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Graft-versus-host Disease

Calcineurin inhibitor-free GVHD prophylaxis with sirolimus, mycophenolate mofetil and ATG in Allo-SCT for leukemia patients with high relapse risk: an observational cohort study

Bone Marrow Transplantation volume 43, pages 717–723 (2009)Cite this article

Abstract

Certain leukemias have a high relapse risk even after allo-SCT, and GVHD prophylaxis with calcineurin inhibitors (CNIs) may interfere with a possible GVL effect. Therefore, we replaced CYA by sirolimus in patients with high relapse risk. In contrast to CNIs, sirolimus promotes the generation of regulatory T-cells and has potent antineoplastic activity. Sirolimus has been used in combination with CNI for GVHD prophylaxis in hematopoietic SCT. However, no CNI-free prophylactic regimen with sirolimus has been evaluated so far. Within the FLAMSA-RIC protocol, 15 patients received GVHD prophylaxis with sirolimus and mycophenolate mofetil (MMF). The underlying diagnoses were relapsed or refractory T-ALL (n=3), AML with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) or mixed-lineage leukemia-partial tandem duplication (MLL-PTD; n=10; 5 with refractory disease) and CML in refractory myeloid blast crisis (n=2). All evaluable patients (n=14) were engrafted. Grades II–IV acute GVHD occurred in 21% and chronic GVHD in 30% of patients. Non-relapse mortality rate was 14%. No thrombotic microangiopathy or sinusoidal obstruction syndrome was observed. Three patients with FLT3-ITD+ AML relapsed after a median of 112 days. At a median follow-up of 10 months after transplantation, 10 patients are alive and in complete remission. In conclusion, sirolimus-based GVHD prophylactic regimens deserve further investigation.

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References

  1. Schmid C, Schleuning M, Ledderose G, Tischer J, Kolb HJ . Sequential regimen of chemotherapy, reduced-intensity conditioning for allogeneic stem-cell transplantation, and prophylactic donor lymphocyte transfusion in high-risk acute myeloid leukemia and myelodysplastic syndrome. J Clin Oncol 2005; 23: 5675–5687.

    Article  PubMed  Google Scholar 

  2. Schmid C, Schleuning M, Schwerdtfeger R, Hertenstein B, Mischak-Weissinger E, Bunjes D et al. 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.

    Article  CAS  PubMed  Google Scholar 

  3. Ali SM, Sabatini DM . Structure of S6 kinase 1 determines whether raptor-mTOR or rictor-mTOR phosphorylates its hydrophobic motif site. J Biol Chem 2005; 280: 19445–19448.

    Article  CAS  PubMed  Google Scholar 

  4. Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 2004; 14: 1296–1302.

    Article  CAS  PubMed  Google Scholar 

  5. Zeiser R, Nguyen VH, Beilhack A, Buess M, Schulz S, Baker J et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 2006; 108: 390–399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Johnson RW . Sirolimus (Rapamune) in renal transplantation. Curr Opin Nephrol Hypertens 2002; 11: 603–607.

    Article  PubMed  Google Scholar 

  7. Trotter JF . Sirolimus in liver transplantation. Transplant Proc 2003; 35: S193–S200.

    Article  Google Scholar 

  8. Cutler C, Li S, Ho VT, Koreth J, Alyea E, Soiffer RJ et al. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood 2007; 109: 3108–3114.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Benito AI, Furlong T, Martin PJ, Anasetti C, Appelbaum FR, Doney K et al. Sirolimus (rapamycin) for the treatment of steroid-refractory acute graft-versus-host disease. Transplantation 2001; 72: 1924–1929.

    Article  CAS  PubMed  Google Scholar 

  10. Johnston LJ, Brown J, Shizuru JA, Stockerl-Goldstein KE, Stuart MJ, Blume KG et al. Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2005; 11: 47–55.

    Article  CAS  PubMed  Google Scholar 

  11. Couriel DR, Saliba R, Escalon MP, Hsu Y, Ghosh S, Ippoliti C et al. Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease. Br J Haematol 2005; 130: 409–417.

    Article  CAS  PubMed  Google Scholar 

  12. Jurado M, Vallejo C, Pérez-Simón JA, Brunet S, Ferra C, Balsalobre P et al. Sirolimus as part of immunosuppressive therapy for refractory chronic graft-versus-host disease. Biol Blood Marrow Transplant 2007; 13: 701–706.

    Article  CAS  PubMed  Google Scholar 

  13. Hidalgo M, Rowinsky EK . The rapamycin-sensitive transduction pathway as a target for cancer therapy. Oncogene 2000; 19: 6680–6686.

    Article  CAS  PubMed  Google Scholar 

  14. Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 2001; 98: 10314–10319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Podsypanina K, Lee RT, Politis C, Hennessy I, Crane A, Puc J et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten−/− mice. Proc Natl Acad Sci USA 2001; 98: 10320–10325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Raymond E, Alexandre J, Faivre S, Vera K, Materman E, Boni J et al. Safety and pharmacokinetics of escalated doses of weekly intravenous infusion of CCI-779, a novel mTOR inhibitor, in patients with cancer. J Clin Oncol 2004; 22: 2336–2347.

    Article  CAS  PubMed  Google Scholar 

  17. Platzbecker U, Haase M, Herbst R, Hänel A, Voigtmann K, Thiede CH et al. Activity of sirolimus in patients with myelodysplastic syndrome—results of a pilot study. Br J Haematol 2005; 128: 625–630.

    Article  CAS  PubMed  Google Scholar 

  18. Haritunians T, Mori A, O′Kelly J, Luong QT, Giles FJ, Koeffler HP . Antiproliferative activity of RAD001 (everolimus) as a single agent and combined with other agents in mantle cell lymphoma. Leukemia 2007; 21: 333–339.

    Article  CAS  PubMed  Google Scholar 

  19. Xu Q, Simpson S-E, Scialla TJ, Bagg A, Carroll M . Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood 2003; 102: 972–980.

    Article  CAS  PubMed  Google Scholar 

  20. Gingras AC, Raught B, Sonenberg N . Regulation of translation initiation by RAP/mTOR. Genes Dev 2001; 15: 807–826.

    Article  CAS  PubMed  Google Scholar 

  21. Recher C, Beyne-Rauzy O, Demur C, Chicanne G, Dos Santos C, Mansat-De Mas V et al. Antileukemic activity of rapamycin in acute myeloid leukemia. Blood 2005; 105: 2527–2534.

    Article  CAS  PubMed  Google Scholar 

  22. Chan SM, Weng AP, Tibshirani R, Aster JC, Utz PJ . Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukaemia. Blood 2007; 110: 278–286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hong JC, Kahan BD . Sirolimus-induced thrombocytopenia and leukopenia in renal transplant recipients: risk factors, incidence, progression, and management. Transplantation 2000; 69: 2085–2090.

    Article  CAS  PubMed  Google Scholar 

  24. Champion L, Stern M, Israël-Biet D, Mamzer-Bruneel MF, Peraldi MN, Kreis H et al. Brief communication: sirolimus-associated pneumonitis: 24 cases in renal transplant recipients. Ann Intern Med 2006; 144: 505–509.

    Article  PubMed  Google Scholar 

  25. Mahé E, Morelon E, Lechaton S, Sang KH, Mansouri R, Ducasse MF et al. Cutaneous adverse events in renal transplant recipients receiving sirolimus-based therapy. Transplantation 2005; 97: 476–482.

    Google Scholar 

  26. Smith MP, Newstead CG, Ahmad N, Lewington AJ, Tibble S, Lodge JP et al. Poor tolerance of sirolimus in a steroid avoidance regimen for renal transplantation. Transplantation 2008; 85: 636–639.

    Article  CAS  PubMed  Google Scholar 

  27. Tenderich G, Fuchs U, Zittermann A, Muckelbauer R, Berthold HK, Koerfer R . Comparison of sirolimus and everolimus in their effects on blood lipid profiles and haematological parameters in heart transplant recipients. Clin Transplant 2007; 21: 536–543.

    Article  PubMed  Google Scholar 

  28. Kuppahally S, Al-Khaldi A, Weisshaar D, Valantine HA, Oyer P, Robbins RC et al. Wound healing complications with de novo sirolimus versus mycophenolate mofetil-based regimen in cardiac transplant recipients. Am J Transplant 2006; 6: 986–992.

    Article  CAS  PubMed  Google Scholar 

  29. Cutler C, Henry NL, Magee C, Li S, Kim HT, Alyea E et al. Sirolimus and thrombotic microangiopathy after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 551–557.

    Article  CAS  PubMed  Google Scholar 

  30. Marty FM, Bryar J, Browne SK, Schwarzberg T, Ho VT, Bassett IV et al. Sirolimus-based graft-versus-host disease prophylaxis protects against cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation: a cohort analysis. Blood 2007; 110: 490–500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Glucksberg H, Storb R, Fever A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  PubMed  Google Scholar 

  32. Shulman HM, Sullivan KM, Weiden PL, McDonald GB, Striker GE, Sale GE et al. Chronic graft-versus-host syndrome in man. A long term clinicopathologic study of 20 Seattle patients. Am J Med 1980; 69: 204–217.

    Article  CAS  PubMed  Google Scholar 

  33. Kaplan E, Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.

    Article  Google Scholar 

  34. 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: 2912–2919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. De Simone P, Petruccelli S, Precisi A, Carrai P, Doria R, Menichetti F et al. Switch to everolimus for sirolimus-induced pneumonitis in a liver transplant recipient—not all proliferation signal inhibitors are the same: a case report. Transplant Proc 2007; 39: 3500–3501.

    Article  CAS  PubMed  Google Scholar 

  36. Furlong T, Kiem HP, Appelbaum FR, Carpenter PA, Deeg HJ, Doney K et al. Sirolimus in combination with cyclosporine or tacrolimus plus methotrexate for prevention of graft-versus-host disease following hematopoietic cell transplantation from unrelated donors. Biol Blood Marrow Transplant 2008; 14: 531–537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nogueras F, Espinosa MD, Mansilla A, Torres JT, Cabrera MA, Martín-Vivaldi R . Mycophenolate mofetil-induced neutropenia in liver transplantation. Transplant Proc 2005; 37: 1509–1511.

    Article  CAS  PubMed  Google Scholar 

  38. Kreis H, Cisterne JM, Land W, Wramner L, Squifflet JP, Abramowicz D et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000; 69: 1252–1260.

    Article  CAS  PubMed  Google Scholar 

  39. Busca A, Locatelli F, Moscato D, Falda M . Sirolimus-related toxicity in stem cell transplantation. Biol Blood Marrow Transplant 2005; 11: 647–649.

    Article  PubMed  Google Scholar 

  40. Basara N, Baurmann H, Kolbe K, Yaman A, Labopin M, Burchardt A et al. Antithymocyte globulin for the prevention of graft-versus-host disease after unrelated hematopoietic stem cell transplantation for acute myeloid leukemia: results from the multicenter German cooperative study group. Bone Marrow Transplant 2005; 35: 1011–1018.

    Article  CAS  PubMed  Google Scholar 

  41. Cao W, Mohacsi P, Shorthouse R, Pratt R, Morris RE . Effects of rapamycin on growth factor-stimulated vascular smooth muscle cell DNA synthesis. Inhibition of basic fibroblast growth factor and platelet-derived growth factor action and antagonism of rapamycin by FK506. Transplantation 1995; 59: 390–395.

    Article  CAS  PubMed  Google Scholar 

  42. Haririan A, Morawski K, West MS, El-Amm JM, Doshi MD, Cincotta E et al. Sirolimus exposure during the early post-transplant period reduces the risk of CMV infection relative to tacrolimus in renal allograft recipients. Clin Transplant 2007; 21: 466–471.

    Article  PubMed  Google Scholar 

  43. Hill JA, Hummel M, Starling RC, Kobashigawa JA, Perrone SV, Arizón JM et al. A lower incidence of cytomegalovirus infection in de novo heart transplant recipients randomized to everolimus. Transplantation 2007; 84: 1436–1442.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Professor C Thiede, University of Dresden, for performing the chimerism analysis.

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  1. Centre for Bone Marrow and Blood Stem Cell Transplantation, Deutsche Klinik für Diagnostik, Wiesbaden, Germany

    M Schleuning, D Judith, Z Jedlickova, T Stübig, M Heshmat, H Baurmann & R Schwerdtfeger

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Correspondence to M Schleuning.

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Schleuning, M., Judith, D., Jedlickova, Z. et al. Calcineurin inhibitor-free GVHD prophylaxis with sirolimus, mycophenolate mofetil and ATG in Allo-SCT for leukemia patients with high relapse risk: an observational cohort study. Bone Marrow Transplant 43, 717–723 (2009). https://doi.org/10.1038/bmt.2008.377

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