Treatment of Recurrent, Refractory, or Progressive Childhood LCH
Recurrent Low-Risk Organ Involvement
Reactivation of single-system and multisystem LCH
Reactivation of Langerhans cell histiocytosis (LCH) after complete response has been reported; usually occurring within the first 9 to 12 months after stopping treatment. The percentage of patients with reactivations was 9% to 17.4% for single-site disease; 37% for single-system, multifocal disease; 46% for multisystem (nonrisk organ) disease; and 54% for patients with risk-organ involvement. Forty-three percent of reactivations were in bone, 11% in ears, 9% in skin, and 7% developed diabetes insipidus; a lower percentage of patients had lymph node, bone marrow, or risk-organ relapses. The median time to reactivation was 12 to 15 months in nonrisk patients and 9 months in risk patients. One-third of patients had more than one reactivation varying from 9 to 14 months after the initial reactivation. Patients with reactivations were more likely to have long-term sequelae in the bones, diabetes insipidus, or other endocrine, ear, or lung problems.
A comprehensive review of the German-Austrian-Dutch (Deutsche Arbeits-gemeinschaft für Leukaemieforschung und-therapie im Kindesalter [DAL]) and Histiocyte Society clinical trials revealed a reactivation rate of 46% at 5 years for patients with multisystem LCH, with most reactivations occurring within 2 years of first remission. A second reactivation occurred in 44%, again within 2 years of the second remission. Involvement of the risk organs in these reactivations occurred only in those who were initially in the high-risk group (meaning they had liver, spleen, or bone marrow involvement at the time of original diagnosis).[Level of evidence: 3iiiDiii] Most reactivations, even in patients with high-risk disease who initially responded to therapy, were in bone, skin, or other nonrisk locations.
The percentage of reactivations in multisystem disease was identical in the Japanese trial, [Level of evidence: 1iiA] and the LCH-II trial  (45% and 46%, respectively). There was not a statistically significant difference in reactivations between the high-risk and low-risk groups. Both the DAL-HX and Japanese studies concluded that intensified treatment increased rapid response, particularly in young children and infants younger than 2 years, and together with rapid switch to salvage therapy for nonresponders, reduced mortality for patients with high-risk multisystem LCH.
Treatment of low-risk organ involvement
The optimal therapy for patients with relapsed or recurrent LCH has not been determined. Several regimens exist, including the following:
- Patients with recurrent bone disease who recur 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 mercaptopurine nightly.
- An alternative treatment regimen employs vincristine, prednisone, and cytosine arabinoside. The prednisone dose is reduced from the dose used in the original publication.
- Bisphosphonate therapy is also effective for treating recurrent LCH bone lesions. In a survey from Japan, bisphosphonate therapy successfully treated the bone lesions in 12 of 16 patients. Skin and soft tissue LCH lesions also resolved in the responding patients. None of the patients had risk-organ disease. Most patients received six cycles of pamidronate at 1 mg/kg/course, given at 4-week intervals. Eight of the 12 patients remained disease free at a median of 3.3 years. Other bisphosphonates, such as zoledronate and oral alendronate, have also been successful in treating bone LCH.[9,10]
- Cladribine at 5 mg/m2/day for 5 days per course has also been shown to be effective therapy for recurrent low-risk LCH (multifocal bone and low-risk multisystem LCH) with very little toxicity. Cladribine therapy should, if possible, be limited to a maximum of six cycles to avoid cumulative and potentially long-lasting cytopenias.
- A phase II trial of thalidomide for patients with LCH (ten low-risk patients; six high-risk patients) who failed primary and at least one secondary regimen demonstrated complete (four of ten) and partial (three of ten) responses for the low-risk patients. Complete remission was defined as healing of bone lesions on plain radiographs (n = 3) or complete resolution of skin rash (n = 4, including 3 with bone lesions that had complete resolution). Partial response was defined as healing of bone lesion, but then worsening of a skin rash that was partially resolved. However, dose-limiting toxicities, such as neuropathy and neutropenia, may limit the overall usefulness of thalidomide. This agent is not used in pediatric patients to a significant degree.
- Clofarabine is a proven effective therapy for patients with multiple relapses of low-risk or high-risk organs.
Refractory High-Risk Organ Involvement
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 DAL Group studies have shown that these children have only a 10% chance of surviving. Results from 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, compared with 52% for good responders.[Level of evidence: 1iiA] All studies suggest that patients with poorly responsive disease need to be changed early to salvage strategies at 6 weeks for progressive disease and no later than 12 weeks for those without at least a good response.
Cladribine and 2’-deoxycoformycin have been tested as salvage therapies for LCH.[11,15]; [Level of evidence: 3iiiDiv] A case series reported that patients with multiple reactivations or high-risk disease could be effectively treated with continuous-infusion cladribine for 3 days. Seven of ten patients on this trial required no more therapy.[Level of evidence: 3iiiDii]
Patients with refractory high-risk organ (liver, spleen, or bone marrow) involvement and resistant multisystem low-risk organ involvement have been treated with an intensive acute myeloid leukemia–like protocol. Prompt change of therapy to cladribine and cytosine arabinoside appeared to provide an improvement in overall survival (OS).; [Level of evidence: 3iiiDii]; [Level of evidence: 3iiiDiv] This is a very intense regimen and requires that physicians are able to treat infectious and metabolic complications. Responses may be delayed.
Six patients with multiorgan LCH resistant to other agents, including cladribine, were reported to respond to treatment with clofarabine.; [Level of evidence: 3iiiDii] An additional 11 patients with recurrent multisystem high-risk and low-risk disease had a 90% OS. If confirmed in prospective trials, the reduced toxicity of this regimen, compared with the cladribine/cytarabine combination, could be advantageous despite the cost of the drug.
Hematopoietic stem cell transplantation (HSCT) has been used in patients with multisystem high-risk organ involvement that is refractory to chemotherapy.[7,23-25] The use of reduced-intensity conditioning, especially for patients that have received intensive chemotherapy just before HSCT, may reduce toxic deaths and improve outcome.
Treatment Options Under Clinical Evaluation
New targeted therapies under investigation include the following:
- RAS pathway inhibitors: The discovery that most patients with LCH have BRAF V600E or other mutations that result in activation of the RAS pathway, suggests that new therapies that target molecules within this pathway will become an important part of LCH therapy in the near future. NCT01677741 is currently open in the United States and Canada for adults with LCH and children with recurrent LCH. Although three adults with LCH and Erdheim-Chester disease had favorable responses to vemurafinib, the 30% incidence of squamous cell carcinoma in melanoma patients receiving this drug needs to be taken into account with moderate- to long-term use in children.
- Tyrosine kinase inhibitors: Several reports suggested that LCH, including central nervous system LCH, could be successfully treated with the tyrosine kinase inhibitor imatinib, while other reports failed to show an effect.[29,30]
- Pollono D, Rey G, Latella A, et al.: Reactivation and risk of sequelae in Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (7): 696-9, 2007. [PUBMED Abstract]
- Minkov M, Steiner M, Pötschger U, et al.: Reactivations in multisystem Langerhans cell histiocytosis: data of the international LCH registry. J Pediatr 153 (5): 700-5, 705.e1-2, 2008. [PUBMED Abstract]
- Morimoto A, Ikushima S, Kinugawa N, et al.: Improved outcome in the treatment of pediatric multifocal Langerhans cell histiocytosis: Results from the Japan Langerhans Cell Histiocytosis Study Group-96 protocol study. Cancer 107 (3): 613-9, 2006. [PUBMED Abstract]
- 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]
- 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]
- 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]
- Kudo K, Ohga S, Morimoto A, et al.: Improved outcome of refractory Langerhans cell histiocytosis in children with hematopoietic stem cell transplantation in Japan. Bone Marrow Transplant 45 (5): 901-6, 2010. [PUBMED Abstract]
- Farran RP, Zaretski E, Egeler RM: Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol 23 (1): 54-6, 2001. [PUBMED Abstract]
- Morimoto A, Shioda Y, Imamura T, et al.: Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan. Pediatr Blood Cancer 56 (1): 110-5, 2011. [PUBMED Abstract]
- Sivendran S, Harvey H, Lipton A, et al.: Treatment of Langerhans cell histiocytosis bone lesions with zoledronic acid: a case series. Int J Hematol 93 (6): 782-6, 2011. [PUBMED Abstract]
- Weitzman S, Braier J, Donadieu J, et al.: 2'-Chlorodeoxyadenosine (2-CdA) as salvage therapy for Langerhans cell histiocytosis (LCH). results of the LCH-S-98 protocol of the Histiocyte Society. Pediatr Blood Cancer 53 (7): 1271-6, 2009. [PUBMED Abstract]
- McClain KL, Kozinetz CA: A phase II trial using thalidomide for Langerhans cell histiocytosis. Pediatr Blood Cancer 48 (1): 44-9, 2007. [PUBMED Abstract]
- Simko SJ, Tran HD, Jones J, et al.: Clofarabine salvage therapy in refractory multifocal histiocytic disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman disease. Pediatr Blood Cancer 61 (3): 479-87, 2014. [PUBMED Abstract]
- 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]
- 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]
- Mottl H, Starý J, Chánová M, et al.: Treatment of recurrent Langerhans cell histiocytosis in children with 2-chlorodeoxyadenosine. Leuk Lymphoma 47 (9): 1881-4, 2006. [PUBMED Abstract]
- 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]
- 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]
- Apollonsky N, Lipton JM: Treatment of refractory Langerhans cell histiocytosis (LCH) with a combination of 2-chlorodeoxyadenosine and cytosine arabinoside. J Pediatr Hematol Oncol 31 (1): 53-6, 2009. [PUBMED Abstract]
- Imamura T, Sato T, Shiota Y, et al.: Outcome of pediatric patients with Langerhans cell histiocytosis treated with 2 chlorodeoxyadenosine: a nationwide survey in Japan. Int J Hematol 91 (4): 646-51, 2010. [PUBMED Abstract]
- Rodriguez-Galindo C, Jeng M, Khuu P, et al.: Clofarabine in refractory Langerhans cell histiocytosis. Pediatr Blood Cancer 51 (5): 703-6, 2008. [PUBMED Abstract]
- Abraham A, Alsultan A, Jeng M, et al.: Clofarabine salvage therapy for refractory high-risk langerhans cell histiocytosis. Pediatr Blood Cancer 60 (6): E19-22, 2013. [PUBMED Abstract]
- 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]
- 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]
- Caselli D, Aricò M; EBMT Paediatric Working Party: The role of BMT in childhood histiocytoses. Bone Marrow Transplant 41 (Suppl 2): S8-S13, 2008. [PUBMED Abstract]
- 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]
- Haroche J, Cohen-Aubart F, Emile JF, et al.: Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 121 (9): 1495-500, 2013. [PUBMED Abstract]
- Janku F, Amin HM, Yang D, et al.: Response of histiocytoses to imatinib mesylate: fire to ashes. J Clin Oncol 28 (31): e633-6, 2010. [PUBMED Abstract]
- Wagner C, Mohme H, Krömer-Olbrisch T, et al.: Langerhans cell histiocytosis: treatment failure with imatinib. Arch Dermatol 145 (8): 949-50, 2009. [PUBMED Abstract]
- Baumann M, Cerny T, Sommacal A, et al.: Langerhans cell histiocytosis with central nervous system involvement--complete response to 2-chlorodeoxyadenosine after failure of tyrosine kinase inhibitor therapies with sorafenib and imatinib. Hematol Oncol 30 (2): 101-4, 2012. [PUBMED Abstract]