J Korean Med Sci.  2023 Sep;38(36):e281. 10.3346/jkms.2023.38.e281.

Is Treosulfan-Based Conditioning Attractive as a Reduced-Intensity Conditioning Regimen in Korea?

• Kim SH
• Ji YS
• Yun J
• Choi SH
• Lim SH
• Kim CK
• Park SK

• KMID: 2545783
• DOI: http://doi.org/10.3346/jkms.2023.38.e281

Abstract

Background
Allogeneic hematopoietic stem cell transplantation (HSCT) was not actively performed in elderly acute myeloid leukemia (AML) or myelodysplastic syndrome patients who are at a high-risk based on hematopoietic cell transplantation-specific comorbidity index (HCT-CI). The advent of reduced-intensity conditioning (RIC) regimens has made HSCT applicable in this population. However, the selection of appropriate conditioning is a major concern for the attending physician. The benefits of combination of treosulfan and fludarabine (Treo/Flu) have been confirmed through many clinical studies. Korean data on treosulfan-based conditioning regimen are scarce.
Methods
A retrospective study was conducted to compare the clinical outcomes of allogeneic HSCT using RIC between 13 patients receiving Treo/Flu and 39 receiving busulfan/ fludarabine (Bu/Flu).
Results
In terms of conditioning-related complications, the frequency of ≥ grade 2 nausea or vomiting was significantly lower and the duration of symptoms was shorter in the Treo/ Flu group than in the Bu/Flu group. The incidence of ≥ grade 2 mucositis tended to be lower in the Treo/Flu group. In the analysis of transplant outcomes, all events of acute graft versus host disease (GVHD) and ≥ grade 2 acute GVHD occurred more frequently in the Treo/ Flu group. The frequency of Epstein-Barr virus reactivation was significantly higher in the Treo/Flu group (53.8% vs. 23.1%, P = 0.037). Non-relapse mortality (NRM) at 12 months was higher in the Treo/Flu group (30.8% vs. 7.7%, P = 0.035). Significant prognostic factors included disease type, especially secondary AML, disease status and high-risk based on HCT-CI, ≥ grade 2 acute GVHD, and cases requiring ≥ 2 immunosuppressive drugs for treating acute GVHD. In the comparison of survival outcomes according to conditioning regimen, the Bu/Flu group seemed to show better results than the Treo/Flu group (60% vs.46.2%, P = 0.092 for overall survival; 56.4% vs. 38.5%, P = 0.193 for relapse-free survival). In additional analysis for only HCT-CI high-risk groups, there was no difference in transplant outcomes except that the Treo/Flu group tended to have a higher NRM within one year after transplantation. Survival outcomes of both groups were similar.
Conclusion
This study suggests that Treo/Flu conditioning may be an alternative to Bu/Flu regimen in elderly patients with high-risk who are not suitable for standard conditioning.

Keyword

Treosulfan; Reduced-Intensity Conditioning (RIC); Hematopoietic Stem Cell Transplantation (HSCT); Elderly; Myelodysplastic Syndrome (MDS); Acute Myeloid Leukemia (AML)

Figure

• 

  Fig. 1 Clinical outcomes according to conditioning regimens. (A) Overall survival. (B) Relapse-free survival. (C) The estimated cumulative incidence of relapse. (D) Non-relapse mortality.Bu/Flu = busulfan/fludarabine, Treo/Flu = treosulfan/fludarabine.

• 

  Fig. 2 Comparison of overall survival in different subgroups. (A) Comparison between standard risk and high-risk group based on HCT-CI. (B) Comparison between Treo/Flu and Bu/Flu groups in acute myeloid leukemia patients. (C) Comparison between Treo/Flu and Bu/Flu groups in patients performing haplo-identical transplantation. (D) Comparison between Treo/Flu and Bu/Flu groups in patients aged 65 and older. (E) Comparison between Treo/Flu and Bu/Flu groups in high-risk patients based on HCT-CI. Based on HCT-CI score, standard risk was classified as 2 points or less, and high-risk was classified as 3 points or more.Bu/Flu = busulfan/fludarabine, HCT-CI = hematopoietic cell transplantation-specific comorbidity index, Treo/Flu = treosulfan/fludarabine.

Reference

1. Shimoni A, Nagler A. Optimizing the conditioning regimen for allogeneic stem-cell transplantation in acute myeloid leukemia; dose intensity is still in need. Best Pract Res Clin Haematol. 2011; 24(3):369–379. PMID: 21925090.

2. Alyea EP, Kim HT, Ho V, Cutler C, DeAngelo DJ, Stone R, et al. Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2006; 12(10):1047–1055. PMID: 17067911.

3. Aoudjhane M, Labopin M, Gorin NC, Shimoni A, Ruutu T, Kolb HJ, et al. Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT). Leukemia. 2005; 19(12):2304–2312. PMID: 16193083.

4. Shimoni A, Hardan I, Shem-Tov N, Yeshurun M, Yerushalmi R, Avigdor A, et al. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity. Leukemia. 2006; 20(2):322–328. PMID: 16307018.

5. Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, et al. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012; 13(10):1035–1044. PMID: 22959335.

6. Hamadani M, Craig M, Phillips GS, Abraham J, Tse W, Cumpston A, et al. Higher busulfan dose intensity does not improve outcomes of patients undergoing allogeneic haematopoietic cell transplantation following fludarabine, busulfan-based reduced toxicity conditioning. Hematol Oncol. 2011; 29(4):202–210. PMID: 21360728.

7. Wachowiak J, Sykora KW, Cornish J, Chybicka A, Kowalczyk JR, Gorczyńska E, et al. Treosulfan-based preparative regimens for allo-HSCT in childhood hematological malignancies: a retrospective study on behalf of the EBMT pediatric diseases working party. Bone Marrow Transplant. 2011; 46(12):1510–1518. PMID: 21297673.

8. Nemecek ER, Guthrie KA, Sorror ML, Wood BL, Doney KC, Hilger RA, et al. Conditioning with treosulfan and fludarabine followed by allogeneic hematopoietic cell transplantation for high-risk hematologic malignancies. Biol Blood Marrow Transplant. 2011; 17(3):341–350. PMID: 20685259.

9. Shimoni A, Vago L, Bernardi M, Yerushalmi R, Peccatori J, Greco R, et al. Missing HLA C group 1 ligand in patients with AML and MDS is associated with reduced risk of relapse and better survival after allogeneic stem cell transplantation with fludarabine and treosulfan reduced toxicity conditioning. Am J Hematol. 2017; 92(10):1011–1019. PMID: 28631269.

10. Nagler A, Labopin M, Beelen D, Ciceri F, Volin L, Shimoni A, et al. Long-term outcome after a treosulfan-based conditioning regimen for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Cancer. 2017; 123(14):2671–2679. PMID: 28329410.

11. Yerushalmi R, Shem-Tov N, Danylesko I, Avigdor A, Nagler A, Shimoni A. Fludarabine and treosulfan compared with other reduced-intensity conditioning regimens for allogeneic stem cell transplantation in patients with lymphoid malignancies. Bone Marrow Transplant. 2015; 50(12):1526–1535. PMID: 26237166.

12. Boztug H, Sykora KW, Slatter M, Zecca M, Veys P, Lankester A, et al. European Society for Blood and Marrow Transplantation analysis of treosulfan conditioning before hematopoietic stem cell transplantation in children and adolescents with hematological malignancies. Pediatr Blood Cancer. 2016; 63(1):139–148. PMID: 26398915.

13. Westerhof GR, Ploemacher RE, Boudewijn A, Blokland I, Dillingh JH, McGown AT, et al. Comparison of different busulfan analogues for depletion of hematopoietic stem cells and promotion of donor-type chimerism in murine bone marrow transplant recipients. Cancer Res. 2000; 60(19):5470–5478. PMID: 11034090.

14. Sjöö F, Hassan Z, Abedi-Valugerdi M, Griskevicius L, Nilsson C, Remberger M, et al. Myeloablative and immunosuppressive properties of treosulfan in mice. Exp Hematol. 2006; 34(1):115–121. PMID: 16413398.

15. Beelen DW, Trenschel R, Stelljes M, Groth C, Masszi T, Reményi P, et al. Treosulfan or busulfan plus fludarabine as conditioning treatment before allogeneic haemopoietic stem cell transplantation for older patients with acute myeloid leukaemia or myelodysplastic syndrome (MC-FludT.14/L): a randomised, non-inferiority, phase 3 trial. Lancet Haematol. 2020; 7(1):e28–e39. PMID: 31606445.

16. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant. 1995; 15(6):825–828. PMID: 7581076.

17. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005; 11(12):945–956. PMID: 16338616.

18. Deeg HJ, Scott BL, Fang M, Shulman HM, Gyurkocza B, Myerson D, et al. Five-group cytogenetic risk classification, monosomal karyotype, and outcome after hematopoietic cell transplantation for MDS or acute leukemia evolving from MDS. Blood. 2012; 120(7):1398–1408. PMID: 22767498.

19. Sorror ML, Storb RF, Sandmaier BM, Maziarz RT, Pulsipher MA, Maris MB, et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol. 2014; 32(29):3249–3256. PMID: 25154831.

20. McClune BL, Weisdorf DJ, Pedersen TL, Tunes da Silva G, Tallman MS, Sierra J, et al. Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome. J Clin Oncol. 2010; 28(11):1878–1887. PMID: 20212255.

21. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005; 106(8):2912–2919. PMID: 15994282.

22. Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG, et al. Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. Blood. 2004; 104(5):1550–1558. PMID: 15150081.

23. Ciurea SO, Shah MV, Saliba RM, Gaballa S, Kongtim P, Rondon G, et al. Haploidentical transplantation for older patients with acute myeloid leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2018; 24(6):1232–1236. PMID: 28918304.

24. Srour SA, Saliba RM, Bittencourt MC, Perez JM, Kongtim P, Alousi A, et al. Haploidentical transplantation for acute myeloid leukemia patients with minimal/measurable residual disease at transplantation. Am J Hematol. 2019; 94(12):1382–1387. PMID: 31595538.

25. Brissot E, Labopin M, Ehninger G, Stelljes M, Brecht A, Ganser A, et al. Haploidentical versus unrelated allogeneic stem cell transplantation for relapsed/refractory acute myeloid leukemia: a report on 1578 patients from the Acute Leukemia Working Party of the EBMT. Haematologica. 2019; 104(3):524–532. PMID: 30361416.

26. Düver F, Weißbrich B, Eyrich M, Wölfl M, Schlegel PG, Wiegering V. Viral reactivations following hematopoietic stem cell transplantation in pediatric patients - a single center 11-year analysis. PLoS One. 2020; 15(2):e0228451. PMID: 32017805.

27. Ru Y, Zhang X, Song T, Ding Y, Zhu Z, Fan Y, et al. Epstein-Barr virus reactivation after allogeneic hematopoietic stem cell transplantation: multifactorial impact on transplant outcomes. Bone Marrow Transplant. 2020; 55(9):1754–1762. PMID: 32066862.

28. Elmahdi S, Muramatsu H, Narita A, Torii Y, Ismael O, Kawashima N, et al. Correlation of rabbit antithymocyte globulin serum levels and clinical outcomes in children who received hematopoietic stem cell transplantation from an alternative donor. Pediatr Transplant. 2016; 20(1):105–113. PMID: 26518333.

29. Hiwarkar P, Gaspar HB, Gilmour K, Jagani M, Chiesa R, Bennett-Rees N, et al. Impact of viral reactivations in the era of pre-emptive antiviral drug therapy following allogeneic haematopoietic SCT in paediatric recipients. Bone Marrow Transplant. 2013; 48(6):803–808. PMID: 23178547.

30. Park BK, Kim HS, Kim S, Lee JW, Park YS, Jang PS, et al. Allogeneic hematopoietic stem cell transplantation in congenital hemoglobinopathies with myeloablative conditioning and rabbit anti-thymocyte globulin. Blood Res. 2018; 53(2):145–151. PMID: 29963521.

31. Suh JK, Im HJ, Kang SH, Kim H, Choi ES, Koh KN. Treosulfan-based conditioning regimen for allogeneic hematopoietic stem cell transplantation in children with non-malignant diseases. Bone Marrow Transplant. 2022; 57(4):681–684. PMID: 35132202.