Efficacy and Safety of ATRA+ATO/RIF+venetoclax combination therapy in the treatment of adult acute promyelocytic leukemia

Abstract Objective: To evaluate the efficacy and safety of the triple-combination therapy consisting of all-trans retinoic acid (ATRA), arsenic trioxide (ATO)/realgar-indigo naturalis formula (RIF), and venetoclax in adult patients with acute promyelocytic leukemia (APL). Methods: From February 2025 to July 2025, twenty-six adult APL patients admitted to the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences, received induction therapy with ATRA+ATO/RIF+venetoclax. The treatment regimen included ATRA (30 mg/m²/day for 4–6 weeks), ATO (0.15 mg/kg/day intravenous infusion) or RIF (60 mg/kg/day orally) total for 4-6weeks, and venetoclax (72 hours after oral administration of ATRA, starting at 100 mg/d on first day and escalating to 200 mg/d for 1 week in low-risk group, 400 mg/d for 1 week in high-risk group). After achieving remission with induction therapy, the low-risk group received two courses of consolidation chemotherapy (ATRA 2 weeks on/2 weeks off, RIF 3 weeks on/1 week off, Venetoclax 200mg 1 week on/3 weeks off. The high-risk group received 3 cycles (Venetoclax 400mg 1 week on/3 weeks off, ATRA and RIF were same as the low-risk group). The primary endpoint was complete remission (CR) rates. We also analyzed the time to correction of coagulopathy the incidence of differentiation syndrome (DS). Diagnosis of DS was made according to the presence of the following signs and symptoms described by Frankel et al. Meeting at least two criteria: dyspnoea, unexplained fever, weight gain greaterthan 5 kg, unexplained hypotension, acute renal failure, and a chest radiograph demonstrating pulmonary infiltrates or pleuropericardial effusion. Results: The cohort comprised 26 patients, stratified into low-risk (n=23) and high-risk (n=3) groups. Baseline characteristics revealed a median age of 48 (range: 36-56) years old with the following hematologic parameters: median WBC count 2.2(range: 0.9-6.3)×10⁹/L, hemoglobin 87 (range: 70-109) g/L, and platelet count 20 (range: 10-40)×10⁹/L. During induction chemotherapy, the peak in leucocyte count was reached in the vast majority of cases within the first week from diagnosis, with only a minority of patients presenting it in the second or third week. The median time to peak leukocyte count was 4 (range: 2–5) days with a median peak leukocyte level of 8.2 (range: 1.6–21.4) ×10⁹/L. One high-risk patient exhibited a progressive leukocyte increase from 35×10⁹/L to 100×10⁹/L, which was subsequently controlled with the addition of cytarabine. The median time to coagulopathy correction was 9 (range: 6–13) days. Treatment-related adverse events including Arsenic-related hepatotoxicity, occurred in 5(19.2%) patients; none of the enrolled patients developed QTc prolongation (defined as absolute value >480 ms) or cardiac adverse events. Beyond these findings, leukocytosis with fever occurred in 4 cases (15.4%), no instances of differentiation syndrome were observed. Additionally, no deaths occurred during the induction phase (within 30 days) with a median hospitalization duration of 14 (range: 11–16) days. After completion of induction chemotherapy, morphologic complete remission (CR) was achieved in all (100%) patients, flow cytometry-based minimal residual disease (MRD) negativity rate was 100%, while complete molecular remission (CMR, PML-RARα negativity by quantitative reverse-transcription PCR) was achieved in 13 (50%) patients. In subsequent follow-up, 21 patients achieved CMR, the median time to achieve CMR was 49 days (range: 42–72). Conclusion: The ATRA + ATO/RIF + venetoclax triple regimen shortened the time to peak leukocyte count and reduced the incidence of differentiation syndrome, compared to previous anthracycline-based combination chemotherapy regimens. The regimen demonstrated rapid hematologic remission and a favorable safety profile in APL induction therapy, showed no significant difference in the median time to achieve CMR. Randomized controlled trials are warranted to validate its potential as a novel first-line treatment option for APL, particularly in high-risk patients. [Keywords]: All-trans retinoic acid; Arsenic trioxide; Venetoclax; Acute promyelocytic leukemia.