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

2. Case:
28 year old white male h/o pancolitis UC diagnosed 2006, treated with:
2006: Corticosteroids , Asacol, 6MP--continued active disease
: Infliximab—continued steroid-requirement
: 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

3. 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.

4. Case (con’t):

5. Case (con’t):

6. 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?

7. 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

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

9. 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

10. 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?

11. 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

12. 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?

13. Cyclosporine:
Most experience/evidence from transplant and dermatology literature
Case reports only in IBD literature
Confounded by multiple medications
Cockburn 1989
Paul 2003
Population
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

14. 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 ( )
Stern RS et al., 2006
Lymphoma
general population
3.65 ( )a
0.85 ( )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 ( )
Bernatsky S et al., 2008
Hematologic malignant neoplasms
rheumatoid arthritis patients
1.12 ( )
Buchbinder R et al., 2008
5.1 ( )
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

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

16. 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 ( )
Discontinued therapy
2,809 2
1.0 ( )
Beaugerie L et al. Lancet 2009

17. 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, 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 Abstract Mo641.

18. Meta-analysis results NHL rate per 10,000 patient-years
Anti-TNFs:
Meta-analysis (infliximab, adalimumab, certolizumab):
Combination immunosuppression:
SIR 6.6 ( ) to SIR 10.2 ( )
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
Anti-TNF vs. immunomodulators
1.7
Randomized controlled trials
5.2
2.6
Cohort studies
4.6
2.3
Case series studies
18.8
9.4
Siegel C. et al. Clin Gastro Hep 2009
Herrinton Am J Gastro 2011
Beaugerie, Lancet 2009

19. 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

20. Hepatosplenic T-Cell Lymphoma
Extranodal T-cell lymphoma
Not EBV-related
Ochenrider et al. Clin Lymphoma Myeloma Leuk. 2010;10(2):
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

21. 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

22. 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?

23. 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)