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    Langerhans Cell Histiocytosis Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Treatment of Childhood LCH


    Treatment of high-risk multisystem disease

    Spleen, liver, and bone marrow (may or may not include skin, bone, lymph node, lung, or pituitary gland)

    • The standard therapy length recommended for LCH involving the spleen, liver, or bone marrow (high-risk organs) is now 12 months based upon the DAL-HX-83 and HISTSOC-LCH-III studies.[13,17] In the Histiocyte Society LCH-II and LCH-III studies, the standard arm consisted of vinblastine and prednisone as described above under multifocal bone, but 6-mercaptopurine was added to the continuation phase of the protocol.
    • The LCH-II study was a randomized trial to compare treatment of patients with vinblastine, prednisone, and mercaptopurine or vinblastine, prednisone, mercaptopurine, and etoposide.[26][Level of evidence: 1iiA]

      There was no statistical significance in outcomes (response at 6 weeks, 5-year probability of survival, relapses, and permanent consequences) between the two treatment groups. Hence, etoposide has not been used in subsequent Histiocyte Society trials. Late review of the results, however, reported reduced mortality of patients with risk-organ involvement in the etoposide arm. Although controversial, a comparison of patients in the LCH-I trial with patients in the LCH-II trial suggested that increased treatment intensity promoted additional early responses and reduced mortality.

      It is important to note that those studies included lungs as risk organs. However, subsequent analyses have shown that lung involvement lacks prognostic significance.[27]

    • The LCH-III study randomly assigned risk organ-affected patients to either vinblastine/prednisone/6-mercaptopurine or vinblastine/prednisone/6-mercaptopurine plus methotrexate (intravenous during the induction phase and oral in the continuation phase).[2] The response rates at 6 and 12 weeks and overall survival were not improved; however, there were significantly increased grade 3 and grade 4 toxicities in patients who received methotrexate.

      An important finding of the LCH-III study was that the mortality of patients with high-risk LCH on both arms of the study was significantly reduced compared with the earlier LCH-II study, even though the standard arm utilizes the same drugs. Possible explanations for reduced mortality include the following:

      • A second 6-week induction phase of weekly vinblastine with prednisone given for 3 days per week. This reinduction phase was given to all patients who did not achieve a status of no active disease by the end of the 6-week induction phase, before going onto the every-3-weeks maintenance courses. The rate of no active disease increased after the second induction phase and this course may have played a significant role in the reduced mortality rate.
      • Better supportive care.
      • Earlier change to an effective salvage strategy for nonresponsive lesions.

      It should be noted that although survival was improved in the LCH-III study, only 60% of patients had no active disease in risk organs after a year of therapy and 25% to 29% of patients relapsed.

    • The Japan LCH Study Group (JLSG) reported 5-year response and overall survival rates of 78% and 95%, respectively, for patients with multisystem disease treated on the JLSG-96 trial (6-week induction regimen of cytosine arabinoside, vincristine, and prednisolone followed by 6 months of maintenance therapy with cytarabine, vincristine, prednisolone, and low-dose intravenous methotrexate). If patients had a poor response to the initial regimen, they were switched to a salvage regimen of intensive combination doxorubicin, cyclophosphamide, methotrexate, vincristine, and prednisolone.[28]

      Similar to the LCH-III study, the important finding of this study was the decreased mortality compared with previous JLSG studies and to the LCH-II study. This was attributed to the early change to a more effective salvage therapy for patients with nonresponsive disease, as well as better supportive care.[28]

    • Some patients develop a "macrophage activation" of their marrow. This may be confusing to clinicians who may think the patient has hemophagocytic lymphohistiocytosis and LCH. The best therapy for this life-threatening manifestation is not clear, because it tends not to respond well to standard hemophagocytic lymphohistiocytosis therapy. Clofarabine, anti-CD52 antibody alemtuzumab, or reduced-intensity allogeneic stem cell transplant could be considered.[29]
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