Background: Acute myeloid leukemia (AML),which is the most common type of acute leukemia, is a clonal malignant hematological disease originated from hematopoietic stem cells, characterized with blocked differentiation, excessive proliferation, organs infiltration. "3+7" regimen [anthracyclines + cytarabine (Ara-c)] is the first choice of induction chemotherapy in young adult de novo AML, and cytarabine is always given by continuous intravenous infusion. It has been reported the concentration of Ara-CTP (active metabolite with anti-leukemia effect) was higher after subcutaneous injection than during continuous intravenous infusion for about 5 hours [Liliemark JO, Semin Oncol], and the subcutaneous injection is much more convenient and inexpensive for patients comparing to continuous intravenous infusion. However, no prospective, multicenter clinical evidenceto evaluate the efficacy and safety of subcutaneous injection administration compared with intravenous infusion of cytarabine.
Objective: To evaluated whether subcutaneous injection of cytarabine is noninferior to intravenous infusion of cytarabine in "3+7" induction regimen for young adult patients with de novo AML.
Design, setting and participants: Open-label, prospective, multicenter, noninferior, randomized clinical trial conducted in 10 hematological centers in China. Eligible patients (n=240) with de novo AML (exclude acute promyelocytic leukemia) has been enrolled. Patients were recruited between March 2015 and August 2017, with final follow-up in June 2020.
Interventions: Patients were randomized to receive idarubicin 10 mg/m2 for 3 days and cytarabine 100 mg/m2/d by continuous intravenous infusion daily for 7 days (n=120) or idarubicin 10 mg/m2 for 3 days and cytarabine 100mg/m2/d subcutaneous injection every 12 hours for 7 days (n=120).
Main outcomes and measures: The primary end point was the percentage of patients who achieved complete remission (CR). The noninferiority margin for the difference in CR was -15%. Secondary end points included overall survival (OS), event-free survival (EFS) and adverse events.
Results: Among 240 randomized patients, the baseline characteristics including sex, age, ECOG, white blood cell, blasts percentage, FAB subtype, karyotype and NPM1, FLTS-ITD, c-kit, CEBPA, DNMT3A, IDH1 and IDH2 mutations were similar between two groups. CR was achieved by 86 of 120 (71.7%) patients in subcutaneous injection group vs 85/120(70.8%) in intravenous injection (difference, 0.9%[1-sided 95% CI, -8.8% to ∞]); p value for noninferiority=0.003) after first cycle of induction therapy. CR was achieved by 93 of 120 (77.5%) patients in subcutaneous injection group vs 91/120(75.8%) in intravenous injection group (difference, 1.7% [1-sided 95% CI, -7.3% to ∞]); p value for noninferiority=0.001) after first two cycles of induction therapy. 3-year OS were 60% [95% CI:50%-69%]in subcutaneous injection group vs 58% [95% CI:49%-67%] in intravenous injection group (Figure 1A). After adjustment for sex, age, region, white blood cell, ECOG, platelet, FAB subtype, integrated risk and transplantation, the adjusted hazard ratio (AHR) of OS for subcutaneous vs intravenous was 0.95 [95% CI:0.62-1.47]. 3-year EFS were 49% [95% CI:39%-58%]in subcutaneous injection group vs 44% [95% CI:35%-53%] in intravenous injection group (Figure 1B). After adjustment for sex, age, region, white blood cell, ECOG, platelet, FAB subtype, integrated risk and transplantation, the HAR of EFS for subcutaneous vs intravenous was 0.84[95% CI:0.58-1.22]. No differences of hematologic toxicity, non-hematologic toxicity and early death rate were observed between two groups.
Conclusions: The efficacy of subcutaneous injection of cytarabine was non inferior to continuous intravenous infusion of cytarabine for the standard induction therapy in young adult de novo AML. The toxicity is equivalent between two groups. Subcutaneous injection of cytarabine offers a convenient and inexpensive alternative therapy to young adult de novo AML.
Trial registration: The trial was registered in the Chinese Clinical Trial Register, number ChiCTR-IPR-17012643.
No relevant conflicts of interest to declare.
