Cladribine as the first line treatment in multifocal or multiorgan Langerhans cell histiocytosis in adult patients

Czech version

Authors: Z. Adam ¹; P. Szturz ¹; J. Ďuraš ²; Z. Řehák ³; R. Koukalová ³; L. Pour ¹; M. Krejčí ¹; M. Navrátil ¹; Z. Adamová ⁴; R. Hájek ¹; J. Mayer ¹
Authors‘ workplace: Interní hematoonkologická klinika Lékařské fakulty MU a FN Brno, pracoviště Bohunice, přednosta prof. MUDr. Jiří Mayer, CSc. ¹; Oddělení klinické hematologie FN Ostrava, přednosta prim. MUDr. Jaroslav Gumulec, Ph. D. ²; Oddělení nukleární medicíny a pozitronové emisní tomografie Masarykova onkologického ústavu Brno, přednosta prim. MUDr. Karol Bolčák ³; Chirurgické oddělení Nemocnice Vsetín, přednosta prim. MUDr. Jaroslav Sankot ⁴
Published in: Vnitř Lék 2010; 56(Supplementum 2): 141-151
Category: Langerhans cell histiocytosis and some other Hematology rare diseases

Overview

Introduction:
Vinblastin and prednisone are the traditional treatment choices in Langerhans cell histiocytosis (LCH). Cladribine has also been shown to be highly effective. It was originally used as the second and higher lines treatment and achieved high treatment response. The first report on excellent results achieved with cladribine as the first line treatment was published in 2003. Based on this report and our own experience with high efficacy of cladribine when administered as the second and higher line treatment, we use cladribine since 2003 not only for adult patients with relapsing multifocal or multiorgan form of LCH but also as part of the first line treatment of multifocal and multisystemic forms of LCH.

Patients and methodology:
Ten patients (9 men and 1 woman) have been treated with cladribine since 2001. Median age at diagnosis was 31.5 (5–45) years. The disease involved multiple organs in 8 patients and had an aggressive multifocal bone-involving form in 2 patients. Cladribine was administered in the dose of 5 mg/m²/day s.c. for 5 consecutive days in 28-day intervals. In 2 patients in whom the treatment was insufficient, the 3^rd cycle of cladribine monotherapy was followed by a combination treatment with cladribine 5 mg/m²/day, cyclophosphamide 300 mg/day and dexamethasone 20 mg/day, all 1^st–5^th day. We planned a maximum of 6 cycles. Median of administered cladribine cycles was 5 (4–6).

Results:
In 2 patients, the disease had an aggressive character at the diagnosis, and thus a collection of haematopoietic stem cells from peripheral blood was performed before cladribine administration. In total, 9 patients have now completed their treatment and, of these, 8 (88%) are in complete remission. The treatment was ineffective in one patient only – it relapsed within 60 days from treatment completion. This patient received three cycles of the CHOEP regimen (cyclophosphamide, adriamycin, vincristine, etoposide and prednisone) and the treatment was completed with high-dose BEAM chemotherapy (carmustine, cytarabine, etoposide, melphalan). The patient has now been in complete remission for 5 months from the completion of the high-dose therapy. Treatment response was observed in all 3 patients with CNS involvement, in 2 patients with LHC focus in pituitary infundibulum and in 1 patient with LCH focus in temporal lobe.

Conclusion:
Cladribine is a suitable treatment modality for multiorgan and multifocal forms of LCH. Complete remission was achieved in 88% of the 9 evaluable patients. Treatment response was achieved in all three patients with CNS lesions. Addition of cyclophosphamide and dexamethasone after the 4th cycle improved treatment response in 2 patients, although this response was sustained on longer term basis in one patient only. Ascertaining the usefulness of adding cyclophosphamide and dexamethasone to cladribine in patients with LCH will require evaluation of this treatment on a larger sample of patients.

Key words:
cladribine – 2-chlorodeoxyadenosine – Langerhans cell histiocytosis – diabetes insipidus

Sources

1. Aricò M, Girschikofsky M, Généreau T et al. Langerhans cell histiocytosis in adults. Report from the International Registry of the Histiocyte Society. Eur J Cancer 2003; 39: 2341–2348.

2. Haupt R, Nanduri V, Calevo MG et al. Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society-Late Effect Study Group. Pediatr Blood Cancer 2004; 42: 438–444.

3. Allen CE, McClain KL. Langerhans cell histiocytosis: a review of past, current and future therapies. Drugs Today (Barc) 2007; 43: 627–643.

4. Carrera CJ, Terai C, Piro LD et al. Potent toxicity of 2-chlorodeoxyadenosine toward human monocytes in vitro and in vivo. A novel approach to immunosuppressive therapy. J Clin Invest 1996; 86: 1480–1488.

5. Liliemark J. The clinical pharmacokinetics of cladribine. Clin Pharmacokinet 1997; 32: 120–131.

6. Bryson MH, Sorkin EM. Cladribine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in haematological malignancies. Drugs 1993; 46: 872–894.

7. Liliemark J, Albertoni F, Hassan M et al. On the bioavailability of oral and subcutaneous 2-chloro-2’-deoxadenosine in humans: alternative routes of administration. J Clin Oncol 1992; 10: 1514–1518.

8. Robak T, Lech-Maranda E, Korycka A et al. Purine nucleoside analogs as immunosuppressive and antineoplastic agents: mechanism of action and clinical activity. Curr Med Chem 2006; 13: 3165–3189.

9. Adam Z. Hematologické choroby nízkého stupně malignity. Standardní léčebné postupy a zhodnocení účinnosti 2-chlorodeoxyadenosinu. Brno: Lékařská fakulta MU 1998.

10. McClain KL. Drug therapy for the treatment of Langerhans cell histiocytosis. Expert Opin Pharmacother 2005; 6: 2435–2441.

11. Saven A, Burian C. Cladribine activity in adult Langerhans-cell histiocytosis. Blood 1999; 93: 4125–4130.

12. Weitzman S, Wayne AS, Arceci R at 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 1999; 33: 476–481.

13. 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 2010; 91: 646–651.

14. 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 2009; 53: 1271–1276.

15. Rodriguez-Galindo C, Jeng M, Khuu P et al. Clofarabine in refractory Langerhans cell histiocytosis. Pediatr Blood Cancer 2008; 51: 703–716.

16. McCowage GB, Frush DP, Kurtzberg J. Successful treatment of two children with Langerhans’ cell histiocytosis with 2’-deoxycoformycin. J Pediatr Hematol Oncol 1996; 18: 154–158.

17. Pardanani A, Phyliky RL, Li CY et al. 2-chlorodeoxyadenosine therapy for disseminated Langerhans cell histiocytosis. Mayo Clin Proc 2003; 78: 301–306.

18. Watts J, Files B. Langerhans cell histiocytosis: central nervous system involvement treated successfully with 2-chlorodeoxyadenosine. Pediatr Hematol Oncol 2001; 18: 199–204.

19. Dhall G, Finlay JL, Dunkel IJ et al. Analysis of outcome for patients with mass lesions of the central nervous system due to Langerhans cell histiocytosis treated with 2-chlorodeoxyadenosine. Pediatr Blood Cancer 2008; 50: 72–79.

20. Ottaviano F, Finlay JL. Diabetes insipidus and Langerhans cell histiocytosis: a case report of reversibility with 2-chlorodeoxyadenosine. J Pediatr Hematol Oncol 2003; 25: 575–577.

21. 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 2004; 43: 81–84.

22. Rajendra B, Duncan A, Parslew R et al. Successful treatment f central nervous system juvenile xanthogranulomatosis with cladribine. Pediatr Blood Cancer 2009; 52: 413–415.

23. Aerni MR, Aubry MC, Myers JL et al. Complete remission of nodular pulmonary Langerhans cell histiocytosis lesions induced by 2-chlorodeoxyadenosine in a non-smoker. Respir Med 2008; 102: 316–319.

24. Lazor R, Etienne-Mastroianni B, Khouatra C et al. Progressive diffuse pulmonary Langerhans cell histiocytosis improved by cladribine chemotherapy. Thorax 2009; 64: 274–275.

25. Robak T, Kordek R, Robak E et al. Langerhans cell histiocytosis in a patient with systemic lupus erythematosus: a clonal disease responding to treatment with cladribine, and cyclophosphamide. Leuk Lymphoma 2002; 43: 2041–2046.

26. Tam CS, Seymour JF, Prince HM et al. Treatment-related myelodysplasia following fludarabine combinations chemotherapy. Haematologica 2006; 91: 1546–1550.

27. Bowcock SJ, Rassam SM, Lim Z et al. High incidence of therapy-related myelodysplasia and acute leukemia in general haematology clinic patients treated with fludarabine and cyclophosphamide for indolent lymphoproliferative disorders. Br J Haematol 2006; 134: 242–243.

28. Yoshimi A, Kumano K, Motokura T et al. ESHAP therapy effective in patient with Langerhans cell sarcoma. Int J Hematol 2008; 87: 532–537.

29. Saven A, Figueroa ML, Piro LD et al. 2-chlorodeoxyadenosine to treat refractory histiocytosis X. N Engl J Med 1993; 329: 734–735.

30. Saven A, Piro LD. 2-chlorodeoxyadenosine: a newer purine analog active in the treatment of indolent lymphoid malignancies. Ann Intern Med 1994; 120: 784–791.

31. Saven A, Foon KA, Piro LD. 2-chlorodeoxyadenosine-induced complete remissions in Langerhans-cell histiocytosis. Ann Intern Med 1994; 121: 430–432.

32. Dallafior S, Pugin P, Cerny T et al. Successful treatment of a case of cutaneous Langerhans cell granulomatosis with 2-chlorodeoxyadenosine and thalidomide. Hautarzt 1995; 46: 553–560.

33. Dimopoulos MA, Theodorakis M, Kostis E et al. Treatment of Langerhans cell histiocytosis with 2 chlorodeoxyadenosine. Leuk Lymphoma 1997; 25: 187–189.

34. Conias S, Strutton G, Stephenson G. Adult cutaneous Langerhans cell histiocytosis. Australas J Dermatol 1998; 39: 106–108.

35. Grau J, Ribera JM, Tormo M et al. Results of treatment with 2-chlorodeoxyadenosine in refractory or relapsed Langerhans cell histiocytosis. Study of 9 patients. Med Clin (Barc) 2001; 116: 339–342.

36. Chang SE, Koh GJ, Choi JH et al. Widespread skin-limited adult Langerhans cell histiocytosis: long-term follow-up with good response to interferon alpha. Clin Exp Dermatol 2002; 27: 135–137.

37. Rodriguez-Galindo C, Kelly P, Jeng M et al. Treatment of children with Langerhans cell histiocytosis with 2-chlorodeoxyadenosine. Am J Hematol 2002; 69: 179–184.

38. Robak T, Kordek R, Robak E et al. Langerhans cell histiocytosis in a patient with systemic lupus erythematosus: a clonal disease responding to treatment with cladribine, and cyclophosphamide. Leuk Lymphoma 2002; 43: 2041–2046.

39. Goh NS, McDonald CE, MacGregor DP et al. Successful treatment of Langerhans cell histiocytosis with 2-chlorodeoxyadenosine. Respirology 2003; 8: 91–94.

40. Sander CS, Kaatz M, Elsner P. Successful treatment of cutaneous langerhans cell histiocytosis with thalidomide. Dermatology 2004; 208: 149–152.

41. Mottl H, Rob L, Stary J et al. Langerhans cell histiocytosis of vulva in adolescent. Int J Gynecol Cancer 2007; 17: 520–524.

42. Aouba A, Larousserie F, Le Guern V et al. Spumous histiocytic oligoarthritis coexisting with systemic Langerhans’ cell histiocytosis: case report and literature review. Joint Bone Spine 2009; 76: 701–704.

43. Frost JD, Wiersma SR. Progressive Langerhans cell histiocytosis in an infant with Klinefelter syndrome successfully treated with allogeneic bone marrow transplantation. J Pediatr Hematol Oncol 1996; 18: 396–400.

44. Stine KC, Saylors RL, Williams LL et al. 2-chlorodeoxyadenosine (2-CDA) for the treatment of refractory or recurrent Langerhans cell histiocytosis (LCH) in pediatric patients. Med Pediatr Oncol 1997; 29: 288–292.

45. Choi SW, Bangaru BS, Wu CD et al. Gastrointestinal involvement in disseminated Langerhans cell histiocytosis (LCH) with durable complete response to 2-chlorodeoxyadenosine and high-dose cytarabine. J Pediatr Hematol Oncol 2003; 25: 503–506.

46. 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 2005; 41: 2682–2689.

47. Mottl H, Ganevová M, Radvanská J et al. Treatment results of Langerhans cell histiocytosis with LSH II protocol. Čas Lék Čes 2005; 144: 753–755.

48. Mottl H, Starý J, Chánová M et al. Treatment of recurrent Langerhans cell histiocytosis in children with 2-chlorodeoxyadenosine. Leuk Lymphoma 2006; 47: 1881–1884.

49. Biswas G, Khadwal A, Arora B et al. Activity and toxicity of 2-CDA in Langerhans cell histiocytosis: a single institutional experience. Indian J Cancer 2007; 44: 137–141.

50. Apollonsky N, Lipton JM. Treatment of refractory Langerhans cell histiocytosis (LCH) with a combination of 2-chlorodeoxyadenosine and cytosine arabinoside. J Pediatr Hematol Oncol 2009; 31: 53–56.

51. Pant C, Madonia P, Bahna SL et al. Langerhans cell histiocytosis, a case of Letterer Siwe disease. J La State Med Soc 2009; 161: 211–212.

52. Betticher DC, Fey MF, von Rohr A et al. High incidence of infections after 2-chlorodeoxyadenosine (2-CDA) therapy in patients with malignant lymphomas and chronic and acute leukaemias. Ann Oncol 1994; 5: 57–64.

53. Braiteh F, Kurzrock R. CASE 1. Langerhans cell histiocytosis of the thyroid. J Clin Oncol 2006; 24: 522–523.

54. Dewan M, Al-Ghamdi AA, Zahrani MB. Lessons to be learned – Langerhans’ cell histiocytosis. J R Soc Promot Health 2008; 128: 41–46.

55. Nagarajan R, Neglia J, Ramsay N et al. Successful treatment of refractory Langerhans cell histiocytosis with unrelated cord blood transplantation. J Pediatr Hematol Oncol 2001; 23: 629–632.

56. Saven A, Piro LD. 2-chlorodeoxyadenosine: a potent antimetabolite with major activity in the treatment of indolent lymphoproliferative disorders. Hematol Cell Ther 1996; 38 (Suppl 2): S93–S101.

57. Williams W, Craver RD, Correa H et al. Use of 2-chlorodeoxyadenosine to treat infantile myofibromatosis. J Pediatr Hematol Oncol 2002; 24: 59–63.

58. Fichter J, Doberauer C, Seegenschmiedt H. Langerhans cell histiocytosis in adults: An interdisciplinary challenge. Dtsch Arztebl 2007; 104: A2347–A2353.