Efficacy of Venetoclax combined with Homoharringtonine and Cytarabine for Younger Adults with Newly Diagnosed AML

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Efficacy of Venetoclax combined with Homoharringtonine and Cytarabine for Younger Adults with Newly Diagnosed AML

https://doi.org/10.21203/rs.3.rs-5224506/v1

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Venetoclax (VEN) based induction therapy have shown a promising treatment for patients with acute myeloid leukemia (AML). However, the optimal VEN combination is urgently needed. We aimed to investigate the effective and tolerability of venetoclax combined with homoharringtonine plus cytarabine (VHA) regimen for newly diagnosed AML. We retrospectively analyzed the outcomes of 55 ND AML patients treated with VHA regimen. The overall response rate (ORR) was 92.7% (51/55, 95% CI 82%-98%). The composite complete remission (CRc) rate was 87.3% (48/55, 95% CI 76%-95). 44 (91.7%, 95% CI 67-90) of 48 patients who reached complete remission (CR) and measurable residual disease (MRD)-negative was attained in 85.4% of CRc patients (41/48, 95% CI72-94). ORR and CRc were 95% (19 of 20 patients)[95% CI 75%-100%] and 75% (15 of 20 patients) [95% CI 51%-91%] in patients with adverse risk. The most common grade 3-4 adverse events were febrile neutropenia (32.7%), pneumonia (16.3%) and sepsis (9.1%). Median overall survival (OS) was 26 months and event-free survival (EFS) was not reached. 1-year overall survival was 83%, 1-year event-free survival was 82%. These preliminary data suggest that the VHA regimen leads to a very high rate of CR and low toxicity. Especially for adverse risk patients, it provide an opportunity for allogeneic haematopoietic stem cell transplantation (allo-HSCT).

Venetoclax

Homoharringtonine

Cytarabine

Acute myeloid leukemia

Intensive induction used for younger or fit patients with acute myeloid leukemia (AML) are based on a backbone of 7 + 3 regimens consist of anthracyclines (daunorubicin or idarubicin) and cytarabine, with complete response (CR) rates of 60%-70% and a median overall survival (OS) of 16–24 months [1]. A number of clinical trials have shown that induction chemotherapy using a three-drug combination (eg, etoposide or tioguanine) could improve complete remission and OS [2]. However, this combination has poor tolerability because of the higher treatment-related toxicity. Finding new regimen that might improve complete remission and decrease toxicities has actively pursued.

The B-cell lymphoma-2 (BCL-2) inhibitor venetoclax (VEN) combined with lower-intensity treatment regimens (azacitidine, decitabine, or low-dose cytarabine) has approved for unfit, older patients with AML [3, 4]. Importantly, venetoclax-based combinations have been associated with superior response rates and survival in various hematological malignancies. In light of these results, there is considerable interest in expanding use of venetoclax-based therapies in other treatment settings of AML, especially patients younger than age 60 years [5, 6]. Homoharringtonine (HHT), a Chinese medicine extracted from Cephalotaxus species, HHT-based induction regimens have been widely used to treat adult AML [7]. Moreover, HHT has reported to have significant synergistic effects with venetoclax [8, 9]. Therefore, we investigated whether venetoclax combined with homoharringtonine plus cytarabine (VHA) induction regimens can also achieve good results while reducing adverse effects in ND AML patients.

We retrospectively analyzed newly diagnosed patients with AML (aged under 60 years) who presented to First Hospital of Suzhou University between July 2021 and July 2023. The inclusion criteria were co

nfirmation of AML by WHO criteria, previously untreated, > 18 to ≤ 60 years, Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2, treated with VHA regimen. The study, was approved by the Ethics Committee of the First Affiliated Hospital of Soochow University.

The primary endpoint was the overall response rate (ORR) 28 days after study treatment. The secondary endpoint was 1-year OS, event-free survival (EFS) and adverse events. ORR included CR, CRi, and partial remission (PR). Composite remission rate (CRc) was considered as marrow complete response with or without count recovery (CR and CRi). Non-remission (NR) was defined as a failure to obtain CRc or PR. Response criteria were defined by the European LeukemiaNet (ELN) 2022 guidelines. Measurable residual disease (MRD) was detected by multi- parameter flow cytometry (MFC). OS was defined as the number of days from randomization to the date of death; EFS was defined as the number of days from randomization to treatment failure, relapse, or death. Adverse events were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). OS and EFS were estimated using the Kaplan-Meier method. The results were generated by SPSS Statistics 25.

VHA regimen conducted as VEN 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3–21; HHT 1mg/m² on days 1–5; cytarabine 100mg/m² on days 1–5). Dose interactions between venetoclax and concomitant medications were considered. After reaching complete remission, patients received 2–3 cycles of intermediate dose cytarabine (1–2 g/m², every 12 h, for a total of six doses) ± idarubicin (8 mg/m², daily for 2 days). Subsequently, patients received allogeneic haematopoietic stem cell transplantation (allo-HSCT) according to measurable residual disease status and if a donor was available. All patients received supportive care measures per institutional guidelines including prophylactic anti-infective agents, blood product transfusions, and growth factor support. All patients provided written informed consent in accordance with the Declaration of Helsinki. The last follow-up date is August 30, 2023.

3 .1 | Patient characteristics

A total of 55 patients with ND AML received the VHA regimen, included 33 males and 22 females, with a median age of 41 years (range 18–59). Of these patients, 53 patients had de novo AML, 2 patients had secondary AML (AML-MRC and transformed AML). The mean WBC count was 10.22×10⁹/L (range 0.78–159.5), bone marrow blast was 54% (range 12.5–92%). The majority of patients were favorable risk (43.6%, 24/55), remaining were adverse risk (36.4%, 20/55) and intermediate risk (20%, 11/55) according to 2022 European LeukemiaNet (ELN) risk stratification. The most frequently mutated genes were FLT3-ITD/TKD (17/55, 30.9%), IDH1/2 (8/55, 14.5%), KIT (7/55, 12.7%), DNMT3A (6/55, 10.9%), ASXL1 (5/55, 9.1%), NRAS (5/55, 9.1%), WT1 (4/55, 7.3%), on the molecular analysis. The baseline characteristics of patients are summarised in Table 1.

Table 1

Demographics of patients treated with VHA regimen
Characteristics	All patients (N = 55)
Age
Median (years)	41 (18–59)
Sex, n(%)
Male	33
Female	22
Baseline bone marrow blast cell proportion
blast Median (%, range)	54%(12.5–92)
< 30%(n, %)	11 (20%)
≥ 30% to < 50	14 (25.5%)
≥ 50%	30 (54.5%)
WBC count (10⁹/L)
Median (range)	10.22(0.78–159.5)
AML type
De novo AML	53
Secondary AML	2
ELN risk, n (%)
Favourable	24
Intermediate	11
Adverse	20
Molecular abnormalities, No (%)
FLT3-ITD	14 (25.5%)
KIT	7 (12.7%)
DNMT3A	6 (10.9%)
IDH2	5 (9.1%)
ASXL1	5 (9.1%)
NRAS	5 (9.1%)
FLT3-TKD	5 (9.1%)
WT1	4 (7.3%)

3.2 | Response Assessment and Survival

After a cycle of VHA regimen, the responses were evaluated in 55 patients, none died during treatment. The ORR was 92.7% (51/55, 95% CI 82%-98%). The composite CR rate (CRc) for the whole cohort was 87.8% (48/55)[95% CI 76%-95%], including 44 CR (80%, 44/55) [95% CI 76%-95%]and 4 CRi (7.3%, 4/55). There were additional 3 (5.5%, 3/55) patients achieved PR. In all responders, 85.4% (41/48) [95% CI72%-94%] patients were MRD negative. Efficacy outcomes by subgroups were shown in Fig. 1, the ORR was 91.7% (22 of 24 patients) [95% CI 73%-90%] in favorable risk, 91% (8 of 11 patients) [95% CI 59%-100%] in patients with intermediate risk, and 95% (19 of 20 patients)[95% CI 75%-100%] in patients with adverse risk.

Three patients who got partial remission to the VHA regimen, two both had intermediate risk gene mutations (FLT3-ITD mutation) and the other PR patient had adverse gene rearrangement (MLL-AF6 gene rearrangement) similar to in a previous report⁵. Subsequently the patients received salvage treatment with Gilteritinib or Selinexor combined with HMAs and received CR. Four patients showed no response (NR) after one cycle of VHA induction therapy. Among 4 patiens, 2 patients with RUNX1-RUNX1T1 mutation, one patient received one cycle of IAG regimen (idarubicin 5 mg qd d1-7; cytarabine 10mg/m² q12h d1-7; G-CSF 300 µg qd d1-14) then achieved CR. The other patient was resistant to re-induction therapy and died 3 months later. The third one had TLS-ERG gene rearrangement (MLL-AF6 gene rearrangement) while receiving CRi after one cycle of selinexor and daretozumab, and then received allo-HSCT. The last patient receiving CR after one cycle of VHA re-induction therapy.

Detailed mutational landscapes and dynamic responses assessment of enrolled patients were presented in Fig. 2. Eight patients with RUNX1-RUNX1T1 mutation were enrolled, who had a lower CRc rate (75%, 6/8). Four patients had decreased gene expression (RUNX1-RUNXT1 transcript) 1000-fold by PCR at the molecular level after one cycle of VHA induction therapy. Two patients showed no response to the VHA regimen, and two patients relapse in the short term who did not reached complete molecular remission (gene expression < 0.01%).

With a median follow-up of 13 months (range 3–26). Median durations of OS and EFS were 26 months and non-reached. 1-year OS was 83%, 1-year EFS was 82%. Survival outcomes by subgroups were shown in Fig. 3. A total of 35 patients (63.6%) eventually proceeded to allo-HSCT after consolidation therapy. Thirty-one patients who achieved CRc and 4 patients who were refractory to VHA reigmen and received alternative salvage therapy received allo-HSCT in CR in 34 cases and active disease in one case.

3.3 | Toxicities

Adverse events (AEs) of the VHA regimen were listed in Table 2. Grade 3–4 neutropenia, anemia, and thrombocytopenia occurred in 81.8%, 69%, and 83.6% of patients, respectively. Serious AEs included febrile neutropenia (32.7%, 18/55), pneumonia (10.9%, 6/55), sepsis (9.1%, 5/55), fungal infection (3.6%, 2/55), gastrointestinal bleeding (1.82%, 1/55), facial neuritis (1.82%, 1/55) and retinal hemorrhage (1.82%, 1/55). One death occurred within 100 days due to acinetobacter baumannii sepsis, who died in CRi approximately 3 months after VHA regimen. The median time to absolute neutrophil count recovery (≥ 0.5 × 10⁹/L) in patients who had a response following induction therapy was 18.0 (7–25) days, the median time to recovery of 50 ×10⁹/L or more platelets was 15.5 (7–28.0) days after induction. No tumor lysis syndrome occurred.

Table 2

Adverse events
Adverse Events (AEs)	N = 55(%)
Any AEs	55 (100%)
AEs with grade ≥ 3
Haaematological adverse events
WBC count decreased	48(87.2%)
Neutrophil count decrease	45(81.8%)
Platelet count decrease	46(83.6%)
Anemia	38(69%)
Febrile neutropenia	18(32.7%)
Pneumonia	6(10.9%)
Sepsis	5(9.1%)
Fatigue	3(5.45%)
Skin and soft tissue infection	3(5.45%)
Diarrhoea	2(3.6% )
Fungal infection	2(3.6%)
Hypertension	2(3.6%)
Esophatitis	1(1.82%)
Dizziness	1(1.82%)
Facial neuritis	1(1.82%)
Gastrointestinal bleeding	1(1.82%)
retinal hemorrhag	1(1.82%)

Table 3

Adverse events
Adverse Events (AEs)	N = 55(%)
Any AEs	55 (100%)
AEs with grade ≥ 3
Haaematological adverse events
WBC count decreased	48(87.2%)
Neutrophil count decrease	45(81.8%)
Platelet count decrease	46(83.6%)
Anemia	38(69%)
Febrile neutropenia	18(32.7%)
Pneumonia	6(10.9%)
Sepsis	5(9.1%)
Fatigue	3(5.45%)
Skin and soft tissue infection	3(5.45%)
Diarrhoea	2(3.6% )
Fungal infection	2(3.6%)
Hypertension	2(3.6%)
Esophatitis	1(1.82%)
Dizziness	1(1.82%)
Facial neuritis	1(1.82%)
Gastrointestinal bleeding	1(1.82%)
retinal hemorrhag	1(1.82%)

Venetoclax-based has shown significant improvement in CRc and OS in ND AML. For fit adults with AML, three studies evaluated venetoclax plus intensive chemotherapy including FLAG-IDA (fludarabine, cytarabine, granulocyte colony-stimulating factor, idarubicin), CLIA (cladribine, high-dose cytarabine, idarubicin) and “3 + 7”(daunorubicin and cytarabine) chemotherapy, showing complete remission rates of 69%, 84% and 91%, respectively [10–12]. Meanwhile, our center reported the first study of venetoclax plus decitabine improve survival benefits in younger adults with ND ELN adverse-risk AML [13]. Althrough, an optimised intensive therapy with the hope of achieving high CR rates and that is well tolerated is needed to be explored.

Homoharringtonine (HHT)-based induction regimens have been widely used for patients with acute myeloid leukaemia. Jin Jie et al reported the regimen of homoharringtonine, cytarabine, and aclarubicin is a treatment option for young, newly diagnosed patients with acute myeloid leukaemia [14, 15]. Subsequently, more and more studies have confirmed the role of homoharringtonine in AML [16]. Homoharringtonine-based regimens for ND fit adults AML were recommended by Chinese 2021 treatment guidelines [17]. Interestingly, HHT combined with venetoclax exerted its antileukemia effect by inducing apoptosis through the treatment of AML in vitro and in vivo [18]. Hua Jin et al showed VAH (venetoclax, azacitidine and homoharringtonine) regimen is a promising and well-tolerated regimen in R/R AML, with high CRc and encouraging survival [19]. However, data regarding newly diagnosed adults patients with AML after venetoclax combned with homoharringtonine induction is limited. We therefore performed a retrospective analysis of a cohort of 55 patients receiving VHA treatment to evaluate its efficacy and tolerance.

In the present study, the overall response rate (ORR) rate was 92.7% with a single induction course was achieved in younger adult patients with de novo AML, the composite CR (CRc) was 87.8%. Among the patients with CRc, the CR rate of 80% and the MRD negativity was observed in 85.4%. As we know, in patients of comparable age treated with venetoclax-based induction regimen, typically 69–91% CR rate and 91–97% ORR. Therefore, the CR rate of 80% and ORR 92.7% in this study was a quite good result. Some studies including our own report suggested that the sensitivity to venetoclax-based therapy was related with adverse-risk AML [13]. Analysis of data from this study taking into account cytogenetic risk group showed that VHA regimen with higher CRc rates in adverse risk subgroups. For the patients with favorable risk group, VHA regimen produced 91.7% CR rate and 91.7% ORR, Intermediate risk group, only 63.6% CR rate and 91% ORR. What excites us is that, for the patients with adverse risk AML, with 75% CR rate and 95% ORR, which is better than previously reported CR (75–81%) and ORR (75–93%). In this study, our results align with the previous reports that AML patients with adverse risk with a higher CR rate.

However, patients with monocytic phenotype AML or RUNX1::RUNX1T1 recurrent genetic abnormalities had a lower CRc rate [6, 13]. AML with RUNX1-RUNX1T1 mutation usually displays a high heterogeneity to standard induction therapy, although it is usually associated with a good prognosis. Some clinical trials have shown that VEN based induction regimens do not significantly improve CR. In our study, four patients showed no response to VHA regimen, one patient with TLS-ERG rearrangement, one patients with monocytic phenotype, the others two patients were RUNX1::RUNX1T1 recurrent genetic abnormalities. The results showed that VHA regimen may provide a low CR rate and unfavorable molecular response for these patients.

To avoide the potential for increased side-effect profile, especially infections and myelosuppression, we implemented a reduced venetoclax dosing from 28 to 21 days per course as previous reported [19]. Grade 3–4 adverse events were mainly febrile neutropenia and infectious complications, which were similar to other venetoclax-based combination therapy for AML.

Our findings suggest that VHA therapy may be as potentially the preferred choice to induce newly diagnosed AML patients considering its high response rate and the low toxicity. Imoprtantly, the improved CRc and outcome in patients with adverse risk group highlighted the potential benefits of VHA regimens, and further validation is needed. As our study was retrospective and had few patients in the group, future studies needed to confirm this finding.

FUNDING

This work was supported in part by Science and Technology Development Project of Suzhou (Grant No.SKY2022134); Targeted therapy and Modified Allogeneic Hematopoietic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia (Grant No. H230094); Jiangsu Province Elderly Health Research Project (Grant No. LKM2023015).

ETHICS APPROVAL STATEMENT

The study has been approved by the Ethics Committee of the First Affiliated Hospital of Soochow University (No. 026/2013).

CONFLICT OF INTEREST

The authors declare no conflicts of interests.

DATA AVAILABILITY STATEMENT

The datasets used and/or analysed during the current study are available from the corresponding author([email protected] ) on reasonable request.

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No competing interests reported.

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Efficacy of Venetoclax combined with Homoharringtonine and Cytarabine for Younger Adults with Newly Diagnosed AML

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Abstract

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1 | INTRODUCTION

2 | PATIENTS AND METHODS

3 | RESULTS

3 .1 | Patient characteristics

3.2 | Response Assessment and Survival

3.3 | Toxicities

4 | DISCUSSION

Declarations

References

Additional Declarations

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