The Acute Promyelocytic Leukemia (APL) Asian Consortium analyzed a contemporaneous cohort of newly diagnosed patients with APL treated with and without frontline arsenic trioxide (ATO) in 6 centers. The objectives were to define the impact of ATO on early deaths and relapses and its optimal positioning in the overall treatment strategy. In a 21.5-year period, 324 males and 323 females at a median age of 45.5 years (range, 18.1-91.8; low/intermediate risk, n = 448; high risk, n = 199) were treated. Regimens included frontline all-trans retinoic acid (ATRA)/chemotherapy and maintenance with/without ATO (n = 436), ATRA/IV-ATO/chemotherapy (ATRA/IV-ATO; n = 61), and ATRA/oral-ATO/ascorbic acid with ATO maintenance (oral-AAA; n = 150). The ATRA/chemotherapy group had significantly more frequent early deaths within 60 days (8.3% vs 3.3%; P = .05), inferior 60-day survival (91.7% vs 98.4%/96%; P < .001), inferior 5-year relapse-free survival (RFS; 76.9% vs 92.8%/97.8%; P < .001), and inferior 5-year overall survival (OS; 84.6% vs 91.4%/92.3%; P = .03) than ATO-containing groups (ATRA/IV-ATO and oral-AAA). The addition of oral-ATO maintenance partly mitigated the inferior 5-year RFS resulting from the omission of ATO during induction (ATRA/chemotherapy/non-ATO maintenance vs ATRA/chemotherapy/ATO maintenance vs ATRA/IV-ATO vs oral-AAA, 71.1% vs 87.9% vs 92.8% vs 97.8%; P < .001). The favorable survival impacts of ATO were observed in all risk groups. In conclusion, ATO decreased early deaths, improved 60-day survival, and resulted in significantly superior RFS and OS. This trial was registered at www.clinicaltrials.gov as #NCT04251754.

1. Tallman, M. S., & Altman, J. K. (2009). How I treat acute promyelocytic leukemia. Blood, 114(25), 5126–5135.
2. Khoury, J. D., Solary, E., Abla, O., et al. (2022). The 5th edition of the World Health Organization classification of haematolymphoid tumours: Myeloid and histiocytic/dendritic neoplasms. Leukemia, 36(7), 1703–1719.
3. Tallman, M. S., Andersen, J. W., Schiffer, C. A., et al. (2002). All-trans retinoic acid in acute promyelocytic leukemia: Long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood, 100(13), 4298–4302.
4. Lengfelder, E., Haferlach, C., Saussele, S., et al. (2009). High-dose Ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: Long-term results of the German AMLCG. Leukemia, 23(12), 2248–2258.
5. Lo-Coco, F., Avvisati, G., Vignetti, M., et al. (2010). Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: Results of the AIDA-2000 trial of the GIMEMA Group. Blood, 116(17), 3171–3179.
6. Kelaidi, C., Chevret, S., De Botton, S., et al. (2009). Improved outcome of acute promyelocytic leukemia with high WBC counts over the last 15 years: The European APL Group experience. Journal of Clinical Oncology, 27(16), 2668–2676.
7. Hu, J., Liu, Y. F., Wu, C. F., et al. (2009). Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America, 106(9), 3342–3347.
8. Iland, H. J., Bradstock, K., Supple, S. G., et al. (2012). All-trans-retinoic acid, idarubicin, and intravenous arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood, 120(8), 1570–1580.
9. Lo-Coco, F., Avvisati, G., Vignetti, M., et al. (2013). Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. The New England Journal of Medicine, 369(2), 111–121.
10. Abaza, Y., Kantarjian, H., Garcia-Manero, G., et al. (2017). Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood, 129(10), 1275–1283.
11. Burnett, A. K., Russell, N. H., Hills, R. K., et al. (2015). Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia in all risk groups (AML17): Results of a randomised, controlled, phase 3 trial. The Lancet Oncology, 16(13), 1295–1305.
12. Silva, W. F. da, Rosa, L. I. da, Marquez, G. L., et al. (2019). Real-life outcomes on acute promyelocytic leukemia in Brazil: Early deaths are still a problem. Clinical Lymphoma, Myeloma & Leukemia, 19(2), e116–e122.
13. Corrêa de Araujo Koury, L., Ganser, A., Berliner, N., & Rego, E. M. (2017). Treating acute promyelocytic leukaemia in Latin America: Lessons from the International Consortium on Acute Leukaemia experience. British Journal of Haematology, 177(6), 979–983.
14. Geer, M. J., Foucar, C. E., Devata, S., et al. (2021). Clinical availability of ATRA for patients with suspected acute promyelocytic leukemia: Why guidelines may not be followed. Journal of the National Comprehensive Cancer Network, 19(11), 1272–1275.
15. Sanz, M. A., Fenaux, P., Tallman, M. S., et al. (2019). Management of acute promyelocytic leukemia: Updated recommendations from an expert panel of the European LeukemiaNet. Blood, 133(15), 1630–1643.
16. Cyranoski, D. (2007). Arsenic patent keeps drug for rare cancer out of reach of many. Nature Medicine, 13(9), 1005–1006.
17. Gill, H., Yim, R., Lee, H. K. K., et al. (2018). Long-term outcome of relapsed acute promyelocytic leukemia treated with oral arsenic trioxide-based reinduction and maintenance regimens: A 15-year prospective study. Cancer, 124(11), 2316–2326.
18. Gill, H., Kumana, C. R., Yim, R., et al. (2019). Oral arsenic trioxide incorporation into frontline treatment with all-trans retinoic acid and chemotherapy in newly diagnosed acute promyelocytic leukemia: A 5-year prospective study. Cancer, 125(17), 3001–3012.
19. Gill, H. S., Yim, R., Kumana, C. R., Tse, E., & Kwong, Y. L. (2020). Oral arsenic trioxide, all-trans retinoic acid, and ascorbic acid maintenance after first complete remission in acute promyelocytic leukemia: Long-term results and unique prognostic indicators. Cancer, 126(14), 3244–3254.
20. Gill, H., Raghupathy, R., Lee, C. Y., et al. (2023). Acute promyelocytic leukaemia: Population-based study of epidemiology and outcome with ATRA and oral ATO from 1991 to 2021. BMC Cancer, 23(1), 141.
21. Siu, C. W., Au, W. Y., Yung, C., et al. (2006). Effects of oral arsenic trioxide therapy on QT intervals in patients with acute promyelocytic leukemia: Implications for long-term cardiac safety. Blood, 108(1), 103–106.
22. Kumana, C. R., Mak, R., Kwong, Y. L., & Gill, H. (2020). Resurrection of oral arsenic trioxide for treating acute promyelocytic leukaemia: A historical account from bedside to bench to bedside. Frontiers in Oncology, 10, 1294.
23. ClinicalTrials.gov. (2022). The Acute Promyelocytic Leukaemia Asian Consortium (APL-AC) project (Clinical trial registration No. NCT04251754). https://classic.clinicaltrials.gov/ct2/show/NCT04251754
24. Sanz, M. A., Fenaux, P., Tallman, M. S., et al. (2019). Management of acute promyelocytic leukemia: Updated recommendations from an expert panel of the European LeukemiaNet. Blood, 133(15), 1630–1643.
25. Sanz, M. A., Montesinos, P., Rayon, C., et al. (2010). Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: Further improvements in treatment outcome. Blood, 115(25), 5137–5146.
26. Gill, H., Yim, R., Chin, L., et al. (2023). S133: An entirely oral regimen of oral ATO, ATRA and ascorbic acid in risk-adapted treatment of newly diagnosed APL resulted in excellent clinical/molecular responses with durable remission. HemaSphere, 7(Suppl. 3), e462409a.
27. Sanz, M. A., & Montesinos, P. (2010). Risk-adapted treatment for low- and intermediate-risk acute promyelocytic leukemia. Clinical Lymphoma, Myeloma & Leukemia, 10(Suppl. 3), S130–S134.
28. Mendes, F. R., da Silva, W. F., da Costa Bandeira de Melo, R., et al. (2022). Predictive factors associated with induction-related death in acute myeloid leukemia in a resource-constrained setting. Annals of Hematology, 101(1), 147–154.
29. Koury, L. C. d. A., Kim, H. T., Undurraga, S., et al. (2024). Clinical networking results in continuous improvement of the outcome of patients with acute promyelocytic leukemia. Blood, 144(12), 1257–1270.
30. Guarnera, L., Lehmann, S., Döhner, K., et al. (2023). Long-term outcome of 1296 patients newly diagnosed with APL: A Harmony Alliance study. Blood, 142(Suppl. 1), 727.
31. Naymagon, L., Moshier, E., Tremblay, D., & Mascarenhas, J. (2019). Predictors of early hemorrhage in acute promyelocytic leukemia. Leukemia & Lymphoma, 60(10), 2394–2403.
32. Chang, H., Kuo, M. C., Shih, L. Y., et al. (2012). Clinical bleeding events and laboratory coagulation profiles in acute promyelocytic leukemia. European Journal of Haematology, 88(4), 321–328.
33. Hou, W., Zhang, Y., Jin, B., et al. (2019). Factors affecting thrombohemorrhagic early death in patients with acute promyelocytic leukemia treated with arsenic trioxide alone. Blood Cells, Molecules, and Diseases, 79, 102351.
34. Mantha, S., Goldman, D. A., Devlin, S. M., et al. (2017). Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era. Blood, 129(13), 1763–1767.
35. Gurnari, C., Breccia, M., Di Giuliano, F., et al. (2021). Early intracranial haemorrhages in acute promyelocytic leukaemia: Analysis of neuroradiological and clinico-biological parameters. British Journal of Haematology, 193(1), 129–132.
36. Sun, J., Zhu, J., Zhou, D., et al. (2019). Factors affecting early death and survival of patients with acute promyelocytic leukemia treated with ATRA-based therapy regimens. Clinical Lymphoma, Myeloma & Leukemia, 19(1), e63–e70.
37. Jacomo, R. H., Melo, R. A., Souto, F. R., et al. (2007). Clinical features and outcomes of 134 Brazilians with acute promyelocytic leukemia who received ATRA and anthracyclines. Haematologica, 92(10), 1431–1432.
38. Lehmann, S., Ravn, A., Carlsson, L., et al. (2011). Continuing high early death rate in acute promyelocytic leukemia: A population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia, 25(7), 1128–1134.
39. Park, J. H., Qiao, B., Panageas, K. S., et al. (2011). Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood, 118(5), 1248–1254.
40. Chen, Y., Kantarjian, H., Wang, H., Cortes, J., & Ravandi, F. (2012). Acute promyelocytic leukemia: A population-based study on incidence and survival in the United States, 1975–2008. Cancer, 118(23), 5811–5818.
41. McClellan, J. S., Kohrt, H. E., Coutre, S., et al. (2012). Treatment advances have not improved the early death rate in acute promyelocytic leukemia. Haematologica, 97(1), 133–136.
42. Paulson, K., Serebrin, A., Lambert, P., et al. (2014). Acute promyelocytic leukaemia is characterized by stable incidence and improved survival that is restricted to patients managed in leukaemia referral centres: A pan-Canadian epidemiological study. British Journal of Haematology, 166(5), 660–666.
43. Rahme, R., Thomas, X., Recher, C., et al. (2014). Early death in acute promyelocytic leukemia in French centers: A multicenter study in 399 patients. Leukemia, 28(12), 2422–2424.
44. Guru Murthy, G. S., Szabo, A., Michaelis, L., et al. (2020). Improving outcomes of acute promyelocytic leukemia in the current era: Analysis of the SEER database. Journal of the National Comprehensive Cancer Network, 18(2), 169–175.
45. Kayser, S., Rahme, R., Martinez-Cuadron, D., et al. (2020). Outcome of older patients aged 70 years or older with APL treated frontline with or without arsenic trioxide: An international collaborative study. Leukemia, 34(9), 2333–2341.
46. Altman, J. K., Rademaker, A., Cull, E., et al. (2013). Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed, contributing to early hemorrhagic death. Leukemia Research, 37(9), 1004–1009.
47. Gill, H., Yung, Y., Chu, H. T., et al. (2021). Characteristics and predictors of early hospital deaths in newly diagnosed APL: A 13-year population-wide study. Blood Advances, 5(14), 2829–2838.
48. Rego, E. M., Kim, H. T., Ruiz-Argüelles, G. J., et al. (2013). Improving acute promyelocytic leukemia outcome in developing countries through networking: Results of the International Consortium on APL. Blood, 121(11), 1935–1943.
49. Platzbecker, U., Avvisati, G., Cicconi, L., et al. (2017). Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: Final results of the randomized Italian-German APL0406 trial. Journal of Clinical Oncology, 35(6), 605–612.
50. Gao, Y., Xi, Y., Chen, W., Meng, Y., & Su, Y. (2024). Early predictor for differentiation syndrome in newly diagnosed acute promyelocytic leukaemia patients treated with single-agent arsenic trioxide. Annals of Hematology, 103(10), 3947–3954.
51. Zhang, J., Zhang, Y., Wang, W., Li, C., & Zhang, Z. (2018). Double-sided personality: Effects of arsenic trioxide on inflammation. Inflammation, 41(4), 1128–1134.
52. Sanz, M. A., & Montesinos, P. (2014). How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood, 123(18), 2777–2782.
53. Kwaan, H. C., Weiss, I., & Tallman, M. S. (2019). The role of abnormal hemostasis and fibrinolysis in morbidity and mortality of acute promyelocytic leukemia. Seminars in Thrombosis and Hemostasis, 45(6), 612–621.
54. Kwaan, H. C., & Cull, E. H. (2014). The coagulopathy in acute promyelocytic leukaemia: What have we learned in the past twenty years? Best Practice & Research Clinical Haematology, 27(1), 11–18.
55. Sanz, M. A., Montesinos, P., Vellenga, E., et al. (2008). Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: Long-term outcome of the LPA99 multicenter study by the PETHEMA Group. Blood, 112(8), 3130–3134.
56. de Botton, S., Sanz, M. A., Chevret, S., et al. (2006). Extramedullary relapse in acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy. Leukemia, 20(1), 35–41.
57. Montesinos, P., Diaz-Mediavilla, J., Deben, G., et al. (2009). Central nervous system involvement at first relapse in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline monochemotherapy without intrathecal prophylaxis. Haematologica, 94(9), 1242–1249.
58. Au, W. Y., Tam, S., Fong, B. M., & Kwong, Y. L. (2008). Determinants of cerebrospinal fluid arsenic concentration in patients with acute promyelocytic leukemia on oral arsenic trioxide therapy. Blood, 112(9), 3587–3590.
59. Yanada, M., Tsuzuki, M., Fujita, H., et al. (2013). Phase 2 study of arsenic trioxide followed by autologous hematopoietic cell transplantation for relapsed acute promyelocytic leukemia. Blood, 121(16), 3095–3102.
60. Ramadan, S. M., Di Veroli, A., Camboni, A., et al. (2012). Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia in the ATRA and ATO era. Haematologica, 97(11), 1731–1735.
61. Ganzel, C., Mathews, V., Alimoghaddam, K., et al. (2016). Autologous transplant remains the preferred therapy for relapsed APL in CR2. Bone Marrow Transplantation, 51(9), 1180–1183.