Abstract: Langerhans cell histiocytosis (LCH) confined to the skeleton has excellent survival, yet optimal management of multifocal bone disease and lesions at traditionally defined “special sites” remains uncertain due to limited prospective data. We report prospective results from an international pilot trial embedded within the Histiocyte Society LCH-III study (2001-2008) evaluating 6 months of vinblastine-prednisolone in children with single-system skeletal LCH. Among 455 enrolled patients, 381 were evaluable. Early response at week 6 was achieved in 83% of cases. Five-year overall survival was 100%, and event-free survival (EFS) was 71%. Multifocal bone lesions (MFB) were the dominant predictor of relapse (5-year EFS: 63% vs 87% without MFB; P < .001), whereas isolated central nervous system (CNS)-risk skeletal lesions did not independently affect EFS. In contrast, the cumulative incidence of central diabetes insipidus at 5 years was 5% overall but was significantly higher in patients with CNS-risk lesions, particularly when combined with MFB. These prospective data demonstrate that in single-system skeletal LCH, disease extent and lesion location confer distinct risks, with skeletal multiplicity determining relapse propensity, and anatomic location determining the risk of permanent endocrine sequelae. This study provides a prospective international benchmark for systemic therapy and supports risk-adapted treatment strategies that minimize long-term morbidity while avoiding unnecessary treatment escalation. This trial was registered at www.ClinicalTrials.gov as NCT00276757.

ABSTRACT:We evaluated long-term outcomes of 288 children with refractory-Langerhans cell histiocytosis (R-LCH) from 26 countries, who were prescribed off-label MAPK inhibitors (MAPKis) according to clinical indications. MAPKi indications included 148 R-risk-organ-positive (R-RO+), 67 R-risk-organ-negative (R-RO-), 13 lung destruction (lung), 9 sclerosing cholangitis (SC), 49 neurodegeneration (ND), and 2 diabetes insipidus (DI) cases. Median ages at diagnosis and MAPKi onset were 1.3 and 2.3 years, respectively, with median follow-up of 3.7 years (1166 person-years). Agents mostly prescribed as monotherapies were 184 prescriptions of vemurafenib, 115 of dabrafenib, 3 of encorafenib, 42 of cobimetinib, 45 of trametinib, and/or 1 prescription of binimetinib; followed 51 times by various chemotherapies or hematopoietic stem-cell transplantation, or 28 times by combined anti-BRAF-anti-MEK. Short-term responses (<8 weeks) ranged from 98% (R-RO+ and R-RO-), to 30% (lung) to none (ND, DI, and SC); although long-term lung and ND responses could be observed. Skin rash was the most frequent adverse event (∼55%), and 7 others included 1 case of cardiomyopathy and 6 of retinitis. Five developed MAPKi-unrelated tumors and 9 patients died. Five-year survival was 98%. After 113 patients with R-LCH discontinued MAPKi, 69 experienced disease reactivation. None of the various empirical maintenance therapies were able to prevent secondary reactivation. Among the 143 assessable patients without ND-LCH at MAPKi onset, 60 developed ND (45%, 5-year risk). MAPKis appeared to be safe and effective in children with R-RO+/RO-LCH, whereas other indications' responses were less frequent or occurred later. Further studies are needed to find effective maintenance-therapy approaches, particularly to prevent frequently observed secondary ND.

Background: Rare histiocytic disorders (RHDs) are diverse myeloid neoplasms that include Juvenile xanthogranuloma (JXG), Erdheim-Chester Disease (ECD), Rosai-Dorfman disease (RDD), Malignant histiocytoses (MH), ALK+ histiocytosis, indeterminate cell histiocytosis (ICH) and mixed histiocytosis (MXH). Methods: IRHDR data were collected retrospectively and prospectively including clinical features, diagnosis with central pathology (CP) review, treatments and outcomes. Descriptive statistics of data registered during the first 9 years are presented. Results: From April 2015 - June 2024, 214 patients were enrolled, 133 completed CP review; 111 confirmed RHD and 22 excluded. We present 192 RHD patients; median age at diagnosis was 11 years (0.11-77 years), 112 (58.3%) were males. JXG family patients (n=66): 2 KRAS+, 1 BRAF-other+, 1 MAP2K1+, 1 CSFR1+. Thirty-six were cutaneous (2 had JMML): 11 (31%) did well with observation, and 13 (36%) severe cases responded well to surgery +/- steroids. One progressive nodular had partial response (PR) to MEK-inhibitor (MEK-I). Five had reticulohistiocytoma: 2 had observation (complete response - CR), and 2 oral chemotherapy (1 PR; 1 resistant had PR after everolimus). Sixteen were systemic: 3 (19%) had vinblastine/steroids - LCH-III (CR), 1 surgery (CR), and 2 observation (1 CR; 1 stable disease - SD); 7 (44%) had relapsed/refractory (R/R) disease: 2 had cladribine or surgery (PR), and 5 others were refractory to cladribine or clofarabine (1 PR after MEK-I). Two systemic JXG were post-ALL, 1 died from toxicity and 1 is alive (SD). Three had adult JXG: 2 musculoskeletal had surgery/observation (CR), and 1 cutaneous had RET-kinase inhibitor (CR). Five intraocular: 3 had surgery (CR/PR), 2 resistant to oral chemotherapy had MEK-I (1 CR; 1 SD after intrarterial melphalan). ECD patients (n=41): 16 BRAF-V600E+, 3 MAP2K1+, 1 KRAS+. Five were localized, 19 systemic, and 15 CNS. BRAF/MEK-I induced more responses (81% overall response rate - ORR) than conventional therapies (interferon-α, chemotherapy, anakinra, radiation; 55% ORR) as first-line or salvage therapy. RDD patients (n=51): 2 BRAF-V600E+, 2 KRAS+, 1 MAP2K1+. Twenty-four were nodal: 7 (29%) had observation (SD), 12 (50%) had surgery +/- steroids (variable responses), 1 had clofarabine (PR), and 1 had chemotherapy followed by MEK-I (died from progressive disease - PD). Twenty-seven were systemic: 11 (41%) had oral chemotherapy (73% ORR), 3 (27%) R/R had cladribine (all PR); 2 had surgery (75% ORR), 5 observation (40% ORR); 2 had indomethacin or radiotherapy (SD); 5 (19%) R/R received BRAF/MEK-I (60% ORR); 1 refractory to surgery and cladribine (died from PD). MH patients (n=16): 3 KRAS+, 1 BRAF-V600E+. Twelve histiocytic subtype, 2 Langerhans cell, 1 interdigitating cell and 1 indeterminate cell tumour. Eight MH were localized: 3 had surgery +/- chemotherapy (2 CR, 1 relapse had PDL-1 inhibitor), 3 steroids +/- chemotherapy (1 CR, 1 SD, 1 PD with CR after cladribine). One R/R to cladribine/radiotherapy (SD), and 1 post-ALL MH was refractory to cladribine (died from PD). Seven MH were systemic: 3 had ALL-like therapy (2 CR, 1 SD), 2 chemotherapy + steroids (1 SD, 1 died from PD), and 1 had MEK-I (PR then relapsed). One with CNS+ MH had surgery followed by BRAF/MEK-I (CR). ALK+ histiocytosis patients (n=7): 5 localized: 2 musculoskeletal had observation (1 CR, 1 SD), 1 ocular had crizotinib (PR), 1 localized to the trachea had surgery (CR). Two CNS+ had LCH-III +/- surgery (1 CR; 1 R/R had PR to lorlatinib then relapsed). ICH patients (n=6): 1 BRAF-V600E+, 1 BRAF-other+, 1 MAP2K1+. 100% ORR was seen in 4 localized with observation or steroids, and 2 systemic/CNS with LCH-III. MXH patients (n=5): 2 BRAF-V600E+, 1 BRAF-other+, 1 MAP2K1+. One had localized RDD/LCH, 4 were systemic: 3 ECD/LCH, 1 ECD/RDD. Most MXH were refractory to conventional therapies, with durable responses to BRAF/MEK-I. After a median follow-up of 29.6 months, 94.8% of patients (n=182) are alive in CR/SD. Event-free survival is 84%; 28 (15%) relapsed. Five patients died, 4 from PD, and 1 from toxicity. Conclusions:RHDs are characterized by pathological, clinical and molecular diversity, with variable responses to conventional therapies. Most refractory systemic cases respond to ALK/BRAF/MEK-I. Further mutational analysis may identify novel targeted therapies, which could be helpful for resistant RHDs.

Progressive nodular histiocytosis is a rare variant of non-Langerhans cell histiocytosis that affects the skin and mucous membranes and displays a progressive clinical course and poor response to treatment. We describe a case of severe progressive nodular histiocytosis harboring a KRAS p.G12S mutation in a 9-year-old boy, refractory to chemotherapy, who was successfully treated with the MEK inhibitor cobimetinib. This is the first report of the use of MEK inhibition for this histiocytosis subtype in a pediatric patient.

OBJECTIVE: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. STUDY DESIGN: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. RESULTS: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 <2 years at diagnosis (13% vs 6% in those aged >2 years; 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). CONCLUSIONS: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.

Targeted therapies with MAPK inhibitors have proven to modulate the clinical manifestations of patients with Langerhans cell histiocytosis (LCH). We explored the presence of BRAFV600E mutation in our cohort of patients with LCH and cholestasis, sclerosing cholangitis, or liver fibrosis that presented resistance to chemotherapy. The BRAFV600E mutation was detected either in the diagnosis (skin and bone) or liver biopsy in our cohort of 13 patients. Thus, we observed a high incidence of BRAFV600E mutation in 100% either in diagnostic biopsy (skin and bone) or liver biopsy in patients with progressive liver disease, sequela, or liver transplant requirement.

Langerhans cell histiocytosis (LCH) is a disorder of the mononuclear phagocyte system that can affect almost any organ and system. The most common central nervous system (CNS) manifestation in LCH is the infiltration of the hypothalamic-pituitary region leading to destruction and neurodegeneration of CNS tissue. The latter causes the most frequent endocrinological manifestation, that is, central diabetes insipidus (CDI), and less often anterior pituitary hormone deficiency (APD). The reported incidence of CDI is estimated between 11.5 and 24% and is considered a risk factor for neurodegenerative disease and APD. Three risk factors for development of CDI are recognized in the majority of the studies: (1) multisystem disease, (2) the occurrence of reactivations or active disease for a prolonged period, and (3) the presence of craniofacial bone lesions. Since CDI may occur as the first manifestation of LCH, differential diagnosis of malignant diseases like germ cell tumours must be made. APD is almost always associated with CDI and can appear several years after the diagnosis of CDI. Growth hormone is the most commonly affected anterior pituitary hormone. Despite significant advances in the knowledge of LCH in recent years, little progress has been made in preventing long-term sequelae such as those affecting the hypothalamic-pituitary system.