How is refractory Langerhans cell histiocytosis (LCH) treated?

Updated: Jun 12, 2020
  • Author: Christopher R Shea, MD; Chief Editor: William D James, MD  more...
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LCH-S-98, a prospective, phase II Histiocyte Society study evaluated 2-chlorodeoxyadenosine (2-CdA) as salvage monotherapy for patients with risk-organ involvement refractory to initial therapy with three agents (excluding 2-CdA) or patients with recurrent, low-risk LCH (ie, patients with non–risk-organ involvement, including multifocal bone disease). [73] The study concluded that 2-CdA is active as salvage therapy for LCH, but that it is more effective in low-risk patients or patients with multifocal bone disease. Those patients with risk-organ involvement who responded to 2-CdA therapy had a good prognosis, while those who were refractory typically had grim outcomes. Notably, patients older than 2 years and those with a longer time between diagnosis and 2-CdA therapy had better responses, presumably because their disease was less aggressive. [73]

Combination therapy with 2-chlorodeoxyadenosine and cytosine arabinoside (ARA-C) has been studied in patients with refractory, risk-organ‒positive LCH. The overall 5-year survival rate was 85%; thus, the combination of 2-chlorodeoxyadenosine and ARA-C appears to be an effective therapy for refractory multisystem LCH, albeit one associated with high toxicity. [74]

A retrospective study evaluating the efficacy of 2-CdA (+/- arabinoside) in treating refractory LCH in 17 Japanese patients similarly concluded that 2-CdA is effective for the treatment of refractory disease. [75] Notably, patients whose disease reactivated following the conclusion of their initial therapy had improved outcomes compared with those patients who had primary refractory disease or those who experienced reactivation during their initial chemotherapy. This same study also suggested that 2-CdA may be effective in the treatment of LCH with CNS involvement. [75]

In LCH patients with a very poor prognosis (rapid disease progression, refractory to conventional treatment, or with disseminated risk-organ involvement), bone marrow transplantation (BMT) or reduced-intensity condition stem cell transplantation has shown promise as effective salvage therapy. [76, 77, 78] A retrospective review of 87 instances of hematopoietic stem cell transplant (HSCT) for LCH provides cautious optimism about the benefits of this procedure. [79] Specifically, the authors note that survival after HSCT has improved with time, and almost 75% of children now survive following transplantation, which the authors attribute in part to better supportive care following HSCT. Comparing myeloablative condition regimens with reduced intensity conditioning (RIC) regimens, there appeared to be no differences in transplantation-related mortality, although those undergoing RIC had higher relapse rates. These findings may reflect a selection bias where patients at higher risk were more cautiously treated with RIC regimens. Although a hopeful option for patients refractory to typical chemotherapy, the authors caution that the ideal conditioning regimen remains undefined; timing of such transplantations have also not been rigorously evaluated. [79, 80]

Resistant LCH may also be treated with a combination of cyclosporin A, antithymocyte globulin, and prednisolone if patients do not have a matched donor for BMT.

Thalidomide has also been proposed as an agent for treating refractory/relapsing multisystem disease, but its efficacy appears to be limited to low-risk patients with only skin or bone involvement. Its use also is associated with significant toxicities, including pancytopenia and pulmonary failure. [81]


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