Transcript Literature Review
Literature Review
Peter R. McNally, DO, FACP, FACG University Colorado Denver School of Medicine Center for Human Simulation Aurora, Colorado 80045
Siegel CA
1&2
, Marden SM
2
, Persing SM
2
, Larson RJ
2
, Sands BE
3
.
Risk of Lymphoma Associated with Combination of Anti Tumor Necrosis Factor and Immunomodulator Therapy for the Treatment of Crohn’s Disease: A Meta-Analysis Clin Gastroenterol and Hepatol. 2009;7:874-881. 1 Dartmouth-Hitchcock IBD Center, Lebanon, New Hampshire, 2 Dartmouth Institute for Health Policy and Practice, Hanover, NH, 3 MGH Crohn’s and Colitis Center and Gastrointestinal Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Mass.
Introduction
Crohn’s disease is a chronic inflammatory disorder afflicting roughly 600,000 Americans.
The disorder strikes men and women in equal proportions, usually between the ages of 15-35 yrs.
The disease is chronic without cure and medical treatment is directed at blocking excessive intestinal inflammation.
Even with effective medical therapy, surgery is required in 50-60% of patients with this disorder.
Anti-TNF α drugs have been an major medical advance in the treatment of moderate to severe Crohn’s disease, but concerns over increased risk for malignancy and infection with anti-TNF α drugs have tempered clinical use.
Lichtenstein GR, et al. Management of Crohn’s Disease in Adults. AM J Gastroenterol. 2009 Feb;104(2):465-83.
Introduction
Anti-TNF α drugs have been associated with small, but significant increased risk for infections, especially TB and opportunistic infections.
Anti-TNF α drugs have been association with an increased incidence for malignancy, specifically Non Hodgkin's Lymphoma (NHL) and Non Melanoma Skin Cancer (NMSC).
Estimation of the true risk for malignancy with Anti-TNF α drugs is confounded by study design, limited longitudinal follow up, and the co-administration of other treatments known to independently increase this risk [Azathioprine (AZA), 6-mercaptopurine (6MP), methotrexate (MTX)].
Lichtenstein GR, et al. Management of Crohn’s Disease in Adults. AM J Gastroenterol. 2009 Feb;104(2):465-83.
Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81.
Aim
The authors sought to determine the most reliable estimate of Anti-TNF α related rates of NHL in patients with Crohn’s disease from an extensive literature search: MEDLINE, EMBASE, Cochrane Collaboration and Web of Science.
Comparisons were made with expected cancer rates derived from the National Cancer Institute (NCI), Surveillance Epidemiology and End Results (SEER) data base. http://seer.cancer.gov/csr/1975_2006/index.html
Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81.
Study Design: Meta-Analysis
Requirements for Inclusion in Meta-Analysis 1.
• • •
Study Design Randomized Clinical Trial (RCT) Prospective or Retrospective Cohort Case Series of Consecutive pts 2.
3.
4.
5.
All Articles or Abstracts must be published
• • •
Anti-TNF α Treatment Infliximab (IFX) Adalimumab (ADA) Certolizumab (CTZ) Only Crohn’s disease patients Outcomes reported & median follow up > 48 wk
Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81.
Study Design: Meta-Analysis
Publications from MEDLINE, Ovid, EMBASE, Cochrane (n=664) Manuscripts excluded by screening n=589 Studies included for review N=55 Unique abstracts from Web of Science n=6 35 studies excluded after detailed review Studies meeting all inclusion criteria N=26
Total of 26 studies involving 8,905 pts
Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81.
Results: Meta-Analysis
Characteristics of Included Studies
Total of 26 studies involving 8,905 pts Study Type
►
RCT n = 9
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Cohort
►
Case Series n = 3 n = 14
Patient Mean age 36.9 yr Mean duration of disease 9.3 yr Treatment
► ►
IFX ADA n = 22 studies n = 3 studies
►
CTZ n = 1 study
►
77% of pts concomitantly treated with immunomodulator drug.
Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81.
Study Analysis
Standardized Incidence Ratio (SIR)
Ratio of Observed Events to Expected Events in a population
SIR = # Observed Events
Example:
# Expected Events ►
If 5 malignancies observed in a study trial
►
If 20 malignancies expected in a general population
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Then SIR = 0.25
Meaning
SIR = 5 Observed Events 20 Expected Events ►
When SIR < 1.0, # observed events less than expected
►
When SIR > 1.0, # observed events greater than expected
http://seer.cancer.gov/seerstat/mp-sir.html
Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81.
Results: Rates of NHL Observed vs. Expected
Observed NHL
13 lymphomas in 21,178 pt-yrs
Rate 6.1 NHL per 10,000 pt yrs
Expected NHL Comparator
SEER 1.9 per 10,000 pt-yrs
http://seer.cancer.gov/. (Accessed on 6 November 2007)
SIR = 6.1 Observed Events = 3.2
1.9 Expected Events
Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81.
Results: Rates of NHL for SEER, Immunomodulator, and Anti-TNF α Treated Patients
SEER (all ages) IM alone Anti-TNF vs. SEER Anti-TNF vs. IM alone NHL rate 10,000 pt-yr 1.9
SIR - 3.6
6.1
6.1
- 3.23
1.7
95% CI - - 1.5-6.9
0.5-7.1
Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81.
Results: Age/Gender Specific NHL Rate & SIR
Age Pooled NHL / 10000 pt yr SEER NHL / 1000 pt-yrs SIR 95% CI 20-54 ♂ ♀ 55-64 ♂ ♀ 65-74 ♂ ♀ 75+ ♂ ♀ 5.9
3.1
23 8.5
27 20.9
91.5
0 1.1
0.8
4.3
3.2
8.4
6.3
13.2
9.26
5.4
3.8
5.4
2.7
3.2
3.3
6.9
1.3-18.1
0.7-15.9
0.6-15.9
0.1-15.9
0.1-18.4
0.1-19.0
0.2-39.3
-
9 10 11 12 13 1 2 3 4 5 6 7 8 Age 55 51 42 32 61 70 25 79 24 47 61 54 71
Characteristics of Crohn’s Pts with NHL
M/F F F F M M M M M F M M M F Agent IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX IFX ADA IM use AZA AZA NO NR MX + ?IM
AZA NR AZA AZA AZA 6MP AZA Type NHL B cell NK cell B cell B cell NR B cell Parotid B cell NR NR T cell T cell NR Death related to NHL NR Yes Yes No Yes Yes No No No no Yes Yes No Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881
Siegel CA, et al. Clin Gastro Hepatol. 2009;7:874-81.
Study Results: Rates SEER, Immunomodulator, & Anti-TNF Treated Patients
30 25 20 15 10 5 0 0 Ljung,et al.
20 40 60 80 100 120 ABsolute Rate NHL per 10,000 pt-yrs 140 160 Ljung et al. IFX in IBD: clinical outcome in a population based cohort from Stockholm County. Gut 2004;53:849-853. In this study 3 cases of NHL seen over 202 pt-yrs translated into 149 cases per 10,000 pt-yrs or SIR = 78.
Rate of NHL by Subgroup Analysis of Study Design
Design NHL Pt-Yrs RCT 2 3860 NHL per 10,000 pt-yrs 5.2
SIR to SEER 2.6
Cohort 7 Case Series* 4 15,192 2125 4.6
18.8
2.3
9.4
95% CI 0.19-35.7
0.44-22.7
1.35-104 * 3 of the 4 NHL cases reported in the Case Series were from the Ljung study group causing the confidence intervals to widen significantly. Ljung, et al.. Gut. 2004;53:849-853.
Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881
Sensitivity Analysis Excluding Studies With > 15% Drop-Out Rate
Age SIR 95% CI all 20-54 55-64 65-74 75+ NHL rate/ 10,000 All studies >15% drop out All studies >15% drop out All studies >15% drop out All studies >15% drop out All studies >15% drop out SEER rate/ 10,000 6.1
9.4
5.9
7.3
23 72 27 106 92 370 1.9
1.1
4.3
8.4
13.2
1.5-6.9
1.8-12.3
1.3-18.1
0.7-30.6
0.6-20.5
2.0-64.4
0.1-18.4
0.3-72.3
0.2-39.3
0.7-159 Message: There is a dramatic increase in NHL SIR as patients get older ( > 55yr ).
Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881
Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881
Study Summary
Use of Anti-TNF α drugs for the treatment of Crohn's’ disease is associated with an increased risk for NHL.
Absolute risk for NHL among these patients is:
6.1 per 10,000 pt-yrs (NHL Meta-Analysis) or 3x greater than the expected
1.9 per 10,000 pt-yrs (NHL SEER rate)
Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881
Study Summary
The majority of pts with NHL were receiving BOTH Anti-TNF α and Immunomodulator Rx.
10 of 13 (77%) reported NHL patients were on both Anti-TNF α & Immunomodulator Rx.
2 of 13 (15%) reported NHL patients were on Anti TNF α, but Immunomodulator Rx use was not reported.
1 of 13 (8%) reported NHL patients were on ONLY Anti-TNF α.
Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881
Study Summary
Overall risk for NHL for Crohn’s patients given both Anti-TNF α and an Immunomodulator Rx seems to be greater for men and patients older than 55 yrs.
At least 4 patients were discovered to have NHL after the 1 st infusion of Anti-TNF α. This might suggest that the effect of even one dose may be significant to increase lymphoma risk or alternatively that a significant number of NHL pts in this report were just pre-clinical.
Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881
Reviewer Comments
Siegel, et al, do not answer the following questions?
1.
• •
What is the risk for NHL among newly diagnosed “naïve” Crohn’s patients receiving only Anti-TNFα drugs?
77% of the patients with NHL in this study received both Anti-TNF α & Immunomodulator Rx.
Only one of the 13 (7%) reported cases of NHL was receiving ONLY Anti-TNF α.
Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881
Reviewer Comments
2.
The investigators included one Case Series study with obvious outlier data. When the data from the Ljung study are excluded from the Case Series data, the SIR to SEER NHL rate is calculated to be 2.7 which is comparable to the rates derived for both the RCT and Cohort groups, 2.6 and 2.3 respectively.
Design RCT Cohort Case Series* Case Series** NHL 2 7 4 1 Pt-Yrs 3860 15,192 2125 1923 NHL per 10,000 pt-yrs 5.2
4.6
18.8
5.2
SIR to SEER 2.6
2.3
9.4
2.7
* Calculations includes Ljung T, et al, data. ** Calculations excludes Ljung, et al, data
Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881
Reviewer Comments
3.
The first Anti-TNF α drug approved for the treatment of Crohn’s Disease (IFX) is chimeric. It is more commonly associated with neutralizing antibody formation than ADA or CTZ. This lead to the common practice of Anti TNF α immunomodulator co-therapy. 4.
Now we are left to retrospectively review the influence of past practices/conventions of combination therapy as they relate to risk for NHL and opportunistic infections. As shown in this study combination Anti-TNF α and Immunomodulators are associated with an increased risk for HNL – albeit small 6.1 per 10,000 pt-yr vs. 1.9 per 10,000 pt-yr (SEER).
5.
The risk for NHL for “naive” Crohn’s pts receiving mono Anti-TNF α ( ADA or CTZ) needs to be examined.
Siegel CA, et al. Clinical Gastro Hep. 2009;7:874-881
Reviewer Comments
6.
Recent reports of the Sonic trial suggest that IFX and Immunomodulator combination therapy is better at maintaining remission than mono therapy.
7.
With future Studies, it may be prudent to consider stratification of Anti-TNF α and Immunomodulator naive Crohn’s patients by Montreal Criteria, Vienna Classification or surrogate disease activity markers into mono- or combination therapy. Only then will be able determine the true risk benefit ratio of these drugs in the treatment of this chronic and often disabling disease.