Risk-adapted combined therapy with arsenic trioxide and all-trans-retinoic acid for de novo acute promyelocytic leuкaemia

Introduction. Non-chemotherapy for acute promyelocytic leukaemia (APL) with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) provides for a high patient survival rate at lesser toxicity as effectively or superior to standard chemotherapy programmes.

Aim — assessment of the ATO–ATRA risk-adapted exposure protocol in management of de novo acute promyelocytic leucaemia.

Materials and methods. A prospective study included 51 primary APL patients aged 18–76 years. The program included remission induction (ATO 0.15 mg/kg intravenously, ATRA 45 mg/m2 orally) for 30–60 days in a low-risk (until remission) and 60 days — in a high-risk cohort that had idarubicin therapy added on days 2 and 4. Remission consolidation was attained with four (low-risk) or five (high-risk) courses. Minimal residual disease was monitored with real-time PCR at all phases.

Results. The high-risk cohort was assigned 15 (29.4 %), the low-risk cohort — 36 (70.6 %) patients. Therapy induction till APL morphological remission was performed in 48/51 (94 %) patients. Molecular APL remission was achieved in 47 (92 %) patients, 100 % in the low-risk and 80 % in high-risk cohort. Early mortality was 6 % (n = 3), death in remission — 2 % (n = 1). Differentiation syndrome (DS) occurred in 16 (31.7 %) patients, more frequently in the high-risk vs. low-risk cohort (53.3 % and 22.2 %, respectively, p = 0.05; odds ratio 4.0 [1.1–14.4]). DS developed on days 1–20 (3 days median) of therapy. DS risk factors: a high-risk status, haemorrhagic syndrome and infection at the disease onset. A median follow-up time in survivors was 12.9 months (2.5–34.3), a six-month overall survival — 92 % (95 % CI: 85–100 %). A six-month overall survival was 100 and 73 % in the low- and high-risk cohorts, respectively (95 % CI: 54–100 %, p = 0.001). APL relapse not registered, 47 (92 %) patients survived and achieved the first molecular remission.

Conclusion. A differentiated risk-adapted approach to APL therapy with cytostatic treatment added in high-risk patients only provided for a 100 % molecular remission and relapse-free survival. Therapy failures (early mortality and death in remission) affected high-risk patients due to a severe individual condition at the time of APL diagnosis.

1. Savchenko V.G., Parovichnikova E.N. Acute promyelocytic leukemia. Litterra. Moscow; 2009 (In Russian).

2. Lo-Coco F., Avvisati G., Vignetti M., et al. 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. 2010; 116(17): 3171–9. DOI: 10.1182/blood-2010-03-276196.

3. Sanz M.A., Montesinos P., Rayón C., et al. 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 behalf of the PETHEMA and HOVO. Blood. 2010; 115(25): 5137–46. DOI: 10.1182/blood-2010-01-266007.

4. Sanz M.A., Grimwade D., Tallman M.S., et al. Management of acute promyelocytic leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2009; 113(9): 1875–92. DOI: 10.1182/blood-2008-04-150250.

5. Guerci A., Raffoux E., Sanz M., et al. Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: The European APL Group experience. Blood. 2010; 115(9): 1690–6. DOI: 10.1182/blood-2009-07-233387.

6. Parovichnikova E.N., Troitskaya V.V., Sokolov A.N., et al. AIDA protocol-based treatment of adults with acute promyelocytic leukemia. Terapevticheskiy arkhiv. 2013; (7): 10–7 (In Russian).

7. Ma Y., Liu L., Jin J., et al. All-trans retinoic acid plus arsenic trioxide versus alltrans retinoic acid plus chemotherapy for newly diagnosed acute promyelocytic leukemia: A meta-analysis. PLoS One. 2016; 11(7): 1–10. DOI: 10.1371/journal.pone.0158760.

8. Eghtedar A., Rodriguez I., Kantarjian H., et al. Incidence of secondary neoplasms in patients with acute promyelocytic leukemia treated with all-trans retinoic acid plus chemotherapy or with all-trans retinoic acid plus arsenic trioxide. Leuk Lymphoma. 2015; 56(5): 1342–5. DOI: 10.3109/10428194.2014.953143.

9. Lo-Coco F., Avvisati G., Vignetti M., et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 2013; 369(2): 111–21. DOI: 10.1056/NEJMoa1300874.

10. Burnett A.K., Russell N.H., Hills R.K., 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.

11. Platzbecker U., Avvisati G., Cicconi L., et al. 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. J Clin Oncol. 2017; 35(6): 605–12. DOI: 10.1200/JCO.2016.67.1982.

12. Jing Y., Wang L., Xia L., et al. Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo. Blood. 2001; 97(1): 264–9.

13. Sanz M.A., Fenaux P., Tallman M.S., 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.

14. Lurie R.H., Cancer C. Acute Myeloid LeukemiaVersion 3.2020, 12/23/19 © 2019 National Comprehensive Cancer Network® (NCCN®). 2020.

15. Iland H.J., Collins M., Bradstock K., et al. Use of arsenic trioxide in remission induction and consolidation therapy for acute promyelocytic leukaemia in the Australasian Leukaemia and Lymphoma Group (ALLG) APML4 study: A non-randomised phase 2 trial. Lancet Haematol. 2015; 2(9): e357–66. DOI: 10.1016/S2352-3026(15)00115-5.

16. Daver N., Kantarjian H., Marcucci G., et al. Clinical characteristics and outcomes in patients with acute promyelocytic leukaemia and hyperleucocytosis. Br J Haematol. 2015; 168(5): 646–53. DOI: 10.1111/bjh.13189.

17. Iland H.J., Seymour J.F., Wei A. Optimal approach for high-risk acute promyelocytic leukemia. Curr Opin Hematol. 2014; 21(2): 102–13. DOI: 10.1097/MOH.0000000000000025.

18. Abaza Y., Kantarjian H.M., Garcia-Manero G., 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.

19. Zhu H., Hu J., Li X., et al. All-trans retinoic acid and arsenic combination therapy benefits low-to-intermediate-risk patients with newly diagnosed acute promyelocytic leukaemia: A long-term follow-up based on multivariate analysis. Br J Haematol. 2015; 171(2): 277–80. DOI: 10.1111/bjh.13375.

20. Roberts T.F., Sprague K., Schenkein D., et al. Hyperleukocytosis during induction therapy with arsenic trioxide for relapsed acute promyelocytic leukemia associated with central nervous system infarction. Blood. 2000; 96(12): 4000–1. DOI: 10.1182/blood.v96.12.4000.h8004000a_4000_4001.

21. Iland H.J., Bradstock K., Supple S.G., 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.

22. Norsworthy K.J., Altman J.K. Optimal treatment strategies for high-risk acute promyelocytic leukemia. Curr Opin Hematol. 2016;23(2):127–36. DOI:10.1097/MOH.0000000000000215.

23. Soignet S.L., Maslak P., Wang Z.G., et al. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med. 1998; 339(19): 1341–8. DOI: 10.1056/NEJM199811053391901.

24. Larson R.S., Tallman M.S. Retinoic acid syndrome: Manifestations, pathogenesis, and treatment. Best Pract Res Clin Haematol. 2003; 16(3): 453–61. DOI: 10.1016/S1521-6926(03)00043-4.

25. Sanz M.A., Montesinos P. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood. 2014; 123(18): 2777–82. DOI: 10.1182/blood-2013-10-512640.

26. Niu C., Yan H., Yu T., et al. Studies on treatment of acute promyelocytic leukemia arsenic trioxide: Remission induction, follow-up, and molecular monitoring in 11 newly diagnosed and 47 relapsed acute promyelocytic leukemia patients. Blood. 1999; 94(10): 3315–24.

27. Hu J., Liu Y., Wu C., et al. Long-term efficacy and safety of all-trans retinoic acid / arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. PNAS. 2009; 106(9): 3342–7. DOI: 10.1073/pnas.0813280106.

28. Thomas A. How can we improve on the already impressive results in pediatric ALL? ASH Educ Progr B. 2015; 414–9. DOI: 10.1182/asheducation-2015.1.414.

29. Troitskaya V.V., Parovichnikova E.N., Sokolov A.N., et al. Risk-adapted therapy for APL (ATRA-ATO-CT) with mandatory molecular monitoring. A research protocol. In: Diagnostic algorithms and treatment protocols for blood diseases. Ed. Savchenko V.G. Moscow, Praktika; 2018. P. 961–94 (In Russian).

30. Galstian G.M., Novikov V.A., Troitskaia V.V., et al. Lung ultrasound diagnosis of pneumonia in pregnant women with haematological malignancy. Terapevticheskiy arkhiv. 2015; 87(1): 79–87. (In Russian).

31. Polevodova OA, Galstyan GM, Troitskaya VV, et al. Haemostasis disorders in patients with de novo acute leucaemias. Klinicheskaya Onckogematologiya. 2021; 14(2): 231–8. DOI: 10.21320/2500-2139-2021-14-2-231-238. (In Russian).

32. Rizack T., Mega A., Legare R., et al. Management of hematological malignancies during pregnancy. Am J Hematol. 2009; 84: 830–41. DOI: 10.1002/ajh.21547.

33. Parovichnikova E.N., Savchenko V.G., Isaev V.G. et al. Results of 2nd randomised trial by the Russian Research Group of Haematology Centres in therapy for acute promyelocytic leucaemias. Gematologiya i transfusiologiya. 2007; 52(6): 3–9. (In Russian)

34. Sidorova A.A., Troitskaya V.V., Parovichnikova E.N. et al. Results of AIDA protocol-based treatment of acute promyelocytic leucaemia. Gematologiya i transfuziologiya. 2016; 61(1): 177. (In Russian).

35. Ghavamzadeh A., Alimoghaddam K., Rostami S., et al. Phase II study of single-agent arsenic trioxide for the front-line therapy of acute promyelocytic leukemia. J Clin Oncol. 2011; 29(20): 2753–7. DOI: 10.1200/JCO.2010.32.2107.

36. Estey E., Garcia-Manero G., Ferrajoli A., et al. Use all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood. 2006; 107(9): 3469–73. DOI: 10.1182/blood-2005-10-4006.

37. Mathews V., George B., Chendamarai E., et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: Longterm follow-up data. J Clin Oncol. 2010; 28(24): 3866–71. DOI: 10.1200/JCO.2010.28.5031.

38. Ravandi F., Estey E., Jones D., et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol. 2009; 27(4): 504–10. DOI: 10.1200/JCO.2008.18.6130.

39. Spirin M.V., Galstyan G.M., Polevodova O.A. et al. Peripherally inserted central venous catheters for stable vascular approach in haemorrhagic syndrome patients. Gematologiya i transfuziologiya. 2017; 62(4): 203–10. DOI: 10.18821/0234-5730-2017-62-4-203-210. (In Russian).

40. Connelly S., Zancosky K., Farah K. Arsenic-induced pancreatitis. Case Rep Gastrointest Med. 2011; 2011: 1–3. DOI: 10.1155/2011/758947