Successful allogeneic bone marrow transplantation in patients with severe gram-negative sepsis and septic shock

G.M. Galstyan, P.M. Makarova, L.A. Kuzmina, Ye.N. Parovichnikova, G.A. Klyasova, O.S. Pokrovskaya, M.Yu. Drokov, V.A. Novikov, V.V. Troitskaya, I.E. Kostina, and V.G. Savchenko

Hematology Research Center, Ministry of Health, Moscow, Russian Federation


ABSTRACT

We present two cases of successful allogeneic bone marrow transplantation in the patients with severe gram-negative sepsis and septic shock. The features of the post-transplantation period and management of patients are described.


Keywords: allogeneic hematopoietic stem cell transplantation, conditioning, sepsis, septic shock, post-transplantation period, neutropenic enterocolitis, prolonged neutropenia, Pseudomonas aeruginosa, acute respiratory failure, invasive pulmonary aspergillosis, invasive lung ventilation, noninvasive ventilation, mesenchymal stromal cells.

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REFERENCES

  1. Morena M.T., Gatti R.A. A History of Bone Marrow Transplantation. Hematol. Oncol. Clin. 2011; 25: 1–15.
  2. Wingard J.R., Majhail N.S., Brazauskas R. et al. Long-Term Survival and Late Deaths After Allogeneic Hematopoietic Cell Transplantation. J. Clin. Oncol. 2011; 29: 2230–9.
  3. Gyurkocza B., Rezvanil A., Storb R.F. Allogeneic hematopoietic cell transplantation: the state of the art. Exp. Rev. Hematol. 2010; 3(3): 285–99.
  4. Савченко В.Г., Любимова Л.С., Паровичникова Е.Н. и др. Трансплантации аллогенных и аутологичных гемопоэтических стволовых клеток при острых лейкозах (итоги 20-летнего опыта). Тер. арх. 2007; 79: 30–5. [Savchenko V.G., Lyubimova L.S., Parovichnikova Ye.N., et al. Transplantation of allogeneic and autologous hematopoietic stem cells in acute leukemias (summary of 20-year experience). Ter. arkh., 2007; 79: 30–5. (In Russ.)].
  5. Blume K.G., Forman S.J., Appelbaum F.R. The evaluation and counseling of candidates for hematopoietic cell transplantation. Thomas’ Hematopoietic Cell Transplantation, 3rd ed. Malden: Blackwell, 2004: 449–67.
  6. Ball E.D., Lister J., Law P. Evaluation of patients before hematopoietic stem cell transplantation. Hematopoietic Stem Cell Therapy. New York: Churchill Livingstone, 2001: 225–32.
  7. Majhail N.S., Rizzo J.D. Surviving the cure: long term follow up of hematopoietic cell transplant recipients. Bone Marrow Transplant. 2013: 1–7.
  8. Soubani A.O., Kseibi E., Bander J.J. et al. Outcome and Prognostic Factors of Hematopoietic Stem Cell Transplantation Recipients Admitted to a Medical ICU. Chest 2004; 126(5): 1604–11.
  9. Marena C., Zecca M., Carenini M.L. et al. Incidence of, and risk factors for, nosocomial infections among hematopoietic stem cell transplantation recipients, with impact on procedure-related mortality. Infect. Control Hosp. Epidemiol. 2001; 22: 510–7.
  10. Huynh T.N., Weigt S.S., Belperio J.A., Territo M., Keane M.P. Outcome and Prognostic Indicators of Patients with Hematopoietic Stem Cell Transplants Admitted to the Intensive Care Unit. J. Transplant. 2009; 2009: 917294.
  11. Afessa B., Azoulay E. Critical Care of the Hematopoietic Stem Cell Transplant Recipient. Crit. Care Clin. 2010; 26: 133–50.
  12. Degoricija V., Sharma M., Legac A. et al. Survival analysis of 314 episodes of sepsis in medical intensive care unit in university hospital: impact of intensive care unit performance and antimicrobial therapy. Croat. Med. J. 2006; 47(3): 385–97.
  13. Shirazi M.H., Ranjbar R., Ghasemi A. et al. A Survey of Bacterial Infections in Bone Marrow Transplant Recipients. Iran. J. Publ. Health 2007; 36: 77–81.
  14. Ali N., Adil S.M., Shaikh M.U., Moosajee M., Masood N. Outcome of match related allogeneic stem cell transplantation procedures performed from 2004 till 2011. Exper. Hematol. Oncol. 2012; 1: 13.
  15. George B., Mathews V., Srivastava A., Chandy M. Infections among allogeneic bone marrow transplant recipients in India. Bone Marrow Transplant. 2004; 33: 311–5.
  16. Donnelly P. Bacterial complications of transplantation: diagnosis and treatment. J. Antimicrob. Chemother. 1995; 36: 59–72.
  17. van Kraaij M.G., Dekker A.W., Verdonck L.F. et al. Infectious gastroenteritis: an uncommon cause of diarrhoea in adult allogeneic and autologous stem cell transplant recipients. Bone Marrow Transplant. 2000; 26(3): 299–303.
  18. Schulenburg A., Turetschek K., Wrba F. et al. Early and late gastrointestinal complications after myeloablative and nonmyeloablative allogeneic stem cell transplantation. Ann. Hematol. 2004; 83(2): 101–6.
  19. Holler E., Kolb H.J., Greinix H. et al. Bleeding events and mortality in SCT patients: a retrospective study of hematopoietic SCT patients with organ dysfunctions due to severe sepsis or GVHD. Bone Marrow Transplant. 2009; 43(6): 491–7.
  20. Mikulska M., Del Bono V., Bruzzi P. et al. Mortality after bloodstream infections in allogeneic haematopoietic stem cell transplant (HSCT) recipients. Infection 2012; 40: 271–8.
  21. Legrand M., Max A., Peigne V. et al. Survival in neutropenic patients with severe sepsis or septic shock. Crit. Care Med. 2012; 40(1): 43–9.
  22. Reikvam H., Hatfiel K.J., Kittang A.O., Hovland R., Bruserud O. Acute myeloid leukemia with the t(8;21) translocation: clinical consequences and biological implications. doi: 10.1155/2011/104631. Epub, May 3, 2011.
  23. Cho E.K., Bang S.M., Ahn J.Y. et al. Prognostic value of AML 1/ETO fusion transcripts in patients with acute myelogenous leukemia. Korean J. Intern. Med. 2003; 18(1): 13–20.
  24. Программное лечение заболеваний системы крови. Под ред. В.Г. Савченко. М.: Практика, 2012: 720–34. [Programmnoye lecheniye zabolevaniy sistemy krovi. Pod red. V.G. Sav chenko (Program therapy for hematological malignancies. Ed. by: V.G. Savchenko). M.: Praktika, 2012: 720–34.]
  25. De Pauw B., Walsh T.J., Donnelly J.P. et al. European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Revised Definitions of Invasive Fungal Disease from the European Organization for Research and Treatment of Cancer/ Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin. Infect. Dis. 2008; 46(12): 1813–21.
  26. Afessa B., Tefferi A., Dunn W.F. et al. Intensive care unit support and Acute Physiology and Chronic Health Evaluation III performance in hematopoietic stem cell transplant recipients. Crit. Care Med. 2003; 31(6): 1715–21.
  27. Leung A.N., Gosselin M.V., Napper C.H. et al. Pulmonary Infections after Bone Marrow Transplantation: Clinical and Radiographic Findings. Radiology 1999; 210: 699–710.
  28. Champlin R.E., Perez W.S., Passweg J.R. et al. Bone marrow transplantation for severe aplastic anemia: a randomized controlled study of conditioning regimens. Blood 2007; 109(10): 4582–5.
  29. Georges G.E., Storb R. Stem cell transplantation for aplastic anemia. Int. J. Hematol. 2002; 75(2): 141–6.
  30. Quenot J.P., Binquet C., Kara F., Martinet O. The epidemiology of septic shock in French intensive care units: the prospective multicenter cohort EPISS study. Crit. Care. 2013; 17: R65.
  31. Jawad I., Luksic I., Rafnsson S.B. Assessing available information on the burden of sepsis: global estimates of incidence, prevalence and mortality. Glob. Health 2012; 2(1): 10404.
  32. Ghosh I., Raina V., Kumar L. et al. Profile of infections and outcome in high-risk febrile neutropenia: experience from a tertiary care cancer center in India. Med. Oncol. 2012; 29: 1354–60.
  33. Klastersky J., Ameye L., Maertens J. et al. Bacteraemia in febrile neutropenic cancer patients. Int. J. Antimicrob. Agents 2007; 30: 51–9.
  34. Sakamoto M., Saruta K., Nakazawa Y. et al. Sepsis Associated with Hematological Malignancies: Prophylaxis of Pseudomonas aeruginosa Sepsis. 69th General Meeting of the Japanese Association for Infectious Diseases (Fukuoka). Kansenshogaku Zasshi 1996; 70(2): 116–22.
  35. Клясова Г.А. Инфекции при гемобластозах и депрессиях кроветворения: клиника, диагностика и лечение: Автореф. дис. ¼ д-ра мед. наук. М., 2009. [Klyasova G.A. Infektsii pri gemoblastozakh i depressiyakh krovetvoreniya: klinika, diagnostika i lechenie. Dokt. diss. (Infections in hematological malignancies and depressed hematopoiesis. Dr. med. sci. diss.). M., 2009]
  36. Mokart D., Craenenbroeck T. Prognosis of acute respiratory distress syndrome (ARDS) in neutropenic cancer patients. Eur. Respir. J. 2012; 40(1): 169–76.
  37. Regazzoni C.J., Irrazabal C., Luna C.M., Poderoso J.J. Cancer patients with septic shock: mortality predictors and neutropenia. Supp. Care Cancer 2004; 12: 833–9.
  38. Groeger J.S., Lemeyow S., Price K., Nierman J. Multicenter outcome study of cancer patients admitted to the intensive care unit: a probability of mortality model. Clin. Oncol. 1998; 16: 761–70.
  39. Gronlykke L., Brandstrup S.L., Perner A. Data from clinical database on septic shock are valid. Dan. Med. J. 2012; 59(10): A4522.
  40. Горелов В.Г. Эффективность искусственной вентиляции легких при острой дыхательной недостаточности у больных гемобластозами: Автореф. дис. ¼ канд. мед. наук. М., 1994. [Gorelov V.G. Effektivnost iskusstvennoy ventilyatsii legkikh pri ostroy dykhatelnoy nedostatochnosti u bolnykh gemoblastozami. Kand. diss. (Efficacy of mechanical lung ventilation in acute respiratory failure in patients with hematological malignancies. Cand med. sci.diss.). M., 1994]
  41. Бычинин М.В., Галстян Г.М., Шулутко Е.М., Клясова Г.А., Городецкий В.М. Катетеризация артерий у гематологических больных. Гематол. и трансфузиол. 2013; 58: 14–22. [Bychinin M.V., Galstyan G.M., Shulutko Ye.M., Klyasova G.A., Gorodetzky V.M. Artery catheterization in hematological patients. Gematol. i transfuziol. 2013; 58: 14–22. (In Russ.)].
  42. Shirley H., Mei J. Mesenchymal Stem Cells Reduce Inflammation while Enhancing Bacterial Clearance and Improving Survival in Sepsis. Am. J. Respir. Crit. Care Med. 2010; 182(8): 1047–57.
  43. Gilbert C., Vasu T.S., Baram M. Use of mechanical ventilation and renal replacement therapy in critically ill hematopoietic stem cell transplant recipients. Biol. Blood Marrow Transplant. 2013; 19(2): 321–4.
  44. Azoulay E., Alberti C., Bornstain C. et al. Improved survival in cancer patients requiring mechanical ventilatory support: impact of noninvasive mechanical ventilatory support. Crit. Care Med. 2001; 29(3): 519–25.
  45. Avivi I., Oren I., Haddad N., Rowe J.M. Stem Cell Transplantation Post Invasive Fungal Infection Is a Feasible Task. Am. J. Hematol. 2004; 75: 6–11.
  46. Bjerke J.W., Meyers J.D., Bowden R.A. Hepatosplenic candidiasis — a contraindication to marrow transplantation? Blood 1994; 84: 2811–4.
  47. Wang J.T., Yao M., Tang J.L., Chang S.C., Hung C.C. Prior invasive fungal infection is not a contraindication for subsequent allogeneic bone marrow transplantation in adult patients with hematologic malignancies. J. Clin. Oncol. 2001; 19(1): 4000–1.
  48. Aki Z.S., Sucak G.T., Yegin Z.A. et al. Hematopoietic Stem Cell Transplantation in Patients With Active Fungal Infection: Not a Contraindication for Transplantation. Transplant. Proceed. 2008; 40: 1579–85.
  49. El-Cheikh J., Castagna L., Wang L. et al. Impact of prior invasive aspergillosis on outcome in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplant. Leuk. Lymphoma 2010; 51(9): 1705–10.
  50. Lee J.Y., Jung C.W., Kim K., Jang J.H. Impact of previous invasive pulmonary aspergillosis on the outcome of allogeneic hematopoietic stem cell transplantation. Korean J. Hematol. 2012; 47(4): 255–9.
  51. Dellinger R.P., Levy M.M., Rhodes A. et al. Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012. Intens. Care Med. 2013; 39(2): 165–228.
  52. Pittenger M.F., Mackay A.M., Beck S.C. et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–7.
  53. Deans R.J., Moseley A.B. Mesenchymal stem cells: biology and potential clinical uses. Exp. Hematol. 2000; 28: 875–84.
  54. Jones B.J., McTaggart S.J. Immunosuppression by mesenchymal stromal cells: from culture to clinic. Exp. Hematol. 2008; 36: 733–41.
  55. Петинати Н.А. Профилактика реакции трансплантат против хозяина у больных гемобластозами после трансплантации аллогенных гемопоэтических стволовых клеток с помощью мультипотентных мезенхимальных стромальных клеток донора: Автореф. дис. ¼ канд. мед. наук. М., 2013. [Petinati N.A. Profilaktika reaktsii transplantat protiv khozyaina u bolnykh gemoblastozami posle transplantatsii allogennykh gemopoeticheskikh stvolovykh kletok s pomoshchyu multipotentnykh mezenkhimalnykh stromalnykh kletok donora. Kand. diss. (Prevetion of graft-versus-host disease in patients with hematological malignancies after transplantation of allogeneic hematopoietic stem cells using multipotent mesenchymal stromal donor cells. Cand med. sci. diss.). M., 2013].
  56. Kuzmina L.A., Petinati N.A., Parovichnikova E.N. et al. Multipotent Mesenchymal Stromal Cells for the Prophylaxis of Acute Graft-versus-Host Disease — A Phase II Study. Stem Cells Int. 2012; 2012: 968213.
  57. Kebriaei P., Robinson S. Treatment of graft-versus-host-disease with mesenchymal stromal cells. Cytotherapy 2011; 13(3): 262–8.
  58. Lucchini G., Dander E., Rovelli A. et al. Platelet-lysate-expanded mesenchymal stromal cells as a salvage therapy for severe resistant graftversus-host disease in a pediatric population. Biol. Blood Marrow Transplant. 2010; 16: 1293–301.
  59. Toubai Т., Paczesny S., Shono Y. et al. Mesenchymal stem cells for treatment and prevention of graft-versus-host disease after allogeneic hematopoietic cell transplantation. Curr. Stem Cell Res. Ther. 2009; 4: 252–9.
  60. Osuchowski M.F., Welch K., Siddiqui J., Remick D.G. Circulating cytokine/inhibitor profiles reshape the understanding of the sirs/cars continuum in sepsis and predict mortality. J. Immunol. 2006; 177: 1967–74.
  61. Chien M.H., Bien M.Y., Ku C.C. et al. Systemic human orbital fat-derived stem/stromal cell transplantation ameliorates acute inflammation in lipopolysaccharide-induced acute lung injury. Crit. Care Med. 2012; 40(4): 1245–53.
  62. Kim E.S., Sil Y. Intratracheal transplantation of human umbilical cord blood-derived mesenchymal stem cells attenuates Escherichia coli induced acute lung injury in mice. Respir. Res. 2011; 12: 108.
  63. Adult stem cell transplantation in severe blood poisoning. 2011-MSC-1 Erasmus MC Rotterdam. http://www.trialregister.nl/ 64. OHRI, Ottawa to lead first stem cell therapy trial for septic shock/2012. http://nationalhealthwatch.ca/

In vitro model of myelofibrosis using human platelet lysate

Ye.N. Bulycheva, N.T. Siordiya, E.G. Lomaia, A.Yu. Zaritskiy, and P.A. Butylin

V.A. Almazov Federal Heart, Blood and Endocrinology Center, Saint Petersburg, Russian Federation


ABSTRACT

The development and studies of the myelofibrosis (MF) in vitro model is an important issue, since such model can lead to understanding of pathogenesis and identifying the new targets for therapy.

Objectives. Here, we studied the properties of mesenchymal stromal cells (MSCs) cultured in the medium containing the human platelet lysate (HPL).

Design and methods. Bone marrow MSCs from healthy donors and a patient with primary myelofibrosis (PMF) were cultured in the media containing various HPL concentrations. We measured the proliferative activity, the collagen type I and III expression, and capability to differentiate into the osteogenic or adipogenic lineages. The concentrations of the vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-b), and hepatocyte growth factor (HGF) were measured in HPL from 17 patients with primary myelofibrosis or post-polycythemia vera myelofibrosis (post-PV MF) using the specific ELISA kits.

Results. The highest MSC proliferative rate was found in the cultures with high HPL concentrations (10–20 %). The ratio of collagen type III/collagen type I expression was the highest in the cultures containing 10 % HPL. The use of HPL for MSCs culturing caused no changes in their osteogenic differentiation capability, but the increase in the HPL concentration resulted in the decreased capability to differentiate into the adipogenic lineage. Further, we observed the significantly increased VEGF and bFGF concentrations in HPL from MF patients, compared to the age-matched healthy controls (2.5- and 2.4-fold, respectively, < 0.01), while the TGF-b and HGF concentrations showed the trend towards an increase, but with no significant difference from the controls. MSCs cultured with HPL from MF patients showed a higher proliferative rate compared to HPL from healthy donors. MSCs from the PMF patient tended to proliferate more actively compared to the cells from healthy donors.

Conclusion. MSCs culturing using varying HPL concentrations can be used as an adequate MF in vitro model, since it leads to pro-fibrotic changes in the bone marrow stromal cells.


Keywords: primary myelofibrosis, platelet lysate, mesenchymal stromal cells, myelofibrosis in vitro model.

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Refernces

  1. Kutti J., Ridell B. Epidemiology of the myeloproliferative disorders: essential thrombocythaemia, polycythaemia vera and idiopathic myelofibrosis. Biol. 2001; 49: 164–6.
  2. Johansson P., Kutti J., Andreasson B. et al. Trends in the incidence of chronic Philadelphia chromosome negative (Ph-) myeloproliferative disorders in the city of Goteborg, Sweden, during 1983–99. Inter. Med. 2004; 256: 161–5.
  3. Cervantes F., Dupriez B., Passamonti F. et al. Improving survival trends in primary myelofibrosis: an international study. Clin. Oncol. 2012; 30: 2981–7.
  4. Barosi G., Ambrosetti A., Finelli C. et al. The Italian Consensus Conferen ce on Diagnostic Criteria for Myelofibrosis with Myeloid Metaplasia. J. Haematol. 1999; 104(4): 730–7.
  5. Колосков А.В. Мегакариоциты и фиброз костного мозга. Гематол. и трансфузиол. 1997; 42: 29–31. [Koloskov A.V. Megakariotsity i fibroz kostnogo mozga (Megakaryocytes and bone marrow fibrosis. In: Hematol. & transfuziol.). Gematol. i transfuziol. 1997; 42: 29–31.]
  6. Reilly J.T. Idiopathic myelofibrosis: pathogenesis to treatment. Oncol. 2006; 24: 56–63.
  7. Le Bousse-Kerdiles M.-C., Martyre M.-C., Samson M. Cellular and molecular mechanisms underlying bone marrow and liver fibrosis: a review. Cytokine Netw. 2008; 19: 69–80.
  8. Yan X.Q., Lacey D., Fletcher F. et al. Chronic exposure to retroviral encoded MGDF (mpl-ligand) induces lineage-specific growth and differentiation of megakaryocytes in mice. Blood 1995; 86; 4025–33.
  9. Vannucchi A.M., Bianchi L., Paoleti F. et al. Impaired GATA-1 expression and myelofibrosis in an animal model. Biol. 2004; 52: 275–9.
  10. Xing S., Wanting T.H., Zhao W. et al. Transgenic expression of Jak2V617F causes myeloproliferative disorders in mice. Blood 2008; 111: 5109–17.
  11. Wernig G., Mercher T., Okabe R. et al. Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood 2006; 107: 4274–81.
  12. Kirabo A., Park S.O., Wamsley H.L. et al. The small molecule inhibitor G6 significantly reduces bone marrow fibrosis and the mutant burden in a mouse model of Jak2-mediated myelofibrosis. AJP 2012; 181: 858–65.
  13. Triviai I., Stubing Th., Niebuhr B. et al. A mouse model for human myelofibrosis. 18th Congress of EHA 2013: Abstract P248.
  14. Xia W., Li H., Wang Zh. et al. Human platelet lysate supports ex vivo expansion and enhances osteogenic differentiation of human bone
  15. Sankaranarayanan K., Chandana T., Gency Ponrose G. et al. Humanized substitutes for animal sera in human mesenchymal stem cell culture and differentiation. Cell Biol. Intern. 2011; Manuscript CBI20100649.
  16. Jenhani F., Durand V., Ben Azouna N. et al. Human cytokine expression profile in various conditioned media for in vitro expansion bone marrow and umbilical cord blood immunophenotyped mesenchymal stem cells. Proceed. 2011; 43: 639–43.
  17. Doucet Ch., Ernou I., Zhang Y. et al. Platelet lysates promote mesenchymal stem cell expansion: a safety substitute for animal serum in cell-based therapy applications. Cell. Physiol. 2005; 205: 228–36.
  18. Horn P., Bokermann G., Cholewa D. et al. Impact of individual platelet lysates on isolation and growth of human mesenchymal stromal cells. Cytotherapy 2010; 12: 888–98.
  19. Schmitt A., Jouault H., Guichard J. et al. Pathologic interaction between megacaryocytes and polymorphonuclear leukocytes in myelofibrosis. Blood 2000; 96: 1342–7.