Treatment of Langerhans Cell Histiocytosis

1. Treatment of Langerhans Cell Histiocytosis Tanya Wildes September 23, 2005

2. Case Presentation HPI: 67 y.o. female presented with dysphagia in 5/05. She was found to have a mass of the L palatine tonsil and tongue base. Also had L cervical lymphadenopathy. Tonsil biopsy was initially read as Langerhans sarcoma. Biopsy was reviewed at BJH and was felt to be Langerhans histiocytosis given absence of malignant cytologic features. Cells were positive for CD1a and S100.

3. Staging Neck CT 7/6/05 Conglomerate lymph node 4.8 x 3.5 cm in L jugular chain with displacement of carotid artery and compression of internal jugular vein. Prominent L tonsil. CT Chest 7/6/05 No obvious pulmonary involvement. Diffuse metastatic involvement of the liver.

4. Prior to initiation of therapy, the patient developed shortness of breath and presented to an outside hospital. She was found to have a number of metabolic derangements and was transferred to BJH for further evaluation. On arrival (7/12/05), she was obtunded and unable to provide further history. Case presentation

5. Physical Exam VS 35.5 P 161 RR 28 BP 83/44 HEENT � large L ant cervical mass Pulm � tachypneic, shallow respirations CV � tachycardic, RR Abd � obese, liver edge palpable 4 cm below costal margin. Ext � 2+ BLE pitting edema

6. Labs ABG 6.98/13/109/<5 Na 144 K 4.0 CL 93 HCO3 9 BUN 75 Cr 2.8 Glu <30 Anion Gap 42 WBC 51.6 45%N/11%L/14%M Hgb 11.0 Hct 32.9 Plt 123 PT 31.5 INR 3.22 PTT 37.7

7. Labs Alb 2.3 Protein 4.5 T Bili 1.5 D Bili 1.2 AlkPhos 585 AST 896 ALT 452 Ionized Ca 3.31 Phos 10.1 Uric Acid 21.2 LDH 2687 Lactic Acid 27.0 Smear � anisocytosis, polychromasia, nucleated RBCs; bizarre circulating WBC.

8. Hospital Course Pt was intubated immediately upon arrival. Tumor lysis syndrome - started on a bicarbonate drip and rasburicase. Renal Failure � due to uric acid nephropathy. Coagulopathy � due to hepatic synthetic dysfunction. Transaminitis � due to liver infiltration with Langerhans cells.

9. Hospital Course Chemotherapy 7/13/05 Vinblastine 6 mg/m2 Etoposide 150mg/m2 Continued mechanical ventilation and vasopressor support Initiated on hemodialysis for oliguria

10. Hospital Course Given grave prognosis and multi-organ system failure, the family decided to withdrawal ventilatory and vasopressor support. The patient expired on 7/15/05. An autopsy was performed.

11. Post-mortem examination Lung Microscopic foci of Langerhans cells Liver Weighed 3300g (normal <1700g) Numerous nodules measuring up to 9mm and diffuse infiltration with Langerhans cells replacing much of the hepatic parenchyma Areas of necrosis. Kidneys Microscopic foci of Langerhans cells

12. Post-mortem examination Lymphoid/ hematopoietic Spleen weighed 450 g (nl <200g), extensive infiltration with Langerhans cells. BM sections demonstrate extensive replacement by Langerhans cells. Subcarinal, pericardial and portal lymph nodes replaced by Langerhans cells. Peripancreatic LN filled with Langerhans cells and extending into adjacent soft tissue. Endocrine Pituitary gland shows collections of Langerhans cells adjacent to the pituitary. As with initial biopsy, there was no cytologic atypia or high mitotic rate to warrant the diagnosis of Langerhans cell sarcoma or malignant histiocytosis.

13. Langerhans Cell Histiocytosis Langerhans cells � dendritic cells precursors normally found in epidermis, thymic epithelium and bronchial mucosa LCH cells - the pathologic counterpart to langerhans cells Can be more widely distributed in bone, skin, brain, liver and lung. Both LCs and LCH cells express CD1a; LCH cells also have abnormal levels of or expression patterns of CD1b, CD2, CD4, CD11a, CD11b, CD24, CD32, LFA-1, LFA-3, B7/BB1, CCR6, CCR7.

14. Pathogenesis of LCH Pathogenesis of LCH unclear Previously thought to be inflammatory or autoimmune Monoclonal bone marrow derived precursor cells Immune dysregulation Cytokine production: GM-CSF and TNF alpha

15. The disease formerly known as� Histiocytosis X Eosinophilic granuloma Localized lesions in bone or lung Presents age 5-10 Hand-Schuller-Christian syndrome Classic triad: diabetes insipidus, exophthalmos, and skull lesion Presents age 3-6 Letterer-Siwe disease Acute, fulminant course with rash, lymphadenopathy, solid organ involvement Presents age 0-1

16. Age at diagnosis

17. Presenting symptoms in adult cohort

18. Clinical Course and Treatment Presenting features and course are highly variable. Spontaneous remissions can occur. Localized disease more likely to remit. Treatment should be considered in: Symptomatic localized disease Multifocal disease There are no randomized or prospective studies of treatment in adults.

19. Localized disease Lymph node Excision Skin Excision Psoralen/ PUVA Bone lesions Curettage or excision Radiation therapy

20. Multisystem Disease Corticosteroids Usually modest, short-term benefit Cytotoxic chemotherapy Cladribine Cyclosporine Etoposide Interferon alpha Vinblastine Vinblastine/ Etoposide/ Prednisone/ Methotrexate Vincristine/ Cytarabine/ Prednison Prednisone/ Etoposide/ Cyclosporine

21. Response to Systemic Treatments in adult cohort

22. Potential New Targets for Therapy CD52 - Alemtuzumab Vascular Endothelial Growth Factor Thalidomide TNF-alpha antagonists

23. Alemtuzumab (Campath) CD52 is a small membrane glycoprotein expressed on lymphocytes, monocytes, some dendritic cells and epithelial cells of the epididymis/vas deferens. Alemtuzumab - humanized monoclonal antibody directed at CD52. Does not bind to normal skin LCs. Pathologic specimens (both frozen and fixed) from patients with LCH were stained with anti-CD52 antibody.

24. CD52 staining of LCH cellsin paraffin-embedded specimens

25. CD52 staining of LCH cellsin frozen specimens Lymph node biopsy LHC cells were positive for both CD1a and CD52

26. Alemtuzumab This anti-CD52 activity may prove a useful target for therapy of patients who are refractory to current therapy. As of yet, no published case reports of alemtuzumab being used for LCH.

27. Vascular Endothelial Growth Factor in Langerhans Cell Histiocytosis Study Ten patient enrolled (all pediatric) 5 with single system disease 5 with multisystem disease. Fixed tissue retrospectively assessed for VEGF production.

28. Vascular Endothelial Growth Factor

29. Vascular Endothelial Growth Factor All the specimens from patients with multi-system disease expressed VEGF. Only 2/5 of the specimens from patients with single system disease expressed VEGF.

30. Vascular Endothelial Growth Factor in Langerhans Cell Histiocytosis LCH cells demonstrated VEGF expression in the cytoplasm. Dendritic cells and macrophages within the lesions did not express VEGF. Blood vessel density within lesions was greater than at margins. Evidence of increased angiogenic processes within the LCH lesions raises the possibility of anti-angiogenic agents as adjuvant therapy in multisystem disease.

31. Thalidomide Thalidomide has anti-inflammatory, immunomodulatory and anti-angiogenic properties. At high doses, thalidomide modulates dendritic cells, increasing IL-12 production and reducing IL-10 secretion, which may contribute to its antitumor effects. A number of reports have detailed success with thalidomide in localized LCH.

32. Case Report of Thalidomide in recurrent multisystem disease 73 y.o. woman presented with diffuse lymphadenopathy,pulmonary infiltrates and pruritis. Lung and mediastinal lymph node biopsy confirmed Langerhans cell histiocytosis. Therapy CVP x 4 with persistent pruritis Vinblastine/prednisone x 1 cycle

33. Case Report of thalidomide therapy Recurred one month after vinblastine with pulmonary recurrence. Treated with thalidomide 100mg po qd and prednisone 12.5mg po qd. After 2 months of therapy, CT demonstrated improvement in pulmonary infiltrates.

34. Case report of treatment with etanercept A 5 month old girl with multifocal Langerhans cell histiocytosis with spleen, liver, bone marrow and skin involvement had recurrence after induction with vinblastine and steroids. She was treated with etanercept 0.4 mg/kg SQ twice a week with resolution of fever, regression of splenic involvement and healing of bone lesions.

35. Etanercept Elevation in expression of the inflammatory cytokine TNF-alpha has been reported in T cells within LCH lesions. Immunostaining was performed on LCH cells from an infant with refractory LCH. 5% of patients LCH cells demonstrated intracellular accumulation of TNF-alpha.

36. In summary LCH is rare in adults. Pathophysiology is incompletely understood. Current therapy depends on extent of disease. Response to chemotherapy with vinblastine, etoposide and steroids are most reported. As our understanding of the disease improves, new targets for therapy are emerging.

37. Resources Attias, D, et al. The role of vascular endothelial growth factor in langerhans cell histiocytosis. J Ped Hem Onc 2005; 27(2): 62-66. Baumgartner, I. et al. Langerhans�-cell histiocytosis in adults. Med Ped Onc 1997; 28:9-14. Fraulini ME et al. A case of disseminated Langerhans� cell histiocytosis treated with thalidomide. Eur J Haematol 2005; 74:172-174. Henter, JI et al. Successful treatment of Langerhans�-cell histiocytosis with etanercept. NEJM. 2001; 345(21)1577-8. Howarth, DM, et al. Langerhans cell histiocytosis: diagnosis, natural history, management and outcome. Cancer 1999; 85(10):2278-2289. Islinger, RB et al. Langerhans cell histiocytosis in patients older than 21 years. Clin Orth Rel Res 2000; 379:231-235. Jordan, MB et al. Anti-CD52 antibody, alemtuzumab, binds to langerhans cells in langerhans cell histiocytosis. Ped Blood Cancer 2005; 44:251-254. Malpas, JS and Norton, AJ. Langerhans cell histiocytosis in adults. Med Ped Onc 1996; 27:540-546.