Loss of Response to Biologics versus Increased Risk of Lymphoma in Children With IBD

Abstract

Inflammatory bowel disease in children can be marked by aggressive disease both at presentation and over time. Risk stratification of individual patients may help identify when early biologic therapy is justified. Currently, combination biologic and immunomodulator therapy for moderate-to-severe Crohn's disease is the most effective treatment regimen. The clinician's conundrum arises from the recent understanding that rare but serious adverse events do occur with use of these strong immune suppressive drugs and may be more prevalent with combination therapy. An understanding of the natural history of Crohn's disease and ulcerative colitis and the benefits and risks of the current medical armamentarium is essential to provide optimal care for each child with inflammatory bowel disease.

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everal studies have suggested that there is an increased risk of lymphoma in IBD patients both on thiopurine alone and in combination with anti-TNF.[72,73] Beaugerie et al. studied a large prospective cohort of adults with IBD with median follow-up of 35 months.[74] The three groups included: thiopurine continued (5867) with 9% also on anti-TNF; thiopurine discontinued (2809) with 12% also on anti-TNF; and never on thiopurines (10,810) with <1% on anti-TNF. Duration of disease ranged from 7.5 to 10.5 years among the three groups. Twenty three lymphomas were reported (14 non-Hodgkin's lymphoma [NHL] and one Hodgkin's lymphoma) on continued thiopurines compared with two NHL in discontinued thiopurines and six NHL in never thiopurines. The youngest case was in a 20-year-old male. The multivariate adjusted hazard ratio was 5.26 (2.2–12.6) in those continuing thiopurines compared with others. Furthermore, ten out of 15 lymphoma cases in the continuing thiopurine group exhibited post-transplant lymphoproliferative disorder with EBV positivity. Only two out of eight cases were EBV positive in the naive thiopurine group. The authors concluded that the thiopurines increased the risk of developing lymphoproliferative disease with risk factors including EBV presence, older age, male gender and longer duration of IBD.[74]

Dayharsh et al. described a similar association between EBV and the risk of lymphoma.[75] In a retrospective review of adults at the Mayo clinic, 18 patients with lymphoma were identified: EBV infection was found in five out of six patients on thiopurine for a median of 3.5 years, versus two out of 12 patients never receiving thiopurines. The authors hypothesized that post-transplant lymphoproliferative disorder probably occurs because of reduced cell-mediated immune surveillance allowing EBV-infected lymphocytes (especially B cells) to proliferate.[75]

In the pediatric literature, Ashworth et al. performed a retrospective review at a single pediatric hospital to examine the relationship between IBD and lymphoma.[76] Among the 1374 patients, 58% had CD, 34% had UC and 3% were IBD undetermined. Two lymphoma cases were observed among 2574 patient-years of taking thiopurine (2 per 4441 past years of ever taking thiopurine). Both patients were male, aged 12 and 18 years old, with CD and UC, respectively. Both patients had been taking thiopurines (22 and 28 months thiopurine use) but were EBV negative. A third patient had hemophagocytic lymphohistiocytosis on thiopurines. Compared with the Surveillance Epidemiology and End Results Program data (0.58 per 10,000 patient-years) the rate of lymphoma was three out of 10,000 patient-years in total and 4.5 lymphoma per 10,000 patient-years on thiopurines. Interestingly, no malignancies were observed in 1140 patient-years of combination anti-TNF and thiopurine therapy or 694 patient-years of MTX therapy

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Expert commentary & Five-year View: Weighing Benefits & Risks of Therapeutic Options in CD & UC

In the child with moderate-to-severe CD, the option to utilize anti-TNF therapy may save the child from a lifetime of disabling morbidity, which can occur in the face of undertreatment of their CD. If the clinician chooses to use anti-TNF therapy, it is important to maximize the efficacy of anti-TNF therapy with use of scheduled dosing, pretreatment hydrocortisone and consideration of upfront, concomitant therapy with an immunomodulator agent.

Here arises the clinician's conundrum for the child with CD who is failing long-term maintenance monotherapy with thiopurines. Four options for clinical therapy should be considered:

The clinician can switch to anti-TNF monotherapy with the understanding that immunogenicity is more likely to occur over the long term;

The clinician can opt for dual therapy with anti-TNF therapy and long-term thiopurine. This approach will more likely improve the long-term efficacy of the anti-TNF agent but also expose the child to a rare but real risk of lymphoma (in particular hepatosplenic T-cell lymphoma);

The clinician can add an anti-TNF agent with continuation of a thiopurine for 6 months, and then switch to anti-TNF monotherapy. This option seems to reduce the risk of immunogenicity without seriously increasing the risk of developing lymphoma;

Finally, the clinician can switch the patient to dual therapy with anti-TNF and long-term low-dose MTX. This approach may reduce the risk of immunogenicity and may prolong efficacy of the anti-TNF agent.



View the profile of a disease-modifying therapy
The rheumatologic literature provides some reassurance regarding the safety of combination therapy with an anti-TNF agent and MTX. However, there may be unique additional factors contributing to the development of malignancy in patients with IBD on combination therapy . These factors include the inflammatory process itself and/or the potentially large exposure to abdominal radiation. The literature does tell us that combination therapy with an anti-TNF agent and thiopurine is more effective, but can carry a cost on safety, especially in children.[85] Data on the efficacy and safety of MTX in combination with anti-TNF therapy in patients with CD is not fully known and should be studied with a particular focus on safety in children.

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