High-Risk PML Patients Switching from Natalizumab to Alemtuzumab: an Observational Study
High-Risk PML Patients Switching from Natalizumab to Alemtuzumab: an Observational Study
Francesca Sperli . Antonio Bertolotto 0
0 S. Malucchi (&) M. Capobianco M. Lo Re M. Malentacchi A. di Sapio M. Matta F. Sperli A. Bertolotto University Hospital San Luigi Gonzaga, SCDO Neurologia 2-Regional Multiple Sclerosis Center , Regione Gonzole 10, 10043 Orbassano, TO , Italy
Introduction: The choice of therapy in patients withdrawing from natalizumab treatment is still an open question and neurologists need strategies to manage this group of patients. The aim of this study is to evaluate if alemtuzumab is able to control the disease when used in patient who have stopped natalizumab. Methods: 16 patients stopped natalizumab treatment after a median number of 20 infusions (range 12-114); all the patients were responders to natalizumab (neither clinical nor radiological activity during natalizumab therapy) and the reason for stopping was the risk of PML for all of them. Patients were switched to alemtuzumab after a median wash-out period of 70 days (range 41-99 days); patients underwent brain MRI every three
Alemtuzumab; Multiple Sclerosis; Natalizumab; PML
months during natalizumab treatment and
then just before starting alemtuzumab in order
to exclude signs suggestive of PML; then,
contrast-enhanced brain MRI was planned 6
and 12 months after alemtuzumab infusion.
Results: At present, 8 out of 16 patients have a
follow-up [6 months and 2 out of 8 reached
1-year follow-up; 5 have a follow-up of
3–6 months and 3 have a follow-up \3 months.
Brain MRI at 6 months after alemtuzumab is
available for 8 out of 16 patients and in all of
them, neither signs of disease activity nor new
lesions are present; in 2 out of 8 patients, brain
MRI at 12 months is also available, showing no
sign of disease activity. Clinical evaluation
performed at 6 and at 12 months (when
available) showed stability, in particular neither
relapses nor increase in EDSS were observed.
Conclusions: Alemtuzumab was able to control
the disease course in patients who stopped
natalizumab; of course, as this is a
single-centre study and the number of patients
is small, these findings are very preliminary and
need further confirmation.
Alemtuzumab was approved by the EMA in
2013 for active relapsing-remitting multiple
sclerosis (RRMS) patients. It is considered an
induction treatment, since it causes lymphocyte
depletion followed by cellular repopulation .
For this reason, the ideal candidate is an active
patient in an early phase of the disease. In the
real world, alemtuzumab is also used as a ‘‘third
line’’ therapy, when many prior treatments
At present, neurologists also have other
highly active drugs , but there are no
head-to-head studies directly comparing the
efficacy of alemtuzumab with other efficacious
therapies such as natalizumab or fingolimod.
Therefore, the decision to choose the most
suitable medication largely depends on other
factors, such as the potential side effects.
Patients with long-term natalizumab
exposure and anti-JCV seropositivity who stop
natalizumab for the risk of PML are a category of
patients for whom no specific therapeutic
strategy has been established. For this
category, management is largely customized
for the individual patient and alemtuzumab is
an option, although no published data are
In this study we present our data showing that
alemtuzumab is able to control disease course in a
group of 16 patients previously treated with
natalizumab and with an aggressive disease
course before starting natalizumab.
This is an observational study. The study used a
sample of 16 RRMS patients with a median EDSS
of 2.0 (8 female and 8 male) who stopped
natalizumab treatment after a median number
of 20 infusions (range 12–114). The
demographic and clinical characteristics of
patients are shown in Table 1.
Inclusion criteria were: age C18 years,
treatment with natalizumab for at least one
year, positive JCV index, no evidence of clinical
and radiological activity in the last 6 months of
natalizumab treatment, contrast-enhancement
brain MRI performed just before alemtuzumab
administration without any sign of PML, and an
aggressive disease course before natalizumab
therapy. Exclusion criteria were: pregnancy or
breastfeeding, clinically significant or unstable
medical or surgical conditions able to preclude
safe and complete study participation.
The decision to stop natalizumab was taken
after a consultation between the neurologist
and patient, in which the risks and benefits of
continuing or interrupting natalizumab were
explained. For all the patients, the reason for
interrupting natalizumab was the high risk of
PML. The switch to alemtuzumab was planned
after a wash-out period of 2 months.
Patients underwent brain MRIs every three
months during the natalizumab treatment and
just before starting alemtuzumab in order to
exclude any sign suggestive of PML. A
contrast-enhancement brain MRI was then
undertaken 6 and 12 months after the
alemtuzumab infusion, in order to evaluate signs
of disease reactivation (Fig. 1: study design). Brain
MRIs were performed with the same 1.5 Tesla
(T) scanner using the same protocol in each
patient: the protocol included axial T2-weighted
scans, coronal flair-weighted scans, DWI
sequences and post-contrast T1-weighted scans.
Compliance with Ethics Guidelines
This article does not contain any new studies
with human or animal subjects performed by
any of the authors.
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IS immunosuppressive therapy
Fig. 1 Study design
The median wash-out period from the last
natalizumab infusion to starting alemtuzumab
was 70 days (range 41–99): in this period, no
relapse was observed. Furthermore, brain MRI
performed just before starting alemtuzumab
was unchanged compared to the previous one.
The first patient was treated with
alemtuzumab on September 2015 and the last
one on October 2016 and the range of follow-up
is 7 days–12.6 months; at present, 8 out of 16
patients have a follow-up [6 months and 2 out
of 8 reached 1-year follow-up; 5 have a
follow-up of 3–6 months and 3 have a
follow-up \3 months.
The brain MRI undertaken 6 months after
alemtuzumab is available for 8 out of 16 patients
and in all of them, neither signs of disease
activity nor new lesions are present; in 2 out of
8 patients, the brain MRI at 12 months is also
available, showing no sign of disease activity.
Clinical evaluation performed at 6 months
and at 12 months showed stability, in
particular, neither relapses nor increase in
EDSS were observed.
The therapeutic landscape of multiple sclerosis
(MS) is dramatically changing and becoming
more and more complex for many reasons: (1)
very early treatment is highly recommended
]; (2) the number of therapeutic options has
increased and the therapeutic algorithm is not
fully established ; (3) very effective drugs are
available; (4) tolerance toward the disease
activity has been reduced, with the
introduction of the criteria of no evidence of
disease activity (NEDA) ; (5) neurologists
have to face not only disease control but also
the potential side-effects of new drugs.
Natalizumab represents an example of this
changing scenario; it is a very effective drug,
used to treat patients with an aggressive disease.
The positive impact of the drug is clearly
evident on many parameters: annualized
relapse rate, EDSS, number of new lesions or
enhancing lesions, quality of life [
limitations are the risk of PML and the
therapeutic management of patients after drug
interruption. To address the former limitation,
neurologists can now stratify patients’ risk of
PML according to the JCV index, previous
immunosuppressive therapy and duration of
natalizumab exposure [
To address the second limitation, it is
well-known that disease recurs after
withdrawing natalizumab [
] and in order
to limit this problem, the literature
recommends to start a new treatment very
early after natalizumab interruption [
However, which treatment is the most
suitable is still a matter of great debate, as no
guidelines exist about patients’ therapeutic
management. Therefore, the decision on how
to treat and when to start treatment mainly
derives from the neurologist’s own experience
and the characteristics of the individual MS
Many studies about switching from
natalizumab to other DMDs (interferons,
glatiramer acetate, methylprednisolone) have
been published showing disease reactivation
]. Studies about switching from
natalizumab to fingolimod showed a lower risk
of recurrence of disease activity and that a
shorter wash-out period (\12 weeks) predicted a
minor risk of disease reactivation [
A recent study by Alping et al. [
a population of 256 patients who shifted from
natalizumab to fingolimod (55% of cases) or to
rituximab (45% of cases) due to the risk of PML.
The study shows that within 1.5 year from
natalizumab cessation, 1.8% of rituximab
patients experienced a clinical relapse versus
17.6% of fingolimod-treated patients and that
1.4% of the rituximab group had
contrast-enhancing lesions versus 24.2% of the
We observed a smaller population of 10
patients who shifted to rituximab after a
wash-out period of 2 months since
interrupting natalizumab. We observed no
clinical relapses nor contrast-enhancing or
new lesions in any of the patients during the
1-year follow-up period [
The use of rituximab in patients with high
risk of PML can be criticized; however, in
rituximab-treated patients, PML was only
observed in patients previously treated with
immunosuppressive therapies for
lymphoproliferative disorders, systemic lupus
erythematosus or rheumatoid arthritis, and in
no MS-affected patient [
In this study, we used alemtuzumab after
natalizumab interruption. Patients in our study
share some common characteristics: a very
aggressive disease course before starting
natalizumab, a high risk of PML, a
stable phase of the disease during the
natalizumab therapy and a very high quality
of life. We had to take into consideration the
need to treat a very severe disease and the safety
profile of the drug to which we were switching,
as well as to balance the risk of using aggressive
drugs with the risk of a recurrence of disease
activity if using less aggressive treatments.
Alemtuzumab is a very effective drug used
successfully in patients with highly aggressive
] and the main side effect is the
risk of autoimmunity . Based on these data,
we decided to use alemtuzumab and to start it 2
months after the last natalizumab infusion.
It is known that PML can occur a few months
after withdrawing natalizumab, and that
carryover PML can develop when patients
have stopped natalizumab and already started
a new DMT [
]. A recent study by Raisch et al.
] reports cases of PML associated with
biological therapies; a case of PML during
alemtuzumab has been reported in a patient
previously treated with natalizumab. As far as
we know, in this patient, the symptoms of PML
were already present when alemtuzumab was
started but they were considered symptoms a
As alemtuzumab induces long-term
immunosuppression with delayed immune
reconstitution, if carryover PML develops after
the alemtuzumab treatment, JCV cannot be
counteracted by T cells. For this reason, some
authors suggest the use of alemtuzumab after a
bridging period of 6–12 months of oral
treatment with fingolimod, dymethylfumarate
or teriflunomide and to test JCV PCR in the CSF
of seropositive patients before switching to
]. Others recommend
delaying the start of alemtuzumab after a
wash-out period from natalizumab of
6 months [
In our opinion, switching patients with
aggressive disease to lower-efficacy drugs after
interrupting natalizumab exposes them to too
high risk of disease reactivation, as well as
delaying alemtuzumab therapy by 6 months
after the interruption of natalizumab.
Furthermore, switching to fingolimod does not
exclude the risk of carryover PML [
addition to exposing patients with aggressive
MS to the risk of disease reoccurrence.
Regarding the detection of JCV PCR in CSF, it
is known that a negative CSF does not exclude
PML, and that in the early stage of PML, JCV
may not be evident in CSF because the viral load
is below the sensitivity of the virus assay.
Furthermore, if radiological findings suggest
PML, CSF may be negative [
]. In our study,
we choose not to perform JCV PCR detection in
the CSF before switching to alemtuzumab
because of the risk of false negative. However,
to minimize the risk of carryover PML, a strict
radiological monitoring was planned through
brain MRI performed every 3 months during
natalizumab and just before starting
alemtuzumab. Obviously, patients must be
well-informed about risks and advantages
derived from interrupting natalizumab and
switching to alemtuzumab, and the decision
to stop natalizumab and start alemtuzumab
must be completely shared between the
patient and neurologist.
Our study is ongoing and the results are only
partial, but initial data are very promising as no
patient had radiological signs or clinical
symptoms of disease reactivation/progression,
no patient experienced severe side effects and
no patient developed PML.
Even though our population is small, no
other data about the use of alemtuzumab after
natalizumab have been described in the
literature until now, except for a poster
], where the authors describe
13 patients shifted from natalizumab to
alemtuzumab because of inadequate disease
control. We think it is important to share our
experience as the process of decision-making in
therapeutic choices is very complex and data
from ‘‘real world’’ can increase experience and
knowledge of the whole neurological
No funding or sponsorship was received for this
study or publication of this article. All named
authors meet the International Committee of
Medical Journal Editors (ICMJE) criteria for
authorship for this manuscript, take
responsibility for the integrity of the work as a
whole, and have given final approval for the
version to be published.
Design and supervision of the study: AB.
Clinical managements of patients: MM, MC,
MLR, MM, FS, AdS; Wrote the paper: SM.
Disclosures. Simona Malucchi has received
speaking honoraria and/or consultant fees
from Biogen, Merck Serono, Novartis, Teva,
and Genzyme. Marco Capobianco has received
speaking honoraria and/or consultant fees
from Biogen, Merck Serono, Novartis, Teva,
Genzyme, and Almirall. Marianna Lo Re has
received travel expenses from Biogen,
Novartis, and Teva. Maria Malentacchi has
received speaking honoraria from Biogen.
Alessia di Sapio has received speaking
honoraria and/or consultant fees from
Biogen, Merck Serono, and Novartis.
Manuela Matta has received speaking
honoraria from Biogen. Francesca Sperli has
received speaking honoraria from Biogen.
Antonio Bertolotto has received honoraria
for serving in the scientific advisory boards
of Almirall, Bayer, Biogen, and Genzyme with
approval by the Director of AOU San Luigi
University Hospital, and has received speaker
honoraria from Biogen, Genzyme, Novartis,
and Teva; his institution has received grant
support from Bayer, Biogen, Merck, Novartis,
and Teva from the Italian Multiple Sclerosis
Society, Fondazione Ricerca Biomedica
ONLUS, and San Luigi ONLUS.
Compliance with Ethics Guidelines. This
article does not contain any new studies with
human or animal subjects performed by any of
Data Availability. The datasets during and/
or analysed during the current study are
available from the corresponding author on
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indicate if changes were made.
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