1. Literature Review Peter R. McNally, DO, FACP, FACG University Colorado Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045

2. Siegel CA 1&2, Marden SM 2, Persing SM 2, Larson RJ 2, Sands BE 3. Risk of Lymphoma Associated with Combination of Anti- Tumor Necrosis Factor and Immunomodulator Therapy for the Treatment of Crohn’s Disease: A Meta-Analysis Clin Gastroenterol and Hepatol. 2009;7:874-881. 1 Dartmouth-Hitchcock IBD Center, Lebanon, New Hampshire, 2 Dartmouth Institute for Health Policy and Practice, Hanover, NH, 3 MGH Crohn’s and Colitis Center and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Mass.

3. Introduction  Crohn’s disease is a chronic inflammatory disorder afflicting roughly 600,000 Americans.  The disorder strikes men and women in equal proportions, usually between the ages of 15-35 yrs.  The disease is chronic without cure and medical treatment is directed at blocking excessive intestinal inflammation.  Even with effective medical therapy, surgery is required in 50-60% of patients with this disorder.  Anti-TNFα drugs have been an major medical advance in the treatment of moderate to severe Crohn’s disease, but concerns over increased risk for malignancy and infection with anti-TNFα drugs have tempered clinical use. Lichtenstein GR, et al. Management of Crohn’s Disease in Adults. AM J Gastroenterol. 2009 Feb;104(2):465-83.

4. Introduction  Anti-TNFα drugs have been associated with small, but significant increased risk for infections, especially TB and opportunistic infections.  Anti-TNFα drugs have been association with an increased incidence for malignancy, specifically Non Hodgkin's Lymphoma (NHL) and Non Melanoma Skin Cancer (NMSC).  Estimation of the true risk for malignancy with Anti-TNFα drugs is confounded by study design, limited longitudinal follow up, and the co-administration of other treatments known to independently increase this risk [Azathioprine (AZA), 6-mercaptopurine (6MP), methotrexate (MTX)]. Lichtenstein GR, et al. Management of Crohn’s Disease in Adults. AM J Gastroenterol. 2009 Feb;104(2):465-83.

5. Aim  The authors sought to determine the most reliable estimate of Anti-TNFα related rates of NHL in patients with Crohn’s disease from an extensive literature search: MEDLINE, EMBASE, Cochrane Collaboration and Web of Science.  Comparisons were made with expected cancer rates derived from the National Cancer Institute (NCI), Surveillance Epidemiology and End Results (SEER) data base. http://seer.cancer.gov/csr/1975_2006/index.html http://seer.cancer.gov/csr/1975_2006/index.html Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81.

6. Study Design: Meta-Analysis Requirements for Inclusion in Meta-Analysis 1.Study Design Randomized Clinical Trial (RCT) Prospective or Retrospective Cohort Case Series of Consecutive pts 2.All Articles or Abstracts must be published 3.Anti-TNFα Treatment Infliximab (IFX) Adalimumab (ADA) Certolizumab (CTZ) 4.Only Crohn’s disease patients 5.Outcomes reported & median follow up > 48 wk Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81.

7. Study Design: Meta-Analysis Total of 26 studies involving 8,905 pts Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81. Publications from MEDLINE, Ovid, EMBASE, Cochrane (n=664) Manuscripts excluded by screening n=589 Studies included for review N=55 35 studies excluded after detailed review Unique abstracts from Web of Science n=6 Studies meeting all inclusion criteria N=26

8. Results: Meta-Analysis  Characteristics of Included Studies Total of 26 studies involving 8,905 pts Study Type ► RCTn = 9 ► Cohort n = 3 ► Case Seriesn = 14 Patient Mean age 36.9 yr Mean duration of disease 9.3 yr Treatment ► IFX n = 22 studies ► ADA n = 3 studies ► CTZ n = 1 study ► 77% of pts concomitantly treated with immunomodulator drug. Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81.

9. Study Analysis  Standardized Incidence Ratio (SIR) Ratio of Observed Events to Expected Events in a population Example: ► If 5 malignancies observed in a study trial ► If 20 malignancies expected in a general population ► Then SIR = 0.25 Meaning ► When SIR < 1.0, # observed events less than expected ► When SIR > 1.0, # observed events greater than expected Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81. SIR = # Observed Events # Expected Events SIR = 5 Observed Events 20 Expected Events http://seer.cancer.gov/seerstat/mp-sir.html

10. Results: Rates of NHL Observed vs. Expected  Observed NHL 13 lymphomas in 21,178 pt-yrs Rate 6.1 NHL per 10,000 pt yrs  Expected NHL Comparator SEER 1.9 per 10,000 pt-yrs http://seer.cancer.gov/. (Accessed on 6 November 2007) Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81. SIR = 6.1 Observed Events = 3.2 1.9 Expected Events

11. Results: Rates of NHL for SEER, Immunomodulator, and Anti-TNFα Treated Patients Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81. NHL rate 10,000 pt-yr SIR95% CI SEER (all ages) 1.9-- IM alone3.6-- Anti-TNF vs. SEER 6.13.231.5-6.9 Anti-TNF vs. IM alone 6.11.70.5-7.1

12. Results: Age/Gender Specific NHL Rate & SIR Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81. AgePooled NHL / 10000 pt yr SEER NHL / 1000 pt-yrs SIR95% CI 20-54 ♂ ♀ 5.9 3.1 1.1 0.8 5.4 3.8 1.3-18.1 0.7-15.9 55-64 ♂ ♀ 23 8.5 4.3 3.2 5.4 2.7 0.6-15.9 0.1-15.9 65-74 ♂ ♀ 27 20.9 8.4 6.3 3.2 3.3 0.1-18.4 0.1-19.0 75+ ♂ ♀ 91.5 0 13.2 9.26 6.9 - 0.2-39.3 -

13. Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881 Characteristics of Crohn’s Pts with NHL AgeM/FAgent IM use Type NHL Death related to NHL 170MIFXAZA B cell NR 225MIFXAZA NK cell Yes 379MIFXNO B cell Yes 424FIFXNR No 547MIFXMXNRYes 661MIFX + ?IM B cell Yes 754MIFXAZAParotidNo 871FIFXNR No 955FIFXAZANRNo 1051FIFXAZANRno 1142FIFXAZA T cell Yes 1232MIFX6MP Yes 1361MADAAZANRNo

14. Study Results: Rates SEER, Immunomodulator, & Anti-TNF Treated Patients Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81. Ljung et al. IFX in IBD: clinical outcome in a population based cohort from Stockholm County. Gut 2004;53:849-853. In this study 3 cases of NHL seen over 202 pt-yrs translated into 149 cases per 10,000 pt-yrs or SIR = 78. Ljung,et al.

15. Rate of NHL by Subgroup Analysis of Study Design Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881 * 3 of the 4 NHL cases reported in the Case Series were from the Ljung study group causing the confidence intervals to widen significantly. Ljung, et al.. Gut. 2004;53:849-853. DesignNHLPt-YrsNHL per 10,000 pt-yrs SIR to SEER 95% CI RCT238605.22.60.19-35.7 Cohort715,1924.62.30.44-22.7 Case Series*4212518.89.41.35-104

16. Sensitivity Analysis Excluding Studies With > 15% Drop-Out Rate Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881 AgeNHL rate/ 10,000 SEER rate/ 10,000 SIR95% CI allAll studies >15% drop out 6.1 9.4 1.91.5-6.9 1.8-12.3 20-54All studies >15% drop out 5.9 7.3 1.11.3-18.1 0.7-30.6 55-64All studies >15% drop out 23 72 4.30.6-20.5 2.0-64.4 65-74All studies >15% drop out 27 106 8.40.1-18.4 0.3-72.3 75+All studies >15% drop out 92 370 13.20.2-39.3 0.7-159 Message: There is a dramatic increase in NHL SIR as patients get older ( > 55yr ).

17. Study Summary  Use of Anti-TNFα drugs for the treatment of Crohn's’ disease is associated with an increased risk for NHL.  Absolute risk for NHL among these patients is: 6.1 per 10,000 pt-yrs (NHL Meta-Analysis) or 3x greater than the expected 1.9 per 10,000 pt-yrs (NHL SEER rate) Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881

18. Study Summary  The majority of pts with NHL were receiving BOTH Anti-TNFα and Immunomodulator Rx. 10 of 13 (77%) reported NHL patients were on both Anti-TNFα & Immunomodulator Rx. 2 of 13 (15%) reported NHL patients were on Anti-TNFα, but Immunomodulator Rx use was not reported. 1 of 13 (8%) reported NHL patients were on ONLY Anti-TNFα. Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881

19. Study Summary  Overall risk for NHL for Crohn’s patients given both Anti-TNFα and an Immunomodulator Rx seems to be greater for men and patients older than 55 yrs.  At least 4 patients were discovered to have NHL after the 1 st infusion of Anti-TNFα. This might suggest that the effect of even one dose may be significant to increase lymphoma risk or alternatively that a significant number of NHL pts in this report were just pre-clinical. Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881

20. Reviewer Comments Siegel, et al, do not answer the following questions? 1.What is the risk for NHL among newly diagnosed “naïve” Crohn’s patients receiving only Anti-TNFα drugs? 77% of the patients with NHL in this study received both Anti-TNFα & Immunomodulator Rx. Only one of the 13 (7%) reported cases of NHL was receiving ONLY Anti-TNFα. Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881

21. Reviewer Comments 2.The investigators included one Case Series study with obvious outlier data. When the data from the Ljung study are excluded from the Case Series data, the SIR to SEER NHL rate is calculated to be 2.7 which is comparable to the rates derived for both the RCT and Cohort groups, 2.6 and 2.3 respectively. Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881 DesignNHLPt-YrsNHL per 10,000 pt-yrs SIR to SEER RCT238605.22.6 Cohort715,1924.62.3 Case Series*4212518.89.4 Case Series**119235.22.7 * Calculations includes Ljung T, et al, data. ** Calculations excludes Ljung, et al, data

22. Reviewer Comments 3.The first Anti-TNFα drug approved for the treatment of Crohn’s Disease (IFX) is chimeric. It is more commonly associated with neutralizing antibody formation than ADA or CTZ. This lead to the common practice of Anti- TNFα immunomodulator co-therapy. 4.Now we are left to retrospectively review the influence of past practices/conventions of combination therapy as they relate to risk for NHL and opportunistic infections. As shown in this study combination Anti-TNFα and Immunomodulators are associated with an increased risk for HNL – albeit small 6.1 per 10,000 pt-yr vs. 1.9 per 10,000 pt-yr (SEER). 5.The risk for NHL for “naive” Crohn’s pts receiving mono Anti-TNFα ( ADA or CTZ) needs to be examined. Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881

23. Reviewer Comments 6.Recent reports of the Sonic trial suggest that IFX and Immunomodulator combination therapy is better at maintaining remission than mono therapy. 7.With future Studies, it may be prudent to consider stratification of Anti-TNFα and Immunomodulator naive Crohn’s patients by Montreal Criteria, Vienna Classification or surrogate disease activity markers into mono- or combination therapy. Only then will be able determine the true risk benefit ratio of these drugs in the treatment of this chronic and often disabling disease. Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881