Barts-MS rose-tinted-odometer 0/★
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.
van den Brand et al. Cancer Risk After Cyclophosphamide Treatment in Idiopathic Membranous Nephropathy. Clin J Am Soc Nephrol, 9 (6), 1066-73 2014 Jun 6.
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.
Le Bouc et al. No increase in cancer incidence detected after cyclophosphamide in a French cohort of patients with progressive multiple sclerosis. Mult Scler. 2012 Jan;18(1):55-63.
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.