A Review of Current and Emerging Therapeutic Options for Hemophagocytic Lymphohistiocytosis

Abstract

Objective: To provide an overview of clinical sequelae and emerging treatment options for hemophagocytic lymphohistiocytosis (HLH). Data Sources: A literature search was conducted using the search terms “hemophagocytic lymphohistiocytosis,” “hemophagocytic syndrome,” “macrophage activation syndrome,” and “treatment” on Ovid and PubMed from January 1, 2017, through September 28, 2022. Study Selection and Data Extraction: Relevant clinical trials, meta-analyses, case reports, review articles, package inserts, and guidelines to identify current and emerging therapeutic options for the management of HLH. Data Synthesis: Genetic disorders and secondary causes may trigger HLH in both children and adults. Notable improvements in the diagnosis of HLH were seen with implementation of the HLH-2004 standard diagnostic criteria; however, timely and accurate identification of HLH remain significant barriers to optimal management. Multiagent immunochemotherapy are the backbone of aggressive therapy for acutely ill patients with HLH. Relevance to Patient Care and Clinical Practice: The global coronavirus 2019 (COVID-19) pandemic and emerging immune effector cell therapies have served to highlight the concerns with immune dysregulation and subsequent HLH precipitation. Without prompt identification and treatment, HLH can be fatal. Historically, the clinician’s armamentarium for managing HLH was sparse, with etoposide-based protocols serving as the standard of care. Relapsed or refractory disease portends a poor prognosis and requires additional treatment options. Second- or subsequent-line options now include hematopoietic stem cell transplantation, emapalumab, alemtuzumab, anakinra, ruxolitinib, and tocilizumab. Conclusions: Improvements in diagnostic methods and novel immunosuppressive treatment strategies, including noncytotoxic immunochemotherapy, have transformed the therapeutic landscape. Unfortunately, many unanswered questions remain. Additional studies are required to optimize dosing, schedules, treatment sequences, and indications for novel treatment options.

Case report: Ruxolitinib plus dexamethasone as first-line therapy in haemophagocytic lymphohistiocytosis

“…Sixteen of these studies used RUX in sHLH as a first-line or salvage setting, with a dozen case reports each consisting of a single patient. However, reports using RUX as a first-line therapy among patients with active malignancy or primary HLH are scarce ( 7 ). Herein, we report 2 cases of HLH (1 case of sHLH associated with natural killer (NK)/T-cell lymphoma, and 1 case of primary HLH with missense variants in the perforin gene ( PRF1 ), highlighting the contribution of RUX plus dexamethasone (DXM) in controlling hyperinflammation in sHLH or primary HLH.…”

Inundate and Deluge-Hemophagocytic Lymphohistiocytosis

“…Keywords: Kangaroo Mother Care; Neonates; Growth; Outcome; Cameroon Histiocytes configuring familial hemophagocytic lymphohistiocytosis demonstrate a characteristic phenotype with immune reactive CD11b, CD21, CD25, CD30, CD35, CD36 and S100 protein. In contrast, histiocytes may delineate absent or diminished intracellular staining for perforin, a feature which appears indicative of genetic mutations within protein encoding gene [5,6]. Upon flow cytometry, decimated expression of CD107a (LAMP1), confined to surface of cytotoxic NK / T-cells is observed.…”

“…Additionally, few instances may depict decimated enunciation of CD5 and CD7, especially within circulating and bone marrow CD8+ T-cells. Hemophagocytic lymphohistiocytosis requires segregation from conditions such as sepsis, Myeloproliferative Neoplasm (MPN), myelodysplastic syndrome (MDS), Rosai-Dorfman disease, Langerhans cell histiocytosis, Leishmaniasis or histoplasmosis [5,6]. Biochemical evaluation exemplifies specific alterations as hypofibrinogenemia, hypertriglyceridemia, significantly elevated serum ferritin, elevated hepatic transaminases, elevated Lactate Dehydrogenase (LDH), elevated serum soluble CD25 or Interleukin 2 (IL2) receptor.…”

“…Biochemical evaluation exemplifies specific alterations as hypofibrinogenemia, hypertriglyceridemia, significantly elevated serum ferritin, elevated hepatic transaminases, elevated Lactate Dehydrogenase (LDH), elevated serum soluble CD25 or Interleukin 2 (IL2) receptor. Chromium 51 (51Cr) release assay depicts decimated or absent NK cell activity [5,6]. Upon plain radiography, features such as hepatosplenomegaly, generalized lymph node enlargement, pleural effusion accompanied by alveolar interstitial opacities, thickened gallbladder wall, hyperechoic renal parenchyma, ascites, nonspecific periventricular white matter abnormalities, decimated brain volume and enlargement of extra-axial fluid spaces may be discerned [5,6].…”

“…Chromium 51 (51Cr) release assay depicts decimated or absent NK cell activity [5,6]. Upon plain radiography, features such as hepatosplenomegaly, generalized lymph node enlargement, pleural effusion accompanied by alveolar interstitial opacities, thickened gallbladder wall, hyperechoic renal parenchyma, ascites, nonspecific periventricular white matter abnormalities, decimated brain volume and enlargement of extra-axial fluid spaces may be discerned [5,6]. Secondary hemophagocytic lymphohistiocytosis mandates prompt therapeutic intervention of concurrent disease.…”