What is the recommended dosage of anakinra (Kineret) for secondary hemophagocytic lymphohistiocytosis (HLH)?
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Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome of excessive immune activation that can be life-threatening.1,2 Most commonly, HLH impacts infants, but is also observed in children and adults. Diagnosis of HLH can be challenging, as there is a large variation in presentation and severity. HLH may typically present as an acute illness with accompanying fever associated with multiple organ involvement, and initial signs and symptoms can present like common infections, complicating diagnosis. In primary HLH, etiology is thought to be due to genetic factors and most often due to autosomal recessive genetic mutations. Secondary HLH is described as acquired, often resulting from infections, malignancies, or autoimmune diseases. Macrophage-activation syndrome-associated HLH is another term used for autoimmune disease-induced HLH. Classification may not fall neatly into primary or secondary HLH, as there are many overlapping risk factors, and infection can be a trigger for both. Persistent activation of inflammatory cell types, including macrophages, natural killer cells, and cytotoxic lymphocytes can lead to excess cytokine release, creating a cytokine storm, which is likely responsible for multiorgan failure in individuals with HLH.
The overall frequency of HLH, while unknown, is thought to be rare.1,2 However, secondary HLH is associated with a very high acute all-cause mortality of approximately 40% in adults, rising to as high as 85% when incited by malignancy. Supportive intensive care is often required to treat patients with secondary HLH or macrophage-activation syndrome-HLH. Identification of underlying triggers and prompt treatment directed at these triggers is critical. Additional immunosuppressive or immunomodulatory HLH-directed therapy may also be warranted.
Anakinra has been used as HLH-directed therapy for the treatment of secondary HLH or macrophage-activation syndrome-HLH, yet specific dosing recommendations are lacking.1 The purpose of this article is to describe the literature and associated dosage of anakinra in patients with secondary HLH and macrophage-activation syndrome-HLH.
Anakinra in HLH
Anakinra (Kineret) is a disease-modifying antirheumatic, interleukin-1 (IL-1) receptor antagonist.3 It is US Food and Drug Administration (FDA) approved for use in rheumatoid arthritis, cryopyrin-associated periodic syndromes, and deficiency of IL-1 receptor antagonist. Its use in secondary HLH is an off-label indication.1,2 Since IL-1 is central to cytokine storm syndrome in patients with HLH, anakinra is thought to target and terminate hyperinflammation associated with IL-1 in HLH. The evidence evaluating anakinra in patients with secondary HLH or macrophage-activation syndrome is limited to several case reports/series and a systematic review of case reports.
Systematic reviews
Charlesworth and Kavirayani (2023) identified 29 case reports/series with 87 patients (median age, 22 years; range, 22 months to 84 years) with secondary HLH who received intravenous (IV) anakinra as part of treatment.4 The goal of the narrative systematic review was to collate data on the use of IV anakinra in these patients. Many of the underlying triggers precipitating secondary HLH or macrophage-activation syndrome-HLH were identifiable, and included significant infection (43.2%), rheumatological causes (33.3%), oncological causes (8.6%), or another known trigger (14.8%). Adverse reactions attributed to anakinra were reported in 9 cases (10.3%), most of which were minor. The overall survival was 67.8% of the 87 cases reported, but the timing reporting survival varied from 1 to 2 weeks following anakinra treatment to full recovery after many years. The pediatric patients had a greater overall survival (77%) compared to adult patient (61.5%). Of the cases reported, the administered dose of IV anakinra was available for 77.9% of cases. All doses were normalized to mg/kg/day to allow dose comparisons. After normalization, the daily dose of IV anakinra ranged from 1.7 to 48 mg/kg/day (median, 6.86 mg/kg/day). Anakinra dosing was significantly higher in younger patients, but this relationship was only significant amongst patient with infection triggers, when examined by underlying cause. For infection-precipitated HLH, the anakinra dose was significantly higher with reducing age. Most patients received IV bolus dosing (n=75, 87.2%), with some (n=11) reported as receiving continuous IV infusion.
Case series
Numerous additional retrospective case studies and chart review studies have evaluated anakinra dosing in patients with secondary HLH.5-8 Identified large case series (2 or more patients) not included in the above systematic review are summarized in the Table.
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| Table. Case reports evaluating anakinra for secondary HLH or MAS-HLH.5-8 | ||||
|---|---|---|---|---|
| Study design and duration | Subjects | Interventions | Results | Conclusions |
| Miettunen 20115 Retrospective case series Patients followed for a median of 22 (range, 2 to 40) months | N=12 pediatric patients with rheumatic disease-associated MAS-HLH (age range, 6 months to 17 years) | Anakinra 2 mg/kg/day (max dose, 100 mg/day) once daily, subcutaneously All patients initially received corticosteroids and other immunosuppressants with limited benefit | Median hospitalization stay before anakinra was 11 (range, 1 to 27) days. All patients achieved MAS remission after addition of anakinra within a median of 13 (range, 2 to 19) days, and were in remission at the final follow-up | Anakinra 2 mg/kg/day once daily subcutaneously, combined with other immunosuppressants, led to remission of MAS-HLH in 12 pediatric patients with underlying rheumatic disease |
| Wohlfarth 20176 Retrospective case series Length of ICU stay (range, 3 to 118 days) | N=8 adult patients with HLH who received ICU treatment (median age, 38 years; range, 20 to 58 years) 63% (n=5) had a precipitating factor identified | Anakinra absolute dose of 100 to 200 mg three times daily, subcutaneously (median daily dose per kg body weight, 6 mg; range, 4 to 8 mg/kg/day) All patients initially received corticosteroids and IVIG with limited benefit | Median duration of anakinra administration in ICU survivors was 18 (range, 7 to 42) days | Anakinra combined with IVIG and/or corticosteroids resulted in a 50% survival rate in 8 critically ill adults with secondary HLH |
| Bami 20207 Retrospective chart review Follow-up, 3.5 to 5.5 years | N=6 pediatric patients with secondary HLH (median age, 1.8 years; range, 0.8 to 14.9 years) | Initial treatment with anakinra 6 to 10 mg/kg/day divided over 4 doses, subcutaneously 5 of the 6 children were also treated with dexamethasone | Average treatment duration was 8 weeks; 3-year overall survival was 83% (n=5/6) No patient required escalation of therapy to etoposide and all patients achieved remission. Anakinra was well tolerated without significant adverse events | Anakinra as a first-line treatment is feasible for treatment of pediatric secondary HLH |
| Baverez 20228 Retrospective chart review Median follow-up, 10 months | N=21 patients with secondary HLH (median age, 45 years) | Anakinra subcutaneously, at doses of 100 mg/day (n=14), 200 mg/day (n=5), or 2 to 5 mg/kg/day in children (n=3) Used as monotherapy in 5 patients, in combination with corticosteroids as initial treatment in 5 patients, and as second-line or beyond in 11 patients | 19/21 patients (90.5%) experienced remission after anakinra. In 3 of these patients, the dosage was doubled to achieve remission Fever resolved in 19 patients within a median of 1 day | Anakinra, alone or in combination with corticosteroids, led to favorable outcomes for patients with secondary HLH |
| Abbreviations: HLH=hemophagocytic lymphohistiocytosis; ICU=intensive care unit; IVIG=IV immune globulin; MAS=macrophage-activated syndrome. | ||||
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Relevant guidelines
In 2022, the Histiocyte Society published a consensus-based guideline for the recognition, diagnosis, and management of HLH in critically ill children and adults, which was endorsed by the Society of Critical Care Medicine.2 Within the guidelines, the authors provided recommended therapies and dosages based on available case reports of varying HLH severity. as summarized in the Table below.
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| Table. Recommended therapies for secondary HLH.2 | ||
|---|---|---|
| HLH type | Severitya | Therapy |
| Secondary HLH | Mild | Consider addition of corticosteroid therapy |
| Moderate | Dexamethasone 10 mg/m2 daily, divided every 12 hours, or equivalent methylprednisolone dosing (2 mg/kg/d) Consider addition of anakinra 2 to 10 mg/kg/d, divided in 2 to 4 daily doses (subcutaneous or IV) | |
| Severe, progressive, or refractory | Addition of etoposide with dose reduction as follows: 100 mg/m2 once weekly in older teens 75 mg/m2 once weekly in adults 50 mg/m2 once weekly in the elderly Renal dose reduction is recommended; dose reduction for hypoalbuminemia, hyperbilirubinemia alone, other evidence of liver dysfunction, and/or cytopenias is not recommended | |
| Macrophage-activation syndrome-HLH | Mild | Corticosteroids (such as methylprednisolone 30 mg/kg/d with maximum 1 g/d, for 3 to 5 days) with or without IVIG |
| Moderate | Consider addition of anakinra (dosing as above) and/or cautiously dosed cyclosporine (2 mg/kg/d in 2 divided doses, with a goal of serum levels 100 to 150 ng/mL) and/or consideration of tocilizumab | |
| Severe, progressive, or refractory | Consider addition of etoposide or cyclophosphamide | |
| Abbreviations: HLH=hemophagocytic lymphohistiocytosis; IV=intravenous; IVIG=IV immune globulin; pSOFA=pediatric sequential organ failure assessment; SOFA=sequential organ failure assessment. aMild defined as no evidence of organ dysfunction except coagulation/hematologic system; Moderate defined as evidence of moderate organ dysfunction (SOFA or pSOFA score 2 or less per organ system excluding coagulation/hematologic system) and possible need for supplemental oxygen; Severe defined as evidence of severe organ dysfunction (SOFA or pSOFA score 3 or more of at least 1 organ system excluding coagulation/hematologic system) and/or any need for organ replacement therapy due to organ failure, including positive-pressure ventilation, renal replacement therapy, vasopressors, and extracorporeal life support. |
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Conclusion
Numerous case series highlight the efficacy of anakinra as monotherapy, or in combination with other immunosuppressants, as initial or second-line and beyond therapy for individuals with secondary HLH. Consensus-based guidelines from the Histiocyte Society recommend anakinra 2 to 10 mg/kg/day, in 2 to 4 daily doses, administered subcutaneously or IV. In general, case reports and systematic reviews of case reports support this dosing strategy, although some report even higher doses in certain patients. To appropriately determine anakinra’s place in therapy, prospective studies are needed comparing anakinra to other recommended treatment options, yet, due to the life-threatening nature of HLH, anakinra remains a viable option in this patient population.
References
- Mehta P, Cron RQ, Hartwell J, Manson JJ, Tattersall RS. Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome. Lancet Rheumatol. 2020;2(6): e358-e367. doi: 10.1016/S2665-9913(20)30096-5
- Hines MR, von Bahr Greenwood T, Beutel G, et al. Consensus-based guidelines for the recognition, diagnosis, and management of hemophagocytic lymphohistiocytosis in critically ill children and adults. Crit Care Med. 2022;50(5):860-872. doi: 10.1097/CCM.0000000000005361
- Anakinra. Package insert. Biovitrum AB; 2020.
- Charlesworth JEG, Kavirayani A. Intravenous anakinra for the treatment of haemophagocytic lymphohistiocytosis/macrophage activation syndrome: a systematic review. Eur J Haematol. 2023;111(3):458-476. doi: 10.1111/ejh.14029
- 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):417-417. doi: 10.1093/rheumatology/keq218
- Wohlfarth P, Agis H, Gualdoni GA, et al. Interleukin 1 receptor antagonist anakinra, intravenous immunoglobulin, and corticosteroids in the management of critically ill adults with hemophagocytic lymphohistiocytosis. J Intensive Care Med. 2019;34(9):723-731. doi: 10.1177/0885066617711386
- Bami S, Vagrecha A, Soberman D, et al. The use of anakinra in the treatment of secondary hemophagocytic lymphhistiocytosis. Pediatr Blood Cancer. 2020;67(11):e28581. doi: 10.1002/pbc.28581
- Baverez C, Grall M, Gerfaud-Valentin M, et al. Anakinra for the treatment of hemophagocytic lymphohistiocytosis: 21 cases. J Clin Med. 2022;11(19):5799. doi: 10.3390/jcm11195799
Prepared by:
Rachel Brunner, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois Chicago College of Pharmacy
August 2024
The information presented is current as of July 12, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.