Azacitidine, Homoharringtonine and Cytarabine Combined with Granulocyte Colony-Stimulating Factor As Frontline Treatment for Older Patients with Acute Myeloid Leukemia: A Prospective, Multicenter, Single-Arm Phase III Study in China

Background:

Treatment of older patients or those deemed unfit for intensive chemotherapy with acute myeloid leukemia (AML) remains challenging. A number of novel treatments are therefore being explored, such as DNA hypomethylating agents (HMAs) and B-cell leukemia/lymphoma-2 (BCL-2) inhibitor and gemtuzumab ozogamicin. Complete remission (CR) and CR with incomplete count recovery (CRi) rate is 54-67%, and median overall survival (OS) is 10.1-14.7 months (DiNardo CD, et al. N Engl J Med 2020;383:617-629; Wei AH, et al. J Clin Oncol 2019;37:1277-1284; Sylvie D Freeman. Blood. 2023;142(20):1697-1707). In China, homoharringtonine (HHT), which has been shown to overcome some adverse prognostic factors, is widely used in treating AML (Shuqing Lü, et al. J Hematol Oncol 2014;7:2). HHT and cytarabine (Ara-C) combined with granulocyte colony-stimulating factor (G-CSF) (HAG) regime is proved to be beneficial for treating relapsed or refractory AML patients (Mixue Xie, et al. PLoS One 2016;11(10):e0164238).

Objective:

To evaluate the efficacy and toxicity of azacitidine combined with HAG regime in patients over 60 years of age with untreated AML ineligible for intensive induction chemotherapy.

Design, setting and participants:

An open label, prospective, multicenter, single-arm phase III clinical trial was conducted at 11 clinical medical centers in China from May 2020 to April 2024. Patients newly diagnosed with AML, aged over 65, or between 60 and 65 without eligibility for standard chemotherapy, were enrolled in this study.

Interventions:

Patients received azacitidine 70mg/m²/day (no more than 100mg) subcutaneously, days 1-7, G-CSF 5μg/kg/day (Suspension of medication if white blood cells > 20*10⁹/L) subcutaneously, days 3-10, HHT1.4mg/m²/day by intravenous continuous infusion, days 4-8, Ara-C 10mg/m²/12h by intravenous continuous infusion, days 4-10. One cycle of treatment per month for one year, with a total of no less than 9 cycles as induction and consolidation treatment. Maintenance therapy is azacitidine 70 mg/m²/day (no more than 100mg) for seven consecutive days every month up to 1 year, with a total of no less than 10 cycles. The primary endpoint was overall response rate (ORR; include CR, CRi and partial response) after two cycles of azacitidine combined with HAG treatment.

Main outcomes and measures:

70 eligible patients were enrolled including 39 males and 31 females and the median age was 69 years old (61-84 years). Favorable, intermediate, and adverse risk groups were represented by 20.9%, 35.8%, and 43.3%, respectively. ORR was 80.3% for two cycles, and 71.2% for one cycle. CR rate was 60.6% for two cycles, and 47.0% for one cycle. In the adverse risk group, ORR was 77.8% and CR rate was 53.8% for two cycles. The 30-day mortality rate was only 2.9%. After a median follow-up of 11 months (0.4-45.4 months), the median OS was 28.7 months and the median event-free survival was 14.1 months. Both response rates and survival times appear to be better than those reported for venetoclax combined with azacytidine. In addition, this protocol was well tolerated. Although more than 92% of patients had grade 3 or above neutropenia, anemia, or thrombocytopenia, only two early deaths were reported. One patient died from cerebral hemorrhage and another from pulmonary infection and pulmonary hemorrhage, both of which occurred during the myelosuppression period following chemotherapy. In the first cycle of chemotherapy, 34 case times of grade 3-4 non-hematological adverse events were reported, representing 18.6% of reported events. Among them, lung infections (12.0%) and septicaemia (1.6%) were the most common.

Conclusions:

Azacitidine combined with HAG regime is effective and well tolerated in older, medically unfit patients with acute myeloid leukemia. More randomized control clinical trials are needed to confirm the advantages of this regimen over venetoclax combined with azacytidine.