Multiple Sclerosis and Demyelinating Diseases 3 Flashcards
Cladribine: indications, dosage
RRMS amd active SPMS
Indicated for the treatment of relapsing forms of multiple sclerosis, to include relapsing-remitting disease and active secondary progressive disease, in adults.
Because of its safety profile, use of MAVENCLAD is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS
(FDA)
Δοσολογία:
Η συνιστώμενη σωρευτική δόση είναι 3,5 mg/kg σωματικού βάρους για 2 έτη, χορηγούμενη ως 1 περίοδος θεραπείας των 1,75 mg/kg ανά έτος.
Κάθε περίοδος θεραπείας αποτελείται από 2 εβδομάδες θεραπείας, μία στην αρχή του πρώτου μήνα και μία στην αρχή του δεύτερου μήνα του αντίστοιχου έτους θεραπείας.
Εάν είναι ιατρικά απαραίτητο (π.χ. για την ανάκαμψη των λεμφοκυττάρων), η περίοδος θεραπείας κατά το έτος 2 μπορεί να καθυστερήσει για έως και 6 μήνες.
Κάθε εβδομάδα θεραπείας αποτελείται από 4 ή 5 ημέρες κατά τις οποίες ο ασθενής λαμβάνει 10 mg ή 20 mg (ένα ή δύο δισκία) ως εφάπαξ ημερήσια δόση, ανάλογα με το σωματικό βάρος.
Μετά την ολοκλήρωση των 2 περιόδων θεραπείας, δεν απαιτείται περαιτέρω θεραπεία με κλαδριβίνη κατά τα έτη 3 και 4.
Η επανέναρξη της θεραπείας μετά το έτος 4 δεν έχει μελετηθεί.
Cladribine: mechanism of action, monitoring
νουκλεοσιδικό ανάλογο της δεοξυαδενοσίνης
Cytotoxic to T and B lymphocytes by impairing DNA synthesis
Typically, the nadir of lymphocyte counts occurs 2 to 3 months after the start of each treatment cycle.
Oral cladribine can penetrate the blood-CNS barrier.
Monitoring:
Before initiating each course:
* CBC including lymphocyte count (before each treatment course, 2 and 6 months after the start of each yearly course [if 2-month lymphocyte <200 cells/mm3, monitor monthly until month 6], and periodically during and after treatment);
* liver function tests (serum aminotransferase, alkaline phosphatase, and total bilirubin levels) (prior to each treatment course and as clinically appropriate).
* Evaluate HIV, tuberculosis, hepatitis B and hepatitis C status (prior to each treatment course);
* evaluate varicella zoster virus (VZV) antibody status (prior to treatment initiation). Patients who are negative to VZV antibodies should be vaccinated
* Verify pregnancy status (prior to each treatment course in patients who could become pregnant).
* MRI (at baseline [within 3 months] prior to first treatment course).
Following initiation:
- evaluate for PML
- monitor for acute infections
- follow standard guidelines for cancer screening
Cladribine: side effects (>10%) and contraindications
Decreased hemoglobin
decreased platelet count
lymphocytopenia
Hypersensitivity reaction
Infection
Headache
Upper respiratory tract infection
Contraindications:
Current malignancy; pregnancy; individuals of reproductive potential who do not plan to use effective contraception during therapy and for 6 months after the last dose in each treatment course; HIV infection; active chronic infections (eg, hepatitis or tuberculosis); breastfeeding (during treatment or for 10 days after last dose)
Vaccination and Cladribine
Vaccination with live or live-attenuated vaccines should be 4 weeks before therapy initiation, and these vaccines are contraindicated during oral cladribine treatment
Cladribine: κριτήρια για έναρξη και συνέχιση θεραπείας
Οι αριθμοί των λεμφοκυττάρων πρέπει να είναι
* φυσιολογικοί πριν την έναρξη της θεραπείας κατά το έτος 1,
* τουλάχιστον 800 κύτταρα/mm³ πριν την έναρξη της θεραπείας κατά το έτος 2.
Εάν είναι απαραίτητο, η περίοδος θεραπείας κατά το έτος 2 μπορεί να καθυστερήσει για έως και 6 μήνες για να επιτραπεί η ανάκαμψη των λεμφοκυττάρων.
Εάν αυτή η ανάκαμψη χρειάζεται περισσότερο από 6 μήνες, ο ασθενής δεν πρέπει να λάβει δισκία κλαδριβίνης πλέον.
Ocrelizumab: indications, dosage
- CIS, RRMS, active SPMS, primary progressive MS
- IV: 300 mg once on day 1, followed by 300 mg once 2 weeks later; subsequent doses of 600 mg are administered once every 6 months (beginning 6 months after the first 300 mg dose)
Ocrelizumab: mechanism of action, monitoring, pregnancy
Lytic monoclonal antibody targeting CD20 molecule on surface of B cells
Monitoring:
Before initiating:
- Hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) tests (prior to therapy initiation); do not administer to patients with active hepatitis B virus confirmed by positive results for HBsAg and anti-HB tests;
- Perform latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline).
- Monitor quantitative serum immunoglobulins (baseline, throughout treatment as clinically necessary, especially in patients with opportunistic or recurrent infections, after discontinuation of therapy until B-cell repletion).
- Assess for active infection prior to treatment.
Following initiation:
- Monitor for infusion reactions during infusion and for at least 1 hour following the end of the infusion.
- Monitor for signs/symptoms of immune-mediated colitis (evaluate promptly if colitis is suspected), infection, malignancy, and progressive multifocal leukoencephalopathy (PML).
- Perform brain MRI (at first signs/ symptoms suggestive of PML and as clinically indicated to monitor for early signs of PML).
Not recommended in pregnancy
Ocrelizumab: side effects (>10%), contraindications
- Skin infection
- Decreased neutrophils, decreased serum immunoglobulins (IgM most affected)
- Infusion-related reaction
- Infection
- Upper respiratory tract infection
Contraindications: patients with active hepatitis B virus infection and those with a history of life threatening infusion reaction to ocrelizumab
How is humoral immunity preseved in treatment with ocrelizumab?
Administration of ocrelizumab produces profound and sustained depletion of B cells.
Importantly, plasma cells are spared, which allows for preservation of humoral immunity.
Ofatumumab: indications, dosage
- CIS, RRMS, active SPMS
- SUBQ: Initial: 20 mg once weekly for 3 doses (weeks 0, 1, and 2); maintenance: 20 mg once monthly starting at week 4
Ofatumumab: mechanism of action, monitoring, pregnancy
Lytic monoclonal antibody targeting CD20 molecule on surface of B cells
Monitoring
Before initiating:
* Monitor quantitative serum immunoglobulins (at baseline, throughout treatment as clinically necessary, especially in patients with opportunistic or recurrent infections, after discontinuation of therapy until B-cell repletion);
* HBsAg, hepatitis B core antibody (HBcAb), and other hepatitis B markers as per local guidelines (baseline and as clinically necessary);
* latent infection screening (eg, hepatitis, tuberculosis) in high-risk populations or in countries with high tuberculosis burden (baseline).
Following initiation:
Monitor for signs/symptoms of PML (eg, altered mental status, motor deficits [hemiparesis or monoparesis], limb/gait ataxia, and/or vision disturbances); monitor MRI (as clinically indicated).
Not recommended in pregnancy
Ofatumumab: side effects (>10%)
- Infection, serious infection
- Injection site reaction (systemic [chills, fatigue, fever, myalgia]: local: [erythema, pain, pruritus, swelling]:
- Headache
Alemtuzumab: indications, dosage
- RRMS and active SPMS after suboptimal response to two or more other agents
- IV: 12 mg daily for 5 consecutive days (total 60 mg), followed 12 months later by 12 mg daily for 3 consecutive days (total 36 mg). Subsequent treatment courses of 12 mg daily for 3 consecutive days (total 36 mg) may be administered if necessary
Alemtuzumab: mechanism of action, monitoring
- Monoclonal antibody that lyses cells expressing
CD52 causing widespread and sustained depletion of lymphocytes, followed first by slow repopulation of B cells and eventually of T cells - CBC with differential, lymphocyte subsets, LFTs, TSH, creatinine, urinalysis
Alemtuzumab: side effects
- autoimmune conditions, such as immune thrombocytopenia (αυτοάνοση θρομβοπενική πορφύρα) and anti-glomerular basement membrane disease
- increased risk of malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders
- stroke
- Pruritus, skin rash, urticaria
- Thyroid disease
- Diarrhea, nausea
- Urinary tract infection
- Lymphocytopenia
- Infusion-related reaction
- Antibody development
- Fungal infection, herpes virus infection
- Fatigue, headache, insomnia
- Arthralgia, back pain, limb pain
- Nasopharyngitis, oropharyngeal pain, sinusitis, upper respiratory tract infection
- Fever
Alemtuzumab: for which infection should prophylaxis be taken after initiation
Prophylaxis for herpes virus for at least 2 months or until CD4+ lymphocyte counts are 200
Has PML ever been reported in Ocrelizumab patients?
Case report JAMA neurology 2021
Which MS drugs are considered immunomodulatory and which immunosuppresing?
Immunomodulatory: Interferons and glatiramer acetate
They are not associated with opportunistic infections or increased cancer rates.
Immunosuppresing: Rest