Harinder Gill
Nigel Russell
Yok-Lam Kwong- 1Department of Medicine, School of Clinical Medicine, Li Ka Shing (LKS) Faculty of Medicine, the University of Hong Kong, Hong Kong, Hong Kong SAR, China
- 2Department of Haematology, Nottingham City Hospital and University of Nottingham, Nottingham, United Kingdom
Editorial on the Research Topic
Acute promyelocytic leukemia - towards a chemotherapy-free approach to cure in all patients, Volume II
In the real-world setting, early death (ED) is an important factor compromising the outcome of newly-diagnosed acute promyelocytic leukemia (APL). In population-based studies of unselected patients with newly-diagnosed APL, ED rates of 10-60% were reported (1–14). The development of international recommendations for managing APL has led to a gradual improvement of ED with time, falling from 28% in the 1990s to approximately 15% in past two decades (14–16).. Risk factors for EDs included older age, high-risk disease, poor performance status and co-existing infections (17). Furthermore, factors that increased fatal hemorrhages, including high leucocyte count, elevated lactate dehydrogenase, low fibrinogen, impaired coagulation parameters and APL differentiation syndrome (APL-DS), also increased EDs (18–22). Delays in the administration of all-trans retinoic acid (ATRA) was also a major factor contributing to EDs at the community care level (22, 23). In large epidemiologic studies, delayed ATRA administration, leukocytosis and hemostatic abnormalities were major predictors for ED. In this volume, Wen et al. highlighted the contributions of Sanz low- and intermediate-risks and other clinical and hematologic parameters to EDs.
APL-DS is another important cause of mortality and morbidity in newly-diagnosed APL. Leukocytosis at presentation is a key predictor of APL-DS, which may be attenuated or prevented by the early use of chemotherapy. However, the impact chemotherapy-free induction with ATRA and arsenic trioxide (ATO) on the incidence, duration and sequelae of APL-DS is not well-defined. LaBella et al. retrospectively compared two cohorts of patients receiving ATRA/ATO with or without chemotherapy as induction therapy, with respect to changes in hematological parameters and the incidence and duration of APL-DS.
Less than 2% of patients with APL by morphology harbor gene fusion transcripts other than PML::RARA. These atypical fusion transcripts significantly impact on responses to ATRA and ATO. Guarnera et al. comprehensively reviewed acute myeloid leukemia (AML) with RARA rearrangements or rearrangements involving other members of the retinoic acid receptors including RARB and RARG. Ding et al. further described a case of AML with HNRNPC::RARG that morphologically mimicked APL. RNA sequencing is an important diagnostic tool for patients with AML driven by gene fusions. Liu et al. described the utility of RNA-sequencing in identifying novel fusions not detectable with conventional karyotyping, using AML with FIP1L1::RARA as an example.
With evolving therapeutic strategies, the demographics and epidemiology of APL are also changing. Ethnic differences in the incidences of APL are emerging, together with a shift in the peak age at presentation to the elderly (5, 14, 24). Furthermore, the curability of APL brings into focus the long-term safety of treatment, especially the development of second primary cancers (25, 26). Kumana et al. described how changes the introduction of oral-ATO-based regimens impacted on the epidemiology and prevalence of APL in Hong Kong. They further explored the potential repurposing of oral-ATO in other conditions, which included nucleophosmin-1 (NPM1)-mutated AML, multiple myeloma, mantle cell lymphoma, lung cancers, systemic lupus erythematosus, graft-versus-host disease and idiopathic pulmonary fibrosis (27–39).
To conclude this volume, Iyer et al. and Masetti et al. summarized the current treatment paradigms and future directions in the management of adult and pediatric patients with APL. The advent of ATO has significantly changed frontline protocols, with most induction regimens currently incorporating intravenous ATO with ATRA with or without chemotherapy (40–44), which have resulted in complete remission rates of 90–100% and long-term survivals of 86–97%. The role of oral-ATO formulated in Hong Kong has also emerged (45), and shown to be efficacious for APL in first relapse (R1), inducing second complete remission (CR2) in more than 90% of patients (46, 47). In the CR1 maintenance setting, oral-ATO-based regimens were safe and resulted in favorable survivals (48). Oral-ATO has been advanced into frontline protocols since 2013 with excellent long-term outcome (49, 50). In the real-world setting, oral-ATO-based induction in newly diagnosed APL reduced EDs, prevented relapses and improved overall survivals (51).
Author contributions
HG conceived the Research Topic, wrote and approved the manuscript. NR and Y-LK co-edited the Research Topic and approved the manuscript. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Jacomo RH, Melo RA, Souto FR, de Mattos ER, de Oliveira CT, Fagundes EM, et al. Clinical features and outcomes of 134 brazilians with acute promyelocytic leukemia who received ATRA and anthracyclines. Haematologica (2007) 92(10):1431–2. doi: 10.3324/haematol.10874
2. Serefhanoglu S, Buyukasik Y, Goker H, Sayinalp N, Haznedaroglu IC, Aksu S, et al. Clinical features and outcomes of 49 Turkish patients with acute promyelocytic leukemia who received ATRA and anthracyclines (PETHEMA protocol) therapy. Leuk Res (2010) 34(12):e317–9. doi: 10.1016/j.leukres.2010.07.027
3. Lehmann S, Ravn A, Carlsson L, Antunovic P, Deneberg S, Mollgard L, et al. Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish adult acute leukemia registry. Leukemia (2011) 25(7):1128–34. doi: 10.1038/leu.2011.78
4. Park JH, Qiao B, Panageas KS, Schymura MJ, Jurcic JG, Rosenblat TL, et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood (2011) 118(5):1248–54. doi: 10.1182/blood-2011-04-346437
5. Chen Y, Kantarjian H, Wang H, Cortes J, Ravandi F. Acute promyelocytic leukemia: a population-based study on incidence and survival in the United States, 1975-2008. Cancer (2012) 118(23):5811–8. doi: 10.1002/cncr.27623
6. Jeddi R, Ghedira H, Ben Amor R, Ben Abdennebi Y, Karima K, Mohamed Z, et al. Treatment of acute promyelocytic leukemia with AIDA based regimen. Update of a Tunisian single center study. Mediterr J Hematol Infect Dis (2011) 3(1):e2011033. doi: 10.4084/MJHID.2011.033
7. McClellan JS, Kohrt HE, Coutre S, Gotlib JR, Majeti R, Alizadeh AA, et al. Treatment advances have not improved the early death rate in acute promyelocytic leukemia. Haematologica (2012) 97(1):133–6. doi: 10.3324/haematol.2011.046490
8. Pagoni M, Garofalaki M, Panitsas F, Manola K, Psarra K, Economopoulos P, et al. Acute promyelocytic leukemia: an experience on 95 greek patients treated in the all-trans-retinoic acid era. Mediterr J Hematol Infect Dis (2011) 3(1):e2011053. doi: 10.4084/MJHID.2011.053
9. Imagawa J, Harada Y, Shimomura T, Tanaka H, Okikawa Y, Harada H. High early death rate in elderly patients with acute promyelocytic leukemia treated with all-trans retinoic acid combined chemotherapy. Int J Hematol (2013) 98(2):264–6. doi: 10.1007/s12185-013-1390-0
10. Paulson K, Serebrin A, Lambert P, Bergeron J, Everett J, Kew A, et al. 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. Br J Haematol (2014) 166(5):660–6. doi: 10.1111/bjh.12931
11. Karim F, Shaikh U, Adil SN, Khurshid M. Clinical characteristics, outcome and early induction deaths in patients with acute promyelocytic leukaemia: a five-year experience at a tertiary care centre. Singapore Med J (2014) 55(8):443–7. doi: 10.11622/smedj.2014105
12. Bajpai J, Sharma A, Kumar L, Dabkara D, Raina V, Kochupillai V, et al. Acute promyelocytic leukemia: an experience from a tertiary care centre in north India. Indian J Cancer (2011) 48(3):316–22. doi: 10.4103/0019-509X.84938
13. Rahme R, Thomas X, Recher C, Vey N, Delaunay J, Deconinck E, et al. Early death in acute promyelocytic leukemia (APL) in French centers: a multicenter study in 399 patients. Leukemia (2014) 28(12):2422–4. doi: 10.1038/leu.2014.240
14. Guru Murthy GS, Szabo A, Michaelis L, Carlson KS, Runaas L, Abedin S, et al. Improving outcomes of acute promyelocytic leukemia in the current era: analysis of the SEER database. J Natl Compr Canc Netw (2020) 18(2):169–75. doi: 10.6004/jnccn.2019.7351
15. Sanz MA, Fenaux P, Tallman MS, Estey EH, Lowenberg B, Naoe T, et al. Management of acute promyelocytic leukemia: updated recommendations from an expert panel of the European LeukemiaNet. Blood (2019) 133(15):1630–43. doi: 10.1182/blood-2019-01-894980
16. Kayser S, Rahme R, Martinez-Cuadron D, Ghiaur G, Thomas X, Sobas M, et al. Outcome of older (>/=70 years) APL patients frontline treated with or without arsenic trioxide-an international collaborative study. Leukemia (2020) 34(9):2333–41. doi: 10.1038/s41375-020-0758-4
17. Jillella AP, Kota VK. The global problem of early deaths in acute promyelocytic leukemia: A strategy to decrease induction mortality in the most curable leukemia. Blood Rev (2018) 32(2):89–95. doi: 10.1016/j.blre.2017.09.001
18. Naymagon L, Moshier E, Tremblay D, Mascarenhas J. Predictors of early hemorrhage in acute promyelocytic leukemia. Leuk Lymphoma (2019) 60(10):2394–403. doi: 10.1080/10428194.2019.1581187
19. Chang H, Kuo MC, Shih LY, Dunn P, Wang PN, Wu JH, et al. Clinical bleeding events and laboratory coagulation profiles in acute promyelocytic leukemia. Eur J Haematol (2012) 88(4):321–8. doi: 10.1111/j.1600-0609.2011.01747.x
20. Mantha S, Goldman DA, Devlin SM, Lee JW, Zannino D, Collins M, et al. Determinants of fatal bleeding during induction therapy for acute promyelocytic leukemia in the ATRA era. Blood (2017) 129(13):1763–7. doi: 10.1182/blood-2016-10-747170
21. Hou W, Zhang Y, Jin B, Cao W, Lu M, Yan L, et al. Factors affecting thrombohemorrhagic early death in patients with acute promyelocytic leukemia treated with arsenic trioxide alone. Blood Cells Mol Dis (2019) 79:102351. doi: 10.1016/j.bcmd.2019.102351
22. Gill H, Yung Y, Chu HT, Au WY, Yip PK, Lee E, et al. Characteristics and predictors of early hospital deaths in newly diagnosed APL: a 13-year population-wide study. Blood Adv (2021) 5(14):2829–38. doi: 10.1182/bloodadvances.2021004789
23. Altman JK, Rademaker A, Cull E, Weitner BB, Ofran Y, Rosenblat TL, et al. Administration of ATRA to newly diagnosed patients with acute promyelocytic leukemia is delayed contributing to early hemorrhagic death. Leuk Res (2013) 37(9):1004–9. doi: 10.1016/j.leukres.2013.05.007
24. Dinmohamed AG, Visser O. Incidence of acute promyelocytic leukemia across Europe: results of RARECAREnet-a population-based study. Stem Cell Investig (2019) 6:37. doi: 10.21037/sci.2019.10.03
25. Lenzi L, Lee-Jones L, Mostofa MA, de Andrade DP, Ribeiro RC, Figueiredo BC. Second primary malignancy after acute promyelocytic leukemia: a population-based study. Cancers (Basel) (2020) 12(12). doi: 10.3390/cancers12123610
26. Norsworthy KJ, Avagyan A, Bird ST, Li Y, Akhtar S, Liao J, et al. Second cancers in adults with acute promyelocytic leukemia treated with or without arsenic trioxide: a SEER-medicare analysis. Leukemia (2020) 34(11):3082–4. doi: 10.1038/s41375-020-0905-y
27. Munshi NC. Arsenic trioxide: an emerging therapy for multiple myeloma. Oncologist (2001) 6 Suppl 2:17–21. doi: 10.1634/theoncologist.6-suppl_2-17
28. Bobe P, Bonardelle D, Benihoud K, Opolon P, Chelbi-Alix MK. Arsenic trioxide: a promising novel therapeutic agent for lymphoproliferative and autoimmune syndromes in MRL/lpr mice. Blood (2006) 108(13):3967–75. doi: 10.1182/blood-2006-04-020610
29. Lo RK, Kwong YL. Arsenic trioxide suppressed mantle cell lymphoma by downregulation of cyclin D1. Ann Hematol (2014) 93(2):255–65. doi: 10.1007/s00277-013-1866-2
30. Lam SK, Mak JC, Zheng CY, Li YY, Kwong YL, Ho JC. Downregulation of thymidylate synthase with arsenic trioxide in lung adenocarcinoma. Int J Oncol (2014) 44(6):2093–102. doi: 10.3892/ijo.2014.2364
31. Martelli MP, Gionfriddo I, Mezzasoma F, Milano F, Pierangeli S, Mulas F, et al. Arsenic trioxide and all-trans retinoic acid target NPM1 mutant oncoprotein levels and induce apoptosis in NPM1-mutated AML cells. Blood (2015) 125(22):3455–65. doi: 10.1182/blood-2014-11-611459
32. El Hajj H, Dassouki Z, Berthier C, Raffoux E, Ades L, Legrand O, et al. Retinoic acid and arsenic trioxide trigger degradation of mutated NPM1, resulting in apoptosis of AML cells. Blood (2015) 125(22):3447–54. doi: 10.1182/blood-2014-11-612416
33. Chau D, Ng K, Chan TS, Cheng YY, Fong B, Tam S, et al. Azacytidine sensitizes acute myeloid leukemia cells to arsenic trioxide by up-regulating the arsenic transporter aquaglyceroporin 9. J Hematol Oncol (2015) 8:46. doi: 10.1186/s13045-015-0143-3
34. Piao W, Chau D, Yue LM, Kwong YL, Tse E. Arsenic trioxide degrades NPM-ALK fusion protein and inhibits growth of ALK-positive anaplastic large cell lymphoma. Leukemia (2017) 31(2):522–6. doi: 10.1038/leu.2016.311
35. Ye Y, Gaugler B, Mohty M, Malard F. Old dog, new trick: trivalent arsenic as an immunomodulatory drug. Br J Pharmacol (2020) 177(10):2199–214. doi: 10.1111/bph.15011
36. Liu X, Su Y, Sun X, Fu H, Huang Q, Chen Q, et al. Arsenic trioxide alleviates acute graft-versus-host disease by modulating macrophage polarization. Sci China Life Sci (2020) 63(11):1744–54. doi: 10.1007/s11427-019-1691-x
37. Joannes A, Morzadec C, Duclos M, Gutierrez FL, Chiforeanu DC, Le Naoures C, et al. Arsenic trioxide inhibits the functions of lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. Toxicol Appl Pharmacol (2022) 441:115972. doi: 10.1016/j.taap.2022.115972
38. Gill H, Au WY, Cheung WW, Lee EY, Kwong YL. Oral arsenic trioxide-based regimen as salvage treatment for relapsed or refractory mantle cell lymphoma. Ann Oncol (2014) 25(7):1391–7. doi: 10.1093/annonc/mdu142
39. Hamidou M, Neel A, Poupon J, Amoura Z, Ebbo M, Sibilia J, et al. Safety and efficacy of low-dose intravenous arsenic trioxide in systemic lupus erythematosus: an open-label phase IIa trial (Lupsenic). Arthritis Res Ther (2021) 23(1):70. doi: 10.1186/s13075-021-02454-6
40. Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, et al. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U. S. A. (2009) 106(9):3342–7. doi: 10.1073/pnas.0813280106
41. Iland HJ, Bradstock K, Supple SG, Catalano A, Collins M, Hertzberg M, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood (2012) 120(8):1570–80. doi: 10.1182/blood-2012-02-410746
42. Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med (2013) 369(2):111–21. doi: 10.1056/NEJMoa1300874
43. Abaza Y, Kantarjian H, Garcia-Manero G, Estey E, Borthakur G, Jabbour E, et al. Long-term outcome of acute promyelocytic leukemia treated with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab. Blood (2017) 129(10):1275–83. doi: 10.1182/blood-2016-09-736686
44. Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, et al. 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. Lancet Oncol (2015) 16(13):1295–305. doi: 10.1016/S1470-2045(15)00193-X
45. Kumana CR, Mak R, Kwong YL, Gill H. Resurrection of oral arsenic trioxide for treating acute promyelocytic leukaemia: A historical account from bedside to bench to bedside. Front Oncol (2020) 10:1294. doi: 10.3389/fonc.2020.01294
46. Au WY, Kumana CR, Kou M, Mak R, Chan GC, Lam CW, et al. Oral arsenic trioxide in the treatment of relapsed acute promyelocytic leukemia. Blood (2003) 102(1):407–8. doi: 10.1182/blood-2003-01-0298
47. Au WY, Li CK, Lee V, Yuen HL, Yau J, Chan GC, et al. Oral arsenic trioxide for relapsed acute promyelocytic leukemia in pediatric patients. Pediatr Blood Cancer (2012) 58(4):630–2. doi: 10.1002/pbc.23306
48. Au WY, Kumana CR, Lee HK, Lin SY, Liu H, Yeung DY, et al. Oral arsenic trioxide-based maintenance regimens for first complete remission of acute promyelocytic leukemia: a 10-year follow-up study. Blood (2011) 118(25):6535–43. doi: 10.1182/blood-2011-05-354530
49. Gill H, Kumana CR, Yim R, Hwang YY, Chan TSY, Yip SF, et al. 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 (2019) 125(17):3001–12. doi: 10.1002/cncr.32180
50. Gill HS, Yim R, Kumana CR, Tse E, Kwong YL. 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 (2020) 126(14):3244–54. doi: 10.1002/cncr.32937
Keywords: acute promyelocytic leukemia (APL), arsenic trioxide, oral arsenic trioxide, early death, epidemiology, chemotherapy-free
Citation: Gill H, Russell N and Kwong Y-L (2023) Editorial: Acute promyelocytic leukemia - towards a chemotherapy-free approach to cure in all patients, Volume II. Front. Oncol. 13:1238486. doi: 10.3389/fonc.2023.1238486
Received: 11 June 2023; Accepted: 15 June 2023;
Published: 27 June 2023.
Edited and Reviewed by:
Alessandro Isidori, AORMN Hospital, ItalyCopyright © 2023 Gill, Russell and Kwong. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Harinder Gill, gillhsh@hku.hk