How is recurrent or refractory Langerhans cell histiocytosis (LCH) treated?

Updated: Sep 16, 2020
  • Author: Cameron K Tebbi, MD; Chief Editor: Vikramjit S Kanwar, MBBS, MBA, MRCP(UK), FAAP  more...
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The severity of the recurrent disease often dictates the type of therapy that is most likely to be helpful. For example, recurrence of an isolated bone lesion can often be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or intralesional steroid injections. When bone lesions are multiple and cause clinically significant morbidity, systemic therapy can be helpful. In such circumstances, patients often respond to the same drugs that they previously received, such as vinblastine and/or corticosteroids.

A retrospective study by Sedky et al indicated that in children with Langerhans cell histiocytosis, those who suffer multiple reactivations of the disease respond well to repeated use of first-line treatment, with or without methotrexate. The study, which had a median follow-up period of 42 months, involved 80 pediatric patients with the condition who were treated according to the Langerhans cell histiocytosis III protocol; 25 patients experienced reactivation, including 5 who suffered multiple reactivations. [316]

Extensive recurrence of skin disease, including refractory perianal or vulvar involvement, often requires systemic chemotherapy.

When patients do not have an early (ie, by 6 wk of therapy) response to vinblastine, corticosteroids, methotrexate, 6-mercaptopurine, or even etoposide, alternate therapies should be administered. Although several immunomodulatory agents, such as cyclosporine, have been used in patients with refractory disease, the results have been inconsistent. Cytotoxic chemotherapy often needs to be administered as well. Vemurafenib has been reported to be a highly effective agent for the treatment of adults with multisystemic and refractory LCH and polyostotic sclerosing histiocytosis (Erdheim-Chester disease).

Several studies, including an international phase II trial, demonstrated notable activity associated with 2CdA. This agent was originally used to treat patients with refractory hairy-cell leukemia and chronic lymphocytic leukemia. Response rates were more than 50%. Because 2CdA has antiproliferative effects on lympholytic and histiocytic cells, it is a potentially ideal drug to use in Langerhans cell histiocytosis, which is characterized by reactive lymphocytic and dendritic and macrophage components. Response rates to 2CdA have been particularly good in patients with extensive skin and bone disease, and in some patients with pulmonary involvement. Overall response rates have been about 30-40% in children. In a study with a small number of adults, the response rate was less than 70%. In 2 reports, a combination of 2CdA and Ara-C seemed to have major effects in a small group of children with refractory disease, but clinically significant grade 4 toxicities and a sepsis-related death were reported. [302, 317]

For some patients whose disease does not respond to 2CdA alone, the combination of 2CdA and high-dose cytarabine has been effective. A similar regimen has also been effective in patients with relapses of acute myelogenous leukemia. Until additional information is obtained with this drug combination, the true response rate and the duration of response are difficult to determine.

Other approaches to the treatment of patients with refractory Langerhans cell histiocytosis that are being tested or developed and include agents such as thalidomide, which is used to inhibit tumor necrosis factor (TNF)-alpha and INF-gamma production. [318] (INF-gamma is a cytokine produced by a subgroup of lymphocytes to regulate immune responses.) In some studies, only patients with low-risk disease were likely to respond to thalidomide, whereas high-risk patients with organ involvement were not. [319, 320] Emapalumab, a monoclonal antibody that also inhibits INF-gamma, is under investigation for the treatment of hemophagocytic lymphohistiocytosis (HLH).

Further recognition of NF-kappaB pathway may improve the success of targeted therapy for Langerhans cell histiocytosis. [321]

Targeting humanized antibodies against lineage-specific antigens, such as CD1a antigens on Langerhans cell histiocytosis cells, is another treatment being developed. The application of inhibitors of activated cytokine receptors and their downstream signal-transduction pathways is also an important area of future therapeutic trials. Although hematopoietic stem-cell transplantation has been successful in some patients with refractory Langerhans cell histiocytosis, identifying patients who might benefit from such high-risk therapy is difficult, and this treatment is associated with significant acute and chronic complications.

In some studies, children with multisystem LCH and risk organ involvement who had not responded to conventional therapies underwent a reduced intensity conditioning regimen (RIC) followed by allogenic stem cell transplantation, which was associated with lower transplant-related morbidity and mortality as well as an improved outcome. [16]

Specific therapies, including monoclonal antibodies against the CD1a or CD52 epitopes found on Langerhans cells, are emerging. [305]

Local therapy with various agents has been reported. Intralesional infiltration with corticosteroids for treatment of localized LCH has been advocated. [322]

Myeloablative therapy followed by bone-marrow or stem-cell transplantation in disease refractory to the conventional therapy has been reported. [323] However, reporting of positive results are likely to bias such reports.

Intravenous immunoglobulin has been used to treat neurodegenerative LCH. However, to the authors’ knowledge, no formal study has been done to conclusively affirm the benefit of such a treatment. For FHL treatment, a combination of antithymocyte globulin, steroids and cyclosporin has been used. [324]

The need to develop effective treatments and, ultimately, strategies to prevention progressive fibrosis of the lung, sclerosing cholangitis, and fibrosis of the liver, and the neurodegenerative pattern of CNS involvement is immense. Additional clinical trials are needed to determine whether agents such as 2CdA or specific inhibitors of fibrosis can improve the outcomes of patients with these complications.


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