95% CI: 0.006–0.5; P = 0.01; EFS: HR = 0.027, 95% CI: 0.003–0.26, P = 0.002) retained significance (Table S2).
Fig. 3.
Univariate Cox regression analysis of event-free survival and overall survival. The hazard ratio for treatment failure, relapse from CR/CRi or death from any cause was estimated with the univariate Cox regression analysis. Data included are subject to a cutoff date of March 2, 2024. This plot displays the relative risks (hazard ratios) and 95% confidence intervals for various variables in relation to the study outcomes. Each point represents the estimated hazard ratio, with the lines indicating the 95% confidence intervals. The dashed vertical line represents a hazard ratio of 1.0. Abbreviations: WBC: white blood cell; Hb: hemoglobin; PLT: platelet; LDH: lactate dehydrogenase; ELN: European Leukemia Net; MDS: myelodysplastic syndromes; HMA: hypomethylating agent; ECOG: Eastern Cooperative Oncology Group performance-status scores; CR: complete remission; CRi: Complete Remission with Incomplete Hematologic Recovery; MRD: Measurable Residual Disease; (A) Univariate Cox regression analysis of event-free survival for patients with new diagnosed AML treated with VEN -AZA. (B) Univariate Cox regression analysis of overall survival curves for patients with new diagnosed AML treated with VEN-AZA. (C) Univariate Cox regression analysis of event‐free survival curves for patients with relapse/refractory AML treated with VEN-AZA. (D) Univariate Cox regression analysis of overall survival curves for patients with relapse/refractory AML treated with VEN-AZA
In the univariate survival analysis of patients with R/R AML, two or more prior lines of therapy predicted inferior EFS and OS following VEN-AZA therapy, whereas six or more therapy cycles and achievement of CR/CRi were associated with superior EFS and OS (Fig. 3C and D). In the subsequent multivariable analysis, achieving CR/CRi (OS: HR = 0.099; 95% CI: 0.01–0.8; P = 0.031; EFS: HR = 0.02, 95% CI: 0.002–0.19, P<0.001) retained its significance (Table S3).
Adverse effects
All 50 patients were included in the safety analysis. Every patient in the ND and R/R groups experienced at least one AE of any grade. The most commonly reported grade ≥ 3 haematologic AEs in both groups included neutropenia (79.31% and 100%, respectively), thrombocytopenia (65.51% and 90.48%, respectively), anaemia (68.97% and 100%, respectively), and febrile neutropenia (44.83% and 42.86%, respectively). The most common grade ≥ 3 non-haematologic AEs were respiratory system infections (31.03% and 47.62%, respectively), bacteraemia (17.24% and 9.52%, respectively), and skin and soft tissue infections (10.34% and 19.05%, respectively). One patient experienced a fatal intracranial haemorrhage during grade 4 bone marrow suppression (Table 3). The overall incidence of probable or confirmed invasive fungal infections was 32%, with incidences of 31% in the ND group and 33.33% in the R/R group. For patients with severe neutropenia exceeding 7 days, febrile neutropenia, ineffective antibacterial treatment, and invasive fungal infections (IFI), CYP3A inhibitor (CYP3Ai) antifungal therapy should be administered. Thirty-one patients (62%) patients received CYP3Ai, including 15 (30%) who received moderate CYP3Ai and 16 (32%) who received strong CYP3Ai.
Table 3.
Adverse events (counts refer to the number of patients who experienced AEs)
| Event | Newly diagnosed | R/R | ||
|---|---|---|---|---|
| All grades, no.(%) | ≥grade 3, no.(%) | All grades, no.(%) | ≥grade 3, no.(%) | |
| All adverse events | ||||
| Hematologic adverse events, no.(%) | 27(93.10%) | 22(75.86%) | 21(100.00%) | 21(100.00%) |
| Leukopenia | 24(82.76) | 22(75.86%) | 20(95.24%) | 19(90.48%) |
| Anemia | 27(93.10%) | 20(68.97%) | 21(100.00%) | 21(100.00%) |
| Thrombocytopenia | 21(72.41%) | 19(65.51%) | 20(95.24%) | 19(90.48%) |
| Neutropenia | 24(82.76%) | 23(79.31%) | 21(100.00%) | 21(100.00%) |
| Nonhematologic adverse events, no.(%) | ||||
| Respiratory tract infections | 11(37.93%) | 9(31.03%) | 12(57.14%) | 10(47.62%) |
| Urinary tract infections | 2(6.90%) | 1(3.45%) | 2(9.52%) | 2(9.52%) |
| Bacteraemia | 5(17.24%) | 5(17.24%) | 2(9.52%) | 2(9.52%) |
| Soft tissue infections | 3(10.34%) | 3(10.34%) | 5(23.80%) | 4(19.05%) |
| Febrile neutropenia | 13(44.83%) | 13(44.83%) | 9(42.86%) | 9(42.86%) |
| Myocardial injury/ infarction | 4(13.79%) | 1(3.45%) | 4(19.05%) | 0 |
| Nausea, vomiting/diarrhea | 10(34.48%) | 3(10.34%) | 15(71.43%) | 4(19.05%) |
| Tumor lysis syndrome | 1(3.45%) | 1(3.45%) | 0 | 0 |
| Cerebral hemorrhage | 1(3.45%) | 1(3.45%) | 0 | 0 |
| Rash | 0 | 0 | 1(4.76%) | 1(4.76%) |
The safety population included all patients who received at least one dose of venetoclax -azacitidine. Abbreviations: R/R, relapse/refractory
Outcome of patients with AML following VEN-AZA therapy failure
In the ND cohort, four patients developed resistance to VEN-AZA, while 11 relapsed (Figure S1). Three patients with refractory disease did not receive salvage therapy and died within 3 months owing to disease progression and severe infection. Twelve patients (1 refractory and 11 relapsed) received subsequent treatment. One patient with refractory received VEN-AZA plus selinexor treatment and achieved a PR after one cycle, but died due to sepsis, with an OS of 2.66 months. Among the 11 relapsed patients, two received VEN-AZA with chidamide or gilteritinib, one of whom achieved CRi, resulting in an ORR of 50%. Four patients were re-treated with the VEN-AZA regimen, one of whom independently discontinued VEN-AZA, resumed treatment following disease progression, and achieved CR after two cycles. Three patients who received VEN-AZA did not respond to treatment and died owing to disease progression. One patient received VEN monotherapy and four patients received supportive care only, although none responded to the treatment and all died (Table 4). The median OS after VEN-AZA failure for all 15 patients was 1.6 months (range, 0–8.27 months).
Table 4.
The outcome of patients with AML following failure of VEN-AZA therapy
| Type | No. | sex | Age (y) |
Efficacy1 (AZA-VEN) |
Therapy choice (AZA-VEN failure/ withdrawal) |
Efficacy2 | Follow-up | OS2 (months) |
|---|---|---|---|---|---|---|---|---|
| ND | 1 | F | 70 | NR | VEN-AZA-Selinexor | PR | Death, sepsis | 2.66 |
| 2 | F | 74 | CR | VEN-AZA-Chidamide | NR | Death, PD | 1.57 | |
| 3 | M | 72 | CRi | VEN-AZA- Gilteritinib | CRi | Death, PD | 8.27 | |
| 4 | F | 67 | CR | VEN-AZA*1 cycle-> CAG 1 cycle | NR | Death, PD | 6.50 | |
| 5 | M | 69 | CR | VEN-AZA 1 cycle -> CAG 1 cycle | NR | Death, PD | 2.77 | |
| 6 | M | 88 | CR | VEN-AZA | CR | alive, CR | 2.23 | |
| 7 | F | 77 | CR | VEN-AZA | NR | Death, PD | 2.7 | |
| 8 | M | 80 | PR | VEN | NR | Death, PD | 1.53 | |
| 9 | M | 70 | CRi | Supportive Care | NR | Death, PD | 1.63 | |
| 10 | M | 74 | CR | Supportive Care | NR | Death, covid-19 | 0.80 | |
| 11 | M | 89 | CRi | Hydroxycarbamide | NR | Death, PD | 1.6 | |
| 12 | M | 63 | CR | Hydroxycarbamide | NR | Death, PD | 1.1 | |
| R/R | 1 | M | 64 | NR | CAG 1 cycle -> HA 3cycle-> Selinexor | CRi | Death, PD | 6.4 |
| 2 | M | 49 | NR | CAG | NR | Death, Suicide | 0.67 | |
| 3 | F | 59 | CR | VEN-AZA1 cycle-> VEN-AZA-Enasidenib 5cycles | CRi | Alive, PD | 8.63 | |
| 4 | F | 73 | CRi | VEN-AZA-Gilteritinib -> CD33-ADC | CRi | Alive, PD | 5.73 | |
| 5 | F | 69 | CRi | VEN-AZA | NR | Death, PD | 7.4 | |
| 6 | M | 72 | CRi | VEN-AZA | NR | Death, PD | 3.43 | |
| 7 | F | 70 | CRi | CD33-ADC | PR | Death, PD | 3.87 | |
| 8 | F | 31 | PR | CAR/NK | NR | Alive, allo-ASCT | 2.4 | |
| 9 | F | 64 | PR | Supportive Care | NR | Death, PD and Sepsis | 4.43 | |
| 10 | M | 67 | CRi | Supportive Care | NR | Death, PD | 0.57 |
Efficacy 1 refers to the efficacy of AZA-VEN therapy; Efficacy 2 represents the effectiveness of therapy administered subsequent to the failure of VEN-AZA therapy; Abbreviations: F, female; M, male; CR, complete remission; CRi, complete remission with incomplete hematologic recovery; PR, partial remission; NR, not response; R/R, relapse/refractory; ND, newly diagnosed; PD, Progressive Disease; allo-ASCT, allogeneic stem cell transplant; VEN, venetoclax; AZA, azacitidine
In the R/R cohort, 10 patients developed resistance to VEN-AZA treatment and eight relapsed (Figure S1). Of the 10 patients who underwent subsequent treatment, two with refractory received chemotherapy (CAG/HA), of whom one achieved CRi after one cycle of treatment but died 6.4 months later due to disease progression. The other patient did not respond to the therapy and died by suicide due to depression caused by persistent nonresponse. Among the eight patients who relapsed, two received VEN-AZA with enasidenib or gilteritinib, and both achieved CRi. One patient died 8.63 months later because of disease progression, whereas the other experienced disease progression after 2 months, entered a CD33-ADC clinical trial, and remained alive with an OS duration of 5.73 months. Two patients did not respond to VEN-AZA and died owing to disease progression. Two patients participated in clinical trials (CAR-NK and CD33-ADC therapies) with an ORR of 50% and two received supportive care only (Table 4). The median OS after failure of second-line or higher VEN-AZA was 0.67 months (range, 0–8.63 months).
Discussion
This retrospective, real-world study demonstrated that patients with ND AML treated with VEN-AZA at our single centre had a median OS of 11.93 months. This finding is consistent with real-world outcomes reported by Yu (OS: 11.5 months, Tianjin, China) [14] and Zeidan (11.3 months, USA) [21], which both reported durations shorter than the 14.7 months in the VIALE-A clinical trial [18]. The shorter OS observed in real-world studies, including in our study, may be attributed to the inclusion of trial-ineligible patients. Our study enrolled patients who were previously treated with HMA for MDS and those aged ≥ 75 years with an ECOG performance status of 3 or 4, while the VIALE-A study excluded such patients [18]. In patients with R/R AML, the median OS was 9.1 months (95%CI, 3.01–15.19 months), similar to the 9.1 months reported for refractory AML and longer than the 6.3 months observed in relapsed AML in the AVALON study [15]. In patients with R/R, the median age was 10 years lower than that of ND patients, and VEN-AZA offered a way to mitigate resistance to intensive chemotherapy, which could result in remission, in line with the AVALON study results [15]. With respect to OS, achieving CRc and undergoing six or more therapy cycles were associated with improved OS, consistent with the findings of Gangat [16, 22].
The ORR, CRc, and MRD (< 0.1%) negativity rates were 85.7%, 67.9%, and 26.3%, respectively, in patients with ND AML. Yu et al.. reported a high remission rate in previously untreated patients with AML who were ineligible for standard induction therapy, with an ORR of 87.5% and CR rate of 68.8% [14]. The ORR and CRc in these two studies were similar to those in the VIALE-A (CRc 66.8%, CR 38.8%) [23] and Gangat’s (CRc 60%, CR 36%, Mayo Clinic) studies. The MRD-negative rate of 26.3% in ND AML and 11.11% in R/R AML, which is higher than VIALE-A study (23.4%) [18] but lower than that reported by Yu et al.. (MRD 58.3%) [14], Yu Wenjing et al.. (MRD 47.1% in ND AML and 33.3% in R/R AML) [24], and Gangat et al.. (77%) [16]. VIALE-A and most other studies used flow cytometry to assess MRD, with Gangat et al. incorporating quantitative PCR for specific mutations. MRD negativity rates vary widely, likely due to differences in patient characteristics, sample sizes, and assessment methodologies. Notably, Yu [14] showed that patients aged ≥ 75 years with ECOG scores ≥ 3 were more likely to have MRD positivity. In our study, 14 patients (48.3%) had an ECOG score of 3–4, and the small sample size may have contributed to the lower MRD negativity rate. These findings highlight the necessity for standardised MRD assessment methods in future studies to ensure consistency and comparability across clinical trials. Achieving MRD negativity in patients with AML treated with VEN-based combinations is associated with improved survival [25]. Therefore, it is important to explore new drug combinations for achieving negative MRD results. Meanwhile, the ORR and CRc in relapsed or refractory AML were 52.4% and 42.9%, respectively, consistent with the AVALON study, with an ORR of 51.5% and 41.8% and CR of 38.2% and 34.2% in refractory and relapse patients, respectively [15].
Haematological and non-haematological toxicities occurred in almost all patients treated with VEN-AZA and were generally manageable. The most commonly reported grade ≥ 3 AEs were haematologic AEs and infections. The most common infections in ND AML were respiratory system infections (31.03%), followed by bacteraemia (17.24%), skin and soft tissue infections (10.34%), and urinary tract infections (3.45%), similar to the findings of Candoni A et al. [26].
The incidence of probable or confirmed invasive fungal infection was 32%, which was higher than that reported by On et al. [27]. Additionally, 31 (62%) patients received CYP3Ai, which was higher than the incidence reported in the VIALE-A study (20%) [28]. This difference is because, in our study, 60% (14/29) of the patients had a moderate or severe neutropenia and 38% had agranulocytosis before the therapy with VEN-AZA regimen. All patients experienced at least one AE, including neutropenia (88%) and febrile neutropenia (44%); additionally, 32% of the patients developed probable or confirmed invasive fungal infections, likely due to prolonged bone marrow suppression increased vulnerability to infections. Previously, Jonas et al.. showed that concomitant moderate or strong CYP3Ai and VEN dose reduction in patients with AML may not impair remission or survival [28]. Candoni et al.. showed that infectious complications may affect patient outcomes and survival in the HMA-VEN-treated group and that secondary AML is a predictive factor for infection [26, 29]. Therefore, VEN dosing schedules may improve therapeutic efficacy.
Fifteen (51.7%) of the 29 patients with treatment-naïve AML experienced R/R following VEN-AZA therapy: four (13.8%) patients had primary refractory disease and 11 (45.8%) had disease progression or relapse after the initial response. The median OS after VEN-HMA failure for all 15 patients was 1.6 months (range, 0–8.27 months). Previously, Gangat showed that 71 (69%) of 103 patients with ND AML experienced either refractory (N = 43, 42%) or relapse (n = 28, 27.2%) following VEN-HMA therapy, with a median OS of 3.1 months [30]. Furthermore, Maiti et al. included 95 patients with ND AML treated with VEN-HMA frontline, 41 (43%) of whom experienced relapse or refractory, eight (8.4%) had primary refractory, and 33 (34.7%) had relapse after initial response. The median OS after VEN-HMA failure for all 41 patients was 2.4 months (range, 0.1–21.2) [31]; however, 18 (85.7%) of the 21 patients with AML following second-line/beyond VEN-AZA therapy experienced R/R: 10 (47.6%) had primary refractory, and 8 (38.1%) had disease progression or relapse after the initial response. The salvage therapy outcomes in patients with treatment-naïve AML after AZA-VEN suggested best outcomes for VEN-AZA combined with a targeted drug, whereas salvage induction chemotherapy after second-line or beyond AZA-VEN failure was feasible, with results similar to those of the study reported by Christine [32]. This may be because AZA-VEN and induction chemotherapy target different subclones as complementary sequential therapies.
Our study provides real-world data from a single-centre cohort in China. The study cohort included a diverse patient population, encompassing both with ND and R/R AML, which may better reflect general everyday clinical practice. One of the main contributions of our study is the investigation of treatment strategies after VEN-AZA failure. Although this topic has been briefly touched upon in previous studies, our research provides treatment responses and survival of the combination therapies used after failure (such as VEN-AZA combined with gilteritinib, chidamide, or selinexor) or clinical trials, which is a key aspect of our study that differentiates it from prior studies [14–16]. Notably, our findings offer guidance for clinicians in selecting subsequent therapies for the treatment of patients with AML.
This study had several limitations that should be noted when interpreting our findings. First, as a single-centre study, it may have been subject to biases in patient selection and treatment practices, thus limiting its generalisability to a wider population. The relatively small sample size limited the statistical power of our study and restricted its ability to detect significant differences between subgroups, identify rare AEs, or assess the efficacy of specific salvage therapies. The absence of a comparison group made it difficult to assess the relative effectiveness of VEN-AZA therapy. Larger multicentre comparative studies are therefore required to validate our findings. Second, In the multivariate Cox regression analysis, we included CR/CRi, cycle of therapy ≥ 6, PLT < 40 × 109/L, HMA history, and MDS history; however, we did not adjust for all potential confounders, including certain variables such as age, ECOG status, and genetic mutations, as these variables had P values greater than 0.1 in univariate Cox regression analysis. We recognise that the exclusion of these variables may have introduced potential confounding factors into the survival analysis. Future studies with larger cohorts may allow a more comprehensive adjustment of these variables. Finally, the efficacy of specific salvage therapies is preliminary, and requires further validation to draw definitive conclusions regarding their effectiveness.
Conclusions
VEN-AZA demonstrates favourable efficacy and safety in patients with AML, thus serving as a viable induction therapy option not only for treatment-naïve elderly patients with AML, but also for patients with R/R disease. In addition, VEN-AZA treatment can be used as a bridge for allogeneic haematopoietic stem cell transplantation. Salvage therapy following VEN-HMA failure remains relatively uncommon, and the OS in this context is limited. Therefore, there is a critical need to explore novel drugs and conduct further clinical trials to improve patient outcomes. The preliminary findings of this study require validation through larger multicentre investigations to determine the generalisability of our findings.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Acknowledgements
Not applicable.
Abbreviations
- AEs
Adverse events
- AML
Acute myeloid leukemia
- AZA
Azacitidine
- CI
Confidence Intervals
- CR
Complete remission
- CRc
Composite complete remission
- CRi
Complete Remission with Incomplete Hematologic Recovery
- DOR
Duration of response
- EFS
Event-free survival
- ELN
European Leukemia Network
- HMA
Hypomethylating agent
- HR
Hazard Ratios
- IQR
Interquartile range
- MDS
Myelodysplastic syndrome
- MRD
Minimal residual disease
- NCCN
National Comprehensive Cancer Network
- ND
Newly diagnosed
- ORR
Overall response rate
- OS
Overall survival
- PR
Partial remission
- R/R
Relapse or refractory
- VEN
Venetoclax
Author contributions
Conception/design: Ru Feng, Hui Liu, Jie-Fei Bai. Provision of study material or patients: Jie-Fei Bai, Ting Wang, Jiang-Tao Li, Chun-Li Zhang, Hui Liu, Ru Feng, Long Qian, Ya-Zi Yang. Collection and/or assembly of data: Jie-Fei Bai, Long Qian, Jiang-Tao Li, Bao-Li Xing, Shang-Yong Ning, Lei Pei, Xiao-Dong Xu. Data analysis and interpretation: Jie-Fei Bai, Xiao-Ya Yun, Fei Zhao, Wei-Dong Ding. Manuscript writing: Jie-Fei Bai, Ting Wang. Final approval of manuscript: Jie-Fei Bai, Ting Wang, Jiang-Tao Li, Chun-Li Zhang, Long Qian, Ya-Zi Yang, Xiao-Ya Yun, Jing-Jing Yin, Fei Zhao, Wei-Dong Ding, Bao-Li Xing, Shang-Yong Ning, Lei Pei, Xiao-Dong Xu, Hui Liu, Ru Feng.
Funding
This work was supported by the grants from the National High Level Hospital Clinical Research Funding (No.BJ-2023-078, No.BJ-2024-191, No.BJ-2022-127), the Beijing Natural Science Foundation (No. 7232137, No. 7222158), CAMS Innovation Fund for Medical Sciences (CIFMS, No.2024-I2M-C&T-A-009 ).
Data availability
Data will be shared on reasonable request to the corresponding author.
Declarations
Ethical approval and consent to participate
This study was approved by the Ethics Committee of Beijing Hospital, National Center of Gerontology. The relevant reference number was 2023BJYYEC-224-0. all participants signed a written informed consent form in accordance with the Declaration of Helsinki.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jie-Fei Bai and Ting Wang contributed equally to this work.
Contributor Information
Hui Liu, Email: liuhui8140@126.com.
Ru Feng, Email: frbld@sina.com.
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Supplementary Materials
Data Availability Statement
Data will be shared on reasonable request to the corresponding author.