A multicenter study of patients with multisystem Langerhans cell histiocytosis who develop secondary hemophagocytic lymphohistiocytosis

Abstract

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1apositive (CD1a + )/CD207 + histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH). METHODS: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015. RESULTS: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% ± 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH-associated HLH. Patients with MS-LCH who met the criteria for HLH had significantly poorer 5-year survival compared with patients with MS-LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001). CONCLUSIONS: Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH-associated HLH. Cancer 2019;125:963-971.

Hemophagocytic Lymphohistiocytosis in Langerhans Cell Histiocytosis: A Case Report and Review of the Literature

“…The combination of HLH and LCH was associated with a poor prognosis. 17 Taken together, it appears HLH in LCH is not as unusual as originally thought. Since these diagnoses share common histologic and diagnostic findings but require different treatment strategies, knowledge of their potential relationship, and which patients are at highest risk, is critical to timely diagnosis and treatment.…”

Delayed Diagnosis of Langerhans Cell Histiocytosis Presenting With Thyroid Involvement and Respiratory Failure: A Pediatric Case Report

“…Consequently, in some cases of LCH, disease progression and affected organ system dysfunction may lead to potentially life-threatening complications, such as hemophagocytic lymphohistiocytosis. 17 In our case, the patient may have been on a trajectory toward active or progressive LCH with subsequent multisystem involvement. Therefore, early identification and treatment of LCH are critical to improve clinical outcomes.…”

High-risk LCH in infants is serially transplantable in a xenograft model but responds durably to targeted therapy

“…5 Furthermore, some children may experience significant morbidity such as diabetes insipidus (DI), anterior pituitary dysfunction, 6 and end-stage liver disease. 7 A rare but potentially fatal complication of systemic LCH is secondary hemophagocytic lymphohistiocytosis (HLH), [8][9][10] which has been shown to occur in children with multisystem LCH with a cumulative incidence of 9.3%. 10 Primary HLH arises from cytotoxic T-cell and macrophage hyperactivation because of deficiencies in normal negative regulatory signaling, whereas secondary HLH reflects massive immune system activation in response to an insult such as infection or malignancy.…”

“…7 A rare but potentially fatal complication of systemic LCH is secondary hemophagocytic lymphohistiocytosis (HLH), [8][9][10] which has been shown to occur in children with multisystem LCH with a cumulative incidence of 9.3%. 10 Primary HLH arises from cytotoxic T-cell and macrophage hyperactivation because of deficiencies in normal negative regulatory signaling, whereas secondary HLH reflects massive immune system activation in response to an insult such as infection or malignancy. 11 The development of HLH in the setting of multisystem LCH is associated with a poorer prognosis and ultimately decreased overall survival.…”

“…11 The development of HLH in the setting of multisystem LCH is associated with a poorer prognosis and ultimately decreased overall survival. 10 Genomic alterations resulting in activation of the mitogen-activated protein kinase pathway are a key molecular pathogenic feature of the histiocytic neoplasms and in LCH usually involve activating mutations in BRAF [12][13][14] and MAP2K1. [15][16][17][18] While targeted therapy with BRAF V600E-specific inhibitors has demonstrated significant responses in adults 19,20 and children with LCH, 21,22 longitudinal experience with targeted therapy in infants with riskorgan (RO) positive LCH remains limited.…”