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Information sheet
Alemtuzumab Infusion for aggressive relapsing MS
Indications.
Patients who have shown break-through disease activity on natalizumab ( two or
more relapses and evidence of increased activity on MRI scanning - new T2 lesions
and/or Gadolinium enhancing lesions). Such patients may or may not have
neutralizing antibodies to natalizumab.
Alemtuzumab binds to CD52, a non-modulating antigen that is present on the
surface of essentially all B and T lymphocytes, a majority of monocytes,
macrophages, and NK cells, and a subpopulation of granulocytes, causing
complement mediated lysis. CD52 expression is not present on erythrocytes or
hematopoetic stem cells. Following a single infusion of 60mgs of alemtuzumab there
is a rapid and prolonged depletion of CD4 T-cells lasting a median of 61 months and
of CD8 T-cells for 30 months. B lymphocytes initially decline mildly but increase to
exceed pre-treatment levels by 124% at 27 months. Overall the effect is to reduce Tcell mediated immune processes (such as occurs in MS), which may make patients
more susceptible to atypical infections (see below).
Patients should be fully informed of the side-effects seen with this drug and risks of
therapy before commencing treatment
Protocol (administered as an in-patient)
First treatment
Baseline and daily full blood count, LFTs, U+E.
Baseline MRI Brain (at least within 3 months of starting treatment).
Baseline Chest X-ray.
Solumedrone (methylprednisolone) 1000mgs intravenously concurrently with
alemtuzumab for first three days of treatment,
Alemtuzumab 12 mgs intravenously daily for five days
Subsequent yearly treatment for a total of two to three courses.
Follow-up: Clinical: 3 monthly post-treatment and six monthly thereafter.
Monitoring:
Monthly full blood count,
Quarterly thyroid function tests and measurement of anti-thyroperoxidase and TSH
receptor antibodies.
Yearly testing consisted of antinuclear, extractable nuclear and anti glomerular
basement antibodies.
SIDE-EFECTS and ADVERSE REACTIONS
Infusion side-effects (due to cytokine release)
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Rashes are common, seen in 44% of the series of Hirst et al.,2008 usually occuring in
the infusion period. Headaches during infusion, chest tightness, wheeze, pyrexia
with rigors. Abnormal liver function tests.
Transient worsening of pre-existing neurological deficits due to a cytokine release
effect, usually prevented by the concomitant infusion of steroids in protocol.
Short term adverse effects
Infective episodes.: urinary and chest infections, mouth ulcers, thrush, recurrence
of digital warts.
Thrombocytopenia
Longer term side-effects
Auto-immune disorders
The autoimmune diseases observed after the administration of alemtuzumab are
predominantly antibody-mediated, and they respond to B-cell depletion.
Autoreactive B cells can function without T-cell help; thus, the emergence of
autoreactive B cells during the reconsititution of lymphocytes may cause
autoimmunity after treatment with alemtuzumab.
Hyperthroidism (increased activity of the throid gland). Most striking is a report of
a 33% incidence of Graves disease with raised TSH receptor antibodies developing
at a mean of 18 months post treatment in a cohort of 27 patients but other
subsequent studies have shown a much lower frequency of thyroid abnormalities
There is one report of renal failure due to anti-glomerular basement antibodies,
requiring renal transplantation in a woman who was given 100 mgs of alemtuzumab
for her MS.
Idiopathic Thrombocytopenic Purpura (ITP): Antibody mediated depletion of
circulating platelets causing a bleeding disorder which can be life threatening.
However this is rare, 3/334 patients in one study, and the prevalence of low platelet
counts in other studies is low and the counts were only mildly reduced
Regular monthly monitoring of platelet counts are needed.
Other immunological changes include changes in auto-antibodies unaccompanied
by symptoms.
Very long term effects
Alemtuzumab causes long term lymphocyte suppression. The number of MS
patients treated with this drug and the duration of follow-up in MS patients has
been relatively short. The risks for long term effects in relation to
immunosuppression such as malignancy, opportunistic infections or progressive
multifocal leucoencephalopathy are unknown.
References:
Clatworthy MR, Wallin EF, Jayne DR. Anti-glomerular basement membrane disease
after alemtuzumab. N Engl J Med. 2008;359:768-9.
Menge T, Weber MS, Hemmer B, Kieseier BC, von Büdingen HC, Warnke C, Zamvil
SS, Boster A, Khan O, Hartung HP, Stüve O. Disease-modifying agents for multiple
sclerosis: recent advances and future prospects. Drugs 2008;68:2445-68.
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CAMMS223 Trial Investigators, Coles AJ, Compston DA, Selmaj KW, Lake SL, Moran
S, Margolin DH, Norris K, Tandon PK. Alemtuzumab vs. interferon beta-1a in early
multiple sclerosis. N Engl J Med. 2008;359:1786-801.
Buttmann M, Rieckmann P. Treating multiple sclerosis with monoclonal antibodies.
Expert Rev Neurother. 2008;8:433-55.
Hirst CL, Pace A, Pickersgill TP, Jones R, McLean BN, Zajicek JP, Scolding NJ,
Robertson NP. Campath 1-H treatment in patients with aggressive relapsing remitting
multiple sclerosis. J Neurol 2008;255:231-8.
Jones JL, Coles AJ. Campath-1H treatment of multiple sclerosis. Neurodegener Dis.
2008;5:27-31. Review.
Muraro PA, Bielekova B. Emerging therapies for multiple sclerosis. Neurotherapeutics.
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Coles AJ, Cox A, Le Page E, Jones J, Trip SA, Deans J, Seaman S, Miller DH, Hale G,
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Coles AJ, Wing MG, Molyneux P, Paolillo A, Davie CM, Hale G, Miller D, Waldmann
H, Compston A. Monoclonal antibody treatment exposes three mechanisms
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