RECRUITINGINTERVENTIONAL

Modified LCH-III Regimen With or Without Luvometinib for Multisystem Pediatric Langerhans Cell Histiocytosis

Modified LCH-III Regimen Versus Modified LCH-III Regimen Combined With Luvometinib in the Treatment of Multisystem Pediatric Langerhans Cell Histiocytosis: A Multicenter, Open-Label, Randomized Controlled Clinical Trial

About This Trial

Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder in children, caused by excessive proliferation and accumulation of Langerhans cells (a type of immune cell) in various body tissues. The annual incidence is about 2.6-8.9 cases per million children.Clinical presentation varies widely. Mild (low-risk) cases may resolve spontaneously or cause minimal issues with excellent outcomes. Severe multisystem LCH involves multiple organs, particularly high-risk sites such as liver, spleen, or bone marrow, leading to poorer prognosis and potential life-threatening complications without appropriate treatment.Standard first-line therapy for many children is prednisone (a corticosteroid) plus vinblastine (chemotherapy). Trials like LCH-III show near-100% survival in low-risk disease, but long-term survival drops to \~80% in high-risk cases. Reactivation occurs in \~37% of low-risk patients post-treatment, and \~50% of children eventually develop resistance, resulting in progression or relapse. Treatment failure heightens risks of long-term sequelae, including growth retardation, endocrine dysfunction, and neurological damage, severely impacting quality of life. More than half of LCH cases harbor the BRAF V600E mutation, activating the MAPK pathway abnormally. This has driven development of targeted MAPK inhibitors (e.g., vemurafenib, dabrafenib, trametinib), which demonstrate strong efficacy and acceptable safety (mainly manageable skin rash) in relapsed/refractory pediatric cases, with no reported secondary malignancies to date. These agents provide rapid symptom relief and durable control, though monotherapy often fails to eradicate abnormal cells in multisystem disease, leading to relapse after discontinuation. No MAPK inhibitors were previously approved specifically for LCH. In 2025, luvometinib (developed by Fosun Pharma, China; a selective MEK1/2 inhibitor) received approval in China for adult LCH and histiocytic neoplasms. Adult studies showed \~83% objective response rate and \~74% progression-free at ≥12 months, with mostly mild side effects (skin issues, hypertriglyceridemia) and no discontinuations due to serious toxicity. Laboratory evidence indicates MAPK overactivation confers apoptosis resistance to LCH cells; combining MAPK inhibitors with chemotherapy may enhance cell killing and leverage chemotherapy-induced immune microenvironment changes for better clearance. Small studies and real-world data in refractory LCH support this: combination regimens yielded low relapse rates (especially with prolonged therapy), 100% responses in some pediatric cohorts with sustained remission and no added severe toxicity, and notably lower relapse (20% vs 75% with inhibitor alone) in our center's early experience with LCH-III backbone plus MAPK inhibitor. This multicenter randomized trial will enroll children with multisystem LCH, assigning them to modified standard LCH-III chemotherapy alone or the same regimen combined with luvometinib, to evaluate whether adding this targeted agent improves outcomes.

Who May Be Eligible (Plain English)

Who May Qualify: 1. Children aged 0-18 years, of either sex. 2. Pathologically confirmed diagnosis of Langerhans cell histiocytosis (LCH) with positive staining for CD1a and/or CD207 (Langerin), and no prior treatment specifically directed against LCH. 3. Multisystem involvement of LCH, as determined by clinical and imaging evaluation. 4. Provision of written willing to sign a consent form (by parent/legal guardian and, where appropriate, assent from the child), with willingness to comply with the study treatment regimen and follow-up assessments. Who Should NOT Join This Trial: 1. Presence of any other significant underlying medical condition, including but not limited to primary weakened immune system disorders, congestive heart failure, renal insufficiency, chronic viral hepatitis, HIV infection, or status post solid organ transplantation. 2. History of a second (secondary) malignancy. 3. QTcF interval \> 0.47 seconds on electrocardiogram performed prior to enrollment. 4. Ophthalmologic screening prior to enrollment revealing retinal vein occlusion, retinal pigment epithelial detachment, or other clinically significant ocular abnormalities that, in the opinion of the investigator, contraindicate participation. 5. LCH harboring Class 3 MEK pathway mutations, specifically the following alterations: L98\_I103del, L98\_K104del, P105\_A106del, P105\_I107delinsL, L101\_I103delinsF, E102\_I103delinsF, E102\_I103del, E102\_I103delinsV, E102\_I103delinsVN, E102\_K104delinsQ, or I103\_A106del. 6. Refusal or inability to provide written willing to sign a consent form (or assent, as applicable). Always talk to your doctor about whether this trial is right for you.

Original Eligibility Criteria

View original clinical language

Inclusion Criteria: 1. Children aged 0-18 years, of either sex. 2. Pathologically confirmed diagnosis of Langerhans cell histiocytosis (LCH) with positive staining for CD1a and/or CD207 (Langerin), and no prior treatment specifically directed against LCH. 3. Multisystem involvement of LCH, as determined by clinical and imaging evaluation. 4. Provision of written informed consent (by parent/legal guardian and, where appropriate, assent from the child), with willingness to comply with the study treatment regimen and follow-up assessments. Exclusion Criteria: 1. Presence of any other significant underlying medical condition, including but not limited to primary immunodeficiency disorders, congestive heart failure, renal insufficiency, chronic viral hepatitis, HIV infection, or status post solid organ transplantation. 2. History of a second (secondary) malignancy. 3. QTcF interval \> 0.47 seconds on electrocardiogram performed prior to enrollment. 4. Ophthalmologic screening prior to enrollment revealing retinal vein occlusion, retinal pigment epithelial detachment, or other clinically significant ocular abnormalities that, in the opinion of the investigator, contraindicate participation. 5. LCH harboring Class 3 MEK pathway mutations, specifically the following alterations: L98\_I103del, L98\_K104del, P105\_A106del, P105\_I107delinsL, L101\_I103delinsF, E102\_I103delinsF, E102\_I103del, E102\_I103delinsV, E102\_I103delinsVN, E102\_K104delinsQ, or I103\_A106del. 6. Refusal or inability to provide written informed consent (or assent, as applicable).

Treatments Being Tested

DRUG

Prednisone

Corticosteroid administered orally as part of the modified LCH-III regimen

DRUG

Vincristine

Intravenous vinca alkaloid chemotherapy agent used in the modified LCH-III regimen

DRUG

Mercaptopurine

Oral purine analog antimetabolite used in the maintenance phase of therapy for multisystem LCH

DRUG

Luvometinib

Oral selective MEK1/2 inhibitor added to the experimental arm. Administered daily in combination with modified LCH-III chemotherapy for multisystem Langerhans cell histiocytosis.

Locations (11)

West China Second Hospital, Sichuan University

Chengdu, China

Affiliated Hospital of Guizhou Medical University

Guiyang, China

Anhui Provincial Children's Hospital

Hefei, China

The Second Affiliated Hospital of Anhui Medical University

Hefei, China

Jiangxi Provincial Children's Hospital

Jiangxi, China

Kunming Children's Hospital

Kunming, China

The Second Affiliated Hospital of Guangxi Medical University

Nanning, China

The First Affiliated Hospital of Xinjiang Medical University

Ürümqi, China

Xi'an Children's Hospital

Xi'an, China

Xi'an Northwest Women's and Children's Hospital

Xi'an, China

Zunyi Medical University Affiliated Hospital, Guizhou Provincial Children's Hospital

Zunyi, China