Transcript Document

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