Published Ahead of Print on January 19, 2018 as 10.1212/WNL.0000000000004950
ARTICLE

Activation of disease during therapy with
alemtuzumab in 3 patients with multiple sclerosis
Thomas Wehrum, MD,* Lena-Alexandra Beume, MD,* Oliver Stich, MD, Irina Mader, MD,
Mathias Mäurer, MD, Adam Czaplinski, MD, Cornelius Weiller, MD, and Sebastian Rauer, MD

®

Neurology 2018;90:e1-e5. doi:10.1212/WNL.0000000000004950

Abstract
Objective
To report 3 patients with multiple sclerosis showing severe activation of disease during immunotherapy with alemtuzumab.
Methods
Retrospective case series.

Correspondence
Dr. Wehrum
thomas.wehrum@
uniklinik-freiburg.de

RELATED ARTICLE

Editorial

Defining response profiles
after alemtuzumab Rare
paradoxical disease
exacerbation
Page 309

Results
Patient 1, a 21-year-old woman, developed severe cognitive impairment, sight deterioration,
severe gait ataxia, urinary retention, and extensive progression of cerebral lesion load, including
new lesions that exhibited gadolinium ring enhancement and dominance of CD19/20-positive
B lymphocytes, 6 months after induction of alemtuzumab. Patient 2, a 28-year-old man,
developed left-sided hemihypesthesia and ;60 new cerebral and spinal lesions including
lesions with gadolinium ring enhancement 6 months after induction of alemtuzumab. Patient 3,
a 37-year-old woman, developed ataxia and numbness of the left thigh, 16 new gadoliniumpositive supratentorial lesions, and partly ring-enhancing and dominance of CD19/20-positive
B lymphocytes 6 months after induction of alemtuzumab.
Conclusion
This is a case series reporting severe activation of disease during immunotherapy with alemtuzumab. All patients showed onset of symptoms 6 months after induction of alemtuzumab,
strikingly similar MRI lesion morphology, and unexpected high total B cell count, which may
suggest a B-cell-mediated activation of disease. Whether this is due to different rates of B- and
T cell repopulation has to be the subject of further research. Moreover, further effects on the
interactions between the adaptive and innate immunity as well as between B and T cell lineages
might explain the observed disease activation.

*These authors contributed equally to this work.
From the Departments of Neurology and Neuroscience (T.W., L.-A.B., O.S., C.W., S.R.) and Neuroradiology (I.M.), Medical Center–University of Freiburg, Faculty of Medicine, University
of Freiburg; Department of Neurology (M.M.), Stiftung Juliusspital Würzburg, Germany; and Neurozentrum Bellevue (A.C.), Zürich, Switzerland.
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

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Glossary
MS = multiple sclerosis; RRMS = relapsing-remitting multiple sclerosis.

Alemtuzumab is a humanized monoclonal antibody that targets
the CD52 antigen on the surface of most lymphocyte lineages,
leading to rapid and prolonged lymphocyte depletion. It is administered over 2 IV treatment courses at a 12-month interval1
and is currently considered to be one of the most effective
immunotherapeutics for relapsing-remitting multiple sclerosis
(RRMS).2 Treatment with alemtuzumab can be associated with
serious side effects, among them an increased risk of developing
autoimmune disorders.1 Two recent articles report a total
of 11 cases of disease activation following treatment with
alemtuzumab.3,4 We present 3 additional cases with strikingly
similar features (i.e., time of onset of disease activation, lesion
morphology, and response to B-cell-depleting therapy).

Methods
We present a retrospective case series of 3 patients with
RRMS showing severe activation of disease during immunotherapy with alemtuzumab.

Results
Our patients had a long history of RRMS (7–15 years) with
multiple relapses and had previously received treatment with
different disease-modifying drugs. Details on each patient are
given in the table. The decision to start the treatment with
alemtuzumab was made after the previous treatments either
failed or had to be discontinued because of side effects.
Baseline MRI (1–4 weeks before first dose) showed multiple
sclerosis (MS)–typical lesions (Magnetic Resonance Imaging
in Multiple Sclerosis [MAGNIMS] criteria) in the deep and
peripheral white matter (;50 including 4 gadoliniumenhancing lesions in patient 1; ;30 and ;40 without gadolinium enhancement in patients 2 and 3), 2 lesions in
thalamus and midbrain in patient 1, and 3 and ;10 lesions
(2 with gadolinium enhancement) in the cervical and thoracic
medulla in patients 1 and 2. The optic nerves were not affected. Strikingly, the symptoms of all 3 patients deteriorated
6 months after the first course of alemtuzumab. The Expanded Disability Status Scale increased by 0.5–6.0 points.

Table Characteristics of the 3 presented cases
Patient 1

Patient 2

Patient 3

Age, y/sex

21/F

28/M

37/F

Diagnosis of
RRMS, y

2008

2011

2010

Case history

Multiple relapses with cognitive impairment,
sight deterioration, gait ataxia, and severe
fatigue since 2008

Multiple relapses with spinal para- and
left-sided hemihypesthesia, fine motor
impairment, and optic neuritis since
2003

2 Relapses in 2010 with ataxia and
hypesthesia of the left thigh

Medication
history (reasons
for change of
medication)

4 Months interferon-β (elevated liver enzymes),
6 months glatiramer acetate (treatment
failure), 5 years natalizumab (seroconversion to
anti-JCV+), fingolimod (allergic reaction on first
dose), 6 months dimethyl fumarate (treatment
failure), alemtuzumab first dose October 2014

3 Years fingolimod (treatment failure),
1 year dimethyl fumarate (treatment
failure), alemtuzumab first dose March
2015

3 Years natalizumab (seroconversion to
anti-JCV+), 1 year fingolimod (treatment
failure), alemtuzumab first dose July
2014

EDSS before
alemtuzumab

1.0

1.5

2.0

Symptom onset

6 Months after alemtuzumab

6 Months after alemtuzumab

6 Months after alemtuzumab

Clinical
presentation
(initial
symptoms)

Cognitive impairment, sight deterioration, gait
ataxia, and urinary retention (EDSS 7.0)

Left-sided hemihypesthesia (EDSS 2.0)

Ataxia, numbness left thigh (EDSS 2.5)

Lymphocyte
phenotyping

Dominance of CD19/20-positive B lymphocytes

Not performed

Dominance of CD19/20-positive B
lymphocytes

Therapy

Plasmapheresis for 7 days and repeated highdose methylprednisolone treatment (1,000 mg/
day), induction of rituximab (375 mg/m2 BSA)

High-dose methylprednisolone
treatment (1,000 mg/day), induction of
rituximab (375 mg/m2 BSA)

High-dose methylprednisolone
treatment (1,000 mg/day), induction of
rituximab (375 mg/m2 BSA)

Course after
rituximab

No new relapses (clinically or on MRI) during 18
months follow-up (EDSS 1.0)

No new relapses (clinically or on MRI)
during 12 months follow-up (EDSS 1.5)

No new relapses (clinically or on MRI)
during 12 months follow-up (EDSS 2.0)

Abbreviations: BSA = body surface area; EDSS = Expanded Disability Status Scale; JCV = JC virus; RRMS = relapsing-remitting multiple sclerosis.

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Cerebral MRI showed extensive progression of lesion load
(figure 1): 15, ;60, and 16 new lesions in the deep and
peripheral white matter of both hemispheres, including 14,
;20, and 2 with gadolinium enhancement (some solid
appearing, some with ring enhancement) in patients 1–3.
New spinal lesions (;30) were only present in patient 2. The
optic nerves were not affected. CSF analysis ruled out JC virus
and other viral, bacterial, parasitic, and fungal infections as
well as lymphoma; no autoantibodies (e.g., thyroid) were
detected in the patients. Furthermore, serum lymphocyte
phenotyping revealed dominance of CD19/20-positive
B lymphocytes in 2 cases. All patients improved clinically
after plasmapheresis (7 days) or treatment with high-dose
methylprednisolone. The disease activity stabilized (clinically
and on MRI) under B-cell-depleting treatment with rituximab, which was initiated 1 to 2 months after deterioration

and resulted in sufficient B cell depletion. No relapses were
reported after a follow-up period of at least 1 year.

Discussion
The authors of one recent case series in The Lancet Neurology3
presenting also with rapid clinical deterioration 6 months after
the initial course of alemtuzumab hypothesized a B-cellmediated pathogenesis of disease activation. Due to the
striking similarity of our reported cases, we discuss the facts
favoring this hypothesis but also present alternative explanations. First, the pharmacodynamics of alemtuzumab support
a B-cell-mediated pathogenesis in our cases: alemtuzumab
leads to a CD52-selective depletion of B and T lymphocytes.5
Reconstitution of T cells is slow, with CD4+ T cells and
CD8+ T cells reaching 9% and 13% of baseline levels after 3

Figure 1 Cerebral MRI before and after alemtuzumab

Images before and after alemtuzumab are provided for
cases 1–3 (A–C). Fluid-attenuated inversion recovery
(FLAIR) images (A.a, B.a, C.a) were obtained directly
before the first dose of alemtuzumab. FLAIR images (A.
b, B.b, C.b) were obtained 6 months after the first dose,
when a relapse occurred, and show massive progression of lesion load (white arrows) including gadolinium ring enhancement (A.c, B.c, C.c).

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months and 36% and 71% after 12 months. Repopulation of
B lymphocytes, on the other hand, usually occurs more rapidly, with a return of the total B cell count to normal levels
after 3 months and to above normal values (165% of baseline)
after 12 months.6 In one of our patients, details regarding
the lymphocyte count were available at different points in
time. In line with the literature,6 CD4+ T cells and CD8+
T cells were slow to reconstitute, reaching 23% and 19% by
month 6. However, the total B cell count (baseline 0.28 ×
109/L) had risen to 0.72*109/L (257%) after 6 months, and
accordingly was more than twice as high as the B cell count
reported in the literature6 by month 6 (figure 2). The
reconstituting B cell pool is initially dominated by mature
naive cells,6 possibly responsible for the B-cell-mediated autoimmunity in alemtuzumab treatment (e.g., idiopathic
thrombocytopenic purpura, Goodpasture syndrome, thyroid
disease).1 Yet it is currently not understood why B-cellmediated autoimmunity does not lead to an exacerbation of
MS. B cell counts at the time of disease activation were not
provided in the 2 other recent case series on disease activity
during immunotherapy with alemtuzumab.3,4 However, in
one series, the authors state that in 4 patients lymphocytes
reconstituted more rapidly than expected (3 months),4 which
may be a sign of overshooting B cell response. Also, the
gadolinium ring-enhancing cerebral lesions, which are seen in
other B-cell-mediated diseases involving the CNS, may be
further evidence of a B-cell-mediated pathogenesis7 and were
also reported or depicted in the case series.3,4 However, ringenhancing lesions may not be exclusive to B-cell-mediated
disease8; therefore their value as a biomarker may be limited.
Finally, clinical observations support a B-cell-mediated pathogenesis. In one case, plasmapheresis led to a significant reduction of symptoms in the acute phase, which suggests that
humoral factors may have played a crucial role in the pathophysiology; interestingly, plasmapheresis in the acute phase of
deterioration was also applied in 1 of the 2 cases published in

The Lancet Neurology and led to marked clinical improvement.3 In all cases, B-cell-depleting therapy with rituximab
was initiated and stabilized the course of the disease, which
was also true for 2 patients in 1 of the 2 other case series.3
However, it remains unclear if a further early alemtuzumab
course would have been another possible treatment option, as
it also results in B cell depletion and according to the literature
some patients need more than 2 courses to achieve disease
stability.9
Although these observations may support a B-cell-mediated
pathogenesis, disease activation could also be explained by
a compartment problem, seeing that all patients had received
fingolimod in the past. A substantial number of lymphocytes
could remain hidden from the intravascular therapeutic effects
of alemtuzumab as a result of selective lymphoid sequestration and may later egress from lymph nodes and initiate
rebound inflammatory activity, as suggested by a case series
on disease activation after switching from fingolimod to
alemtuzumab.4 Interestingly, all of our patients received
fingolimod prior to alemtuzumab, although only one
patient switched directly from fingolimod to alemtuzumab
(patient 3) and treatment with fingolimod was stopped on
day 1 in patient 1. Similarly, 10 out of the 11 published cases3,4
had also received fingolimod prior to alemtuzumab, undermining this hypothesis.
Also, alemtuzumab has been shown to exacerbate neuromyelitis optica spectrum disorder in single patients. This
finding was interpreted as indicative for a suppression of the
adaptive immunity and possible activation of monocytes by
alemtuzumab, reflecting on the fact that CD52 is also
expressed at lower levels on monocytes as well as natural killer
cells and macrophages.10 Alemtuzumab might thus have further effects on the interactions between the adaptive and innate immunity as well as interaction between B and T cell
lineages than known so far, which might explain the observed
disease activation.

Figure 2 B cell count during alemtuzumab treatment

When discussing treatment options with the patient, practitioners should consider not only nonresponse, but also the
potential reactivation of disease treated with alemtuzumab.
Identifying patients at risk of disease activation using reliable
biomarkers (i.e., lymphocyte phenotyping and specific MRI
features) remains a major challenge. Finally, the pathogenesis
of disease activation after alemtuzumab needs further study,
including identification of specific targets of treatment in this
subgroup of patients at risk of disease activation.

B cell count at baseline (before alemtuzumab), at month 6 (onset of disease
activity), at month 7 (after first course of rituximab), and at month 11 (during
therapy with rituximab) in patient 2 (dark, dots); B cell count after 6 months
(onset of disease activity) in patient 3 (green, square); and B cell count (±SD)
at baseline and months 3, 6, 9, and 12 as reported in the literature6 (red,
triangle).

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Author contributions
Each author contributed significantly to the submitted work:
Drs. Wehrum, Beume, Stich, Weiller, and Rauer treated the
case patient at the Freiburg center, conceived the study, analyzed the data, and drafted the manuscript. Dr. Mader evaluated the MRI, analyzed the data, and revised the manuscript.
Dr. Mäurer treated the case patient at the Würzburg center,
conceived the study, analyzed the data, and revised the
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manuscript. Dr. Czaplinski treated the case patient at the
Zürich center, conceived the study, analyzed the data, and
revised the manuscript.

GmbH, Biogen Idec, Genzyme, Merck Serono, Novartis,
Sanofi-Aventis, and Teva. Go to Neurology.org/N for full
disclosures.

Acknowledgment
The authors thank Dr. Konrad Whittaker for proofreading the
final version of this manuscript.

Received April 8, 2017. Accepted in final form October 18, 2017.

Study funding
No targeted funding reported.

References
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2.

3.

Disclosure
T. Wehrum and L. Beume report no disclosures relevant to
the manuscript. O. Stich reports receiving consulting and
lecture fees and grant and research support from Baxter, Bayer
Vital GmbH, Biogen Idec, Genzyme, Merck Serono, Novartis,
Sanofi-Aventis, and Teva. I. Mader received a lecture fee from
UCB Pharma, Monheim, Germany. M. Mäurer reports receiving consulting and lecture fees and grant and research
support from Baxter, Bayer Vital GmbH, Biogen Idec, Genzyme, Merck Serono, Novartis, Sanofi-Aventis, and Teva. A.
Czaplinski and C. Weiller report no disclosures relevant to the
manuscript. S. Rauer reports receiving consulting and lecture
fees and grant and research support from Baxter, Bayer Vital

Neurology.org/N

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