Mitoxantrone liposome, subcutaneous cytarabine and G-CSF (CMG) combined with venetoclax as first-line treatment in secondary Acute Myeloid Leukemia (sAML) or elderly AML patients: A multicenter, prospective, single-arm clinical trial with concurrent

Abstract Objective: The prognosis of secondary acute myeloid leukemia (sAML) including AML with antecedent myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) history, and therapy related AML (t-AML) is still very poor, overlapping with elderly AML, although CPX-351 showing OS advantage in these patients' group. Considering the unavailable of CPX-351 in China, and the toxicities of standard azacytidine combined with venetoclax (AZA+VEN) regimen, the optimal treatment in sAML and elderly AML is still being investigated. The aim of this study was to investigate the activity and safety of mitoxantrone liposome, subcutaneous injection cytarabine and G-CSF combined with Venetoclax（CMG+VEN）in patients with secondary or elderly AML. Patients and Methods: Two patients cohort were enrolled in this study,including AML who were older than 60 years and fit for chemotherapy, as well as AML with antecedent MDS or MPN history, and t-AML. The CMG+VEN regimen was mitoxantrone liposome 15mg/m2 on day 1, cytarabine 10mg/m2, subcutaneous injection, q12h, on days 1-7, G-CSF 5ug/kg from d0 until the WBC count of patients was above 20×109/L. Venetoclax was also added on day2 100 mg, 200mg day3, 400mg from day4 to 10. The primary endpoint was composite complete remission (complete remission plus complete remission with incomplete blood count recovery). The secondary endpoint were overall response, measurable residual disease (MRD) by flow cytometry, event-free survival, overall survival, and safety. This trial was registered with ClinicalTrials.gov, NCT06329999. Results: A total of 63 patients were enrolled, including 30 males and 33 females, with a median age of 64 (19-75) years old. Among them, there were 28 cases of de novo AML and 35 cases of sAML, including 24 myelodysplastic-related AML (AML-MR) patients, 6 post-myeloproliferative neoplasms (post-MPN) AML patients, and 5 t-AML patients. According to the European Leukemia Net (ELN) 2022 risk stratification, the favorable prognosis group, the intermediate prognosis group and the adverse prognosis group were 26.2% (16/61), 19.7% (12/61) and 54.1% (33/61), respectively. The overall response rate (ORR) after induction therapy was 74.2% in all patients group. The composite complete remission rate (CRc) and MRD negative rate were 72.6% and 65.4%, respectively. One patient (1.6%) died during induction. Grade 3 or 4 adverse events were mainly hematological toxicities. Comparing with the matched 63 patients including age and ELN risk stratification during the same period who using standard AZA+VEN regimen as induction therapy, no statistically significant difference in CRc and ORR between two groups was found. However, MRD negative rate in CMG+VEN group was significantly higher than AZA+VEN group (P=0.033), and hospitalization duration in CMG+VEN group was significantly shorter than AZA+VEN group (P=0.014). With a median follow-up of 9.5 months (IQR 4.5–15), the estimated 1-year overall survival was 81% (95% CI 74–89%) and 1-year event-free survival was 57% (48–70%). Conclusions: CMG+VEN represents a more safe alternative regimen in sAML and elderly AML patients, showing higher MRD negative rate and deserving further investigation.