A Case of Lymphoma in IBD David T. Rubin MD Meenakshi Bewtra, MD MPH

Case: 28 year old white male h/o pancolitis UC diagnosed 2006, treated with: 2006: Corticosteroids , Asacol, 6MP--continued active disease 2006-2007: Infliximab—continued steroid-requirement 2007-2009: 6MP—incomplete response; continued steroid-requirement 2009: C.difficle infection 2011: adalimumb—incomplete response; continued steroid-requirement 2012: carbohydrate diet; Salmonella infection In 2012, diagnosed with HL Currently treated with ABVD; continues on prednisone Flex sig and colonoscopy: inflammation in rectosigmoid

Case (con’t): PMHx/PSHx: otherwise unremarkable FamHx: colorectal cancer (maternal grandfather); non-melanoma skin cancer (maternal grandfather, mother) SocHx: non-smoker ROS: otherwise non-contributory PE: unremarkable Pathology: WBC 18; Hgb 9.2; Hct 30.7; Plt 648; Alb 3.3; AlkPhos 152; ALT 97; AST 44 Most recent flexible sigmoidoscopy: rectosigmoid biopsies—severely active UC with necrotic exudate.

Case (con’t):

Case (con’t):

Outline: Baseline risk for lymphoma in IBD Mechanism for lymphoma development in immunosuppression Published risks of lymphoma for IBD immunosuppressant medications What to do next?

IBD and lymphoma: baseline risk? Population-based cohorts or Tertiary centers: Closer surveillance Over-reporting Earlier diagnosis Longer duration of disease Increased use of immunosuppression Confounding due to co-existing diseases

IBD and lymphoma: baseline risk? Loftus et al Am J Gastroenterol 2000;95:2308–12 Olmstead County 1940-1993: 1 NHL in 6662 IBD patient-years (crude risk 0.002) Mayo Clinic 1976-1997: 61 NHL in 15,000 patients seen (crude risk 0.004) Bewtra M, and Lewis JD Gastroenterol Clin N Am 38 (2009) 669–689

IBD and lymphoma: baseline risk? Potentially a higher risk of lymphoma in IBD Tertiary care centers Numerous limitations/confounders Despite this, the absolute risk remains LOW General population age-adjusted annual incidence of lymphoma (SEER): 20 per 100,000

Outline: Baseline risk for lymphoma in IBD Mechanism for lymphoma development in immunosuppression Published risks of lymphoma for IBD immunosuppressant medications What to do next?

Mechanism for lymphoma development Defective immune system = increased risk of lymphoma Defective immunologic tumor cell surveillance Specifically implicated in Epstein-Barr (EBV) virus-positive lymphoma Human herpes virus infection in >90% of population Immunosuppression allows emergence of lymphoproliferative disorders associated with EBV

Outline: Baseline risk for lymphoma in IBD Mechanism for lymphoma development in immunosuppression Published risks of lymphoma for IBD immunosuppressant medications What to do next?

Cyclosporine: Most experience/evidence from transplant and dermatology literature Case reports only in IBD literature Confounded by multiple medications Cockburn 1989 Paul 2003 Population 5000 + transplant 1252 psoriasis Risk 0.5% (m); 0.1% (w) 28 RR SIR 2.0 (0.2–7.2) Cockburn et al. J Autoimmun 1989;2:723–31 Paul et al. J Invest Dermatol 2003;120: 211–6

Methotrexate: Limited data in IBD Psoriasis and RA: more experience Lack of sample size and follow-up time Confounding by other medications Psoriasis and RA: more experience Author Disease Outcome Comparison Group RR/OR/SIR/IRR Stern RS et al., 1982 Psoriasis Noncutaneous malignancy psoriatic patients 0.96 (0.5-2.0) Stern RS et al., 2006 Lymphoma general population 3.65 (1.34-9.90)a 0.85 (0.37-1.67)b Hannuksela-Svahn et al., 2000 Non-Hodgkin’s lymphoma 2.2 (1.4, 3.4) Wolfe F et al., 2004 Rheumatoid arthritis 1.7 (0.9-3.2) Bernatsky S et al., 2008 Hematologic malignant neoplasms rheumatoid arthritis patients 1.12 (0.93-1.34) Buchbinder R et al., 2008 5.1 (2.2-10.0) abased on patients with >36 months exposure to MTX Bewtra M, Lewis JD, Expert Rev Clin Immunol. 2010 bbased on patients with <36 months exposure to MTX Jul;6(4):621-31

Azathioprine/6-MP: 1:4,357 (age 20-29) 1:355 (age > 65) Bewtra M, Lewis JD, Expert Rev Clin Immunol. 2010 Jul;6(4):621-31

Number of Lymphomas (absolute) Azathioprine/6-MP: CESAME study At Cohort Entry: N Number of Lymphomas (absolute) HR (95% CI) Never exposed 10,810 6 Reference On current therapy 5,867 16 5.3 (2.0-13.9) Discontinued therapy 2,809 2 1.0 (0.2-5.1) Beaugerie L et al. Lancet 2009

Risk of Lymphoma Returns to Normal after Stopping Thiopurines 36,891 VA patients with UC with a median follow up of 6.7 years and a median age of 60 years at inclusion 4,734 patients using thiopurines; median duration of exposure : 0.97 years 142 confirmed lymphoma cases Thiopurine use Incidence Rate (per 1000 py) Unexposed 0.6 During 2.3 After stopping 0.3 Is There Any Residual Risk of Lymphoma After Stopping Thiopurines? a Nationwide Retrospective Cohort From the Veterans' Affairs Healthcare System  10:45 | 641 |  Nabeel Khan1, 2, Yordanka N. Koleva1, Ali Abbas2, 1 Affiliation 1Gastroenterology, Southeast Louisiana Veterans Health Care System, New Orleans, LA; 2Gastroenterology and Hepatology, Tulane University, New Orleans, LA Abstract: Background: 
Thiopurine treatment is associated with increased risk of lymphoma. There is limited data regarding whether this effect persists after discontinuation of thiopurines. Our aim was to identify incidence of lymphoma after stopping thiopurines and to compare it with the incidence while taking the medication.
Methods
Ulcerative colitis (UC) patients who were followed-up in the Veterans Affairs (VA) healthcare system and used thiopurines between 2001 and 2011 were identified using ICD9 codes. We used retrospective cohort study design. Patients were followed-up from the index date of thiopurine filling from the VA pharmacy to the date of lymphoma diagnosis or October, 1st, 2011. Lymphoma cases were firstly identified by ICD9 codes and then by manual chart review to confirm the diagnoses and the dates. Person-year contribution was calculated for the included patients and the incidence rate of lymphoma was calculated while taking thiopurines and for the period after stopping them. Age, sex, race adjusted hazard ratio comparing the risk of lymphomas while taking thiopurines versus the risk after stopping them was calculated using time dependent Cox regression analysis. 
Results
We included 4,734 patients in the analysis with mean thiopurine use duration of 1.6 year (median of one year) and mean of follow-up after thiopurines stopping of 3.9 years (median 3.6 years). Majority were Caucasian (78%), males (93%) with median age at inclusion of 55 years. Total person-year of follow-up analyzed was 7,777.3 while on and 17,949.7 after stopping thiopurines. Lymphoma cases identified were 18 while on and 5 after stopping thiopurines. Incidence rate of lymphoma was 2.3 per 1000 person-year while on thiopurines compared to only 0.3 per 1000 person-year after stopping thiopurines. Age, sex and race adjusted hazard ratio of lymphoma while on thiopurines was 8.2 (p<0.001) compared to after stopping it (Table). 
Conclusion
In this nationwide cohort, the risk of lymphoma after stopping thiopurines was comparable to the risk of lymphoma in Inflammatory Bowel Disease patients who never took thiopurines as reported in the literature. There was an eight-fold increase in the risk of lymphoma for the period while on therapy compared to the period after stopping therapy. Khan, N. et al. Presented at DDW May 2013. Abstract Mo641.

Meta-analysis results NHL rate per 10,000 patient-years Anti-TNFs: Meta-analysis (infliximab, adalimumab, certolizumab): Combination immunosuppression: SIR 6.6 (4.4-8.8) to SIR 10.2 (1.2-36.9) Meta-analysis results NHL rate per 10,000 patient-years SIR 95% CI SEER (all ages) 1.9 Immunomodulators alone 3.6 Anti-TNF vs. SEER 6.1 3.23 1.5-6.9 Anti-TNF vs. immunomodulators 1.7 0.5-7.1 Randomized controlled trials 5.2 2.6 0.19-35.7 Cohort studies 4.6 2.3 0.44-22.7 Case series studies 18.8 9.4 1.35-104.0 Siegel C. et al. Clin Gastro Hep 2009 Herrinton Am J Gastro 2011 Beaugerie, Lancet 2009

Combination Therapy: Therapy # Lymphoma SIR 95% CI Never on thiopurine or TNF (1) 6 1.5 0.5 – 3.2 Never on thiopurine or TNF (2) 33 1.0 0.96 – 1.1 Current thiopurine w/o TNF (1) 13 6.5 3.5 – 11.2 Current thiopurine w/o TNF (2) 4 1.4 1.2 – 1.7 Current TNF w/o thiopurine (2) -- Current TNF + prior thiopurine (2) 1 5.2 3.5 – 6.8 Current thiopurine + TNF (1) 2 10.2 1.2 – 36.9 Current thiopurine + TNF (2) 6.6 4.4 – 8.8 (1) Beaugerie et al, Lancet 2009 (2) Herrinton Am J Gastro 2011

Hepatosplenic T-Cell Lymphoma Extranodal T-cell lymphoma Not EBV-related Ochenrider et al. Clin Lymphoma Myeloma Leuk. 2010;10(2):144-148 28 cases reported, all in CD All exposed to thiopurine 22 exposed to anti-TNF therapy 3 in patients treated with adalimumab Majority (93%) male Median age: 22 years old Herrinton L et al, Pharmacoepi Drug Safety 2012: 0.3 (95%CI, 0.11–0.65) per million person- years (baseline population) 48 per million-person years (1 case reported) 1: 20,964

Hepatosplenic T-Cell Lymphoma In patients < 35 years of age: Risk of thiopurine monotherapy: 1:7,404 Risk of combination therapy: 1:3,534 Parakkal D et al, Eur J Gastro and Hep 2011

Outline: Baseline risk for lymphoma in IBD Mechanism for lymphoma development in immunosuppression Published risks of lymphoma for IBD immunosuppressant medications What to do next?

After diagnosis of lymphoma: Consult Oncology. Continue therapy: Previously treated lymphoma and inactive > 1 year Stop therapy: New lymphoma EBV+ on 6-MP If HSTCL, avoid future 6MP (? anti-TNF)