BISPHOSPHONATES IN LANGERHANS CELL HISTIOCYTOSIS: AN INTERNATIONAL RETROSPECTIVE CASE SERIES

Main Article Content

Deepak Chellapandian http://orcid.org/0000-0003-3518-9790
Polyzois Makras
Gregory Kaltsas
Cor van den Bos
Lamia Naccache
Raajit Rampal
Anne-Sophie Carret
Sheila Weitzman
R. Maarten Egeler
Oussama Abla

Keywords

Langerhans cell histiocytosis, bisphosphonate, chemotherapy, bone pain of LCH, disease reactivation

Abstract

Background: Bone is the most common organ of involvement in patients with Langerhans cell histiocytosis (LCH), which is often painful and associated with significant morbidity from pathological fractures. Current first-line treatments include chemotherapy and steroids that are effective but often associated with adverse effects, whereas the disease may reactivate despite an initial response to first-line agents. Bisphosphonates are osteoclast inhibitors that have shown to be helpful in treating bone lesions of LCH. To date, there are no large international studies to describe their role in treating bone lesions of LCH. Method: We conducted a multicenter retrospective review of 13 patients with histologically proven LCH, who had received bisphosphonates either at diagnosis or at disease reactivation. Results: Ten patients (77%) had a single system bone disease, and 3 (23%) had bone lesions as part of multisystem disease. Median follow-up time post-bisphosphonate therapy was 4.6 years (range, 0.8 to 8.2 years). Treatment with bisphosphonates was associated with significant pain relief in almost all patients. Twelve  (92%) achieved resolution of active bone lesions, and 10 out of them had no active disease for a median of 3.5 years (range, 0.8 to 5 years). One patient did not respond. No major adverse effects were reported in this series.  Conclusion: Bisphosphonates are well-tolerated drugs that can significantly improve bone pain and induce remission in active bone LCH. Future prospective studies evaluating the role of bisphosphonates in LCH are warranted.

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References

1. Abla O, Weitzman S (2015) Treatment of Langerhans cell histiocytosis: role of BRAF/MAPK inhibition. Hematology / the Education Program of the American Society of Hematology American Society of Hematology Education Program 1:565-570

2. Weitzman S, Egeler RM (2008) Langerhans cell histiocytosis: update for the pediatrician. Current opinion in pediatrics 20:23-29

3. Egeler RM, Thompson RC, Jr., Voute PA, Nesbit ME Jr. (1992) Intralesional infiltration of corticosteroids in localized Langerhans' cell histiocytosis. J Pediatr Orthop 12:811-814

4. Abla O, Egeler RM, Weitzman S (2010) Langerhans cell histiocytosis: Current concepts and treatments. Cancer treatment reviews 36:354-359

5. Shaw NJ, Bishop NJ (2005) Bisphosphonate treatment of bone disease. Arch Dis Child 90:494-499

6. Elomaa I, Blomqvist C, Porkka L, Holmström T (1989) Experiences of clodronate treatment of multifocal eosinophilic granuloma of bone. J Intern Med 225:59-61

7. Farran RP, Zaretski E, Egeler RM (2001) Treatment of Langerhans cell histiocytosis with pamidronate. J Pediatr Hematol Oncol 23:54-56

8. Arzoo K, Sadeghi S, Pullarkat V (2001) Pamidronate for bone pain from osteolytic lesions in Langerhans'-cell histiocytosis. The New England journal of medicine 345:225

9. Kamizono J, Okada Y, Shirahata A, Tanaka Y (2002) Bisphosphonate induces remission of refractory osteolysis in langerhans cell histiocytosis. J Bone Miner Res 17:1926-1928

10. Montella L, Merola C, Merola G, Petillo L, Palmieri G (2009) Zoledronic acid in treatment of bone lesions by Langerhans cell histiocytosis. Journal of bone and mineral metabolism 27:110-113

11. da Costa CE, Annels NE, Faaij CM, Forsyth RG, Hogendoorn PC, Egeler RM (2005) Presence of osteoclast-like multinucleated giant cells in the bone and nonostotic lesions of Langerhans cell histiocytosis. J Exp Med 201:687-693

12. Trotti A, Colevas AD, Setser A, Rusch V, Jaques D, Budach V, Langer C, Murphy B, Cumberlin R, Coleman CN, Rubin P (2003) CTCAE v3.0: development of a comprehensive grading system for the adverse effects of cancer treatment. Semin Radiat Oncol 13:176-181

13. Gadner H, Minkov M, Grois N, Pötschger U, Thiem E, Aricò M, Astigarraga I, Braier J, Donadieu J, Henter JI, Janka-Schaub G, McClain KL, Weitzman S, Windebank K, Ladisch S; Histiocyte Society (2013) Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood 121:5006-5014

14. Morimoto A, Shioda Y, Imamura T, Kanegane H, Sato T, Kudo K, Nakagawa S, Nakadate H, Tauchi H, Hama A, Yasui M, Nagatoshi Y, Kinoshita A, Miyaji R, Anan T, Yabe M, Kamizono J; LCH Committee, Japanese Pediatric Leukemia/Lymphoma Study Group (2011) Nationwide survey of bisphosphonate therapy for children with reactivated Langerhans cell histiocytosis in Japan. Pediatr Blood Cancer 56(1):110-115

15. Abildgaard N, Rungby J, Glerup H, Brixen K, Kassem M, Brincker H, Heickendorff L, Eriksen EF, Nielsen JL (1998) Long-term oral pamidronate treatment inhibits osteoclastic bone resorption and bone turnover without affecting osteoblastic function in multiple myeloma. Eur J Haematol 61:128-134

16. Drake MT, Clarke BL, Khosla S (2008) Bisphosphonates: mechanism of action and role in clinical practice. Mayo Clin Proc 83:1032-1045

17. Mercadante S (1997) Malignant bone pain: pathophysiology and treatment. Pain 69:1-18

18. Egeler RM, Favara BE, van Meurs M, Laman JD, Claassen E (1999) Differential In situ cytokine profiles of Langerhans-like cells and T cells in Langerhans cell histiocytosis: abundant expression of cytokines relevant to disease and treatment. Blood 94:4195-4201

19. Makras P, Polyzos SA, Anastasilakis AD, Terpos E, Kanakis G, Schini M, Papatheodorou A, Kaltsas GA (2012) Serum osteoprotegerin, RANKL, and Dkk-1 levels in adults with Langerhans cell histiocytosis. The Journal of clinical endocrinology and metabolism 97:E618-621

20. Makras P, Salagianni M, Revelos K, Anastasilakis AD, Schini M, Tsoli M, Kaltsas G, Andreakos E (2015) Rationale for the application of RANKL inhibition in the treatment of Langerhans cell histiocytosis. The Journal of clinical endocrinology and metabolism 100:E282-286

21. Ishii R, Morimoto A, Ikushima S, Sugimoto T, Asami K, Bessho F, Kudo K, Tsunematu Y, Fujimoto J, Imashuku S (2006) High serum values of soluble CD154, IL-2 receptor, RANKL and osteoprotegerin in Langerhans cell histiocytosis. Pediatr Blood Cancer 47(2):194-199

22. Lindahl K, Kindmark A, Rubin CJ, Malmgren B, Grigelioniene G, Söderhäll S, Ljunggren Ö, Åström E (2016) Decreased fracture rate, pharmacogenetics and BMD response in 79 Swedish children with osteogenesis imperfecta types I, III and IV treated with Pamidronate. Bone 87:11-18

23. Palomo T, Andrade MC, Peters BS, Reis FA5, Carvalhaes JT, Glorieux FH, Rauch F, Lazaretti-Castro M (2016) Evaluation of a Modified Pamidronate Protocol for the Treatment of Osteogenesis Imperfecta. Calcif Tissue Int. 98:42-8

24. Coleman RE (2004) Bisphosphonates: clinical experience. Oncologist 9 (Suppl 4):14-27

25. Luo RB, Lin T, Zhong HM, Yan SG, Wang JA (2014) Evidence for using alendronate to treat adult avascular necrosis of the femoral head: a systematic review. Med Sci Monit 20:2439-2447

26. King AE, Umland EM (2008) Osteonecrosis of the jaw in patients receiving intravenous or oral bisphosphonates. Pharmacotherapy 28:667-677

27. Chahine C, Cheung MS, Head TW, Schwartz S, Glorieux FH, Rauch F (2008) Tooth extraction socket healing in pediatric patients treated with intravenous pamidronate. The Journal of pediatrics 153:719-720