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#Post#: 1521--------------------------------------------------
Severe B-cell-mediated CNS disease secondary to alemtuzumab
DIR By: agate
Date: January 13, 2017, 2:11 pm
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A letter in the Correspondence section of Lancet Neurology
(January 13, 2017) by researchers at Oxford University and in
Germany discusses a couple of severe adverse events connected
with alemtuzumab therapy for MS:
[References and figures omitted]
--- Quote ---
> Correspondence
>
> Severe B-cell-mediated CNS disease secondary to alemtuzumab
therapy
>
> Aiden Haghikia, Calliope A Dendrou, Ruth Schneider, Thomas
Grüter, Thomas Postert, Mike Matzke, Heike Stephanik, Lars
Fugger, Ralf Gold
>
> Alemtuzumab is a pan-lymphocyte depleting anti-CD52 antibody,
and is approved as an escalation therapy for patients with
multiple sclerosis with active disease defined by clinical or
imaging features. In phase 3 clinical trials, the drug was more
effective than interferon beta-1a in reducing relapses and brain
volume loss. However, concerns have been raised due to its
numerous adverse effects.
>
> On Dec 17, 2015, a 41-year-old man was referred to our clinic
with an apparent acute deterioration of his disease. He had been
diagnosed with multiple sclerosis in 2004, after optic neuritis
of his right eye with typically disseminated T2 lesions
fulfilling diagnostic criteria, prolonged visual evoked
potentials (VEPs) and motor evoked potentials, and oligoclonal
band (OCB) positivity.
>
> Despite receiving several immunomodulatory therapies during
the following decade, including interferon beta-1a,
mitoxantrone, glatiramer acetate, and dimethyl fumarate, he had
several relapses and displayed continuing MRI activity. A first
course of alemtuzumab was given between July 27, 2015, and July
31, 2015 (figure A and E). On Dec 17, 2015, the patient
presented with severe dysarthria, marked cognitive symptoms,
apraxia, and left-dominant tetraparesis. MRI revealed 20 new
contrast-enhancing T1 lesions, most of which were
ring-enhancing. He was treated intravenously with 7000 mg
methylprednisolone. Due to lack of responsiveness to the
steroid, and as the presence of ring-enhancing lesions is known
to correlate with efficacy of plasma exchange, we performed
plasmapheresis and one cycle of immunoadsorption. This treatment
led to marked improvement of clinical symptoms and lesion
restitution by MRI. To stabilise the disease course, the
B-cell-depleting antibody rituximab was given. This treatment
resulted in a near absence of contrast-enhancing lesions and,
by Sept 27, 2016, the patient was almost free of the symptoms
that prompted admission 9 months earlier.
>
> A second patient, a 25-year-old woman, presented to our clinic
with tetraparesis predominantly affecting the legs in July 6,
2015. She had been diagnosed with multiple sclerosis in 2011 on
the basis of hypesthesia of the legs and left hand, two spinal
cord lesions (one of which was contrast-enhancing), 15 cerebral
T2 lesions fulfilling McDonald criteria, prolonged VEP, and OCB
positivity. She had received several different treatments since
diagnosis, including interferon beta-1a, natalizumab, and
fingolimod—switching between these drugs due to manifestation of
depression and a high anti-JC virus antibody index. Showing
continued disease activity while on fingolimod, she received an
initial course of alemtuzumab between Dec 1, 2014, and Dec 5,
2014. Upon admission to our clinic in July 6, 2015, she was
treated with 3000 mg methylprednisolone, leading to symptom
improvement but with residual deficits. On Sept 22, 2015, she
was admitted with newly occurring left-sided hemiataxia and
hemihypesthesia, and was treated with methylprednisolone and
plasma exchange. However, the symptoms re-occurred on Nov. 1,
2015 and were treated with a higher methylprednisolone dose. Due
to logistical difficulties, a follow-up MRI was not done until
April 18, 2016, but this MRI revealed several contrast-enhancing
lesions, including some with ring-enhancing characteristics
(data not shown). In view of her continued clinical and
paraclinical disease activity, the patient was treated with
rituximab on June 2, 2016, after which her symptoms improved,
and she has since stabilised as determined by clinical and MRI
measures.
>
> These two patients might represent the first recognised cases
of severely exacerbated CNS inflammation after alemtuzumab
therapy in multiple sclerosis. Our findings of marked
improvement of the patients after plasmapheresis and rituximab
therapy indicate a predominantly B-cell-driven pathology.
Alemtuzumab-dependent, B-cell-mediated autoimmune diseases have
been identified for several tissues other than the CNS. The
exacerbated inflammation seen in our patients is consistent with
the time frame in which B-cell repopulation and peripheral
expansion occur following alemtuzumab treatment. Thus, it
remains to be determined if the disease observed in these two
patients after treatment is due to worsening of multiple
sclerosis or to the development of secondary CNS-directed
autoimmunity.
>
> Notably, a rare genetic or infectious aetiology was not found,
as evaluated by whole genome analyses (data not shown),
suggesting that further cases might be identified, and that
apparent relapses after alemtuzumab treatment should be promptly
evaluated by MRI for the presence of ring-enhancing lesions. A
specific rescue therapy comprising plasma exchange with
consecutive B-cell depletion can then be initiated to help
prevent irreversible disability.
>
> _____________________
>
> AH received speaker's fees from Bayer Healthcare and Biogen
Idec, and limited research grants from Genzyme. CAD, RS, TG, TP,
MM, HS, and LF declare no competing interests. RG received
speaker's fees and board honoraria from Baxter, Bayer Schering,
Biogen Idec, Chugai, CLB Behring, Genzyme, Merck Serono,
Novartis, Talecris, TEVA, and Wyeth. RG's department received
grant support from Bayer Schering, BiogenIdec, Genzyme, Merck
Serono, Novartis, and TEVA.
--- End Quote ---
The entire letter with references and figures can be seen here
HTML http://www.thelancet.com/journals/laneur/article/PIIS1474-4422(16)30382-9/fulltext?elsca1=etoc.
#Post#: 1530--------------------------------------------------
Re: Severe B-cell-mediated CNS disease secondary to alemtuzumab
DIR By: agate
Date: January 19, 2017, 8:23 pm
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An article about this appears in Medical News Today, January 19,
2017:
--- Quote ---
> Researchers discover severe side effects of approved multiple
sclerosis medication
>
> The multiple sclerosis (MS) therapy alemtuzumab can trigger
severe, unpredictable side effects. This was the finding by a
team led by Prof Dr Aiden Haghikia and Prof Dr Ralf Gold from
the Department of Neurology of the Ruhr-Universität Bochum at
St. Josef's Hospital. In the journal Lancet Neurology, the
scientists report on two patients for whom the infusion of
alemtuzumab significantly worsened symptoms. The team also
describes a treatment that successfully curbed the harmful side
effects.
>
> "This therapeutic algorithm could help MS patients around the
world who develop similar side effects under alemtuzumab," says
Haghikia.
>
> How alemtuzumab works
>
> Alemtuzumab is a therapeutic antibody that docks to the
protein CD52 on the surface of certain immunocytes, mainly T and
B lymphocytes, leading to the depletion of almost all
lymphocytes.
>
> It was already known from the approval studies that a quarter
of the treated patients display mostly minor side effects,
called secondary autoimmune processes: immunocytes turn against
cells produced naturally in the body, predominantly in the
thyroid gland; but the kidneys and platelets can also be
affected.
>
>
> A new inflammation mode
>
> The two patients described in the Lancet Neurology study
received alemtuzumab because they had highly active MS, i.e.
despite numerous previous treatments, they suffered from severe
illness relapses with inflammation in the central nervous
system. Six months after the treatment, these symptoms had
worsened significantly. Using MRI, the researchers discovered a
kind of new inflammation mode: they found vast areas in the
brain with numerous ring enhancing lesion. The patients had not
displayed this pattern in their previous medical history.
>
> It is currently unclear whether the observed adverse events
represent increased MS activity or an independent secondary
autoimmune process.
>
> Side effects curbed
>
> In both cases, the neurologists were able to curb the side
effects, and the observed ring-shaped deposits in the brain
receded. Even a year after the treatment, the patients were
still in a stable condition. Besides a blood plasma exchange,
they treated both with the antibody rituximab that is directed
against B lymphocytes. The researchers suspect that precisely
these immunocytes were responsible for the observed side effect.
>
> The authors propose that the measures they applied could also
benefit other patients who develop similar adverse events under
alemtuzumab.
>
> ...
>
> Cooperation partners
>
> During the work, the Bochum-based team cooperated with the
Oxford Centre for Neuroinflammation at the University of Oxford,
with the Neurological Clinic in the St. Vincenz Hospital in
Paderborn and the University of Magdeburg.
--- End Quote ---
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