Key points: In this review, the authors focus on adult-onset secondary hemophagocytic lymphohistiocytosis (HLH) and explore the latest updates on its pathophysiology, triggers, clinical presentation, diagnosis, and management. Please note that primary HLH is reviewed separately in a companion article in this series. ● Secondary HLH more commonly presents in adults and is a heterogeneous disorder with various potential triggers ranging from infections to malignancy, autoimmune disease, immunodeficiency, and medications. ● The pro-inflammatory “cytokine storm” created by persistent immune activation causes prolonged fevers with temperatures above 38.5°F, a near-universal clinical finding at initial presentation (over 95% of cases). ● The activated macrophages not only contribute to the inflammatory milieu, but infiltrate into reticuloendothelial organs such as the spleen, liver, and lymph nodes, manifesting as splenomegaly, hepatomegaly, and lymphadenopathy, respectively. ● Macrophages also infiltrate the bone marrow and phagocytose both mature and precursor hematopoietic cells, which in conjunction with suppression of hematopoiesis by inflammatory cytokines, contribute to eventual multilineage cytopenias and associated symptoms. ○ Of note, cytopenia takes time to develop and may not always be observed in the early stages of HLH; in fact, reactive leukocytosis may be observed early in the disease course in response to acute inflammation. ● From the laboratory perspective, a progressive rise in serum ferritin is a hallmark of HLH. The median ferritin in HLH on presentation ranges from 5000-14000ug/L. ● In patients with suspected HLH, a search for underlying diseases and environmental triggers can consolidate the clinical picture. In the United States, the most commonly associated conditions include malignancy, infections, autoimmune disorders, prior organ transplant, and congenital immunodeficiency syndromes. Of these triggers, congenital immunodeficiency syndromes have been associated with the highest in-hospital mortality rate, followed closely by malignancy and infections. Other less common causes of secondary HLH include pregnancy and certain therapeutics, such as drugs and immunotherapy. ○ In up to 36% of patients, an underlying trigger or associated condition is not identified, even after systematic and thorough evaluation. ● In cases of secondary HLH associated with malignancy, the underlying malignancy is often not immediately obvious at presentation and may only be identified after systematic evaluation, which can include peripheral blood flow cytometry, positron emission tomography–computed tomography imaging, and/or tissue biopsy. ○ An elevated soluble interleukin-2 receptor (sIL-2R)/ferritin increases suspicion for an underlying lymphoid malignancy, as the mean sIL-2R/ferritin ratio has been shown to be significantly higher in lymphoma-associated HLH compared to HLH in the absence of malignancy (8.6 versus 0.7, respectively). ● The updated HLH-2024 criteria have only been validated in children with familial HLH, where fulfillment of 5 of the 7 remaining diagnostic criteria was associated with 99% accuracy when tested against cases of infection and other causes of systemic inflammation. ○ The Hscore (diagnostic score) is not intended for use as a diagnostic criterion, and the HLH-2004/HLH-2024 (in combination with clinical gestalt) remains the diagnostic framework utilized in most studies on adult HLH. ● The general approach to treatment is two-fold – 1) management of the underlying condition suspected to trigger HLH (e.g. malignancy, infection, or autoimmune processes) and 2) administration of HLH-directed therapy targeting the underlying immune dysfunction and inflammation. ○ The HLH-94 protocol is the standard treatment for HLH initially developed by the International Histiocyte Society in the pediatric population, and consists of induction with etoposide and dexamethasone (with the option to administer up to 4 doses of intrathecal methotrexate for abnormal cerebrospinal fluid findings or neurologic symptoms). In individuals with primary HLH or refractory disease, this is typically followed by maintenance therapy with etoposide, dexamethasone and cyclosporine A, as a bridge to eventual consolidation with allogeneic hematopoietic stem cell transplant (HSCT). ○ In adult secondary HLH, there is no established standard treatment regimen. Treatment of the precipitating cause and associated cytokine storm are critical and should be prioritized. The HLH-94 protocol has been adopted for use in select cases of adult secondary HLH, with limitations. Specifically, HLH-94 is a highly toxic regimen, particularly in older adults or individuals with organ dysfunction. As such, HLH-94 is frequently deferred in favor of anti-inflammatory agents (e.g. corticosteroids, ruxolitinib) and continued management of underlying triggers, at least until lymphoid malignancy can be definitively ruled out. ○ For certain malignancies such as lymphoma, etoposide (which depletes activated T cells) can be incorporated into the standard-of-care chemotherapy regimen. For example, dose adjusted EPOCH +/- rituximab followed by autologous stem cell transplant in patients with non-Hodgkin lymphoma-associated HLH has demonstrated high efficacy and safety in a phase II trial. ○ Clinicians frequently encounter the dilemma of starting multiagent chemotherapy in the setting of significant renal and liver dysfunction, which impact drug metabolism and augment toxicities. In such cases, conventional steroids, anti-inflammatory immunosuppressive agents (e.g. ruxolitinib, anakinra, intravenous immunoglobulin), or dose-reduced etoposide may be started until anti-neoplastic chemotherapy can be safely given. ○ In contrast to primary pediatric HLH where allogeneic HSCT is typically the definitive therapy after disease control is achieved (given the underlying genetic drivers), it is performed less frequently in secondary HLH. HSCT is typically only considered for adults with relapsed/refractory secondary HLH, or in some cases as consolidation for lymphoma or leukemia-associated HLH. |
