Mortality: what risk would you be prepared to take?

Barts-MS rose-tinted-odometer: ZERO-★’S (Black Tuesday – a tear for my beloved country #000000)

As you are aware by now I am a proponent of flipping the pyramid and using high-efficacy DMTs first-line including immune-reconstitution therapies (IRTs) such as alemtuzumab and AHSCT. I justify the latter two options based on the fact that given sufficient time the vast majority of pwMS will become disabled and  the real cost of MS to people with MS cannot be underestimated; loss of employment, poor relationships, cognitive impairment, fatigue, depression, anxiety, etc. I think you get the gist; MS is a bad disease. 

Alemtuzumab and HSCT are the two standout treatment options that offer pwMS the best chances of long-term remission and in some pwMS it may offer a cure. What impresses me about these two options is their impact on the end-organ, i.e. brain volume loss. After rebaselining at 12 months, pwMS treated with these two options lose brain volume on average at a rate that is within the normal range for age. The other DMTs don’t do this. The downside is that these two treatment options come with more risks. These two real-world studies below report 2 deaths out of 121 (2.5%) alemtuzumab-treated patients in Finland and 3 out of 120 HSCT-treated patients in London. Would you be willing to take these chances of dying to treat your MS with the potential for long term remission, possibly a cure and to protect your most precious end-organ the brain? 

Rauma et al. Safety of alemtuzumab in a nationwide cohort of Finnish multiple sclerosis patients. J Neurol. 2021 Jul 13. doi: 10.1007/s00415-021-10664-w.

Background: Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice.

Objectives: To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients.

Methods: In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files.

Results: Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1-3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented.

Conclusions: SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.

Nicholas et al. Autologous Haematopoietic Stem Cell Transplantation in Active Multiple Sclerosis: a Real-world Case Series. Neurology. 2021 Jul 12;10.1212/WNL.0000000000012449. 

Objective: to examine outcomes in people with multiple sclerosis (PwMS) treated with autologous hematopoietic stem cell transplantation (AHSCT) in a real-world setting.

Methods: retrospective cohort study on PwMS treated with AHSCT at two centers in London, UK, consecutively between 2012 and 2019 who had ≥ 6 months of follow-up or died at any time. Primary outcomes were survival free of MS relapses, MRI new lesions and worsening of expanded disability status scale (EDSS). Adverse events rates were also examined.

Results: the cohort includes 120 PwMS; 52% had progressive MS (primary or secondary) and 48% had relapsing-remitting MS (RRMS). At baseline, the median expanded disability status scale (EDSS) was 6.0; 90% of the evaluable cases showed MRI activity in the 12 months preceding AHSCT. Median follow-up after AHSCT was 21 months (range 6-85). MS relapse-free survival was 93% at 2 years and 87% at 4 years after AHSCT. No new MRI lesions were detected in 90% of subjects at 2 years and 85% at 4 years. EDSS progression-free survival (PFS) was 75% at 2 years and 65% at 4 years. EBV reactivation and monoclonal paraproteinemia were associated with worse PFS. There were 3 transplant-related deaths within 100 days (2.5%), all following fluid overload and cardiac or respiratory failure.

Conclusions: efficacy outcomes of AHSCT in this real-world cohort are similar to those reported in more stringently selected clinical trial populations, although the risks may be higher.

Classification of evidence: this study is rated Class IV because of the uncontrolled, open-label design.

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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 and are not meant to be interpreted as personal clinical advice. 

Which side of the fence are you on?

Barts-MS rose-tinted-odometer: zero-★s (still seeing red)

Apologies some more definitions: 

Side of the fence: used to refer to either of the opposing positions or interests involved in a particular situation.

Status quo: the current situation; the way things are now. The MS community, i.e. patients and HCPs are content with the status quo and aren’t looking for a change. 

NEDA: no evident MS disease activity

The question you need to ask yourself is which side of the fence are you on? MS is a focal inflammatory disease of the central nervous system vs. MS is a smouldering disease process and focal inflammatory events are in response to what is causing the disease. If you favour the former you will be happy with being NEDA-2, i.e. having no relapses or new focal inflammatory lesions. If you are in the latter camp you will want to focus on end-organ damage and preserving your brain and spinal cord volume for old age. 

The wider MS community seems to prefer the current dogma and status quo; i.e. that MS is a focal inflammatory disease and that everything we see can be explained by relapses and focal MRI activity. I think this is wrong and have argued this from not only a scientific point of view but also from a philosophical one. 

Deciding which side of the fence you are on may make an enormous difference to your outcome. It is clear that not all DMTs are made equal when it comes to preserving brain volume and hence brain reserve. 

Did you know that pwMS lose brain volume at a 2-7x faster rate than age-matched controls from the general population? Accelerated brain volume loss predicts and is strongly associated with cognitive impairment and long term disability. The following picture shows you just how much brain someone with MS can lose over an 18 month period. 

If we moved our treatment target to go beyond NEDA to focus on protecting the end-organ so that pwMS may have a brain that is in good enough condition to withstand the ageing process in later life I suspect the treatment landscape would change dramatically. To achieve this we need to diagnose MS and treat it early and effectively and in many cases, we need to flip the pyramid and use high efficacy therapies at the beginning, in particular agent such as alemtuzumab and AHSCT, which have been shown to protect the end-organ better than other DMTs. 

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An ethical quandary

Barts-MS rose-tinted-odometer: ★★

The two case studies below are creating an ethical quandary in my MS practice. Can you help me please?

Case 1

The first is the 40-year old woman with MS who is NEDA-2 (no evident disease activity) on DMF (Tecfidera) with no documented relapses in the last 4 years and a series of annual MRI scans with no new or enlarging T2 MS lesions. However, there has been a worsening of her disability; increasing bladder problems and a progressive spastic paraparesis (weak legs). Her EDSS has moved from 4.0 to 5.5 in the last three years. She has self-diagnosed herself as having secondary progressive MS and wants to switch to siponimod. Unfortunately, according to the current NICE approval and NHSE guidelines, this patient is ineligible for siponimod because she has inactive MS (NEDA-2). 

Do I recommend she stops her DMF so that her MS can reactivate, which will then make her eligible for siponimod? Most MSologists would say yes, mainly because the development of SPMS is one of NHS England’s stopping criteria. The problem I have is we, the patient and I,  have no idea how active her MS will become if and when her MS reactivates. For example, she could have a catastrophic spinal relapse that leaves her doubly incontinent and quadriplegic or it may be on the other side of the spectrum, i.e. one or two new asymptomatic MRI lesions on her annual MRI follow-up. If you were in her position would you stop your treatment to develop active MS? 

Case 2

The second is the 40-year old woman who started natalizumab as a first-line therapy 11 years ago after presenting with two disabling relapses in a four-month period. She has done exceptionally well on natalizumab, i.e. she is NEDA-3 (no relapses, no MRI activity and no change in her EDSS). In fact, her original disabilities from the two relapses recovered. At present she is fully functional, working full-time and very active physically. For example, she plays competitive tennis in her local sports club and ran the London marathon 2 years ago. Her current EDSS is 1.0.

The problem is that her serial annual MRI studies demonstrate that she has progressive macroscopic (visible by the naked eye) brain volume loss. Being an intelligent woman and a self-taught MS expert she knows this is a poor prognostic sign and she wants to stop natalizumab and have HSCT or alemtuzumab. She is aware from reading The MS-Blog (formerly the Barts-MS blog) that alemtuzumab and HSCT have a greater impact than natalizumab on end-organ damage or brain volume loss. After HSCT and alemtuzumab treatment brain volume loss is on average in the normal range (please see BEYOND NEDA).

Would you allow this patient to switch treatments? Under the current London MS HSCT guidelines she would not be eligible for HSCT as she has not failed natalizumab; please note, progressive brain volume loss is not considered a treatment failure. What about alemtuzumab? Applying the strict NHSE guidelines she would not be eligible for alemtuzumab as her MS is inactive at present. However,  one could argue that we need to go back to 2010 when she started natalizumab and ask ourselves now would she have been eligible back then if alemtuzumab had been available? The answer is yes as she had what we call rapidly evolving severe MS; in 2021 someone with rapidly evolving severe MS could be treated with alemtuzumab first-line.  Should we apply treatment criteria retrospectively? 

This patient is JCV negative. If, however, she seroconverted to being JCV positive it would be easier to justify to NHS England for the switch to alemtuzumab, i.e. NHSE guidelines support the principle of derisking PML. The one thing I can’t tell this patient is whether or not alemtuzumab or HSCT will have an impact on her brain volume loss as we simply don’t have the data from a cohort of patients making the switch from natalizumab to alemtuzumab 10+ years into their disease. In other words will the smouldering or real MS that causes the accelerated brain volume loss respond to a potent IRT treatment strategy 11 years after diagnosis? This patient understands there is no data on natalizumab-switchers to support her request, but she is willing to take the risk of either alemtuzumab or HSCT. What do I advise her?

HELP! It is not easy being an MSologist. Please note these two scenarios are based on real patients of mine and are not hypothetical and represent the MS world I live and practice in. 

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Refusenik

Barts-MS rose-tinted-odometer: ★★

She is only 24 years of age; a graduate trainee in a marketing company. She has a promising future ahead of her. She lives in London and has a long term partner; they met at University. She knows he is the one for her and they are planning to get engaged in the next 1 to 2 years. Like most graduate trainees they find London expensive and share a house with four other people. She has found lockdown very stressful not because she has had to work from home with four other people, but because she was diagnosed with MS in February last year. 

Despite starting DMF (Tecfidera) in June 2020, she had a very disabling relapse over the Christmas period with lower limb weakness and new-onset bladder symptoms. She has also noted a fine tremor in her right hand. Her latest MRI showed several new lesions and a large lesion in her thoracic spinal cord. Her consultant neurologist has offered her ocrelizumab. However, after doing her own online research including reading The MS-Blog (formerly known as the Barts-MS blog) she has asked to be treated with alemtuzumab. Her consultant has said no and pointed out their centre has virtually stopped using alemtuzumab because as a treatment it is too risky and there are much safer options.

Out of desperation this patient went to see a colleague of mine in private who said of course she can have alemtuzumab and she has now been referred to our centre for treatment. We are now in the process of doing the baseline bloods and will hopefully get this patient treated with her first course of alemtuzumab in the next few weeks. Tragically this poor woman has lost time. What would happen if in the interim she has a further catastrophic spinal cord relapse that leaves her paralysed? Who would be responsible? 

I am beginning to refer to my colleagues who are not prepared to offer and use alemtuzumab and HSCT as the ‘refuseniks’. What they don’t realise is that they are putting themselves and their institutions at risk from legal challenge. How come? When NICE (National Institute of Health and Care Excellence) was created it was done so via an act of parliament. NICE’s primary aim was to get rid of the curse of postcode prescribing and variable access to treatments. Therefore if a therapy has been NICE approved the NHS has a legal obligation to offer people a specific treatment if they are eligible for that treatment. Therefore, in the case above her previous consultant is breaking the law and putting not only him or herself at risk of a legal challenge, but the relevant NHS Trust as well.

In 2021 why are neurologists still so paternalistic? Not allowing patients to choose their own treatment is against one of the central tenets of modern medicine.  In reality, it is not the neurologist or the institution where the neurologist works who are taking a risk when someone is treated with alemtuzumab, it is the patient who is taking the risk. Don’t they understand this? It is getting to the point in time when we are going to have to start naming and shaming these refusenik neurologists. Hopefully, when the national audit figures from blueteq, NHS England’s database of high-cost drugs, is published those centres who are not prescribing alemtuzumab or offering referral for HSCT will be exposed. I am of the opinion that if you are not using alemtuzumab or HSCT in a proportion of your patients with highly active MS then you and your centre are not managing MS the way it should be managed in 2021.

I am sure not all of my neurology colleagues will agree with me; do you?

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Curing MS

Barts-MS rose-tinted-odometer: ★★★★★

I have been asked many times if we can cure someone who has MS. I have tried to explain what an MS cure may look like many times on this blog and have actually published articles defending the definition. 

I explained in a previous post that you may be cured of your MS, but still, have worsening or progressive disease. The difference between progressive disease, which is due to previous MS damage and ageing is that the former should burn out, i.e. after a period of time, your worsening disability should eventually stop or flat-line. In comparison, MS-induced premature ageing is unlikely to stop. In comparison defining a cure in people who are young, with reserve capacity, who have been treated earlier is a much easier task. 

From a biological perspective you can be cured but still have neurological deficits from previous damage, which need to be targeted with so-called ‘repair’ and ‘neuroregenerative’ therapies. These are separate processes and are independent of a so-called biological cure. 

Based on our current understanding of MS a cure can only really occur in relation to IRTs (immune reconstitution therapies; e.g. alemtuzumab, cladribine & HSCT), i.e. treatments that are given as short courses that address the underlying ‘cause’ of MS. Maintenance treatments that need to be given continuously can’t cure MS, because when you stop the treatment MS disease activity tends to return and in some cases, particularly with anti-trafficking agents (natalizumab and fingolimod), to a greater extent than before, which we call MS rebound.

For arguments sake let’s say we have treated a group of pwMS early in the course of their disease with an IRT and they have gone into long-term remission with no evident disease activity (NEDA). How long should we wait before declaring a victory over their MS; 10, 15, 20 or 25 years? In the past, we have proposed defining a cure as NEDA at 15 years post-treatment as a starting point (see our MSARD Editorial below). Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a standard end-point that could potentially be accepted by the wider MS community. However, this may be wishful thinking many in the field are saying that we can’t cure MS, therefore, we should not even be having this discussion. Do you agree? 

The average time to the onset of secondary progressive MS is ~14-15 years so one would expect to see a significant proportion of people manifesting with SPMS in this 15-year timeframe. If we have gotten the autoimmune hypothesis wrong and IRTs don’t work then I would estimate at least a third of treated subjects should have SPMS at 15 years. The problem with 15 years is that it is a long wait if you have MS. Many pwMS want to know ‘now’ if an IRT offers a cure, therefore we need data to convince the naysayers to support the ‘cure hypothesis’. Hopefully, convincing data, such as the HSCT data below, will change their minds and get them to at least offer IRTs to more of their patients.

In the past, I have proposed a deep phenotyping project to look at pwMS who are NEDA-2 post-IRT to see if we can find any evidence of ongoing inflammatory, or neurodegenerative, MS disease activity. I proposed interrogating them in detail and comparing them to a similar cohort of pwMS who are being treated with maintenance DMTs. Deep phenotyping is simply a term that refers to the interrogation of the CNS to see if the IRT has stopped ongoing damage and protected reserve capacity.

The study that has come closest to reaching this 15-year time point is the Canadian myeloablative HSCT cohort (see below). Mark Freedman, the principal investigator, has told me that all of these patients remain NEDA-2 (no relapses or MRI activity) although some have worsened in relation to their disability, which may be a result of previous damage and not ongoing MS disease activity. However, the most impressive observation is that this cohort of patients, who all had very active MS prior to HSCT, has ‘normalised’ their rate of brain volume loss or atrophy after an initial precipitous drop in brain volume due to pseudoatrophy and/or chemotherapy-induced neurotoxicity. Mark Freedman has also said that about a third of these patients, who have had lumbar punctures, have lost their OCBs (personal communication). However, the spinal fluid analyses have all been done quite early after HSCT hence we don’t know how many subjects who have reached 10 years of follow-up or more have persistent OCBs. Wouldn’t this be an interesting fact to know?

When the 10-year lumbar puncture and spinal fluid analysis was done in a group of Polish subjects treated with intravenous cladribine, 50% had lost their spinal fluid oligoclonal IgG bands (OCBs) at 10 years and this group of OCB-negative patients tended to have stable disease compared to those who hadn’t lost their OCBs. This is why we are doing the SIZOMUS (Ixazomib) and the DODO (high-dose ocrelizumab) studies to try and scrub the CNS clean of pathogenic B-cells and plasma cells that may be driving low-grade smouldering MS. Exciting? You bet! These two studies are one of the reasons I get up in the morning, look at myself in the mirror and say nobody can say Barts-MS isn’t doing innovative MS research. 

The question I am now asking myself is switching a definition of a cure to a biological one a better strategy? This is a new line of thinking that has been brewing in my head for the last 12 months or so. If EBV is the cause of MS can we simply put pwMS into remission and clear them of EBV? This is why I want to do the iTeri and similar studies, i.e. to give an IRT and follow it with a drug that prevents EBV reactivation (antiviral) or scrubs B-cells of EBV (EBNA-1 antagonists). 

I am sure many cynics will be saying no not Prof G thinking aloud. Yes, I am thinking aloud. If only a minority of pwMS treated with IRTs go into long-term remission why can we increase the proportion by using the induction-maintenance approach that targets the cause of MS? What do you think?

If you agree with this strategy I am going to need help to get the iTeri concept study funded.  

DEFINING A CURE:

Banwell et al. Editors’ welcome and a working definition for a multiple sclerosis cure. Multiple Sclerosis and Related Disorders. 2013; 2(2):65-67.

…. Defining a cure in MS is a difficult task. How long should we wait before declaring a victory; 15, 20 or 25 years? Oncologists have back-tracked on this issue and instead of a cure they now prefer to use the term NEDD, or no evidence of detectable disease, at a specific time-point knowing full well that a limited number of subjects will relapse and present with recurrent disease after this point. We propose using the term NEDA, or no evident disease-activity, at 15 years as a starting point for defining a cure. Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a usual endpoint. In addition, the median time to the onset of secondary progressive MS is ~10-11 years (Kremenchutzky, Rice et al. 2006) and is well within the 15-year time window of our proposed definition of a cure. At present NEDA is defined using a composite of a) no relapses, or b) no EDSS progression, or c) no MRI activity (new or enlarging T2 lesions or no Gd-enhancing lesions) (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). This description is currently based on data that is routinely collected in contemporary clinical trials (Havrdova, Galetta et al. 2009; Giovannoni, Cook et al. 2011). The definition of NEDA will evolve with technological innovations and clinical practice, and in the future, it will almost certainly include MSer-related outcomes, grey matter disease activity, an index of brain atrophy and hopefully a CSF biomarker profile…..

References:

Giovannoni, G., S. Cook, et al. (2011). “Sustained disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with cladribine tablets in the CLARITY study: a post-hoc and subgroup analysis.” Lancet Neurol 10(4): 329-337.

Havrdova, E., S. Galetta, et al. (2009). “Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study.” Lancet Neurol 8(3): 254-260

Kremenchutzky, M., G. P. Rice, et al. (2006). “The natural history of multiple sclerosis: a geographically based study 9: observations on the progressive phase of the disease.” Brain 129(Pt 3): 584-594.

THE CURE #1?

Atkins et al. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial. Lancet. 2016 Aug 6;388(10044):576-85. 

BACKGROUND: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis.

METHODS: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930.

FINDINGS: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no GdGd-enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.

INTERPRETATION: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease’s aggressive nature.

THE CURE #2?

Rejdak et al. Cladribine induces long lasting oligoclonal bands disappearance in relapsing multiple sclerosis patients: 10-year observational study. Mult Scler Relat Disord. 2019 Jan;27:117-120. 

Background: There has been long-term interest in cladribine as a drug for the treatment of MS. The current study focused on the effect of cladribine on oligoclonal bands (OCB) expression in the CSF in relapsing-remitting MS (RRMS) patients observed over 10 years.

Methods: 29 treatment-naive subjects with RRMS were prospectively enrolled and received induction therapy with subcutaneous parenteral cladribine (at a cumulative dose of 1.8 mg/kg; divided into 6 courses every 5 weeks given for 4-6 days, depending on patients’ body weight). Selected patients received maintenance doses in the follow-up period.

Results: Isoelectric focusing revealed that 55% of patients did not have OCB in CSF after cladribine treatment as compared to baseline testing when 100% of patients were positive for OCB. There were no significant differences in Expanded Disability Status Scale scores at baseline and at the end of treatment cycle between OCB-positive vs. OCB-negative subgroups. At the last follow-up, OCB-negative patients had lower disability compared to OCB-positive patients (p = 0.03).

Conclusion: Cladribine-induced immune reconstitution leads to long lasting suppression of intrathecal humoral response, which might be an additional mechanism that enhances the therapeutic effect on disease progression in RRMS patients.

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The Star-MS trial: to be HSCTed or not

Barts-MS rose-tinted-odometer: ★★★

There is little doubt in my mind that HSCT is the most effective DMT we have for treating MS. The latter is based on NEDA (no evident disease activity) rates post-HSCT and brain volume loss data after year one. HSCT appears to put the majority of treated patients into long-term remission and normalises end-organ damage as measured by brain volume loss. In addition, a not insignificant proportion of HSCT-treated patients may be cured depending on how you want to define an MS cure. Despite these data most MSologists however, consider HSCT too risky to refer patients for treatment and hence prefer to go with the more acceptable risk profile of licensed DMTs. This is why HSCT hasn’t taken off as a mainstream treatment for MS and remains a niche treatment. 

What is not known is that HSCT may yet prove to be one of the most cost-effective DMTs we have. Although quite expensive, with most of the costs front-loaded, HSCT does lead to significant cost savings in the long-term (see study below). I wonder if healthcare systems will clock this and take the bold step of underwriting more HSCT treatments for MS with the promise of long term cost savings? The problem we have in medicine is that healthcare budgets typically run on an annual cycle and so costs savings unless made the same year often don’t influence treatment decisions. 

“Why should I spend more money today to only save money in the 5 years time? My responsibility is to this year’s or maybe next year’s budget not the budget in 5 years time.”

The counter-argument to this is should be if I don’t save my brain volume this year or next year, by the time I get to year 5 in my disease course it will be too late. At the moment MS brain and spinal cord damage are irreversible. Yes, time really is brain.

What do you do as a person with MS who has decided to be treated with HSCT, but your neurologist says no? Do you find a neurologist who will say yes? Do you travel abroad and take the private route? Or do you accept your neurologist’s advice and go for the safer, but ultimately more expensive, licensed but less effective DMT? 

The good news is that we in the UK will soon be starting the StartMS trial, which will compare autologous stem cell transplantation (AHSCT) versus alemtuzumab or ocrelizumab in relapsing-remitting MS. This means at least some of you will be offered the opportunity to be randomised to AHSCT or ocrelizumab/alemtuzumab. A major outcome of this study will be a cost-comparison to see how much money it will save the NHS. Exciting or not? Some people are arguing that we don’t need this study as the information is already available. Not sure I agree. Sometimes doing your own research and generating your own data is what is required to change behaviour, i.e. the wide adoption of HSCT as a treatment for MS. 

Orlewska et al. Impact of Immunoablation and Autologous Hematopoietic Stem Cell Transplantation (AHSCT) on Treatment Cost of Multiple Sclerosis: Real-World Nationwide Study. Value Health Reg Issues. 2021 Apr 14;25:104-107.

Objectives: To provide real-world data on the impact of autologous hematopoietic stem cell transplantation (AHSCT) on treatment costs of patients with multiple sclerosis (MS) in Poland.

Methods: Medical data of 105 patients who underwent AHSCT in the years 2011 to 2016 were obtained from the National Health Fund (NHF) database. Treatment costs were calculated from the public payer’s perspective per patient-year for the total available period as well as 12 months before and after AHSCT. The statistical analysis was performed using MATLAB 2016b.

Results: Mean treatment-related costs covered by the NHF per patient-year before and after the transplantation were €4314.9 and €1188.8 , respectively. The average cost of disease-modifying drugs per patient was reduced from €2497.9/year before to €65.3/year after AHSCT.

Conclusions: Although the initial cost of AHSCT is high, the costs involving AHSCT and post-AHSCT treatment could, according to our analysis, pay off in 3.9 years, when compared to the costs of disease-modifying drug therapy in aggressive MS. The study provides evidence that the AHSCT can lead to significant savings in treatment costs of aggressive MS from the public payer’s perspective.

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HSCT makes the recommended list

Barts-MS rose-tinted-odometer: ★★★★★

Good news for people with MS living in the US. The National Multiple Sclerosis Society is acknowledging that autologous hematopoietic stem cell transplant (AHSCT) is an effective treatment for MS as is recommending  AHSCT a useful treatment option for pwMS who have substantial breakthrough disease activity despite treatment with high-efficacy DMTs or have contraindications to high-efficacy disease-modifying therapies. The acknowledge that pwMS younger than 50 years with shorter durations of disease (<10 years) have the most to gain from AHSCT. 

The big question is will insurers and national funders pay for HSCT in the US based on this recommendation or will they still need FDA approval? 

The good news for pwMS living in the UK is that the NHS already covers the cost of HSCT and MS is on the list of approved autoimmune diseases for treatment with HSCT. The problem in the UK is not necessarily the access to the treatment, but to get risk-averse neurologists to refer pwMS for the procedure or am I wrong?

Miller et al. Autologous Hematopoietic Stem Cell Transplant in Multiple Sclerosis Recommendations of the National Multiple Sclerosis Society. JAMA Neurol. Published online October 26, 2020. doi:10.1001/jamaneurol.2020.4025

Importance:  Autologous hematopoietic stem cell transplant (AHSCT) for multiple sclerosis has gained increasing interest in recent years. Despite the availability of many US Food and Drug Administration–approved disease-modifying therapies, some patients do not respond adequately and others may have very early aggressive disease that prompts consideration of alternative, highly effective, long-lasting therapy. The National Medical Advisory Committee of the National Multiple Sclerosis Society has reviewed recent literature on AHSCT for the purpose of making recommendations about its use based on current knowledge, as well as pointing out areas of controversy and issues requiring further research.

Observations:  Studies on AHSCT have repeatedly demonstrated high efficacy and a durable outcome in people with relapsing multiple sclerosis. Recent studies have shown considerable improvement in the safety of the procedure, with much lower mortality rates than were reported earlier. Consensus is emerging about the characteristics of the best candidates for the procedure. Questions remain about the ideal protocol, particularly about the best conditioning regimen to be used to kill immune cells. Larger randomized clinical trials are needed to address the question of whether AHSCT has advantages over the most efficacious disease-modifying agents currently available. One such trial (Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for Multiple Sclerosis [BEAT-MS) is currently in progress.

Conclusions and Relevance:  The National Multiple Sclerosis Society believes that AHSCT may be a useful treatment option for people with relapsing multiple sclerosis who demonstrate substantial breakthrough disease activity (ie, new inflammatory central nervous system lesions and/or clinical relapses) despite treatment with high-efficacy disease-modifying therapy or have contraindications to high-efficacy disease-modifying therapies. The best candidates are likely people younger than 50 years with shorter durations of disease (<10 years). The procedure should only be performed at centers with substantial experience and expertise. Ideally, recipients of the procedure should be entered into a single database, and further research is needed to establish ideal cell mobilization and immune-conditioning regimens.

CoI: multiple

Twitter: @gavinGiovannoni  Medium: @gavin_24211

Beyond the B-cell: cognitive dissonance

I continue to be amazed when I hear senior MS neurologists make the claim they have never prescribed alemtuzumab or referred any of their patients for HSCT and don’t intend to do so either. These same neurologists seem to be happy with natalizumab and ocrelizumab as their #1 high-efficacy go to DMTs. When I challenge them with the exceptional longterm outcomes for pwMS treated early with alemtuzumab or HSCT I get a glazed look, which I now learnt is cognitive dissonance

“Cognitive dissonance refers to a situation involving conflicting attitudes, beliefs or behaviours. This produces a feeling of mental discomfort leading to an alteration in one of the attitudes, beliefs or behaviours to reduce the discomfort and restore balance. For example, when people smoke (behaviour) and they know that smoking causes cancer (cognition), they are in a state of cognitive dissonance.” Source: Simply Psychology

It is quite clear that both ocrelizumab and natalizumab are very effective DMTs at switching-off focal inflammatory disease activity in MS; a large number of pwMS on these therapies are NEDA-2 (relapse-free and no new T2 lesions on MRI). This is interpreted by these neurologists and the wider MS community that MS is all sorted. Go away, get on with your life and be happy.

What these neurologists don’t tell their patients on ocrelizumab and natalizumab that despite no relapses or new MRI lesions the accelerated brain volume loss due to MS is continuing unabated. These neurologists and their patients are being lulled into a sense of false security because they believe MS is focal inflammatory disease, when in fact the real MS is the smouldering disease, which drives end-organ damage. 

I have addressed these topics many times on this blog. If you are interested in reading some of my back catalogue of posts on this particular topic you can start with the posts below or you could watch a recent lecture I have given on the topic.  

It is clear that not all DMTs are made equal when it comes to preventing end-organ damage. At the top of the league table are alemtuzumab and HSCT (~0.2-0.25% loss per annum). Both these treatments are NIRTs (non-selective immune reconstitution therapies). 

Natalizumab is probably next with an annual brain volume loss in the region of 0.25-0.30% per annum. Ocrelizumab (anti-CD20) comes next with a rate of brain volume loss of ~0.374% per annum (see latest data below). 

Why do natalizumab and ocrelizumab, despite being very effective anti-inflammatory DMTs have only a moderate impact on end-organ damage? This and other observations have convinced me that MS is not focal inflammation, which represents the immune system’s response to what is causing MS. I suspect there is something going in the CNS of pwMS that is the real MS; I refer to this hypothesis as the ‘Field Hypothesis’.

What these observations are telling us that peripheral B-cells are an important part of the immune response to the cause of MS, but B-cells are not necessarily involved in driving the true MS pathology, which is causing the progressive brain volume loss. 

What does this mean for the well-informed person with MS? Firstly, you and your neurologist may not want to dismiss alemtuzumab and HSCT as a first-line, or at least early, treatment option. These non-selective highly effective IRTs differ from anti-CD20 therapies in that they target both B and T cells. I suspect we need to target both these cells types early in the course of the disease to really get on top of the real MS. 

I am aware of the appeal of anti-CD20 therapies and natalizumab in that they are safer and easier to use because of less monitoring, however, this may come at a cost in the long-term. Please remember that once you have lost brain you can’t get it back. With alemtuzumab and HSCT, the risk is frontloaded, and balanced against the potential long-term gains in efficacy, which are unprecedented. Choosing a DMT on a rung or two lower down on the therapeutic ladder gives you better short-term safety and makes the life of your MS neurologist less stressful, because of less monitoring and fewer risks, but at a potential long-term cost to your brain and spinal cord.  

This is why making an informed decision about which DMT you choose is a very complicated process and subject to subtle and often hidden effects of cognitive biases; cognitive dissonance is just one of these biases. The one bias I am very aware of is the ‘Gambler’s Dilemma’, be careful not to be lulled into a false sense of security by your beliefs; most gamblers eventually end-up losing.

In reality, we need to move treatment target in MS way beyond NEDA-2 to target end-organ damage, i.e. brain volume loss, T1 black holes, the slowly expanding lesions (SELs), neurofilament levels, cognition, sickness behaviour, OCBs, etc. Our treatment aim should be to ‘Maximise Brain Health’ across your life and not just the next few years. 

As yet we don’t know what the impact of alemtuzumab and HSCT are on the pathology of smouldering MS, but these agents must be doing something to these pathologies based on clinical and MRI outcomes (see below). Despite this data gap, I think we have enough empirical evidence that alemtuzumab and HSCT are doing some fundamental to the pathology of MS.  

Coming back to cognitive dissonance. It could be argued that if an MS neurologist or MS centre does not offer alemtuzumab or HSCT to at least some of their patients then they are not providing their patients with sufficient choice. In addition, they will almost certainly not accept the concept of smouldering MS being the real MS.

OCRELIZUMAB BRAIN VOLUME DATA

Hauser et al. Five-years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension. Neurology 2020; First published July 20, 2020, DOI: https://doi.org/10.1212/WNL.0000000000010376

Objective: To assess over 3 years of follow-up, the effects of maintaining or switching to ocrelizumab (OCR) therapy on clinical and MRI outcomes and safety measures in the open-label extension (OLE) phase of the pooled OPERA studies in relapsing multiple sclerosis.

Methods: After 2 years of double-blind, controlled treatment, patients continued OCR (600 mg infusions every 24 weeks) or switched from interferon (IFN) β-1a (44 μg 3 times weekly) to OCR when entering the OLE phase (3 years). Adjusted annualized relapse rate, time to onset of 24-week confirmed disability progression/improvement (CDP/CDI), brain MRI activity (gadolinium-enhanced and new/enlarging T2 lesions), and percentage brain volume change were analyzed.

Results: Of patients entering the OLE phase, 88.6% completed Year 5. The cumulative proportion with 24-week CDP was lower in patients who initiated OCR earlier, vs patients initially receiving IFN β-1a (16.1% vs 21.3% at Year 5; p=0.014). Patients continuing OCR maintained, and those switching from IFN β-1a to OCR attained near complete and sustained suppression of new brain MRI lesion activity from Year 3 to 5. Over the OLE phase, patients continuing OCR exhibited less whole brain volume loss from double-blind study baseline vs those switching from IFN β-1a (–1.87% vs –2.15% at Year 5; p<0.01). Adverse events were consistent with past reports and no new safety signals emerged with prolonged treatment.

Conclusion: Compared with patients switching from IFN β-1a, earlier and continuous OCR treatment up to 5 years provided sustained benefit on clinical and MRI measures of disease progression.

Classification of evidence: This study provides Class III evidence that earlier and continuous treatment with ocrelizumab provided sustained benefit on clinical and MRI outcomes of disease activity and progression compared with patients switching from IFN β-1a. The study is rated Class III because of the initial treatment randomization disclosure that occurred after inclusion in OLE.

HSCT BRAIN VOLUME DATA 

Lee et al. Brain atrophy after bone marrow transplantation for treatment of multiple sclerosis. Mult Scler. 2017 Mar;23(3):420-431.

BACKGROUND:  A cohort of patients with poor-prognosis multiple sclerosis (MS) underwent chemotherapy-based immune ablation followed by immune reconstitution with an autologous hematopoietic stem cell transplant (IA/aHSCT). This eliminated new focal inflammatory activity, but resulted in early acceleration of brain atrophy.

OBJECTIVE: We modeled the time course of whole-brain volume in 19 patients to identify the baseline predictors of atrophy and to estimate the average rate of atrophy after IA/aHSCT.

METHODS: Percentage whole-brain volume changes were calculated between the baseline and follow-up magnetic resonance imaging (MRI; mean duration: 5 years). A mixed-effects model was applied using two predictors: total busulfan dose and baseline volume of T1-weighted white-matter lesions.

RESULTS: Treatment was followed by accelerated whole-brain volume loss averaging 3.3%. Both the busulfan dose and the baseline lesion volume were significant predictors. The atrophy slowed progressively over approximately 2.5 years. There was no evidence that resolution of edema contributed to volume loss. The mean rate of long-term atrophy was -0.23% per year, consistent with the rate expected from normal aging.

CONCLUSION: Following IA/aHSCT, MS patients showed accelerated whole-brain atrophy that was likely associated with treatment-related toxicity and degeneration of “committed” tissues. Atrophy eventually slowed to that expected from normal aging, suggesting that stopping inflammatory activity in MS can reduce secondary degeneration and atrophy.

ALEMTUZUMAB BRAIN VOLUME LOSS

Arnold et al. Superior MRI outcomes with alemtuzumab compared with subcutaneous interferon β-1a in MS. Neurology. 2016 Oct 4;87(14):1464-1472.Neurology. 2016 Oct 4;87(14):1464-1472.

OBJECTIVE: To describe detailed MRI results from 2 head-to-head phase III trials, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis Study I (CARE-MS I; NCT00530348) and Study II (CARE-MS II; NCT00548405), of alemtuzumab vs subcutaneous interferon β-1a (SC IFN-β-1a) in patients with active relapsing-remitting multiple sclerosis (RRMS).

METHODS: The impact of alemtuzumab 12 mg vs SC IFN-β-1a 44 μg on MRI measures was evaluated in patients with RRMS who were treatment-naive (CARE-MS I) or who had an inadequate response, defined as at least one relapse, to prior therapy (CARE-MS II).

RESULTS: Both treatments prevented T2-hyperintense lesion volume increases from baseline. Alemtuzumab was more effective than SC IFN-β-1a on most lesion-based endpoints in both studies (p < 0.05), including decreased risk of new/enlarging T2 lesions over 2 years and gadolinium-enhancing lesions at year 2. Reduced risk of new T1 lesions (p < 0.0001) and gadolinium-enhancing lesion conversion to T1-hypointense black holes (p = 0.0078) were observed with alemtuzumab vs SC IFN-β-1a in CARE-MS II. Alemtuzumab slowed brain volume loss over 2 years in CARE-MS I (p < 0.0001) and II (p = 0.012) vs SC IFN-β-1a.

CONCLUSIONS: Alemtuzumab demonstrated greater efficacy than SC IFN-β-1a on MRI endpoints in active RRMS. The superiority of alemtuzumab was more prominent during the second year of both studies. These findings complement the superior clinical efficacy of alemtuzumab over SC IFN-β-1a in RRMS.

CLINICALTRIALSGOV IDENTIFIER: NCT00530348 and NCT00548405.

CLASSIFICATION OF EVIDENCE: The results reported here provide Class I evidence that, for patients with active RRMS, alemtuzumab is superior to SC IFN-β-1a on multiple MRI endpoints.

ALEMTUZUMAB MRI END-ORGAN DATA

Vavasour et al. A 24-month advanced magnetic resonance imaging study of multiple sclerosis patients treated with alemtuzumab. Mult Scler. 2018 Apr 1:1352458518770085. doi: 10.1177/1352458518770085.

BACKGROUND: Tissue damage in both multiple sclerosis (MS) lesions and normal-appearing white matter (NAWM) are important contributors to disability and progression. Specific aspects of MS pathology can be measured using advanced imaging. Alemtuzumab is a humanised monoclonal antibody targeting CD52 developed for MS treatment.

OBJECTIVE: To investigate changes over 2 years of advanced magnetic resonance (MR) metrics in lesions and NAWM of MS patients treated with alemtuzumab.

METHODS: A total of 42 relapsing-remitting alemtuzumab-treated MS subjects were scanned for 2 years at 3 T. T1 relaxation, T2relaxation, diffusion tensor, MR spectroscopy and volumetric sequences were performed. Mean T1 and myelin water fraction (MWF) were determined for stable lesions, new lesions and NAWM. Fractional anisotropy was calculated for the corpus callosum (CC) and N-acetylaspartate (NAA) concentration was determined from a large NAWM voxel. Brain parenchymal fraction (BPF), cortical thickness and CC area were also calculated.

RESULTS: No change in any MR measurement was found in lesions or NAWM over 24 months. BPF, cortical thickness and CC area all showed decreases in the first year followed by stability in the second year.

CONCLUSION: Advanced MR biomarkers of myelin (MWF) and neuron/axons (NAA) show no change in NAWM over 24 months in alemtuzumab-treated MS participants.

CoI: multiple

HSCT is shifting the Bell curve

Barts-MS rose-tinted-odometer  ★ ★ ★

The good news is that the use of autologous HSCT to treat autoimmune diseases rose (by 19%) in the European Bone Marrow Transplant registry in 2018. Importantly, this rise was predominantly due to HSCT treatment for multiple sclerosis. This would indicate that at least at the very right of the bell curve there is increasing use of a more aggressive approach to treating MS. If this indicates that the bell curve has shifted to the right it means that more pwMS are being treated with highly effective treatments and I suspect that many are getting onto these as first-line therapies. 

What will this mean at a population level? I suspect that over time the prognosis of MS will improve and an increasing number of patients treated with IRTs (cladribine, alemtuzumab and HSCT) will be rendered free of detectable disease in the longterm. If and whether we will be able to claim that a proportion of these pwMS are cured of having MS will depend on the MS community coming up with a widely accepted definition of what an MS cure looks like. 

How IRTs actually work will remain a moot point. Immunologists will claim that they deplete pathogenic autoimmune T and B lymphocytes and reset regulatory immunological networks. Proponents of the EBV hypothesis will claim they all work by targeting pathogenic memory B cells that harbour EBV. Sorting out these competing theories will really require targeted EBV studies, the sort that has been developed by Atara Bio. Another strategy will be using anti-viral agents active against EBV; this will include both existing and new anti-EBV therapies. 

If I have to bet on the outcome I would favour the EBV hypothesis. There are simply too many holes in the autoimmune theory of MS and the epidemiology backing EBV as the cause of MS is now so overwhelming that the wider MS community is finally getting behind EBV vaccination as a possible preventive strategy. I hope you agree.

Passweg et al. and the European Society for Blood and Marrow Transplantation (EBMT). The EBMT activity survey on hematopoietic-cell transplantation and cellular therapy 2018: CAR-T’s come into focus. Bone Marrow Transplant. 2020 Feb 17. 

Hematopoietic-cell transplantation (HCT) is widely used for acquired and congenital disorders of the hematopoietic system. Number of transplants performed in Europe and associated countries continues to rise with 47,468 HCT in 42,901 patients [19,630 allogeneic (41%) and 27,838 autologous (59%)] reported by 701 centers in 50 countries in 2018. Main indications were myeloid malignancies 10,679 (25%; 97% allogeneic), lymphoid malignancies 27,318 (64%; 20% allogeneic), solid tumors 1625 (4%; 2.9% allogeneic), and nonmalignant disorders 3063 (7%; 81% allogeneic). This year’s analysis focuses on cellular therapies with the marked growth in CAR T-cell therapies from 151 in 2017 to 301 patients reported in 2018. Other cellular therapy numbers show less significant changes. Important trends in HCT include a 49% increase in allogeneic HCT for chronic phase CML (although transplant numbers remain low) and a 24% increase in aplastic anemia. In autologous HCT, there is an ongoing increase in autoimmune diseases (by 19%), predominantly due to activity in multiple sclerosis. This annual report reflects current activity and highlights important trends, useful for health care planning.

CoI: multiple

HSCT Units can you please show me the data?

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.

CoI: multiple