Etoposide‐based treatment of adult HLH is associated with high biochemical response but poor survival outcomes

Nicholson, Matthew C.; Naeije, Leonie; Hayden, Anna; Mattman, André; Dix, David; Chen, Luke Y C

doi:10.1002/jha2.57

Cited by 7 publications

(6 citation statements)

References 12 publications

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“…Moreover, the efficacy of the HLH-94 protocol in secondary HLH is unclear. In alignment with the findings described by Bubik et al and Nicholson et al initial response with the HLH-94 protocol was high (>50%); however, OS at 1 year was significantly reduced (29%-35%), in part due to disease relapse, organ dysfunction, and infection 11,12. In our cohort, CI of relapse was 50% in patients who received the HLH-94 protocol, all of whom passed with active disease shortly after.…”

supporting

confidence: 90%

Anakinra versus etoposide‐based therapy added to high‐dose steroids for the treatment of secondary hemophagocytic lymphohistiocytosis

Lee,

Cao,

Vittayawacharin

et al. 2023

European J of Haematology

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Objective Hemophagocytic lymphohistiocytosis (HLH) is a rare life‐threatening, hyperinflammatory syndrome usually treated with high‐dose steroids (HDS), often complemented with adjunct therapies, such as etoposide (HLH‐94 protocol). Anakinra has been reported to effectively treat HLH; however, has not been comparatively examined with etoposide‐based therapies. We sought to evaluate the effectiveness and durability of these treatment approaches. Methods We performed a retrospective analysis of all adult patients diagnosed with secondary HLH between January 2011 and November 2022 who received anakinra and HDS, the HLH‐94 protocol, HDS alone, or supportive care. Results Thirty adult patients with secondary HLH were included. Cumulative incidence (CI) of response at 30 days was 83.3%, 60%, and 36.4% for patients treated with anakinra, the HLH‐94 protocol, and HDS alone, respectively. CI of relapse at 1 year was 50%, 33.3%, and 0% with the HLH‐94 protocol, HDS, and anakinra and HDS, respectively. Overall survival at 1 year was higher with anakinra and HDS compared to the HLH‐94 protocol, yet was not statistically significant (77.8% vs. 33.3%; hazard ratio: 0.29; p = .25). Conclusion Treatment with anakinra and HDS in adults with secondary HLH was associated with higher response rates with longer survival compared with alternative therapies and should be further investigated in this setting.

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supporting

confidence: 90%

Anakinra versus etoposide‐based therapy added to high‐dose steroids for the treatment of secondary hemophagocytic lymphohistiocytosis

Lee,

Cao,

Vittayawacharin

et al. 2023

European J of Haematology

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“…Anti-lymphoproliferative treatments, such as etoposide and cyclosporin A, would solely be of interest in lymphoma or EBV-associated HLH, alone or associated with an etiological treatment (rituximab for EBV, specific chemotherapy for lymphoma), although results were not significant in ICU patients (33). These therapies should not be used in sepsis-related and infection-related HLH as they are associated with greater death (60,61). The most severe and hyperinflammatory cases of sepsis-associated HLH could benefit from therapies that target cytokine storms, such as anakinra (anti-IL-1), tocilizumab (anti-IL-6), and/or ruxolitinib (anti-JAK2) (16,62,63).…”

Section: Discussionmentioning

confidence: 99%

High Mortality of HLH in ICU Regardless Etiology or Treatment

et al. 2021

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Background: Adult hemophagocytic lymphohistiocytosis (HLH) is highly lethal in the ICU. The diagnostic and therapeutic emergency that HLH represents is compounded by its unknown pathophysiological mechanisms. Here, we report on a large cohort of adult HLH in the ICU (ICU-HLH). We analyzed prognostic factors associated with mortality to define the diagnostic and therapeutic challenges in this specific population.Methods: This retrospective study included adult patients diagnosed with HLH in four ICUs in Marseille, France between 2010 and 2020. Patients who fulfilled the HLH-2004 criteria (≥ 4/8) and/or had an HScore ≥ 169 were diagnosed with HLH. HLH was categorized into four groups according to etiology: sepsis-associated HLH, intracellular infection-associated HLH, malignancy-associated HLH, and idiopathic HLH.Results: Two hundred and sixty patients were included: 121 sepsis-associated HLH (47%), 84 intracellular infection-associated HLH (32%), 28 malignancy-associated HLH (11%), and 27 idiopathic HLH (10%). The ICU mortality rate reached 57% (n = 147/260) without a statistical difference between etiological groups. Independent factors associated with mortality in multivariate analysis included age (OR (5 years) = 1.31 [1.16–1.48], p < 0.0001), SOFA score at ICU admission (OR = 1.37 [1.21–1.56], p < 0.0001), degradation of the SOFA score between ICU arrival and HLH diagnosis (Delta SOFA) (OR = 1.47 [1.28–1.70], p < 0.0001), the presence of bone-marrow hemophagocytosis (OR = 5.27 [1.11–24.97], p = 0.04), highly severe anemia (OR = 1.44 [1.09–1.91], p = 0.01), and hypofibrinogenemia (OR = 1.21 [1.04–1.41], p = 0.02).Conclusions: In this large retrospective cohort study of critically ill patients, ICU-HLH in adults was associated with a 57% mortality rate, regardless of HLH etiology or specific treatment. Factors independently associated with prognosis included age, presence of hemophagocytosis in bone-marrow aspirates, organ failure at admission, and worsening organ failure during the ICU stay. Whether a rapid diagnosis and the efficacy of specific therapy improve outcome is yet to be prospectively investigated.

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“… 14 In adult patients receiving the HLH-94 protocol, 1-year OS rates are dismal ranging between 29% and 35%. 2 , 15 , 16 In addition, the high cumulative exposure to etoposide from the HLH-94 protocol has been implicated in significantly increasing the risk of secondary hematologic malignancy.…”

Section: Discussionmentioning

confidence: 99%

Improved survival outcomes with anakinra over etoposide-based therapies for the management of adults with hemophagocytic lymphohistiocytosis: a retrospective multicenter research network study

Lee

2024

Therapeutic Advances in Hematology

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Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare life-threatening, hyperinflammatory syndrome for which etoposide-based regimens have historically been the standard of care. Recent reports have described positive outcomes with the utilization of ruxolitinib or anakinra although these studies are often limited to small samples. Objectives: We aimed to compare the efficacy of ruxolitinib, anakinra, and etoposide-based therapies for the management of HLH in adult patients. Design: We performed a population-based, multicenter, retrospective cohort study utilizing the TriNetX Networks database. Methods: Adult patients (⩾18 years) diagnosed with HLH who received first-line treatment with ruxolitinib, anakinra, or etoposide between 2008 and 2023 were analyzed. The primary endpoint was overall survival (OS) at 1 year. A 1:1 propensity-score matching analysis was utilized. Results: Anakinra ( p = 0.020) but not ruxolitinib ( p = 0.19) resulted in a significantly higher 1-year OS when compared with etoposide-based therapies. Conclusions: Anakinra is effective for the management of adult patients with HLH.

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Etoposide‐based treatment of adult HLH is associated with high biochemical response but poor survival outcomes

Cited by 7 publications

References 12 publications

Anakinra versus etoposide‐based therapy added to high‐dose steroids for the treatment of secondary hemophagocytic lymphohistiocytosis

Anakinra versus etoposide‐based therapy added to high‐dose steroids for the treatment of secondary hemophagocytic lymphohistiocytosis

High Mortality of HLH in ICU Regardless Etiology or Treatment

Improved survival outcomes with anakinra over etoposide-based therapies for the management of adults with hemophagocytic lymphohistiocytosis: a retrospective multicenter research network study

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