A Case of Lymphoma in IBD

David T. Rubin MDMeenakshi 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):

• Baseline risk for lymphoma in IBD• Mechanism for lymphoma development in

immunosuppression• Published risks of lymphoma for IBD

immunosuppressant medications• What to do next?

Outline:

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?

Bewtra M, and Lewis JD Gastroenterol Clin N Am 38 (2009) 669–689

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)

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:

Author Disease Outcome Comparison Group RR/OR/SIR/IRRStern RS et al., 1982

Psoriasis Noncutaneous malignancy

psoriatic patients 0.96 (0.5-2.0)

Stern RS et al., 2006

Psoriasis Lymphoma general population 3.65 (1.34-9.90)a

0.85 (0.37-1.67)b

Hannuksela-Svahn et al., 2000

Psoriasis Non-Hodgkin’s lymphoma

general populationpsoriatic patients

2.2 (1.4, 3.4)0

Wolfe F et al., 2004

Rheumatoid arthritis

Lymphoma general population 1.7 (0.9-3.2)

Bernatsky S et al., 2008

Rheumatoid arthritis

Hematologic malignant neoplasms

rheumatoid arthritis patients

1.12 (0.93-1.34)

Buchbinder R et al., 2008

Rheumatoid arthritis

Non-Hodgkin’s lymphoma

general population 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

• Limited data in IBD– Lack of sample size and follow-up time– Confounding by other medications

• Psoriasis and RA: more experience

Azathioprine/6-MP:

Bewtra M, Lewis JD, Expert Rev Clin Immunol. 2010 Jul;6(4):621-31

1:4,357 (age 20-29)1:355 (age > 65)

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

• 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

17

Risk of Lymphoma Returns to Normal after Stopping Thiopurines

Thiopurine use Incidence Rate (per 1000 py)

Unexposed 0.6During 2.3After stopping 0.3

Khan, N. et al. Presented at DDW May 2013. Abstract Mo641.

Anti-TNFs:

Meta-analysis results NHL rate per 10,000 patient-years

SIR 95% CI

SEER (all ages) 1.9Immunomodulators alone 3.6Anti-TNF vs. SEER 6.1 3.23 1.5-6.9Anti-TNF vs. immunomodulators 6.1 1.7 0.5-7.1

Randomized controlled trials 5.2 2.6 0.19-35.7Cohort studies 4.6 2.3 0.44-22.7Case series studies 18.8 9.4 1.35-104.0

Siegel C. et al. Clin Gastro Hep 2009Herrinton Am J Gastro 2011Beaugerie, Lancet 2009

• Meta-analysis (infliximab, adalimumab, certolizumab):

• Combination immunosuppression:– SIR 6.6 (4.4-8.8) to SIR 10.2 (1.2-36.9)

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) 0 0 --

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) 1 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)