Multisystem Langerhans cell histiocytosis in children: current treatment and future directions.

Langerhans cell histiocytosis (LCH) is a rare (about 3-5 cases per million children aged 0-14 years), non-malignant disease characterized by proliferation and accumulation of clonal dendritic cells, extreme clinical heterogeneity, and an unpredictable course. Three large-scale, international, prospective therapeutic studies (LCH-I to III) for multisystem LCH (MS-LCH) have been conducted by the Histiocyte Society since 1991. The cumulative lessons from these studies are summarized in this review. Patients with MS-LCH represent a heterogeneous group with respect to disease severity and outcome, therefore treatment stratification and risk-tailored treatment are mandatory. The risk for mortality can be predicted based on involvement of 'risk organs' (e.g. hematopoietic system, liver, and/or spleen) at diagnosis and on response to initial therapy (assessed after 6-12 weeks of treatment). Thus, patients without involvement of risk organs (low-risk group) are not at risk for mortality but need systemic therapy in order to control the disease activity and avoid reactivations and permanent consequences. Patients with risk organ involvement (risk group) are at risk for mortality, and lack of therapy response defines a subgroup with a particularly dismal prognosis (high-risk group). Those patients in the risk group who respond to therapy and survive are at risk for reactivations and permanent consequences. The LCH-I study compared the efficacy of vinblastine and etoposide, and concluded that they are equivalent single-agent treatments for children with MS-LCH. However, the results of this trial were inferior with respect to response rate at week 6, disease reactivation rate, and sequelae, when compared with historical trials using more intensive regimens. The combination of prednisolone and vinblastine was established as a standard first-line treatment through the LCH-II and LCH-III studies. The regimen consists of one to two 6-week courses (continuous oral corticosteroids 40 mg/m2/day for 4 weeks, tapered over 2 weeks plus weekly vinblastine intravenous push) of initial therapy, followed by a continuation phase (three weekly pulses of oral prednisolone 40 mg/m2/day for 5 days plus a vinblastine injection). The addition of a third drug to the standard combination (etoposide in LCH-II and methotrexate in LCH-III) failed to significantly improve survival in the risk group. The remaining mortality in the risk group is about 20%, and up to 40% in the high-risk group. Concerning low-risk MS-LCH, comparison of results of the LCH-II study with historical data suggested that the remaining reactivation rate of about 50% (and possibly permanent consequences) could be reduced by prolongation of the total treatment duration. To study this hypothesis, in the low-risk group of the LCH-III study standard maintenance therapy was randomly given for a total treatment duration of 6 and 12 months. Unpublished preliminary data from this recently closed trial suggested that prolongation of the treatment duration may significantly improve reactivation-free survival. In summary, several studies have shown that systemic therapy is indicated for all patients with MS-LCH. A standard two-drug regimen consisting of an initial 'intensive' phase for 6-12 weeks, followed by a less intensive 'maintenance phase' for a total treatment duration of at least 12 months is recommended for patients treated outside of clinical trials. Non-responders, particularly those with progressive disease in risk organs, are eligible for experimental salvage approaches. Remaining questions will be addressed in the upcoming LCH-IV trial, which is in the process of intensive preparation.