Blood Res.  2022 Sep;57(3):197-206. 10.5045/br.2022.2022060.

Treatment for relapsed acute promyelocytic leukemia: what is the best post-remission treatment?

• Min GJ
• Cho BS
• Park SS
• Park S
• Jeon YW
• Yahng SA
• Shin SH
• Yoon JH
• Lee SE
• Eom KS
• Kim YJ
• Lee S
• Min CK
• Cho SG
• Lee JW
• Kim HJ

• KMID: 2533247
• DOI: http://doi.org/10.5045/br.2022.2022060

Abstract

Background
Arsenic trioxide (ATO) is the standard treatment for relapsed acute promyelocytic leukemia (APL). However, consensus on post-remission therapies is still lacking.
Methods
We evaluated 52 patients who experienced relapse following initial treatment of APL between 2000 and 2019 at Catholic Hematology Hospital. Among them, 41 patients received reinduction treatment, 30 with ATO-based regimen, whereas 11 with conventional intensive chemotherapy (IC).
Results
The ATO reinduction group showed a significantly higher second molecular complete remission (mCR2) rate, superior neutrophil and platelet recovery, and a lower infection rate than the IC reinduction group. No significant differences were observed in survival outcomes after post-remission treatment among the ATO-based (N=19), autologous (N=12), and allogeneic (N=6) hematopoietic stem cell transplantation (HSCT) groups. In the ATO-based and autologous HSCT groups, among patients with mCR2 after ATO reinduction, nine and five patients experienced a second relapse, respectively (50.7% vs. 41.7%, P =0.878). Among these patients, seven received salvage allogeneic HSCT; six remained alive. The other seven patients received ATO without HSCT. Five died from disease progression, and two survived and have been in mCR2 since.
Conclusion
Post-remission treatment outcomes of patients with relapsed APL were not significantly different, regardless of the treatment option, suggesting the feasibility of ATO-based treatment without HSCT in mCR2. Allogeneic HSCT may be an effective salvage treatment modality for patients with a second relapse. Owing to a few cases of relapsed APL, multicenter prospective studies may help elucidate the efficacy of each post-remission treatment.

Keyword

Acute promyelocytic leukemia; Relapse; Arsenic trioxide; Stem cell transplantation; Post-remission therapy

Figure

• 

  Fig. 1 Flow chart of acute promyelocytic leukemia patients who relapsed after administration of first-line treatment.

• 

  Fig. 2 Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia based on consolidation regimen.

Reference

1. Sanz MA, Grimwade D, Tallman MS, et al. 2009; Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 113:1875–91. DOI: 10.1182/blood-2008-04-150250. PMID: 18812465.

2. Soignet SL, Frankel SR, Douer D, et al. 2001; United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 19:3852–60. DOI: 10.1200/JCO.2001.19.18.3852. PMID: 11559723.

3. Park JH, Qiao B, Panageas KS, et al. 2011; Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood. 118:1248–54. DOI: 10.1182/blood-2011-04-346437. PMID: 21653939. PMCID: PMC3790946.

4. Lengfelder E, Lo-Coco F, Ades L, et al. 2015; Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet. Leukemia. 29:1084–91. DOI: 10.1038/leu.2015.12. PMID: 25627637.

5. Yilmaz M, Kantarjian H, Ravandi F. 2021; Acute promyelocytic leukemia current treatment algorithms. Blood Cancer J. 11:123. DOI: 10.1038/s41408-021-00514-3. PMID: 34193815. PMCID: PMC8245494. PMID: bd414a8599f449e2881eb64206256651.

6. 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. 121:3095–102. DOI: 10.1182/blood-2012-11-466862. PMID: 23412094.

7. Holter Chakrabarty JL, Rubinger M, Le-Rademacher J, et al. 2014; Autologous is superior to allogeneic hematopoietic cell trans-plantation for acute promyelocytic leukemia in second complete remission. Biol Blood Marrow Transplant. 20:1021–5. DOI: 10.1016/j.bbmt.2014.03.025. PMID: 24691221. PMCID: PMC4097890.

8. Sanz J, Labopin M, Sanz MA, et al. 2021; Hematopoietic stem cell transplantation for adults with relapsed acute promyelocytic leukemia in second complete remission. Bone Marrow Transplant. 56:1272–80. DOI: 10.1038/s41409-020-01162-0. PMID: 33323947.

9. Breccia M, Cicconi L, Minotti C, Latagliata R, Giannì L, Lo-Coco F. 2011; Efficacy of prolonged therapy with combined arsenic trioxide and ATRA for relapse of acute promyelocytic leukemia. Haematologica. 96:1390–1. DOI: 10.3324/haematol.2011.045500. PMID: 21659361. PMCID: PMC3166113.

10. Aribi A, Kantarjian HM, Estey EH, et al. 2007; Combination therapy with arsenic trioxide, all-trans retinoic acid, and gemtuzumab ozogamicin in recurrent acute promyelocytic leukemia. Cancer. 109:1355–9. DOI: 10.1002/cncr.22524. PMID: 17326049.

11. Lee S, Kim YJ, Eom KS, et al. 2006; The significance of minimal residual disease kinetics in adults with newly diagnosed PML-RARalpha- positive acute promyelocytic leukemia: results of a prospective trial. Haematologica. 91:671–4. PMID: 16627255.

12. Stevens-Kroef M, Simons A, Rack K, Hastings RJ. 2017; Cytogenetic nomenclature and reporting. Methods Mol Biol. 1541:303–9. DOI: 10.1007/978-1-4939-6703-2_24. PMID: 27910032.

13. Sanz MA, Lo Coco F, Martín G, et al. 2000; Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood. 96:1247–53. PMID: 10942364.

14. Douer D, Zickl L, Schiffer CA, et al. 2011; Late relapses following all-trans retinoic acid for acute promyelocytic leukemia are uncommon, respond well to salvage therapy and occur inde-pendently of prognostic factors at diagnosis: long-term follow-up of north american intergroup study I0129. Blood (ASH Annual Meeting Abstracts). 118(Suppl):83. DOI: 10.1182/blood.V118.21.83.83.

15. Lo-Coco F, Cicconi L, Breccia M. 2016; Current standard treatment of adult acute promyelocytic leukaemia. Br J Haematol. 172:841–54. DOI: 10.1111/bjh.13890. PMID: 26687281.

16. Raffoux E, Rousselot P, Poupon J, et al. 2003; Combined treatment with arsenic trioxide and all-trans-retinoic acid in patients with relapsed acute promyelocytic leukemia. J Clin Oncol. 21:2326–34. DOI: 10.1200/JCO.2003.01.149. PMID: 12805334.

17. Shen ZX, Chen GQ, Ni JH, et al. 1997; Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 89:3354–60. DOI: 10.1182/blood.V89.9.3354. PMID: 9129042.

18. Sanz J, Montesinos P, Sanz MA. 2021; Role of Hematopoietic stem cell transplantation in acute promyelocytic leukemia. Front Oncol. 11:614215. DOI: 10.3389/fonc.2021.614215. PMID: 33816245. PMCID: PMC8012800. PMID: 5b9b92d280384e4186e86f379285fce2.

19. Fouzia NA, Sharma V, Ganesan S, et al. 2021; Management of relapse in acute promyelocytic leukaemia treated with up-front arsenic trioxide-based regimens. Br J Haematol. 192:292–9. DOI: 10.1111/bjh.17221. PMID: 33216980. PMCID: PMC7894296.

20. Ganzel C, Mathews V, Alimoghaddam K, et al. 2016; Autologous transplant remains the preferred therapy for relapsed APL in CR2. Bone Marrow Transplant. 51:1180–3. DOI: 10.1038/bmt.2016.96. PMID: 27088379. PMCID: PMC5014591.

21. Thirugnanam R, George B, Chendamarai E, et al. 2009; Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide- based regimen. Biol Blood Marrow Transplant. 15:1479–84. DOI: 10.1016/j.bbmt.2009.07.010. PMID: 19822309.

22. Fujita H, Asou N, Iwanaga M, et al. 2013; Role of hematopoietic stem cell transplantation for relapsed acute promyelocytic leukemia: a retrospective analysis of JALSG-APL97. Cancer Sci. 104:1339–45. DOI: 10.1111/cas.12230. PMID: 23837667. PMCID: PMC7656542.

23. de Botton S, Fawaz A, Chevret S, et al. 2005; Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retro-spective analysis of the European acute promyelocytic leukemia group. J Clin Oncol. 23:120–6. DOI: 10.1200/JCO.2005.03.127. PMID: 15534358.