Translational research in childhood cancer and histiocytic diseases – Nikolas Herold Research group

Research team leader 
Jan-Inge Henter; MD PhD, Professor, Senior consultant at the Karolinska University Hospital

Team members
Tatiana von Bahr Greenwood, MD PhD - Postdoc, Pediatrician
Désirée Gavhed, PhD - Research coordinator, Senior research specialist
Elisabet Bergsten, PhD - Data manager, Research specialist

Affiliated
AnnaCarin Horne, MD PhD - Pediatrician, Consultant
Marie Meeths, MD PhD - Pediatrician
Magdalini Lourda, PhD - Senior research specialist 
Egle Kvedaraite, MD PhD - Resident in Pathology 
Alexandra Löfstedt, MD PhD - Pediatrician 
Daniel Hagey, PhD - Research specialist 
Christina Egnell Gustafsson, MD PhD - Pediatrician
Katarina Zivkovic, MS - Medical student

Alumni
Selma Olsson Åkefeldt, MD PhD - Pediatrician, Consultant

PhD students
Malin Sveijer, MD - Pediatrician
Maria Sjöborg Alpman, MD - Pediatrician, Consultant
Mikaela Winderud, MD - Pediatrician
Erik Larsson, MD - Pediatrician

We have a deep and long-lasting interest in primary HLH, with the aim to reduce mortality and morbidity. Familial HLH (FHL) is a rapidly fatal disease that most typically affects infants and young children, with a median survival of 1-2 months without adequate treatment. 

We have led the development of the international diagnostic guidelines for FHL (1991, 2004, and 2024). We have also contributed to the use of cytotoxicity assays of natural killer cells and cytotoxic T cells in the diagnostics of FHL.

We have also, in collaboration with clinical scientists worldwide, coordinated the international treatment studies HLH-94 and HLH-2004 with the major aim to improve survival. These treatment protocols are based on an initial therapy with etoposide and dexamethasone followed by stem cell transplantation (SCT), In 2024, results of the HLH Registry showed a pre-SCT survival of 91% in primary HLH patients with etoposide as first-line therapy, and a SCT-survival of 85%, resulting in an impressive 3-year survival of 77% in this severe disease.

We have also studied the biology of HLH. In 1996 we suggested that FHL might be caused by an apoptosis defect and in 1999 we were able to show that FHL is caused by a deficiency in apoptosis triggering. Subsequently, in collaboration with other research groups, in 1999 and 2005 mutations in the genes encoding perforin and syntaxin-11 (STX11), respectively, were reported in FHL patients. In 2011 we reported that an inversion of the gene UNC13D is the most common genetic cause of FHL in Swedish patients.

Notably, mutations in FHL-causing genes are associated with an increased risk of developing malignancies. We have shown that apparently healthy carriers of FHL-causing genes have an increased risk of developing lymphomas, possibly due to a moderately deficient surveillance of cancer transformed cells.

Unfortunately, many survivors of FHL develop neurological complications due to inflammation in the brain during the disease course. Currently we try to evaluate how to best reduce these neurological complications. We also want to further explore to what extent carriership of FHL genes is associated with increased risk of malignancies and other health problems. 

The clinical hallmark of HLH is massive inflammation (“hyperinflammation”). We are increasingly interested in various forms of secondary HLH, including infection-associated HLH, malignancy-associated HLH and autoimmune-associated HLH, in children as well as adults. 

We want to improve survival in infection-associated HLH, malignancy-associated HLH, and autoimmune-associated HLH as well as HLH associated with novel biological treatments such as CAR-HLH. We also aim to better understand the underlying biology of secondary HLH.

In international collaboration we have prepared recommendations for the use of etoposide-based treatment in HLH, recommendations for management of secondary HLH in adults, and recommendations for management of HLH in intensive care units (ICU). We have also studied HLH in severe dengue fever as well as in malignancy-associated HLH and rheuma-associated HLH. 

We want to take advantage of our solid knowledge on HLH and hyperinflammation and expand that knowledge to other relevant patient groups. Our ultimate goal is to improve the outcome, in all respects, of patients affected by hyperinflammation.

Review of Hemophagocytic Lymphohistiocytosis (HLH)

Henter JI. Hemophagocytic Lymphohistiocytosis. N Engl J Med. 2025 Feb 6;392(6):584-598. doi: 10.1056/NEJMra2314005. PMID: 39908433.

Primary HLH

Henter JI, Sieni E, Eriksson J, Bergsten E, Hed Myrberg I, Canna SW, Coniglio ML, Cron RQ, Kernan KF, Kumar AR, Lehmberg K, Minoia F, Naqvi A, Ravelli A, Tang YM, Bottai M, Bryceson YT, Horne A, Jordan MB. Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited. Blood. 2024 Nov 28;144(22):2308-2318. doi: 10.1182/blood.2024025077. PMID: 39046779; PMCID: PMC11619794. 

Chiang SCC, Covill LE, Tesi B, Campbell TM, Schlums H, Nejati-Zendegani J, Mördrup K, Wood S, Theorell J, Sekine T, Al-Herz W, Akar HH, Belen FB, Chan MY, Devecioglu O, Aksu T, Ifversen M, Malinowska I, Sabel M, Unal E, Unal S, Introne WJ, Krzewski K, Gilmour KC, Ehl S, Ljunggren HG, Nordenskjöld M, Horne A, Henter JI, Meeths M, Bryceson YT. Efficacy of T-cell assays for the diagnosis of primary defects in cytotoxic lymphocyte exocytosis. Blood. 2024 Aug 22;144(8):873-887. doi: 10.1182/blood.2024024499. PMID: 38958468

Böhm S, Wustrau K, Pachlopnik Schmid J, Prader S, Ahlmann M, Yacobovich J, Beier R, Speckmann C, Behnisch W, Ifversen M, Jordan M, Marsh R, Naumann-Bartsch N, Mauz-Körholz C, Hönig M, Schulz A, Malinowska I, Hines M, Nichols KE, Gil-Herrera J, Talano JA, Crooks B, Formankova R, Jorch N, Bakhtiar S, Kühnle I, Streiter M, Nathrath M, Russo A, Dürken M, Lang P, Lindemans C, Henter JI, Lehmberg K, Ehl S. Survival in primary hemophagocytic lymphohistiocytosis, 2016 to 2021: etoposide is better than its reputation. Blood. 2024 Mar 7;143(10):872-881. doi: 10.1182/blood.2023022281. PMID: 37992218.

Secondary HLH

Henter JI. Intercontinentally validated diagnostic criteria for secondary hemophagocytic lymphohistiocytosis-So welcome! J Intern Med. 2025 Jan 29. doi: 10.1111/joim.20066. Epub ahead of print. PMID: 39877947.

Löfstedt A, Jädersten M, Meeths M, Henter JI. Malignancy-associated hemophagocytic lymphohistiocytosis in Sweden: incidence, clinical characteristics, and survival. Blood. 2024 Jan 18;143(3):233-242. doi: 10.1182/blood.2023020715. PMID: 37595287 

Scala JJ, Eckrich MJ, Lipak K, Yates B, Yuan C, Wang HW, Dahiya S, Henter JI, Huo JS, Frank MJ, Shah NN. Treatment strategies for progressive immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome: case series. Haematologica. 2024 Oct 1;109(10):3439-3445. doi: 10.3324/haematol.2023.284784. PMID: 38813719

Hines MR, Knight TE, McNerney KO, Leick MB, Jain T, Ahmed S, Frigault MJ, Hill JA, Jain MD, Johnson WT, Lin Y, Mahadeo KM, Maron GM, Marsh RA, Neelapu SS, Nikiforow S, Ombrello AK, Shah NN, Talleur AC, Turicek D, Vatsayan A, Wong SW, Maus MV, Komanduri KV, Berliner N, Henter JI, Perales MA, Frey NV, Teachey DT, Frank MJ, Shah NN. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome. Transplant Cell Ther. 2023 Jul;29(7):438.e1-438.e16. doi: 10.1016/j.jtct.2023.03.006. PMID: 36906275

Hines MR, von Bahr Greenwood T, Beutel G, Beutel K, Hays JA, Horne A, Janka G, Jordan MB, van Laar JAM, Lachmann G, Lehmberg K, Machowicz R, Miettunen P, La Rosée P, Shakoory B, Zinter MS, Henter JI. Consensus-Based Guidelines for the Recognition, Diagnosis, and Management of Hemophagocytic Lymphohistiocytosis in Critically Ill Children and Adults. Crit Care Med. 2022 May 1;50(5):860-872. doi: 10.1097/CCM.0000000000005361. PMID: 34605776

Palmblad K, Schierbeck H, Sundberg E, Horne AC, Erlandsson Harris H, Henter JI, Andersson U. Therapeutic administration of etoposide coincides with reduced systemic HMGB1 levels in macrophage activation syndrome. Mol Med. 2021 May 11;27(1):48. doi: 10.1186/s10020-021-00308-0. PMID: 33975537

Horne A, von Bahr Greenwood T, Chiang SCC, Meeths M, Björklund C, Ekelund M, Erensjö P, Berg S, Hagelberg S, Bryceson YT, Andersson U, Henter JI. Efficacy of Moderately Dosed Etoposide in Macrophage Activation Syndrome-Hemophagocytic Lymphohistiocytosis. J Rheumatol. 2021 Oct;48(10):1596-1602. doi: 10.3899/jrheum.200941. PMID: 33589555

Increased knowledge about hemophagocytic lymphohistiocytosis can save lives - Karolinska Universitetssjukhuset

Description of the disease

Langerhans cell histiocytosis (LCH) is a potentially fatal disease with a highly variable clinical picture. Bone and skin are the most common organs affected, and other organs that may be involved include the liver, spleen, lungs (particularly in smokers), the pituitary gland and the CNS. The most feared complication is a slowly progressive neurodegeneration affection around 10% of children with LCH.

Biology

LCH is viewed as an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. 

Treatment

The classical treatment typically involves mild chemotherapy, such as vinblastine, methotrexate, 6-mercaptopurine, corticosteroids, and vincristine, but very toxic chemotherapy such as high doses of cytarabine and 2-CdA in combination have been suggested as salvage therapy.

Importantly, the targeted inhibition of the MAPK pathway has improved survival further, and mortality in LCH is nowadays minimal. However, the best way to prevent and treat neurodegenerative CNS-LCH is still not well known.

Our research on LCH

Our main goals are to elucidate etiology and pathophysiologic mechanisms of LCH, and to reduce mortality and late effects.

Improve survival and reduce permanent consequences of children with LCH. We participate actively in the international multicenter study LCH-IV on treatment and natural history of pediatric LCH patients, in which we coordinate the part on CNS-LCH. (Clinical trial “LCH-IV International Collaborative Treatment Protocol for Children and Adolescents with LANGERHANS CELL HISTIOCYTOSIS”, EudraCT 2011-001699-20). 

We evaluate targeted inhibition of the MAPK pathway in LCH in general, and more specifically regarding neurodegenerative CNS-LCH. 

We study the underlying biology of LCH with the aim to improve the treatment of patients with LCH.  

Assessing and monitoring neurodegeneration in CNS-LCH during the disease course is important, but tools for assessment of ongoing neurodegeneration are limited. Together with the Sahlgrenska University Hospital in Gothenburg we have reported that assessment of neurofilament light protein (NFL) in the cerebrospinal fluid and plasma can serve as biomarkers for assessing and monitoring neurodegeneration in CNS-LCH. 

Since some children with LCH develop neurodegeneration, we want to evaluate the long-term Quality of life of children treated for LCH.

We also want to, in broad European collaboration, develop a large European CNS-LCH Registry for children with, and with increased risk of, neurodegenerative CNS-LCH, with the aim to learn how to best prevent, monitor and treat neurodegenerative CNS-LCH. 

Hagey DW, Kvedaraite E, Akber M, Görgens A, Javadi J, Von Bahr Greenwood T, Björklund C, Åkefeldt SO, Hannegård-Hamrin T, Arnell H, Dobra K, Herold N, Svensson M, El Andaloussi S, Henter JI, Lourda M. Myeloid cells from Langerhans cell histiocytosis patients exhibit increased vesicle trafficking and an altered secretome capable of activating NK cells. Haematologica. 2023 Sep 1;108(9):2422-2434. doi: 10.3324/haematol.2022.282638. PMID: 36924254 

Kvedaraite E, Milne P, Khalilnezhad A, Chevrier M, Sethi R, Lee HK, Hagey DW, von Bahr Greenwood T, Mouratidou N, Jädersten M, Lee NYS, Minnerup L, Tan Y, Dutertre CA, Benac N, Hwang YY, Lum J, Loh AHP, Jansson J, Teng KWW, Khalilnezhad S, Xu W, Resteu A, Tey HL, Guan NL, Larbi A, Howland SW, Arnell H, Andaloussi SEL, Braier J, Rassidakis G, Galluzzo L, Dzionek A, Henter JI, Chen J, Collin M, Ginhoux F. Notch-dependent cooperativity between myeloid lineages promotes Langerhans cell histiocytosis pathology. Sci Immunol. 2022 Dec 23;7(78):eadd3330. doi: 10.1126/sciimmunol.add3330. PMID: 36525505

Sveijer M, von Bahr Greenwood T, Jädersten M, Kvedaraite E, Zetterberg H, Blennow K, Lourda M, Gavhed D, Henter JI. Screening for neurodegeneration in Langerhans cell histiocytosis with neurofilament light in plasma. Br J Haematol. 2022 Aug;198(4):721-728. doi: 10.1111/bjh.18247. PMID: 35582775

Henter JI, Kvedaraite E, Martín Muñoz D, Cheng Munthe-Kaas M, Zeller B, Nystad TA, Björklund C, Donnér I, Lourda M, Zetterberg H, Blennow K, Herold N, Gavhed D, von Bahr Greenwood T. Response to mitogen-activated protein kinase inhibition of neurodegeneration in Langerhans cell histiocytosis monitored by cerebrospinal fluid neurofilament light as a biomarker: a pilot study. Br J Haematol. 2022 Jan;196(1):248-254. doi: 10.1111/bjh.17781. PMID: 34435355

Åkefeldt SO, Ismail MB, Belot A, Salvatore G, Bissay N, Gavhed D, Aricò M, Henter JI, Valentin H, Delprat C. Neutralizing Anti-IL-17A Antibody Demonstrates Preclinical Activity Enhanced by Vinblastine in Langerhans Cell Histiocytosis. Front Oncol. 2022 Jan 21;11:780191. doi: 10.3389/fonc.2021.780191. eCollection 2021. PMID: 35127485