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Graft-Versus-Host Disease

A phase I/II double-blind, placebo-controlled study of recombinant human interleukin-11 for mucositis and acute GVHD prevention in allogeneic stem cell transplantation

Bone Marrow Transplantation volume 29, pages 373–377 (2002)Cite this article

Abstract

Interleukin-11 (IL-11) decreases cytokine release and increases survival in murine BMT models. In these systems, it reduces gut permeability, partially polarizes T cells to a Th2 phenotype, down-regulates IL-12, prevents mucositis, and accelerates recovery of oral and bowel mucosa. We conducted a randomized double-blind pilot study of rhIL-11 administered with cyclosporine/MTX prophylaxis after cytoxan/TBI conditioning and allogeneic stem cell transplantation for hematologic malignancies. Patients received rhIL-11, 50 μg/kg subcutaneously daily or placebo in a 3:1 ratio. Treatment was administered prior to the start of conditioning and continued up to 21 days. The study was designed to assess safety with stopping rules for cardiac arrhythmias and mortality. Although projected to accrue 20 patients, only 13 patients (10 IL-11, three placebo) were enrolled because the early stopping rule for mortality was triggered. Of 10 evaluable patients who received IL-11, four died by day 40 and one died on day 85. Deaths were attributable to transplant-related toxicity. One of three placebo recipients died of suicide, the other two are alive. Patients receiving IL-11 had severe fluid retention and early mortality, making it impossible to determine whether IL-11 given in this schedule can reduce the rate of GVHD. Grade B–D acute GVHD occurred in two of eight evaluable patients on IL-11 and one of three patients on placebo. The primary adverse events of the study were severe fluid retention resistant to diuresis (average weight gain 9 ± 4%) and multiorgan failure in five of 10 evaluable patients. The use of IL-11 as GVHD prophylaxis in allogeneic transplantation cannot be recommended as administered in this trial.

Bone Marrow Transplantation (2002) 29, 373–377. doi:10.1038/sj.bmt.1703394

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References

  1. Cleveland MG, Annabale CR, Klimpel GR . In vivo and in vitro production of IFN-beta and IFN-gamma during graft vs host disease J Immun 1988 141: 3349 3356

    CAS  PubMed  Google Scholar 

  2. Dickinson AM, Sviland L, Dunn J et al. Demonstration of direct involvement of cytokines in graft-versus-host reactions using an in vitro skin explant model Bone Marrow Transplant 1991 7: 209 216

    CAS  PubMed  Google Scholar 

  3. Holler E, Kolb HJ, Mittermüller J et al. Modulation of acute graft-versus-host disease after allogeneic bone marrow transplantation by tumor necrosis factor α (TNFα) release in the course of pretransplant conditioning: role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing TNFα (MAK 195F) Blood 1995 86: 890 899

    CAS  PubMed  Google Scholar 

  4. McKenzie RC, Sauder DN . The role of keratinocyte cytokines in inflammation and immunity J Invest Dermatol 1990 95: 105s 107s

    Article  CAS  PubMed  Google Scholar 

  5. Piguet PF, Grau GE, Allet B, Vassali PJ . Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease J Exp Med 1987 166: 1280 1289

    Article  CAS  PubMed  Google Scholar 

  6. Remberger M, Ringdén O, Markling L . TNFα levels are increased during bone marrow transplantation conditioning in patients who develop acute GVHD Bone Marrow Transplant 1995 15: 99 104

    CAS  PubMed  Google Scholar 

  7. Smith SR, Terminelli C, Kenworthy-Bott L, Phillips DL . A study of cytokine production in acute graft-vs-host disease Cell Immunol 1991 134: 336 348

    Article  CAS  PubMed  Google Scholar 

  8. Sykes M, Szot GL, Nguyen PL, Pearson DA . Interleukin-12 inhibits murine graft-versus-host disease Blood 1995 86: 2429 2438

    CAS  PubMed  Google Scholar 

  9. Yang YG, Dey B, Sergio JJ, Sykes M . Interleukin-12 prevents severe acute graft-versus-host disease (GVHD) and GVHD-associated immune dysfunction in a fully major histocompatibility complex haplotype-mismatched murine bone marrow transplantation model Transplantation 1997 64: 1343 1352

    Article  CAS  PubMed  Google Scholar 

  10. Yang YG, Sergio JJ, Pearson DA et al. Interleukin-12 preserves the graft-versus-leukemia effect of allogeneic CD8 T cells while inhibiting CD4-dependent graft-versus-host disease in mice Blood 1997 90: 4651 4660

    CAS  PubMed  Google Scholar 

  11. Antin JH, Weinstein HJ, Guinan EC et al. Recombinant interleukin-1 receptor antagonist in the treatment of steroid-resistant graft-versus-host disease Blood 1994 84: 1342 1348

    CAS  PubMed  Google Scholar 

  12. McCarthy PL Jr, Williams L, Harris-Bacile M et al. A clinical phase I/II study of recombinant human interleukin-1 receptor in glucocorticoid-resistant graft-versus-host disease Transplantation 1996 62: 626 631

    Article  CAS  PubMed  Google Scholar 

  13. Pan L, Delmonte J Jr, Jalonen CK, Ferrara JLM . Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T-lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease Blood 1995 86: 4422 4429

    CAS  PubMed  Google Scholar 

  14. Sonis ST, Peterson RL, Edwards LJ et al. Defining mechanisms of action of interleukin-11 on the progression of radiation-induced oral mucositis in hamsters Oral Oncol 2000 36: 373 381

    Article  CAS  PubMed  Google Scholar 

  15. Hill GR, Ferrara JL . The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation Blood 2000 95: 2754 2759

    CAS  PubMed  Google Scholar 

  16. Hill GR, Cooke KR, Teshima T et al. Interleukin-11 promotes T cell polarization and prevents acute graft-versus-host disease after allogeneic bone marrow transplantation J Clin Invest 1998 102: 115 123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hill G, Cooke K, Crawford J et al. IL-11 reduces the severity of graft-versus-host disease following allogeneic BMT Blood 1997 90: (Suppl. 1) 204a

    Google Scholar 

  18. Rowlings P, Przepiorka D, Klein J et al. IBMTR severity index for grading acute graft-versus-host disease: retrospective comparison with Glucksberg grade Br J Haematol 1997 97: 855 864

    Article  CAS  PubMed  Google Scholar 

  19. Przepiorka D, Weisdorf D, Martin P et al. 1994 Consensus Conference on Acute GVHD Grading Bone Marrow Transplant 1995 15: 825 828

    CAS  PubMed  Google Scholar 

  20. Sonis ST, Oster G, Fuchs H et al. Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation J Clin Oncol 2001 19: 2201 2205

    Article  CAS  PubMed  Google Scholar 

  21. 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: 204 217

    Article  CAS  PubMed  Google Scholar 

  22. Peterson R, Bozza M, Dorner A . Interleukin-11 induces intestinal epithelial cell growth arrest though effects on retinoblastoma protein phosphorylation Am J Pathol 1996 149: 895 902

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Du X, Coerschuk C, Orazi A, Williams D . A bone marrow stromal-derived growth factor, interleukin-11, stimulates recovery of small intestinal mucosal cells after cytoablative therapy Blood 1994 83: 33 37

    CAS  PubMed  Google Scholar 

  24. Potten CS . Interleukin-11 protects the clonogenic stem cells in murine small-intestinal crypts from impairment of their reproductive capacity by radiation Int J Cancer 1995 62: 356 361

    Article  CAS  PubMed  Google Scholar 

  25. Orazi A, Du X, Yang Z et al. Interleukin-11 prevents apoptosis and accelerates recovery of small intestinal mucosa in mice treated with combined chemotherapy and radiation Lab Invest 1996 75: 33 42

    CAS  PubMed  Google Scholar 

  26. Du X, Liu Q, Yang Z et al. Protective effects of interleukin-11 in a murine model of ischemic bowel necrosis Am J Physiol 1997 272: 545 552

    Google Scholar 

  27. Potten CS . Protection of the small intestinal clonogenic stem cells from radiation-induced damage by pretreatment with interleukin 11 also increases murine survival time Stem Cells 1996 14: 452 459

    Article  CAS  PubMed  Google Scholar 

  28. Sonis S, Muska A, O'Brien J et al. Alteration in the frequency, severity and duration of chemotherapy-induced mucositis in hamsters by interleukin-11 Eur J Cancer B Oral Oncol 1995 32B: 261 266

    Article  Google Scholar 

  29. Sonis ST, Van Vugt AG, McDonald J et al. Mitigating effects of interleukin 11 on consecutive courses of 5-fluorouracil-induced ulcerative mucositis in hamsters Cytokine 1997 9: 605 612

    Article  CAS  PubMed  Google Scholar 

  30. Rapoport A, Watelet L, Linder T et al. Analysis of factors that correlate with mucositis in recipients of autologous and allogeneic marrow transplants Blood 1997 90: (Suppl. 1) 222a

    Google Scholar 

  31. Vredenburgh JJ, Hussein A, Fisher D et al. A randomized trial of recombinant human interleukin-11 following autologous bone marrow transplantation with peripheral blood progenitor cell support in patients with breast cancer Biol Blood Marrow Transplant 1998 4: 134 141

    Article  CAS  PubMed  Google Scholar 

  32. Dykstra KH, Rogge H, Stone A et al. Mechanism and amelioration of recombinant human interleukin-11 (rhIL-11)-induced anemia in healthy subjects J Clin Pharmacol 2000 40: 880 888

    Article  CAS  PubMed  Google Scholar 

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Author notes

  1. JLM Ferrara

    Present address: Bone Marrow Transplant Program, University of Michigan Medical Center, 1500 East Medical Center Dr, Ann Arbor, MI 48109, USA

Authors and Affiliations

  1. Department of Adult Oncology and Biostatistical Science, Departments of Medicine and Surgery, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA, USA

    JH Antin, SJ Lee, D Neuberg, E Alyea, RJ Soiffer, S Sonis & JLM Ferrara

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Antin, J., Lee, S., Neuberg, D. et al. A phase I/II double-blind, placebo-controlled study of recombinant human interleukin-11 for mucositis and acute GVHD prevention in allogeneic stem cell transplantation. Bone Marrow Transplant 29, 373–377 (2002). https://doi.org/10.1038/sj.bmt.1703394

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