Clinical Management of Relapsed/Refractory Hemophagocytic Lymphohistiocytosis in Adult Patients: A Review of Current Strategies and Emerging Therapies

Abstract

Introduction Haemophagocytic lymphohistiocytosis (HLH) is a severe disorder with high mortality. The aim of this review is to update clinical management of relapsed/refractory HLH in adults, with a focus on current and new therapies. Methods We searched relevant articles in Embase and PUBMED with the MESH term “hemophagocytic lymphohistiocytosis; refractory; relapsing; adult.” Results One hundred eight papers were found; of these, 22 were retained for this review. The treatment of HLH in adult is based on the HLH-94 regimen. The response rate is lower than in pediatric patients, and 20–30% are refractory to this therapy. DEP regimen and allogenic hematopoietic stem cell transplantation (HSCT) are associated with complete response and partial response in 27% and 49.2%, respectively. However, many patients fail to achieve a stable condition before HSCT, and mortality is higher in them. New drugs have been developed, such as emapalumab, ruxolitinib, and alemtuzumab, and they may be used as bridges to the curative HSCT. They are relatively well tolerated and have few or mild side effects. With these agents, the rate of partial response ranges from 14.2% to 100%, while the rate of complete response is highly variable according to study and medication used. The number of patients who achieved HSCT ranged from 44.8% to 77%, with a survival rate of 55.9% to 100%. However, the populations in these studies are mainly composed of mixed-age patients (pediatric and adult patients), and studies including only adult patients are scarce. Conclusion Relapsed or refractory HLH in adult patients is associated with poor outcome, and consolidation with HSCT may be required in some cases. Mortality related to HSCT is mainly due to active HLH disease before HSCT and post HSCT complications. New drugs, such as empalumab, ruxolitinib, and alemtuzumab are interesting since these agents may be used as bridges to HSCT with increases in the numbers of patients proceeding to HSCT and survival rate.

Short-term, Low-Dose Etoposide in Refractory Adult-Onset Still’s Disease-Associated Macrophage Activation Syndrome, a Case Series Study

“…When AOSD patients enter into the stage of MAS, and have a lack of or inadequate response to the initial glucocorticoid treatment, should we increase the dosage of steroid to high-dose pulse methylprednisolone (for example: 500mg/d-1 g/d for 3-5 consecutive days), or should we start HLH-04 protocol since all these patients met the criteria of HLH? [6,11,19] In the current study, we found that adopting a revised HLH-04 protocol in these AOSD associated MAS patients was very effective and safe. Compared to historic controls, patients in short-term (2 weeks), low dose etoposide group had signi cantly higher survival rate and quicker improvement in terms of clinical manifestations and laboratory results, as well as signi cantly less exposure to glucocorticoid.…”

“…Recent years have seen several case series and clinical trials supporting the use of the IL-1 antagonist anakinra in the treatment of MAS complicated with sJIA or AOSD [5] . IL-18 antagonists, IFN-γ inhibition, and the JAK inhibitor ruxolitinib are also promising treatment options [6] ; Anti-IL-6 treatment of MAS is controversial [7] . While these novel biologics might be effective against MAS, many of them have not been approved [8] .…”

Use of glucocorticoids and azithromycin in the therapy of COVID-19

“…The infection promoted by the virus induces an excessive immune reaction in the host, which in turn generates a "cytokine storm," composed of pro-inflammatory cytokines that act on cardiovascular cells, as well as in secondary hemophagocytic lymphohistiocytosis [20]. Patients with severe COVID-19 infection tend to have much higher plasma levels of the cytokines IL-6, IL-8, IL-10, and TNF-α than patients without severity.…”

Clinical Characteristics of Adult Hemophagocytic Lymphohistiocytosis in the Emergency Department

“… 10 Most cases of HLH in adults for which a clear trigger can be identified are associated with a secondary cause, 11 and familial HLH may be also triggered by infection or autoimmune disease. 12 …”

“…10 Most cases of HLH in adults for which a clear trigger can be identified are associated with a secondary cause, 11 and familial HLH may be also triggered by infection or autoimmune disease. 12 HLH can involve multiple tissues and organs and has various symptoms, so obtaining a rapid and accurate diagnosis at the early stage is difficult because HLH patients mostly have high fever, fatigue caused by anemia, bleeding tendency (eg, gastrointestinal) and skin ecchymosis. Initially, HLH patients may visit the emergency department (emergency department) for medical help and then be transferred to a specialist ward.…”