1 pro: an ibd patient on a biologic and/or an immunomodulator, who develops a malignancy: skin...

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Pro: An IBD patient on a biologic and/or an immunomodulator, who develops a

malignancy:skin cancersolid tumorlymphoma

may continue or restart these medications, if needed to treat IBD

Miguel Regueiro, MD, FACG, AGAFProfessor of MedicineClinical Head, IBD CenterUniversity of Pittsburgh Medical Ctr

Do I really have a chance of winning a debate when my side is to continue meds when CA develops?

Thank you for slides

• Jim Lewis

• Jean Fred Colombel

• Corey Siegel (also for photos of Tom!)

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Important questions in pts who develops cancer on IBD meds:

1. Did the medicine cause the cancer?

2. What is the risk of:

- continuing the med in terms of worsening cancer or

- discontinuing the med in terms of worsening IBD?

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Let’s consider three types of cancer:

-Skin Cancer

-Lymphoma

- Solid Tumors

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Case

• 50 year old male

• 30 year history of small bowel Crohn’s

• 1 prior bowel resection

• Current meds – 6MP + Adalimumab

• 3 BM per day

• Colonoscopy – few scattered aphthous ulcers (i1) in the neo-TI

Case (cont)

• 2 years prior diagnosed with Non Melanoma Skin Cancer (Basal Cell Ca)

• 2 weeks ago newly diagnosed with Squamous Cell Cancer

Is skin cancer caused by or are patients at increased risk from…

-azathioprine/6MP

-Methotrexate

-antiTNFs

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Thiopurines and Skin Cancer

NMSC MELANOMA

Long M. Gastroenterology 2012:143:390-9. Singh H Gastroenterology 2011:141:1612-20Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8Peyrin-Biroulet L. Am J Gastroenterol 2012 doi: 10.1038/ajg.2012.181

Timing of Thiopurines and NMSC (esp. older ages)

Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8

CESAME

Anti-TNF and Skin Cancer (IBD data)

NMSC MELANOMA

Long M. Gastroenterology 2012:143:390-9. Singh H Gastroenterology 2011:141:1612-20Peyrin-Biroulet L. Gastroenterology 2011:141:1621-8Peyrin-Biroulet L. Am J Gastroenterol 2012 doi: 10.1038/ajg.2012.181

NR

Clinical Questions

• Is skin cancer risk increased by therapy?– Thiopurines – yes

– Methotrexate – don’t know, probably not

– Biologics – no NMSC, maybe melanoma

• If so, does the risk of continuing therapy outweigh the benefits?– In this case – consider stopping thiopurine

Uncertain if risk will decline

– Annual skin exam and regular use of sunscreen and hats

Skin: Stop or Continue? What I do-Consult with Dermatology and then.….

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NMSC – Basal Cell Squamous Cell Melanoma

Thiopurine

antiTNF


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Thiopurine Continue or start:Active or Past, as long as Dermatology monitoringMTX prob ok

Stop:Only if significant recurrence or potential for disfiguring sequelae

antiTNF


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Thiopurine

antiTNF Continue or start:Active or Past, as long as Dermatology monitoring

Stop:NO, rarely necessary to stop


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NMSC – Basal Cell Squamous Cell

Melanoma

Thiopurine Start:-eradicated/resected/no mets-melanoma free for > 1 yrStop/Restart: -Hold for new onset?-Maybe ok to continue -Restart if melanoma free-Stop for metastatic ds

antiTNF


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NMSC – Basal Cell Squamous Cell

Melanoma

Thiopurine

antiTNF Start:-eradicated/resected/no mets-melanoma free for > 1 yrStop: -New Onset-?Restart if melanoma free > 1 yr-Do not restart <1yr or mets

Lymphoma

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Questions

Does immunosuppressant therapy increase the risk of lymphoma?

Do the benefits outweigh the risks? What do you do when a lymphoma

develops in the setting of IBD meds?

AZA/6-MP are probably related to Lymphoma (Meta-analysis): SIR 4.06

AuthorAuthor ObservedObserved ExpectedExpected

ConnellConnell 00 0.520.52

KinlenKinlen 22 0.240.24

FarrellFarrell 22 0.050.05

LewisLewis 11 0.640.64

FraserFraser 33 0.650.65

KorelitzKorelitz 33 0.610.61

TotalTotal 1111 2.712.71

SIR = 4.06, 95% CI 2.01 – 7.28Kandiel A et al. Gut. 2005:54:1121-25

CESAME – 6MP/AZA OnlyLymphoma: HR 5.3

At cohort entry

N # Lymphomas

HR (95% CI)

Never exposed to thiopurines

10,810 6 Reference

On therapy with thiopurines

5,867 16 5.3 (2.0 – 13.9)

Previously discontinued thiopurines

2,809 2 1.0 (0.2 – 5.1)

Beaugerie L. Lancet 2009 DOI:10.1016/S0140-6736(09)61302-7

• 8905 patients representing 20,602 pt-years of exposure

• 13 Non-Hodgkin’s lymphomas

• Mean age 52, 62% male

• 10/13 exposed to IM* (really a study of combo Rx)

Risk of NH Lymphoma with anti-TNF + IM treatment for Crohn’s Disease: A Meta-Analysis

NHL rate per 10,000

SIR 95% CI

SEER all ages 1.9 - -

IM alone 3.6 - -

Anti-TNF + IM vs SEER 6.1 3.23 1.5-6.9

Anti-TNF+ IM vs IM alone 6.1 1.7 0.5-7.1

Siegel et al, CGH 2009;7:874. *not reported in 2

6.1 per 10,000 pt-years

CESAME – Combo 6MP/AZA and antiTNF: SIR = 10.2

Therapy Patients # Lymph SIR 95% CI

Never thiopurine or TNF

22,706 6 1.5 0.5 – 3.2

Current thiopurine without TNF

14,729 13 6.5 3.5 – 11.2

Current thiopurine + TNF

1,929 2 10.2 1.2 – 36.9

Beaugerie L. Lancet 2009 DOI:10.1016/S0140-6736(09)61302-7

Clinical Questions

• Does immunosuppressant therapy increase the risk of lymphoma?– Thiopurines – yes, but risk may revert after

discontinuation

– antiTNFs – Probably not

– Combination – Yes and probably more than monotherapy

Risk:Benefit Ratio

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Hepatosplenic T Cell Lymphoma

• 41 cases from FDA AERS among patients with IBD1

– Thiopurine alone 17– Anti-TNF alone 1– Combination therapy 23

• Characteristics2

– Median age 22.5 (12 – 58)– 93% male– Median time since initiation of thiopurines ~6 years

1. Deepak P. Am J Gastroenterol 2013; 108:99–1052. Kotlyar D. Clin Gastroenterol Hepatol 2011;9:36–41

Lymphoma - Number Needed to Harm

Males Only 15-19 y.o. M(per 105)

20-24 y.o. M (per 105)

Lymphoma other than HSTCL

Annual incidence NHL + HD USA 5.2 7.0

Annual incidence NHL + HD with thiopurines (x4‡) 20.8 28.0

Annual mortality from lymphoma without thiopurines* 1.3 1.75

Annual mortality from lymphoma with thiopurines* 5.2 7.0

Excess deaths from thiopurine induced lymphoma 3.9 5.25

NNT to cause one death / year 25,641 19,074

‡ Kandiel A et al. Gut. 2005:54:1121-25* 5 year survival = 68% for NHL, 85% for HD, estimated at 75% for this example

‡ Kandiel A et al. Gut. 2005:54:1121-25* 5 year survival = 68% for NHL, 85% for HD, estimated at 75% for this example

What to do if lymphoma develops while taking IMM/antiTNF?

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Case – Stop or Continue?

• 39 yo male CD in remission on 6MP/IFX for 8 yrs.

• Now with weight loss, sweats, and low grade fevers

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Crohn’s ds case: NHL while taking 6MP/IFX.

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After consulting with the oncologist….

…we stopped the 6MP/antiTNF, but after 3 months of chemorx, the

antiTNF was resumed. We did not restart the 6MP.

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On CT: Hepatosplenic T cell lymphoma – enlarged spleen, otherwise nonspecific.

Thiopurine must be stopped!

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Solid Tumors

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Case Continue or Stop?

• 58 yo female with severe UC who has been on IFX/6MP (50mg/d) for past 1yr

• Just diagnosed with intraductal breast CA (T1N0MX)

• Strong FHx breast CA, pt opts for bilateral mastectomy

• After consultation with oncology, the decision is to cont meds

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No clear association between thiopurines/antiTNFs and solid tumors

in IBD

Study Types of cancer

Number of patients

Statistically significant

Armstrong 2010 lung, breast 1955 NO

Fraser 2002breast,

bronchial, renal6262 NO

Connell 1994gastric, lung,

breast, cervical755 NO

Lymphoma: Stop or Continue? 3 types, Consult with Oncology and then.….

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Hepatosplenic TCNo relation to EBV

After acute EBVInitially EBV -

PTLD-likeInitially EBV +

Thiopurine

antiTNF


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Thiopurine Young Males

Extremely rare (<.0001%)

Usually in combo with anti-TNFs

Not with MTX/antiTNF

Fatal

antiTNF


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Thiopurine Young males

Hemophagocytic lymphohistiocytosis Very rare (<.001%)

Should we check EBV prior to starting in our young males?

antiTNF


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Thiopurine Older pts, long duration of 6MP

Rare (<.01%)

Males > Females

antiTNF


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ThiopurineStop

Never Restart

antiTNF


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ThiopurineStop, lymphoma may regress

Never Restart

antiTNF


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ThiopurineStop, lymphoma may resolve

Never Restart

antiTNF


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Thiopurine

antiTNFStop, probably never restart


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Thiopurine

antiTNFStop, but restart once lymphoma resolves


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Thiopurine

antiTNFContinue, only stop if progression of lymphoma

Solid Tumor: Stop or Continue? Consult with Oncology and then.….

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Solid Tumors, e.g. Breast, Lung, Renal Probably no relationship to IBD meds

Thiopurine -Continue if curative resection, no need to stop

antiTNF -Continue if curative resection, no need to stop


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Thiopurine-Stop if metastatic ds and/or chemotherapy

antiTNF-Stop if metastatic ds and/or chemotherapy


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Thiopurine-Restart once chemo done and no active cancer (? > 1 yr)

antiTNF-Restart once chemo done and no active cancer (? > 1 yr)

Should we continue or stop IBD meds if a cancer develops?

Depends on IBD

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Deep Remission

If in deep remission, maybe stopping IBD meds is ok and not

restarting them

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Not in deep remission or disabling IBDSkin Cancer

• Basal or Squamous Cell• Resected/Controlled

– CONTINUE all meds• Not controlled and/or disfiguring

– STOP azathioprine/6MP– CONTINUE anti-TNFs

• Melanoma• Resected/Eradicated > 1 year

– CONTINUE all meds• Multiple Skin Sites/Rapid Recurrence/Mets

– STOP anti-TNFs– CONTINUE – 6MP/AZA/MTX?

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Not in deep remission or disabling IBDLymphoma

• Acute EBV and lymphoma: • STOP AZA/6MP

• CONTINUE anti-TNF, after lymphoma resolved (may not even need to stop?)

• Hepatosplenic T Cell lymphoma:• STOP AZA/6MP and anti-TNF

• PTLD-like lymphoma (likely EBV):• STOP AZA/6MP

• CONTINUE anti-TNF, after lymphoma resolved (may not even need to stop?)

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Not in deep remission or disabling IBDSolid Tumors

6MP/AZA:- CONTINUE 6MP/AZA/MTX - Stop during chemo

Anti-TNFs- CONTINUE if tumor resected/eradicated

- STOP if metastatic ds or chemorx

- RESTART once cancer eradicated/chemorx stopped

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When you vote on who will win this debate

make sure you consider both halves of the debate, but also the

2 sides of TOM ULLMAN

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Which half will you see today?…..

….the honest, kind, thoughtful, Tom Ullman?

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Or ??????

…maybe that dazed look wasn’t because Tom just ran a race,

but…..

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Playboy Ullman starring in American Hustle

1 pro: an ibd patient on a biologic and/or an immunomodulator, who develops a malignancy: skin...

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