Sunday, 19 October 2014

ClinicSpeak: natalizumab PML update - September 2014

September 2014 natalizumab PML update: underestimating the PML risk? #ClinicSpeak #MSBlog #MSResearch

"The following are the latest risk figures for PML as a result of being treated with natalizumab. Please note that the embedded slideshow is for health professionals only; if you are not a health professional Biogen-Idec don't want you to see this presentation. If you are a MSer you should be reading my previous post that has been designed for MSers."


Headline information


"As of the 2nd September 2014 there have been 495 cases of natalizumab-associated PML. This represents an increase of 20 cases over the last 2 months. Over 129,100 MSers have been exposed to natalizumab. The following graph demonstrates the number of new PML cases per month seems to be relatively stable, despite a gradual and linear increase in number of exposed MSers. Clearly the ratio is decreasing which indicates that the PML de-risking programme is working; in other words less MSers at risk of PML are staying on the natalizumab. Herein lies the problem; this means that the proportion of JCV-ve MSers on natalizumab is increasing. However the total number of MSers on treatment is used in the denominator to calculate the risk of getting PML. If this denominator is changing by including an increasing proportion of MSers who are not at risk of getting PML it will give a falsely low risk of PML. What we need are monthly updates of the PML risk, by excluding all JCV-ve MSers from the analysis. Unfortunately, Biogen-Idec are unable to access this information, despite them providing the JCV antibody assay free. Why? They don't have consent from the MSers who are being tested for JCV to use their data in this way."




"The following ratios are my attempt to explain why I think we are under-estimating the PML risk. At present Biogen-Idec is calculating the PML risk using the top equation. What I would like to see are PML risks calculated using the lower equation."


"The mortality associated with PML was 23% in July; in July 109 MSers have died as result of PML. It appears as if Biogen-Idec have now stopped reporting the number of deaths. Please note that the majority of the PML survivors have a poor functional outcome. You need to keep these figures in context of well over 129,100 MSers been treated with natalizumab worldwide with over 362,000 years of natalizumab exposure."


"Since NHS England gave us permission to switch high-risk natalizumab patients to fingolimod, we are continuing to de-risk our natalizumab-treated population. We are hoping by doing this to prevent anyone at our centre from getting PML. Despite this some MSers are not prepared to stop natalizumab, simply because they are doing so well on the drug."


"The following is the most important headline data slide for MSers regarding risks based on the three identified PML risk factors:

  1. JCV serostatus
  2. Duration of treatment
  3. Previous exposure to immunosuppression


In addition to this is appears that titres or levels of anti-JCV antibodies also play a role in risk (see below) and this needs to be incorporated into future risk models."


"We have developed a simple infographic to help you integrate all this information. You can download and print this infographic for your own information."




Plavina et al. Use of JC virus antibody index to stratify risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients with multiple sclerosis. ENS 2013 Multiple Sclerosis I: Therapeutics

Objectives: In MSers treated with natalizumab, the presence of anti-JCV antibodies (JCV Ab+), prior use of immunosuppressants (IS), and increased duration of natalizumab treatment, especially greater than 2 years, are known risk factors for progressive multifocal leukoencephalopathy (PML). With polyomaviruses, higher levels of antibodies have been correlated with increased viral burden and increased disease risk. It is not known whether JCV Ab levels correlate with PML risk in natalizumab-treated MSers. The objective of this analysis is to examine the association between JCV Ab index (JCV antibody level as measured using the STRATIFY JCV DX Select assay) and PML risk in natalizumab-treated MSers. 

Methods: Analyses involved JCV Ab index data from JCV Ab+ MSers enrolled in clinical studies or clinical practice. A cross-sectional analysis of JCV Ab index data from MSers without PML was first performed to assess potential relationships between JCV Ab index and known risk factors (natalizumab treatment duration <=24 vs >24 monthly infusions and prior IS use). P values were calculated using a Wilcoxon rank sum test. The association between JCV Ab index and PML was then assessed using all available longitudinal data. Odds ratios (ORs) were estimated from generalised estimating equations with a logit link. The predicted probabilities were then used to update the current PML risk estimates for JCV Ab+ MSers with high/low Ab index by applying Bayes theorem. 

Results: JCV Ab index data were available from 71 natalizumab-treated PML MSers at least 6 months prior to PML diagnosis and from 2522 non-PML JCV Ab+ MSers. JCV Ab index was not found to be associated with number of natalizumab infusions (P=0.39) nor prior IS use (P=0.43), but was significantly associated with PML risk (P<0.001). Estimated ORs were at least 4 for high versus low JCV Ab index in JCV Ab+ MSers. Updated PML risk estimates and longitudinal stability of JCV Ab index will be presented. 

Conclusion: Risk of PML in JCV Ab negative natalizumab-treated MSers is very low (0.07 per 1000). In JCV Ab+ MSers who have low JCV Ab index, the risk of PML is several-fold lower than the risk currently attributed to all JCV Ab+ MSers. Utilisation of JCV Ab index allows for further clinically meaningful stratification of PML risk in JCV Ab+ natalizumab-treated MSers.








"The figures in the bottom table are derived from Table 2 above and present the data in a different way, rather as per thousand an absolute risk. You have to realise that these figures are derived from relatively small numbers, i.e. 51 cases of PML. But the data is what it is and will not be confirmed by anyone else. I assume as more cases emerge the data set will be updated. The implications of this data is that many MSers who are doing well on natalizumab and have low titres, or a low index, may choose to stay on natalizumab rather than switch. In those MSers who are high risk and have elected to stay on natalizumab we have started doing 3 monthly MRI monitoring for early signs of PML. The idea behind the latter strategy is to detect PML very early and wash-out natalizumab. It is clear that if PML is picked up in the asymptomatic phase and managed quickly MSers do much better; this is highlighted in slides 35 and 36 above."

CoI: multiple

OffLabel: cladribine

Cladribine is my fourth off label DMT for treating MS in resource poor environments. #MSBlog #MSResearch #OffLabel

"This post is the fourth in a series of posts to try and help neurologists who treat MS in healthcare environments where they cannot access high-cost innovator DMTs. If you want to know the history of this post please read my post on my visit to South Africa. The other three off-label DMTs are methotrexate, azathioprine and mitoxantrone."

"Many of you will know that oral cladribine got through the development pipeline and was licensed in Russia and Australia before Merck-Serono decided to pull the plug on the drug and withdraw it from all markets. The reason for doing this was complex, but both the EMA and FDA wanted more safety data after the seeing only one phase 3 pivotal study (CLARITY Study, study 1 below). This decision was made before the second phase 3 study in CIS (ORACLE Study, study 2 below) was completed. An apparent signal of secondary malignancies emerged in this first study that was not seen in the second study. I was particularly disappointed with Merck-Serono's decision to pull cladribine, particularly in view of the extraordinary results of the CIS study and the observation that secondary malignancies were not a problem in the second study. This does not mean there the secondary malignancy issue has gone away, however, it is likely to be a small problem similar to that seen with other immunosuppressive drugs. Please note that one of the functions of the immune system is to fight malignancies and when you suppress the immune system you get a higher incidence of secondary malignancies; these tend to come on many years later and predominated by lymphomas and skin cancers. The only way you will find out about the risk of secondary malignancies is via so called post-marketing surveillance studies or registers and not in phase 3 studies. Hence why it is difficult to accept the FDA's and EMA's reasoning."


"We don't have oral cladribine, but that doesn't mean to say you can't use it. What we are suggesting is going back to the subcutaneous formulation that is licensed for treating hairy cell leukaemia. I have uploaded the Royal London Hospital's protocol for your information. We tend to use it patients with relapsing secondary-progressive disease who have failed other therapies, for whom we don't have a licensed therapy. However, in resource poor countries and environments where you can't access licensed DMTs I would use it in active MSers as a first, second or third line therapy. It is clear from the CIS or ORACLE study that the sooner you use cladribine the better the outcome. The main safety signal is infection, particularly herpes infections and low white blood counts. For the herpes infections you need to be vigilant and treat them with anti-virals. In subjects who are seronegative for VZV (varicella-zoster virus) they should be vaccinated against the virus before starting cladribine. In countries with a high background rate of tuberculosis it is important to screen for, and exlcude ative or latent, TB infection. The lymphopaenia (low lymphocyte counts) can be managed by strict redosing guidelines. Please note I would suggest using cladribine as we use alemtuzumab, i.e. as an induction agent. I would only give two years of treatment and then monitor to see if there is any breakthrough disease before administering further courses."



Study1: Giovannoni et al. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med. 2010 Feb 4;362(5):416-26.

BACKGROUND: Cladribine provides immunomodulation through selective targeting of lymphocyte subtypes. We report the results of a 96-week phase 3 trial of a short-course oral tablet therapy in patients with relapsing-remitting multiple sclerosis.

METHODS: We randomly assigned 1326 patients in an approximate 1:1:1 ratio to receive one of two cumulative doses of cladribine tablets (either 3.5 mg or 5.25 mg per kilogram of body weight) or matching placebo, given in two or four short courses for the first 48 weeks, then in two short courses starting at week 48 and week 52 (for a total of 8 to 20 days per year). The primary end point was the rate of relapse at 96 weeks.

RESULTS: Among patients who received cladribine tablets (either 3.5 mg or 5.25 mg per kilogram), there was a significantly lower annualized rate of relapse than in the placebo group (0.14 and 0.15, respectively, vs. 0.33; P<0.001 for both comparisons), a higher relapse-free rate (79.7% and 78.9%, respectively, vs. 60.9%; P<0.001 for both comparisons), a lower risk of 3-month sustained progression of disability (hazard ratio for the 3.5-mg group, 0.67; 95% confidence interval [CI], 0.48 to 0.93; P=0.02; and hazard ratio for the 5.25-mg group, 0.69; 95% CI, 0.49 to 0.96; P=0.03), and significant reductions in the brain lesion count on magnetic resonance imaging (MRI) (P<0.001 for all comparisons). Adverse events that were more frequent in the cladribine groups included lymphocytopenia (21.6% in the 3.5-mg group and 31.5% in the 5.25-mg group, vs. 1.8%) and herpes zoster (8 patients and 12 patients, respectively, vs. no patients).

CONCLUSIONS: Treatment with cladribine tablets significantly reduced relapse rates, the risk of disability progression, and MRI measures of disease activity at 96 weeks. The benefits need to be weighed against the risks. (ClinicalTrials.gov number, NCT00213135.)


Study 2: Leist et al. Effect of oral cladribine on time to conversion to clinically definite multiple sclerosis in patients with a first demyelinating event (ORACLE MS): a phase 3 randomised trial. Lancet Neurol. 2014 Mar;13(3):257-67.


BACKGROUND: Patients who develop relapsing-remitting multiple sclerosis (MS) present with a first clinical demyelinating event. In this double-blind, multicentre, randomised, phase 3 study we investigated the effect of oral cladribine on conversion to clinically definite MS in patients with a first clinical demyelinating event, when given at the same doses shown to be effective in relapsing-remitting MS.

METHODS: Between Oct 21, 2008, and Oct 11, 2010, we recruited patients aged 18-55 years, inclusive, from 160 hospitals, private clinics, or treatment centres in 34 countries. Eligible patients had a first clinical demyelinating event within 75 days before screening, at least two clinically silent lesions of at least 3 mm on a T2-weighted brain MRI scan, and an Expanded Disability Status Scale score of 5.0 or lower. Patients with a first clinical demyelinating event ≤75 days before screening were randomly assigned (1:1:1) to receive cladribine tablets at cumulative doses of 5.25 mg/kg or 3.5 mg/kg or placebo. Randomisation was done with a central web-based randomisation system and was stratified by geographic region. Masking was maintained using a two-physician model. The primary endpoint of this 96-week study was time to conversion to clinically definite MS according to the Poser criteria. This study is registered with ClinicalTrials.gov, number NCT00725985.

FINDINGS: Of 903 participants assessed for eligibility, 616 patients received cladribine 5.25 mg/kg (n=204), cladribine 3.5 mg/kg (n=206), or placebo (n=206). At trial termination on Oct 25, 2011, cladribine was associated with a risk reduction versus placebo for time to conversion to clinically definite MS (hazard ratio [HR] for 5.25 mg/kg=0.38, 95% CI 0.25-0.58, p<0.0001; HR for 3.5 mg/kg=0.33, 0.21-0.51, p<0.0001). Adverse events were reported in 165 (81%) patients in the cladribine 5.25 mg/kg group, 168 (82%) patients in the cladribine 3.5 mg/kg group, and 162 (79%) patients in the placebo group. We noted no increase in risk of adverse events with active treatment versus placebo apart from lymphopenia, which was a severe event in 10 (5%) patients in the 5.25 mg/kg group and four (2%) patients in the 3.5 mg/kg group.

INTERPRETATION: Both doses of cladribine significantly delayed MS diagnosis compared with placebo. The safety profile of cladribine was similar to that noted in a trial in patients with relapsing-remitting MS. Further research could clarify the potential effects of oral cladribine treatment in the early stages of MS.

Study 3: Beutler et al. The treatment of chronic progressive multiple sclerosis with cladribine. Proc Natl Acad Sci U S A. 1996 Feb 20;93(4):1716-20.


A 2-year, placebo-controlled, double-blind, crossover study was started in 1992 to evaluate cladribine, an immunosuppressive drug, in the treatment of chronic progressive multiple sclerosis. In the first year patients were given cladribine 0.10 mg/kg per day for 7 days as four monthly courses for a total of 2.8 mg/kg or placebo. During the second year patients treated with placebo during the first year were given i.v. infusions of 0.10 mg, 0.05 mg, and 0.05 mg of cladribine per kg of body weight per day for 7 consecutive days in three successive monthly courses, for a total dose of 1.4 mg/kg. Patients who had been treated previously with cladribine were crossed over to placebo. Analysis of the results revealed a favorable influence on the neurological performance scores, both in the Kurtze extended disability status and the Scripps neurological rating scale, and on MRI findings in patients treated with cladribine. In the first year the most striking finding was that while clinical deterioration continued in the placebo-treated patients, the condition of patients who received cladribine stabilized or even improved slightly. Toxicity and therapeutic response were dose-related.

Study 4: Sipe et al. Cladribine in treatment of chronic progressive multiple sclerosis. Lancet. 1994 Jul 2;344(8914):9-13.

Chronic progressive multiple sclerosis (MS) is a severely disabling demyelinating disease in which autoimmune processes seem to have a major role. The nucleoside drug cladribine is a potent lympholytic agent with few side-effects. We have studied its efficacy and safety in a randomised double-blind trial. 51 patients (48 entered as matched pairs) received four monthly courses of 0.7 mg/kg cladribine or placebo (saline) given through a surgically implanted central line. Neurologists with no knowledge of which medication the patient was receiving examined the patients monthly and noted two rating scale scores (Kurtzke and Scripps). Cerebrospinal fluid and brain magnetic resonance imaging (MRI) examinations were done at 6 and 12 months. Average neurological scores, demyelinated volumes on MRI, and concentrations of oligoclonal bands in cerebrospinal fluid were stable or improved in the patients receiving cladrabine but continued to deteriorate in patients on placebo. Mean paired (placebo minus matched cladribine) differences at 12 months relative to baseline were 1.0 (SE 0.4) for the Kurtzke scores, -13.9 (2.3) for the Scripps scores, 4.57 (1.17) mL for demyelinated volumes, and 7.3 (3.3) arbitrary units for concentrations of oligoclonal bands. Cladribine was generally well tolerated and clinically significant toxicity occurred in only 1 patient, in whom severe marrow suppression developed with complete recovery after several months. 1 patient died of newly acquired hepatitis B, an event unlikely to be related to cladribine. We conclude that the immunosuppressive drug cladribine influences favourably the course of chronic progressive MS.



CoI: multiple

High Powered MRI still misses things

Yao B, Hametner S, van Gelderen P, Merkle H, Chen C, Lassmann H, Duyn JH, Bagnato F 7 Tesla Magnetic Resonance Imaging to Detect Cortical Pathology in Multiple Sclerosis. PLoS One. 2014 Oct 10;9(10):e108863

BACKGROUND:Neocortical lesions (NLs) are an important pathological component of multiple sclerosis (MS), but their visualization by magnetic resonance imaging (MRI) remains challenging.
OBJECTIVES: We aimed at assessing the sensitivity of multi echo gradient echo (ME-GRE) T2*-weighted MRI at 7.0 Tesla in depicting NLs compared to myelin and iron staining.
METHODS: Samples from two MS patients were imaged post mortem using a whole body 7T MRI scanner with a 24-channel receive-only array. Isotropic 200 micron resolution images with varying T2* weighting were reconstructed from the ME-GRE data and converted into R2* maps. Immunohistochemical staining for myelin (proteolipid protein, PLP) and diaminobenzidine-enhanced Turnbull blue staining for iron were performed.
RESULTS: Prospective and retrospective sensitivities of MRI for the detection of NLs were 48% and 67% respectively. We observed MRI maps detecting only a small portion of 20 subpial NLs extending over large cortical areas on PLP stainings. No MRI signal changes suggestive of iron accumulation in NLs were observed. Conversely, R2* maps indicated iron loss in NLs, which was confirmed by histological quantification.
CONCLUSIONS: High-resolution post mortem imaging using R2* and magnitude maps permits detection of focal NLs. However, disclosing extensive subpial demyelination with MRI remains challenging.
Most clinical MRI scanners are about 1.5 tesla....maybe 3T is you push it. There are now high power scanners and in the UK high power MS Scanners are found in Nottingham and Oxford. However it is not high power enough and still misses a lot that conventional histology staining can see.This was even the case when this is done after death and so MRI in the living breathing person is even more difficult. Cortical damage is difficult to see even with 7 tesla