This document provides guidelines for managing lymphopaenia in multiple sclerosis patients treated with dimethyl fumarate (DMF, Tecfidera). It summarizes clinical trial data showing DMF can decrease lymphocyte counts by about 30% on average. It recommends monitoring complete blood counts regularly for patients on DMF and considering discontinuing treatment if lymphocyte counts persistently fall below 0.8 x 109/L or reach below 0.5 x 109/L. This is due to one reported case of progressive multifocal leukoencephalopathy (PML) in a DMF-treated patient with long-term lymphopaenia below 0.5 x 109/L. The guidelines establish a

1. Guidelines written by Dr. Ben Turner, Professor Gavin Giovannoni, Dr. Klaus Schmierer October 2014
Review October 2016
Barts-MS Clinical Guidance #1-2014
Original guidance published: This is new guidance
Management of lymphopaenia in people with multiple sclerosis treated
with Dimethyl Fumarate or DMF (Tecfidera)
BACKGROUND
As stated in the EMA’s Summary of Product Characteristics (SmPC), dimethyl fumarate
(Tecfidera) may decrease lymphocyte counts (1). Lymphopenia and leucopenia are listed as
common undesirable effects associated with DMF use (≥1/100 to <1/10) (1). In the phase III
placebo-controlled studies, most patients (>98%) had normal lymphocyte values prior to
initiating treatment. Upon treatment with DMF, mean lymphocyte counts decreased over
the first year with a subsequent plateau. On average, lymphocyte counts decreased by
approximately 30% of baseline value. Mean and median lymphocyte counts remained
within normal limits (1). In phase III studies, lymphocyte counts <0.5x109
/l were observed in
<1% of patients treated with placebo and 6% of patients treated with DMF (1, 5). A
lymphocyte count <0.2x109
/l was observed in 1 patient treated with DMF and in no
patients treated with placebo (1-7). Across phase IIb and III studies, an increased
incidence of infections and serious infections was not observed in patients with lymphocyte
counts <0.8x109
/l or <0.5x109
/l. (1-7). Although there is no advice within the SmPC regarding
cessation of therapy following lymphocyte count reductions (1), in view of the recent fatal case
of PML in a patient treated with DMF for over 4-years, who had a persistent lymphopaenia
below <0.5x109
/l this advice will almost certainly be changed. We therefore feel it is
appropriate to make the following recommendations.
The SmPC currently states that prior to initiating treatment with DMF, a recent complete
blood count (i.e. within 6 months) should be available. Assessments of complete blood
counts are also recommended after 6 months of treatment and every 6 to 12 months
thereafter and as clinically indicated (1). As there are no specific recommendations for the
management of reduced lymphocyte counts in patients receiving DMF the management is
therefore at the clinical discretion of the prescribing neurologists.
Tecfidera Summary of Product Characteristics (SmPC)
As stated in the SmPC, Tecfidera may decrease lymphocyte counts (1). Lymphopenia
and leucopenia are listed as common undesirable effects associated with Tecfidera use
(≥1/100 to <1/10) (1). Tecfidera has not been studied in patients with pre-existing low
lymphocyte counts and caution should be exercised when treating these patients (1). In the
placebo-controlled studies, most patients (>98%) had normal lymphocyte values prior to
initiating treatment. Upon treatment with Tecfidera, mean lymphocyte counts decreased
over the first year with a subsequent plateau. On average, lymphocyte counts decreased by
approximately 30% of baseline value. Mean and median lymphocyte counts remained
within normal limits. Lymphocyte counts <0.5x109
/l were observed in <1% of patients
treated with placebo and 6% of patients treated with Tecfidera. A lymphocyte count <0.2x109
/l
was observed in 1 patient treated with Tecfidera and in no patients treated with placebo (1).
The incidence of infections (58% versus 60%) and serious infections (2% versus 2%)
was similar in patients treated with placebo or Tecfidera. An increased incidence of
infections and serious infections was not observed in patients with lymphocyte counts
<0.8x109
/l or <0.5x109
/l. A transient increase in mean eosinophil counts was seen during

2. Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital,
The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital.
Barts-MS Guidelines, #1-2014 version 1.0 written by Dr Ben Turner, Prof Gavin Giovannoni, Dr. Klaus Schmierer 31 October 2014.
Scheduled review October 2016
the first 2 months of therapy (1). There is no advice within the SmPC regarding cessation of
therapy following lymphocyte count reductions (1). However of note, it is advised that if a
patient develops a serious infection, suspending treatment with Tecfidera should be
considered and the benefits and risks should be reassessed prior to re-initiation of therapy.
Patients with serious infections should not start treatment with Tecfidera until the infection(s)
is resolved (1). Prior to initiating treatment with Tecfidera, a recent complete blood count (i.e.
within 6 months) should be available. Assessments of complete blood counts are also
recommended after 6 months of treatment and every 6 to 12 months thereafter and as
clinically indicated (1).
Pivotal Phase III Clinical Trials of Tecfidera in RRMS
DEFINE STUDY
The DEFINE (Determination of the Efficacy and Safety of Oral Fumarate In Relapsing-
Remitting Multiple Sclerosis) study was a global, randomised, double-blind, placebo-
controlled, 2-year Phase III study evaluating the efficacy and safety of oral Tecfidera (240
mg) administered either 2 times daily (BID) or 3 times daily (TID) in patients with RRMS
(2). Haematology laboratory parameters were assessed at baseline, every 4 weeks for the
first 12 weeks, and every 12 weeks thereafter (3). A total of 1234 patients were enrolled
and received at least one dose of the study drug (n = 408 in the placebo arm, n = 410 in the
BID arm, and n = 416 in the TID arm) (2). Mean white blood cell (WBC) and lymphocyte
counts in both Tecfidera groups decreased over the first year and then plateaued, with mean
values remaining within normal limits. Mean WBC and lymphocyte counts decreased by
approximately 10% and 28%, respectively at 1 year (2). WBC counts of less than 3.0
x109
/L or lymphocyte counts of less than 0.5 x 109
/L (corresponding to the National
Cancer Institute Common Toxicity Criteria grade 3 or higher lymphopenia and grade 2 or
higher leukopenia, respectively) were seen in 4% of Tecfidera patients, versus 1% or less
of placebo patients. There were no serious infections in patients with lymphocyte counts
<0.5x109
/L. No patient stopped treatment due to low or decreased WBC or lymphocyte
counts (3).
CONFIRM STUDY
CONFIRM (Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis) was
a global, randomised, double-blind, placebo-controlled, 2-year Phase III study evaluating
the efficacy and safety of oral Tecfidera (240 mg) administered either BID or TID in
patients with RRMS (4). The study also had an open-label comparator arm with glatiramer
acetate (GA). Haematology laboratory parameters were assessed at baseline, every 4
weeks for 12 weeks, and every 12 weeks thereafter (5). A total of 1430 patients were
randomised, and 1417 patients were included in the safety population (n = 363 subjects in
the placebo arm, n = 359 in the Tecfidera BID arm, n = 344 in the TID arm, n = 351 in the
GA arm) (4). Similar to DEFINE, mean WBC and lymphocyte counts in both Tecfidera
groups decreased during the first year and then plateaued; mean values throughout the
study remained within normal limits (4,5). At 1 year of treatment, mean WBC counts and
lymphocyte counts in the Tecfidera groups decreased by approximately 11% to 12% and
28% to 32%, respectively, relative to baseline (4). WBC counts of less than 3.0x109
/L and
lymphocyte counts of less than 0.5 x109
/L (corresponding to the National Cancer Institute
Common Toxicity Criteria grade 2 or higher lymphopenia and grade 3 or higher

3. Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital,
The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital.
Barts-MS Guidelines, #1-2014 version 1.0 written by Dr Ben Turner, Prof Gavin Giovannoni, Dr. Klaus Schmierer 31 October 2014.
Scheduled review October 2016
leukopenia, respectively) were seen in 7-10% and 4-5%, respectively in the BID and TID
Tecfidera groups, versus 1% or less of the patients in the placebo group (4). One patient
stopped treatment due to low or decreased WBC count. No patient stopped treatment
due to low or decreased lymphocyte count. There were no serious infections reported in
patients with lymphocyte counts < 0.5 x 109/L (6).
Integrated Analysis of Tecfidera Phase IIb and III Studies
An integrated analysis of the phase IIb and III studies was conducted to describe the
clinical relevance of lymphocyte count reductions in patients treated with Tecfidera 240 mg
BID or TID (7). A total of 2,428 RRMS patients were randomized and received treatment
with placebo (n=836), Tecfidera BID (n=769), or Tecfidera TID (n=823). In these studies
there was no stopping rule based on low lymphocyte counts. However there were stopping
rules for low WBC counts. Study treatment had to be discontinued in patients with low
WBC counts per the following rules:
• Phase IIb: WBC <1.5x109
/L at any time during the study or WBC counts <2.0x109
/L
sustained for 4 weeks
• Phase III - DEFINE and CONFIRM: WBC count <2.0x109/L sustained for 4
consecutive weeks after study treatment was withheld; or a WBC count <2.0x109/L
confirmed on re-testing
In Tecfidera-treated patients, mean WBC and lymphocyte counts decreased from baseline
by approximately 11% and 30%, respectively, through week 48, then plateaued, but
remained within normal limits throughout the observation period. There was an increased
incidence of lymphopenia categorised as CTC Grades 1, 2, or 3 in Tecfidera-treated
patients relative to placebo. The percentages of patients with at least one, more than one
and consecutive Grade 3 or 4 lymphocyte counts were increased among Tecfidera treated
patients relative to placebo. The incidence of ≥1 Grade 3 or 4 lymphocyte count was 6% for
the Tecfidera BID group versus <1% for placebo. The incidence of CTC Grade 3 or 4
lymphopenia increased over time through Week 48, then stabilised (7). An increased
incidence of infections and serious infections was not observed in patients with lymphocyte
counts <0.8x109
/l or <0.5x109
/L. No serious infections were reported in any Tecfidera-
treated patient with a minimum post-baseline lymphocyte count <0.5 x 109
/L (7). Across the
studies, one patient in the Tecfidera TID group discontinued study drug due to an adverse
event associated with leukopenia. No Tecfidera-treated patients discontinued study drug
due to lymphopenia (7).
Extension study of Pivotal Clinical Trials of Tecfidera in Multiple Sclerosis (ENDORSE)
ENDORSE is an ongoing multicentre, parallel-group, dose-blinded study with up to 5 or
more years of follow up. Eligible patients who completed the 2-year parent studies
(DEFINE and CONFIRM) were enrolled. Patients who received Tecfidera 240 mg BID or TID
for up to 2 years in the parent study remained on the same Tecfidera dose in ENDORSE.
Patients who received placebo (both parent studies) or GA (CONFIRM) were randomised 1:1
to Tecfidera 240 mg BID or TID. Haematology laboratory parameters were assessed at
baseline and every 12 weeks thereafter. (8). In an interim analysis (database lock June
2013), patients continuing on Tecfidera in ENDORSE maintained stable WBC and
lymphocyte counts. Patients new to Tecfidera in ENDORSE had WBC and lymphocyte
counts similar to those seen in the parent studies. WBC counts were < 3.0 x 109
/L in 6-7%

4. Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital,
The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital.
Barts-MS Guidelines, #1-2014 version 1.0 written by Dr Ben Turner, Prof Gavin Giovannoni, Dr. Klaus Schmierer 31 October 2014.
Scheduled review October 2016
of patients in the continued Tecfidera groups and in 7-10% of patients in the new to Tecfidera
groups. Lymphocyte counts were < 0.5 x 109
/L in 6-8% of patients in the continued
Tecfidera groups and in 5-9% of patients in the new to Tecfidera groups (8).
BARTS HEALTH ADVICE
Patients starting DMF should be counselled that there has been one fatal case of PML in a
patient with MS taking DMF for over 4 years, who had a persistent lymphopaenia of less than
< 0.5 x 109
/L, and one patient with psoriasis who developed PML on a propriety formulation of
DMF who also had persistent lymphopaenia (). We believe the risk of PML in patients with a
lymphocyte count above 0.8 x 109
/L is very low. At present we have no evidence that PML risk
is due to a specific action of DMF other than its impact on total lymphocyte counts.
PROTOCOL
1. Before starting DMF an up-to-date (within the last 4 weeks) full blood count (FBC) is
required in addition lymphocyte subset; collecting data on lymphocyte is to allow the
profiling of the immunological effects of DMF in more detail.
2. The monitoring of FBC with lymphocyte counts and subsets should be done at 3
months and 6 months, and then at 6 monthly intervals in patients with lymphocyte
counts above 1.2 x 109
/L. In patients with total lymphocyte counts less than 1.2 x 109
/L
monitoring should be done at 3 monthly intervals.
3. If the lymphocyte counts return to above 1.2 x 109
/L, then 6 monthly monitoring should
be reinstated.
4. If the total lymphocyte count falls below 0.8 x 109
/L, and is confirmed on a second FBC
and the patient wants to stay on DMF it may be worth checking the JCV virus status.
As DMF-related lymphopaenia is a form of immunosuppression the JCV index, as
measured using the STRATIFY JCV assay, cannot be used to assess PML risk (11).
Please note a lymphocyte count cut-off of 0.8 x 109
/L (WHO grade 2) may considered
by some as being too conservative; but until data emerges to show that DMF-related
lymphopaenia is reversible we feel this conservative approach is justified.
5. If lymphocytes remain persistently below 0.8 x 109
/L, consider the risks and benefits of
continuing DMF.
6. If lymphocytes go below 0.5 x 109
/L we recommend stopping DMF.
7. At present we are not aware of any data to indicate that reducing the dose of DMF will
result in the lymphocyte counts recovering. In addition, a lower dose than 240mg BD of
DMF is unlikely to be effective (10).
8. All patients treated with DMF should have annual Gd-enhanced MRI studies according
to our Barts MS MRI protocol, and additional MRI studies if clinically indicated.
ADDITIONAL COMMENTS
We define significant immunosuppression on DMF as persistent lymphopaenia for greater
than 6 months with a total lymphocyte count of less than 1.2 x 109
/L (WHO Grade 1). In
patients with a past history of significant immunosuppression the JCV serology index, as
measured using the STRATIFY JCV assay, cannot be used to complement PML risk profiling
(11).

5. Barts Health NHS Trust: Newham University Hospital, The London Chest Hospital,
The Royal London Hospital, St Bartholomew’s Hospital and Whipps Cross Hospital.
Barts-MS Guidelines, #1-2014 version 1.0 written by Dr Ben Turner, Prof Gavin Giovannoni, Dr. Klaus Schmierer 31 October 2014.
Scheduled review October 2016
REFERENCES
1. Tecfidera Summary of Product Characteristics, January 2014. Available from
www.medicines.org.uk [Accessed 19 March 2014]
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12 or Glatiramer in Multiple Sclerosis. N Engl J Med. 2012;367(12):1087-97.
5. Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12
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R. Safety Profile of BG-12 (Dimethyl Fumarate) in Relapsing-Remitting Multiple
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Multiple Sclerosis, 2−5 October, 2013, Copenhagen, Denmark.
9. European Public Assessment Report – Tecfidera. Assessment Report accessed
at http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
Public_assessment_report/human/002601/WC500162070.pdf [13 March 2014].
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treated with dimethyl fumarate from a compounding pharmacy. N Engl J Med. 2013
Apr 25;368(17):1658-9.
11. Plavina T, Subramanyam M, Bloomgren G, Richman S, Pace A, Lee S, Schlain
B,Campagnolo D, Belachew S, Ticho B. Anti-JCV antibody levels in serum or plasma
further define risk of natalizumab-associated PML. Ann Neurol. 2014 Oct 1. doi:
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