1. 1 Pro: An IBD patient on a biologic and/or an immunomodulator, who develops a malignancy: skin cancer solid tumor lymphoma may continue or restart these medications, if needed to treat IBD Miguel Regueiro, MD, FACG, AGAF Professor of Medicine Clinical Head, IBD Center University of Pittsburgh Medical Ctr

2. Do I really have a chance of winning a debate when my side is to continue meds when CA develops?

3. Thank you for slides Jim Lewis Jean Fred Colombel Corey Siegel (also for photos of Tom!) 3

4. Important questions in pts who develops cancer on IBD meds: 1.Did the medicine cause the cancer? 2.What is the risk of: - continuing the med in terms of worsening cancer or - discontinuing the med in terms of worsening IBD? 4

5. Let’s consider three types of cancer: -Skin Cancer -Lymphoma - Solid Tumors 5

6. Case 50 year old male 30 year history of small bowel Crohn’s 1 prior bowel resection Current meds – 6MP + Adalimumab 3 BM per day Colonoscopy – few scattered aphthous ulcers (i1) in the neo-TI

7. Case (cont) 2 years prior diagnosed with Non Melanoma Skin Cancer (Basal Cell Ca) 2 weeks ago newly diagnosed with Squamous Cell Cancer

8. Is skin cancer caused by or are patients at increased risk from… -azathioprine/6MP -Methotrexate -antiTNFs 8

9. Thiopurines and Skin Cancer NMSC MELANOMA Long M. Gastroenterology 2012:143:390-9. Singh H Gastroenterology 2011:141:1612-20 Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8 Peyrin-Biroulet L. Am J Gastroenterol 2012 doi: 10.1038/ajg.2012.181

10. Timing of Thiopurines and NMSC (esp. older ages) Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8 CESAME SIR and 95% CI

11. Anti-TNF and Skin Cancer (IBD data) NMSC MELANOMA Long M. Gastroenterology 2012:143:390-9. Singh H Gastroenterology 2011:141:1612-20 Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8 Peyrin-Biroulet L. Am J Gastroenterol 2012 doi: 10.1038/ajg.2012.181 NR

12. Clinical Questions Is skin cancer risk increased by therapy? –Thiopurines – yes –Methotrexate – don’t know, probably not –Biologics – no NMSC, maybe melanoma If so, does the risk of continuing therapy outweigh the benefits? –In this case – consider stopping thiopurine  Uncertain if risk will decline –Annual skin exam and regular use of sunscreen and hats

13. Skin: Stop or Continue? What I do- Consult with Dermatology and then.…. 13 NMSC – Basal Cell Squamous CellMelanoma Thiopurine antiTNF

14. Skin: Stop or Continue? What I do- Consult with Dermatology and then.…. 14 NMSC – Basal Cell Squamous CellMelanoma ThiopurineContinue or start: Active or Past, as long as Dermatology monitoring MTX prob ok Stop: Only if significant recurrence or potential for disfiguring sequelae antiTNF

15. Skin: Stop or Continue? What I do- Consult with Dermatology and then.…. 15 NMSC – Basal Cell Squamous CellMelanoma Thiopurine antiTNFContinue or start: Active or Past, as long as Dermatology monitoring Stop: NO, rarely necessary to stop

16. Skin: Stop or Continue? What I do- Consult with Dermatology and then.…. 16 NMSC – Basal Cell Squamous Cell Melanoma ThiopurineStart: -eradicated/resected/no mets -melanoma free for > 1 yr Stop/Restart: -Hold for new onset? -Maybe ok to continue -Restart if melanoma free -Stop for metastatic ds antiTNF

17. Skin: Stop or Continue? What I do- Consult with Dermatology and then.…. 17 NMSC – Basal Cell Squamous Cell Melanoma Thiopurine antiTNFStart: -eradicated/resected/no mets -melanoma free for > 1 yr Stop: -New Onset -?Restart if melanoma free > 1 yr -Do not restart <1yr or mets

18. Lymphoma 18

19. Questions  Does immunosuppressant therapy increase the risk of lymphoma?  Do the benefits outweigh the risks?  What do you do when a lymphoma develops in the setting of IBD meds?

20. AZA/6-MP are probably related to Lymphoma (Meta-analysis): SIR 4.06 AuthorObservedExpected Connell00.52 Kinlen20.24 Farrell20.05 Lewis10.64 Fraser30.65 Korelitz30.61 Total112.71 SIR = 4.06, 95% CI 2.01 – 7.28 Kandiel A et al. Gut. 2005:54:1121-25

21. CESAME – 6MP/AZA Only Lymphoma: HR 5.3 At cohort entry N# Lymphomas HR (95% CI) Never exposed to thiopurines 10,8106Reference On therapy with thiopurines 5,867165.3 (2.0 – 13.9) Previously discontinued thiopurines 2,80921.0 (0.2 – 5.1) Beaugerie L. Lancet 2009 DOI:10.1016/S0140-6736(09)61302-7

22. 8905 patients representing 20,602 pt-years of exposure 13 Non-Hodgkin’s lymphomas  Mean age 52, 62% male 10/13 exposed to IM* (really a study of combo Rx) Risk of NH Lymphoma with anti-TNF + IM treatment for Crohn’s Disease: A Meta-Analysis NHL rate per 10,000 SIR95% CI SEER all ages 1.9-- IM alone 3.6-- Anti-TNF + IM vs SEER 6.13.231.5-6.9 Anti-TNF+ IM vs IM alone 6.11.70.5-7.1 Siegel et al, CGH 2009;7:874. *not reported in 2 6.1 per 10,000 pt-years

23. CESAME – Combo 6MP/AZA and antiTNF: SIR = 10.2 TherapyPatients# LymphSIR95% CI Never thiopurine or TNF 22,70661.50.5 – 3.2 Current thiopurine without TNF 14,729136.53.5 – 11.2 Current thiopurine + TNF 1,929210.21.2 – 36.9 Beaugerie L. Lancet 2009 DOI:10.1016/S0140-6736(09)61302-7

24. Clinical Questions Does immunosuppressant therapy increase the risk of lymphoma? –Thiopurines – yes, but risk may revert after discontinuation –antiTNFs – Probably not –Combination – Yes and probably more than monotherapy

25. Risk:Benefit Ratio 25

26. Hepatosplenic T Cell Lymphoma 41 cases from FDA AERS among patients with IBD 1 –Thiopurine alone 17 –Anti-TNF alone1 –Combination therapy 23 Characteristics 2 –Median age 22.5 (12 – 58) –93% male –Median time since initiation of thiopurines ~6 years 1.Deepak P. Am J Gastroenterol 2013; 108:99–105 2.Kotlyar D. Clin Gastroenterol Hepatol 2011;9:36–41

27. Lymphoma - Number Needed to Harm Males Only 15-19 y.o. M (per 10 5 ) 20-24 y.o. M (per 10 5 ) Lymphoma other than HSTCL Annual incidence NHL + HD USA5.27.0 Annual incidence NHL + HD with thiopurines (x4 ‡ )20.828.0 Annual mortality from lymphoma without thiopurines*1.31.75 Annual mortality from lymphoma with thiopurines*5.27.0 Excess deaths from thiopurine induced lymphoma3.95.25 NNT to cause one death / year25,64119,074 ‡ Kandiel A et al. Gut. 2005:54:1121-25 * 5 year survival = 68% for NHL, 85% for HD, estimated at 75% for this example ‡ Kandiel A et al. Gut. 2005:54:1121-25 * 5 year survival = 68% for NHL, 85% for HD, estimated at 75% for this example

28. What to do if lymphoma develops while taking IMM/antiTNF? 28

29. Case – Stop or Continue? 39 yo male CD in remission on 6MP/IFX for 8 yrs. Now with weight loss, sweats, and low grade fevers 29

30. Crohn’s ds case: NHL while taking 6MP/IFX. 30

31. After consulting with the oncologist…. …we stopped the 6MP/antiTNF, but after 3 months of chemorx, the antiTNF was resumed. We did not restart the 6MP. 31

32. On CT: Hepatosplenic T cell lymphoma – enlarged spleen, otherwise nonspecific. Thiopurine must be stopped! 32

33. Solid Tumors 33

34. Case Continue or Stop? 58 yo female with severe UC who has been on IFX/6MP (50mg/d) for past 1yr Just diagnosed with intraductal breast CA (T1N0MX) Strong FHx breast CA, pt opts for bilateral mastectomy After consultation with oncology, the decision is to cont meds 34

35. No clear association between thiopurines/antiTNFs and solid tumors in IBD StudyTypes of cancer Number of patients Statistically significant Armstrong 2010lung, breast1955NO Fraser 2002 breast, bronchial, renal 6262NO Connell 1994 gastric, lung, breast, cervical 755NO

36. Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.…. 36 Hepatosplenic TC No relation to EBV After acute EBV Initially EBV - PTLD-like Initially EBV + Thiopurine antiTNF

37. Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.…. 37 Hepatosplenic TC No relation to EBV After acute EBV Initially EBV - PTLD-like Initially EBV + ThiopurineYoung Males Extremely rare (<.0001%) Usually in combo with anti-TNFs Not with MTX/antiTNF Fatal antiTNF

38. Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.…. 38 Hepatosplenic TC No relation to EBV After acute EBV Initially EBV - PTLD-like Initially EBV + ThiopurineYoung males Hemophagocytic lymphohistiocytosis Very rare (<.001%) Should we check EBV prior to starting in our young males? antiTNF

39. Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.…. 39 Hepatosplenic TC No relation to EBV After acute EBV Initially EBV - PTLD-like Initially EBV + ThiopurineOlder pts, long duration of 6MP Rare (<.01%) Males > Females antiTNF

40. Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.…. 40 Hepatosplenic TC No relation to EBV After acute EBV Initially EBV - PTLD-like Initially EBV + Thiopurine Stop Never Restart antiTNF

41. Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.…. 41 Hepatosplenic TC No relation to EBV After acute EBV Initially EBV - PTLD-like Initially EBV + Thiopurine Stop, lymphoma may regress Never Restart antiTNF

42. Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.…. 42 Hepatosplenic TC No relation to EBV After acute EBV Initially EBV - PTLD-like Initially EBV + Thiopurine Stop, lymphoma may resolve Never Restart antiTNF

43. Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.…. 43 Hepatosplenic TC No relation to EBV After acute EBV Initially EBV - PTLD-like Initially EBV + Thiopurine antiTNF Stop, probably never restart

44. Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.…. 44 Hepatosplenic TC No relation to EBV After acute EBV Initially EBV - PTLD-like Initially EBV + Thiopurine antiTNF Stop, but restart once lymphoma resolves

45. Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.…. 45 Hepatosplenic TC No relation to EBV After acute EBV Initially EBV - PTLD-like Initially EBV + Thiopurine antiTNF Continue, only stop if progression of lymphoma

46. Solid Tumor: Stop or Continue? Consult with Oncology and then.…. 46 Solid Tumors, e.g. Breast, Lung, Renal Probably no relationship to IBD meds Thiopurine-Continue if curative resection, no need to stop antiTNF-Continue if curative resection, no need to stop

47. Solid Tumor: Stop or Continue? Consult with Oncology and then.…. 47 Solid Tumors, e.g. Breast, Lung, Renal Probably no relationship to IBD meds Thiopurine -Stop if metastatic ds and/or chemotherapy antiTNF -Stop if metastatic ds and/or chemotherapy

48. Solid Tumor: Stop or Continue? Consult with Oncology and then.…. 48 Solid Tumors, e.g. Breast, Lung, Renal Probably no relationship to IBD meds Thiopurine -Restart once chemo done and no active cancer (? > 1 yr) antiTNF -Restart once chemo done and no active cancer (? > 1 yr)

49. Should we continue or stop IBD meds if a cancer develops? Depends on IBD 49

50. Deep Remission If in deep remission, maybe stopping IBD meds is ok and not restarting them 50

51. Not in deep remission or disabling IBD Skin Cancer Basal or Squamous Cell Resected/Controlled –CONTINUE all meds Not controlled and/or disfiguring –STOP azathioprine/6MP –CONTINUE anti-TNFs Melanoma Resected/Eradicated > 1 year –CONTINUE all meds Multiple Skin Sites/Rapid Recurrence/Mets –STOP anti-TNFs –CONTINUE – 6MP/AZA/MTX? 51

52. Not in deep remission or disabling IBD Lymphoma Acute EBV and lymphoma: STOP AZA/6MP CONTINUE anti-TNF, after lymphoma resolved (may not even need to stop?) Hepatosplenic T Cell lymphoma: STOP AZA/6MP and anti-TNF PTLD-like lymphoma (likely EBV): STOP AZA/6MP CONTINUE anti-TNF, after lymphoma resolved (may not even need to stop?) 52

53. Not in deep remission or disabling IBD Solid Tumors 6MP/AZA: -CONTINUE 6MP/AZA/MTX -Stop during chemo Anti-TNFs - CONTINUE if tumor resected/eradicated - STOP if metastatic ds or chemorx - RESTART once cancer eradicated/chemorx stopped 53

54. When you vote on who will win this debate make sure you consider both halves of the debate, but also the 2 sides of TOM ULLMAN 54

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56. Which half will you see today?….. ….the honest, kind, thoughtful, Tom Ullman? 56

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58. Or ?????? …maybe that dazed look wasn’t because Tom just ran a race, but….. 58

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60. 60 Playboy Ullman starring in American Hustle

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