Venetoclax As a Cytoreduction Therapy for Acute Promyelocytic Leukaemia: A Single-Centre Experience.

The prognosis of paediatric acute promyelocytic leukaemia (APL) has been significantly improved with all-trans-retinoic acid (ATRA) and arsenic.1, 2 However, the early death within 30 days of induction therapy continues to present a significant challenge in achieving successful outcomes for all patients with APL.3 As such, the rational utilization of cytoreduction therapy plays a crucial role in reducing early mortality rates of APL.4 Since traditional cytoreduction agents can lead to severe disseminated intravascular coagulation (DIC) and even death, the development of novel cytoreduction agents to minimize early mortality is urgently needed. Venetoclax, a BCL-2 inhibitor, has been demonstrated effective for adult relapsed/refractory APL.5 However, there are no reports on the efficacy and safety of venetoclax in paediatric APL. In this study, we first used low-dose venetoclax as a cytoreduction therapy for APL and obtained a very encouraging result. From December 2021 to March 2023, 11 children with APL were enrolled (Table 1), and treated with arsenic combined with ATRA for induction and consolidation therapy (ChiCTR2100052966) (Figure S1), which was approved by the Medical Ethics Committee of Beijing Children's Hospital, Capital Medical University. Additionally, an informed consent form for the use of venetoclax beyond the instructions was signed by all the patients or their legal guardians. Of the 11 patients with APL, 6 (Cases 1–6) were treated with traditional cytoreduction therapy, and 5 patients (Cases 7–11) were treated with venetoclax cytoreduction therapy (Table 1). Eight of the 11 patients achieved haematological complete remission (HCR) on Day 28 of induction, and all patients achieved molecular complete remission (MCR) on Day 28 of the first consolidation, except for one (Case 1), who finally achieved MCR on the day of repeated consolidation. The median times to achieve HCR and MCR were 28 days (26–69 days) and 68 days (42–104 days) respectively. None of the children had serious adverse events during induction (Table S1). In contrast to conventional cytoreduction therapy, the use of venetoclax cytoreduction therapy resulted in the suspension of ATRA and arsenic in only one out of the five patients, primarily due to suspected or confirmed differentiation syndrome (DS). Conversely, in the group treated with conventional cytoreduction, ATRA and arsenic were suspended in five of the six patients. All patients treated with venetoclax achieved HCR on Day 28 of induction, but only three of the six patients treated with traditional cytoreduction achieved HCR on Day 28 of induction. In addition, leucocyte counts decreased to trough levels on Days 4–5 after one to three doses of venetoclax (Figure 1). Compared with the Case 2 treated with traditional cytoreduction, the Case 8 with venetoclax cytoreduction, who showed consistent clinical features at diagnosis, had no significant increase in leucocyte counts. Furthermore, there was no need to interrupt targeted therapy due to suspected or confirmed DS. The patient achieved HCR on Day 28 of induction and MCR on Day 28 of consolidation. The primary cause of early mortality in APL is typically life-threatening coagulopathy4 with a variety of clinical manifestations, including life-threatening bleeding and venous or arterial thrombosis.6 This study reveals that thrombosis may be an underestimated and potentially life-threatening manifestation of coagulopathy in APL patients, aligning with previous findings.4 Fortunately, all of patients experiencing life-threatening coagulopathy in our study survived and achieved HCR and MCR during continued consolidation therapy. Moreover, our study suggests that venetoclax as cytoreduction regimen exhibits potential advantages, including reduced reliance on platelet and plasma infusion, and a lower incidence of DS. Thus, compared to traditional cytoreduction, venetoclax may be a more favourable option as a cytoreduction therapy for APL patients. In summary, based on our clinical experience, venetoclax demonstrated effective and safety as a cytoreduction therapy for paediatric APL. However, the further confirmation is required through the expansion of the sample size in future studies. Currently, a prospective study in multiple centres across China, led by our hospital (ChiCTR2300069288), to gather additional evidence and validate these findings. Huyong Zheng designed the study. Peijing Qi, Linya Wang and Hongqiao Li collected the data. Linya Wang and Huyong Zheng wrote the paper. All authors treated the patients and reviewed the paper and gave final approval. This work was supported by the National Natural Science Foundation of China (NSFC) (No. 82070154), Beijing Natural Science Foundation (No. 7222056) and Capital's Funds for Health Improvement and Research (CFH) (No. 2022-1-2091). No potential conflict of interest is reported by any of the authors. The primary treatment of acute promyelocytic leukaemia in this study was based on the CCLGA-APL 2021 protocol (ChiCTR2100052966). Besides, to further validate our findings, a prospective study in multiple centres across China, led by our hospital (ChiCTR2300069288). Figure S1. Figure S2. Table S1. Table S2. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.