Advertisement

Treatment of Newly Diagnosed HLH and Refractory Disease

  • Jan-Inge Henter
  • Rebecca A Marsh
  • Tatiana von Bahr Greenwood
Chapter

Abstract

To diagnose and treat a patient with hemophagocytic lymphohistiocytosis (HLH) is a challenge. Nevertheless, since the clinical course may be rapidly fatal and since the presentation may be variable, in particular for secondary HLH, it is important for clinicians in many medical fields to be aware of HLH and its treatment. Here, we review the treatment of patients with newly diagnosed HLH including therapy with corticosteroids, etoposide, cyclosporine A, and intravenous immunoglobulin (used in the HLH-94 and HLH-2004 protocols) as well as T-cell antibody-directed regimens with antithymocyte globulin (ATG) and alemtuzumab. We also report on anti-infectious and supportive therapy, prognostic factors, as well as the challenging treatment of secondary HLH, including infection-associated HLH, malignancy-associated HLH, and rheuma-/autoimmune-associated HLH. Finally, a literature review on salvage therapy for patients that fail to respond to standard HLH treatment is presented, including treatments with ATG, anakinra, and alemtuzumab.

Keywords

Familial hemophagocytic lymphohistiocytosis Hemophagocytic lymphohistiocytosis Epstein-Barr virus Treatment Etoposide Dexamethasone Cyclosporine A Antithymocyte globulin Refractory disease Alemtuzumab 

Abbreviations

ATG

Antithymocyte globulin

CSA

Cyclosporine A

DEP

Doxorubicin, etoposide, and methylprednisolone

EBV

Epstein-Barr virus

FHL

Familial hemophagocytic lymphohistiocytosis

HLH

Hemophagocytic lymphohistiocytosis

IFN

Interferon

IL

Interleukin

IVIG

Intravenous immunoglobulin

MAS

Macrophage activation syndrome

SCT

Hematopoietic stem cell transplantation

sHLH

Secondary HLH

References

  1. 1.
    Janka GE. Familial hemophagocytic lymphohistiocytosis. Eur J Pediatr. 1983;140:221–30.CrossRefPubMedGoogle Scholar
  2. 2.
    Ladisch S, Ho W, Matheson D, Pilkington R, Hartman G. Immunologic and clinical effects of repeated blood exchange in familial erythrophagocytic lymphohistiocytosis. Blood. 1982;60:814–21.PubMedGoogle Scholar
  3. 3.
    Ambruso DR, Hays T, Zwartjes WJ, Tubergen DG, Favara BE. Successful treatment of lymphohistiocytic reticulosis with phagocytosis with epipodophyllotoxin VP 16-213. Cancer. 1980;45:2516–20.CrossRefPubMedGoogle Scholar
  4. 4.
    Henter JI, Elinder G, Finkel Y, Söder O. Successful induction with chemotherapy including teniposide in familial erythrophagocytic lymphohistiocytosis. Lancet. 1986;2(8520):1402.CrossRefPubMedGoogle Scholar
  5. 5.
    Fischer A, Virelizier JL, Arenzana-Seisdedos F, Perez A, Nezelof C, Griscelli C. Treatment of four patients with erythrophagocytic lymphohistiocytosis by a combination of epipodophyllotoxin, steroids, intrathecal methotrexate and cranial irradiation. Pediatrics. 1985;76:263–8.PubMedGoogle Scholar
  6. 6.
    Henter JI, Elinder G. Familial hemophagocytic lymphohistiocytosis. Clinical review based on the findings in seven children. Acta Paediatr Scand. 1991;80:269–77.CrossRefPubMedGoogle Scholar
  7. 7.
    Fischer A, Cerf-Bensussan N, Blanche S, LeDeist F, Bremard-Oury C, Leverger G, et al. Allogeneic bone marrow transplantation for erythrophagocytic lymphohistiocytosis. J Pediatr. 1986;108:267–70.Google Scholar
  8. 8.
    Blanche S, Caniglia M, Girault D, Landman J, Griscelli C, Fischer A. Treatment of hemophagocytic lymphohistiocytosis with chemotherapy and bone marrow transplantation: a single center study of 22 cases. Blood. 1991;78:51–4.PubMedGoogle Scholar
  9. 9.
    Stephan JL, Donadieu J, Ledeist F, Blanche S, Griscelli FA. Treatment of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins, steroids and cyclosporin A. Blood. 1993;82:2319–23.PubMedGoogle Scholar
  10. 10.
    Loechelt BJ, Egeler RM, Filipovich AH, Jyonouchi H, Shapiro RS. Immunosuppression: an alternative maintenance therapy for familial hemophagocytic lymphohistiocytosis (FHL): preliminary results. Med Pediatr Oncol. 1994;22:325–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Henter JI, Söder O, Hansson M, Elinder G, Andersson B, Andersson U. Hypercytokinemia in familial hemophagocytic lymphohistiocytosis. Blood. 1991;78:2918–22.PubMedGoogle Scholar
  12. 12.
    Risdall RJ, McKenna RW, Nesbit ME, Krivit W, Balfour HH Jr, Simmons RL, et al. Virus-associated hemophagocytic syndrome. A benign histiocytic proliferation distinct from malignant histiocytosis. Cancer. 1979;44:993–1002.CrossRefPubMedGoogle Scholar
  13. 13.
    Henter JI, Ehrnst A, Andersson J, Elinder G. Familial hemophagocytic lymphohistiocytosis and viral infections. Acta Paediatr. 1993;82:369–72.CrossRefPubMedGoogle Scholar
  14. 14.
    Imashuku S, Hibi S, Ohara T, Iwai A, Sako M, Kato M, et al. Effective control of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis with immunochemotherapy. Blood. 1999;93:1869–74.PubMedGoogle Scholar
  15. 15.
    Janka GE, Lehmberg K. Hemophagocytic lymphohistiocytosis: pathogenesis and treatment. Hematology Am Soc Hematol Educ Program. 2013;2013:605–11.PubMedGoogle Scholar
  16. 16.
    Henter JI, Elinder G, Öst Å; the HLH Study Group of the Histiocyte Society. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. Semin Oncol. 1991;18:29–33.Google Scholar
  17. 17.
    Henter JI, Horne AC, Aricó M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31.CrossRefPubMedGoogle Scholar
  18. 18.
    Horne AC, Trottestam H, Aricó M, Egeler RM, Filipovich AH, Gadner H, et al. Frequency and spectrum of CNS involvement in 193 children with hemophagocytic lymphohistiocytosis. Br J Haematol. 2008;140(3):327–35.CrossRefPubMedGoogle Scholar
  19. 19.
    Yang S, Zhang L, Jia C, Ma H, Henter JI, Shen K. Frequency and development of CNS involvement in Chinese children with hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2010;54(3):408–15.CrossRefPubMedGoogle Scholar
  20. 20.
    Henter JI, Arico M, Egeler M, Elinder G, Filipovich A, Favara B, et al. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. Med Pediatr Oncol. 1997;28:342–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Henter JI, Samuelsson-Horne AC, Arico M, Egeler RM, Elinder G, Filipovich AH, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immuno-chemotherapy and bone marrow transplantation. Blood. 2002;100:2367–73.CrossRefPubMedGoogle Scholar
  22. 22.
    Trottestam H, Horne AC, Aricó M, Egeler RM, Filipovich AH, Gadner H, et al. Chemo-immunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118(17):4577–84.Google Scholar
  23. 23.
    Janka GE, Lehmberg K. Hemophagocytic syndromes – an update. Blood Rev. 2014;28(4):135–42.CrossRefPubMedGoogle Scholar
  24. 24.
    Chellapandian D, Das R, Zelley K, Wiener SJ, Zhao H, Teachey DT, et al; EBV-HLH Rituximab Study Group. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol. 2013;162(3):376–82.Google Scholar
  25. 25.
    Fujiwara S, Kimura H, Imadome K, Arai A, Kodama E, Morio T, et al. Current research on chronic active Epstein-Barr virus infection in Japan. Pediatr Int. 2014;56(2):159–66.CrossRefPubMedGoogle Scholar
  26. 26.
    Kawa K, Sawada A, Sato M, Okamura T, Sakata N, Kondo O, et al. Excellent outcome of allogeneic hematopoietic SCT with reduced-intensity conditioning for the treatment of chronic active EBV infection. Bone Marrow Transplant. 2011;46:77–83.CrossRefPubMedGoogle Scholar
  27. 27.
    Sung L, King SM, Carcao M, Trebo M, Weitzman SS. Adverse outcomes in primary hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 2002;24(7):550–4.CrossRefPubMedGoogle Scholar
  28. 28.
    Fadeel B, Orrenius S, Henter JI. Induction of apoptosis and caspase activation in cells obtained from familial haemophagocytic lymphohistiocytosis patients. Br J Haematol. 1999;106(2):406–15.CrossRefPubMedGoogle Scholar
  29. 29.
    Johnson TS, Terrell CE, Millen SH, Katz JD, Hildeman DA, Jordan MB. Etoposide selectively ablates activated T cells to control the immunoregulatory disorder hemophagocytic lymphohistiocytosis. J Immunol. 2014;192(1):84–91.CrossRefPubMedGoogle Scholar
  30. 30.
    Kalman VK, Klimpel GR. Cyclosporin A inhibits the production of gamma interferon (IFN gamma), but does not inhibit production of virus-induced IFN alpha/beta. Cell Immunol. 1983;78(1):122–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Imashuku S, Hibi S, Kuriyama K, Tabata Y, Hashida T, Iwai A, et al. Management of severe neutropenia with cyclosporin during initial treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis. Leuk Lymphoma. 2000;36:339–46.CrossRefPubMedGoogle Scholar
  32. 32.
    Henter JI, Chow CB, Leung CW, Lau YL. Cytotoxic therapy for severe avian influenza A (H5N1) infection. Lancet. 2006;367(9513):870–3.CrossRefPubMedGoogle Scholar
  33. 33.
    Mahlaoui N, Ouachée-Chardin M, de Saint BG, Neven B, Picard C, Blanche S, et al. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single center retrospective report of 38 patients. Pediatrics. 2007;120:622–8.CrossRefGoogle Scholar
  34. 34.
    Marsh RA, Allen CE, McClain KL, Weinstein JL, Kanter J, Skiles J, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. 2013;60(1):101–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Lehmberg K, Ehl S. Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. Br J Haematol. 2013;13:289–98.Google Scholar
  36. 36.
    Ramos-Casals M, Brito-Zerón P, López-Guillermo A, Khamashta MA, Bosch X. Adult haemophagocytic syndrome. Lancet. 2014;383(9927):1503–16.CrossRefPubMedGoogle Scholar
  37. 37.
    Zhang K, Jordan MB, Marsh RA, Johnson JA, Kissell D, Meller J, et al. Hypomorphic mutations in PRF1, MUNC13-4, and STXBP2 are associated with adult-onset familial HLH. Blood. 2011;118(22):5794–8.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Ishii E, Ohga S, Imashuku S, Yasukawa M, Tsuda H, Miura I, et al. Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol. 2007;86:58–65.CrossRefPubMedGoogle Scholar
  39. 39.
    Demirkol D, Yildizdas D, Bayrakci B, Karapinar B, Kendirli T, Koroglu TF, et al; Turkish Secondary HLH/MAS Critical Care Study Group. Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome: what is the treatment? Crit Care. 2012;16(2):R52.Google Scholar
  40. 40.
    Edner J, Rudd E, Zheng C, Dahlander A, Eksborg S, Edner A, et al. Severe bacteria-associated hemophagocytic lymphohistiocytosis in an extremely premature infant. Acta Paediatr. 2007 Nov;96(11):1703–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Ravelli A, Grom AA, Behrens EM, Cron RQ. Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment. Genes Immun. 2012 Jun;13(4):289–98.CrossRefPubMedGoogle Scholar
  42. 42.
    Palmblad K, Schierbeck H, Sundberg E, Horne AC, Erlandsson Harris H, et al. High systemic levels of the cytokine-inducing HMGB1 isoform secreted in severe macrophage activation syndrome. Mol Med. 2015;20(1):538–47.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Lehmberg K, Nichols KE, Henter JI, Girschikofsky M, Greenwood T, Jordan M, et al; the Study Group on Hemophagocytic Lymphohistiocytosis Subtypes of the Histiocyte Society. Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica. 2015;100(8):997–1004.Google Scholar
  44. 44.
    Trottestam H, Berglöf E, Horne AC, Beutel K, Lehmberg K, Sieni E, et al. Risk factors for early death in patients with hemophagocytic lymphohistiocytosis. Acta Paediatr. 2012;101(3):313–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Horne AC, Janka G, Egeler RM, Gadner H, Imashuku S, Ladisch S, et al. Hematopoietic stem cell transplantation in hemophagocytic lymphohistiocytosis. Br J Haematol. 2005;129:622–30.CrossRefPubMedGoogle Scholar
  46. 46.
    Behrens EM, Kreiger PA, Cherian S, Cron RQ. Interleukin 1 receptor antagonist to treat cytophagic histiocytic panniculitis with secondary hemophagocytic lymphohistiocytosis. J Rheumatol. 2006;33:2081–4.PubMedGoogle Scholar
  47. 47.
    Miettunen PM, Narendran A, Jayanthan A, Behrens EM, Cron RQ. Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients. Rheumatology (Oxford). 2011;50(2):417–9.CrossRefGoogle Scholar
  48. 48.
    Strout MP, Seropian S, Berliner N. Alemtuzumab as a bridge to allogeneic SCT in atypical hemophagocytic lymphohistiocytosis. Nat Rev Clin Oncol. 2010;7:415–20.CrossRefPubMedGoogle Scholar
  49. 49.
    Gerard LM1, Xing K, Sherifi I, Granton J, Barth D, Abdelhaleem M, et al. Adult hemophagocytic lymphohistiocytosis with severe pulmonary hypertension and a novel perforin gene mutation. Int J Hematol. 2012;95:445–50.CrossRefPubMedGoogle Scholar
  50. 50.
    Wang Y, Huang W, Hu L, Cen X, Li L, Wang J, et al. Multicenter study of combination DEP regimen as a salvage therapy for adult refractory hemophagocytic lymphohistiocytosis. Blood. 2015;126:2186–92.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Jan-Inge Henter
    • 1
  • Rebecca A Marsh
    • 2
  • Tatiana von Bahr Greenwood
    • 1
  1. 1.Childhood Cancer Research Unit, Department of Women’s and Children’s HealthKarolinska Institutet, and Theme of Children’s and Women’s Health, Karolinska University HospitalStockholmSweden
  2. 2.Division of Bone Marrow Transplantation and Immune DeficiencyCincinnati Children’s Hospital Medical CenterCincinnatiUSA

Personalised recommendations