Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study

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Key Points

Early introduction of cyclosporine did not improve HLH outcome in patients treated with the HLH-94 etoposide-dexamethasone backbone (P = .06). HLH-2004 may be improved by risk-group stratification, less therapy reduction weeks 7 to 8 for verified FHL patients, and earlier HSCT.

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Most cited references 36

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Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol.

Helena Trottestam, Annacarin Horne, Maurizio Aricò … (2011)

Hemophagocytic lymphohistiocytosis (HLH) used to have a dismal prognosis. We report the final results of HLH-94, the largest prospective diagnostic/therapeutic HLH study so far. The treatment includes immunosuppressive and cytotoxic therapy aiming at clinical remission, followed by HSCT in patients with familial, persistent, or recurrent disease. Altogether, 249 patients fulfilled inclusion criteria and started HLH-94 therapy (July 1994-December 2003); 227 (91%) were followed-up for ≥ 5 years. At 6.2 years median follow-up, estimated 5-year probability of survival was 54% ± 6%. Seventy-two patients (29%) died before HSCT, 64 within 1 year, 97% of whom had active disease. In 124 patients who underwent HSCT, 5-year survival was 66 ± 8%; tendency to increased survival (P = .064) in patients with nonactive disease at HSCT. Patients with familial disease had a 5-year survival of 50% ± 13%; none survived without HSCT. Patients deceased during the first 2 months more often had jaundice, edema, and elevated creatinine. Forty-nine patients (20%) were alive without signs of HLH activity and off-therapy > 1-year without HSCT; they presented at older age (P < .001), were more often female (P = .011), and less often had CNS disease (P < .001) or hepatomegaly (P = .007). To conclude, HLH-94 chemoimmunotherapy has considerably improved outcome in HLH. Collaborative efforts are needed to further reduce early mortality, HSCT-related mortality, and neurologic late effects.

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Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy.

David T Teachey, Susan R Rheingold, Shannon L Maude … (2013)

Blinatumomab is a CD19/CD3-bispecific T-cell receptor-engaging (BiTE) antibody with efficacy in refractory B-precursor acute lymphoblastic leukemia. Some patients treated with blinatumomab and other T cell-activating therapies develop cytokine release syndrome (CRS). We hypothesized that patients with more severe toxicity may experience abnormal macrophage activation triggered by the release of cytokines by T-cell receptor-activated cytotoxic T cells engaged by BiTE antibodies and leading to hemophagocytic lymphohistiocytosis (HLH). We prospectively monitored a patient during blinatumomab treatment and observed that he developed HLH. He became ill 36 hours into the infusion with fever, respiratory failure, and circulatory collapse. He developed hyperferritinemia, cytopenias, hypofibrinogenemia, and a cytokine profile diagnostic for HLH. The HLH continued to progress after discontinuation of blinatumomab; however, he had rapid improvement after IL-6 receptor-directed therapy with tocilizumab. Patients treated with T cell-activating therapies, including blinatumomab, should be monitored for HLH, and cytokine-directed therapy may be considered in cases of life-threatening CRS. This trial was registered at www.clinicaltrials.gov as #NCT00103285.

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Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis.

Rupali Das, Peng Guan, Leslee Sprague … (2016)

Hemophagocytic lymphohistiocytosis (HLH) comprises an emerging spectrum of inherited and noninherited disorders of the immune system characterized by the excessive production of cytokines, including interferon-γ and interleukins 2, 6, and 10 (IL-2, IL-6, and IL-10). The Janus kinases (JAKs) transduce signals initiated following engagement of specific receptors that bind a broad array of cytokines, including those overproduced in HLH. Based on the central role for cytokines in the pathogenesis of HLH, we sought to examine whether the inhibition of JAK function might lessen inflammation in murine models of the disease. Toward this end, we examined the effects of JAK inhibition using a model of primary (inherited) HLH in which perforin-deficient (Prf1(-∕-)) mice are infected with lymphocytic choriomeningitis virus (LCMV) and secondary (noninherited) HLH in which C57BL/6 mice receive repeated injections of CpG DNA. In both models, treatment with the JAK1/2 inhibitor ruxolitinib significantly lessened the clinical and laboratory manifestations of HLH, including weight loss, organomegaly, anemia, thrombocytopenia, hypercytokinemia, and tissue inflammation. Importantly, ruxolitinib treatment also significantly improved the survival of LCMV-infectedPrf1(-∕-)mice. Mechanistic studies revealed that in vivo exposure to ruxolitinib inhibited signal transducer and activation of transcription 1-dependent gene expression, limited CD8(+)T-cell expansion, and greatly reduced proinflammatory cytokine production, without effecting degranulation and cytotoxic function. Collectively, these findings highlight the JAKs as novel, druggable targets for mitigating the cytokine-driven hyperinflammation that occurs in HLH. These observations also support the incorporation of JAK inhibitors such as ruxolitinib into future clinical trials for patients with these life-threatening disorders.

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Author and article information

Journal

Title: Blood

Publisher: American Society of Hematology

ISSN (Print): 0006-4971

ISSN (Electronic): 1528-0020

Publication date Created: December 21 2017

Publication date (Print): December 21 2017

Volume: 130

Issue: 25

Pages: 2728-2738

Affiliations

[1 ]Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden;

[2 ]Theme of Children’s and Women’s Health, Karolinska University Hospital, Stockholm, Sweden;

[3 ]Direzione Generale, Azienda Sanitaria Provinciale, Ragusa, Italy;

[4 ]Servicio de Pediatria, BioCruces Health Research Institute, Hospital Universitario Cruces, University of the Basque Country, Universidad del Pais Vasco–Euskal Herriko Unibertsitatea (UPV/EHU), Barakaldo, Spain;

[5 ]Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada;

[6 ]Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH;

[7 ]Department of Pediatrics, Graduate School of Medicine, Ehime University, Ehime, Japan;

[8 ]Pediatric Hematology and Oncology, University Medical Center Hamburg, Hamburg, Germany;

[9 ]Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center, Washington, DC;

[10 ]Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX;

[11 ]University Clinic of Pediatrics, St. Anna Children's Hospital, Medical University of Vienna, Vienna, Austria;

[12 ]Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden;

[13 ]Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden;

[14 ]Department of Epidemiology and Public Health, University College London, London, United Kingdom;

[15 ]Department of Pediatrics, Watford General Hospital, Watford, United Kingdom;

[16 ]Department of Pediatric Hematology and Oncology, Hospital de Niños Dr Pedro De Elizalde, Buenos Aires, Argentina;

[17 ]Department of Pediatrics, Hospital de Clinicas Jose de San Martin, Buenos Aires, Argentina;

[18 ]Instituto de Farmacología, Universidad de Buenos Aires, Buenos Aires, Argentina; and

[19 ]Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina

Article

DOI: 10.1182/blood-2017-06-788349

PMC ID: 5785801

PubMed ID: 28935695

SO-VID: 019b03e2-7f1a-4fcb-bc74-2e335f6980ce

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