Background Gaucher disease (GD), the most prevalent lysosomal storage disorder, manifests with cytopenia, organomegaly, and skeletal complications. This study characterizes the Russian GD cohort and evaluates outcomes under national therapy protocols, including predominant use of biosimilar imiglucerase. Materials and methods Data were extracted from the Russian GD Registry (single-center, observational study). All enrolled patients (n=383, >18 years, diagnosis confirmed by glucocerebrosidase assay and genetic testing) were followed prospectively with 12-month assessments (2014–2024; 1,590 visits). Electronic case report forms captured demographics, clinical/laboratory parameters, and therapy details. Data cutoff: December 1, 2024. Results Cohort: 383 patients (M:43%, F:57%), median age 42 years (range: 18–93). Splenectomy rate: 35% (median age at procedure: 12.5 years). Presenting hematologic manifestations: anemia 65%, thrombocytopenia 74% (100% in non-splenectomized), leukopenia 43%. Skeletal morbidity: osteonecrosis (femoral diaphyses) occurred in 72% splenectomized vs. 59% non-splenectomized patients (p=0.128); avascular necrosis affected 41% vs. 10% (p<0.001). Therapy: 321 patients received pathogenetic treatment:enzyme replacement therapy (ERT): 92% (imiglucerase-biosimilar [Russia]: 69%, velaglucerase: 30%, taliglucerase: 1%)substrate reduction therapy (eliglustat): 8% Outcomes: after 7 years of ERT, anemia persisted in 6% and severe thrombocytopenia (platelets <60 × 10³/µL) in 4.5%. Maintenance ERT (15–20 U/kg monthly) was administered to 137 patients (46%) achieving therapeutic goals. Conclusion The Russian GD cohort demonstrates significant splenectomy-associated skeletal morbidity. National access programs enable high treatment coverage (84%), with the remaining 16% having mild type 1 GD not meeting current criteria for initiation of therapy. Biosimilar imiglucerase constitutes 69% of ERT use. Maintenance dosing in nearly half of treated patients underscores its role in sustainable disease control. Real-world outcomes confirm efficacy of this approach, with >93% achieving hematologic stability on long-term therapy.

Background Gaucher disease (GD), a lysosomal storage disorder caused by deficient glucocerebrosidase activity, is associated with polyclonal and monoclonal gammopathies. This results from chronic B-lymphocyte stimulation by macrophage-derived cytokines and chemokines (IL-6, IL-10, CCL18). Materialsandmethods Using data from the Russian Gaucher Disease Registry (cutoff: November 17, 2023), we analyzed 1,171 serum protein immunochemical studies from 336 GD patients (93% of registry participants) at the National Medical Research Center of Hematology. Assessments were performed pre-treatment and during disease-specific therapy (enzyme replacement/substrate reduction). Patients with monoclonal gammopathy were monitored for 24–228 months (median 54). Turnbull interval estimates (right-left censored) assessed gammopathy probability, while repeated-measures regression analyzed paraprotein dynamics. Results Monoclonal gammopathy was detected in 24 patients (7%), with IgG:IgA:IgM paraprotein ratios of 15:7:2. One patient had symptomatic multiple myeloma at GD diagnosis. Median age at gammopathy detection was 47 years (range: 30–71), with slight male predominance (54%); 17% were splenectomized. Gammopathy first appeared: pre-treatment (46%), during enzyme replacement (37%), or substrate-reduction therapy (17%). Paraprotein concentrations increased progressively (mean rate: 0.5 g/L/year). The 15-year probability of monoclonal gammopathy was 18%, significantly higher in patients >40 years (20%; *p*=0.001) and with splenomegaly >200 mm (36%; *p*=0.0007). Conclusion Chronic antigenic stimulation and sphingolipid-driven macrophage dysfunction underlie B-cell dysregulation in GD, explaining its high frequency of monoclonal gammopathies and associated multiple myeloma risk.

BACKGROUND: The femoral head osteonecrosis is the common bone manifestation in Gaucher disease (GD) and the main indication for total hip replacement (THR). The specifics of the surgery and long-term results were insufficiently studied in patients with GD. AIM: To investigate the perioperative period, results of THR and implant longevity in patients with GD. MATERIALS AND METHODS: A retrospective monocenter study included 26patients with GD, who underwent 30primary THR and 9revision hip replacements from 2005 to 2023years. RESULTS: Good results of THR were obtained in 87%. The unsatisfactory results were periprosthetic infection— 2 and loosening— 3. Both periprosthetic infection cases were caused tuberculosis, not diagnosed before surgery. High blood loss was associated with enzyme replacement therapy (ERT). Less than 5years ERT, the blood loss more than 1000ml was 57%, 5–10years, the blood loss more than 1000 was 22%, more than 10years ERT— 0% (p=0.047) The longevity of implants at 3, 6 and 12years after surgery was 97%, 93% and 61%, respectively. In the case of cement type of implants, the longevity for a period of 12years was 33%, in the cementless type— 67%. At 12years the longevity was 43% for the bearing surfaces CoCr /PE and 83% in the case of other bearing surfaces (C/C, C/PE, Mod Me/PE). CONCLUSIONS: THR in GD can significantly improve quality of life after femoral head osteonecrosis. The longest implant longevity were shown cementless implants and bearing surfaces ceramics on ceramics, ceramics on polyethylene and metal with modified surface on polyethylene. A high risk of hemorrhagic complications occurs in patients receiving ERT less than 5years. The risk of periprosthetic infection is 6.7%, and when it is detected, it is necessary to exclude tuberculosis.

Abstract Background Patients with Gaucher disease (GD) require continual monitoring; however, lack of specific disease biomarkers was a significant challenge in the past. Glucosylsphingosine (lyso-Gb1) has been shown to be a reliable, key, specific, and sensitive biomarker for diagnosis, prognosis, and treatment response in clinical studies of patients with GD. We evaluated the change in lyso-Gb1 concentration over time following enzyme replacement therapy in patients with confirmed GD using real-world data from the Gaucher Outcome Survey disease registry. Methods Data for patients aged ≥ 18 years with a confirmed diagnosis of GD and at least two lyso-Gb1 assessments were analyzed retrospectively. Patients were stratified by treatment status at baseline (time of first lyso-Gb1 assessment). Lyso-Gb1 concentrations were measured from dried blood spot (DBS) samples by Centogene AG. Assessments included change in lyso-Gb1 concentration, hemoglobin concentration, platelet counts, and spleen and liver volume from baseline to the last lyso-Gb1 assessment. Results Of 2007 patients enrolled in the Gaucher Outcome Survey as of February 25, 2022, 435 met the inclusion criteria and were included in the study: 318 treated (‘all treated’; 277 receiving treatment at baseline, 41 treatment naive at baseline), 38 receiving treatment at baseline who stopped treatment before the last lyso-Gb1 assessment, and 79 untreated. Lyso-Gb1 concentrations decreased from baseline to the last lyso-Gb1 assessment for all treated patients (median change − 8.6 ng/mL), and increased for untreated patients (median change 25.0 ng/mL) and those who stopped treatment (median change 19.5 ng/mL). Decreases were greater for all treatment-naive than previously treated patients (median change − 120.5 vs. − 3.3 ng/mL) and for velaglucerase alfa–treated patients vs. the overall treated cohort (–32.6 vs. − 8.6 ng/mL). Small improvements in hemoglobin concentrations, platelet counts, and spleen volume were observed for treated patients but not untreated/stopped treatment cohorts. Conclusions In this study, changes in lyso-Gb1 concentrations from DBS were reflective of responses to enzyme replacement therapy initiation or withdrawal in most patients. These findings confirm that the use of DBS samples for routine monitoring of lyso-Gb1 concentrations in patients with GD is feasible in real-world settings and may be useful to assess treatment response.

BACKGROUND: Osteonecrosis of the femoral head in Gaucher disease typeI is an irreversible bone manifestation of the disease. The cause and mechanisms of osteonecrosis in Gaucher disease are still unknown, and their clinical and radiological characteristics must be taken into account when choosing treatment strategy. AIM: To analyze the radial and morphological changes in the proximal femur after osteonecrosis of the femoral head in typeI Gaucher disease. MATERIALS AND METHODS: The study included 251adult patients with typeI Gaucher disease from the Russian National Registry; histological examination of 22removed femoral bone fragments obtained during total hip replacement in 20patients with Gaucher disease and 9 in patients of the control group was performed. RESULTS: Osteonecrosis of the femoral head is detected in 30% of adult patients with Gaucher disease, and in 20% of patients it lead to femoral head collapse. Spongy bone osteosclerosis of the metaphysis, expansion/swelling of the bone marrow cavity with secondary osteopenia and osteoporosis of the proximal femur were often accompanied by osteonecrosis of the femoral head, creating technical difficulties during surgery. The histological picture revealed a picture of chronic bone ischemia of the proximal femoral metaepiphysis, which was confirmed by the identification of common areas of osteosclerosis during X-ray and MRI examination. Bone marrow infiltration by Gaucher cells in histological preparations persisted regardless of the duration of enzyme replacement therapy against the background of preserved regenerative potential of bone tissue. CONCLUSIONS: Тhe revealed features of the X-ray, MRI and histological picture should be taken into account when planning and conducting orthopedic operations for osteonecrosis of the femoral head in patients with type I Gaucher disease.

Background: Acid sphingomyelinase deficiency (ASMD) and Gaucher disease type 1 (GD1) are rare inherited sphingolipid disorders with multisystemic manifestations, including liver disease and dyslipidemia. Despite effective treatments, insufficient disease awareness frequently results in diagnostic delays during which irreversible complications occur. We delineated the shared and distinctive features of hepatic, splenic, and lipoprotein phenotypes in ASMD and GD1. Methods: We analyzed baseline hepatic, splenic, and lipoprotein phenotypes of untreated adults in pivotal trials of ASMD (ASCEND, N=36) and GD1 (ENGAGE, N=40). Results: The mean cohort ages were 34.8 years in ASMD and 31.8 years in GD1. Most patients had normal or low body mass index. Moderate hepatosplenomegaly (mean volume in multiples of normal) was common in both cohorts (hepatomegaly 1.53±0.42 and 1.40±0.32, respectively; splenomegaly 11.45±4.36 and 13.20±5.91, respectively). Liver function tests were mildly elevated in ASMD but normal in GD1. In both disorders, mean HDL cholesterol (mg/dL) was profoundly low (22.23±9.14 ASMD; 26.25±8.08 GD1) and correlated inversely with liver volume (r=−0.45 ASMD, p=0.005; r=−0.50 GD1, p=0.001) and spleen volume (r=−0.60 ASMD, p=0.0001; r=−0.63 GD1, p<0.0001). Mean LDL cholesterol (mg/dL) was elevated in ASMD (145.86±49.80) but low in GD1 (68.85±22.53). HDL cholesterol correlated inversely with serum concentrations of lyso-sphingomyelin in ASMD (r=−0.48, p=0.003) and glucosylsphingosine in GD1 (r=−0.63, p<0.0001). Conclusions: ASMD and GD1 should be considered in differential diagnosis of patients with unexplained liver and lipid abnormalities, especially young, lean adults with very low HDL and hepatosplenomegaly. HDL emerged as a potential biomarker of disease activity in these sphingolipid disorders.

Background: Long-term patient registries are important for evaluating treatment outcomes in patients with rare diseases, and can provide insights into natural disease history and progression in real-world clinical practice. Initiated in 2010, the Gaucher Outcome Survey (GOS) is an ongoing, international, multicenter, observational registry (ClinicalTrials.gov Identifier: NCT03291223) for patients with a diagnosis of Gaucher disease (GD), irrespective of treatment type or status, with a primary objective to monitor safety and long-term effectiveness of velaglucerase alfa. Methods: Here, we evaluated the GOS population 12 years after the registry initiation. Results: As of 25 February 2023, 2084 patients enrolled in the GOS and 1643 received GD-specific treatment. Patients exhibited broad heterogeneity at baseline: age of diagnosis (0 to 85.3 years), hemoglobin concentrations (<80.0 g/L to >150 g/L), platelet counts (<50 × 109/L to >450 × 109/L), and liver and spleen volumes. Most patients treated with enzyme replacement therapy or substrate reduction therapy reported improvements in clinical parameters within 1 year of treatment initiation, maintained over the course of treatment up to 12 years, whereas untreated patients had baseline values closer to standard reference thresholds and showed stability over time. Conclusion: The 12-year data from the GOS confirm the impact of long-term treatment with GD-specific agents and offer insights into disease progression and outcomes in a real-world setting.

Background . Paroxysmal nocturnal hemoglobinuria is a rare clonal disease of the hematopoietic system, with the key manifestations of hemolytic anemia, a high thrombosis rate, and bone marrow failure. Despite the high efficacy of C5‑inhibitors in intravascular hemolysis cessation, a significant proportion of patients remain anemic. Causes of a sub‑optimal response may include C3‑mediated extravascular (intracellular) hemolysis, residual intravascular hemolysis, or bone marrow failure. Aim . To analyze the results of pathogenetic therapy in patients with paroxysmal nocturnal hemoglobinuria. Materials and methods. The study included 55 patients with paroxysmal nocturnal hemoglobinuria receiving complement C5 inhibitors for at least 6 months. Results. Suboptimal hematological response was observed in 31/55 (56 %) patients. The most common cause of anemia in the partial response group was C3‑mediated extravascular hemolysis in 8/10 (80 %), while bone marrow failure predominated (57 %) in the minor response group. Conclusion . The study showed a high frequency of suboptimal response to pathogenetic therapy and necessity of ac‑curate determination of leading cause of persistent anemia in order to modify therapy or switch to other drugs.

Introduction. During enzyme replacement therapy in patients with Gaucher disease (GD) with recombinant glucocerebrosidase (GCase), regression of bone manifestations is possible, but with prolonged therapy osteonecrosis may occur. These changes may be due to impaired differentiation of multipotent mesenchymal stromal cells (MSCs). Aim: to study changes in the MSCs of healthy donors and a patient with GD when cultured in the presence of GCase. Material and methods. MSCs were isolated from the bone marrow of 17 healthy donors and a female patient with GD by a standard method and cultured in the presence of various concentrations of GCase after the second passage from 2 to 7 weeks. Cell proliferation and the ability to differentiate were analyzed, including after induction. The assessment was carried out by differential staining, elution, and expression of differentiation marker genes by real-time PCR. Results. Low concentrations of recombinant GCase (0.25-1.5 U/ml) did not affect the proliferative activity of MSCs. Prolonged cultivation of MSCs in the presence of low doses of GCase led to a change in the differentiation potential of these cells in the direction of adipogenesis. Concentrations of GCase of 3-5 U/ml inhibited the proliferation of MSCs and caused significant changes in cell differentiation. High doses of the enzyme (7-10 U/ml) had a cytotoxic effect and led to cell death within one passage. The proliferative and differentiation potential of the MSCs of a patient with GD differed significantly from the cells of healthy donors in all the parameters studied. Conclusion. The cultivation of donor MSCs in the presence of recombinant GCase alters the proliferation and differentiation potential of these cells. These changes depend on the dose of the enzyme in the medium and the duration of cultivation.

Introduction: The study aimed to assess the safety, immunogenicity, and efficacy of long-term therapy with biosimilar of eculizumab (Elizaria (R)) in paroxysmal nocturnal hemoglobinuria (PNH) patients. Methods: The study included 30 patients with PNH who had completed previous clinical trials. Of these, 25 patients continued receiving the biosimilar product, and 5 patients switched from the originator product Soliris. The maximum duration of follow-up was 104 weeks, during which the investigational product was administered 52 times at a standard dose. Results: Throughout the study, the levels of lactate dehydrogenase, hemoglobin, reticulocytes, and PNH clone remained stable compared to baseline, regardless of the previous therapy (p > 0.05). There were no significant differences in the number of patients with chronic kidney disease at different visits, as well as in the number of patients who received donor red blood cell and platelet transfusions during the study (p > 0.05). There were 2 cases of adverse reactions reported in 2 patients (6.6%): elevated aspartate aminotransferase (3.3%) and alopecia (3.3%). Immunogenicity analysis showed no significant differences in the frequency of antidrug antibody detection compared to baseline (p > 0.05). Conclusion: The study fi ndings confirm the long-term efficacy and safety of biosimilar in patients with PNH. (c) 2024 The Author(s).

Autoimmune hemolytic anemia is a rare disease characterized by the appearance of anti-erythrocyte autoantibodies and subsequent destruction of red blood cells by cells of the immune system. The destruction mechanisms of erythrocytes loaded with autoantibodies are well studied; however, the initial mechanisms that trigger the production of antibodies to own erythrocytes antigens remain unclear. In the pathogenesis of autoimmune hemolytic anemia, an important role is played by impaired immunological tolerance, in which T-lymphocytes play a key role. The study of T-lymphocytes subpopulation in patients with autoimmune hemolytic anemia by flow cytometry can provide valuable information for studying the disease pathogenesis and developing new approaches to its treatment.

Purpose: Most patients with Gaucher disease have progressive and often disabling skeletal manifestations. We examined the long-term effect of eliglustat treatment on bone outcomes in clinical trials in adults with Gaucher disease type 1.Methods: Data from 4 completed phase 2 and 3 trials were evaluated in treatment-naive patients or patients switching to eliglustat from enzyme replacement therapy (ERT).Results: Overall, 319 of 393 (81%) eliglustat-treated patients remained in their trials until completion or commercial eliglustat became available. Mean eliglustat treatment duration ranged from 3.3 to 6.5 years. In treatment-naive patients and ERT-switch patients, frequency and severity of bone pain decreased during eliglustat treatment. Mean lumbar spine T-scores shifted from abnormal to normal in treatment-naive patients and remained in the healthy reference range or improved modestly in ERT-switch patients. Mean total bone marrow burden score shifted from marked-to-severe to moderate in treatment-naive patients and remained moderate in ERT-switch patients. MIP-1 beta (marker of active bone disease) was elevated at baseline and decreased to the healthy reference range in treatment-naive patients and remained in the healthy reference range among ERT-switch patients. Conclusion: These findings confirm the long-term efficacy of eliglustat on skeletal complications of Gaucher disease in treatment-naive and ERT-switch patients.(c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Background: The use of non-chemotherapeutic methods with arsenic trioxide (ATO) and tretinoin (ATRA) for the treatment of acute promyelocytic leukemia (APL) allows achieving remission in more than 90% of patients with de novo APL with less toxicity compared to chemotherapy treatment. However, early mortality remains high in patients with initial leukocytosis more than 10×109/l. Aims: To evaluate the efficacy and toxicity of the ATRA+ATO protocol in patients with de novo APL. Methods: From 2016 to 2022, 79 patients with de novo APL aged 19–78 years (Me – 44) were included in the ATRA+ATO research protocol at the National Research Center for Hematology, M/F — 32/47. According to ELN classification, 71% of patients (n=56) were assigned to the low risk group, and 29% (n=23) were assigned to the high-risk group. Patients completed 1 induction course of 30–60 days (ATO 0.15 mg/kg IV + ATRA 45 mg/m2 PO) until morphological remission achieving in the low risk group, and 60 days in the high risk group and consolidation courses (4 for low risk and 5 for high risk). Patients from the high-risk group got idarubicin 8–12 mg/m2 (1–3 administrations) at the beginning of the induction course for cytoreduction, and patients with clinically significant hyperleukocytosis got cytarabine 100 mg/m2 (1–3 administrations). Results: The induction course was completed in 74 patients (93.7%). Of these, molecular remission was achieved in 73 (98.6%): after the introduction in 62 (84.9%), after the 1st course of consolidation in 10 (13.7%), after 2nd course of consolidation in 1 (1.4%). Early mortality was 6.3% (n=5), death in remission was 1.7% (n=1). All lethal cases were detected in patients from the high-risk group. A 0.83-114 times (median - 7) transient leukocytosis increasion was detected in 68/79 (86%) patients, 7 patients got cytarabine for cytoreduction, ATO was temporarily discontined in 2 patients. Differential syndrome was diagnosed in 26.6% of patients (n=21) on 1–20 (median – 2) day of induction therapy, ATO was temporarily discontinued in 2 patients of them. Infections were observed in 87.3% (n=69) of patients. 14 patients (17.7%) were transferred to the intensive care unit. Signs of cardiac toxicity of therapy were observed in 27.8% of patients (n=22) (QTc prolongation in 20 patients, excitation of the driver’s rhythm - 1, inversion of the T-wave - 1), hepatotoxicity gr. 3-4 — 31.6% (n=25), pancreatitis — 16.5% (n=13). After achieving remission, therapy was continued in an outpatient hospital. Currently, 73 patients (92.4%) are alive, the follow-up period is 0.03–57.7 months (median — 16.7 months), no cases of relapse were observed. 3-year OS in all patients was 92.3%, in the high-risk group – 100%, in the high-risk group – 73%. DFS is 99%. Summary/Conclusion: Risk-adapted strategy for non-chemotherapeutic treatment of acute promyelocytic leukemia based on combination of tretinon and arsinic trioxide allows to achieve 99.0% 3-year disease-free survival in patients as from the low-risk group as from the high-risk group. The main reason for unsuccessful therapy according to the ATO+ATRA protocol was early mortality in patients from the high-risk group.Keywords: ALL-trans retinoic acid (ATRA), Acute promyelocytic leukemia, Arsenic trioxide

On June 24, 2023, an Expert Council was held in St. Petersburg, during which leading experts in the field of hematology discussed current achievements and answered a number of unresolved issues of targeted therapy of paroxysmal nocturnal hemoglobinuria (APG) in order to further improve treatment results in Russia. During the Expert Council, the following aspects of targeted APG therapy were considered: • criteria for the suboptimal response of patients with APG to therapy with inhibitors of the 5th component of complement (C5); • efficacy and safety of the use of pegcetacoplan in APG in patients with insufficient efficacy of inhibitors of the C5 component of complement; • vaccination issues before starting therapy with complement inhibitors and the possibility of conducting treatment with pegcetacoplan at home.

RenduOslerWeber disease or hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant disease. It is characterized by vascular dysplasia with the formation of telangiectasias on the skin, mucous membranes of the respiratory and digestive tracts, arteriovenous malformations (AVMs) in the internal organs, which is manifested by bleeding. Diagnosis is based on Curacao criteria: recurrent and spontaneous nosebleeds, multiple telangiectases on the characteristic localizations, AVMs in one or more of the internal organs, a family history of HHT (i.e. first-degree relative who meets these same criteria for definite HHT). Therapy is aimed at preventing and stopping gastrointestinal, nosebleeds, correction of iron deficiency anemia. A promising method of therapy is the use of angiogenesis inhibitors, in particular bevacizumab. The article presents a description of a clinical case of HHT in a 49-year-old woman with telangiectisia on the mucous membrane of the tongue, gastrointestinal tract and liver AVMs.

Topic: 16. Myeloproliferative neoplasms - Clinical Background: Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are histiocytic diseases characterized by tissue damage due to infiltration with monocyte-derived cells and inflammatory microenvironment. In 2016 both diseases were re-classified in the same group (“L”) due to common recurrent mutations and activation of MAPK-pathway. Different treatment options are available for LCH and ECD, including chemotherapy, anti-cytokine drugs and MAPK-inhibitors. However, there is limited data for MEK-inhibitors, particularly trametinib, in treatment of adults with LCH and ECD. Aims: To evaluate efficacy and safety of trametinib monotherapy in adults with LCH and ECD (“L” - group histiocytosis). Methods: A retrospective study was performed in 10 patients with LCH, ECD or mixed disease (LCH+ECD). Two patients were treatment-naive, 3/10 previously received interferon-alpha or sirolimus, the other five had been treated with chemotherapy. All patients received trametinib at a starting dose of 1 mg/day. Efficacy was evaluated by size changes of all measurable lesions that were detected by CT-scan or MRI. Complete response (CR) was defined as no signs or symptoms of the disease and no detectable lesions by MRI and/or CT-scan. Partial response (PR) was defined as detectable disease with at least 20% reduction of lesions. Results: Ten patients were included with a median age of 39 years (range 28 - 58) and median follow up time of 15 months (range 10 - 31). In 3/8 patients (37,5%) complete response was achieved with non-detectable disease. Other 5/8 (62,5%) had a partial response. Two patients had non-measurable forms of disease – pulmonary involvement only and kidney infiltrates. Both of them had a clinical improvement after trametinib initiation. None of the patients had a progressive disease during trametinib treatment. Adverse events (AE) were observed in 8/10 patients. The most common AE was a skin rash in 6/8 (75%) patients. For all AE’s severity was grade 2 or less. In 5/8 (62,5%) patients AE resolved after dose reduction without efficacy impairment. - № Diagnosis Gender Age Final trametinib dose Adverse events Previous therapy Follow up time, months Best response 1 ECD Male 33 Cycles 1 mg for 21 days than 7 days wash-out Skin rash, periorbital edema Interferon-alpha 2b 29 PR 2 ECD Female 38 1mg/day Skin rash Methylprednisolone, cyclophosphamide 28 PR 3 LCH and ECD Female 37 1 mg EOD Periorbital edema Prednisolone, cyclophosphamide, prospidine, vincristine, cytarabine, interferon, lenalidomide 31 PR 4 LCH Female 54 Cycles 1 mg for 25 days than 5 days wash-out Arthralgias, myalgias Vinblastine, prednisolone, vemurafenib, radiotherapy 19 CR 5 LCH Female 42 1 mg EOD Skin rash Sirolimus 18 N/A 6 ECD Male 46 1mg/day Skin rash, hypertension Nephrostomy only 12 N/A 7 LCH Male 40 1mg/day none Vinblastine, prednisolone, methotrexate, 6-MP, cladribine 11 CR 8 LCH Female 28 1mg/day Skin rash, fluid retention Treatment-naïve 10 PR 9 LCH Male 30 1mg/day none Vinblastine, etoposide, prednisolone 10 PR 10 LCH Female 58 0,5 mg/day Hypertension, skin rash, CPK elevation, myalgia Interferon-alpha 2b, radiotherapy 10 CR Summary/Conclusion: Trametinib is a promising and effective drug for monotherapy in adults with LCH or ECD. Despite only three patients having a complete response, trametinib gives opportunity to control disease with an acceptable toxicity profile. It is worth noting that response to trametinib was non-inferior in patients with previous chemotherapy and even in chemo-resistant patients. Further investigations and prospective trials are required to determine an optimal dosage regimen in adults with “L”-group histiocytosis. Keywords: Mitogen-activated protein kinase (MAPK), Langerhans Cell Histiocytosis, MEK