Biologics in inflammatory disease: infliximab associated risk of lymphoma development
C Bucher1,
L Degen2,
S Dirnhofer3,
M Pless4,
R Herrmann4,
P Schraml5,
P Went5
1Department of Internal Medicine, University Hospital, Basel, Switzerland
2Department of Gastroenterology, University Hospital, Basel, Switzerland
3Institute of Pathology, University Hospital, Basel, Switzerland
4Department of Oncology, University Hospital, Basel, Switzerland
Correspondence to:
Dr P Went
Institute of Pathology, University of Basel, Schönbeinstrasse 40, CH-4031 Basel, Switzerland; pwentuhbs.ch
In their excellent overview of currently available biologic compounds that are in use or under investigation for Crohn's disease (CD), Sandborn and Faubion (Gut 2004;53:1366–73) reconfirm the unique standing of infliximab. They also note the ongoing discussion concerning the increased occurrence of lymphoproliferative disorders in patients who received infliximab.
Recently, we followed a 61 year old patient with a 31 year history of relapsing CD. Initial treatment was with steroids but after 10 years a right sided hemicolectomy necessitated discontinuation of steroids. Five years before the present admission, the patient relapsed with multiple rectovesicular fistulas. Non-Hodgkin lymphoma was absent in the histologic material. Because of a poor response to conventional treatment, including azathioprine (100–200 mg/day), infliximab was added 22 months before the current admission. Total infliximab therapy included three doses of 400 mg (5 mg/kg) within two months and resulted in a marked reduction of CD activity (azathioprine was maintained). On admission 10 months after the last infliximab infusion, the patient relapsed again with ulcerations and multiple rectorectal fistulas. Biopsies showed a polymorphous tumour infiltrate. Tumour cells were positive for CD30 and negative for T and B cell markers as well as the anaplastic large cell lymphoma kinase (ALK) and Epstein-Barr virus (EBV) associated proteins. A multiplex polymerase chain reaction approach revealed a clonal T cell population and an oligoclonal B cell population. Based on these results, the diagnosis was ALK negative anaplastic large cell lymphoma with null/T cell phenotype. Clinical stage was IAE. CHOP-chemotherapy resulted in complete clinical and histological remission, which was evidenced by computer tomography, positron emission tomography, and negative rectal histology. Polymerase chain reaction analysis of the rectal biopsies revealed no T cell receptor rearrangement.
Three months later, the patient presented with postobstructive pneumonia. Transbronchial biopsies showed a diffuse large B cell lymphoma. In contrast with the preceding rectal biopsies, bronchial tumour cells were positive for CD20. EBER, EBNA2, and LMP-1, indicating EBV infection of latency type III, were detected in tumour cells. However, tumour cells were negative for CD30 and ALK protein. Molecular analysis demonstrated a monoclonal immunoglobulin heavy chain rearrangement in the absence of a T cell receptor rearrangement, confirming the diagnosis. The tumour was neither responsive to CHOP-Rituximab nor to the ensuing second and third line chemotherapies. When the patient presented for fourth line chemotherapy, spontaneous partial remission was seen, persisting now for 10 months up to the last clinical follow up in September 2004.
As mentioned by Sandborn and Faubion, the 33 published cases1–9 (table 1) of lymphomas following infliximab therapy raise the question of a contributory role of infliximab in the propagation of lymphoproliferative disorders.
Patients with infliximab therapy and development of lymphoma
We can now add a unique case of a metachronous duplex non-Hodgkin lymphoma of initially T and then B cell phenotype. Imbalanced function of T lymphocytes may have acted as a key feature in this patient as the development of CD and the EBV related B cell non-Hodgkin lymphoma were both closely related to T lymphocytes. This links the case to infliximab as proapoptotic effects on T lymphocytes caused by infliximab have been described. Therefore, the recommendation to routinely give infliximab maintenance therapy and concomitant immunosuppressive treatment to minimise the formation of antichimeric antibodies seems to carry a theoretical risk of elevating the incidence of lymphoma above the background rate. Infliximab was approved by the US Federal Drug Administration five years ago, and up until April 2004 approximately 500 000 patients have been treated. Based on medwatch data, an incidence of non-Hodgkin lymphoma of 6.6/100 000 treated patients was estimated in 2002, which still seems valid if compared with published cases. However, our current knowledge does not allow definitive conclusions to be drawn about the association of infliximab and lymphoma.
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Conflict of interest: None declared.
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