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.
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.
I did a post a few weeks ago about the secondary malignancy risk associated with longterm continuous immunosuppression and included a survey. The following are the results of the survey, which are quite disturbing. It is clear that a significant number of readers of this blog, although aware of the secondary cancer risk, are not been given standardised information about cancer risk and cancer screening. This is another piece of work that needs to be done and done well. Some of the comments are quite telling as well, including some personal critcism.
Who is interested in working on an evidence-based calculator of secondary malignancy risk in relation to MS DMTs? It will at least need to include the following variables:
Gender
Ethnicity
Age
Family history
Environmental risk factors, e.g. sun exposure, HPV vaccination status
Type of immunosuppression, i.e. continuous (anti-CD20, S1P modulators) vs. short-term (alemtuzumab, cladribine)
Intensity of immunosuppression
Duration of immunosuppression
Prior treatment history
Prior cancer history
I suspect many health and life insurance companies have actuarial data on this already and could potentially create a risk calculator using real-life data.
I did a very one-sided post this weekend on the pros of oral cladribine as a treatment for MS during the COVID-19 pandemic. One commentator asked ‘what about the cons?’. As with all immunosuppressive therapies, there is a risk of secondary malignancies. In fact, both the EMA and FDA labels mention secondary malignancies as a complication of cladribine therapy. We think the short-term cancer risk, i.e. within the first 2 years, was driven by the very low numbers of cases in the placebo arms of phase 3 trials. The cancer rate in the cladribine-exposed subjects was in keeping with the expected background rates compared to subjects on other DMTs and people from the general population from data in an international population-based cancer registry (GLOBOCAN). So I am not convinced that cladribine is associated with a short term cancer risk. However, the jury is out in relation to the intermediate to longterm risk. However, the safety data from the extension and post-marketing surveillance studies look very promising and based on the biology and mode-of-action of cladribine I think this risk is likely to be low.
Although cladribine works via DNA mechanisms it is not a mutagen; i.e. it does not cause mutations in DNA. When cladribine is incorporated into DNA it inhibits DNA polymerases, the enzymes that extend the DNA chain. The cell then senses this as a problem and this triggers apoptosis the biological process that causes the cell to trigger a suicide programme called ‘programmed cell death’. The reason why cladribine is so selective for lymphocytes is that the enzyme that activates cladribine is only found in high concentrations in lymphocytes and the other cells that don’t express this enzyme are resistant to cladribine’s effects.
Saying this secondary malignancy is a complication with all immunosuppressive therapies regardless of their mode of action. The reason is that we rely on peripheral tumour immune surveillance, i.e. our immune system find early cancers and attacks and destroys them. Suppress the immune system intensely enough and for long enough and certain cancers will develop. For example, fingolimod, and I suspect the whole S1P modulator class, is associated with skin cancer (basal and squamous), lymphoma and potentially other cancers, e..g. Kaposi’s sarcoma. Anti-CD20 therapies may be linked to breast cancer. Natalizumab, CNS lymphoma. Alemtuzumab, cervical cancer and possibly thyroid cancer, although one could argue the thyroid cancer risks with alemtuzumab may be due to ascertain bias from the high rate of thyroid screening due to thyroid secondary autoimmunity. The only DMTs not associated with secondary malignancies are the immunomodulators, i.e. interferon-beta, glatiramer acetate and teriflunomide.
Is there anything you can do about the immunosuppressive cancer risk? Yes, there is. You need to enrol and stick to your country’s cancer screening programmes. In the UK there are three national programmes; cervical, breast and colon. Breast cancer screening starts at the age of 50 and stops at the age of 70. Colon cancer screening starts at the age of 50 or 60, which depends on where you live in the UK. Cervical cancer screening is for women between 25 and 64 years of age. However, there is a push to extend cervical cancer screening beyond 64 now that cervical smear screening is being replaced with vaginal swabs, which are self-administered, and use PCR testing to detect HPV, the virus that causes cervical cancer. HPV testing is so much more pleasant for women and more reliable and reproducible than looking for abnormal cells under a microscope.
In the UK the prostate cancer screening programme is available on request, i.e. you can request a PSA (prostate-specific antigen) test. National PSA prostate cancer screening was dropped as the PSA assay was too unreliable. It generated too many false positives or detected very small cancers that were unlikely to cause any problems. In comparison, some of the treatments for prostate cancer cause more harm. In fact, most men who die in old age have asymptomatic prostate cancer at post-mortem; if something else rather than the cancer was going to kill these men why bother about detecting cancer? Please note the dropping of the national prostate cancer screening programme has been controversial and some people think it was a mistake. In many countries, PSA screening is still being done at a national level.
In some parts of the UK, there are pilot lung cancer screening programmes with high-resolution spiral chest CT scans being offered. The early results are very impressive in targeted groups at high-risk of lung cancer such as heavy smokers or ex-smokers. I am convinced that lung cancer screening is likely to become routine in the UK in smokers in the not too distant future.
Other groups for cancer screening include high-risk subjects for example patients with dysplastic naevus syndrome of the skin, who are at risk of melanoma, those with well-defined genetic conditions associated with specific cancers, patients with a very strong family history of specific cancers, patients with inflammatory bowel disease, anal cancer screening in HPV and HIV postive men-who-have-sex-with-men, oesophageal cancer screening in patients with Barrett’s oesophagus, etc.
A few years ago I asked our renal transplant team for advice about their cancer screening programme for their transplant patients. In short, they don’t do anything that is outside of the national cancer screening programme. The reason they gave is that when you start screening a younger population than that defined by the national screening programmes you are likely to detect more false positives cancers, which leads to unnecessary intervention that cause more harm. You also create cancer anxiety syndrome; i.e. patients start to worry excessively about developing cancer. I have a few patients on DMTs who suffer from this condition; so it is real.
However, there are some self-screening programmes that you can engage in, for example, self-examination of your breasts and testes for woman and men, respectively, and the regular examination of worrisome skin lesions. The following are just three YouTube videos on how to do breast, testes and skin lesion self-examinations.
As MS HCPs we are meant to prompt you to make sure you are registered with your GP and are enrolled in the screening programmes. Outside of HPV screening in women about to start an immunosuppressive therapy, I tend to forget to do this. This is another example to have proformas of standardised checklists to make sure we don’t forget this important task.
I would be interested to know what your experience has been with regard to your awareness about cancer risk on immunosuppressive therapies, cancer screening and self-examination. In this study below despite the vast majority of the woman being aware of breast self-examination, a large minority didn’t examine their breasts every month. Does this apply to you?
This study aimed to evaluate the awareness and practice of breast self-examination (BSE) and the awareness of screening and risk factors for breast cancer among patients from a mastology clinic and to associate such findings with sociodemographic factors of that population. A total of 202 randomly selected patients from the outpatient clinic of the Mastology Unit of São Paulo School of Medicine were interviewed. A structured questionnaire was used and included questions regarding sociodemographic variables, questions to assess the knowledge and practice of BSE, and knowledge of mammographic screening and risk factors for breast cancer. The vast majority of patients were aware of the existence of BSE (93.1%). BSE was performed by most patients (64.9%), although only 20.3% performed it adequately. Only 21.8% of respondents showed awareness of the best screening method for breast cancer. Furthermore, 17.3% of patients showed adequate awareness of risk factors for breast cancer. The analysis of sociodemographic variables showed that older, postmenopausal, and less-educated women showed better practice of BSE. Overall, the patients had no adequate awareness of BSE, mammographic screening, and risk factors for breast cancer, and the majority failed to practice BSE adequately, particularly the group of patients with the higher level of education. These data show that educational measures regarding the practice of BSE and, especially, mammograms should be emphasized, regardless of education level or family income of the patient.
PS (4-Mar-2021): In response to a request from one of the comments in the survey: “…you could you please comment on cancer risk for anti CD20+ treatments, as well as cancer-related topics for younger pwMS”. I have therefore added the presentation from Professor Hauser from the MSVirtual2020, the 8th Joint ACTRIMS-ECTRIMS Meeting, from September 2020. As you can see the rate of malignancies and female breast cancer in ocrelizumab-treated patients remained broadly within the range reported in the general population from epidemiological data. Please note these patients have been followed for over 7 years. I hope this helps.
I am often asked why given the extraordinary efficacy of HSCT in early RRMS, but not advanced MS, why I don’t refer more of my patients for HSCT early on in the course of their disease. There are several reasons these are the main ones.
Firstly, to be eligible for HSCT under our London guidelines patients have to fail at least two DMTs one of which has to be a high-efficacy DMT (fingolimod, cladribine, natalizumab, ocrelizumab and alemtuzumab).
Secondly, the infertility risk is too high. It is quoted to be in the order of 40-45% and most women and men want to keep their ovaries and testes in a functional state. Although the process of sperm banking and oocyte or egg harvesting, and storage, are routine it takes time to set it up and get it done. In my experience, the harvesting and storage delays treatment by several months. This delay is not ideal for someone with highly active MS. In addition, the costs of sperm and egg banking are not always covered by the NHS. Funding for this is a post-code lottery and depends on where you live.
Thirdly, the mortality that is quoted for HSCT often puts people off. The London team talk about a mortality risk of up to 2%. In reality, the real risk is closer to 0.5%, i.e. a 1 in 200 risk of dying from the procedure. For some people, this risk is unacceptably high.
What I haven’t really discussed with my patients is the secondary cancer risk post-HSCT. As HSCT involves receiving the chemotherapy compound cyclophosphamide the secondary cancer risk can’t be ignored. Cyclophosphamide is an alkylating agent that cross-links DNA. It is a mutagen and is known to cause cancer. Its metabolites are excreted in the urine and increase the risk of bladder cancer rate massively. Although we use mesna to protect the bladder against acute cyclophosphamide toxicity it does not prevent the cancer risk. The bladder risk is particularly high in MS if you have bladder dysfunction with incomplete emptying and/or need to use a catheter.
There is, however, one small French study of 354 people with progressive MS who were treated with cyclophosphamide that looked at cancer risk post-cyclophosphamide. The cumulative incidence of cancer after cyclophosphamide was 3.1% at 5 years and 5.9% at 8 years, which is described as being similar to the expected background rate.
At present we don’t have figures for how high the cancer risk is post-HSCT in pwMS. I suspect the cancer risk is likely to be in the order of 3-5x higher than the background rate. This figure is based on studies in other disease areas. Is this important? Yes, I have many female patients saying no to ocrelizumab on the basis of a possible increased risk of breast cancer with ocrelizumab. Surely, the HSCT units should be auditing their data and providing us with a cancer risk based on the longterm follow-up of their patients? If they want to convince the wider MS community to adopt HSCT and potentially use it as a first-line DMT then we need to know the longterm risks associated with its use.
Background and objectives: Cyclophosphamide treatment improves renal survival in patients with idiopathic membranous nephropathy. However, use of cyclophosphamide is associated with cancer. The incidence of malignancies in patients with idiopathic membranous nephropathy was evaluated, and the cancer risk associated with cyclophosphamide use was estimated.
Design, setting, participants, & measurements: Patients who attended the clinic were included prospectively from 1995 on. A crude incidence ratio for the occurrence of malignancy was calculated. Incidence ratios were subsequently standardized to potential confounders. Latency between cyclophosphamide therapy and the occurrence of cancer was estimated by stratifying for time since the start of treatment. Finally, Poisson regression was used to obtain a multiple adjusted incidence ratio and investigate the dose-response relationship between cyclophosphamide and cancer.
Results: Data were available for 272 patients; the mean age was 51 years, and 70% of the patients were men. Median follow-up was 6.0 years (interquartile range=3.6-9.5), and 127 patients were treated with cyclophosphamide. Cancer incidence was 21.2 per 1000 person-years in treated patients compared with 4.6 per 1000 person-years in patients who did not receive cyclophosphamide, resulting in crude and adjusted incidence ratios of 4.6 (95% confidence interval, 1.5 to 18.8) and 3.2 (95% confidence interval, 1.0 to 9.5), respectively.
Conclusion: Cyclophosphamide therapy in idiopathic membranous nephropathy gives a threefold increase in cancer risk. For the average patient, this finding translates into an increase in annual risk from approximately 0.3% to 1.0%. The increased risk of malignancy must be balanced against the improved renal survival.
BACKGROUND: Cyclophosphamide is still used in progressive forms of multiple sclerosis (MS) in view of its suggested efficacy and safety in the short term. No data exist on its long-term safety in MS, particularly on the risk of malignancy.
OBJECTIVE: The objective of this study was to evaluate cancer incidence in MS after cyclophosphamide treatment.
METHODS: We performed a historical prospective study in a cohort of MS patients treated with cyclophosphamide. We collected demographic data and medical history from medical databases and patient interviews. Reported cancers were histologically confirmed. Cancer incidence was compared with the incidence in the general population by estimating standardized incidence ratios (SIRs).
RESULTS: We included 354 patients, with a median follow-up of 5 years (range 2-15) after cyclophosphamide treatment. Fifteen patients developed a solid cancer, which occurred at a median of 3 years (range 0.5-14) after cyclophosphamide introduction. The cumulative incidence of cancer after cyclophosphamide was 3.1% at 5 years and 5.9% at 8 years. We found no increase in cancer incidence after cyclophosphamide treatment in men (SIR = 0.83, 95% confidence interval [CI] 0.30-1.82), women (SIR = 0.99, 95% CI 0.43-1.95), or men and women combined (SIR = 0.92, 95% CI 0.50-1.54).
CONCLUSION: We found no evidence of an increased risk of cancer associated with cyclophosphamide treatment in MS patients.
