Improved outcome in the treatment of pediatric multifocal Langerhans cell histiocytosis: Results from the Japan Langerhans Cell Histiocytosis Study Group-96 protocol study.

BACKGROUND: The treatment outcome of multifocal childhood Langerhans cell histiocytosis (LCH) has not been satisfactory and has resulted in poor therapeutic responses with high mortality and a high incidence of reactivation with late sequelae. To overcome these issues, the Japan LCH Study Group-96 (JLSG-96) protocol was conducted prospectively from 1996 to 2001 in Japan. METHODS: Newly diagnosed children with multifocal LCH were classified into 2 groups: a single-system multisite (SS-m) group and a multisystem (MS) group. All patients initially were treated on Protocol A, which consisted of 6 weeks of induction therapy with combined cytosine arabinoside, vincristine (VCR), and prednisolone (PSL) followed by 6 months of maintenance therapy. Patients who had a poor response to the induction of Protocol A were switched to a salvage regimen (Protocol B), which consisted of an intensive combination of doxorubicin, cyclophosphamide, VCR, and PSL. RESULTS: In total, 91 patients were treated, including 32 patients in the SS-m group and 59 patients in the MS group. At the median 5-year follow-up, 96.9% of patients in the SS-m group and 78.0% of patients in the MS group had good response status. Diabetes insipidus developed in 3.1% of patients in the SS-m group and in 8.9% of patients in the MS group. The overall survival rate at 5 years for the SS-m and MS groups was 100% and 94.4% +/- 3.2%, respectively. CONCLUSIONS: The JLSG-96 protocol attained very low mortality for pediatric patients with multifocal LCH.

High serum values of soluble CD154, IL-2 receptor, RANKL and osteoprotegerin in Langerhans cell histiocytosis.

BACKGROUND: To determine useful biochemical markers in Langerhans cell histiocytosis (LCH), we analyzed the serum levels of soluble CD154 (sCD154), IL2 receptor (sIL2-R), receptor activator of NF-kappaB ligand (sRANKL), and osteoprotegerin (OPG). PROCEDURE: Our study included 46 newly diagnosed LCH patients (single-system multi-site (SM type): n = 20, and multi-system multi-site (MM type): n = 26) who were treated with the JLSG-02 protocol between 2002 and 2004. The median age of the patients was 3.8 years old (range 0-18). sCD154, sIL2-R, sRANKL, and OPG were measured by ELISA at diagnosis (n = 46) and after 6-weeks of induction therapy (n = 14). RESULTS: The values of sCD154, sIL-2R, sRANKL, and OPG, and the sRANKL/OPG ratio in sera were significantly higher in patients with LCH compared with controls (1.83 +/- 1.38 vs. 0.22 +/- 0.16 ng/ml, P < 0.001; 1,600 +/- 1,060 vs. 420 +/- 160 pg/ml, P < 0.001; 1.72 +/- 1.20 vs. 1.04 +/- 1.09 pmol/L, P = 0.019; 6.34 +/- 2.94 vs. 3.71 +/- 2.03 pmol/L, P < 0.001; and 0.40 +/- 0.45 vs. 0.16 +/- 0.17, P = 0.023, respectively). Serum levels of sIL-2R were significantly elevated in the MM type compared with the SM type (2,050 +/- 1,060 vs. 870 +/- 340 pg/ml, P < 0.001). Serum OPG levels were also significantly elevated in the MM type compared with the SM type (7.58 +/- 2.72 vs. 5.13 +/- 2.69 pmol/L, P = 0.008) and negatively correlated with the number of bone lesions (r = -0.56, P = 0.007). In contrast, the sRANKL/OPG ratios were significantly higher in the SM type than the MM type (0.57 +/- 0.54 vs. 0.19 +/- 0.14, P = 0.002) and positively correlated with the number of bone lesions (r = 0.34, P = 0.040). In patients who responded to the induction therapy, serum levels of sIL-2R, sRANKL, and OPG, and the sRANKL/OPG ratio decreased significantly after the therapy (1,170 +/- 600 vs. 730 +/- 290 pg/ml, P = 0.029; 2.19 +/- 1.06 vs. 1.24 +/- 0.66 pmol/L, P < 0.001; 6.13 +/- 2.40 vs. 4.72 +/- 2.03 pmol/L, P = 0.040; and 0.57 +/- 0.52 vs. 0.41 +/- 0.37, P = 0.02, respectively). In the three patients who did not respond to the induction therapy, the serum levels of sCD154 increased significantly after the therapy (1.3 +/- 1.1 vs. 2.7 +/- 1.2, P = 0.004). CONCLUSIONS: Serum levels of sIL-2R and sCD154 could be useful as indicators of inflammation and sRANKL/OPG ratios as markers of osteolytic activity in LCH patients.