Safety of Newer Disease Modifying Therapies in Multiple Sclerosis
Abstract
:1. Introduction
2. Safety of Newer DMTs
2.1. Safety of DMTs from RCTs, Extension Studies, and Post-Marketing Observations in MS
2.2. Safety Experience from DMT Use in Other Conditions
2.3. Safety Experience from Molecules with Similar Mechanisms of Action
3. Monitoring of Adverse Events
3.1. Cancer Risk Evaluation and Monitoring
3.2. HPV-Related Cervical Dysplasia and Cancer
3.3. Infection Risk Evaluation and Monitoring
3.4. Monitoring of Treatment Effect and Redosing Adaptation with Cell-Depleting Agents
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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DMT, Dosage | Mechanism of Action | Adverse Effects in Multiple Sclerosis Clinical Trials | Adverse Effects in Extension Studies and Case Series/Reports |
---|---|---|---|
Oral therapies | |||
Teriflunomide (AUBAGIO®, Sanofi Genzyme, Massachusetts, United States) 7 or 14 mg PO daily | Dihydro-oratate dehydrogenase inhibitor: inhibits of proliferation of auto-reactive T and B cells [18] | TEMSO and TOWER trials: gastrointestinal symptoms, hair thinning, skin rashe, weight loss, headaches, increased blood pressure, infections, increased liver enzymes, pancytopenia, peripheral neuropathies [19,20,21] | TEMSO extension study: results consistent with the core trial, no new AE after 9 years of follow-up [22] TOPIC extension study: no new safety issues [23] Toxic epidermal necrolysis [24] |
Dimethyl fumarate (TECFIDERA®, Biogen Idec, Massachusetts, United States) 240 mg PO twice daily | - Activates the transcription factor nuclear factor E2-related factor 2 (Nrf2) inducing the expression of endogenous antioxidative factors in vitro - Inhibits the transcription factor nuclear factor κB [25] | DEFINE and CONFIRM trials: Flushing, gastrointestinal symptoms, arthralgia, itching, and lymphopenia [26,27,28] | ENDORSE study: no new AEs after 6 years of follow-up [29] RESPOND study: bacterial sepsis, infectious colitis, pneumonia, urinary tract infection, hypercalcemia, hypokalemia, hydronephrosis, nephrolithiasis, and ovarian cyst rupture [30] 8 cases of PML until the end of 2019 (including one case occurring without lymphopenia), hepatotoxicity [31,32,33,34,35,36] |
Fingolimod (GILENYA®, Novartis, Basel, Switzerland) 0.5 mg PO daily | Functional antagonist of sphingosine-1- phosphate (S1P) S1P1,3–5: retain circulating central memory T cells and naïve T cells in the lymph nodes [37] | FREEDOMS and TRANSFORMS trials: Lymphopenia, increased blood pressure, macular edema, increased liver enzymes, transient bradycardia and atrioventricular block after the first dose, appendicitis, upper and lower respiratory infections, urinary tract infections, influenza infections, headache, herpesvirus infections, rare cases of fatal herpes simplex encephalitis and disseminated varicella zoster infection, basal-cell carcinoma, malignant melanoma [38,39] FREEDOMS II: results similar to previous trial [40] PARADIGMS (pediatric trial): convulsions, agranulocytosis, arthralgia, autoimmune uveitis, macular edema, bladder spasm, dyspepsia, dysuria, increased liver enzymes, gastrointestinal necrosis (intussusception or necrotic bowel), head injury, humerus fracture, hypersensitivity vasculitis, migraine, migraine without aura, muscular weakness, rectal tenesmus, second degree atrioventricular block, small-intestinal obstruction, leukopenia, appendicitis, cellulitis, gastrointestinal infection, oral abscess, viral infection (pharyngitis) [41] | TRANSFORMS extension study over 4.5 years: similar results to previous trials [42] LONGTERMS: no new or unexpected safety concerns over 14 years of follow-up [43] FREEDOMS extension trial: no new AE over 4 years of follow-up [44] ACROSS study: 10 years follow-up showed no new AE [45] MS NEXT study: no new AE [46] Cryptococcal infections, cryptococcal meningoencephalitis, cryptosporidiosis, visceral leishmaniasis, progressive multifocal encephalopathy, immune reconstitution inflammatory syndrome, human papillomavirus virus-related warts, primary cutaneous Epstein-Barr virus-positive diffuse large B-cell lymphoma, melanoma, flare of hepatitis B virus, varicella-zoster virus vasculopathy, T-cell cutaneous and peripheral T-cell lymphomas, cutaneous anaplastic large cell lymphoma, glioblastoma, Kaposi sarcoma, tumefactive demyelination, necrotizing fungal osteomyelitis [47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77] |
Siponimod (MAYZENT®, Novartis, Basel, Switzerland) 2 mg PO daily | Functional antagonist of receptors S1P1 and S1P5 [78] | EXPAND: liver enzyme elevation, bradycardia at treatment initiation, macular edema, nasopharyngitis, hypertension, varicella zoster virus reactivation, and convulsions [79] | No post-marketing data |
Ozanimod (ZEPOSIA®, Celgene Corporation, New Jersey, United States) 0.5 to 1 mg PO daily | Selective modulator of S1P receptors with improved selectivity for S1P1R and S1P5R [80] | RADIANCE and SUNBEAM trials: nasopharyngitis, headache, hypertension, upper respiratory tract infection, influenza-like illness, back pain, headache, and alanine aminotransferase, liver enzymes elevation, bradycardia at treatment initiation, herpes infections, lymphopenia, macular edema, appendicitis, urticaria, Guillain-Barré syndrome, invasive breast carcinoma, keratoacanthoma, basal cell carcinoma, suicidal ideation [81,82,83] | No post-marketing data |
Cladribine (MAVENCLAD®, Merck group, Darmstadt, Germany) 3.5 mg/kg over 2 years PO | Synthetic analogue of deoxyadenosine, causes prolonged depletion of circulating T and B lymphocytes [84] | CLARITY and ORACLE-MS studies: Lymphopenia grade 3 and 4, and decreased lymphocyte count, neutropenia, thrombocytopenia, increased blood creatine phosphokinase, herpes zoster infection and reactivation, malignancies (pancreatic carcinoma, ovarian carcinoma, choriocarcinoma reported) Dose related (5.25 mg/kg): lymphopenia, leukopenia, lymphocyte count decreased, vertigo, tinnitus and hypesthesia [85,86] | CLARITY extension study: similar results to previous trials, follow-up up to 4 years [87] Lichenoid rash [88] |
Infusion therapies | |||
Alemtuzumab (LEMTRADA®, Sanofi Genzyme, Massachusetts, United States) 12 mg IV/day for 5 consecutive days then 12 mg IV/day for 3 days one year later | Humanized monoclonal antibody selectively directed against the CD52 antigen on T- and B-lymphocytes, causes prolonged depletion of circulating T- and B-lymphocytes [89] | CARE-MS I and II: - Infusion-associated reactions (headache, rash, and pyrexia, non-anaphylactoid hypotension with the first infusion) - Infections: upper respiratory, urinary tract, and herpetic infections, mucocutaneous fungal infections, listeriosis, viral meningitis, tuberculosis - Secondary autoimmune disorders: thyroid disease (hypothyroidism, hyperthyroidism, Graves’ disease, thyrotoxicosis, thyroiditis), renal disease (Goodpasture syndrome, membranous nephropathy), immune thrombocytopenic purpura (ITP, with one case of intracranial bleeding), autoimmune hemolytic anemia - Malignancies (thyroid papillary carcinoma, Burkitt lymphoma) [90,91,92] | CARE-MS I and II extension studies, and TOPAZ studies: Similar AEs over 5 years of follow-up, decreased incidence of infections and thyroid disorders (after the third year) [93,94] Organizing pneumonia, alveolar hemorrhage, myocardial infarction, malignancies (basal-cell carcinoma, malignant melanoma, squamous cell carcinoma, thyroid papillary carcinoma), AV block, ischemic colitis, legionella pneumonia sepsis, opportunistic infections (nocardia, listeria infections, invasive pulmonary aspergillosis, primary Toxoplasma gondii infection, Herpes simplex reactivation, VZV reactivation, and CMV reactivation, mucocutaneous candidiasis), acute acalculous cholecystitis, intracerebral hemorrhage during alemtuzumab administration, cervical artery dissection, hemophagocytic lymphohistocytosis, autoimmune hemolytic anemia, agranulocytosis, autoimmune hepatitis, tumefactive demyelination, acquired hemophilia [95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116] |
Natalizumab (TYZABRI®, Biogen Idec, Massachusetts, United States) 300 mg IV monthly | Humanized monoclonal antibody against α4-integrin, inhibits the migration of lymphocytes through the blood-brain barrier into the CNS [117] | AFFIRM, GLANCE, ASCEND, and SENTINEL trials: Infusion reactions, fatigue, headache, arthralgia, hypersensitivity reactions, asymptomatic lymphocytosis, increased liver enzymes, flu-like symptoms, upper respiratory infections, urinary tract infections, anti-natalizumab antibodies, PML [118,119,120,121] | Severe hepatotoxicity in one case, melanoma, primary central nervous system lymphoma, T-cell lymphoma, herpes and varicella-zoster encephalitis and meningitis, cryptococcal meningitis, localized sporotrichosis, tumefactive demyelination [57,122,123,124,125,126,127,128,129,130,131,132,133,134] |
Ocrelizumab (OCREVUS®, Genentech, California, United States) 300 mg IV 2 weeks apart as initial dose then 600 mg IV every 6 months | Recombinant humanized second-generation anti-CD20 monoclonal antibody [135,136] | OPERA I, OPERA II, and ORATORIO trials: infusion-related reaction (pruritus, rash, throat irritation, and flushing, bronchospasm), nasopharyngitis, upper respiratory tract infection, herpes virus-associated infection, urinary tract infection, pneumonia, aspiration pneumonia, headache, antidrug-binding antibodies, invasive ductal breast carcinoma, renal-cell carcinoma, malignant melanoma, basal-cell skin carcinoma, endometrial adenocarcinoma, anaplastic large-cell lymphoma, malignant fibrous histiocytoma, pancreatic carcinoma, pulmonary embolism, pancreatic carcinoma, reactivation of occult hepatitis B virus infection [137,138,139,140] | One case of late-onset neutropenia associated with mucositis and neutropenic fever, hypogammaglobinemia, DRESS, refractory colitis, aseptic meningitis, endocarditis, Parvovirus B19 infection, tumefactive demyelination, HSV-2-encephalitis, psoriasiform dermatitis, reactivation of hepatitis B virus, fulminant hepatitis associated With Echovirus 25, 8 cases of PML (one of them attributable to ocrelizumab) [141,142,143,144,145,146,147,148,149,150,151,152,153,154] |
Disease Modifying Therapy | Routine Screening Prior to Initiation | Routine Monitoring while on Treatment |
---|---|---|
Oral therapies | ||
Teriflunomide (AUBAGIO®, Sanofi Genzyme, Massachusetts, United States) [22,144,196] | Baseline CBC and LFTs (within 6 months before starting therapy) Latent tuberculosis screening with a tuberculin skin test. Baseline blood pressure Pregnancy test, counseling on use of effective contraception in males and females of reproductive potential | CBC if signs/symptoms of hematologic toxicity, LFTs monthly for 6 months, then every 6 months thereafter Periodic blood pressure monitoring Confirm use of effective contraception at each encounter for both male and female patients during therapy |
Dimethyl fumarate (TECFIDERA®, Biogen Idec, Massachusetts, United States) [144,197,198] | Baseline CBC with absolute lymphocyte count Baseline LFTs and renal function tests Pregnancy test, counseling on use of effective contraception in females of reproductive potential | CBC with lymphocyte count after 6 months, every 6 to 12 months thereafter or as clinically indicated LFTs and renal function tests after 3 and 6 months, every 6 to 12 months thereafter and as clinically indicated Confirm use of effective contraception at each encounter for female patients during therapy |
Fingolimod (GILENYA®, Novartis, Basel, Switzerland) [37,42,199,200,201,202] | Baseline CBC and LFTs (within 6 months before starting therapy) Baseline ECG, review of medications (concomitant use of medications causing bradycardia or conduction abnormalities) Baseline ophthalmologic examination (or optical coherence tomography) Baseline skin examination (in most centers) Pregnancy test, counseling on use of effective contraception in females of reproductive potential VZV serology or confirmation of prior exposure. VZV vaccine in non-immunized patients prior to treatment start. Baseline clinical evaluation of respiratory function | CBC after 1, 3 and 6 months and periodically thereafter. LFTs after 1 month then every 3 months for the first year, then periodically thereafter First-dose cardiac monitoring Periodic blood pressure monitoring Ophthalmologic examination (or optical coherence tomography) 3–4 months after initiation, and at any time if patient reports visual disturbances. Regular ophthalmologic follow-up in patients with diabetes mellitus or a history of uveitis Self-check or dermatologist examination annually (in many centers) Confirm use of effective contraception at each encounter for female patients during therapy |
Siponimod (MAYZENT®, Novartis, Basel, Switzerland) [203] | CYP2C9 genetic testing Baseline ECG. Baseline blood pressure Baseline ophthalmologic examination Baseline CBC and LFTs (within 6 months before starting therapy) Pregnancy test, counseling on use of effective contraception in females of reproductive potential VZV serology or confirmation of prior exposure. VZV vaccine in non-immunized patients prior to treatment start Baseline evaluation of respiratory function | First-dose observation in high-risk patients only. Periodic blood pressure monitoring Ophthalmologic examination if clinically indicated CBC and LFT 3–6 months after starting treatment, then every 6–12 months Confirm use of effective contraception at each encounter for female patients during therapy |
Ozanimod (ZEPOSIA®, Celgene Corporation, New Jersey, United States) [46,204,205] | Obtain CBC and LFTs (within 6 months before starting therapy) Baseline ECG and baseline blood pressure Baseline ophthalmologic examination Pregnancy test, counseling on use of effective contraception in females of reproductive potential VZV serology or confirmation of prior exposure. VZV vaccine in non-immunized patients prior to treatment start. Baseline evaluation of respiratory function | CBC and LFT 3–6 months after starting treatment, then every 6–12 months Periodic blood pressure monitoring Ophthalmologic examination id clinically indicated onfirm use of effective contraception at each encounter for female patients during therapy |
Cladribine (MAVENCLAD®, Merck group, Darmstadt, Germany) [206] | CBC including absolute lymphocyte count and LFTs before each dose Pregnancy test, counseling on use of effective contraception in females and males of reproductive potential for at least 6 months after each dose Baseline Antibodies to VZV; VZV vaccination in antibody-negative patients 1 month prior to treatment initiation Tuberculosis screening, Hepatitis B and C panels, and HIV serology Standard age-appropriate cancer screening recommendations | CBC at 2 and 6 months after each dose Confirm use of effective contraception at each encounter for female patients during therapy Anti-herpes prophylaxis with acyclovir in patients with ALC less than 200 cells per microliter, and close monitoring for infections if ALC is below 500 cells per microliter |
Infusion therapies | ||
Natalizumab (TYSABRI®, Biogen Idec, Massachusetts, United States) [84,126,128,207,208,209,210] | Anti-JCV antibody serostatus and index Baseline CBC and LFTs Obtain a recent brain MRI (usually within 3 months) | Anti-JCV antibody testing every 6 to 12 months in seronegative patients for the first 2 years, and every 3–6 months thereafter CBC and LFT after 1, 3 and 6 months and every 6 months thereafter. Brain MRI yearly in JCV seronegative patients for the first 2 years, and every 3–6 months thereafter depending on JCV serostatus and risk of PML Neutralizing antibodies to natalizumab 6 months after initiation or at any time in patients with hypersensitivity reactions or disease exacerbations while on therapy. |
Alemtuzumab (LEMTRADA®, Sanofi, Genzyme, Massachusetts, United States) [116,211] | CBC, TSH, LFTs, creatinine, urine analysis with cell counts and urine protein to creatinine ratio Baseline skin (melanoma screening) and gynecologic (HPV/cervical dysplasia screening) exam Pregnancy test, counseling on use of effective contraception in females of reproductive potential for at least 4 months after each cycle Tuberculosis screening, Hepatitis B and C panels, and HIV serology VZV serology or confirmation of prior exposure. VZV vaccine in non-immunized patients prior to treatment start. Counselling on Listeria monocytogenes infection risk 2 weeks prior treatment initiation and while on treatment (avoidance of undercooked deli meat, seafood, or poultry, dairy products made with unpasteurized milk, and soft cheeses) | TSH every 3 months for 48 months following last course (second or subsequent course) CBC, creatinine and urine analysis with cell counts monthly for 48 months following last course (second or subsequent course). LFTs periodically until 48 months after the last dose Anti-viral prophylaxis with acyclovir 200 mg p.o twice daily for 24 months starting day 1 of first cycle, or for continue for a minimum of two months following treatment or until the CD4+ lymphocyte count is at least 200 cells per microliter, whichever occurs later Perform yearly skin and gynecologic exam Confirm use of effective contraception at each encounter for female patients during therapy |
Ocrelizumab (OCREVUS®, Genentech, California, United States) [212] | Baseline CBC and LFTs Hepatitis B and C and Tuberculosis screening. Pregnancy test, counseling on use of effective contraception in females of reproductive potential for at least 2 months after each cycle Vaccines according to age-appropriate immunization guidelines at least 6 weeks prior to treatment start Age-appropriate breast cancer screening | CBC and LFTs every 6 months Immunoglobulin levels in patients with severe or recurrent infections Confirm use of effective contraception at each encounter for female patients during therapy |
Disease Modifying Therapy | Suggested Strategies |
---|---|
Fingolimod (GILENYA®, Novartis, Basel, Switzerland) | Systematic pre-treatment and annual formal skin examination thereafter in all patients Gynecologic (HPV/cervical dysplasia screening) exam according to guidelines, consider yearly evaluation in high-risk patients, pre-treatment HPV vaccination as appropriate for age Brain MRI with contrast and CSF analysis with cryptococcal testing in the appropriate clinical context |
Cladribine (MAVENCLAD®, Merck group, Darmstadt, Germany) | Consider periodic lymphocyte phenotyping and close monitoring for infectious risk accordingly |
Alemtuzumab (LEMTRADA®, Sanofi, Genzyme, Cambridge, MA, USA) | Consider periodic lymphocyte phenotyping and close monitoring for infectious risk accordingly |
Ocrelizumab (OCREVUS®, Genentech, South San Francisco, CA, USA) | Breast cancer risk stratification and screening/monitoring accordingly. Pre-treatment and periodic immunoglobulin G, M and A levels CD19/CD20+ B cells levels for dosing adaptation |
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Jalkh, G.; Abi Nahed, R.; Macaron, G.; Rensel, M. Safety of Newer Disease Modifying Therapies in Multiple Sclerosis. Vaccines 2021, 9, 12. https://doi.org/10.3390/vaccines9010012
Jalkh G, Abi Nahed R, Macaron G, Rensel M. Safety of Newer Disease Modifying Therapies in Multiple Sclerosis. Vaccines. 2021; 9(1):12. https://doi.org/10.3390/vaccines9010012
Chicago/Turabian StyleJalkh, Georges, Rachelle Abi Nahed, Gabrielle Macaron, and Mary Rensel. 2021. "Safety of Newer Disease Modifying Therapies in Multiple Sclerosis" Vaccines 9, no. 1: 12. https://doi.org/10.3390/vaccines9010012