Histiocyte Society Research Articles

International expert consensus recommendations for the diagnosis and treatment of Langerhans cell histiocytosis in adults

AbstractLangerhans cell histiocytosis (LCH) can affect children and adults with a wide variety of clinical manifestations, including unifocal, single-system multifocal, single-system pulmonary (smoking-associated), or multisystem disease. The existing paradigms in the management of LCH in adults are mostly derived from the pediatric literature. Over the last decade, the discovery of clonality and MAPK-ERK pathway mutations in most cases led to the recognition of LCH as a hematopoietic neoplasm, opening the doors for treatment with targeted therapies. These advances have necessitated an update of the existing recommendations for the diagnosis and treatment of LCH in adults. This document presents consensus recommendations that resulted from the discussions at the annual Histiocyte Society meeting in 2019, encompassing clinical features, classification, diagnostic criteria, treatment algorithm, and response assessment for adults with LCH. The recommendations favor the use of 18F-Fluorodeoxyglucose positron emission tomography-based imaging for staging and response assessment in the majority of cases. Most adults with unifocal disease may be cured by local therapies, while the first-line treatment for single-system pulmonary LCH remains smoking cessation. Among patients not amenable or unresponsive to these treatments and/or have multifocal and multisystem disease, systemic treatments are recommended. Preferred systemic treatments in adults with LCH include cladribine or cytarabine, with the emerging role of targeted (BRAF and MEK inhibitor) therapies. Despite documented responses to treatments, many patients struggle with a high symptom burden from pain, fatigue, and mood disorders that should be acknowledged and managed appropriately.

Laboratory Examination in Hemophagocytic Lymphohistiocytosis

Hemophagocytic Lymphohistiocytosis (HLH) is derived from the word hemophagocytosis, in which macrophagesinfiltrate tissue extensively, and unspecifically phagocyte blood and bone marrow cells. The deviant activation of cytotoxicCD8+ T-cells causing the release of inflammatory cytokines is the core pathogenesis of HLH. Hemophagocyticlymphohistiocytosis is a regulatory disorder of the immune system, with clinical signs and symptoms of extremeinflammation and cytopenia, hepatitis, and severe and life-threatening central nervous system dysfunction. The name of theHLH disorder was recently proposed to be "Hyperinflammatory Lymphohistiocytosis" (also known as HLH). Enforcement ofHLH diagnosis by the Histiocyte Society based on HLH 2004 updated diagnostic criteria consists of five of the following eightdiagnostic criteria: fever, splenomegaly, cytopenia (two or more of three lineages in peripheral blood), hypertriglyceridemiaor hypofibrinogenemia, hyperferritinemia, hemophagocytes in the bone marrow/lien/lymph, the low or non-existentactivity of Natural Killer (NK) cells, increased sCD25. H-score, MH-score, and systemic Juvenile Idiopathic Arthritis(sJIA)/Macrophage Activated Syndrome (MAS) classification criteria are also used to enforce HLH diagnoses.Hemophagocytic lymphohistiocytosis is challenging to recognize and has a high mortality rate, especially in adults, rangingfrom 42 to 88%. Therefore, immediate diagnosis and therapy are essential. The introduction of HLH triggers is criticalbecause treatment is based on the underlying trigger. Cytokine storms due to Coronavirus Disease 19 (COVID-19) infectionhave significant similarities to the clinical and laboratory findings of HLH. Secondary HLH (sHLH) is suspected in severeCOVID-19 patients, so early diagnosis is potentially made based on the H-score.

A Late-Preterm Infant with Ichthyosis, Pancytopenia, and Recurrent Sepsis.

A Late-Preterm Infant with Ichthyosis, Pancytopenia, and Recurrent Sepsis.

Abstracts from the 37th Annual Meeting of the Histiocyte Society Held Virtually on October 11-12, 2021.

Abstracts from the 37th Annual Meeting of the Histiocyte Society Held Virtually on October 11-12, 2021.

Consensus-Based Guidelines for the Recognition, Diagnosis, and Management of Hemophagocytic Lymphohistiocytosis in Critically Ill Children and Adults.

Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome that often requires critical care support and remains difficult to diagnose. These guidelines are meant to aid in the early recognition, diagnosis, supportive care, and treatment of patients with hemophagocytic lymphohistiocytosis in ICUs. The literature searches were performed with PubMed (MEDLINE). Keywords and medical subject headings terms for literature search included "macrophage activation syndrome," hemophagocytic lymphohistiocytosis," and "hemophagocytic syndrome." The Histiocyte Society developed these consensus recommendations on the basis of published reports and expert opinions with level of evidence provided for each recommendation. They were endorsed by the Society of Critical Care Medicine. Testing for hemophagocytic lymphohistiocytosis should be initiated promptly in all patients admitted to ICUs with an unexplained or disproportionate inflammatory response, especially those with rapid clinical deterioration. Meeting five or more of eight hemophagocytic lymphohistiocytosis 2004 diagnostic criteria serves as a valuable diagnostic tool for hemophagocytic lymphohistiocytosis. Early aggressive critical care interventions are often required to manage the multisystem organ failure associated with hemophagocytic lymphohistiocytosis. Thorough investigation of the underlying triggers of hemophagocytic lymphohistiocytosis, including infections, malignancies, and autoimmune/autoinflammatory diseases, is essential. Early steroid treatment is indicated for patients with familial hemophagocytic lymphohistiocytosis and is often valuable in patients with acquired hemophagocytic lymphohistiocytosis (i.e., secondary hemophagocytic lymphohistiocytosis) without previous therapy, including macrophage activation syndrome (hemophagocytic lymphohistiocytosis secondary to autoimmune/autoinflammatory disease) without persistent or relapsing disease. Steroid treatment should not be delayed, particularly if organ dysfunction is present. In patients with macrophage activation syndrome, whose disease does not sufficiently respond, interleukin-1 inhibition and/or cyclosporine A is recommended. In familial hemophagocytic lymphohistiocytosis and severe, persistent, or relapsing secondary macrophage activation syndrome, the addition of prompt individualized, age-adjusted etoposide treatment is recommended. Further studies are needed to determine optimal treatment for patients with hemophagocytic lymphohistiocytosis in ICUs, including the use of novel and adjunct therapies.

Multisystem Langerhans Cell Histiocytosis in high-risk group: A case series of two infants

Background:  Langerhans Cell Histiocytosis (LCH) has diverse manifestations, from asymptomatic to aggressive, which involves many organs. Histopathological examination play s a  crucial role as  a  basic diagnostic standard for LCH. Writing Group of the Histiocyte Society proposes a guideline for diagnosing LCH, divided into presumptive, designated, and definitive diagnosis.  Case Illustration: Two cases of a 14 month-old girl and an 18 month-old girl presented similar clinical manifestation and multi - organ involvement. Dermatological examination revealed red papules and plaques covered by brownish scales and crusts on the scalp and body, erosion in some folds of the body. Histopathological examination of the first case revealed  an  early purpuric phase. S100 immunostaining just revealed hyperplasia of Langerhans cell but still could not support the diagnosis of LCH.  Fine Needle Aspiration Biopsy of the enlarged submandibular lymph node after two months  of observation suggested LCH.  In the second case, histopathological examination revealed proliferation of round-oval nucleated cells, pleomorphic, some reniform nuclei, with amphophilic cytoplasm. S100 and CD1a immunostaining revealed a positive reaction in the proliferative cell s. Discussion: Patients aged 14 and 18 months old indicated almost similar clinical manifestations leading to LCH diagnosis, with different histopathological pictures. The first patient was presumptively diagnosedas high - risk multisystem LCH, but theinitial histopathology results did not support LCH diagnosis. On the other hand, the second patient was definitively diagnosed with high-risk multisystem LCH.  Conclusion: Patient s with clinically suspected LCH without histopathological confirmation should be observed at least six months to reassess the necessity of a follow - up biopsy.   Keywords :  Langerhans Cell Histiocytosis, multisystem organ, histopathology, S100

Serum Ferritin Trends Are Associated with Survival in Adult Hemophagocytic Lymphohistiocytosis

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of excessive and ineffective activation of the immune system resulting in hyper-inflammatory response. Common presenting features include fever, cytopenias, elevated serum ferritin, and splenomegaly. HLH diagnosis is challenging as the available diagnostic criteria lack specificity. In addition, patients have a dismal outcome, and markers predicting survival are lacking. Ferritin concentration is a surrogate marker for inflammation, and repeated measurements might be associated with disease severity and outcome. We explored the prognostic significance of serum ferritin in adult HLH.Methods: We reviewed diagnoses of adult HLH treated at Barnes-Jewish Hospital (St. Louis, Missouri) and Henry Ford Hospital (Detroit, Michigan). We included 98 patients who met the 2004 Histiocyte Society criteria for HLH and had at least 2 serial ferritin values during the admission when diagnosis was established. Admission ferritin was defined as the initial value, and peak ferritin was defined as the highest value during admission. We examined ferritin levels change during admission which could be increasing (peak ferritin being the last ferritin value) or decreasing (ferritin values decreasing after peak ferritin). Predictive factors for survival during hospital admission were evaluated by univariate analysis followed by logistic regression. Analyses were performed using SPSS version 22, and results were considered significant at p <0.05.Results: The median age of patients was 48 years (range, 18-79 years); 64 (65%) were male. The most common clinical and laboratory abnormalities during hospitalization were: hyperferritinemia (100%; median 27,306 µg/L; range 1,823 - 684,000 µg/L), fever (96%), cytopenias (91%), hemophagocytosis (76.7%), elevated triglycerides (72.4%), splenomegaly (67.3%), and hypofibrinogenemia (42.7%). Median duration of hospital stay was 20 days (range, 1 - 89 days); 38 (39%) patients died during admission. Death was attributed to sepsis in 23 patients, lymphoma in 7, bleeding in 4, GVHD in 1, liver failure in 1, metastatic solid tumor in 1, and unknown in 1.Table 1 shows the parameters analyzed as predictors of mortality during hospital stay. In the univariate analysis, we found that age ≥50 years, increasing ferritin levels during admission, and malignancy were associated with higher mortality. At the multivariate regression level, age ≥50 years (OR = 3.31; 95% CI: 1.2 - 9.15; p = 0.021) and increasing ferritin levels (OR = 8.96; 95% CI: 2.97 - 27.02; p <0.0001) correlated with mortality. In addition, patients with declining ferritin levels by more than 50% from the peak were more likely to survive (OR = 2.21; 95% CI: 1.13 - 4.3; p = 0.026).Conclusion: Our results showed that ferritin trends rather than absolute concentration are associated with risks of mortality when HLH is diagnosed during a hospitalization. A declining ferritin trend is associated with lower risk of death and an increasing ferritin trend is associated with an increased risk of death. Prospective investigations of ferritin trends in HLH are warranted. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Additive Prognostic Impact of Gastrointestinal Involvement in Severe Multisystem Langerhans Cell Histiocytosis

To evaluate the prognostic impact of gastrointestinal involvement on the survival of children with Langerhans cell histiocytosis(GI-LCH) registered with the international clinical trials of the Histiocyte Society. This was a retrospective analysis of 2414 pediatric patients registered onto the consecutive trials DAL-HX 83, DAL-HX 90, LCH-I, LCH-II, and LCH-III. Among the 1289 patients with single-system LCH, there was no single case confined to the GI tract; 114 of 1125 (10%) patients with multisystem LCH (MS-LCH) had GI-LCH at initial presentation. GI-LCH was significantly more common in children aged <2years at diagnosis (13% vs 6% in those aged >2years; P<.001) and in those with risk organ involvement (15% vs 6% in those without risk organ involvement; P<.001). The 5-year overall survival (OS) in patients without risk organ involvement was excellent irrespective of GI disease (98% vs 97% in patients with GI-LCH; P=.789). In patients with risk organ involvement, the 5-year OS was 51% in 70 patients with GI-LCH vs 72% in 394 patients without GI-LCH (P<.001). GI-LCH has an additive unfavorable prognostic impact in children with MS-LCH and risk organ involvement. The emerding need for more intensive or alternative treatments mandates prospective evaluation.

Hemophagocytic lymphohistiocytosis: a case series analysis in a pediatric hospital

IntroductionHemophagocytic lymphohistiocytosis (HLH) is a rare clinical laboratory condition with high mortality rates, resulting from ineffective overactivation of the immune system. Data in the Brazilian literature is scarce, contributing to the challenge in standardizing conducts and performing an early diagnosis of HLH. ObjectiveTo describe the clinical, laboratory, and evolutionary findings on HLH patients treated at a pediatric hospital. MethodsThis is an observational, cross-sectional and retrospective study on children diagnosed with HLH, hospitalized between 2009 and 2019. The diagnostic criteria were those described in the Histiocyte Society protocol. The authors evaluated HLH patient laboratory tests, myelograms and bone marrow biopsies, clinical characteristics and therapy. ResultsTwenty-three patients were included, 52.2% of whom were males. The age at diagnosis ranged from one to one hundred and eighty months. Four cases were classified as Primary HLH and nineteen, as Secondary HLH. The main triggers were infections and rheumatological diseases. All children had bicytopenia, and 95.4% had hyperferritinemia. Nineteen patients had liver dysfunction, sixteen had neurological disorders and fourteen had kidney injury. Pulmonary involvement was seen in 61.9%, acting as a worse prognosis for death (p = 0.01). Nine patients underwent the immuno-chemotherapy protocol proposed in the HLH 2004. The time to confirm the diagnosis varied from five to eighty days. The lethality found was 56.3%. ConclusionsThe present study is the most extensive retrospective exclusively pediatric study published in Brazil to date. Despite the limitations, it was possible to demonstrate the importance of discussing HLH as a pediatric emergency.

Successful treatment of congenital systemic juvenile xanthogranulomatosis with pulmonary involvement

Juvenile xanthogranuloma (JXG) is a common form of non-Langerhans cell histiocytosis, which usually presents with spontaneously regressing skin lesions. Systemic involvement is rare and mostly seen in patients with multiple skin nodules. It can spontaneously regress, but sometimes systemic involvement can cause life-threatening symptoms and can be fatal. Herein, we report a case of congenital systemic JXG with multiple skin nodules, soft tissue and pulmonary involvement. She was successfully treated with chemotherapy according to Langerhans cell histiocytosis treatment protocol IV of the Histiocyte Society (LCH-IV).

Linfohisticiotosis hemafagocitica del adulto (LHH). Síndrome y enfermedad

HLH is a specific disease and always a syndrome characterized by excessive immune activation and clinical and analytical data of hyperinflammation that leads to a short survival if the appropriate treatment is delayed or not applied. It has been a poorly diagnosed and its incidence has apparently increased in recent times, perhaps due to its greater recognition. Genetic /familial-based cases occur in childhood from an inherited disorder of a poor cytotoxic function of T / NK cells. In adults, the majority of patients have predisposing causes, such as Epstein Barr virus infection, neoplasms most commonly due to non-Hodgkin lymphoma of T origin, autoimmune processes, and rarely are some patients classified as idiopathic. Therapy is based on the administration of the LHH-94 treatment protocol, promoted by the Histiocytic Society. All cases with a genetic base require the subsequent application of an allogeneic transplantation of hematopoietic progenitors, which is also a therapeutic option for adults with disease resistant, progressive or recurrent.

P041 Alemtuzumab-related haemophagocytic lymphohistiocytosis: negotiating the cytokine storm

Background/Aims Alemtuzumab is an efficacious therapy for relapsing remitting multiple sclerosis (RRMS) preventing neural damage and reducing relapse rate by up to 74%. Administered in 2 treatment cycles 12 months apart and authorised for use in > 40 countries, it is a humanized monoclonal antibody selectively directed against the CD52 antigen of T- and B-Lymphocytes. Significant autoimmune effects of Alemtuzumab are reported 6-60 months post-treatment including secondary autoimmunity (40%), thyroid disease (18-26%), idiopathic thrombocytopenic purpura (1-3%) and anti-glomerular basement membrane disease (1%). There are 2 case reports of haemophagocytic lymphohistiocytosis(HLH) in people with MS triggered by Alemtuzumab. HLH is a clinical syndrome of dysregulated, pathological overactivation of innate immunity leading to cytokine storm, multi-organ failure and a very high mortality rate. Clinical features are difficult to distinguish from, and may coexist with, other syndromes such as sepsis. Recognition requires a high index of clinical suspicion and management through multidisciplinary teams (MDT) using immune suppression. Early recognition and treatment improve outcome. Methods We report a case of HLH in a 30-year-old female 1 year after her first cycle of alemtuzumab (second cycle delayed due to COVID-19 pandemic) for treatment of RRMS. She was well until presentation 2 days post gadolinium-contrasted routine MRI head scan with headache, fever, bacterial pneumonia/empyema and acute kidney injury. Febrile episodes persisted despite antibiotics. Results Investigations revealed hepatosplenomegaly, pancytopenia (Haemoglobin: 80g/L, WBC: 0.9x109/L, neutrophils: 0.67x109/L, lymphocytes: 0.14 X109/L, platelets: 82x109/L), hypertriglyceridaemia (5.5mmol/L) and hyperferritinaemia (94023ng/ml). She fulfilled the Histiocyte Society HLH-2004 diagnostic criteria for HLH (H-score: 238). Initial treatment was IV methylprednisolone (1g) and intravenous immunoglobulin (IVIG) 2g/kg. Ferritin levels initially decreased (66933ng/ml) but re-escalated (93912ng/ml) with clinical deterioration, necessitating additional treatment with subcutaneous Anakinra 4mg/kg(recombinant interleukin-1 receptor antagonist) alongside oral prednisolone 1mg/kg. There was rapid, sustained improvement with resolution of fever but ferritin levels remained highly elevated (45000ng/ml) and cytopaenia was slow to resolve. Marker T cell subsets showed significant T cell depression presumably post-alemtuzumab. MDT discussion locally and nationally through the HLH Across Speciality Collaboration (HASC) led to discharge with careful outpatient monitoring. Further IVIG 2g/kg was administered which led to complete resolution of HLH and treatment wean. Conclusion HLH is an under-recognised complication of alemtuzumab therapy. Severe HLH requires both cytokine storm-directed treatment and identification/treatment of the trigger. Here, HLH was refractory to first line therapy (steroids and IVIG) and required immune modulation. The combination of alemtuzumab-induced immune dysregulation and sepsis were likely triggers, rather than Gadolinium. Supportive regional and national MDT input were required to guide therapy, especially as the patient wished to avoid etoposide (a standard refractory-HLH therapy) to preserve fertility. MDT working enabled early discharge with close monitoring in ambulatory care - a preferred outcome in the coronavirus pandemic. Disclosure N.L. Wong: Grants/research support; In the last 5 years NLW has received educational grant to attend meetings from Eli Lilly. N.J. Morley: Grants/research support; In the last 5 years NJM has received speaker fees and educational grants to attend meetings from ROCHE, AMGEN, AbbVie, TAKEDA, Kite Gilead and Janssen. D.J. Paling: Grants/research support; DJP has recieved speaker fees and educational grants to attend meetings from Biogen, Novartis, Genzyme and Teva. R.S. Tattersall: Grants/research support; In the last 5 years RST has received speaker fees and educational grants to attend meetings from UCB, AbbVie, Pfizer and Janssen.

Use of the JAK Inhibitor Ruxolitinib in the Treatment of Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome driven by overactive T cells and macrophages that abundantly secrete numerous pro-inflammatory cytokines, including interferon (IFN)-gamma, interleukin (IL)-1-beta, IL-2, IL-6, IL-10, IL-18, and tumor necrosis factor (TNF). The release of these and other cytokines underlies many of the clinical and pathologic manifestations of HLH, which if left untreated, can lead to multi-organ failure and death. The advent of etoposide-based regimens, such as the Histiocyte Society HLH-94 and HLH-2004 protocols, has substantially decreased the mortality associated with HLH. Nevertheless, the 5-year survival remains low at ~60%. To improve upon these results, studies have focused on the use of novel cytokine-directed therapies to dampen inflammation in HLH. Among the agents being tested is ruxolitinib, a potent inhibitor of the Janus Kinase (JAK) and Signal Transducer and Activation of Transcription (STAT) pathway, which functions downstream of many HLH-associated cytokines. Here, we review the basic biology of HLH, including the role of cytokines in disease pathogenesis, and discuss the use of ruxolitinib in the treatment of HLH.

Hemophagocytic Syndrome Secondary to Cytomegalovirus Infection in a Patient with Human Immunodeficiency Virus

Hemophagocytic Syndrome (HPS) or Hemophagocytic Lymphohistiocytosis is characterized by a dysregulation of the immune system with activation of macrophages and T lymphocytes, the product of an uncontrollable and excessive inflammatory response to different stimuli. The case of a patient with a history of Human Immunodeficiency Virus (HIV) under current treatment is presented, a clinical picture of 10 days of evolution characterized by fever, anorexia and asthenia, on physical examination skin-mucosa paleness, dehydration, generalized lymphadenopathy, hepatosplenomegaly. Paraclinical tests are performed suggesting reactivation of infection by Cytomegalovirus (CMV), in addition, during its in-hospital evolution, marked pancytopenia is evidenced, with elevated ferritin values, a bone marrow biopsy is performed, observing proliferation of Histiocytes, the patient meets the diagnostic criteria for HPS proposed by the Histiocyte Society in 2004, treatment was instituted, however it presented a torpid evolution and reached death. It is concluded that the diagnosis of HPS is complex; it is usually overlapped by the underlying diseases, as is the case of this HIV patient with reactivation of CMV infection; both viruses by themselves are related to HPS; therefore, knowledge of the clinical and laboratory criteria of this entity is necessary to make an early diagnosis and establish timely treatment, thus reducing mortality.

Abstracts from the 36th Annual Meeting of the Histiocyte Society Virtual Sessions: October 1, 2020 and November 5, 2020.

Abstracts from the 36th Annual Meeting of the Histiocyte Society Virtual Sessions: October 1, 2020 and November 5, 2020.

Adverse Prognostic Factors in Adult Secondary Hemophagocytic Lymphohistiocytosis: Results from Two Tertiary Academic Centers

Adverse Prognostic Factors in Adult Secondary Hemophagocytic Lymphohistiocytosis: Results from Two Tertiary Academic Centers

Sensitivity Analysis of Overall Response Rate (ORR) with Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis (HLH)

Background: Primary HLH is a rare, life-threatening immune disorder characterized by a hyperinflammatory state. In patients with primary HLH, interferon gamma (IFNy) is often markedly elevated and is considered one of the key cytokine driving the hyperinflammatory state. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation to bring patients to allogeneic hematopoietic stem cell transplantation, the only curative therapy. Conventional HLH therapy comprises immunotherapies (namely, dexamethasone and etoposide), which, unfortunately, predispose patients to infections and toxicity. Emapalumab is a fully human, anti-IFNy monoclonal antibody that neutralizes IFNy. Currently, there is no regulatory precedent or validated response criteria for efficacy assessment to guide clinical trials in primary HLH. In the pivotal study of emapalumab in primary HLH, objective response criteria were used to define the primary endpoint of overall response (Locatelli et al NEJM 2020). These response criteria were defined based on the Histiocyte Society HLH diagnostic criteria (Henter et al Pediatr Blood Cancer 2007), clinical considerations from the study's Scientific Steering Committee, and available experience reported with conventional HLH treatments. We now report on findings of a sensitivity analysis of overall response rate (ORR) to emapalumab using various assessment criteria. Methods: The open-label pivotal study included patients aged ≤18 years with a diagnosis of primary HLH and active disease (NCT01818492; Locatelli et al NEJM 2020). The initial dose of emapalumab was 1 mg/kg given intravenously every 3 days. Subsequent doses could be increased to 10 mg/kg if required, based on predefined laboratory and clinical response parameters, for a treatment duration of 8 weeks. In addition to emapalumab, all patients received dexamethasone, and a protocol amendment allowed for concomitant use of other HLH treatments if deemed appropriate by the investigator. ORR at end of treatment was analyzed as per the protocol definition in the 27 patients previously treated with conventional therapies. In addition, several pre-specified and post hoc sensitivity analyses were performed to pressure test the data; including: (i) a pre-specified analysis using a more conservative approach where any patient who received concomitant HLH therapies during the study was imputed as non-responder; (ii) a pre-specified analysis with physician-reported response rates recorded by the study investigators, based on their clinical judgement and previous experience in treating patients with primary HLH; and (iii) a post hoc sensitivity analysis using a previously published definition of overall response (Henter et al Pediatr Blood Cancer 2007). Results: 63% (95% confidence interval [CI], 0.42, 0.81) of 27 treatment-experienced patients had a response according to the pivotal study protocol definition of ORR (Fig. 1). A pre-specified sensitivity analysis on the primary endpoint where any patient who received concomitant HLH therapy and imputed as non-responders showed a magnitude of response similar to that observed in the protocol-defined primary analysis (59.3%; 95% CI 0.39, 0.78; n=22). Use of the response criteria defined by Marsh et al (Pediatr Blood Cancer 2013) in a retrospective analysis of 27 patients with primary HLH also resulted in a similar ORR to the protocol-defined primary endpoint in treatment-experienced patients (70.4%; 95% CI 0.50, 0.86). When platelet count was added to this analysis, the percentage of responders to emapalumab increased to 74.1% (95% CI 0.54, 0.89). The pre-specified analysis of physician-reported response rates was also in line with the primary analysis, with 70.4% (95% CI 0.50, 0.86) of 27 treatment-experienced patients deemed to have a response to emapalumab. Conclusion: The current analyses using different definitions of treatment response support the primary analysis results by having a numerically comparable point estimate to the primary endpoint, therefore confirming the positive benefit of emapalumab in patient's refractory or intolerant to conventional HLH therapies. Taken together, these findings also suggest that the clinically objective ORR, utilized in the pivotal emapalumab trial, may be used as a primary endpoint in primary HLH. Disclosures Locatelli: Jazz Pharmaceeutical: Speakers Bureau; Medac: Speakers Bureau; Miltenyi: Speakers Bureau; Bellicum Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jordan:Sobi: Consultancy. Allen:Sobi: Other: Scientific Steering Committee, Data And Safety Monitoring. Rizzari:Sobi: Consultancy, Other: Advisory Board. Rao:Sobi: Consultancy, Other: Advisory Board. Sevilla:Amgen: Other: Advisory Board; Rocket Pharma: Consultancy; Sobi: Other: Advisory Board; Novartis: Other: Advisory Board. Henry:Sobi: Consultancy. De Benedetti:Abbvie: Research Funding; F Hoffmann-La Roche AG: Research Funding; Novartis Pharma: Research Funding; Pfizer: Research Funding; Sanofi-Aventis: Research Funding; Sobi: Consultancy, Research Funding. Grom:Sobi: Consultancy; Novartis Pharma: Consultancy; AB2Bio: Consultancy. Stoltenberg:Sobi: Current Employment. Vågerö:Sobi: Consultancy. de Min:Sobi: Consultancy.

Clinical Characteristics and Outcomes of 101 Children with Hemophagocytic Lymphohistiocytosis: A Four-Year Single-Center Experience from Egypt

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition, arising either due to genetic mutations or from a variety of underlying diseases. This prospective observational study reports the clinical and laboratory data as well as the outcome of pediatric HLH in Egypt. HLH was diagnosed according to the Histiocyte Society HLH-2004 diagnostic criteria conducted at Alexandria University Children’s Hospital over four years. One-hundred-one patients were enrolled (44 males and 57 females), and the median age at presentation was 13.1 months (range: 1 day − 181.4 months). Almost 75% of the patients had consanguineous parents, and one-third had a history of an affected family member (HLH or HLH-like illness). The median time interval between the first HLH symptom and diagnosis was 34 days. At diagnosis, patients were preliminarily classified as having primary HLH in 61% of patients and secondary HLH in 39% of patients. The diagnosis was confirmed genetically in 57 patients. Seventy-eight percent of patients received the HLH-94 and HLH-2004 protocols, only seven patients have undergone hematopoietic stem cell transplantation. The overall survival was 26.4% by the end of the study; the most common cause of death was uncontrolled disease activity. This descriptive study, on a large cohort of pediatric HLH in Africa and the Middle East, sheds some light on the epidemiological characteristics of HLH patients and the available diagnostic and therapeutic tools. The mortality rate was considerably high, highlighting the importance of early diagnosis and initiation of appropriate therapy.

Pulmonary Langerhans Cell Histiocytosis in the Elderly Smoker

Langerhans cell histiocytosis (LCH), formally referred to histiocytosis X, is a histiocytic disorder with unknown etiology. The pathogenesis is believed to originate from myeloid dendritic cells and is now considered an inflammatory myeloid neoplasm within the revised 2016 Histiocyte Society classification. Pulmonary Langerhans cell histiocytosis (PLCH) is a rare and isolated form of LCH with a strong affiliation with smoking in adults of 20-40 years of age. Characteristic CT chest and histologic findings are instrumental in the early recognition and management of a disease. We herein report a case of a Caucasian smoker female with a significant history of interstitial lung disease (ILD) presented with recurrent and progressive worsening dyspnea. History of ILD and recurring respiratory symptoms raised suspicion of PLCH. CT chest and pathological findings confirmed the diagnosis, and discontinuation of smoking resulted in favorable clinical outcomes.

Clinical characteristics and outcome of pediatric patients diagnosed with Langerhans cell histiocytosis in pediatric hematology and oncology centers in Poland

BackgroundLangerhans cell histiocytosis (LCH) affects 1–2 in 1,000,000 people. The disease is not associated with increased risk of treatment failure (especially among older children), but appropriate procedures implemented in advance can eliminate complications which might appear and significantly worsen the patients’ quality of life. Thus, we sought to evaluate the clinical features, management, and outcome of children with LCH treated in Polish pediatric hematology-oncology centers.Materials and methodsOne hundred eighty two patients with LCH were treated according to the Histiocytic Society Guidelines between 2010 and 2017. The participating centers were requested to provide the following data: demographic, clinical, as well as local or systemic treatment data and patients’ outcome. Overall survival (OS) and event free survival (EFS) were estimated by Kaplan-Meier methods and compared using the log-rank test.ResultsSixty nine percent of children were classified as single system (SS). The patients with SS disease were significantly older as compared to the children with multisystem disease (MS), 6 vs. 2.3 years respectively (p 0.003). Bones were involved in 76% of patients. Systemic treatment was applied to 47% of children with SS disease and 98% with MS disease. Fourteen patients relapsed while two children died. OS and EFS in entire group were 0.99 and 0.91 respectively (with median follow-up 4.3 years).ConclusionThe treatment of LCH in Polish centers was effective, however, new approaches, including mutation analyses and good inter-center cooperation, are needed to identify patients who might require modification or intensification of treatment.