The last several decades have seen enormous gains in knowledge with regard to the biology of Langerhans cell histiocytosis (LCH). However, this increased understanding has not yet translated into dramatic improvements in outcome, particularly for patients with multisystem (MS) disease whose disease is refractory to standard therapy, patients with chronic relapsing disease or those with the late chronic progressive involvement of lung, liver and central nervous system (CNS), who continue to pose a significant dilemma for treating physicians. This chapter will concentrate on the problems of therapy for patients with refractory, multiorgan disease and those with late chronic progressive disease of lung and liver. CNS neurodegenerative diseases are discussed in Chapter 10.

Refractory multiorgan disease

Early cooperative group studies have shown that patients with MS disease clearly benefit from chemotherapy. The mortality for high-risk patients with disseminated disease does not, however, appear to have changed from the early Austro-German cooperative trials, the DAL-HX 83 and 90 trials, to the later LCH-I and II studies of the Histiocyte Society. Thus, about 20% of young children with MS LCH do not respond to modern protocols and often have disease that is resistant to alternative therapies.

An important step forward has been the ability to determine which patients will have poor outcomes. Features which portend a poor outcome include involvement of ‘risk’ organs (such as lung, liver, spleen and hematopoietic system) and failure to respond after 6 weeks of initial therapy (Gadner et al., 2001; Minkov et al., 2002).