ARTHRITIS & RHEUMATISM
`Vol. 46, No. 12, December 2002, pp 3151–3158
`DOI 10.1002/art.10679
`© 2002, American College of Rheumatology
`
`Tumor Necrosis Factor Antagonist Therapy and
`Lymphoma Development
`
`Twenty-Six Cases Reported to the Food and Drug Administration
`
`S. Lori Brown,1 Mark H. Greene,2 Sharon K. Gershon,1 Evelyne T. Edwards,1
`and M. Miles Braun1
`
`Objective. Etanercept and infliximab are tumor
`necrosis factor (TNF) antagonists that have been re-
`cently approved for the treatment of rheumatoid arthri-
`tis (RA) and Crohn’s disease (CD). This study was
`undertaken to investigate the occurrence of lymphopro-
`liferative disorders in patients treated with these agents.
`Methods. Relevant data in the MedWatch post-
`market adverse event surveillance system run by the US
`Food and Drug Administration were reviewed.
`Results. We identified 26 cases of lymphoprolif-
`erative disorders following treatment with etanercept
`(18 cases) or infliximab (8 cases). The majority of cases
`(81%) were non-Hodgkin’s lymphomas. The interval
`between initiation of therapy with etanercept or inflix-
`imab and the development of lymphoma was very short
`(median 8 weeks). In 2 instances (1 infliximab, 1
`etanercept), lymphoma regression was observed follow-
`ing discontinuation of anti-TNF treatment, in the ab-
`sence of specific cytotoxic therapy directed toward the
`lymphoma.
`Conclusion. Although data from a case series
`
`The opinions or assertions presented herein are the private
`views of the authors and are not to be construed as conveying either an
`official endorsement or criticism by the US Department of Health and
`Human Services, the Public Health Service, or the Food and Drug
`Administration.
`1S. Lori Brown, PhD (current address: Center for Devices and
`Radiological Health, FDA), Sharon K. Gershon, PharmD, Evelyne T.
`Edwards, PharmD, M. Miles Braun, MD: Center for Biologics Evalu-
`ation and Research, FDA, Rockville, Maryland; 2Mark H. Greene,
`MD: National Cancer Institute, Rockville, Maryland.
`Address correspondence and reprint requests to M. Miles
`Braun, MD, Division of Epidemiology, Office of Biostatistics and
`Epidemiology, Center for Biologics Evaluation and Research, Food
`and Drug Administration, 1401 Rockville Pike, HFM-210, Rockville,
`MD 20852-1448. E-mail: braunm@cber.FDA.gov.
`Submitted for publication May 9, 2002; accepted in revised
`form August 16, 2002.
`
`such as this cannot establish a clear causal relationship
`between exposure to these medications and the risk of
`lymphoproliferative disease, the known predisposition
`of patients with RA and CD to lymphoma, the known
`excess of lymphoma in other immunosuppressed popu-
`lations, and the known immunosuppressive effects of
`the anti-TNF drugs provide a biologic basis for concern
`and justification for the initiation of additional epide-
`miologic studies to formally evaluate this possible asso-
`ciation.
`
`In 1998 the Food and Drug Administration
`(FDA) approved 2 tumor necrosis factor (TNF) antag-
`onists for human use. Etanercept is a dimeric fusion
`protein of the extracellular ligand binding portion of the
`human TNF receptor (p75), linked to the Fc portion of
`a human IgG molecule. It is indicated for the treatment
`of rheumatoid arthritis (RA) in patients whose disease
`has not responded to other disease-modifying antirheu-
`matic drugs. Infliximab is a chimeric monoclonal anti-
`body that binds specifically and directly to human TNF␣
`and neutralizes its biologic activity. It is indicated for the
`treatment of moderate to severely active Crohn’s disease
`(CD) and of RA.
`Lymphoproliferative disorders, especially non-
`Hodgkin’s lymphoma, occur at an increased rate in
`immunodeficient or immunosuppressed patients (1).
`Patients with RA are also at increased risk of lympho-
`proliferative disease, both non-Hodgkin’s lymphoma
`and Hodgkin’s disease (2–11). Some of this risk appears
`intrinsic to the natural history of untreated RA and has
`been attributed to the dysregulated immune function
`that is part of the pathophysiology of the disease (2–
`5,7,12). An excess risk of lymphoma has also been
`reported in patients with CD, although the risk does not
`
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`Table 1. Lymphomas occurring in patients treated with etanercept*
`
`Patient Age/sex
`
`Lymphoma cell type
`
`Weeks from first
`etanercept dose
`to lymphoma
`diagnosis
`
`Vital
`status
`
`Immunosuppressive
`drugs
`
`MTX
`
`Other
`
`CTD
`
`EBV associated
`with lymphoma
`
`1
`Diffuse large B cell NHL
`69/F
`2
`–
`–
`Alive C
`NR
`2
`Large cell NHL
`84/F
`8
`SLE
`–
`Alive C
`NR
`3
`Diffuse large B cell NHL (recurrent)
`66/F
`4
`NR
`–
`Dead
`–
`NR
`4
`Small T cell NHL
`45/F
`4
`DM
`Dead Unknown CYC
`NR
`5
`Diffuse large B cell NHL
`67/F
`8
`–
`Alive C
`–
`NR
`6
`Diffuse large cell NHL
`61/F
`8
`–
`Alive C
`–
`NR
`7
`B cell NHL, n.o.s.
`69/F
`16
`–
`Alive
`–
`AZA
`NR
`8†
`Follicular mixed small and large cell NHL
`48/F
`8
`SS
`Alive C
`AZA
`NR
`9
`61/M Mantle cell B cell NHL
`8
`–
`Alive C
`Unknown
`NR
`10
`76/F
`NHL, n.o.s.
`12
`Alive P
`Unknown NR
`NR
`11
`50/F
`NHL, n.o.s.
`40
`Alive C
`Unknown NR
`NR
`12‡
`73/M Mantle cell B cell NHL
`3
`Alive P
`AZA, INF NR
`NR
`13
`60/M B cell NHL
`40
`Alive C
`–
`–
`Negative
`14
`57/M Large cell NHL
`8
`Alive C
`–
`–
`NR
`15
`75/F
`Small lymphocytic B cell NHL
`36
`Alive
`–
`–
`SS
`NR
`16
`55/M Diffuse large cell NHL (recurrent)
`NR
`Dead
`–
`–
`–
`NR
`17§
`44/M Type B1 thymoma
`12
`Alive P
`–
`–
`NR
`18
`68/M Hodgkin’s disease, nodular sclerosing subtype
`52
`Alive P
`–
`–
`NR
`* MTX ⫽ methotrexate; CTD ⫽ connective tissue disease (other than rheumatoid arthritis); EBV ⫽ Epstein-Barr virus; NHL ⫽ non-Hodgkin’s
`lymphoma; C ⫽ concurrent with etanercept; NR ⫽ not reported; SLE ⫽ systemic lupus erythematosus; CYC ⫽ cyclophosphamide; DM ⫽
`dermatomyositis; n.o.s. ⫽ not otherwise specified; AZA ⫽ azathioprine; SS ⫽ Sjo¨gren’s syndrome; P ⫽ prior to etanercept; INF ⫽ infliximab.
`† Father reported to have died of non-Hodgkin’s lymphoma at age 53.
`‡ Patient received infliximab therapy for 2 years prior to being switched to etanercept. He developed lymphoma 3 weeks after beginning etanercept
`therapy, and is included in this table because he was taking etanercept at the time lymphoma developed.
`§ Patient showed radiographic and histologic evidence of tumor shrinkage after etanercept was discontinued. Traditional antilymphoma
`chemotherapy was never administered.
`
`appear to be as great as that seen in RA (13,14), and
`contradictory reports have been published (15). In some
`studies, the apparent excess of lymphoma in CD patients
`appears to be, at least in part, independent of exposure
`to immunosuppressive medications (16).
`However, a proportion of
`the RA- or CD-
`associated lymphoproliferative disorders has also been
`attributed to the immunosuppressive effects of the med-
`ications used to treat these diseases, most notably aza-
`thioprine (AZA), cyclophosphamide, and methotrexate
`(MTX) for RA (17–22) and AZA for CD (15,23,24).
`Further support for the hypothesis that medication-
`related immunosuppression plays an etiologic role in
`these settings is the clinical observation that a fraction of
`the lymphomas regress when these treatments are dis-
`continued, without specific antilymphoma chemo-
`therapy having been instituted (25–28).
`immuno-
`Another
`important
`feature of
`suppression-associated lymphomas is the relationship
`between many of these malignancies and infection with
`the Epstein-Barr virus (EBV), a well-established cause
`of lymphoma in immunosuppressed patients, particu-
`larly in those who have undergone organ transplantation
`
`(29,30). Some lymphoproliferative disorders observed in
`patients with RA have been shown to be associated with
`EBV (21,28).
`In the present report, 26 cases of lymphoprolif-
`erative disease in patients receiving etanercept or inflix-
`imab therapy are described. The possible relationship
`between these lymphoproliferative neoplasms and con-
`current therapy with TNF antagonists is explored.
`
`METHODS
`
`We examined MedWatch reports submitted to the
`Food and Drug Administration (FDA) for the biologic prod-
`ucts etanercept and infliximab. MedWatch is the FDA’s post-
`market adverse event surveillance system that receives and
`tabulates submitted reports of possible medication-related
`toxicities. All reports citing neoplasms, benign or malignant,
`were reviewed. Any report with a keyword of lymphoma or that
`mentioned lymphoma in the text was investigated further. The
`cases reported to MedWatch through December 2000 com-
`prise the basis for the current summary.
`Physicians, nonphysician health care practitioners, or
`others who submitted these reports were contacted first by
`phone, to alert them of our investigation. A letter was then
`sent to the adverse event reporter by both fax and mail,
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`TNF ANTAGONIST TREATMENT AND LYMPHOMA DEVELOPMENT
`
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`
`Table 2. Characteristics of the population of patients who developed
`lymphoma after treatment with etanercept or infliximab*
`
`Characteristic
`
`Etanercept
`(n ⫽ 18)
`
`Infliximab
`(n ⫽ 8)
`
`requesting further information on the reported cancer, includ-
`ing 1) the interval between the initiation of etanercept or
`infliximab therapy and lymphoma diagnosis; 2) the site of
`cancer origin; 3) history of a connective tissue disorder other
`than RA; 4) previous or concurrent exposure to immunosup-
`pressive agents; 5) evidence of lymphoma regression after
`etanercept or infliximab was stopped, but prior to antilym-
`phoma therapy; 6) results of any laboratory studies performed
`to assess whether the patient’s lymphoma might have been
`related to EBV infection; and 7) a copy of the lymphoma
`pathology report. Physicians were also asked to send represen-
`tative surgical pathology specimens when available. If there
`was no response to the first letter, a second letter was sent
`requesting the information.
`
`RESULTS
`
`Etanercept-associated lymphoma. Eighteen
`cases of lymphoma occurring after the initiation of
`etanercept therapy were reported to the FDA between
`May 1999 and December 2000 (Table 1). Three patients
`were reported to be deceased. Two deaths occurred in
`patients in whom a previously diagnosed and treated
`non-Hodgkin’s lymphoma recurred after the initiation of
`etanercept therapy (in both patients the lymphoma was
`in remission at the time etanercept was begun) and the
`third occurred in a patient with nodular sclerosing
`Hodgkin’s disease. Lymphoma was diagnosed a median
`of 8 weeks (range 2–52 weeks) after the initiation of
`etanercept treatment.
`The median age of the patients treated with
`etanercept was 64 years. The majority of patients were
`female (61%), and the most common indication for use
`of etanercept agent was RA (83%) (Table 2). Fre-
`quently, patients receiving etanercept were reported to
`be taking MTX concurrently (9 of 18) or to have a
`history of prior exposure to MTX (4 of 18), or other
`immunosuppressive drugs (4 of 18). Sixteen of the
`etanercept-associated lymphoproliferative disorders
`were non-Hodgkin’s lymphoma, with Hodgkin’s disease
`and thymoma represented by 1 case each. The histologic
`subtypes of non-Hodgkin’s lymphoma in these cases
`(Table 1), as reported by the original diagnosing pathol-
`ogist, were generally similar to those previously de-
`scribed in RA patients (7), with diffuse, large B cell
`lymphoma comprising the largest proportion.
`The number of etanercept users in the US
`through January 2001 is estimated by the manufacturer
`to be 95,500. A crude approximation of the lymphoma
`rate among US residents exposed to etanercept would
`therefore be 18/95,500, or ⬃19 cases per 100,000 treated
`persons. This is almost certainly an underestimate, given
`
`2 (25.0)
`1 (12.5)
`–
`3 (37.5)
`1 (12.5)
`1 (12.5)
`
`2 (25.0)
`5 (62.5)
`1 (12.5)
`
`3 (37.5)
`–
`5 (62.5)
`–
`
`3 (37.5)
`3 (37.5)
`–
`2 (25.0)
`2 (25.0)
`4 (50.0)
`
`–
`4 (22.2)
`3 (16.7)
`7 (38.9)
`4 (22.2)
`–
`
`11 (61.1)
`7 (38.9)
`–
`
`15 (83.3)
`2 (11.1)
`–
`1 (5.6)
`
`8 (44.4)
`3 (16.7)
`4 (22.2)
`3 (16.7)
`13 (72.2)
`15 (83.3)
`
`Age, years
`25–40
`41–50
`51–60
`61–70
`ⱖ71
`Not specified
`Sex
`Female
`Male
`Not specified
`Indication for TNF antagonist use
`Rheumatoid arthritis
`Psoriatic arthritis
`Crohn’s disease
`Not specified
`No. of other medications taken
`concurrently
`1–3
`4–7
`ⱖ8
`Not specified
`Past or concurrent MTX use
`Past or concurrent use of any
`immunosuppressive drug
`(including MTX)
`Weeks from first TNF antagonist
`dose to lymphoma diagnosis†
`0–8
`10 (55.6)
`4 (50.0)
`9–16
`3 (16.7)
`–
`17–24
`–
`1 (12.5)
`ⱖ25
`4 (22.2)
`2 (25.0)
`Not specified
`1 (5.6)
`1 (12.5)
`Died
`3 (16.7)
`1 (12)
`* Values are the number (%). TNF ⫽ tumor necrosis factor; MTX ⫽
`methotrexate.
`† Mean ⫾ SD 15.8 ⫾ 15.6 weeks among etanercept users and 6.2 ⫾ 8.8
`weeks among infliximab users.
`
`the known underreporting of adverse events to Med-
`Watch (31).
`Infliximab-associated lymphoma. Eight cases of
`lymphoma occurring after initiation of infliximab treat-
`ment were reported to the FDA between May 1999 and
`December 2000 (Table 3). One patient, with non-
`Hodgkin’s lymphoma, was reported as deceased. These
`lymphomas occurred a median of 6 weeks (range 2–44
`weeks) after the initiation of therapy with infliximab in
`the 7 cases for which this information was provided.
`The median age of the patients with infliximab-
`associated lymphoma was 62 years. The majority of the
`infliximab-treated patients were male (62.5%), and the
`most common treatment indication was CD (62.5%)
`(Table 2). Other immunosuppressive drugs reported as
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`3154
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`BROWN ET AL
`
`Table 3. Lymphomas occurring in patients treated with infliximab*
`
`Patient
`
`Age/sex
`
`Lymphoma cell type
`
`1
`2
`3
`
`4
`5†
`6‡
`
`7
`8
`
`77/M
`NR
`43/F
`
`34/M
`70/M
`29/M
`
`68/F
`62/M
`
`Burkitt’s lymphoma
`Hodgkin’s disease, n.o.s.
`Hodgkin’s disease, nodular
`sclerosis subtype
`Diffuse large B cell NHL
`Diffuse large cell NHL
`Hodgkin’s disease, nodular
`sclerosis subtype
`B cell NHL, n.o.s.
`Large B cell NHL
`
`Weeks from first
`infliximab dose
`to lymphoma
`diagnosis
`
`6
`NR
`44
`
`4
`6
`2
`
`24
`36
`
`Immunosuppressive
`drugs
`
`MTX
`
`Other
`
`CTD
`
`P
`Unknown
`–
`
`–
`Unknown
`–
`
`–
`–
`–
`
`C
`Unknown
`
`6MP
`–
`–
`
`AZA
`AZA
`
`NR
`NR
`–
`
`NR
`–
`NR
`
`–
`NR
`
`Vital
`status
`
`Alive
`Alive
`Alive
`
`Alive
`Alive
`Alive
`
`Alive
`Dead
`
`EBV associated
`with lymphoma
`
`NR
`NR
`NR
`
`Positive
`NR
`NR
`
`NR
`NR
`
`* Table does not include 1 patient who received infliximab therapy for 2 years prior to being switched to etanercept (patient 12, Table 1). This patient
`developed lymphoma 3 weeks after beginning etanercept therapy. 6MP ⫽ 6-mercaptopurine (see Table 1 for other definitions).
`† Patient displayed significant reduction in axillary lymphadenopathy after discontinuation of infliximab, in the absence of standard antilymphoma
`chemotherapy.
`‡ Patient has been reported previously (39).
`
`having been used by these patients included MTX (2 of
`8), AZA (2 of 8), and 6-mercaptopurine (1 of 8). Five of
`the 8 infliximab-associated lymphoproliferative disor-
`ders were non-Hodgkin’s lymphoma, and 3 were
`Hodgkin’s disease.
`The number of infliximab users in the US is
`estimated by the manufacturer to be ⬃121,000 as of
`March 2001. Thus, an estimate of the reported occur-
`rence of lymphoma in infliximab users is 8/121,000, or
`⬃6.6 cases per 100,000 treated persons. As noted above,
`this estimate is likely to be an underestimate based on
`underreporting. The uncertainty that underlies the esti-
`mates for lymphoma among etanercept users and inflix-
`imab users is sufficiently great to prohibit direct com-
`parison of the “rate” of lymphoma associated with the 2
`different drugs.
`It should be noted that 1 subject in this case series
`(patient 12 in Table 1) was treated with both agents. He
`received infliximab for 2 years and then switched to
`etanercept. Lymphadenopathy was noted after the sev-
`enth dose of etanercept. He is tabulated formally among
`the etanercept users since that was the agent he was
`taking when the lymphoma developed.
`Additional information reported. Additional in-
`formation was provided in response to our letter, for 11
`of 18 etanercept cases (61%) and 5 of 8 infliximab cases
`(62.5%). Information on EBV status was received for
`only 2 subjects: 1 etanercept-treated patient was re-
`ported as EBV negative, and 1 infliximab-treated patient
`was reported to be EBV positive.
`In 1 case (patient 17 in Table 1), a thymoma was
`
`observed to shrink and necrose after the discontinuation
`of etanercept. In a second patient (patient 5 in Table 3),
`a significant reduction in axillary lymphadenopathy was
`reported after discontinuation of infliximab. Both “re-
`sponses” occurred in the absence of standard antilym-
`phoma chemotherapy. No other information was re-
`ceived from physicians regarding whether attempts were
`made routinely or systematically to determine if these
`lymphoproliferative disorders regressed after anti-TNF
`therapy was discontinued.
`Among the patients treated with etanercept for
`refractory RA, 2 were reported to have had Sjo¨gren’s
`syndrome, and 1 each had dermatomyositis and systemic
`lupus erythematosus. None of the patients treated with
`infliximab had a reported history of a connective tissue
`disease besides RA. The father of 1 etanercept-treated
`patient was reported to have had non-Hodgkin’s lym-
`phoma. In none of the remaining 25 cases was a signif-
`icant family history of cancer or lymphoproliferative
`neoplasia reported, although in most instances, informa-
`tion on family history of malignancy was simply not
`included.
`Slides or pathology samples were available from 1
`etanercept-treated and 2 infliximab-treated patients. In
`all 3 cases, the pathologic diagnosis rendered by the
`referring pathologist was confirmed by review in the
`National Cancer Institute’s Laboratory of Pathology.
`The lack of pathology specimens from 23 of the 26
`patients precluded a more systematic analysis of those
`data.
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`DISCUSSION
`
`The FDA’s passive postmarket adverse event
`reporting system (MedWatch) received 18 reports of
`lymphoma subsequent to the initiation of etanercept
`therapy and 8 reports of lymphoma subsequent to the
`initiation of infliximab therapy during the 21⁄2 years since
`these novel biologic agents were licensed for clinical use
`in the US. One patient had been exposed to both
`medications. An estimate of the reporting rate for
`lymphoma after etanercept therapy, based on the man-
`ufacturer’s estimates of the number of patients using this
`drug, is 19/100,000. The reporting rate for lymphoma in
`infliximab-treated patients is 6.6/100,000. Incomplete
`ascertainment of cases, and the lack of accurate infor-
`mation regarding the size of the populations exposed to
`these 2 medications, prevented our calculating reliable
`lymphoma rates. Thus, we could not determine whether
`the occurrence of lymphoma in these subjects was
`greater than that which would have been expected based
`on general population incidence rates or among un-
`treated patients with RA or CD. The age-adjusted
`incidence of lymphoma in the US from 1992 to 1998 was
`18.3/100,000 (15.7/100,000 for non-Hodgkin’s lymphoma
`and 2.6/100,000 for Hodgkin’s lymphoma) (32,33).
`Currently available data do not permit us to draw
`definitive conclusions regarding whether these TNF
`antagonists were the proximate cause of the reported
`lymphomas, whether these neoplasms developed as part
`of the natural history of the underlying medical condi-
`tions, or whether they occurred as a complication related
`to other immunosuppressive medications to which these
`patients were exposed. Disentangling the relative contri-
`butions of innate lymphoma susceptibility, other immu-
`nosuppressive medications, and the anti-TNF agents to
`the development of lymphomas is impossible with the
`present data. A further complication is the suggestion
`that lymphoma represents a complication that is specific
`to the subset of RA patients who have severe disease
`(12). Clearly, patients who are currently prescribed
`etanercept or infliximab are those whose RA has proven
`refractory to standard therapy. Thus, it is conceivable
`that the apparent lymphoma cluster observed in this
`setting reflects the selection of a subpopulation of RA
`patients with particularly aggressive disease, rather than
`being related to the treatment received by such patients.
`TNF is a proinflammatory cytokine that has been
`implicated in the etiology of both RA (34,35) and CD
`(36). The activities of TNF are pleiotropic and its role in
`the immune response incompletely understood. It is
`biologically plausible that TNF antagonists, which are
`
`novel immunomodulatory agents, might produce signif-
`icant adverse effects,
`including an increased risk of
`malignancy. It was recently reported that active tuber-
`culosis and other serious infections were observed soon
`after the initiation of treatment with infliximab, suggest-
`ing immunomodulation as a potential contributor to risk
`of infection or reactivation of the disease (37).
`Both RA and CD are recognized as diseases that
`are linked to an altered or dysfunctional immune re-
`sponse. Consequently, the issue of increased risk for
`lymphoproliferative disease has been of interest in both
`disorders (2,7,13,14). Furthermore, because both RA
`and CD are treated with immunosuppressive medica-
`tions, the role of concomitant or prior immunosuppres-
`sive therapy has added a layer of complexity in the effort
`to clarify the causal pathway by which these malignan-
`cies arise (17).
`There are numerous case series reports of the
`occurrence of
`lymphomas, especially non-Hodgkin’s
`lymphomas, in RA patients treated with the folic acid
`analog MTX (5,18–21). The role of EBV infection in
`these patients is also of interest (7,20,21,28). In consid-
`ering whether MTX played an etiologic role in RA-
`associated lymphoma, Georgescu and Paget (28) noted
`that the strongest evidence came from well-documented
`cases in which the lymphoma regressed after the with-
`drawal of MTX treatment (22). The fact that a majority
`of the RA patients in the present series had either prior
`or concurrent exposure to MTX raises the possibility
`that the anti-TNF agents might further compromise
`immune function in patients with latent EBV infection,
`thereby facilitating the evolution of a lymphoprolifera-
`tive disorder. We cannot discern from available data
`whether this might have occurred in the absence of
`MTX exposure.
`An excess of lymphomas in patients with CD has
`also been noted in some studies (13,14), but not all (15).
`As in RA, it has been suggested that the lymphoma
`excess in CD is, at least partially, independent of the
`immunosuppressive therapy used in the disorder (16).
`AZA is the most commonly prescribed immunosuppres-
`sive therapy for CD, and this agent has been implicated
`in the pathogenesis of lymphoma (17,24). Only 3 pa-
`tients in this series are known to have been exposed to
`AZA or its metabolite, 6-mercaptopurine.
`In general, the lymphomas that occur in the
`setting of impaired immune function are B cell, non-
`Hodgkin’s lymphomas, most often large cell lymphomas
`(3,29), and the same is true in the current series, in
`which 21 of 26 cases were non-Hodgkin’s lymphoma. We
`believe, however, that it is appropriate to include the
`
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`3156
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`BROWN ET AL
`
`Table 4. Published studies of lymphoma development after etanercept or infliximab treatment*
`
`Authors, year (ref.)
`
`Targan et al, 1997 (40)
`Rutgeerts et al, 1999 (36)
`Sandborn and Hanauer, 1999 (41)
`Sandborn and Hanauer, 1999 (41)
`Maini et al, 1999 (42)§
`Markham and Lamb, 2000 (35)
`Bathon et al, 2000 (43)
`Lovell et al, 2000 (44)
`
`Agent
`
`Infliximab
`Infliximab
`Infliximab
`Infliximab
`Infliximab
`Infliximab
`Etanercept
`Etanercept
`
`Diagnosis
`
`CD
`CD
`CD
`RA
`RA
`RA
`RA
`JRA#
`
`No. exposed/no.
`developing lymphoma†
`
`No. not exposed/no.
`developing lymphoma
`
`102/0
`73/1
`Part of 394/1‡
`Part of 394/2‡
`340/1¶
`771/1
`415/1
`69/0
`
`6/0
`NA
`ND
`ND
`88/0
`
`217/0
`26/0
`
`* Of the 1,993 patients reported from these various series, 7 developed malignant lymphoma. In none of these reports was the risk of lymphoma
`considered excessive by the authors, but these conclusions are limited by the small number of subjects in each series. Manufacturers have informed
`us that the report by Rutgeerts et al and the one by Sandborn and Hanauer were on the same lymphoma patient, and that the report by Maini et
`al and the one by Markham and Lamb were on the same patient. The report by Targan et al was the initial report of the same study subsequently
`reported by Rutgeerts et al. In the initial protocol, patients received short-term therapy. The later publication described patients from the initial
`cohort who had responded to therapy and were re-treated for an extended period of time. This table does not represent a count of cases, and there
`may be other duplications in reporting. NA ⫽ not applicable; ND ⫽ not determined.
`† The lymphoma was Hodgkin’s disease in the patient reported by Maini et al and subsequently by Markham and Lamb (see above), and
`non-Hodgkin’s lymphoma in all of the others.
`‡ The total patient group included 394 patients, but it was not specified how many of the 394 had Crohn’s disease (CD) and how many had
`rheumatoid arthritis (RA).
`§ Lipsky et al published an update of this series in 2000 (45). No additional cases of lymphoma developed during the extended followup.
`¶ Maini et al cite the occurrence of 3 additional lymphomas (2 non-Hodgkin’s lymphoma, 1 Hodgkin’s disease) among 555 patients treated in 6 prior
`clinical trials, but they do not provide references to these specific studies.
`# Because this was a study of patients with juvenile rheumatoid arthritis (JRA), the patients were much younger than those in other reported series.
`
`Hodgkin’s disease cases in this analysis. This specific
`lymphoma may well occur at an excess rate in RA (8–11)
`and in CD (14).
`One noteworthy clinical feature of the lympho-
`mas observed in this series is the very short interval
`(“latent period”) between the initiation of anti-TNF
`therapy and the development of malignancy. Although
`there likely is a bias toward reporting of events that
`occur soon after the initiation of new medical treatment,
`the similarity between the latent period observed in our
`case series and that which characterizes lymphomas that
`develop post–organ transplantation is striking. In the
`latter setting as well, there is a very short interval
`between initiation of immunosuppressive therapy and
`development of lymphoproliferative neoplasia.
`The majority of posttransplant lymphomas ap-
`pear to be related etiologically to EBV (29,30). In a
`fraction of RA-associated lymphomas (7), and perhaps
`the majority of MTX-related lymphomas (28), there is
`molecular evidence of EBV infection. This led us to
`inquire about the EBV status of the lymphoma patients
`in the current study. We were unable to retrieve suffi-
`cient clinical or laboratory data to address this issue.
`This is a question that should be considered in future
`studies, because the management of EBV-related lym-
`phoma differs from that of spontaneous lymphoma.
`Patients with the former are more likely to benefit from
`a clinical trial of medication withdrawal and observation,
`
`in hopes that a “spontaneous remission” will occur (38),
`thereby sparing a subset of patients the need for cyto-
`toxic chemotherapy.
`immunosuppressive medica-
`Recognizing that
`tions have increased the risk of certain malignancies in
`the past, this complication was monitored during the
`phase II and phase III development of the anti-TNF
`agents. There have been occasional case reports of
`lymphoma in patients receiving infliximab for CD (39).
`These cases were reported to the FDA and are included
`in our series as infliximab cases 6 and 8 (Table 3). In
`addition, the development of lymphoproliferative malig-
`nancy has been reported in a number of the early trials
`conducted to establish the efficacy of these agents
`(Table 4);
`in each of these trials, the investigators
`concluded that there was no significant excess of lym-
`phoma. These analyses were, however, based on very
`small numbers of cases, and thus the reported point
`estimates of risk (which have very wide confidence
`intervals) may not accurately reflect the true risk.
`We have described 26 cases, reported to the
`FDA’s passive surveillance system, of lymphoma in
`patients receiving TNF antagonist therapy. A case series
`such as this cannot establish a cause-and-effect relation-
`ship between drugs, such as etanercept and infliximab,
`and an adverse outcome, such as lymphoma. However,
`associations identified in this manner may prompt cau-
`tion in the clinical use of a particular medication and
`
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`TNF ANTAGONIST TREATMENT AND LYMPHOMA DEVELOPMENT
`
`3157
`
`may provide a rationale for the development of formal
`epidemiologic studies to assess the purported relation-
`ship in a more quantitative manner. The known predis-
`position of patients with RA and CD to lymphoma, the
`known excess of lymphoma in other immunosuppressed
`populations, and the known immunosuppressive effects
`of the anti-TNF drugs provide a biologic basis for
`concern, and ample justification for the development of
`additional studies to formally evaluate this possible
`association.
`Given the nature of the case ascertainment mech-
`anism used in this study, it is unlikely that we have
`identified all pertinent events (31). The purposes of this
`report are 1) to bring to the attention of clinicians who
`prescribe these important new medications the possibil-
`ity that they may be associated with an increased risk of
`lymphoma; 2) to stimulate heightened awareness of this
`possible complication of therapy in order to facilitate
`early diagnosis and treatment (including a trial of with-
`drawal of anti-TNF prior to institution of chemotherapy,
`when clinically practical); 3) to encourage the reporting
`of additional cases, with more clinical detail that might
`shed new light on our observations; and 4) to encourage
`the design of methodologically sound epidemiologic
`studies to test this new hypothesis.
`Finally, there are two specific management op-
`tions which might be considered based on the current
`case series. Two individuals with previously treated
`lymphoma that was in remission at the time anti-TNF
`therapy was initiated very quickly developed recurrent
`disease and died of fulminant lymphoma. Consideration
`should be given to classifying such persons as ineligible
`for treatment with etanercept or infliximab, until the
`possible relationship of these agents to lymphoma risk
`has been clarified. Second, if lymphoma develops in a
`patient receiving anti-TNF therapy, consideration can be
`given to treating this complication by withdrawing the
`medication and monitoring the patient for evidence of
`lymphoma regression, prior to initiating cytotoxic chemo-
`therapy, if the patient’s clinical condition permits.
`Addendum. Since the completion of this investigation
`and writing of the manuscript, additional reports of patients
`receiving anti-TNF medications have continued to accrue
`within the MedWatch database. That database was searched
`for additional cases covering the period November 2001
`through September 2002. Seventy-five candidate reports of
`possible lymphomas related to the administration of anti-TNF
`medications were identified and reviewed. Seven of the cases
`were not lymphomas. Of the remaining 68 cases, 54 were
`classified as “probable” medication-associated lymphomas (29
`infliximab, 25 etanercept), and 14 were classified as “possible”
`medication-associated lymphomas (10 infliximab, 4 etaner-
`cept).
`
`ACKNOWLEDGMENT
`
`We thank Dr. Elaine S. Jaffe (Hematopathology Sec-
`tion, National Cancer Institute) for her review of the pathology
`samples.
`
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