Thomas A. Ullman, M.D. Chief Medical Officer Mount Sinai Doctors Faculty Practice

1. Con: An IBD patient on a biologic and/or an immunomodulator, who develops a malignancy (solid tumor, lymphoma or skin cancer), must stop and never restart these medications Thomas A. Ullman, M.D. Chief Medical Officer Mount Sinai Doctors Faculty Practice Associate Professor of Medicine Icahn School of Medicine at Mount Sinai

2. Disclosures Consulting/Advisory Board/Research Work and Support Pfizer Janssen CDx AbbVie Genentech

3. What we are not asking • Efficacy in IBD • Safety in general IBD patient population

4. Stage at Diagnosis Immunomodulators Anti-TNF Combination Therapy IBD Cancer Treatment Chemotherapy Radiotherapy Hormone Therapy Survival Drugs IBD/Flare Cancer Recurrence/Incidence Cancer 1. Does medical therapy for IBD predispose to developing cancer? 2. Once cancer develops in an IBD patient, is the cancer outcome different? 3. In an IBD patient with a history of cancer, does IBD therapy impact cancer recurrence? 4. In the IBD patient with active cancer does the cancer therapy affect IBD outcomes? 5. If a malignancy develops on IBD therapy, is it ever safe to re-start that agent?

5. Renal Transplant Pts with History of Cancer: High Risk of Recurrent Cancer due to immunosuppression • 823 pts with history of cancer treated prior to renal transplant: • 185 with cancer recurrence (22%) Penn I. Transplantation 1993. 55; 742-7

6. Guidelines in IBD Patients with Hx of Cancer ECCO (2010): Anti-TNF therapy is contraindicated in patients with a history of lymphoma, and “careful consideration should be given to initiating anti-TNF therapy” in those with a history of non-haematopoietic cancer. Dignass et al J Crohns Colitis 4:28, 2010 ACG (2009) & WGO (2009): No recommendations regarding management of IBD in patients with a history of cancer. Lichtenstein et al Am J Gastro 104:465, 2009 Bernstein et al. Inflamm Bowel Dis 16:112, 2009

7. Imuran Black Box Warning • WARNING - MALIGNANCY Chronic immunosuppression with IMURAN, a purine antimetabolite increases risk of malignancy in humans. Reports of malignancy include post-transplant lymphoma and hepatosplenic T-cell lymphoma (HSTCL) in patients with inflammatory bowel disease. Physicians using this drug should be very familiar with this risk as well as with the mutagenic potential to both men and women and with possible hematologic toxicities. Physicians should inform patients of the risk of malignancy with IMURAN. See WARNINGS. Imuran, Prescribing Information

8. Thiopurines: Contraindications • Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, or others) may have a prohibitive risk of malignancy if treated with IMURAN. Imuran, Prescribing Information

9. Important Caveat: • Malignancy within 5 years of study entry and exclusion criterion for EVERY study involved in the meta-analysis

10. Infliximab Prescribing Information • “The potential role of TNF-blocking therapy in the development of malignancies is not known [see Adverse Reactions (6.1)]. Rates in clinical trials for INFLIXIMABcannot be compared to rates in clinical trials of other TNF-blockers and may not predict rates observed in a broader patient population. Caution should be exercised in considering INFLIXIMAB treatment in patients with a history of malignancy or in continuing treatment in patients who develop malignancy while receiving INFLIXIMAB.” Remicade, Prescribing Information

11. Adalimumab Prescribing Information • “The risks and benefits of TNF-blocker treatment including Adalimumab should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer or when considering continuing anti-TNF therapy in patients who develop a malignancy.” AdalimumabPrescribing Information 2011

12. CertolizumabPrescribing Information “The potential role of TNF blocker therapy in the development of malignancies in adults is not known” CertolizumabPrescribing Information

13. Limitations of Existing Studies • Lack of randomized prospective data • Most data come from observational registries • History of cancer = exclusion criterion in clinical trials • Based on theoretical risk of immunosuppression • Most “Guidelines” advised practitioners to avoid using immunosuppressive IBD meds in patients who have a history of cancer • MDs are more likely to treat only patients with lower risk of cancer recurrence with immunosuppressive regimens • Sample sizes too small to ask about specific malignancies • Immunosuppression vs. inflammation • Common cancers: Breast, Prostate, Lung etc.

14. IBD pts with history of cancer:ThiopurineExposure - No Increased Risk of Subsequent Cancer (CESAME) • 19,486 pts with IBD: • Enrolled May 2004-June 2005, followed through December 2007 • 405 with personal history of cancer with at least one follow up visit • Compared risk of developing new/recurrent cancer: • 93 pts exposed to IT (thiopurine): • 6 new cancers • 1 recurrence of meningioma • 312 not exposed to IT • 12 new cancers • 4 recurrent cancers (lymphoma, breast, prostate, small bowel) P=0.98 P=0.26 L Beaugerieet al. Abstract DDW 2012.

15. RA Patients with History of Cancer:Anti-TNF Treatment Did Not Increase Risk of New or Recurrent Cancer (British Registry) • Over 14,000 pts with RA • 293 with prior malignancy • 177 anti-TNF treated • 117 DMARD treated (no anti-TNF) • Rates of incident malignancy compared • 25.3/1000 PY in anti-TNF • 38.3/1000 PY in DMARD • Prior Melanoma: • 3/17 (18%) in anti-TNF developed incident malignancy • 0/10 (0%) in DMARD developed incident malignancy Dixon et al., Arthritis Care & Research 2010. 62;755-63. • BSR Guidelines at time of study read: • “Caution should be exercised….in pts with previous malignancy” • “If pts have been free of any recurrence of their malignancy for 10 yrsthere is no evidence for a contraindication to anti-TNF therapy” DMARD Anti-TNF

16. RA Patients with History of Cancer:Anti-TNF Treatment Did Not Significantly Increase Risk of New or Recurrent Cancer (German Registry) • Biologic or conventional DMARD therapy between May 2001 and December 2006 • Prior malignancy in 122 out of 5,120 pts • 58 pts received anti-TNF • 55 conventional DMARDs • 14 pts exposed to anti-TNF with 15 recurrent cancers • Crude recurrence rates: • 45.5/1000 PY in anti-TNF exposed • 31.4/1000 PY in DMARD exposed • Incidence rate ratio 1.4 (P=0.6) Strangfeld et al. Arthritis Research &Therapy 2010. 12:R5.

18. IBD & Cancer Cancer controlled per oncologist? Yes No Gut 2013. E-pub ahead of print Within 2 years Beyond 2 years Hold IS Treat severe flares with steroids Favor step-up approach* IBD controlled? IBD controlled? Yes No Yes No Follow course** Consider cytotoxic chemotherapy Follow course Consider anti-TNF IBD controlled after chemotherapy? Yes No *Avoid IS associated with the risk of prior cancer. The longer the IS is held, the lower the risk of cancer recurrence. **Hormonal therapy is associated with IBD flare First line: Steroids Second line: Anti-TNF Follow course

19. Recommendations: • Multidisciplinary approach to the safety of using immunosuppression based on: • Cancer type • Overall risk of recurrence • Risk of IBD activity

20. Conclusions • Managing IBD patients with past or current malignancy is an increasingly common problem. • Few studies done in patients with IBD. • Caution using thiopurines if cancer therapy will produce bone marrow suppression. • Fear of using anti-TNFs in patients with current cancer may not be well-founded. • Decisions need to be made on case-by-case basis with oncologist, taking patient’s awareness and preferences into consideration.

21. I’m No Perry Mason • Rubin 6, Ullman 0 • Mercy?

22. Thank You