Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Post-Transplant Complications

A randomized placebo-controlled trial of lisofylline in HLA-identical, sibling-donor, allogeneic bone marrow transplant recipients

Bone Marrow Transplantation volume 25, pages 283–291 (2000)Cite this article

Abstract

the purpose of the study was to evaluate the effect of lisofylline (lsf) on engraftment, regimen-related toxicities (rrt), and mortality in patients undergoing allogeneic bone marrow transplantation (bmt). we performed a multicenter, randomized placebo-controlled trial in 60 patients with hematologic malignancies receiving bmt from hla-identical sibling donors. patients were randomized to receive either placebo, 2 mg/kg lsf or 3 mg/kg lsf every 6 h, beginning before conditioning and continuing to day 21 or hospital discharge. treatment groups were balanced with respect to conditioning regimen and disease stage. however, significantly more patients in the 2 mg/kg lsf group were at high risk for rrt due to performance status ⩾1, age ⩾40 years, and prior exposure to cmv. nausea and vomiting were the only adverse events observed in a higher proportion of lsf-treated patients that led to study withdrawal in six of 42 patients (14%). the times to neutrophil recovery to ⩾500/μl and platelet recovery (>20 000/μl) were not improved by LSF treatment. Nevertheless, no patient who received treatment with 3 mg/kg LSF developed a documented infection between day 0 and 35 or had a serious or fatal infection between day 0 and 100 (P = 0.003 vs placebo for both). The day-100 survival rate was also significantly improved in the 3 mg/kg LSF group (89%), compared with either the 2 mg/kg LSF (48%) or placebo (61%) groups (log-rank test, 3 mg/kg LSF vs placebo, P = 0.026). We conclude that treatment with LSF 3 mg/kg reduced the incidence of infections and improved 100-day survival in patients receiving related-donor allogeneic bone marrow transplantation. Bone Marrow Transplantation (2000) 25, 283–291.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Holler E, Kolb HJ, Moller A et al. Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation Blood 1990 75: 1011–1016

    CAS  Google Scholar 

  2. Nestel FP, Price KS, Seemayer TA, Lapp WS . Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease J Exp Med 1992 175: 405–413

    Article  CAS  Google Scholar 

  3. Sonis S, Lindquist L, Van Vugt A et al. Prevention of chemotherapy-induced ulcerative mucositis by transforming growth factor beta 3 Cancer Res 1994 54: 1135–1138

    CAS  PubMed  Google Scholar 

  4. Maze R, Sherry B, Kwon BS et al. Myelosuppressive effects in vivo of purified recombinant murine macrophage inflammatory protein-1 alpha J Immunol 1992 149: 1004–1009

    CAS  PubMed  Google Scholar 

  5. Metcalf D . Hematopoietic regulators: redundancy or subtlety? Blood 1993 82: 3515 (review)

    Google Scholar 

  6. Holler E, Kolb H, Hintermeier-Knabe R et al. Role of tumor necrosis factor alpha in acute graft-versus-host disease and complications following allogeneic bone marrow transplantation Transplant Proc 1993 25: 1234–1236

    CAS  PubMed  Google Scholar 

  7. Antin JH, Ferrara JL . Cytokine dysregulation and acute graft-versus-host disease Blood 1992 80: 2964–2968

    CAS  PubMed  Google Scholar 

  8. Anscher M, Peters W, Reisenbichler H et al. Transforming growth factor beta as a predictor of liver and lung fibrosis after autologous bone marrow transplantation for advanced breast cancer New Engl J Med 1993 328: 1592–1598

    Article  CAS  Google Scholar 

  9. Herve P, Flesch M, Tiberghien P et al. Phase I–II trial of a monoclonal anti-tumor necrosis factor alpha antibody for the treatment of refractory severe acute graft-versus-host disease Blood 1992 79: 3362–3368

    CAS  PubMed  Google Scholar 

  10. Hill GR, Crawford JM, Cooke KR et al. Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines Blood 1997 90: 3204–3213

    CAS  PubMed  Google Scholar 

  11. Khan BV, Parthasarathy SS, Alexander RW, Medford RM . Modified low density lipoprotein and its constituents augment cytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells J Clin Invest 1995 95: 1262–1270

    Article  CAS  Google Scholar 

  12. Marks JD, Marks CB, Luce JM et al. Plasma tumor necrosis factor in patients with septic shock. Mortality rate, incidence of adult respiratory distress syndrome, and effects of methylprednisolone administration Am Rev Resp Dis 1999 141: 94–97

    Article  Google Scholar 

  13. Riikonen P, Saarinen UM, Teppo AM et al. Cytokine and acute-phase reactant levels in serum of children with cancer admitted for fever and neutropenia J Infect Dis 1992 166: 432–436

    Article  CAS  Google Scholar 

  14. Steinmetz HT, Herbertz A, Bertram M, Diehl V . Increase in interleukin-6 serum level preceding fever in granulocytopenia and correlation with death from sepsis J Infect Dis 1995 171: 225–228

    Article  CAS  Google Scholar 

  15. Netea MG, Kullberg BJ, Blok WL et al. The role of hyperuricemia in the increased cytokine production after lipopolysaccharide challenge in neutropenic mice Blood 1997 89: 577–582

    CAS  PubMed  Google Scholar 

  16. Clarke E, Rice GC, Weeks RS et al. Lisofylline inhibits transforming growth factor beta release and enhances trilineage hematopoietic recovery after 5-fluorouracil treatment in mice Cancer Res 1996 56: 105–112

    CAS  PubMed  Google Scholar 

  17. Rice G, Rosen J, Weeks R et al. CT-1501R selectively inhibits induced inflammatory monokines in human whole blood ex vivo Shock 1994 1: 254–266

    Article  CAS  Google Scholar 

  18. de Vries P, Xu Z, Rice G, Singer J . In vivo therapy with lisofylline (LSF) in mice suppresses the ex vivo release of multi-lineage hematopoietic inhibitory activity induced by cancer chemotherapeutic agents (chemo) from murine splenocytes Blood 1996 88: 114b (Abstr.)

    Google Scholar 

  19. Wattanasirichaigoon S, Menconi MJ, Delude RL, Fink MP . Lisofylline ameliorates ilial ischemia/reperfusion-induced mucosal barrier dysfunction in rats Dig Dis Weekly (in press)

  20. Cicalese L, Yacoub W, Rogers J et al . Protective effect of lisofylline on bacterial translocation Transplantation (in press)

  21. Teicher B . Lisofylline as an adjuvant to high dose cytotoxic therapy Int J Cancer (in press)

  22. Abraham E, Bursten S, Shenkar R et al. Phosphatidic acid signaling mediates lung cytokine expression and lung inflammatory injury after hemorrhage in mice J Exp Med 1995 181: 569–575

    Article  CAS  Google Scholar 

  23. Waxman K, Daughters K, Aswani S, Rice G . Lisofylline decreases white cell adhesiveness and improves survival after experimental hemorrhagic shock Crit Care Med 1996 24: 1724–1728

    Article  CAS  Google Scholar 

  24. Hasegawa N, Oka Y, Nakayama M et al. The effects of post-treatment with lisofylline, a phosphatidic acid generation inhibitor, on sepsis-induced acute lung injury in pigs Am J Respir Crit Care Med 1997 155: 928–936

    Article  CAS  Google Scholar 

  25. List A, Shuster M, Blazar B et al. Phase I concentration-controlled, escalation trial of lisofylline (LSF) in patients (PTS) undergoing allogeneic bone marrow transplantation (BMT) Blood 1994 84: 89a (Abstr.)

    Google Scholar 

  26. Klaus S, Coon M, Bright J et al . Lisofylline inhibits induction of EAE and Th1 differentiation by blocking IL-121 signaling and IFN-gamma secretion Keystone Symposium on Molecular and Cellular Biology 1997 4042: (Abstr.)

  27. Bearman SI, Appelbaum FR, Buckner CD et al. Regimen-related toxicity in patients undergoing bone marrow transplantation J Clin Oncol 1988 6: 1562–1568

    Article  CAS  Google Scholar 

  28. Chao N, Schmidt G, Niland J et al. Cyclosporine, methotrexate, and prednisone compared with cyclosporine and prednisone for prophylaxis of acute graft-versus-host disease New Engl J Med 1993 329: 1225–1230

    Article  CAS  Google Scholar 

  29. Thomas ED, Storb R, Clift RA et al. Bone-marrow transplantation (second of two parts) New Engl J Med 1975 292: 895–902

    Article  CAS  Google Scholar 

  30. Kaplan E, Meier P . Nonparametric estimation from incomplete observations J Am Stat Assoc 1958 53: 457–459

    Article  Google Scholar 

  31. Klingemann HG, Storb R, Fefer A et al. Bone marrow transplantation in patients aged 45 years and older Blood 1986 67: 770–776

    CAS  PubMed  Google Scholar 

  32. Clift RA, Buckner CD, Appelbaum FR et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens Blood 1990 76: 1867–1871

    CAS  PubMed  Google Scholar 

  33. McDonald GB, Hinds MS, Fisher LD et al. Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: a cohort study of 355 patients Ann Intern Med 1993 118: 255–267

    Article  CAS  Google Scholar 

  34. Winston DJ, Ho WG, Champlin RE . Cytomegalovirus infections after allogeneic bone marrow transplantation Rev Infect Dis 1990 12: (Suppl) S776–S792

    Article  Google Scholar 

  35. Bow EJ, Loewen R, Cheang MS et al. Cytotoxic therapy-induced D-xylose malabsorption and invasive infection during remission-induction therapy for acute myeloid leukemia in adults J Clin Oncol 1997 15: 2254–2261

    Article  CAS  Google Scholar 

  36. Donnelly JP, Muus P, Schattenberg A et al. A scheme for daily monitoring of oral mucositis in allogeneic BMT recipients Bone Marrow Transplant 1992 9: 409–413

    CAS  PubMed  Google Scholar 

  37. Sonis ST, Singer JW, Busse P et al . Effects of lisofylline on radiotherapy-induced mucosal toxicity in hamsters Dent Res (in press)

  38. Singer J, List A, Federighi D et al. Serum hydroperoxy and hydroxyoctadecadienoic acids (HPODE and HODE) increase in response to total body irradiation (TBI) and are suppressed by lisofylline (LSF) in allogeneic BMT patients Blood 1996 88: 458a (Abstr.)

    Google Scholar 

  39. Clift R, Bianco J, Appelbaum F et al. A randomized controlled trial of pentoxifylline for the prevention of regimen-related toxicities in patients undergoing allogeneic marrow transplantation Blood 1993 82: 2025–2030

    CAS  PubMed  Google Scholar 

  40. Kalhs P, Lechner K, Stockschlader M et al. Pentoxifylline did not prevent transplant-related toxicity in 31 consecutive allogeneic bone marrow transplant recipients Blood 1992 80: 2683–2684 (letter)

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Arizona Cancer Center, University of Arizona, Tucson, AZ, USA

    AF List & F Andrews

  2. University of Oregon, Portland, OR, USA

    R Maziarz

  3. Loyola University, Chicago, IL, USA

    P Stiff & S Dahlberg

  4. Methodist Hospital, Indianapolis, IN, USA

    J Jansen

  5. Strong Memorial Hospital, Rochester, NY, USA

    J Liesveld

  6. West Penn Cancer Institute, Pittsburgh, PA, USA

    M Schuster

  7. Vanderbilt University, Nashville, TN, USA

    S Wolff

  8. Mayo Clinic, Rochester, MN, USA

    M Litzow

  9. Wayne State University, Detroit, MI, USA

    C Karanes

  10. Cell Therapeutics, Inc., Seattle, WA, USA

    B Kirkhart, JA Bianco & JW Singer

Authors
  1. AF List
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Maziarz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P Stiff
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Jansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Liesveld
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. F Andrews
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Schuster
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S Wolff
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. M Litzow
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. C Karanes
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. S Dahlberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. B Kirkhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. JA Bianco
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. JW Singer
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the Lisofylline Marrow Transplant Study Group

Rights and permissions

Reprints and permissions

About this article

Cite this article

List, A., Maziarz, R., Stiff, P. et al. A randomized placebo-controlled trial of lisofylline in HLA-identical, sibling-donor, allogeneic bone marrow transplant recipients. Bone Marrow Transplant 25, 283–291 (2000). https://doi.org/10.1038/sj.bmt.1702114

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1702114

Keywords

This article is cited by

Search

Advanced search

Quick links