Real-world Study of Darafenib or Trametinib and Clofarabine for High-risk/Recurrent/Refractory Langerhans Cell Histiocytosis in Children

Plain-language summary

Langerhans cell histiocytosis (LCH) is the most common histiocytosis in children, with an incidence of 2.6-8.9 per million. It is an inflammatory myeloid tumor with varied symptoms. Mild cases often resolve spontaneously, while severe cases can affect multiple organs and be life-threatening. LCH affecting the liver, spleen, or hematopoietic system has a poor prognosis and is high-risk group. The LCH-III study showed that low-risk children respond well to prednisone and vinblastine, with nearly 100% survival, but high-risk children's survival is about 80%, with a 30% reactivation rate.Long-term studies reveal that about 50% of patients are resistant to prednisone and vinblastine, leading to progression and recurrence. Except combination of prednisone and vinblastine, cladribine (introduced in 1998) and MAPK inhibitors (introduced in 2014), have lowered the mortality rate of LCH in children. Cladribine, a nucleoside analogue, is used for treating recurrent acute myeloid leukemia in children by disrupting DNA synthesis. In the LCH-98-S regimen, low-risk children with LCH responded well to moderate doses of cladribine, but 44% of high-risk children still faced disease progression. Later studies showed that high-dose cladribine with medium-dose cytarabine increased survival in refractory LCH from 30% to 85%, but also raised chemotherapy toxicity, with some cases experiencing severe hematological toxicity and half of the deaths resulting from chemotherapy complications. Clofarabine, a nucleoside analogue, inhibits ribonucleotide reductase and DNA polymerase, offering stronger anti-tumor effects and fewer side effects than cladribine and fludarabine in treating refractory leukemia. Case reports show that LCH patients unresponsive to cladribine improve with clofarabine treatment at moderate doses (25mg/m2/day). A retrospective study of 58 LCH patients using clofarabine (25mg/m2/day) showed an 87% progression-free survival rate after one year. While the main side effect was grade 3 or higher hematological toxicity, 98.3% of patients tolerated it and completed treatment. Further prospective studies are needed to determine the optimal dose, duration, long-term efficacy, and complications of clofarabine in children with LCH. Research indicates that childhood LCH is often linked to mutations in MAPK pathway genes, with over half of cases involving BRAFV600E mutations. MAPK inhibitors, like vemurafenib, dabrafenib and trametinib, are effective for relapsed and refractory LCH, but they don't eliminate malignant clones, leading to disease reactivation after stopping treatment. Some BRAF-deficient mutation LCH patients resist vemurafenib and dabrafenib, but trametinib can manage the disease in these cases. Activation of the MAPK pathway increases BCL2L1 expression in LCH cells, and rapamycin fails to induce apoptosis in BRAFV600E+ LCH cells, enhancing resistance to cell death. MAPK inhibitors combined with chemotherapy are theoretically more effective at inducing apoptosis in LCH cells and resetting the immune environment to eliminate malignant clones. Two clinical studies confirm their safety and efficacy in treating refractory recurrent LCH. In a follow-up of 10 LCH cases treated with nucleotide analogues and MAPK inhibitors, only 2 patients relapsed after a short treatment duration. Additionally, 19 children with BRAFV600E mutation LCH were treated with cladribine, cytarabine, and vemurafenib, achieving a 100% response rate. Nearly 80% completed treatment without recurrence, and no increase in side effects was observed. Since 2020, our center treated nearly 40 LCH patients with MAPK inhibitors, including 14 combined with LCH-III chemotherapy. Follow-ups show no severe toxic side effects, aligning with literature. However, most high-risk patients, especially those who stopped oral MAPK inhibitors, had disease reactivation. Two high-risk patients with liver involvement achieved complete liver lesion regression with cladribine. This clinical study aims to assess the efficacy and safety of dabrafenib or trametinib and clofarabine for high-risk/recurrent/refractory LCH in children.

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