Erişkin aplastik anemi hastaları allojenik hematopoietik kök hücre nakli sonrası miks kimerik durumda remisyonda kalabilir

Abstract

Amaç: Allojenik kök hücre nakli (AKHN), uygun vericisi bulunan fit ağır aplastik anemili (SAA) ve çok ağır aplastik anemili (VSAA)hastalarda küratif tedavi yöntemi olarak uygulanmaktadır. Yaş, nakil sonrası sağkalımı belirleyen en önemli faktörlerden biridir ve ilerleyen yaş ile birlikte sağkalım oranları azalmaktadır, bu nedenle uygun hastaların geciktirilmeden nakle alınması büyük önem taşımaktadır. AKHN sonrasında miks kimerizm (MK) olması nüs ya da engraftman yetersizliğinin işareti olabilir. Biz bu çalışmada, erişkin SAA ve VSAA hastalarında AKHN sonrasındaki durumunu ve takipte kimerizmin önemini incelemeyi amaçladık. Yöntemler: Merkezimizde AKHN olan 16 AA hastası bu gözlemsel çalışmaya dahil edildi. HLA durumu, hazırlama rejimi, kimerizm ve remisyon durumu kaydedildi. Bulgular: Tüm hastalarda medyan PFS 70,4 ay ve medyan OS 89,7 ay olarak izlendi. Takip süresi boyunca, 9 hasta tam kimerik iken 6 hasta MK ve 1 hastada kimerizm <%5 izlendi. Kimerizmi <%5 olan hastada engraftman kaybı izlenirken, diğer tam kimerik ve miks kimerik hastalar remisyonda izlendi. Sonuç: Minimum toksisite ile engraftmanı sağlayan optimize hazırlama rejimleri kullanılarak daha fazla hasta allo-SCT ile tedavi edilebilir. Çalışmamız, yetişkin AA hastalarının allo-SCT'den sonra, miks kimerik bir durumda bile uzun süre remisyon sağlayabildiğini göstermiştir.

Keywords

• erişkin aplastik anemi
• allojenik kök hücre nakli
• kimerizm

Adult aplastic anemia patients can maintain remission after allogeneic hematopoietic stem cell transplantation in a mixed chimeric state

Abstract

Aim: Allogeneic stem cell transplantation (allo-SCT) is performed as a curative treatment in young, fit, severe aplastic anemia (SAA) and very severe aplastic anemia (VSAA) patients. Age is one of the most significant factors that impact survival after transplantation. With advancing age, survival rates decrease, therefore it is crucial to perform allo-SCT without any delay in appropriate SAA and VSAA patients. Mixed chimerism (MC) in the post-allo-SCT period may be a sign of relapse or graft failure. In this study, we aimed to evaluate the outcome of allo-SCT in adult SAA and VSAA patients and the significance of chimerism monitoring in follow up. Methods: The data of 16 adult AA patients who underwent allo-SCT at our center were included in this observational study. HLA match, conditioning regimens, chimerism and remission status were recorded. Results: Median PFS was 70.4 months and median OS was 89.7 months in all patients. During the follow-up period, 9 patients remained fully chimeric whereas 6 patients had MC. The chimerism level of one patient, who had engraftment failure, was <5%. Both fully chimeric and mixed chimeric patients remained in remission. Conclusion: More AA patients can be treated with allo-SCT with more optimized conditioning regimens that provide sustained engraftment with minimum toxicity. Our study showed that adult AA patients can maintain remission for a long time after allo-SCT, even in a mixed chimeric state.

Keywords

• adult aplastic anemia
• allogeneic stem cell transplantation
• chimerism

References

1. 1. Killick S, Bown N, Cavenagh J, Dokal I, Foukaneli T, Hill A, et al. Guidelines for the diagnosis and management of adult aplastic anemia. Br J Haematol. 2016;172:187–207.
2. 2. Camitta BM, Rappeport JM, Parkman R, Nathan DG. Selection of patients for bone marrow transplantation in severe aplastic anemia. Blood. 1975;45:355–63.
3. 3. Bacigalupo A, Hows J, Gluckman E, Nissen C, Marsh J, Van Lint MT, et al. Bone marrow transplantation (BMT) versus immunosuppression (IS) for the treatment of severe aplastic anemia (SAA): a report of the EBMT SAA working party. Br J Haematol. 1988;70(2):177-82
4. 4. Antin JH, Childs R, Filipovich AH, Giralt S, Mackinnon S, Spitzer T, et al. Establishment of complete and mixed donor chimerism after allogeneic lymphohematopoietic transplantation: recommendations from a workshop at the 2001 Tandem Meetings of the International Bone Marrow Transplant Registry and the American Society of Blood and Marrow Transplantation. Biol Blood Marrow Transplant. 2001;7:473–85.
5. 5. Van Leeuwen JEM, Van Tol MJD , Joosten AM, Wijnen JT, Verweij PJ, Khan PM, et al. Persistence of host-type hematopoiesis after allogeneic bone marrow transplantation for leukemia is significantly related to the recipient's age and/or the conditioning regimen, but it is not associated with an increased risk of relapse, Blood. 1994;83:10;3059–67.
6. 6. Bretagne S, Vidaud M, Kuentz M, Cordonnier C, Henni T, Vinci G, et al. Mixed blood chimerism in T cell-depleted bone marrow transplant recipients: evaluation using DNA polymorphisms, Blood. 1987;70:5;1692–95.
7. 7. Levrat E, Roosnek E, Masouridi S, Mohty B, Ansari M, Villard J, et al. Very Long Term Stability of Mixed Chimerism after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Hematologic Malignancies. Bone Marrow Res. 2015;2015:176526
8. 8. Rihn C, Cilley J, Naik P, Pedicano AV, Mehta J. Definition Of Myeloid Engraftment After Allogeneic Hematopoietic Stem Cell Transplantation. Haematologica. 2004;89(6):763-4

9. 9. Rowlings PA, Przepiorka D, Klein JP, Gale RP, Passweg JR, Henslee-Downey PJ, et al. IBMTR Severity Index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade. Br J Haematol. 1997;97:855.
10. 10. 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):945–56.
11. 11. Bader P, Niethammer D, Willich A, Kreyenberg H, Klingebiel T. How and when should we monitor chimerism after allogeneic stem cell transplantation? Bone Marrow Transplant.2005;35:107-19.
12. 12. McCann SR, Bacigalupo A, Gluckman E, Hinterberger W, Hows J, Ljungman P, et al. Graft rejection and second bone marrow transplants for acquired aplastic anemia: a report from the Aplastic Anaemia Working Party of the European Bone Marrow Transplant Group. Bone Marrow Transplant. 1994;13:233-7.
13. 13. Champlin RE, Horowitz MM, van Bekkum DW, Camitta BM, Elfenbein GE, Gale RP, et al. Graft failure following bone marrow transplantation for severe aplastic anemia: risk factors and treatment results. Blood. 1989;73:606-13.
14. 14. Gluckman E, Horowitz MM, Champlin RE, Hows JM, Bacigalupo A, Biggs JC, et al. Bone marrow transplantation for severe aplastic anemia: influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome. Blood. 1992;79:269-75.
15. 15. Deeg HJ, Socie G, Schoch G, Henry-Amar M, Witherspoon RP, Devergie A, et al. Malignancies after marrow transplantation for aplastic anemia and fanconi anemia: a joint Seattle and Paris analysis of results in 700 patients. Blood. 1996;87:386-92.
16. 16. Gale RP, Ho W, Feig S, Champlin R, Tesler A, Arenson E, et al. Prevention of graft rejection following bone marrow transplantation. Blood. 1981;57:9-12.
17. 17. Storb R, Etzioni R, Anasetti C, Appelbaum FR, Buckner CD, Bensinger W, et al. Cyclophosphamide combined with anti-thymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia. Blood. 1994;84:941-9.
18. 18. Ades L, Mary JY, Robin M, Ferry C, Porcher R, Esperou H, et al. Long-term outcome after bone marrow transplantation for severe aplastic anemia. Blood. 2004;103:2490-7.
19. 19. Kahl C, Leisenring W, Deeg HJ, Chauncey TR, Flowers ME, Martin PJ, et al. Cyclophosphamide and anti-thymocyte globulin as a conditioning regimen for allogeneic marrow transplantation in patients with aplastic anemia: a long-term follow-up. Br J Haematol. 2005;130:747-51.
20. 20. Schrezenmeier H, Passweg JR, Marsh JC, Bacigalupo A, Bredeson CN, Bullorsky E, et al. Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA matched sibling donor transplants for young patients with severe acquired aplastic anemia. Blood. 2007;110:1397-400.
21. 21. Gupta V, Eapen M, Brazauskas R, Carreras J, Aljurf M, Gale RP, et al. Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors. Haematologica. 2010;95:2119-25.
22. 22. Maury S, Bacigalupo A, Anderlini P, Aljurf M, Marsh J, Socié G, et al. Improved outcome of patients older than 30 years receiving HLA-identical sibling hematopoietic stem cell transplantation for severe acquired aplastic anemia using fludarabine-based conditioning: a comparison with conventional conditioning regimen. Haematologica. 2009;94:1312-5.
23. 23. Shin SH, Yoon JH, Yahng SA, Lee SE, Cho BS, Eom KS, et al. Influence of recipient’s age on the outcome of HLA-matched sibling transplants in adult patients with severe aplastic anemia who conditioned with fludarabine-based regimen. Paper presented at: 54th ASH Annual Meeting and Exposition; 2012;1921-2.
24. 24. Bacigalupo A, Locatelli F, Lanino E, Marsh J, Socié G, Maury S, et al. Fludarabine, cyclophosphamide, and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party. Bone Marrow Transplant. 2005;36:947-50.
25. 25. Valcarcel D, Martino R, Caballero D,Mateos MV, Pérez-Simón JA, Canals C, et al. Chimerism analysis following allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning. Bone Marrow Transplant. 2003;31:387–92.
26. 26. Baron F, Baker JE, Storb R, Gooley TA, Sandmaier BM, Maris MB, et al. Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. Blood. 2004;104:2254–62.
27. 27. Childs R, Clave E, Contentin N, Jayasekera D, Hensel N, Leitman S, et al. Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses. Blood. 1999;94:3234–41.
28. 28. Saito B, Fukuda T, Yokoyama H, Kurosawa S, Takahashi T, Fuji S, et al. Impact of T cell chimerism on clinical outcome in 117 patients who underwent allogeneic stem cell transplantation with a busulfan-containing reduced-intensity conditioning regimen. Biol Blood Marrow Transplant. 2008;14:1148–55.
29. 29. Park M, Koh KN, Seo JJ, Im HJ. Clinical implications of chimerism after allogeneic hematopoietic stem cell transplantation in children with non-malignant diseases. Korean J Hematol. 2011;46(4):258-64.
30. 30. Svenberg P, Mattsson J, Ringdén O, Uzunel M. Allogeneic hematopoietic SCT in patients with non-malignant diseases, and importance of chimerism, Bone Marrow Transplant. 2009;44(11):757-63.