when can we use combination therapy for our pediatric ibd patients? athos bousvaros md, mph advances...
TRANSCRIPT
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When can we use combination therapy for our pediatric IBD
patients?
Athos Bousvaros MD, MPHAdvances in IBD Dec 2014
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Disclosures (last 12 months)
• Consultant– Takeda/Millennium– Dyax– Cubist– Peabody Arnold (litigation)
• Research support– Prometheus
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Questions
• Should we use combination therapy in our pediatric IBD patients?
• If so, what kind?– Thiopurines and infliximab– Methotrexate and infliximab
• How does monitoring of biologic levels (therapeutic drug monitoring) impact on our decision?
• Is adalimumab different from infliximab?• How long do we continue combination therapy?
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The “Balancing Act”
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Our options with biologicsPros Cons
Infliximab Works Antibodiesmonotherapy Loss of response
IFX with levels May work better Antibodies
Adalimumab Works Antibodiesmonotherapy
Combination Works best Lymphoma Therapy – AZA/IFX
Combination Works No better than IFXMTX/IFX Decreased antibody monotherapy?
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Reading the literature on biologics, antibodies, loss of response, and drug levels
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Adult studies
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Combination therapy in both CD and UC (adult data – remission rates)
• SONIC (Crohn disease) – Remission 26 weeks– AZA plus infliximab – 57%– Infliximab alone – 44%– Antibodies to IFX – 1% (combination) vs. 15% (mono)
• UC SUCCESS (Ulcerative colitis)* – Remission 16 wks – AZA plus infliximab – 40%– Infliximab alone – 22%– Azathioprine alone – 23%– Ab to IFX – 3% (combination) vs. 19 % (mono)
*Panaccione et al, Gastro 2014;146:392
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UC SUCCESS trial
• 239 adult patients randomized to:– AZA alone – 2.5 mg/kg/day– IFX alone (5mg/kg) – 0,2,6, 14– AZA and IFX together– Double blind, double dummy design
• Inclusion criteria– Moderate to severe disease (Mayo score >= 6)– Stable dose of steroids allowed– No prior rx with MTX, CyA, Tacro, or rectal therapy– AZA naïve for 3 months or more
Panaccione, Gastro 2014; 146:392
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UC SUCCESS in close up
Panaccione, Gastro 2014; 146:392
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US SUCCESS results• Week 16• Remission rates
– 23 % AZA and IFX– 39% combination
• Drops in Mayo score – AZA - 3.00– IFX - 4.3– AZA/IFX - 5.2
• Calprotectin levels lower in combination group– 170 combination– Around 400 other 2 groups
• SAE’s more common in the two azathioprine groups (pancreatitis, anemia, nausea, vomiting)– NO 6MP levels or TPMT assayed
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Loss of response – natural history(Oussalah et al; AJGastro 2010)
• 88 patients treated with combination AZA and infliximab for at least 6 months
• Azathioprine withdrawn in 48 patients• Probability of infliximab failure
– Increasing dose, shortening interval, surgery, or hypersensitivity
– 15% at 12 months– 41% between 24 and 32 months
• Withdrawal of AZA strongly associated with infliximab failure (hazard ratio of 7 in patients that received combination for less than 800 days)
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COMMIT trial (MTX and IFX in Crohn)
• 50 week trial in adults with CD• 126 patients randomized to:
– IFX monotherapy– IFX and MTX (SQ, up to 25 mg/week)
• Primary endpoint – lack of steroid free remission at week 14, or at 50 weeks– 30 % failure in both groups
• However, antibodies lower in IFX + MTX– 4% (combo) vs. 20% (mono) at 1 year
remission
Low CRPFeagan et al Gastro 2014; 146:681-8
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Development of antibodies to adalimumab
• 247 adult and pediatric patients– 205 Crohn, 42 UC
• 330 “loss of response events”– Suspected worsening by physician– “Definite inflammatory LOR” (identification of inflammation by
labs, stool markers, or endoscopy)• Of 142 “LOR events”, 38% were associated with antibodies.
– Concomitant immunomodulators in about 30%– No clear impact of IM on outcome– AAA antibodies > 4 mcg/ml predicted patients who did not
respond to increased dosage of IM.
Yanal et al, CGH 2014, in press
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Pediatric studies
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Infliximab in pediatric Crohn’s(REACH trial)
• Children with active CD – Infliximab 5mg/kg
• 0,2, 6 weeks then q 2 months• 88% response rate after 3 infusions• 56% remission rate after 12 months
• However:– Concomitant immunomodulators used for
duration of study • REACH describes efficacy of
combination therapy (mostly thiopurine)
Hyams et al Gastro 2007;132:863
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Prevalence of antibodies to infliximab in children with IBD
• Boston Children’s Hospital– Cross-sectional cohort of 133
children– All still receiving infliximab as per
their primary physician’s dictates.– 20% had antibodies to infliximab– ATI correlated with lower IFX
levels, but not (as of yet) with loss of response or infusion reactions.
– ? Latency period between development of antibodies, drop in levels, and loss of response. Zitomersky et al, in press, IBD
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Long term outcomes of pediatric infliximab therapy
• 259 patients – CD and UC• 188 on IFX for at least 1 year
– Median duration 29 months– 84% CD, 16% UC
• Results– Half of CD patients underwent dose
intensification to maintain or recapture remission
• Most patients stayed on IFX (about 70% in both groups).
• No effect of low dose oral MTX
Vahabnezhad et al, IBD 2014; 20:606
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IFX level at week 14 may determine clinical outcome in children
• Prospective study of 58 IBD patients (81% CD)
• 13% primary nonresponse• 58% in persistent remission at 1
year of therapy• Median IFX level at week 14
correlated with remission (4.7 mcg/ml for patients in remission at 1 year, vs. 2.6 mcg/ml).
• Immunomodulators correlated with higher level, but this was not statistically significant.
• 26% had detectable antibodies to infliximab by week 54
Singh et al, IBD 2014; 20: 1708
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Adalimumab in pediatric CD(Hyams et al, Gastro 2012; 143:365-74)
• 192 CD patients with active PCDAI (>30)– Approximately 60% on ‘immunosuppressants”– Standard induction, then hi vs. low dose
• Results (clinical remission, high dose)– Week 26
• 57% infliximab naïve, 17% if prior infliximab
– Week 52• 45% infliximab naïve, 19% if prior infliximab
Infection rate about 5%, antibody rate only 3%
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Summarizing
• Good evidence that using combination treatment with thiopurines in patients starting on infliximab– Improves clinical remission rates in CD and UC– Reduces the likelihood of antibody formation
• Data on combination therapy with methotrexate and infliximab is lacking– Perhaps reduction in antibody formation– More studies needed
• Unclear if combination treatment impacts antibody development and clinical outcomes in patients treated with adalimumab
• More studies are needed
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How I like to practice
• Moderate Crohn’s disease treated with an immunomodulator first, then biologic if poor response.– Continuation of combination treatment (eg. AZA and
inflximab) for at least 6 months– Replacement of the thiopurine with low dose MTX
• High risk or severe Crohn’s treated with combination therapy– Extensive disease (especially mid-small bowel disease)– Severe rectal or perianal disease– Steroid-unresponsive disease– Growth failure in mid to late puberty
• Patient preference is important in making the decisions.
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Age < 18 yearsBeginning anti-TNF therapyNo contraindication to MTX use
RANDOMIZE
Anti-TNF plus methotrexate
Anti –TNF plus placebo
Week 104 assessment
Steroid free remission (primary endpoint)
Adverse eventsPatient reported outcomesAntibodies to anti-TNF
Week 104 assessment
Steroid free remission (primary)Adverse eventsPatient reported outcomesAntibodies to anti-TNF
Proposed clinical trial(Kappelman, PI)
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