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How often do immunomodulators and/or biologics cause lymphoma and/or cancer, and can we prevent lymphoma and/or cancer in our patients? James D. Lewis, MD, MSCE Perelman School of Medicine University of Pennsylvania There is never enough time to say everything that you want to say Case 35 y.o. male recently diagnosed with ileocolonic CD Now steroid dependent Treating physician recommends infliximab + azathioprine Patient is concerned about risk of lymphoma Questions Does immunosuppressant therapy increase the risk of lymphoma? Do the benefits outweigh the risks? Is there anything I can do to decrease the risk of lymphoma? AZA/6-MP & Lymphoma: Meta-analysis Author Observed Expected Connell 0 0.52 Kinlen 2 0.24 Farrell 2 0.05 Lewis 1 0.64 Fraser 3 0.65 Korelitz 3 0.61 Total 11 2.71 SIR = 4.06, 95% CI 2.01 – 7.28 Kandiel A et al. Gut. 2005:54:1121-25 CESAME - Lymphoma At cohort entry N # HR (95% CI) Lymphomas 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 Anti-TNF & Lymphoma: Meta-analysis NHL rate – 6.1 per 10,000 p-y of exposure SIR 95% CI Anti-TNF vs SEER 3.2 1.5 – 6.9 Anti-TNF vs IM alone from Kandiel 1.7 0.5 – 7.1 Siegel C. Clin Gastroenterol Hepatol 2009;7:874-81 Combination Therapy and Risk of Lymphoma Therapy # Lymph SIR 95% CI Current thiopurine w/out TNF (1) 13 6.5 3.5 – 11.2 Current thiopurine w/out TNF (2) 4 1.4 1.2 – 1.7 Current thiopurine w/out TNF (3) 17 7.5 4.7 – 12.0 Current TNF w/out thiopurine (2) 0 0 -- Current TNF w/out thiopurine (4) 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 Current thiopurine + TNF (4) 1 5.0 0.1 - 28.0 (1) Beaugerie L. Lancet 2009;374:1617-1625. (2) Herrinton L. Am J Gastroenterol 2011;106(12):2146-2153. (3) Khan N. Gastro 2013;145:1007-15(4) Osterman M. Gastro In press. Clinical Questions Does immunosuppressant therapy increase the risk of lymphoma? Thiopurines – yes, but risk may revert after discontinuation TNF – Possibly Combination – More than TNF monotherapy, possibly more than thiopurine monotherapy Do the benefits outweigh the risks? 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 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 25,641 19,074 Annual incidence NHL + HD with thiopurines (x4‡) NNT to cause one death / year ‡ Kandiel A et al. Gut. 2005:54:1121-25 * 5 year survival = 68% for NHL, 85% for HD, estimated at 75% for this example Relationship of Age and Outcome with Azathioprine Therapy Gain in Quality Adjusted Years 0.09 0.08 0.07 0.06 0.05 0.04 0.03 0.02 0.01 0 -0.01 0 20 40 Age (years) Lewis et al. Gastroenterology 2000;118(6): 1018-24 60 80 The Value of a Short Term Trial Define whether patient will respond to therapy Entails limited risk Pr(lymphoma)=(1/2000p-y) x (.25 p-y) = 1.25 per 10,000 subjects treated for 3 mos Only continue therapy if there is documented benefit Risk of long term therapy weighed against greater probability of benefit Hepatosplenic T Cell Lymphoma Reports to 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; 108:99–105 2. Kotlyar D. Clin Gastroenterol Hepatol 2011;9:36–41 HSTCL Incidence Kaiser Permanente Northern California 6 cases from 2000 - 2006 Overall 0.03 / 105 person-years Men 0.04 / 105 person-years Women 0.01 / 105 person-years IBD – 1 case from 3,652 py of thiopurine exposure (patient also had anti-TNF exposure) CESAME – 0 cases from 26,640 person-years (16,659 currently exposed, 9,981 prior exposure; 44% male) Herrinton LJ. Pharmacoepidemiol Drug Saf 2012; 21: 49–52 Beaugerie L. Lancet 2009;374:1617-1625 CESAME + KPNC 1 case 20,311 person-years of current exposure 44% male in CESAME, KPNC unknown Overall – 4.9 per 100,000 person-years Male – 11.2 per 100,000 person-years Herrinton LJ. Pharmacoepidemiol Drug Saf 2012; 21: 49–52 Beaugerie L. Lancet 2009;374:1617-1625 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 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 25,641 19,074 11.2 11.2 NNT to cause one HSTCL death / year 8,929 8,929 Total NNT to cause one lymphoma death/year 6,623 6,079 Annual incidence NHL + HD with thiopurines (x4‡) NNT to cause one death / year HSTCL Annual incidence HSTCL with thiopurines† ‡ Kandiel A et al. Gut. 2005:54:1121-25 * 5 year survival = 68% for NHL, 85% for HD, estimated at 75% for this example † Estimated from KPNC (Herrinton LJ. Pharmacoepidemiol Drug Saf 2012; 21: 49–52) and CESAME (Beaugerie L. Lancet 2009;374:1617-1625) This is almost certainly an over estimate of HSTCL NNH With and Without HSTCL 30% of incidence as it suggests that approximately y.o. M treated 20-24 y.o. M lymphomas males Males Only that occur among young15-19 (per 10 ) (per 10 ) with thiopurines are HSTCL Lymphoma other than HSTCL 5 Annual incidence NHL + HD USA 5 5.2 7.0 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 25,641 19,074 11.2 11.2 NNT to cause one HSTCL death / year 8,929 8,929 Total NNT to cause one lymphoma death/year 6,623 6,079 Annual incidence NHL + HD with thiopurines (x4‡) NNT to cause one death / year HSTCL Annual incidence HSTCL with thiopurines† ‡ Kandiel A et al. Gut. 2005:54:1121-25 * 5 year survival = 68% for NHL, 85% for HD, estimated at 75% for this example † Estimated from KPNC (Herrinton LJ. Pharmacoepidemiol Drug Saf 2012; 21: 49–52) and CESAME (Beaugerie L. Lancet 2009;374:1617-1625) Hazards of Modes of Transportation Transportation Commercial plane Risk of Death per 100,000 person-years (NNH) 0.15 (666,667) Car Additional risk from talking on cell phone 11 (9,090) 1.3 (76,923) Motorcycle Cohen JT. Health Affairs 2007:26:636-46 450 (222) Clinical Questions Does immunosuppressant therapy increase the risk of lymphoma? Thiopurines – yes, but risk may revert after discontinuation TNF – Possibly Combination – Yes and “probably” more than monotherapy Do the benefits outweigh the risks? In most scenarios Is there anything I can do to decrease the risk of lymphoma? Theory Behind Monitoring EBV Titers Acute Infection EBV Associated Lymphoma EBV viral load Early Rise Immunosuppression Recovery Recovery Time Adapted from Gulley LM. Clin. Microbiol. Rev. 2010, 23(2):350-66 Why does immunosuppression matter? Immune surveillance Percent of patients Epstein-Barr virus associated lymphoma * P<0.05 vs control. # P<0.05 vs. AZA and 5-ASA 80 EBV DNA>0 70 copies/ml # # 60 50 40 EBV DNA >500 * * 30 copies/ml 20 among those 10 with detectable 0 DNA Dayharsh GA. Gastroenterology 2002:122:72-77. Magro F. Inflamm Bowel Dis. 2013;19:1710-6 Decreasing the risk Minimize unnecessary immunosuppression What defines unnecessary immunosuppression? Is there a role for discontinuing therapy in the setting of long term remission? What is the minimum dose of thiopurines or methotrexate needed to augment effectiveness of anti-TNF drugs? Is methotrexate less “lymphomagenic” than thiopurines and equally effective EBV serology testing prior to treating Monitoring EBV titers Is there a role for EBV serology testing to risk stratify? Teens - 20s: High Risk Period for Infection Proportion with Prior Infection 80 70 60 50 40 30 20 10 0 76 64 26 Yale Freshmen Yale Graduates Peace Corps Volunteers Age Year Yale freshmen 17-18 1958-63 Yale graduates 21-26 1968 Peace Corps volunteers 20-34 1964-65 Niederman JC. N Eng J Med 1970;282:361-5 Greater Risk of PTLD in Children, Elderly, and EBV Seronegative Organ transplanted Overall incidence Incidence in children Kidney 0.5 – 1 1 – 10 Marrow or stem cells 0.5 – 1 13 Liver 1.6 – 5 4 – 15 Heart or lung 1.9 - 10 6 - 20 Risk factors for PTLD in adult kidney transplant recipients Risk factor Adjusted HR 95% CI Age > 60 2.2 1.2 – 3.9 EBV seronegative recipient 3.0 1.6 – 5.1 Gulley LM. Clin. Microbiol. Rev. 2010, 23(2):350-66 Caillard SC. Am. J. Transplant 2006;6:2735-42 EBV Serology What we know EBV infection is very common and typically occurs early in life1 Seronegative transplant recipients have a higher risk of PTLD2 De novo infection while immunosuppressed associated with higher incidence of lymphoma3 Should we test EBV serologies prior to treatment in young patients and withhold thiopurines if EBV seronegative? 1. Niederman JC. N Eng J Med 1970;282:361-5 2. Caillard SC. Am. J. Transplant 2006;6:2735-42 3. Ho M. J Infect Dis. 1985; 152(5): 876–886 Should we monitor EBV titers during therapy? Pros and Cons No proven early interventions to prevent PTLD (e.g. antiviral agents) Early detection of PTLD associated with better outcomes More favorable histology / genetic profile Gulley LM. Clin. Microbiol. Rev. 2010, 23(2):350-66 Styczynski J. Bone Marrow Transplant 2009 May;43:757-70. Guidelines on monitoring Some organ and BM transplant guidelines recommend early aggressive monitoring in high risk patients EBV mismatch, splenectomy, T cell depletion, use of ATG or OKT3 No guidelines for IBD Unlikely to be cost-effective (or feasible?) for IBD given lower risk of EBV-related lymphoma Gulley LM. Clin. Microbiol. Rev. 2010, 23(2):350-66 Styczynski J. Bone Marrow Transplant 2009 May;43:757-70. Take Home Points Thiopurines and possibly anti-TNF therapies increase the risk of lymphoma A short trial of therapy has little long term risk of lymphoma and can inform the risk-benefit balance of long term therapy Discontinue ineffective medications unless can justify for other reason, e.g. preventing antibody formation Additional caution may be warranted in young EBV serology negative patients, young males and the elderly