Brychtová Y., Krejčí M., Doubek M., Tomíška M., Navrátil M., Ráčil Z., Dvořáková D., Horký O., Lengerová M., Pospíšilová S., Mayer J.: Long-term results of allogeneic hematopoietic stem cell transplantation after a reduced-intensity conditioning busulfan, fludarabine, and antithymocyte globulin

Czech version

Authors: Y. Brychtová; M. Krejčí; M. Doubek; M. Tomíška; M. Navrátil; Z. Ráčil; D. Dvořáková; O. Horký; M. Lengerová; S. Pospíšilová; J. Mayer
Authors‘ workplace: Interní hematoonkologická klinika, Fakultní nemocnice Brno, Lékařská fakulta Masarykova Univerzita Brno
Published in: Transfuze Hematol. dnes,17, 2011, No. 1, p. 12-19.
Category: Comprehensive Reports, Original Papers, Case Reports

Overview

Reduced-intensity conditioning (RIC) is being widely used for allogeneic stem cell transplantation (SCT). Here we present our long-term experience with RIC regimen consisting of fludarabine (6x30 mg/m2), busulfan (2x4 mg/kg) and antithymocyte globulin (ATG Fresenius, 4x10 mg/kg) (Flu-Bu-ATG) at cohort of 71 patients (pts) with various hematological malignancies, 65 pts had unrelated donor, 6 related donor. Patients were transplanted in period 1998-2008, aim of our work was to evaluate effectivity and toxicity of RIC Flu-Bu-ATG. Median age was 50 years. Overall response rate was 87%; 83% of pts achieved complete and 4% partial response. The incidence of acute and chronic GVHD was 35% and 52%. The cumulative incidence of non-relapse mortality after 1 year and 4 years were 8% and 14%, respectively. With median follow-up of 55.0 months after SCT, 2- and 4-year event-free survival (EFS) was 49.0% and 40.3%, overall survival (OS) was 73.2% and 62.6%. Gender, age at SCT, type of donor, disease status at SCT, previous autologous transplantation, achievement of complete chimerism to day +100 did not significantly influence EFS and OS. On multivariate analysis, no presence of chronic GVHD (p = 0.029, HR:2.5), other diagnosis than CML (p = 0.018, HR:4.6) and dose of CD34+ cells lower than 5x10⁶/kg (p = 0.010, HR:2.8) are statistically significant for shorter OS. In conclusion, the Flu-Bu-ATG protocol can be considered as a RIC regimen combining effective disease control and acceptable toxicity profil.

Key words:
reduced-intensity conditioning, fludarabine, busufan, antithymocyte globulin

Sources

1. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med 2006; 354:1813-1826.

2. Clift RA, Buckner CD, Appelbaum FR, Bearman SI, Petersen FB, Fischer LD. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood 1990; 76: 1876-1871.

3. Burchenal JH, Oettgen HF, Holmberg EA, Hemphill SC, Reppert JA. Effect of total body irradiation on the transplantability of mouse leukemias. Cancer Res 1960; 20: 425-430.

4. Barnes DW, Corp MJ, Loutit JF, Neal FE. Treatment of murine leukaemia with X rays and homologous bone marrow. Brit Med J 1956; 15: 626-627.

5. Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A, Buckner CD. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic marrow grafts. N Engl J Med 1979; 30: 1068-1073.

6. Kolb HJ, Mittermüller J, Clemm C, Holler E, Ledderose G, Brehm G. Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 1990; 76: 2462-2465.

7. Giralt S, Estey E, Albitar M, van Besien K, Rondon G, Anderlini P. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997; 89: 4531-4536.

8. Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant diseases. Blood 1998; 91: 756-763.

9. McSweeney P, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effect. Blood 2001; 97: 3390-3400.

10. Banna GL, Aversa S, Sileni VC, Favaretto A, Ghiotto C, Monfardini S. Nonmyeloablative allogeneic stem cell transplantation (NST) after truly nonmyeloablative and reduced intensity conditioning regimens. Crit Rev Oncol Hematol 2004; 51: 171-189.

11. Barret A, Savani BN. Stem cell transplantation with reduced-intensity conditioning regimens: a review of ten years experience with new transplant concepts and new therapeutic agents. Leukemia 2006; 20:1661-1672.

12. Crawley C, Lalancette M, Szydlo R, Gilleece M, Peggs K, Mackinnon S. Outcome for reduced-intensity allogeneic transplantation for multiple myeloma: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood 2005; 105: 4532-4539.

13. Crawley C, Szydlo R, Lalancette M, Bacigalupo A, Lange A, Brune A. Outcomes of reduced intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT. Blood 2005; 106: 2969-2976.

14. Shimoni A, Hardan I, Shem-Tov N, Rand A, Herscovici C, Yerushalmi R. Comparison between two fludarabine-based reduced-intensity conditioning regimens before allogeneic hematopoietic stem-cell transplantation: fludarabine/melphalan is associated with higher incidence of acute graft-versus-host disease and non-relapse mortality and lower incidence of relapse than fludarabine/busulfan. Leukemia 2007; 21: 2109-2116.

15. Sorror ML, Sandmaier BM, Storer BE, Maris MB, Baron F, Maloney DG. Comorbidity and disease status-based risk stratification of outcomes among patients with acute myeloid leukemia or myelodysplasia receiving allogeneic hematopoietic cell transplantation. J Clin Oncol 2007; 25: 4246-4254.

16. Schmidt C, Schleuning M, Schwerdtfeger R, Hertenstein B, Mischak-Weissinger E, Bunjes D. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Blood 2006; 108: 1092-1099.

17. Tauro S, Craddock C, Peggs K, Begum G, Mahendra P, Cook G. Allogeneic stem cell transplantation using a reduced-intensity conditioning regimen has the capacity to produce durable remissions and long-term disease-free survival in patients with high-risk acute myeloid leukemia and myelodysplasia. J Clin Oncol 2005; 23: 9383-9393.

18. Marks R, Potthoff K, Hahn J, Ihorst G, Bertz H, Spyridonidis A. Reduced-toxicity conditioning with fludarabine, BCNU, and melphalan in allogeneic hematopoietic cell transplantation: particular activity against advanced hematologic malignancies. Blood 2008; 112: 415-425.

19. Or R, Shapira MY, Resnick I, Amar A, Ackerstein A, Samuel S. Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase. Blood 2003; 101: 441-445.

20. Lion T. Summary: reports on quantitative analysis of chimerim after allogeneic stem cell transplantation by PCR amplification of microsatellite markers and capillary electrophoresis with fluorescence detection. Leukemia 2003; 17: 232-254.

21. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J. Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825-828.

22. Shulman HM, Sullivan KM, Weiden PL, Macdonald GB, Strike GE, Sale GE. Chronic graft-versus-host syndrome in man. A long-term clinicopatologic study of 20 Seattle patients. Am J Med 1980; 60: 204-217.

23. Krejci M, Doubek M, Buchler T, Brychtova Y, Vorlicek J, Mayer J. Mycophenolate mofetil for the treatment of acute and chronic steroid-refractory graft-versus-host disease. Ann Hematol 2005; 84: 681-685.

24. Junghanss C, Marr KA, Carter RA, Sandmaier BM, Maris MB, Maloeny DG. Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoeitic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant 2002; 8: 512-520.

25. Mohty M, Jacot W, Faucher C, Bay JO, Zandotti C, Collet L. Infectious complications following allogeneic HLA-identical sibling transplantation with antithymocyte globulin-based reduced intensity preparative regimen. Leukemia 2003; 17: 2168-2177.

26. Martino R, Caballero MD, Canals C, San Miguel J, Sierra J, Rovira M. Reduced-intensity conditioning reduces the risk of severe infections after allogeneic peripheral blood stem cell transplantation. Bone Marrow Transplant 2001; 28: 341-347.

27. Frere P, Baron F, Bonnet C, Hafraoui K, Pereira M, Willems E. Infections after allogeneic hematopoietic stem cell transplantation with a nonmyeloablative conditioning regimen. Bone Marrow Transplant 2006; 37: 411-418.

28. Holtan SG, Hogan WJ, Elliott MA, Ansell SM, Inwards DJ, Porrata LF. CD34(+) cell dose and establishment of full donor chimerism at day +100 are important factors for survival with reduced-intensity conditioning with fludarabine and melphalan before allogeneic hematopoietic SCT for hematologic malignancies. Bone Marrow Transplant 2010; 45: 1699-1703.

29. Tsirigotis P, Shapira MY, Or R, Bitan M, Samuel S, Gesundheit B. The number of infused CD34+ cells does not influence the incidence of GVHD or outcome of allogeneic PBSC transplantation, usinug reduced-intensity conditioning and athithymocyte globulin. Bone Marrow Transplant 2010; 45: 1189-1196.

30. Michallet M, Le QH, Mohty M, Prebet T, Nicolini F, Boiron JM. Predictive factors for outcomes after reduced intensity conditioning hematopoietic stem cell transplantation for hematological malignancies: a 10-year retrospective analysis from the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. Exp Hematol 2008; 36: 535-544.

31. Vigouroux S, Michallet M, Porcher R, Attal M, Ades L, Bernard M. Long-term outcomes after reduced-intensity conditioning allogeneic stem cell transplantation for low-grade lymphoma: a survey by the French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC). Haematologica 2007; 92: 627-634.

32. Hamadani M, Blum W, Philips G, Elder P, Andritsos L, Hofmeister C. Improved nonrelapse mortality and infection rate with lower dose of antithymocyte globulin in patients undergoing reduced-intensity conditioning allogeneic transplantation for hematologic malignancies. Biol Blood Marrow Transplant 2009; 15: 1422-1430.

33. Bacigalupo A. Antilymhocyte/thymocyte globulin for graft versus host disease prophylaxis: efficacy and side effects. Bone Marrow Transplant 2005; 35: 225-231.

34. Finke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zabder AR. Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomized, open-label, multicentre phase 3 trial. Lancet Oncol 2009; 10: 855-864.

35. Baron F, Sandmaier BM. Chimerism and outcomes after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Leukemia 2006; 20: 1690-1700.

36. Valcarcel D, Martino R, Caballero D, Mateos MV, Perez-Simon JA, Canals C. Chimerism analysis following allogeneic peripheral blood stem cell transplantation with rediced-intensity conditioning. Bone Marrow Transplant 2003; 31: 387-392.

37. Valcarcel D, Martino R, Caballero D, Martin J, Ferra C, Nieto JB. Sustained remissions of high-risk acute myeloid leukemia and myelodysplatic syndrome after reduced-intensity conditioning allogeneic hematopoetic transplantation: chronic graft-versus-host disease is the strongest factor improving survival. J Clin Oncol 2008; 26: 577-584.

38. Shimoni A Hardan I, Shem-Tov N, Yeshurun M, Yerushalmi R, Avigdor A. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity. Leukemia 2006; 20: 322-323.

39. Aoudjhane M, Labopin M, Gorin NC. 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: 2304-2312.

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Transfusion and Haematology Today

2011 Issue 1