Postmarketing surveillance and safety data from clinical trials of tumor necrosis factor alpha (TNF-α) antagonists have led to concern that their use is associated with an increased risk of lymphoma. New retrospective data indicate, however, that rheumatoid arthritis (RA) patients treated with these biologics are not at elevated risk for lymphoma when compared to their counterparts not on anti-TNF-α threrapy.1
The present study of several large Swedish cohorts confirms the historical finding that RA patients are at an increased risk of lymphoma in comparison to the general population, and the authors cite other evidence suggesting that this risk increases with disease activity.
"It does give us some comfort that it is high disease activity, not the TNF inhibitors, that may increase lymphoma risk," Vibeke Strand, MD, biopharmaceutical consultant and adjunct clinical professor in the division of immunology at Stanford University School of Medicine in Palo Alto, California, tells CIAOMed. She explains, however, that this association also confounds attempts to assess the risk associated with anti-TNF-α drugs. "The people most likely to get lymphomas are the ones most likely to be treated with TNF inhibitors, so we still can't sort it out, per se," she says.
The study examined 53,067 patients from an inpatient registry who were hospitalized bewteen 1990 and 2003; 3793 from an early arthritis cohort diagnosed between 1995 and 2003; and an additional 4160 RA patients treated with anti-TNF-α drugs between 1999 and 2003.
In total, there were 500 recorded hematopoietic malignancies. When compared with the general population, individuals in the inpatient and early arthritis cohorts were at increased risk of lymphoma (standardized incidence ratio [SIR] = 1.9 and 2.0, respectively) and leukemia (SIR = 2.1 and 2.2, respectively), while patients treated with TNF-α antagonists were at nearly a tripled (SIR = 2.9) risk of lymphoma. However, after controlling for gender, age, and disease duration, the risk following exposure to TNF-α antagonists was not higher than in the other RA cohorts.
Furthermore, the distribution of lymphoma subtypes associated with TNF-inhibitor use is similar to that observed in RA patients not using these drugs, suggesting that that there is no specific mechanism of pathogenesis in these cases. In particular, the unremarkable proportion of Epstein-Barr virus (EBV)-positive lymphomas argues indirectly against immunosuppression as a critical risk factor, as is the case in the post-transplant setting.
Label warning will remain
"This won't change warnings, because we still do see that the SIR for lymphoma ranges between something like 3 to 6, and anything above 2 [can be considered] an increase," says Dr. Strand, a member of the CIAOMed editorial board. "We really don't have any way to definitively prove it's the disease itself and not the treatment."
James D. Lewis, MD, MSCE, assistant professor of medicine and epidemiology at the Center for Clinical Epidemiology and Biostatistics of the University of Pennsylvania in Philadelphia, points out that the findings underscore the significance of analyzing risk/benefit ratios in the application of TNF inhibitors. "There is more to the question than merely whether use of these drugs increases the risk of lymphoma. If the increase in risk is only a small amount, there is greater likelihood that the potential benefits will outweigh the harms," he tells CIAOMed.
Solid cancer risk also similar between cohorts
Another analysis of the same patient population reveals that the risk of developing solid tumors in patients treated with TNF-α inhibitors mirrors that of historic cohorts of RA patients.2 Although it detected only a marginally elevated overall risk for solid tumors, the study did observe a 20% to 50% increased risk for smoke-related cancers and a 70% increased risk for non-melanoma skin cancer.
Furthermore, this cohort had a 20% decreased risk for breast cancer and a 25% decreased risk for colorectal cancer. The authors suggest that the decreased risk of colorectal cancer might be explained by a potentially protective effect of nonsteroidal anti-inflammatory drugs (NSAIDs). By contrast, the study found no decreased risk of colorectal cancer in RA patients taking TNF inhibitors.
"I think that the data are reassuring," says Robert J. Morgan, Jr, MD, section head of neuro-oncology in the division of medical oncology and therapeutics research at the City of Hope Cancer Center in Duarte, California, "Several other anti-inflammatory agents including Vioxx, Bextra and other COX-2 inhibitors have recently been shown to have unacceptable side effect profiles leading to their withdrawal from the market," he says. "Because of this, there is concern that other drugs will also be shown to have unacceptable side effect profiles. Anti-TNF-α drugs are quite active as treatments for rheumatoid arthritis, and these data assure that other uses of these agents can continue to be investigated."
References:
- Askling J, Fored M, Baecklund E, et al. Hematopoietic malignancies in rheumatoid arthritis. Lymphoma risk and characteristics following TNF- antagonists. Ann Rheum Dis. April 20, 2005; [Epub ahead of print]
- Askling J, Fored M, Brandt L, et al. Risks of solid cancers in patients with rheumatoid arthritis and following treatment with TNF-antagonists. Ann Rheum Dis. April 13, 2005; [Epub ahead of print]