Recurrent Low-Risk Organ Involvement
Refractory High-Risk Organ Involvement
Progressive Multisystem Langerhans Cell Histiocytosis

Recurrent Low-Risk Organ Involvement

The optimal therapy for patients with relapsed or recurrent disease has not been determined. Several regimens exist. Patients with recurrent bone disease who reoccur months after stopping vinblastine and prednisone can benefit from treatment with a reinduction of vinblastine weekly and daily prednisone for 6 weeks. If there is no active disease or very little evidence of active disease, treatment can be changed to every 3 weeks with the addition of oral methotrexate weekly and mercaptopurine nightly.[1] An alternative treatment regimen employs vincristine and cytosine arabinoside.[2]

A phase II trial of thalidomide for Langerhans cell histiocytosis (LCH) patients (10 low-risk patients; 6 high-risk patients) who failed primary and at least one secondary regimen demonstrated complete (4 of 10) and partial (3 of 10) responses for the low-risk patients. However, dose-limiting toxicities may limit the overall usefulness of thalidomide.[3]

The current Histiocyte Society clinical trial for patients with refractory high-risk organ (liver, spleen or bone marrow) involvement is an intensive acute myeloid leukemia-like protocol. Prompt change of therapy to 2-CdA and/or cytosine arabinoside may provide an improvement in overall survival.[4] This is a very intense regimen and requires that physicians are able to treat infectious and metabolic complications. Responses may be delayed. Hematopoietic stem cell transplantation (HSCT) has been done for patients with multisystem high-risk organ involvement that is refractory to chemotherapy.[5,6] HSCT has resulted in a relatively high toxic death rate. The use of reduced-intensity conditioning, especially for patients that have received intensive chemotherapy just prior to HSCT, may reduce toxic deaths and improve outcome.[7]

A new treatment plan is indicated when a patient with multisystem involvement shows progressive disease after 6 weeks of standard treatment, or has not had a partial response by 12 weeks. Data from the German-Austrian-Dutch Group studies have shown that these children have only a 10% chance of surviving.[8] Results of the LCH-II trial revealed that patients treated with vinblastine/prednisone who did not respond well by 6 weeks had a 27% chance of survival.[9] Those treated with vinblastine/prednisone/etoposide with a good response at 6 weeks had a 52% chance of survival. A report about the use of 2-CdA and 2’-deoxycoformycin as salvage therapies for LCH has been published.[10] In this trial, these drugs were more often effective for patients with bone, skin, or lymph node involvement. Only one-third of patients with LCH of the liver, bone marrow, spleen, or lung responded. Another study demonstrated that patients with multiple reactivations or high-risk disease could be effectively treated with continuous infusion 2-CdA for 3 days.[11] Seven of 10 patients on this trial required no more therapy.

References

1. Titgemeyer C, Grois N, Minkov M, et al.: Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study. Med Pediatr Oncol 37 (2): 108-14, 2001.  [PUBMED Abstract]
   
   
2. Egeler RM, de Kraker J, Voûte PA: Cytosine-arabinoside, vincristine, and prednisolone in the treatment of children with disseminated Langerhans cell histiocytosis with organ dysfunction: experience at a single institution. Med Pediatr Oncol 21 (4): 265-70, 1993.  [PUBMED Abstract]
   
   
3. McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007.  [PUBMED Abstract]
   
   
4. Bernard F, Thomas C, Bertrand Y, et al.: Multi-centre pilot study of 2-chlorodeoxyadenosine and cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with haematological dysfunction. Eur J Cancer 41 (17): 2682-9, 2005.  [PUBMED Abstract]
   
   
5. Akkari V, Donadieu J, Piguet C, et al.: Hematopoietic stem cell transplantation in patients with severe Langerhans cell histiocytosis and hematological dysfunction: experience of the French Langerhans Cell Study Group. Bone Marrow Transplant 31 (12): 1097-103, 2003.  [PUBMED Abstract]
   
   
6. Nagarajan R, Neglia J, Ramsay N, et al.: Successful treatment of refractory Langerhans cell histiocytosis with unrelated cord blood transplantation. J Pediatr Hematol Oncol 23 (9): 629-32, 2001.  [PUBMED Abstract]
   
   
7. Steiner M, Matthes-Martin S, Attarbaschi A, et al.: Improved outcome of treatment-resistant high-risk Langerhans cell histiocytosis after allogeneic stem cell transplantation with reduced-intensity conditioning. Bone Marrow Transplant 36 (3): 215-25, 2005.  [PUBMED Abstract]
   
   
8. Gadner H, Grois N, Arico M, et al.: A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr 138 (5): 728-34, 2001.  [PUBMED Abstract]
   
   
9. Gadner H, Grois N, Pötschger U, et al.: Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 111 (5): 2556-62, 2008.  [PUBMED Abstract]
   
   
10. Weitzman S, Wayne AS, Arceci R, et al.: Nucleoside analogues in the therapy of Langerhans cell histiocytosis: a survey of members of the histiocyte society and review of the literature. Med Pediatr Oncol 33 (5): 476-81, 1999.  [PUBMED Abstract]
    
    
11. Stine KC, Saylors RL, Saccente S, et al.: Efficacy of continuous infusion 2-CDA (cladribine) in pediatric patients with Langerhans cell histiocytosis. Pediatr Blood Cancer 43 (1): 81-4, 2004.  [PUBMED Abstract]
    
    

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