What is the efficacy of chemotherapeutic agents used to treat Langerhans cell histiocytosis (LCH)?

Updated: Jun 12, 2020
  • Author: Christopher R Shea, MD; Chief Editor: William D James, MD  more...
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Multiple large clinical trials have examined differences in efficacy between chemotherapeutic agents.

One cooperative clinical trial in Europe used vinblastine, etoposide, and prednisolone for 6 weeks, followed by mercaptopurine, vinblastine, and prednisolone for 1 year. If soft tissue was involved, treatment was supplemented with etoposide, and, if the patient has organ dysfunction, methotrexate was added. Initial complete resolution occurred in 86% of patients, with a mortality rate of 9% and a disease-free survival rate of 77% at a median follow-up time of 6 years. [71]

The LCH-I trial sponsored by the Histiocyte Society used etoposide or vinblastine for 24 weeks. These agents produced equivalent responses at week 6 and had similar effects on survival and disease recurrence. Lack of response at 6 weeks was associated with an increased likelihood of treatment failure and a worse prognosis. The survival rate was slightly better in the aforementioned European trial than in LCH-I, but the difference was not statistically significant. A greater probability of developing diabetes insipidus occurred in the LCH-I trial. [32]

The LCH-II randomized clinical trial compared the effectiveness of 24 weeks of combined therapy with vinblastine, oral prednisone, and mercaptopurine, versus the same combination with the addition of etoposide. The overall survival in patients treated with etoposide was marginally improved compared with treatment without it; this effect was more pronounced in those patients with risk-organ involvement. However, although the addition of etoposide produced slightly more favorable therapeutic responses, it did not decrease the likelihood of disease recurrence. [72] Ultimately, the Histiocyte Society concluded that early therapy intensification (when compared with the LCH-I trial) had a positive effect on survival. [72] However, the addition of etoposide appeared to be of minimal therapeutic benefit and it use was not included in the recommendations of the Histiocyte Society released in April 2009.

The LCH-III study, a prospective, randomized clinical trial, evaluated the efficacy of adding methotrexate to vinblastine and prednisone in the treatment of LCH in multisystem-risk patients. It also included evaluation of the optimal duration of treatment (6 mo vs 12 mo) using prednisone and vinblastine for multisystem low-risk patients. Finally, it includes a pilot study for patients with single-system multifocal bone disease and localized special sites, including the CNS. Results of LCH-III resulted in the following recommendations from the Histiocyte Society:

  • Risk patients should be treated with oral prednisone daily and intravenous vinblastine weekly for 6 weeks. Patients who continue to have active disease should repeat this regimen for another 6 weeks. Patients who have no active disease after 6-week induction therapy should begin continuation treatment with oral 6-mercaptopurine daily, supplemented with pulses of oral prednisone and intravenous vinblastine, for 12 months of total treatment. The addition of methotrexate to LCH treatment is not recommended in current practice.

  • Low-risk patients should be treated with oral prednisone and intravenous vinblastine for 12 months total.

  • Patients with multifocal bone disease or CNS risk should be treated with oral prednisone daily and intravenous vinblastine weekly for 6 weeks. Patients should then be supplemented with pulses of oral prednisone and intravenous vinblastine for 6 months of total treatment.

LCH-IV, an international treatment protocol sponsored by Dana-Farber Cancer Institute for children and adolescents with LCH (ClinicalTrials.gov identifier NCT02205762), is currently recruiting participants. In this randomized, interventional study, patients who do not respond to standard first-line prednisone and vinblastine will be switched to the combination of cytosine arabinoside and 2-chlorodeoxyadenosine. Other stratifications of the study design include treatments with mercaptopurine and methotrexate, indomethacin, hematopoietic stem cell transplantation, and intravenous immunoglobulin.

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