Factors influencing overall survival and GvHD development after allogeneic hematopoietic stem cell transplantation – single centre experience

Czech version

Authors: M. Homolová ¹; E. Bojtárová ²; M. Kováčová ²; K. Klučková ¹; M. Suchánková ¹; M. Kušíková ²; M. Mistrík ²; I. Shawkatová ¹
Authors‘ workplace: Imunologický ústav LF UK, Bratislava, Slovenská republika ¹; Klinika hematológie a transfuziológie LF UK, SZU a UN Bratislava, Slovenská republika ²
Published in: Klin Onkol 2024; 38(2): 118-125
Category: Original Articles
doi: https://doi.org/10.48095/ccko2024118

Overview

Backgrounds: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a substantial therapeutic procedure for the treatment of a wide spectrum of severe diseases. Despite advancements in treatment and supportive care, alloHSCT still carries a considerable mortality risk, primarily caused by graft-versus-host disease (GvHD). Our retrospective analysis aimed to identify the factors influencing overall survival and GvHD development in HLA-identical sibling alloHSCT. We have analyzed patients’ and donors’ age, AB0 compatibility, recipient-donor gender match, stem cell source, time from the diagnosis to alloHSCT, conditioning regimen type, GvHD prophylaxis, and relapse. Patients and methods: Our study included 96 patients (54 male, 42 female) who underwent HLA-identical sibling alloHSCT. The median follow-up was 64.5 months (range 1–218 months), and the median age of both recipients and donors was 34 years. Malignant hematological diseases were the most common indications for alloHSCT. Results: GvHD and its complications accounted for the highest number of deaths (N = 24; 46.2%), followed by relapse (N = 18; 34.6%). Acute GvHD developed in 30 patients (31.3%), while chronic GvHD occurred in 25 patients (26.0%), resulting in a total of 45 patients (46.9%) experiencing GvHD. Male recipients with female donors had significantly worse overall survival compared to other patients (P = 0.01; HR = 2.33). Overall survival was better in patients transplanted within 1 year from the diagnosis compared to those transplanted after 1 year (P = 0.03; HR = 1.93). No factor reached statistical significance regarding the impact on acute GvHD, chronic GvHD, or overall GvHD. Conclusion: We confirmed that sex mismatch, specifically in the case of a female donor and a male recipient, significantly negatively affects overall survival after alloHSCT. Additionally, overall survival is significantly shorter when the interval between the diagnosis and alloHSCT exceeds one year.

Keywords:

GVHD – overall survival – hematopoietic stem cell transplantation

Sources

1. Juric MK, Ghimire S, Ogonek J et al. Milestones of hematopoietic stem cell transplantation – from first human studies to current developments. Front Immunol 2016; 7: 470. doi: 10.3389/fimmu.2016.00470.

2. Abou-Mourad YR, Lau BC, Barnett MJ et al. Long-term outcome after allo-SCT: close follow-up on a large cohort treated with myeloablative regimens. Bone Marrow Transplant 2010; 45 (2): 295–302. doi: 10.1038/bmt.2009.128.

3. Penack O, Peczynski C, Mohty M et al. How much has allogeneic stem cell transplant –related mortality improved since the 1980s? A retrospective analysis from the EBMT. Blood Adv 2020; 4 (24): 6283–6290. doi: 10.1182/bloodadvances.2020003418.

4. Fuerst D, Mueller C, Beelen DW et al. Time-dependent effects of clinical predictors in unrelated hematopoietic stem cell transplantation. Haematologica 2016; 101 (2): 241–247. doi: 10.3324/haematol.2015.130401.

5. Amouzegar A, Dey BR, Spitzer TR. Peripheral blood or bone marrow stem cells? Practical considerations in hematopoietic stem cell transplantation. Transfus Med Rev 2019; 33 (1): 43–50. doi: 10.1016/j.tmrv.2018.11.003.

6. Grube M, Wolff D, Ahrens N et al. AB0 blood group antigen mismatch has an impact on outcome after allogeneic peripheral blood stem cell transplantation. Clin Transplant 2016; 30 (11): 1457–1465. doi: 10.1111/ctr.12840.

7. Bastida JM, Cabrero M, Lopez-Godino O et al. Influence of donor age in allogeneic stem cell transplant outcome in acute myeloid leukemia and myelodisplastic syndrome. Leuk Res 2015; 39 (8): 828–834. doi: 10.1016/ j.leukres.2015.05.003.

8. Lazaryan A, Weisdorf DJ, DeFor T et al. Risk factors for acute and chronic Graft-versus-Host disease after allogeneic hematopoietic cell transplantation with umbilical cord blood and matched sibling donors. Biol Blood Marrow Transplant 2016; 22 (1): 134–140. doi: 10.1016/ j.bbmt.2015.09.008.

9. Jagasia M, Arora M, Flowers ME et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood 2012; 119 (1): 296–307. doi: 10.1182/blood-2011-06-364265.

10. Shawkatová I, Bojtárová E, Kováčová M et al. Individual HLA alleles and risk of graft-versus-host disease after haematopoietic stem cell transplantation from HLA--identical siblings. Biologia 2020; 75 (11): 2045–2052. doi: 10.2478/s11756-020-00510-1.

11. Olerup O, Zetterquist H. HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative to serological DR typing in clinical practice including donor-recipient matching in cadaveric transplantation. Tissue Antigens 1992; 39 (5): 225–235. doi: 10.1111/j.1399-0039.1992.tb01940.x.

12. Glucksberg H, Storb R, Fefer A et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation 1974; 18 (4): 295–304. doi: 10.1097/00007890-197410000-00001.

13. Shulman HM, Sullivan KM, Weiden PL et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69 (2): 204–217. doi: 10.1016/0002-9343 (80) 90380-0.

14. Zhang H. Impact of donor and recipient characteristics on graft-versus-host disease and survival in HLA-matched sibling hematopoietic stem cell transplantation. Transfus Apher Sci 2020; 59 (3): 102743. doi: 10.1016/j.transci.2020.102743.

15. Young JH, Logan BR, Wu J et al. Infections after transplantation of bone marrow or peripheral blood stem cells from unrelated donors. Biol Blood Marrow Transplant 2016; 22 (2): 359–370. doi: 10.1016/j.bbmt.2015. 09.013.

16. Shouval R, Fein JA, Labopin M et al. Outcomes of allogeneic haematopoietic stem cell transplantation from HLA-matched and alternative donors: a European Society for Blood and Marrow Transplantation registry retrospective analysis. Lancet Haematol 2019; 6 (11): e573–e584. doi: 10.1016/S2352-3026 (19) 30158-9.

17. Wong FL, Teh JB, Atencio L et al. Conditional survival, cause-specific mortality, and risk factors of late mortality after allogeneic hematopoietic cell transplantation. J Natl Cancer Inst 2020; 112 (11): 1153–1161. doi: 10.1093/jnci/djaa022.

18. Karam E, Laporte J, Solomon SR et al. Who is a better donor for recipients of allogeneic hematopoietic cell transplantation: a young HLA-mismatched haploidentical relative or an older fully HLA-matched sibling or unrelated donor? Biol Blood Marrow Transplant 2019; 25 (10): 2054–2060. doi: 10.1016/j.bbmt.2019.05.031.

19. Styczynski J, Tridello G, Koster L et al. Death after hematopoietic stem cell transplantation: changes over calendar year time, infections and associated factors. Bone Marrow Transplant 2020; 55 (1): 126–136. doi: 10.1038/s41409-019-0624-z.

20. Darmon M, Bourmaud A, Georges Q et al. Changes in critically ill cancer patients’ short-term outcome over the last decades: results of systematic review with meta-analysis on individual data. Intensive Care Med 2019; 45 (7): 977–987. doi: 10.1007/s00134-019-05653-7.

21. Saillard C, Darmon M, Bisbal M et al. Critically ill allogenic HSCT patients in the intensive care unit: a systematic review and meta-analysis of prognostic factors of mortality. Bone Marrow Transplant 2018; 53 (10): 1233–1241. doi: 10.1038/s41409-018-0181-x.

22. Kröger N, Iacobelli S, Franke GN et al. Dose-reduced versus standard conditioning followed by allogeneic stem-cell transplantation for patients with myelodysplastic syndrome: a prospective randomized phase III study of the EBMT (RICMAC trial). J Clin Oncol 2017; 35 (19): 2157–2164. doi: 10.1200/JCO.2016.70.7349.

23. Sengsayadeth S, Savani BN, Blaise D et al. Reduced intensity conditioning allogeneic hematopoietic cell transplantation for adult acute myeloid leukemia in complete remission – a review from the Acute Leukemia Working Party of the EBMT. Haematologica 2015; 100 (7): 859–869. doi: 10.3324/haematol.2015.123331.

24. Kröger N, Solano C, Wolschke C et al. Antilymphocyte globulin for prevention of chronic Graft-versus-Host disease. N Engl J Med 2016; 374 (1): 43–53. doi: 10.1056/NEJMoa1506002.

25. Remberger M, Afram G, Sundin M et al. High incidence of severe chronic GvHD after HSCT with sibling donors. A single center analysis. Bone Marrow Transplant 2016; 51 (11): 1518–1521. doi: 10.1038/bmt.2016.159.

26. Maziarz RT. Blood and marrow transplant handbook. Cham: Springer 2015.

27. Fuji S, Fujiwara H, Nakano N et al. Early application of related SCT might improve clinical outcome in adult T-cell leukemia/lymphoma. Bone Marrow Transplant 2016; 51 (2): 205–211. doi: 10.1038/bmt.2015.265.

28. Stolzel F, Platzbecker U, Mohr B et al. Early intervention with allogeneic hematopoietic cell transplantation during chemotherapy-induced aplasia in patients with high-risk acute myeloid leukemia. Leukemia 2013; 27 (10): 2068–2072. doi: 10.1038/leu.2013.142.

29. Krejčí M, Doubek M, Tomíška M et al. Dlouhodobé výsledky alogenních transplantací krvetvorných buněk u 533 pacientů: zkušenost jednoho centra. Transfuze Hematol Dnes 2018; 24 (4): 284–296.

30. Kollman C, Howe CW, Anasetti C et al. Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age. Blood 2001; 98 (7): 2043–2051. doi: 10.1182/blood.v98.7.2043.

31. Loren AW, Bunin GR, Boudreau C et al. Impact of donor and recipient sex and parity on outcomes of HLA-identical sibling allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006; 12 (7): 758–769. doi: 10.1016/j.bbmt.2006.03.015.

32. Eisner MD, August CS. Impact of donor and recipient characteristics on the development of acute and chronic graft-versus-host disease following pediatric bone marrow transplantation. Bone Marrow Transplant 1995; 15 (5): 663–668.

33. Weisdorf D, Hakke R, Blazar B et al. Risk factors for acute graft-versus-host disease in histocompatible donor bone marrow transplantation. Transplantation 1991; 51 (6): 1197–1203. doi: 10.1097/00007890-199106000-00010.

34. Wang Y, Wu DP, Liu QF et al. Donor and recipient age, gender and AB0 incompatibility regardless of donor source: validated criteria for donor selection for haematopoietic transplants. Leukemia 2018; 32 (2): 492–498. doi: 10.1038/leu.2017.199.

35. Miller RA. The aging immune system: primer and prospectus. Science 1996; 273 (5271): 70–74. doi: 10.1126/science.273.5271.70.

36. Lipschitz DA, Udupa KB, Indelicato SR et al. Effect of age on second messenger generation in neutrophils. Blood 1991; 78 (5): 1347–1354.

37. Friedman JS, Alpdogan O, van den Brink MR et al. Increasing T-cell age reduces effector activity but preserves proliferative capacity in a murine allogeneic major histocompatibility complex-mismatched bone marrow transplant model. Biol Blood Marrow Transplant 2004; 10 (7): 448–460. doi: 10.1016/j.bbmt.2004.03.005.

38. Kröger N, Zabelina T, de Wreede L et al. Allogeneic stem-cell transplantation for older advanced MDS patients: improved survival with young unrelated donor in comparison with HLA-identical siblings. Leukemia 2013; 27 (3): 604–609. doi: 10.1038/leu.2012.210.

39. Mehta J, Gordon LI, Tallman MS et al. Does younger donor age affect the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies beneficially? Bone Marrow Transplant 2006; 38 (2): 95–100. doi: 10.1038/sj.bmt.1705388.

40. Alousi AM, Le-Rademacher J, Saliba RM et al. Who is better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer? Blood 2013; 121 (13): 2567–2573. doi: 10.1182/blood-2012-08-453860.

41. Chang YJ, Xu LP, Liu DH et al. Platelet engraftment in patients with hematologic malignancies following unmanipulated haploidentical blood and marrow transplantation: effects of CD34+ cell dose and disease status. Biol Blood Marrow Transplant 2009; 15 (5): 632–638. doi: 10.1016/j.bbmt.2009.02.001.

42. Wang YT, Zhao XY, Zhao XS et al. The impact of donor characteristics on the immune cell composition of mixture allografts of granulocyte-colony-stimulating factor-mobilized marrow harvests and peripheral blood harvests. Transfusion 2015; 55 (12): 2874–2881. doi: 10.1111/trf.13251.

43. Canaani J, Savani BN, Labopin M et al. Donor age determines outcome in acute leukemia patients over 40 undergoing haploidentical hematopoietic cell transplantation. Am J Hematol 2017; 93 (2): 246–253. doi: 10.1002/ajh.24963.

44. Kasamon YL, Luznik L, Leffell MS et al. Nonmyeloablative HLA-haploidentical bone marrow transplantation with high-dose posttransplantation cyclophosphamide: effect of HLA disparity on outcome. Biol Blood Marrow Transplant 2010; 16 (4): 482–489. doi: 10.1016/j.bbmt.2009.11.011.

45. Wang Y, Chang YJ, Xu LP et al. Who is the best donor for a related HLA haplotype-mismatched transplant? Blood 2014; 124 (6): 843–850. doi: 10.1182/blood-2014-03-563130.

46. Randolph SSB, Gooley TA, Warren EH et al. Female donors contribute to a selective graft-versus-leukemia effect in male recipients of HLA matched, related hematopoietic stem cell transplants. Blood 2004; 103 (1): 347–352. doi: 10.1182/blood-2003-07-2603.

47. Carlens S, Rihgdén O, Remberger M et al. Risk factors for chronic graft-versus-host disease after bone marrow transplantation: a retrospective single-center analysis. Bone Marrow Transplant 1998; 22 (8): 755–761. doi: 10.1038/sj.bmt.1701423.

48. Miklos DB, Kim HT, Miller KH et al. Antibody responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-host disease and disease remission. Blood 2005; 105 (7): 2973–2978. doi: 10.1182/blood-2004-09-3660.

49. Nakasone H, Remberger M, Tian L et al. Risks and benefits of sex-mismatched hematopoietic cell transplantation differ by conditioning strategies. Haematologica 2015; 100 (11): 1477–1485. doi: 10.3324/haematol.2015.125294.

50. Nakasone H, Tian L, Sahaf B et al. Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans. Blood 2015; 125 (20): 3193–3201. doi: 10.1182/blood-2014-11-613323.

51. Friedrich P, Guerra-Garcia P, Stetson A et al. Young female donors do not increase the risk of graft-versus-host disease or impact overall outcomes in pediatric HLA- -matched sibling hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2018; 24 (1): 96–102. doi: 10.1016/j.bbmt.2017.09.014.

52. Sahaf B, Yang Y, Arai S et al. H-Y antigen-binding B cells develop in male recipients of female hematopoietic cells and associate with chronic graft vs. host disease. Proc Natl Acad Sci USA 2013; 110 (8): 3005–3010. doi: 10.1073/pnas.1222900110.

53. Mansouri M, Villard J, Ramzi M et al. Impact of donor KIRs and recipient KIR/HLA class I combinations on GVHD in patients with acute leukemia after HLA-matched sibling HSCT. Hum Immunol 2020; 81 (6): 285–292. doi: 10.1016/j.humimm.2020.03.004.

54. Sorror ML, Maris MB, Storb R et al. Hematopoietic cell transplantation (HCT) -specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106 (8): 2912–2919. doi: 10.1182/blood-2005-05-2004.

55. Gratwohl A. The EBMT risk score. Bone Marrow Transplant 2012; 47 (6): 749–756. doi: 10.1038/bmt.2011. 110.