Risks associated

with MS treatment

Luisa Klotz University of Muenster Muenster, Germany

Dr. Klotz received compensation for giving lectures, serving on advisory boards, travel support for attending meetings and research funding from Biogen, Genzyme/SanofiAventis, MerckSerono, and Novartis.

• Describe the on-target and off-target side effects of different immunosuppressant treatments used for MS

• Define the main mechanisms linking immunosuppression and oncogenesis

• Illustrate the main mechanisms linking immunosuppression and specific opportunistic infections (ie, tuberculosis, PML)

• Illustrate the main mechanisms linking immunomodulation and other autoimmune disorders (ie, thyroiditis)

Learning objectives

Which therapy for which patient when (and in what sequence): German therapy guidelines KKNMS 2016

Gold, Hemmer, Wiendl, German treatment guidelines for MS Update 2014, Aktuelle Neurologie 2014

Immunotherapies Blood count

Liver function Renal function

Cardiac Fingolimod

Mitoxantrone JCV

Natalizumab

Hepatic Daclizumab

VZV Fingolimod

Alemtuzumab Autoimmunity Alemtuzumab

Thyroid Alemtuzumab

Daclizumab SPC. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003862/WC500210598.pdf;

Fingolimod SPC. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002202/WC500104528.pdf;

Alemtuzumab SPC. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003718/WC500150521.pdf;

Natalizumab SPC. https://www.medicines.org.uk/emc/medicine/18447/ SPC/Natalizumab+300+mg+concentrate+for+solution+for+infusion/;

Mitoxantrone SPC. http://www.ema.europa.eu/docs/en_GB/ document_library/Referrals_document/Mitoxantrone_30/WC500205489.pdf

HIV, human immunodeficiency virus; JCV, John Cunningham virus; SPC, summary of product characteristics; VZV, varicella zoster virus

Newer agents may have specific testing requirements due to their MoA and AE profile

Fingolimod Natalizumab Alemtuzumab Application Oral IV IV

Frequency 1 x/day 1 x/month 1 cycle/year

Contra-indications

• Severe liver insufficiency

•Malign diseases •Chronic or severe active infections •Immunodeficiencies •AV block II. or III. grade; therapy with certain

antiarrhythmic drugs • COPD (chronic respiratory diseases) •Macular edema

•Opportunistic infections (incl. HSV/VZV; TBC) within 3 months or mycotic infections within 6 months prior to therapy

• Currently active infections •Active malignancy • Status after organ transplantation (current

immunosuppression)

•Acute and chronic infections • Coagulation deficiency •Uncontrolled autoimmune diseases

•Malignancy •Negative VZV serology • Severe liver/kidney insufficiency

Side effects

• Transient atrioventricular block •Hypertonia • Infections (suspected herpes) •Macular edema • Liver enzymes • Leukopenia

•(PML)

•Allergic reaction

•PML • Infusion reaction

•ITP •Autoimmune thyroid disorders •Goodpasture Syndrome •Cytopenia •Herpes infections

Controls

• ECG/RR surveillance for the first 6 hrs

•BC and liver enzymes at Month 2 and 4 after therapy onset; then every 3 months

• Yearly MRI • Examination of the eye 3–4 months after

therapy onset, afterwards: regular controls only in case of risk for DM; uveitis

•Derma after 1 year

•BC every 3–6 months • Liver enzymes every 4 weeks for 3 months,

then every 3 months • Yearly MRI; after 2 years of therapy: MRI

every 3 months

•HPV screening before therapy onset Within 4 years after the last infusion: •Monthly BC •Monthly kidney enzymes • TSH every 3 months

MS therapeutics in (highly) active patients

Fingolimod SPC. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002202/WC500104528.pdf;

Alemtuzumab SPC. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/003718/WC500150521.pdf; Natalizumab SPC. https://www.medicines.org.uk/emc/medicine/18447/SPC/T00+mg+concentrate+for+solution+for+infusion/

BC, blood count; ECG, electrocardiogram; HPV, human papilloma virus; ITP, immune thrombocytopenic purpura; MRI, magnetic resonance imaging; PML, progressive multifocal leukoencephalopathy; TBC, tuberculosis; TSH, thyroid stimulating hormone

• Overall risk for infections is increased

• Reason: Reduced numbers of circulating lymphocytes due to MoA

– However, lymphocyte function within the lymphatic organs is not compromised!

– Blood count testing necessary, lymphocytes should be >200/microliter!

– Close monitoring and appropriate treatment of occurring infections

Specific risks in fingolimod treatment: (Viral) infections

Mehling M, et al. Neurology 2011;76(8 Suppl 3):S20–7 MoA, mechanism of action

• In Phase 3 studies, two fatal herpes virus infections occurred under a higher dose of fingolimod

• In the postmarketing situation, there is a clear increase in the incidence of herpes virus infections, mainly VZV reactivations

• However, there is no increase in severe/fatal infections1

• Consequences:

– Only VZV-positive patients should receive fingolimod

– Patient counselling and monitoring of treatment if infection occurs

Specific risks in fingolimod treatment: (Viral) infections

1. Arvin AM, et al. JAMA Neurol 2015;72:31–9

• So far, 216 cases of basalioma under fingolimod have been collected (Feb 2016)

• Reason for this specific risk is unknown

• Patients should be aware; dermatological controls should be performed once a year

Specific risks in fingolimod treatment: Basalioma

1. Presence of asymptomatic JCV infection

2. Viral factors: VP1 mutations,

RR permutations

3. Host factors:

Immune function, genetics

4. Drug effects that reduce CNS immune surveillance

For each etiological step there is a possibility to find biomarkers for identifying at risk patients

• PML risk is clearly increased, 698 cases in 167,500 treated patients (Dec 2016)

• Reason: Lymphocytes essential for immune surveillance are kept out of the CNS

Specific risks in natalizumab treatment: PML

Data from Schwab et al., unpublished CNS, central nervous system

• PML risk is clearly increased, 698 cases in 167,500 treated patients (Dec 2016)

• Reason: Lymphocytes essential for immune surveillance are kept out of the CNS

• Established risk factors:

– Treatment duration >2 years

– Prior treatment with immunosuppressive drugs

– Seropositivity for anti-JCV antibodies

• Additional risk factors:

– JCV antibody titer (in patients without immunosuppressants)

– CD62L/L-selectin

Specific risks in natalizumab treatment: PML

June 2016: 667 PML cases

Incidence 4.22/1000

Feb 2

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Apr 2

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Khalili K, et al. Neurology 2007;68:985–90; Kappos L, et al. Lancet Neurol 2007;6:431–41; Adapted from Berger JR, Khalili K. Discovery Med 2011;67:495–503; Sundqvist E, et al. PLoS Pathog 2014;10:e1004084.

Specific risks in natalizumab treatment: PML

• High titer of anti-JCV antibodies indicates high risk of developing PML

• The biomarker only applies to patients without prior immune suppression

Specific risks in natalizumab treatment: PML – Role of JCV titer

Plavina T, et al. Ann Neurol 2014;76:802–12

• A mean of 10% initially anti-JCV-negative patients switch serostatus to

JCV-positive p.a.

• Re-testing in JCV-negative patients is recommended every 6 months

Specific risks in natalizumab treatment: PML – Rise in seroconversion

Schwab, et al., N2 2016; Schwab, et al. Poster P1595, P1620 ECTRIMS; Schwab, et al. Manuscript in preparation

Low expression of CD62L on thawed CD4+ T cells might be a predictive biomarker for enhanced PML risk

Specific risks in natalizumab treatment: PML – Role of CD62L expression on CD4+ T cells

Schwab, et al. 2013; Schneider-Hohendorf, et al. 2014; Spadaro, et al. 2015; Schwab, et al. 2016; Pignolet, et al. 2016

Specific risks in natalizumab treatment: PML – Proposed algorithm

• Statistically, CD62L-low patients have a 55-fold higher risk of developing PML

• Patients who have been classed high risk could consider switching to a

different therapy to avoid most cases of PML Schwab N, et al. Mult Scler 2016;22:1048–60 RRMS, relapsing-remitting multiple sclerosis

2. Depletion1

Lymphocyte precursor

CD52

CD52

B

T

1. Selection1,2

Plasma cells

CD

52

B

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Monocytes

Macrophages

Neutrophils

Lymphocyte precursor

T

Months

0 3 6 9 12 15 18 21 24 1 13

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ll C

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)

CD4 LLN

CD8 LLN

CD19 LLN

Effect of alemtuzumab treatment on mean lymphocyte counts5

Effect of alemtuzumab treatment on the innate immune system3,4

Neutrophils NR = (1.8, 8.0)

Monocytes NR = (0.2, 1.1) Eosinophils NR = (0.05, 0.55) Basophils NR = (0, 0.2) 0

0.5

1.0

1.5

2.0

4.0

4.5

5.0

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Specific risks in alemtuzumab treatment: MoA

1. Havrdova E, et al. Ther Adv Neurol Disord 2015;8:31-45; 2. Hu Y, et al. Immunology 2009;128:260-70; 3. Coles AJ, et al. Lancet 2012;380:1829-39; 4. Lycke J, et al. EFNS 2012, Platform. SC346. 5. Selmaj K, et al. EAN 2015, Poster F3151

Months

LLN, lower limit of normal

Lymphocyte repopulation begins within weeks after alemtuzumab treatment – Over time, T- and B-cell counts reached normal range and

plateaued1,2

T-cell precursor

Pre/Pro B cell

Lymphocyte precursor

Stem cell

3. Repopulation1

B

T

B

T

CD4 lymphocytes in PBMC3

Months

Alemtuzumab courses

0 12 18 24 36 48 6

0

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Patients receiving 2 courses (no alemtuzumab retreatment and no DMT)2

CD4 LLN

Start of second course

412 406 339 353 337 362 398 359 No. of patients

CD4 CD8 CD19

CD8 LLN CD19 LLN

1. Havrdova E, et al. Ther Adv Neurol Disord 2015;8:31-45; 2. Boyko, et al. ECTRIMS 2016, P654; 3. Durelli L. AAN 2016, S2.008

DMT, disease-modifying therapy; PBMC, peripheral blood mononuclear cell

Specific risks in alemtuzumab treatment: MoA

• Based on the MoA, side effects of alemtuzumab are currently explained by the following mechanisms:

• Infections (including serious and opportunistic infections) • Reduced numbers of lymphocytes due to depletion

• Due to preserved innate immune system and incomplete depletion in lymphatic tissues, infection rate is not as much increased as one would expect with this MoA!

• Secondary autoimmunity (thyroid disorders, ITP, GN) • Lymphopenia-associated homeostatic proliferation of lymphocytes

• Distinct repopulation kinetics of B cells and T cells (B cells recover faster)

• Increased IL-21 levels

• Depletion of tolerogenic CD8 T cells

Specific risks in alemtuzumab treatment: Pathophysiology of side effects

GN, glomerulonephritis

• Alemtuzumab use is associated with the risk of

– Infusion-associated reactions (IARs) (~90%)

– Infections (73%) • Serious infections (2.8%)

– Secondary autoimmune diseases • Thyroid disorders (36%)

• ITP (1–2%)

• Nephropathies including anti-glomerular basement membrane (anti-GBM) disease (0.3%)

Specific risks in alemtuzumab treatment: Frequencies of relevant side effects

• Frequent infections under alemtuzumab were nasopharyngitis, UTI, upper respiratory tract infections, sinusitis, oral herpes simplex, flu and bronchitis

• Incidence of local herpes infections was reduced upon prophylactic treatment with aciclovir

Specific risks in alemtuzumab treatment: Frequencies of relevant side effects

1. Wiendl H, et al. ECTRIMS 2015, Spain, Barcelona, Platform

59,4 55,1

47,9 46 42,1

1,8 1,1 1,4 1,5 1,3 0

10

20

30

40

50

60

70

Year 1 Year 2 Year 3 Year 4 Year 5

Infection

Serious infection

Pat

ien

ts (

%)

UTI, urinary tract infection

Incidence of infection and serious infection per year (CARE-MS I and II, pooled data)1

• Few cases of opportunistic infections have been described under alemtuzumab:

• Tuberculosis • Listeria meningitis1 • 1 PML case

Specific risks in alemtuzumab treatment: Rare but relevant opportunistic infections

1. Rau, et al. IJMS 2015

• Most patients could be treated with standard conservative treatment (80%)

• about 20% of patients did not

need any treatment

• Less than 3–4% of patients developed severe thyroid disease

• Thyroid monitoring resulted in early diagnosis and effective management of thyroid events

Specific risks in alemtuzumab treatment: Autoimmune diseases

Menagement of thyroid adverse events

Conventional oral treatment

Iodo-ablation

Thyroidectomy

No treatment

Some patients received more than 1 treatment

Senior PA, AAN 2016, Vancouver, Canada, P2.086

• Consequent monitoring of patients is mandatory for 4 years after last infusion!

• Monthly control of blood count, thrombocytes, creatinine, GFR, urine microscopy

• Every 3 months, control of thyroid parameters (TSH, if abnormal, T3, T4, TSH-R, TPO-Ab, Tg-Ab)

• Yearly control of HPV status in females

• Moreover, treatment response has to be monitored clinically and radiologically (clinically every 3 months, MRI depending on pre-treatment disease activity at least every 6 months)

Specific risks in alemtuzumab treatment: Specific monitoring

GFR, glomerular filtration rate; Tg-Ab, thyroglobulin antibody; TPO-Ab, thyroid peroxidase antibody; TSH-R, thyroid-stimulating hormone receptor

Immune cells and infection types

Deficit Bacteria Viruses

Neutrophil deficitsa • Enteric gram-negative bacteria • Staphylococcus

Abnormal T cells or monocytes

• Mycobacteria • Nocardia • Listeria

• Herpes: HSV1; HSV2; CMV; VZV • JC virus

Disorders of humoral immunity

• Streptococcus pneumoniae • Neisseria meningitidis • Haemophilus influenzae

aAbsolute neutropenia or functional abnormalities. CMV, cytomegalovirus; VZV, varicella zoster virus; JC, John Cunningham virus. Berger J: Neurological complications of systemic illness. Noseworthy J (ed.) Neurological Therapeutics: Principles and Practice. 2nd Edition. Informa Healthcare. 2006

Risk of infections with MS treatments can vary depending on the effects on the immune system and specific immune cell

types