Venetoclax for arsenic‐resistant acute promyelocytic leukaemia

Arsenic plus all-trans retinoic acid (ATRA) as front-line treatment for acute promyelocytic leukaemia (APL) achieves a cure rate of over 90%.1 However, some patients still experience relapse due to arsenic resistance with or without PML mutations.2, 3 Patients with arsenic resistance have also been shown to be resistant to ATRA and conventional chemotherapies, and their survival outcomes were very poor.3 Novel drugs to overcome arsenic resistance are urgently needed. Venetoclax, a bcl2 inhibitor, has become a front-line treatment for elderly acute myeloid leukaemia (AML) patients,4 and it can suppress oxidative phosphorylation and selectively target leukaemic stem cells. High bcl2 expression and oxidative phosphorylation dependence of APL cells render venetoclax a promising candidate. In vitro, NB4 or primary APL cells were more sensitive to venetoclax than non-APL cells.5 Moreover, we found that PML-A216V/T-mutated APL cells from arsenic-resistant patients exhibited high sensitivity to venetoclax and high resistance to ATRA, arsenic trioxide and daunorubicin (Figure 1D). Venetoclax could induce apoptosis of PML-mutated APL cells at a clinically feasible concentration (1–5 μM). Clinically, we empirically found that a priming regimen of CAG (cytarabine, aclarubin and granulocyte colony-stimulating factor) could eliminate minimal residual disease in APL patients. Therefore, we performed a pilot study to evaluate the venetoclax plus CAG regimen (V-CAG) for the treatment of arsenic-resistant relapsed and refractory APL. The study was approved by the Institutional Review Board of the First Affiliated Hospital, Zhejiang University School of Medicine (No.960) and was conducted in accordance with the principles of the Declaration of Helsinki. From January 2020 to May 2021, nine patients were enrolled. The V-CAG regimen is shown in Figure 1A. The median age of the patients was 35 years, and the number of relapses is three (range 1–6). All patients were resistant to arsenic prior to receiving the V-CAG treatment. Eight patients achieved complete remission (CR), among whom three achieved complete molecular remission (CMR), and one achieved partial remission (PR) (Figure 1B). The haematological toxicities were mild (Figure 1C). Three patients had infections (grade 2–3), and no tumour lysis syndrome occurred during V-CAG treatment. One to two cycles of the V-CAG regimen was used as a post-remission treatment. Two patients received allo-HSCT, and the others received venetoclax as one month on and one month off cycles as maintenance therapy. As of 20 July 2021, nine patients were alive (eight in continuous CR, one in PR). Here, we demonstrated for the first time that venetoclax-based treatment can overcome arsenic resistance in APL patients with a high CR rate and potential survival advantage. We previously reported that 11 out 13 arsenic-resistant APL patients died rapidly when treated with conventional chemotherapy.2 However, in this study, all nine arsenic-resistant patients achieved CR/PR and were still alive after receiving venetoclax-based treatment. Moreover, the V-CAG regimen showed good safety with mild marrow suppression, and no tumour lysis syndromes or deaths occurred. A larger sample size and longer follow-up period are warranted. This work was supported by grants from the Leading Innovative and Entrepreneur Team Introduction Programme of Zhejiang (2020R01006 and 2019R01001 to Hong-Hu Zhu). The authors declare no competing financial interests. Hong-Hu Zhu, Hua Naranmandura and Jie Jin had full access to all of the data and take responsibility for the data integrity and analysis; Qian Qian Wang, Hua-Feng Wang and Jian-Zhi Zhao contributed to the molecular analysis and data collection, and all authors contributed to the final draft.