Adolescents With Loss of Response to Infliximab

Report
Thiopurines have no role in the
management of Pediatric IBD
Robert N. Baldassano, MD
Colman Professor of Pediatrics
University of Pennsylvania, Perelman School of Medicine
Director, Center for Pediatric IBD
The Children's Hospital of Philadelphia
Thiopurines have a limited role in the
management of Pediatric IBD
Robert N. Baldassano, MD
Colman Professor of Pediatrics
University of Pennsylvania, Perelman School of Medicine
Director, Center for Pediatric IBD
The Children's Hospital of Philadelphia
I have the following financial relationships to
disclose
•
•
•
•
Janssen Pharmaceuticals
Takeda Pharmaceuticals
AbbVie, Inc.
Avaxia Biologics, Inc.
Products or services produced by this company are relevant to my
presentation
Balancing the Risks/Benefits of Therapy
in Patients With IBD
Serious AEs
• Opportunistic infections
• Lymphoma
• Skin cancer
• Autoimmune disease
Efficacy
• Induction of remission
• Maintenance of remission
• Mucosal healing
• Promote growth
Questions you need to address before
treating a patient:
• What are the risks of serious infection with IM and anti-TNFα
therapy?
• What is the risk of malignancy with IM alone?
Thiopurines
Methotrexate
• What is the risk of malignancy with anti-TNFα alone?
• What is the risk of combination therapy with IM and antiTNFα?
With thiopurine
With methotrexate
• Can we mitigate these risks?
Risks are important to patients – even small risk!!
FEAR!
It is all about cancer.
Courtesy of J. Hyams
Is There Risk of Malignancy
With Thiopurines?
• Azathioprine is known to be a human
carcinogen based on sufficient evidence of
carcinogenicity from studies in humans.
• First listed in the Fourth Annual Report on
Carcinogens (1985)
• Initial evidence from transplantation but over
time with chronic inflammatory disorders
Report on Carcinogens, Twelfth Edition (2011)
http://ntp.niehs.nih.gov/go/roc12
Multiple Mechanisms of Carcinogenesis
With Thiopurines
• DNA damage
• Decreased immunosurveillance
– TP are cytotoxic for NK and cytotoxic T cells
• restrict proliferation of EBV infected and immortalized B cells
• Emergence of oncogenic viruses (EBV)
• Taking 6MP/AZA results in 6-TG accumulating in cellular
DNA in skin
– 6-TG has an absorption peak at 342 nm
• ultraviolet radiation (320-400 nm)
– Results in a significant absorption of ultraviolet radiation
leading to DNA-damage
Karran and Attard. Nat Rev Cancer 2008;8:24, Allan and Travis, Nat Rev Cancer 2005;5:943
Is Thiopurine Rx Mutagenic?
Mutagenicity assay
Mutant clonal cell expansion
Cross sectional in vivo study of peripheral blood mononuclear cells in 119 adults and
children with IBD
Nguyen T el al. Cancer Res 2009;69(17):7004-12
Age-adjusted Lymphoma Rate
Overall rates: Unexposed 0.6/1000 PYF, During 2.31/1000PYF, after 0.28/
1000 PYF
SIR for NHL during TP 7.4 (95% CI 4.6-11.9) compared to SEER age standardized data
Khan et al. Gastroenterology 2013;145:1007
Adjusted Risk of Lymphoma: Hazard
Ratio Per Years of Exposure
United States Veteran Affairs Health System: 36, 891 pts with UC, 88%>40yr,
93% male, 76% white
Khan et al. Gastroenterology 2013;145:1007
Non-melanoma Skin Cancer: CESAME
French National Cohort
Yearly
Incidence
Per
1,000
Pt-years
Peyrin-Biroulet et al. Gastroenterology 2011;141:1621
Increased Malignancy Risk with
Adalimumab Combination Therapy
Compared to Monotherapy
Pooled data from ADA RCT 3050 pt years. Median
f/u 1.5 yrs. Compared to SEER (general population)
No increased risk for ADA monotherapy for
NMSC or any malignancy
ADA + IM: 3x increased risk for malignancy other
than NMSC
ADA + IM: 5X increased risk for NMSC
ADA + IM: 8X increased risk for lymphoma
Osterman et al. Gastroenterology 2014:146:941
Hepatosplenic T Cell Lymphoma:
The 900 Pound Gorilla in the Room That
Changed Everything for Pediatricians
Courtesy of J. Hyams
Hepatosplenic T Cell Lymphomas
• Most common associations
–
–
–
–
–
–
Male, 10-35 y of age (69.5%)
Hepatosplenomegaly
Cytopenia
Elevated aminotransferases
No adenopathy
Symptoms (fever, weight loss, night sweats)
• Aggressive course, median survival 16 months,
almost universally fatal
Belhadj K, et al. Blood. 2003;102:4261–4269.
Incidence of HSTCL
• SEER data: Non-Hodgkin’s lymphoma incidence
10-19 yrs: 20/1,000,000 (1:50,000)
20-29 yrs: 30/1,000,000 (1:33,000)
• Peripheral T cell lymphomas: 10-15% of NHL
• HSTCL: 5% of peripheral T cell lymphomas or <1% of
all NHL
• Therefore, incidence of HSTCL 1:5,000,000
• In U.S. 50,000 to 100,000 children with IBD. One
would therefore expect one case every 50-100 years
as background incidence
Courtesy of J. Hyams
Hepatosplenic T-Cell Lymphoma in IBD
Risk Estimates for HSTCL in IBD
The riskon
appears
to be
particularly
increased in1:45,000
All patients
thiopurine
only
Rx
patients receiving thiopurines, either as monotherapy
All patients on infliximab ± thiopurine
1:21,947
or in combination with anti-TNF agents. IBD patients
All males
<35 longterm
yrs on thiopurine
only therapy
Rx
1:7404
receiving
thiopurine
are possibly
at
even greater
All males
<35 yrs risk.
on thiopurine + anti-TNF
1:3534
Kotlyar D et al. Clin Gastroenterol Hepatol 2011;9:36-41
Conclusions
• Thiopurine use is associated with increased
cancer risk.
• Risk of cancer with mtx appears to be small to
negligible, but more data are needed
• Anti-TNF therapy alone does not appear to
increase cancer risk
• Anti-TNF + thiopurine is associated with
increased cancer risk, though not clear what
amount is from thiopurine alone. Particularly
problematic in young males
6-MP: Maintenance Therapy
in Children With Crohn’s Disease
If it is too good to be true!
Endpoint ?????
Predicting the Crohn’s Disease Activity Index
From the Harvey-Bradshaw Index (HBI)
1.00
Fractional
Survival
Conclusion: ” HBI is not recommended for prospective
0.75
trials in
Crohn’s disease”
Best
WR IBD 2006;12;4:304-310
0.50
6-MP
Control
0.25
0.00
0
100
200
300
400
500
600
Modified Harvey Bradshaw
(Not a validated disease
activity index)
Remission???
No difference in linear
growth
Sample size??? n=55
Selection bias
Wide confidence interval
Remission Duration (days)
P=.007
Markowitz J et al. Gastroenterology. 2000;119:895.
AZTEC
Early use of Azathioprine
in Adults With Crohn’s Disease
• RCT n = 131 newly dx. patients, 18 month study
– 2.5 mg/kg/day AZA vs. Control
– Endpoint: steroid-free remission and CDAI<150
• Remission rates (Aza vs. Control p=0.48)
– 44% in the Azathioprine group
– 37% in the placebo group
• Conclusion
– Azathioprine was no more effective than placebo at
18 months
Panes J et al, Gastro 2013;145:766
Early Aza vs Conventional Management of
Crohn’s disease: A randomized Controlled Trial
RCT n = 132 newly dx. patients, 3
year study
– 2.5 mg/kg/day AZA vs. Conventional
therapy
– Endpoint: steroid-free remission and
CDAI<150
Conclusion:
Early AZA use was no more effective than
conventional therapy in increasing time of clinical
remission
Cosnes J, et al. gastro 2013;145:758
RISK study
One Year CS-free Remission:
Effect of Early Therapy
70
P<0.001
# in Remission
60
50
P=NS
40
30
85%
41%
37%
20
10
0
Anti-TNFα monotherapy
(68 triads)
IM monotherapy
No Immunotherapy
Walters TD, et al, Gastro 2014;146:383
RISK study
Effect of Early Therapy on
Growth Parameters at 1 Year
1.2
No linear growth on thiopurines
Mean change z score
1
0.8
Mean change Htz
0.6
Mean change Wtz
0.4
0.2
Mean change BMIz
p=.002
p=.NS
0
-0.2
(68 triads)
Anti TNF
monotherapy
IM monotherapy
p=.NS
No Immunotherapy
Walters TD, et al, Gastro 2014;146:383
Risk Mitigation Strategy
• Consider stopping thiopurines when clinically possible
Reduced risk after time off therapy
• Consider drug holiday; change to mtx
• Yearly skin checks
• Avoid ionizing radiation
• Consider primary anti-TNF therapy in moderate to
severe IBD prior to thiopurine*; role of combination
with mtx to increase durability needs further data
• Potential role of emerging drugs in decreasing cancer
risk from therapy (e.g., anti-adhesion molecule
therapy)
Courtesy of J. Hyams
*off label use

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