1. Thiopurines have no role in the management of Pediatric IBD Robert N. Baldassano, MD Colman Professor of Pediatrics University of Pennsylvania, Perelman School of Medicine Director, Center for Pediatric IBD The Children's Hospital of Philadelphia

2. Thiopurines have a limited role in the management of Pediatric IBD Robert N. Baldassano, MD Colman Professor of Pediatrics University of Pennsylvania, Perelman School of Medicine Director, Center for Pediatric IBD The Children's Hospital of Philadelphia

3. I have the following financial relationships to disclose Products or services produced by this company are relevant to my presentation Janssen Pharmaceuticals Takeda Pharmaceuticals AbbVie, Inc. Avaxia Biologics, Inc.

4. Balancing the Risks/Benefits of Therapy in Patients With IBD Serious AEs Efficacy Opportunistic infections Lymphoma Skin cancer Autoimmune disease Induction of remission Maintenance of remission Mucosal healing Promote growth

5. Questions you need to address before treating a patient: What are the risks of serious infection with IM and anti-TNFα therapy? What is the risk of malignancy with IM alone? Thiopurines Methotrexate What is the risk of malignancy with anti-TNFα alone? What is the risk of combination therapy with IM and anti- TNFα? With thiopurine With methotrexate Can we mitigate these risks? Risks are important to patients – even small risk!!

6. FEAR! It is all about cancer. Courtesy of J. Hyams

7. Is There Risk of Malignancy With Thiopurines? Azathioprine is known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans. First listed in the Fourth Annual Report on Carcinogens (1985) Initial evidence from transplantation but over time with chronic inflammatory disorders Report on Carcinogens, Twelfth Edition (2011) http://ntp.niehs.nih.gov/go/roc12

8. Multiple Mechanisms of Carcinogenesis With Thiopurines DNA damage Decreased immunosurveillance – TP are cytotoxic for NK and cytotoxic T cells restrict proliferation of EBV infected and immortalized B cells Emergence of oncogenic viruses (EBV) Taking 6MP/AZA results in 6-TG accumulating in cellular DNA in skin – 6-TG has an absorption peak at 342 nm ultraviolet radiation (320-400 nm) – Results in a significant absorption of ultraviolet radiation leading to DNA-damage Karran and Attard. Nat Rev Cancer 2008;8:24, Allan and Travis, Nat Rev Cancer 2005;5:943

9. Is Thiopurine Rx Mutagenic? Cross sectional in vivo study of peripheral blood mononuclear cells in 119 adults and children with IBD Mutagenicity assayMutant clonal cell expansion Nguyen T el al. Cancer Res 2009;69(17):7004-12

10. Age-adjusted Lymphoma Rate Khan et al. Gastroenterology 2013;145:1007 Overall rates: Unexposed 0.6/1000 PYF, During 2.31/1000PYF, after 0.28/ 1000 PYF SIR for NHL during TP 7.4 (95% CI 4.6-11.9) compared to SEER age standardized data

11. Adjusted Risk of Lymphoma: Hazard Ratio Per Years of Exposure Khan et al. Gastroenterology 2013;145:1007 United States Veteran Affairs Health System: 36, 891 pts with UC, 88%>40yr, 93% male, 76% white

12. Non-melanoma Skin Cancer: CESAME French National Cohort Peyrin-Biroulet et al. Gastroenterology 2011;141:1621 Yearly Incidence Per 1,000 Pt-years

13. Increased Malignancy Risk with Adalimumab Combination Therapy Compared to Monotherapy Pooled data from ADA RCT 3050 pt years. Median f/u 1.5 yrs. Compared to SEER (general population) No increased risk for ADA monotherapy for NMSC or any malignancy ADA + IM: 3x increased risk for malignancy other than NMSC ADA + IM: 5X increased risk for NMSC ADA + IM: 8X increased risk for lymphoma Osterman et al. Gastroenterology 2014:146:941

14. Hepatosplenic T Cell Lymphoma: The 900 Pound Gorilla in the Room That Changed Everything for Pediatricians Courtesy of J. Hyams

15. Hepatosplenic T Cell Lymphomas Most common associations – Male, 10-35 y of age (69.5%) – Hepatosplenomegaly – Cytopenia – Elevated aminotransferases – No adenopathy – Symptoms (fever, weight loss, night sweats) Aggressive course, median survival 16 months, almost universally fatal Belhadj K, et al. Blood. 2003;102:4261–4269.

16. Incidence of HSTCL SEER data: Non-Hodgkin’s lymphoma incidence 10-19 yrs: 20/1,000,000 (1:50,000) 20-29 yrs: 30/1,000,000 (1:33,000) Peripheral T cell lymphomas: 10-15% of NHL HSTCL: 5% of peripheral T cell lymphomas or <1% of all NHL Therefore, incidence of HSTCL 1:5,000,000 In U.S. 50,000 to 100,000 children with IBD. One would therefore expect one case every 50-100 years as background incidence Courtesy of J. Hyams

17. Hepatosplenic T-Cell Lymphoma in IBD Risk Estimates for HSTCL in IBD All patients on thiopurine only Rx1:45,000 All patients on infliximab ± thiopurine1:21,947 All males <35 yrs on thiopurine only Rx1:7404 All males <35 yrs on thiopurine + anti-TNF1:3534 Kotlyar D et al. Clin Gastroenterol Hepatol 2011;9:36-41 The risk appears to be particularly increased in patients receiving thiopurines, either as monotherapy or in combination with anti-TNF agents. IBD patients receiving longterm thiopurine therapy are possibly at even greater risk.

18. Conclusions Thiopurine use is associated with increased cancer risk. Risk of cancer with mtx appears to be small to negligible, but more data are needed Anti-TNF therapy alone does not appear to increase cancer risk Anti-TNF + thiopurine is associated with increased cancer risk, though not clear what amount is from thiopurine alone. Particularly problematic in young males

19. P=.007 Markowitz J et al. Gastroenterology. 2000;119:895. 6-MP: Maintenance Therapy in Children With Crohn’s Disease 0100200300400500600 0.00 0.25 0.50 0.75 1.00 6-MP Control Remission Duration (days) Fractional Survival n=55 Modified Harvey Bradshaw (Not a validated disease activity index) Endpoint ????? Remission??? No difference in linear growth Sample size??? Selection bias Wide confidence interval If it is too good to be true! Predicting the Crohn’s Disease Activity Index From the Harvey-Bradshaw Index (HBI) Conclusion: ” HBI is not recommended for prospective trials in Crohn’s disease” Best WR IBD 2006;12;4:304-310

20. Early use of Azathioprine in Adults With Crohn’s Disease RCT n = 131 newly dx. patients, 18 month study – 2.5 mg/kg/day AZA vs. Control – Endpoint: steroid-free remission and CDAI<150 Remission rates (Aza vs. Control p=0.48) – 44% in the Azathioprine group – 37% in the placebo group Conclusion – Azathioprine was no more effective than placebo at 18 months Panes J et al, Gastro 2013;145:766 AZTEC

21. Early Aza vs Conventional Management of Crohn’s disease: A randomized Controlled Trial RCT n = 132 newly dx. patients, 3 year study – 2.5 mg/kg/day AZA vs. Conventional therapy – Endpoint: steroid-free remission and CDAI<150 Conclusion: Early AZA use was no more effective than conventional therapy in increasing time of clinical remission Cosnes J, et al. gastro 2013;145:758

22. One Year CS-free Remission: Effect of Early Therapy RISK study 85% 41% 37% P<0.001 P=NS # in Remission (68 triads) Walters TD, et al, Gastro 2014;146:383

23. Effect of Early Therapy on Growth Parameters at 1 Year RISK study p=.002 p=.NS Mean change z score (68 triads) Walters TD, et al, Gastro 2014;146:383 No linear growth on thiopurines

24. Risk Mitigation Strategy Consider stopping thiopurines when clinically possible Reduced risk after time off therapy Consider drug holiday; change to mtx Yearly skin checks Avoid ionizing radiation Consider primary anti-TNF therapy in moderate to severe IBD prior to thiopurine*; role of combination with mtx to increase durability needs further data Potential role of emerging drugs in decreasing cancer risk from therapy (e.g., anti-adhesion molecule therapy) *off label use Courtesy of J. Hyams