Barts-MS rose-tinted-odometer: ★★★★★ (seeing grey – it’s a very grey Saturday)
Whenever you bring up the topic of using more effective DMTs or flipping the pyramid you get pushed back because of the potential risks associated with these treatments. One risk is the big-C or secondary cancers. It is therefore very reassuring that an analysis of the FDA adverse event reporting system database revealed no safety signal for increased cancer risk among the approved MS DMTs.
The only potential safety signal that was detected in a so-called sensitivity analysis concerned interferon-beta-1a (Rebif/Avonex/Plegridy) and alemtuzumab.
The message is that the cancer risk associated with MS DMTs is probably quite low and not nearly as high as the risk associated with more potent immunosuppressive therapies and the so-called mutagenic therapies. Please note none of our licensed DMTs is mutagenic. Please note this analysis does not include AHSCT, which typically uses cyclophosphamide to mobilise stem cells and to ablate the immune system. There is clear evidence that people who have had AHSCT are at increased risk of developing a secondary malignancy, which is almost certainly a consequence of exposure to cyclophosphamide and other chemotherapy agents given as part of the procedure.
This analysis also puts the FDA cladribine black box warning into perspective, i.e. the real-life data suggests there is no increased cancer risk with cladribine and supports my interpretation of the data that cladribine is not associated with secondary cancer risk. The apparent cladribine cancer risk in the phase 3 or CLARITY trial was driven by the fact that there were zero cases in the placebo arm, which was the outlier. Let’s hope this data will allow pwMS to put the ‘potential cancer risk’ of DMTs into perspective and give them the confidence to access more effective therapies earlier on in the course of their MS.
It has now become abundantly clear that the earlier the average person with MS is treated with a high efficacy DMT the better their outcome. The message is treat-early and treat-effectively.
Stamatellos et al. Disease-modifying agents for multiple sclerosis and the risk for reporting cancer: a disproportionality analysis using US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Br J Clin Pharmacol. 2021 May 16.
Aim: While the efficacy of Disease-Modifying Therapies (DMTs) for patients with Multiple Sclerosis (MS) is established, little is known about their long-term safety. Cancer-risk after DMTs use remains unclear. This study aims to investigate whether the prescription of DMTs for patients with MS increases the risk of reporting cancer.
Methods: Data from the FDA adverse-event reporting system were extracted from 2004 until 2020. After data cleaning, the crude and adjusted Reported Odds Ratios (cROR, aROR) for cancer were calculated for DMTs with Interferon-beta1a as the reference drug. Sensitivity analyses investigated the group of reports with multiple registered DMTs, the effect of indication restriction, and the results when using the rest of the DMTs as reference.
Results: For malignant tumors, aROR (CI 95%) were: Cladribine 0.46 (0.18-0.95) Dimethyl fumarate 0.30(0.27-0.34), Fingolimod 0.61(0.53-0.70), Glatiramer 0.50(0.43-0.58), Alemtuzumab 0.84(0.64-1.08), Interferonbeta-1b 0.49(0.42-0.56), Natalizumab 0.36(0.34-0.39), Ocrelizumab 0.48(0.29-0.74), pegInterferonbeta-1a 0.35(0.26-0.48), Siponimod 0.89(0.47-1.54), Teriflunomide 0.25(0.21-0.30) adjusted to age, gender and concomitant medications. In the sensitivity analysis, when the rest of the drugs were used as a reference, Interferon-beta1a and pegInterferon-beta1a had aROR (CI 95%): 2.60 (2.47-2.74, p<0.001), and Alemtuzumab 1.47 (1.13-1.88, p=0.003).
Conclusions: No safety signal for increased cancer-risk was detected among the approved DMTs, although more robust evidence is needed. A potential safety signal detected in the sensitivity analysis concerning Interferon-beta1a, Alemtuzumab, requires further evaluation with more robust evidence.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.