P564: HOMOHARRINGTONINE AND CYTARABINE COMBINED WITH VENETOCLAX (HAV) FOR ADULT PATIENTS WITH DE NOVO AML

Background: 20-30% of de novo acute myeloid leukemia (AML) patients still do not achieve complete remission (CR) using standard induction regimens. Homoharringtonine (HHT) has been extensively applied in the therapy of hematological diseases in China for more than 50 years. Recent clinical trials have shown that venetoclax combined with intensive chemotherapy including FLAG-IDA, CLIA, and DA induction achieved a 90% CR rate in de novo adult AML and was well-tolerated. Whether veneclax combined with HHT and cytarabine (HAV) can synergistically improve the remission rate of de novo AML patients and reduce adverse events deserves further exploration. Aims: To investigate the safety and efficacy of HAV regimen (HHT and cytarabine combined with venetoclax) in adult patients with de novo AML. We evaluated patients’ characteristics, overall response (ORR = CRc + MLFS), composite CR (CRc = CR + CRi + CRp), the negativity rates of MRD (MFC, <0.1%), venetoclax pharmacokinetics, relapse-free survival (RFS), overall survival (OS), non-hematological toxicities, and the mortality rates during the first two months. Methods: Single-arm, prospective clinical trial conducted in the First Affiliated Hospital of Chongqing Medical University and Southwest Hospital, Third Military Medical University (Army Medical University). Eligible patients (18-60 years old) with de novo AML (exclude acute promyelocytic leukemia) were enrolled since April 1, 2021, with final follow-up in Feb 26, 2023. Patients were treated with HHT 2-2.5mg/m2 on days 1-3 (d1-3) and cytarabine 100-200 mg/m2/d on d1-7 plus venetoclax 100mg/d on d1-14 (coadministration with oral Posaconazole 200mg three times a day). No additional molecular inhibitors were administered. No G-CSF was used during the induction therapy. The trial was registered in the Chinese Clinical Trial Register (ChiCTR2100048208). Results: Thirty-six patients were enrolled, and 34 cases were evaluated as 2 patients died of severe infections shortly after HAV regimen initiated. The median age was 47.5 years old (range, 18-57), with poor risk in 35.3% (12/34) of patients (European Leukemia Net 2022 risk). The most common gene mutations were FLT3 20.6% (7/34), AML1/ETO 14.7% (5/34), NPM1 17.6% (6/34), NRAS 11.8% (4/34), KRAS 11.8% (5/34), DNMT3A 11.8% (4/34), IDH1 5.9% (2/34), and IDH2 5.9% (2/34). Other characteristics of patients were listed in Table 1. Both ORR and CRc rates were 97.1% (33/34). 11 out of 12 (91.7%) patients with poor risk achieved CRc. Only one poor-risk patient with PTPN11 mutation failed to achieve CR and died of severe infection. MRD negativity was confirmed in 48.5% (16/33) of CRc patients. Blast count reduction to <5% was observed in 53.8% (7/13) on day 14 and in 97.1% (33/34) on day 30 by bone marrow evaluations. 13 patients underwent allo-HSCT and 4 of them died of severe aGVHD (n=3) or leukemia relapse (n=1). 2 patients underwent auto-HSCT. After 10.6 months of median follow-up, the median OS and RFS have not been reached (Figure 1). The most common grade 3-5 non-hematological adverse events were febrile neutropenia (97.1%, 33/34) and bacteremia/sepsis (14.7%, 5/34). The incidence of septic shock, severe pneumonia, and intra-abdominal infection were 11.8%, 14.7%, and 11.7%, respectively. Day 30 and day 60 mortality rates were 0% (0/34) and 2.9% (1/34), respectively. The mean blood concentration of venetoclax (Cmax/Cmin) was 1329.4/844.3 ng/ml (range, 594-2580/324-1630) on day 4 and 1584.4/1148.8 ng/ml (range, 952-2190/534-1690) on day 9. Summary/Conclusion: HAV was effective and well-tolerated in young adult patients with de novo AML, producing high rates of CR and encouraging OS and RFS.Keywords: Acute myeloid leukemia