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Journal of Cancer Research and Clinical Oncology

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Open Access 01-04-2020 | Septicemia | Original Article – Clinical Oncology

Hemophagocytic lymphohistiocytosis in adults: collaborative analysis of 137 cases of a nationwide German registry

Authors: Sebastian Birndt, Thomas Schenk, Babett Heinevetter, Frank M. Brunkhorst, Georg Maschmeyer, Frank Rothmann, Thomas Weber, Markus Müller, Jens Panse, Olaf Penack, Roland Schroers, Jan Braess, Norbert Frickhofen, Stephan Ehl, Gritta Janka, Kai Lehmberg, Mathias W. Pletz, Andreas Hochhaus, Thomas Ernst, Paul La Rosée

Published in: Journal of Cancer Research and Clinical Oncology | Issue 4/2020

Abstract

Purpose

Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome emerging from a deregulated immune response due to various triggers. In adults, systematic data are sparse, which is why recommendations on diagnosis and management have been adopted from pediatric guidelines. A nationwide clinical registry with associated consulting service as collaborative initiative of HLH-specialized pediatricians and hematologists was initiated to better characterize HLH in adults.

Methods

Patients with proven or suspected HLH were registered by 44 institutions. Both HLH-2004 diagnostic criteria and the HScore (www.saintantoine.aphp.fr/score/) were used to confirm HLH diagnosis. Data referring to underlying disease, treatment, outcome, clinical presentation and laboratory findings were recorded.

Results

The study included 137 patients and provides the first systematic data on adult HLH in Germany. Median age was 50 years with a wide range (17–87 years), 87 patients (63.5%) were male. Most common triggering diseases were infections in 61 patients (44.5%) and malignancies in 48 patients (35%). Virtually all patients had elevated ferritin concentrations, and 74% had peak concentrations greater than 10,000 µg/l. At time of analysis, 67 of 131 patients (51%) had died. Patients with malignancy-associated HLH had the shortest median survival (160 days), however no statistically significant difference between subgroups was observed (p = 0.077). Platelets under 20*10⁹/l and low albumin concentrations (< 20 g/l) were associated with poor overall and 30-day survival.

Conclusion

Close multidisciplinary case consultation and cooperation is mandatory when treating adult HLH patients. Early contact with reference centers is recommended, especially in relapsing or refractory disease.

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Allen CE, Yu X, Kozinetz CA, McClain KL (2008) Highly elevated ferritin levels and the diagnosis of hemophagocytic lymphohistiocytosis. Pediatric Blood Cancer 50:1227–1235. https://doi.org/10.1002/pbc.21423CrossRefPubMed

Arca M et al (2015) Prognostic factors of early death in a cohort of 162 adult haemophagocytic syndrome: impact of triggering disease and early treatment with etoposide. Br J Haematol 168:63–68. https://doi.org/10.1111/bjh.13102

Bachier Rodriguez L, Ritchie EK (2016) A case series of adult secondary hemophagocytic lymphohistiocytosis treated at weill cornell medical college. Blood 128:4874–4874CrossRef

Bergsten E et al (2017) Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study. Blood 130:2728–2738. https://doi.org/10.1182/blood-2017-06-788349

Berliner N, Kurra C, Chou D (2016) CASE RECORDS of the MASSACHUSETTS GENERAL HOSPITAL. Case 1–2016. An 18-year-old man with fever abdominal pain, and thrombocytopenia. N Engl J Med 374:165–173. https://doi.org/10.1056/NEJMcpc1501306CrossRefPubMed

Bode SF et al (2014) Hemophagocytic lymphohistiocytosis in imported pediatric visceral leishmaniasis in a nonendemic area. J Pediatr 165(147–153):e141. https://doi.org/10.1016/j.jpeds.2014.03.047CrossRef

Bodley Scott R, Robb-Smith AHT (1939) Histiocytic medullary reticulosis. The Lancet 234:194–198. https://doi.org/10.1016/S0140-6736(00)61951-7CrossRef

Brisse E, Wouters CH, Matthys P (2016) Advances in the pathogenesis of primary and secondary haemophagocytic lymphohistiocytosis: differences and similarities. Br J Haematol 174:203–217. https://doi.org/10.1111/bjh.14147CrossRefPubMed

Busiello R, Fimiani G, Miano MG, Arico M, Santoro A, Ursini MV, Pignata C (2006) A91V perforin variation in healthy subjects and FHLH patients. Int J Immunogenet 33:123–125. https://doi.org/10.1111/j.1744-313X.2006.00582.x

Cetica V et al (2016) Genetic predisposition to hemophagocytic lymphohistiocytosis: report on 500 patients from the Italian registry. J Allergy Clin Immunol 137:188–196 e184. https://doi.org/10.1016/j.jaci.2015.06.048

Daver N et al (2017) A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults. Cancer 123:3229–3240. https://doi.org/10.1002/cncr.30826CrossRefPubMed

Delavigne K et al (2014) Hemophagocytic syndrome in patients with acute myeloid leukemia undergoing intensive chemotherapy. Haematologica 99:474–480. https://doi.org/10.3324/haematol.2013.097394CrossRefPubMedPubMedCentral

Ehl S et al (2018) Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: consensus statements by the HLH steering committee of the histiocyte society. J Allergy Clin Immunol Pract 6:1508–1517. https://doi.org/10.1016/j.jaip.2018.05.031CrossRefPubMed

Emile JF et al (2016) Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 127:2672–2681. https://doi.org/10.1182/blood-2016-01-690636CrossRefPubMedPubMedCentral

Fardet L et al (2010) Reactive haemophagocytic syndrome in 58 HIV-1-infected patients: clinical features, underlying diseases and prognosis Aids 24:1299–1306. https://doi.org/10.1097/QAD.0b013e328339e55b

Fardet L et al (2014) Development and validation of the HScore, a score for the diagnosis of reactive hemophagocytic syndrome. Arthritis Rheumatol 66:2613–2620. https://doi.org/10.1002/art.38690

Frimmel S, Schipper J, Henschel J, Yu TT, Mitzner SR, Koball S (2014) First description of single-pass albumin dialysis combined with cytokine adsorption in fulminant liver failure and hemophagocytic syndrome resulting from generalized herpes simplex virus 1 infection. Liver Transpl 20:1523–1524. https://doi.org/10.1002/lt.24005

Gars E, Purington N, Scott G, Chisholm K, Gratzinger D, Martin BA, Ohgami RS (2018) Bone marrow histomorphological criteria can accurately diagnose hemophagocytic lymphohistiocytosis. Haematologica 103:1635–1641. https://doi.org/10.3324/haematol.2017.186627CrossRefPubMedPubMedCentral

Greil C, Roether F, La Rosee P, Grimbacher B, Duerschmied D, Warnatz K (2017) Rescue of cytokine storm due to hlh by hemoadsorption in a CTLA4-deficient patient. J Clin Immunol 37:273–276

Gupta A, Weitzman S, Abdelhaleem M (2008) The role of hemophagocytosis in bone marrow aspirates in the diagnosis of hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 50:192–194. https://doi.org/10.1002/pbc.21441CrossRefPubMed

Halacli B et al (2016) Investigation of hemophagocytic lymphohistiocytosis in severe sepsis patients. J Crit Care 35:185–190. https://doi.org/10.1016/j.jcrc.2016.04.034CrossRefPubMed

Han AR et al (2007) Lymphoma-associated hemophagocytic syndrome: clinical features and treatment outcome. Ann Hematol 86:493–498. https://doi.org/10.1007/s00277-007-0278-6CrossRefPubMed

Hayden A et al (2017) Soluble interleukin-2 receptor is a sensitive diagnostic test in adult HLH. Blood Adv 1:2529–2534. https://doi.org/10.1182/bloodadvances.2017012310

Hayden A, Park S, Giustini D, Lee AY, Chen LY (2016) Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: a systematic scoping review. Blood Rev 30:411–420 https://doi.org/10.1016/j.blre.2016.05.001

Henkes M, Finke J, Warnatz K, Ammann S, Stadt UZ, Janka G, Brugger W (2015) Late-onset hemophagocytic lymphohistiocytosis (HLH) in an adult female with Griscelli syndrome type 2 (GS2). Ann Hematol 94:1057–1060. https://doi.org/10.1007/s00277-014-2284-9

Henter JI et al (2007) HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 48:124–131. https://doi.org/10.1002/pbc.21039

Janka GE, Lehmberg K (2014) Hemophagocytic syndromes—an update Blood Rev 28:135–142. https://doi.org/10.1016/j.blre.2014.03.002

Jing-Shi W, Yi-Ni W, Lin W, Zhao W (2015) Splenectomy as a treatment for adults with relapsed hemophagocytic lymphohistiocytosis of unknown cause. Ann Hematol 94:753–760. https://doi.org/10.1007/s00277-014-2276-9CrossRefPubMed

Jordan M et al (2015) A novel targeted approach to the treatment of hemophagocytic lymphohistiocytosis (HLH) with an anti-interferon gamma (IFNγ) monoclonal antibody (mAb), NI-0501: first results from a Pilot phase 2 study in children with primary HLH. Blood 126:LBA-3–LBA-3

La Rosee P (2015a) First prospective clinical trial in adult HLH. Blood 126:2169–2171. https://doi.org/10.1182/blood-2015-09-666503CrossRefPubMed

La Rosee P (2015b) Treatment of hemophagocytic lymphohistiocytosis in adults. Hematol Am Soc Hematol Educ Prog 2015:190–196. https://doi.org/10.1182/asheducation-2015.1.190CrossRef

La Rosee P (2016) Alleviating the storm: ruxolitinib in HLH. Blood 127:1626–1627. https://doi.org/10.1182/blood-2016-02-697151CrossRefPubMed

Lachmann G, Spies C, Schenk T, Brunkhorst FM, Balzer F, La Rosee P (2018) Hemophagocytic lymphohistiocytosis: potentially underdiagnosed in intensive care units. Shock 50:149–155. https://doi.org/10.1097/SHK.0000000000001048CrossRefPubMed

Lee DW et al (2014) Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124:188–195. https://doi.org/10.1182/blood-2014-05-552729CrossRefPubMedPubMedCentral

Lehmberg K, Ehl S (2013) Diagnostic evaluation of patients with suspected haemophagocytic lymphohistiocytosis. Br J Haematol 160:275–287. https://doi.org/10.1111/bjh.12138CrossRefPubMed

Lehmberg K et al (2015) Consensus recommendations for the diagnosis and management of hemophagocytic lymphohistiocytosis associated with malignancies. Haematologica 100:997–1004. https://doi.org/10.3324/haematol.2015.123562CrossRefPubMedPubMedCentral

Li J, Wang Q, Zheng W, Ma J, Zhang W, Wang W, Tian X (2014) Hemophagocytic lymphohistiocytosis: clinical analysis of 103 adult patients Medicine 93:100–105. https://doi.org/10.1097/MD.0000000000000022

Li F et al (2015) Clinical characteristics and prognostic factors of adult hemophagocytic syndrome patients: a retrospective study of increasing awareness of a disease from a single-center in China. Orphanet J Rare Dis 10:20. https://doi.org/10.1186/s13023-015-0224-yCrossRefPubMedPubMedCentral

Lin M et al (2017) Clinical utility of soluble interleukin-2 receptor in hemophagocytic syndromes: a systematic scoping review. Ann Hematol 96:1241–1251. https://doi.org/10.1007/s00277-017-2993-y

Machaczka M, Vaktnas J, Klimkowska M, Hagglund H (2011) Malignancy-associated hemophagocytic lymphohistiocytosis in adults: a retrospective population-based analysis from a single center. Leuk Lymphoma 52:613–619. https://doi.org/10.3109/10428194.2010.551153CrossRefPubMed

Oto M, Yoshitsugu K, Uneda S, Nagamine M, Yoshida M (2015) Prognostic factors and outcomes of adult-onset hemophagocytic lymphohistiocytosis: a retrospective analysis of 34 cases. Hematol Rep 7:5841. https://doi.org/10.4081/hr.2015.5841

Otrock ZK, Eby CS (2015) Clinical characteristics, prognostic factors, and outcomes of adult patients with hemophagocytic lymphohistiocytosis. Am J Hematol 90:220–224 https://doi.org/10.1002/ajh.23911

Otrock ZK, Hock KG, Riley SB, de Witte T, Eby CS, Scott MG (2017) Elevated serum ferritin is not specific for hemophagocytic lymphohistiocytosis. Ann Hematol. https://doi.org/10.1007/s00277-017-3072-0CrossRefPubMed

Parikh SA, Kapoor P, Letendre L, Kumar S, Wolanskyj AP (2014) Prognostic factors and outcomes of adults with hemophagocytic lymphohistiocytosis. Mayo Clin Proc 89:484–492. https://doi.org/10.1016/j.mayocp.2013.12.012CrossRefPubMed

Park HS et al (2012) Clinical features of adult patients with secondary hemophagocytic lymphohistiocytosis from causes other than lymphoma: an analysis of treatment outcome and prognostic factors. Ann Hematol 91:897–904. https://doi.org/10.1007/s00277-011-1380-3CrossRefPubMed

Ramos-Casals M, Brito-Zeron P, Lopez-Guillermo A, Khamashta MA, Bosch X (2014) Adult haemophagocytic syndrome. Lancet 383:1503–1516. https://doi.org/10.1016/S0140-6736(13)61048-XCrossRefPubMed

Riviere S, Galicier L, Coppo P, Marzac C, Aumont C, Lambotte O, Fardet L (2014) Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients. Am J Med 127:1118–1125. https://doi.org/10.1016/j.amjmed.2014.04.034

Schram AM et al (2016) Haemophagocytic lymphohistiocytosis in adults: a multicentre case series over 7 years. Br J Haematol 172:412–419. https://doi.org/10.1111/bjh.13837

Schram AM, Campigotto F, Mullally A, Fogerty A, Massarotti E, Neuberg D, Berliner N (2015) Marked hyperferritinemia does not predict for HLH in the adult population. Blood 125:1548–1552. https://doi.org/10.1182/blood-2014-10-602607CrossRefPubMed

Sepulveda FE, de Saint BG (2017) Hemophagocytic syndrome: primary forms and predisposing conditions. Curr Opin Immunol 49:20–26. https://doi.org/10.1016/j.coi.2017.08.004CrossRefPubMed

Shabbir M, Lucas J, Lazarchick J, Shirai K (2011) Secondary hemophagocytic syndrome in adults: a case series of 18 patients in a single institution and a review of literature. Hematol Oncol 29:100–106 https://doi.org/10.1002/hon.960

Sin JH, Zangardi ML (2017) Ruxolitinib for secondary hemophagocytic lymphohistiocytosis: first case report. Hematol Oncol Stem Cell Ther. https://doi.org/10.1016/j.hemonc.2017.07.002CrossRefPubMed

Tamamyan GN et al (2016) Malignancy-associated hemophagocytic lymphohistiocytosis in adults: relation to hemophagocytosis, characteristics, and outcomes. Cancer 122:2857–2866. https://doi.org/10.1002/cncr.30084

Teachey DT et al (2013) Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 121:5154–5157. https://doi.org/10.1182/blood-2013-02-485623CrossRefPubMedPubMedCentral

Trottestam H et al (2011) Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood 118:4577–4584 https://doi.org/10.1182/blood-2011-06-356261

Tschistowitsch T, Bykowa O (1928) Retikulose als eine Systemerkrankung der blutbildenden. Organe Virchows Arch A 267:91–105. https://doi.org/10.1007/bf02029855CrossRef

Tsuji T, Hirano T, Yamasaki H, Tsuji M, Tsuda H (2014) A high sIL-2R/ferritin ratio is a useful marker for the diagnosis of lymphoma-associated hemophagocytic syndrome. Ann Hematol 93:821–826. https://doi.org/10.1007/s00277-013-1925-8

Wang Y et al (2014) Genetic features of late onset primary hemophagocytic lymphohistiocytosis in adolescence or adulthood. PLoS ONE 9:e107386. https://doi.org/10.1371/journal.pone.0107386CrossRefPubMedPubMedCentral

Zhang K et al (2011a) Hypomorphic mutations in PRF1, MUNC13–4, and STXBP2 are associated with adult-onset familial HLH. Blood 118:5794–5798. https://doi.org/10.1182/blood-2011-07-370148

Zur Stadt U, Beutel K, Weber B, Kabisch H, Schneppenheim R, Janka G (2004) A91V is a polymorphism in the perforin gene not causative of an FHLH phenotype. Blood 104:1909. https://doi.org/10.1182/blood-2004-02-0733. (Author reply 1910)

Title: Hemophagocytic lymphohistiocytosis in adults: collaborative analysis of 137 cases of a nationwide German registry
Authors: Sebastian Birndt
Thomas Schenk
Babett Heinevetter
Frank M. Brunkhorst
Georg Maschmeyer
Frank Rothmann
Thomas Weber
Markus Müller
Jens Panse
Olaf Penack
Roland Schroers
Jan Braess
Norbert Frickhofen
Stephan Ehl
Gritta Janka
Kai Lehmberg
Mathias W. Pletz
Andreas Hochhaus
Thomas Ernst
Paul La Rosée
Publication date: 01-04-2020
Publisher: Springer Berlin Heidelberg
Keywords: Septicemia
Septicemia
Hemophagocytic Lymphohistiocytosis
Cytokines
Hemophagocytic Lymphohistiocytosis
Published in: Journal of Cancer Research and Clinical Oncology / Issue 4/2020
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-020-03139-4

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Hemophagocytic lymphohistiocytosis in adults: collaborative analysis of 137 cases of a nationwide German registry

Abstract

Purpose

Methods

Results

Conclusion

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Abstract

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Conclusion

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