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Review Article
A Recent Update on Histiocytic Disorder in Children: Focus on Diagnosis and Treatment
Clin Pediatr Hematol Oncol 2020;27:32-42.
Published online April 30, 2020
© 2020 Korean Society of Pediatric Hematology-Oncology

Hoi Soo Yoon

Department of Pediatrics, Kyung Hee University College of Medicine, Seoul, Korea
Correspondence to: Hoi Soo Yoon
Department of Pediatrics, Kyung Hee University College of Medicine, 23 Kyungheedae-ro, Dongdaemungu, Seoul 02447, Korea
Tel: +82-2-958-8206
Fax: +82-2-958-8304
E-mail: snoopyi@hanmail.net
ORCID ID: orcid.org/0000-0003-1688-3226
Received April 6, 2020; Revised April 13, 2020; Accepted April 21, 2020.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
The histiocytosis is rare disorder characterized by the accumulation of macrophages, dendritic cells, or monocyte-derived cells in various tissues and organs of children and adults. Classifying histiocytic disorders is difficult and has changed over time as an understanding of the biology of these cells has evolved. The most recently revised 2016 WHO classification of histiocytosis and neoplasms of the macrophage-dendritic cell lineages has proposed grouping this diverse group of over 100 clinical entities into five main groups based on clinical, histologic, and molecular relevance. Comprehensive genomic studies for histiocytosis have been described and our understanding of the pathogenesis and biology has increased over the past decade. These advances will be able to make precision medicine and targeted therapy possible in patients with histiocytosis. Among the histiocytosis, this review mainly focuses on the updated diagnosis and treatment of Langerhans cell histiocytosis (LCH) and hemophagocytic lymphohistiocytosis (HLH) in children.
Keywords: Histiocytic disorder, Langerhans cell histiocytosis, Hemophagocytic lymphohistiocytosis, Children
Introduction

Histiocytosis encompasses a group of diverse proliferative disorders characterized by the accumulation and infiltration of variable numbers of monocytes, macrophages, and dendritic cells in the affected tissues of children and adults. Their clinical behavior ranges from mild to disseminated and, sometimes, life-threatening forms [1-3]. The first classification of histiocytosis, published in 1987 by the Working Group of the Histiocyte Society (HS), consisted of 3 categories: Langerhans cell (LC) or non-LC-related, and malignant histiocytosis (MH) [1]. In 2010, a major breakthrough came with the discovery of recurrent BRAFV600E mutations in Langerhans cell histiocytosis (LCH); this finding paved the way for a revised classification of histiocytic disorders [4]. Histiocytosis is now categorized into five groups with an emphasis on targetable mutations of the mitogen-activated protein kinase (MAPK) pathway: 1) Langerhans-related (L group), 2) cutaneous and mucocutaneous (C group), 3) Rosai-Dorfman disease (R group), 4) malignant histiocytosis (M group), and 5) hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) (H group) (Table 1) [5]. Considerable advances in the understanding of their genetics have led to increased clinical recognition of these conditions and our understanding of these diseases has now evolved from the concept of a primary inflammatory condition to that of a clonal neoplastic disease [6]. This understanding has led to the development of effective mechanism-based therapeutic strategies for patients with histiocytic diseases. This article focuses on the updated diagnosis and treatment for LCH and HLH in children.

Table 1 . Revised classification of histiocytosis and neoplasms of the macrophage-dendritic cell lineage.

GroupDisease
L GroupLangerhans cell histiocytosis (LCH)
Indeterminate cell histiocytosis (ICH)
Erdheim-Chester disease (ECD)
Mixed LCH/ECD
C GroupCutaneous non-LCH
- XG family: JXG, AXG, SRH, BCH, GEH, PNH
- N-XG family: cutaneous RDD, NXG, other NOS
Cutaneous non-LCH with major systemic component
R groupFamilial Rosai-Dorfman Disease (RDD)
Sporadic RDD
- Classical RDD
- Extra-nodal RDD
- RDD with neoplasia or immune disease
- Unclassified
M groupPrimary malignant histiocytosis
Secondary malignant histiocytosis
H groupPrimary hemophagocytic lymphohistiocytosis (HLH)
Secondary HLH
HLH of unknown/uncertain origin

AXG, adult xanthogranuloma; BCH, benign cephalic histiocytosis; GEH, generalized eruptive histiocytosis; JXG, juvenile xanthogranuloma; NXG, necrobiotic xanthogranuloma; PNH, progressive nodular histiocytosis; SRH, solitary reticulohistiocytoma. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages [5]..


Langerhans Cell Histiocytosis (LCH)

For several decades, LCH has been considered to be a reactive clonal proliferation of LCs. However, an ongoing debate over the grouping of LCH was finally settled in favor of neoplasm after the discovery of the BRAFV600E mutation in 2010 [4]. Almost any organ can be affected, and the clinical presentation reflects the tissue-specific inflammatory phenomenon. A definitive diagnosis is made by the combination of clinical presentation, histology, and immunohistochemistry.

1) Pathology and biology

A diagnosis of LCH is made by typical positive staining with CD1a or CD207 [7]. With the development of new technology for accurate detection of cell-free DNA, BRAFV600E mutation analysis has shown to be an effective tool for diagnosis and monitoring of disease activity in patients with LCH [8]. The pathogenic cells are known to originate from a myeloid-derived precursor and are uniformly characterized by activation of the MAPK/ERK (extracellular-signal-regulated kinase) signaling pathway [9,10]. In up to two-thirds of cases, mutations in MAP2K1 or less frequently in other members of the pathway, such as ARAF (A-Raf proto-oncogene, serine/threonine kinase), have been described. About one-quarter of patients have no known genomic mutations.

2) Clinical presentation

The clinical manifestations of LCH depend on the organ involved and the extent of involvement. Bone is the most commonly involved organ; bony involvement is present in 80% of cases, and a painful bony lesion is the most common presentation. Skin is the second most frequently involved organ; the presentation may be a rash (generalized, papular, ulcerative, or vesicular) and/or seborrheic involvement of the scalp. Features of weight loss, diarrhea, edema, dyspnea, jaundice (conjugated hyperbilirubinemia), cytopenias, hepatosplenomegaly, lymphadenopathy, polydipsia, and polyuria indicate specific organ involvement. LCH of the central nervous system (CNS) can present as a neurodegenerative disease (ND-LCH) and/or intracranial tumorous lesions. Patients with ND-LCH may develop clinical symptoms of dysarthria, ataxia, dysmetria, and behavior changes. Due to its heterogenous presentation, from self-limited to disseminated disease, LCH has been clinically classified according to the number of lesions and sites of involvement coupled with the number of risk organs affected [10]. At present, patients of LCH are risk-stratified according to the extent of disease [single system versus (vs.) multisystem] and risk organ (RO) involvement (presence or absence of involvement of the liver, spleen, or bone marrow), in which “risk” refers to higher risk of mortality [11].

3) Treatment

(1) Single-system LCH

① Skin-limited LCH: In most cases, isolated LCH skin lesion regress spontaneously and warrant only observation. Infants, however, require close observation because a large proportion of them are likely to progress to high-risk, disseminated disease [12]. Patients who have symptomatic/refractory skin lesion have been treated with topical steroids, tacrolimus, nitrogen mustard, thalidominde, psoralen and ultraviolet A (PUVA) therapy, surgical excision, oral corticosteroids, or minimal systemic chemotherapy [11,12].

② Single bone lesion: Single bone LCH usually resolves with curettage and/or intralesional corticosteroid injections [13]. Patients with single bone lesion have only a 10% chance of reactivation [14]. Radiation therapy may be effective in older children with single vertebral lesions that have not caused complete collapse of the vertebra or with a lesion in the greater trochanter of the femur at risk for pathologic fracture [15]. A few case reports showed that indomethacin was a useful therapy for LCH involving the bony skeleton and may have a role as first-line treatment in single system bone disease [16,17].

(2) Multisystem LCH

① Multiple bone lesions or bone and other low-risk site: The standard recommended therapy for low-risk multisystem LCH, which is based on the LCH-III trial findings, is 12 months of therapy with vinblastine/prednisone; this has reduced the reactivation rate from the historical 50% to 30% [18]. The LCH-IV trial is currently ongoing with regards to whether further prolongation of this mild treatment may further reduce reactivation. In stratum II, the response to a uniform initial second line therapy (prednisolone, cytarabine, and vincristine) for those patients without risk organ involvement is studied following a randomized comparison of maintenance therapy with either indomethacin or mercaptopurine and methotrexate for studying the inhibitory effect of indomethacin on reactivation. Some reports described that bisphosphonates can significantly improve bone pain and induce remission in active bone LCH and may be an effective treatment for reactivated LCH with bone lesions [19-21].

(3) High-risk LCH

The current standard therapy for high-risk LCH consists of treatment with vinblastine, prednisone, and mercaptopurine for 1 year based on the LCH-III trial [18]. Prolongation of the treatment duration from 6 months in LCH-II to 12 months in LCH-III was beneficial. But, adding etoposide (LCH-II) and methotrexate (LCH-III) did not improve the response or relapse-free survival of high-risk patients [22,23].

(4) CNS lesion

Diabetes insipidus (DI) is the most frequent initial sign of LCH in the CNS [24]. Due to risks of pituitary biopsy, it is reasonable to initiate LCH therapy empirically in such patients and monitor for early response by brain magnetic resonance imaging (MRI). Mass lesions of the brain may respond to vinblastine/prednisone, cladribine, cytarabine, and clofarabine [25,26].

① CNS-risk lesions: The current standard of care for patients with so-called CNS-risk lesions such as the mastoid, sphenoid, orbit, clivus, or temporal bone is 12 months of therapy with vinblastine and corticosteroids [18]. These patients have increased risk of developing DI and/or ND-LCH. The LCH-III study, in which a year of vinblastine/prednisone was used, showed a further reduction of DI incidence to 12%, when compared with surgery alone [26].

② ND-LCH: ND-LCH is a syndrome of progressive, devastating neurodegeneration of unknown etiology.

A brain MRI demonstrates hyperintensity of the dentate nucleus and white matter of the cerebellum on FLAIR and T2-weighted images, or hyperintense lesions of the basal ganglia on T1-weighted images [27]. Intravenous g-globulin (IVIG) and retinoic acid have been reported to stabilize progression of ND-LCH [28,29]. Some studies reported that vincristine/cytarabine was associated with improvement in clinical symptoms and MRI images [30]. In LCH-IV study, additionally the effectiveness of 2-CdA in tumorous CNS-LCH and of IVIG and intravenous cytarabine (Ara-C) in ND-LCH will be prospectively studied.

③ Salvage therapy: In LCH-III study, the probability of a reactivation was 54% in patients without RO involvement who treated with 6 months, but, 37% in those who treated with 12 months [18,23]. Many studies reported that reactivation of patients with LCH tends to occur in the first 2 years [18,31]. Salvage therapy for LCH usually includes agents active against the myeloid cells, such as cytarabine, cladribine, and clofarabine [32-34]. Hematopoietic stem cell transplantation (HSCT) can be another option. However, most data for salvage therapy has small case series or retrospective studies [35,36] (Table 2).

Table 2 . Salvage therapy for relapsed/refractory Langerhans cell histiocytosis.

RegimenStudy (n)ResponseSRRemark
2-CdA (5 mg/m2×5 d) [33]ProspectiveRO+ 22% (RR)2-yr OS2-CdA for RO-multisystem, multifocal bone is effective, RR good Age >2 yr at 2-CdA
LCH-S-2005RO− 62% (RR)RO+ 48%
RO+ (n=46)RO− 97%
RO− (n=37)
2-CdA/Ara-C (9 mg/m2, 1g/m2/d×5 d) [34]ProspectiveRR 92%5yr-OS 85%2-CdA/Ara-C is effective for RO+ multisystem LCH
LCH-S-2005No active: n=2, Better: 23,High toxicity (grade 4 hematologic toxicity, severe infection)
(n=27, RO+)Stable: 2
Clofarabine (25 mg/m2/d×5 d) [35]RetrospectiveCR (61%)1-yr PFS 76%All patients developed grade 4 neutropenia
LCH (n=11),PR (22%)1-yr OS 91%
RO+ (n=3)
RO− (n=8)
HSCT
MAC vs. RIC (CIBMTR & EBMT) [36]Retrospective (after 2000)Relapse rate3-yr OSOS, PFS of MAC and RIC similar.
MAC (n=41) vs. RIC (n=26)MAC (8%) vs. RIC (28%)MAC 77%Relapse rate after RIC marginally higher MAC
RIC 71%
MAC vs. RIC (Japan) [37]RetrospectiveOS
MAC (n=11) vs. RIC (n=19)MAC 63.6%
RIC 56.8%
FFS
MAC 54.6%
RIC 56.8%

CIBMTR, center for international blood and marrow transplant research; CR, complete response; EBMT, european blood and marrow transplant; MAC, myeloablative conditioning; OS, overall survival; PFS, progression free survival; PR, partial response; RIC, reduced intensity conditioning; RR, response rate; RO, risk organ..


(5) Targeted therapy

With the identification of BRAFV600E and other mutations in the MAPK pathway in LCH, early phase trials were begun to find the role of targeted therapy in the clinical field.

BRAF Inhibition: A phase 2 trial in BRAF-mutant ECD/LCH showed disease regression in 86% patients, with no one progressing during Vemurafenib (VMF) therapy [37]. In an international observation study, VMF seemed safe and effective in children with refractory BRAFV600E positive LCH. However, the majority of patients who discontinued VMF experienced LCH reactivation [38]. Moreover, despite the small size of the study, a very high risk of secondary skin tumors (approximately 30%) has been observed in adults with melanoma [39]. A trial of dabrafenib in a pediatric LCH is ongoing, with early patients showing an encouraging response (NCT01677741).

MEK inhibition: The efficacy of MEK inhibitors trametinib and cobimetinib was first reported in non-LCH histiocytosis [40]. An ongoing trial of cobimetinib in adult patients with histiocytic disorders has shown response [41]. In BRAFV600E-mutant melanoma, dual blockade of the MAPK pathway using a BRAF plus MEK inhibitor results in higher efficacy and less toxicity compared with monotherapy with a BRAF inhibitor [42,43]. The efficacy of combined BRAF-MEK inhibition has not been fully explored in BRAF-mutant histiocytosis.

4) Future directions

The ongoing LCH-IV trial has broad goals that aim to determine optimal therapy for all patients, as stratified: high-risk multisystem, low-risk multisystem, low-risk single system, and LCH with special site involvement, particularly focusing on the difficult problem of diffuse CNS disease. The randomized studies in the LCH-IV protocol strive to optimize the outcomes of first line treatments by testing prolonging (12 vs. 24 months) and intensifying (6-mercaptopurine) treatment of high risk patients, and by comparing treatment duration (6 vs. 12-months) for single system disease. The protocol is also testing a randomized study of new combinations as second-line treatment for those individuals with low-risk disease either reactivating or not initially responding. Targeted therapy must be considered not as a replacement but as additional tool that should be used judiciously. The choice of the optimal timing of targeted therapy (as salvage, up-front, or maintenance) and whether it should be treated alone or combination with chemotherapy needs to be studied.

Hemophagocytic Lymphohistiocytosis (HLH)

HLH is a syndrome describing patients with severe systemic hyperinflammation that it is characterized by unremitting fever, cytopenias, hepatosplenomegaly, coagulopathy, and elevations in typical biomarkers including ferritin and soluble interleukin-2 receptor (sIL-2R). The high mortality rate makes prompt recognition and treatment of this hyperinflammatory syndrome essential [44]. HLH is classified into primary and secondary forms. Primary HLH is a hereditary immune disorder, whereas secondary HLH develops as a complication in various conditions such as infection, malignancy, autoimmune disease, and post-HSCT [45,46].

1) Pathogenesis

Patients with active HLH have markedly elevated serum inflammatory cytokines, namely, interferon (IFN)‐g, tumor necrosis factor (TNF)‐α, IL‐1β, IL‐2, IL‐6, IL‐12, IL‐16, and IL‐18 [43]. This cytokine storm arises from the excessive secretion of cytokines by uncontrolled activated cytotoxic T lymphocyte (CTL) and natural killer (NK) cells that in turn hyperactivate macrophages. Of the various cytokines that are elevated in HLH, IFN‐g plays a particularly key role in the development of HLH [47,48].

2) Diagnosis

The HS established a set of clinical and laboratory criteria to help the diagnosis of the syndrome of HLH for its HLH-94 and 2004 clinical trials and this has been modified partly in 2009 [40-42]. However, the diversity of the clinical presentation of HLH has led to confusion. Patients presenting in early disease may not yet show 5 of 8 criteria, and some patients may never meet this criteria, including those with atypical presentations such as isolated CNS disease or acute liver failure [49-52]. Fever above 38.3°C is nearly universal in untreated HLH. While splenomegaly and hepatomegaly are very common in HLH, adenopathy is not [45]. Cytopenias are ubiquitous in HLH. Lack of cytopenias should make one doubt a diagnosis of HLH, except in the special case of isolated, CNS-only disease [53]. Some laboratory tests are used to help in the diagnosis of HLH and are also useful biomarkers for disease activity monitoring. Most patients have much higher levels of ferritin than the threshold suggests (>500 μg/L); however, serum ferritin is also driven by iron overload states and can be elevated in many inflammatory contexts. A serum ferritin level greater than 500 μg/L is over 90% sensitive, but its specificity is only robust at levels greater than 2,000-10,000 μg/L, and in adults, levels greater than 10,000 μg/L are still most commonly associated with malignancy [54,55]. Recently, higher levels of ferritin (e.g.,>3,000 μg/L) have been suggested [56]. One study compared 123 patients with HLH to 320 patients with other hyperferritinemic conditions. At 2,000 μg/L, a trade-off was reached with sensitivity at 70% and specificity at 68% for HLH in that study [57]. Elevated sIL-2R should always be observed in untreated HLH since T-cell activation in central to HLH pathogenesis [58,59]. However, an extremely elevated sIL-2R (>10 to 20-fold above normal) in noninfantile patients suggests undiagnosed lymphoma, especially when ferritin is not similarly elevated [60,61]. Very low or absent NK cell function can indicate a genetic HLH disease, but, other acute illness and various treatments can also temporarily impair NK numbers and function, and a low result has been found to have poor specificity (43%) [62, 63]. A recent study reported that perforin and CD107a tests are more sensitive and no less specific compared with NK cytotoxicity testing for screening for genetic HLH and suggested they be considered for addition to current HLH criteria [62]. New laboratory options such as IL-18 levels, which reflect inflammasome activation, or CXCL9, which indicates pathway activity, and IFN‐g are being more frequently used. A total IL-18 level greater than 24,000 pg/mL distinguished MAS from primary HLH with 83% sensitivity and 94% specificity, and the ratio of IL-18 to CXCL9 has been used to differentiate patients with rheumatologic disease and MAS from patients with HLH. IL-18 binding protein (IL-18BP) was found to be more elevated in FHL and malignancy-associated HLH [64]. Work-up of some other cytokines such as IL-10 and IFN‐g can be helpful in the differential diagnosis of HLH from sepsis [65,66]. The sensitivity and specificity of these biomarkers in the diagnostic criteria should be elucidated and updated through evidence-based international consensus and further study. Fig. 1 displays an updated diagnostic algorithm for consideration of HLH in suspected patients.

Figure 1. Algorithm for diagnostic work-up of HLH.

3) Treatment

Immediate treatment of HLH is generally warranted once a diagnosis is made, while it is important to rule out HLH disease mimics or malignancies before starting therapy in order to avoid inappropriate treatment and/or obscuring the underlying diagnosis [45]. The mainstays of HLH treatment consist of immunosuppressive, chemotherapeutic agents and biologics that aim to control the cytokine storm and eliminate activated T-cells and macrophages [45].

(1) Chemoimmunotherapy

Currently, standard therapy for HLH consists of dexamethasone and etoposide based on the experience of the HS HLH-94 and HLH-2004 studies [67,68]. The 5-year overall survival (OS) rate in children with (n=168) and without (n=201) family history/genetically verified primary HLH was 59% and 64%, respectively [68]. The HS recently published formal recommendations for the use of etoposide-based treatment, and CSA upfront therapy in HLH-2004 is no longer recommended due to toxicity, and the HLH-94 is the standard of care [69]. Though aggressive treatment is needed for most patients, initial therapy with dexamethasone alone with close monitoring may be appropriate before starting etoposide in patients who are not infants and not severely ill [53]. Patients with CNS involvement receive additional intrathecal treatment with methotrexate and steroid, and need treatment of seizures or therapies for specific neurologic deficits [68]. Treatment of HLH should be accompanied by appropriate therapy of the identified underlying trigger. Rituximab containing chemoimmunotherapy can be helpful in the treatment of EBV-HLH [70-72]. IVIG, therapeutic plasma exchange, and/or corticosteroids may be used to temper cytokine storm while the work-up continues. Anakinra (recombinant IL-1 receptor antagonist) can be used for secondary HLH, especially when given early in the disease course [73]. Anakinra is currently being studied in a randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT02780583) to test its safety and efficacy in the treatment of secondary HLH/MAS in children and adults. Patients with multi-organ failure may require organ-specific therapy.

(2) Treatment of CNS-HLH

The clinical presentation of CNS disease in HLH is highly variable. Furthermore, occurrence of neurological symptoms is not included as a diagnostic criteria of HLH. However, it is important to suspect HLH in a child with unexplained neurologic manifestations, especially patients with fever, cytopenia, and hepatosplenomegaly. To make a diagnosis of CNS-HLH, a lumbar puncture with cerebrospinal fluid (CSF) analysis and MRI should always be done in all cases regardless of the presence or absence of neurological signs or symptom [74]. Treatment options for CNS-HLH include, those commonly used in systemic HLH, including corticosteroids, etoposide, cyclosporine A, anti-thymocyte globulin (ATG), and alemtuzumab. In addition, intrathecal treatment with methotrexate and corticosteroids has become a standard care and is likely to be beneficial [75]. Therapy must be started without delay to prevent late effects in HLH. An ongoing trial (NCT01818492) is an anti-IFN-g antibody (NI-0501), which is currently being tested. Another very promising agent is the Janus kinase (JAK)1/2 inhibitor ruxolitinib shown in a recent study of two murine models of HLH to be effective. In the Rab27a-/-mice, CNS involvement was significantly reduced with ruxolitinib therapy [76]. HSCT also represents an important CNS-HLH treatment [77].

(3) HSCT

HSCT is mandatory in patients with primary HLH, recurrent or progressive HLH despite recommended chemoimmunotherapy, and CNS involvement [56,67,78-80]. The pediatric HLH-94 trial reported a 5-year OS of 66% of those who underwent HCT [81]. Other studies reported similar outcomes with 5-year OS ranging from 49% to 64% with myeloablative conditioning (MAC) approaches, with the vast majority of mortality occurring in the first 6 months after HCT [82,83]. Several studies also note feasibility of umbilical cord transplant for HLH, with retrospective series reporting 65% to 71% long-term OS [84, 85]. The Cincinnati Children’s group showed potential superiority of reduced intensity conditioning (RIC) for HLH in a retrospective review which identified 43% estimated 3-year survival for patients transplanted with MAC (n=14) compared with 92% for patients transplanted with RIC (n=26) in 2010 [86]. RIC regimens are generally recommended as they are associated with better survival, though they can be complicated by high rates of mixed chimerism and graft failure since then [87,88]. Future study with the RIC approach is expected to improve the level and stability of donor engraftment. To avoid delays in proceeding to HSCT, human leukocyte antigen (HLA) typing and initiation of the stem cell donor search should be done as soon as it is suspected that a patient has a genetic form of HLH.

(4) Salvage therapy

It is clear that approximately 25-50% of patients will fail to achieve a complete response to standard therapy and may require additional treatment with the same drugs or alternative “salvage” agents. Relapses may respond to intensification of standard therapy, or may require additional or alternative therapies [89].

① Alemtuzumab: Alemtuzumab is a therapeutic monoclonal antibody directed against the CD52 antigen, a small GPI-anchored protein which is expressed on lymphocytes including T cells, NK cells, and B cells. A larger case series (n=22) of pediatric and young adult patients, who received alemtuzumab for salvage therapy of primary HLH, has been reported [90]. A partial response was achieved in 14 of 22 patients (64%) [90]. The remaining patients failed to respond or had improvement in only one sign or symptom of HLH [90]. Seventy-seven percent of patients survived to undergo allo-HSCT. Patients experienced an acceptable spectrum of complications, including CMV and adenovirus viremia [90]. However, the observation time to determine a response was limited to 2 weeks in this case series given that most patients moved quickly to allo-HSCT [90].

② Ruxolitinib: JAK 1/2 inhibitor, has shown promise in mouse models of primary and secondary HLH [91]. In murine models, ruxolitinib has been shown to both prevent and treat HLH by decreasing cytokine production and inflammation via inhibition of signal transducer and activator of transcription 1 (STAT1) signaling [92]. Two case reports described the use of ruxolitinib for patients with refractory HLH [93,94]. They reported that patients with refractory HLH became afebrile, followed by rapid improvements in respiratory, liver, and hemodynamic function within 24 hours of ruxolitinib treatment [93,94]. The most recent study for ruxolitinib showed that the overall response rate (RR) of the 34 patients was 73.5% (25/34 patients), with 14.7% (5/34 patients) in complete response (CR) and 58.8% (20/34 patients) in PR [95]. All patients experienced an acceptable spectrum of complications [95]. However, the remission depth is not sufficient, thus the authors hoped to combine ruxolitinib with the previous DEP (doxorubicin-etoposide-methylprednisolone) regimen to treat HLH [95].

③ Emapalumab: Emapalumab is a fully human immunoglobulin G1 monoclonal antibody that noncompetitively inhibits IFN‐g [92]. Administration of antibodies to deplete CD8+ T cells, as well as neutralization of IFN‐g, rescued the HLH-like pathology and improved survival in mice [92]. The safety and efficacy of emapalumab was assessed in a phase 2/3 trial (NCT01818492) in pediatric patients with presumed primary HLH [96-99]. The trial included 34 patients with presumed primary HLH and active disease who were treatment or were intolerant to standard treatments [99]. The median age of the study population was 1 year of age. Genetic mutations were present in 79% of patients. The overall RR was 63% (95% confidence interval, 42% to 81%; P=0.0134) and 12-month survival was 73%. Serious adverse reactions occurred in 53% of emapalumab recipients and included infections, gastrointestinal hemorrhage, and multiple organ dysfunction. Emapalumab is now approved for use in patients with adult or pediatric primary HLH that is refractory, recurrent, or progressive or in those who have intolerance to conventional therapy.

4) Future directions

HLH in children remains a challenge, but significant advances have been made in the last 20 years. Advances in rapid screening diagnostics makes it possible to quickly evaluate patients for many inherited diseases, and newer biomarkers are helping to elucidate the physiologic processes in patients with HLH. Novel targeted treatment agents are being developed. Well-designed clinical trials through international cooperation between investigators will bring further improved outcomes for patients with HLH.

Conflict of Interest Statement

The author has no conflict of interest to declare.

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  • Hoi Soo Yoon