Who should receive early anti-TNF therapy: With what benefits and risks?

Ted Denson, MDCincinnati Children’s Hospital Medical CenterUniversity of Cincinnati College of Medicine

Disclosures

• Grant support: NIH & CCFA• Adapted from NASPGHAN 2013 talk by Jeff Hyams

IBD: Treatment Goals

• Clinical remission: no disease activity• Excellent quality of life • Intestinal healing• Normal growth and development• Prevent surgeries and hospitalizations• Minimal side effects• Acceptable financial cost

Therapeutic Options

• Option 1: Prednisone followed by 5-ASA• Option 2:Prednisone followed by 6-MP/Aza• Option 3: Prednisone followed by methotrexate• Option 4: Exclusive enteral nutrition followed by

IM• Option 5: Anti-TNFα monotherapy• Option 6: Anti-TNFα plus thiopurine• Option 7: Anti-TNF α plus methotrexate• Option 8: Intensive helminth therapy

Label for Infliximab Therapy in Children

• Approved for pediatric use in 2006• Infliximab is indicated for reducing signs and

symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn’s disease (CD) who have had an inadequate response to conventional therapy.

Accelerated Step-up Therapy for CD

Dis

ease

Sev

erit

y

Thiopurines ThiopurinesCorticosteroids Enteral Nutrition

Methotrexate

Anti-TNF

Surgery

Focus Questions

• How should we position anti-TNFα therapy in 2013? Rescue (i.e., after conventional therapy) vs. primary (at diagnosis)

• Can we identify patients who will receive the greatest benefit from early anti-TNFα therapy?

• What are the risks of early anti-TNFα therapy? • Should we give monotherapy or combination

therapy? Do benefits outweigh risks?• Can we stop anti-TNFα therapy?

REACH: Response and Remission

88

64

33

59 56

24

0102030405060708090

100

Week 10 Week 54 q8 Week 54 q12

Response Remission

*Reduction from baseline of ≥ 15 points in PCDAI score and a PCDAI score ≤ 30.†PCDAI score ≤ 10.

% o

f Pa

tien

ts

n = 99 n = 66 n = 29n = 33 n = 17 n = 12

p = 0.002

p < 0.001

* †

Hyams et al. Gastroenterology 2007;132:863-873

Imagine Trial

ADA-EXP LD ADA-EXP HD ADA -N LD ADA-N HD05

101520253035404550

52 Week Remission

Remission

17% 19% 28% 45%

P=0.8

P=0.065

Hyams et al. Gastroenterology 2012;143:365EXP= IFX experienced, N=IFX naïve

2008-2012: 552 childrenNewly Diagnosed with Crohn’s Disease Enrolled in CCFA RISK

Study

Crohn’s disease: 552 children with complete data and 1 yr f/u

Anti-TNFα onlyn = 68

No early immunotherapy

n = 236

Early IM onlyn=248

Propensity Score Matching

Anti-TNFα onlyn = 68

No early immunotherapy n = 68

IM onlyn = 68

Additional Treatment Characteristics of Study Triads

Early Therapy n=204

Agents used in 1st 3 months

Additional agents 3-6 months

Additional agents 6-12 months

Total other agents 3-12 months

Anti-TNFα only n=68

67 IFX1 ADA

0 Thio4 MTX

1 Thio2 MTX

1 Thio6 MTX

IM onlyN=68

54 Thio14 MTX

6 IFX0 ADA

13 IFX1 ADA

19 IFX1 ADA

No immuno-therapyN=68

48 5-ASA8 EEN

11 Thio8 MTX7 IFX1 ADA1 IFX + IM2 ADA + IM

3 Thio5 MTX4 IFX1 ADA4 IFX + IM

14 Thio13 MTX11 IFX2 ADA5 IFX+IM2 ADA+IM

Hyams et al. Gastroenterology 2013

Treatment Yes (n=136) No (n=68)

Early anti-TNFα only (n=68)

58 (85%) 10 (15%)

Early IM only (n=68)

41 (60%) 27 (40%)

No early immunotherapy(n=68)

37 (54%) 31 (46%)

CS-free, Surgery free

(p=0.0003)

12 Month Outcomes For The Three Early Therapy Approaches: PCDAI≤10

Without Resection (n=204 for 68 propensity score matched triads)

No difference between early IM and no early IM

Hyams et al. Gastroenterology 2013

Growth Parameters of Study Triads at Diagnosis/One Year

Early Therapy

Height z-score

Weight z-score

BMI z-score

Anti-TNFα only (n=68)

-0.16 (1.1)+0.14 (0.4)*

-0.56 (1.4) -0.79 (1.5)

IM only (n=68)

-0.29 (1.1)-0.02 (0.4)

-0.72 (1.3) -0.81 (1.3)

No immuno-therapy (n=68)

-0.32 (1.1)-0.06 (1.1)

-0.67 (1.1) -0.68 (1.1)

Difference between groups

P=0.6P=0.039

P=0.8 P=0.8

*p=0.002, anti-TNFα group only

What Does That Mean?

• In clinically similar populations of children with Crohn’s disease, early (<3 mon) therapy with anti-TNFα was superior to early IM or no early immunotherapy despite later addition of those agents: PCDAI remission, CRP, growth

• There was no particular clinical or laboratory characteristic that helped predict response or non-response to an initial therapeutic decision

• It doesn’t mean that everyone should get anti-TNFα therapy, rather that we need to better define further characteristics of patients, such as genetics, serology, microbiome. Confirmatory studies will be required.

Pooled Adverse Events for Pediatric IFX and ADA

Dubinsky et al IBD 2013

Infliximab Black Box Warning• WARNING: SERIOUS INFECTIONS and MALIGNANCY• SERIOUS INFECTIONS• Increased risk of serious infections leading to hospitalization or death, including tuberculosis

(TB), bacterial sepsis, invasive fungal infections (such as histoplasmosis) and infections due to other opportunistic pathogens.

• Discontinue infliximab if a patient develops a serious infection. • Perform test for latent TB; if positive, start treatment for TB prior to starting infliximab.

Monitor all patients for active TB during treatment, even if initial latent TB test is negative. • MALIGNANCY• Lymphoma and other malignancies, some fatal, have been reported in children and

adolescent patients treated with tumor necrosis factor (TNF) blockers, including infliximab. • Postmarketing cases of fatal hepatosplenic T-cell lymphoma (HSTCL) have been reported in

patients treated with TNF blockers including infliximab. All infliximab cases were reported in patients with Crohn’s disease or ulcerative colitis, the majority of whom were adolescent or young adult males. All had received azathioprine or 6-mercaptopurine concomitantly with infliximab at or prior to diagnosis.

T-Cell NHL Reported to FDA AERS with TNF-α Inhibitors: The REFURBISH Study

Deepak et al. Am J Gastroenterol 2013:108:99

The Option Grid for Shared Decision Making

Dubinsky et al IBD 2013

UK Markov Model for Cost Effectiveness of Anti-TNF Therapy

Bodger et al Alimen Pharm Ther 2009

Anti-TNF is Cost Effective for up to 4 Years

Bodger et al Alimen Pharm Ther 2009

Surgical care: ~44% of lifetime costsICER: incremental cost-effectiveness ratioQALY: quality-adjusted life-years

Is the Reward Worth the Risk?

REWARD

RISK REWARD

RISK

DO IT DON’T DO IT

Crohn’s Disease Progresses on “Conventional Therapy” in Children: 1988-2002

Vernier-Massouille et al. Gastroenterology 2008;135:1106

Inflammatory

Stricturing

Penetrating

34% at 5 yrs

Infliximab Reduces Risk for Surgery

Gupta et al Gastroenterology 2006

Higher Anti-microbial Serologies (QSS) are Associated with Increased Risk for Complications

Dubinsky et al Clin Gastro Hep 2008

Systems Dynamics Model for Disease Complications

Siegel et al IBD 2011

Benefit of Early anti-TNF May Increase as QSS Increases

Siegel et al IBD 2011

Patient Decision Aid

Siegel et al IBD 2011

Study:

Genetic makeup

Bacteria in bowel

Immune reactivity

Environmental Exposures

1100 children with Crohn’s at diagnosis

3 years160 – 200 patients with complication / surgery

CCFA Sponsored Clinical Research Network:PRO-KIIDS: Aim to Discover and Validate New Diagnostic & Prognostic Tools

Take home messages

• Anti-TNFα therapy is highly successful in inducing and maintaining remission in most pediatric patients with CD

• Select the correct patient to treat. Rescue vs. primary • Patients with significant growth failure and higher risk

of disease complications may derive greater relative benefit

• Consider anti-TNF withdrawal once treatment goals are met (catch-up growth, mucosal healing) in carefully selected patients: biologic exit strategy