Mylotarg
Mylotarg
Generic Name
Mylotarg
Mechanism
- Target: CD33 receptor expressed on >90 % of AML blasts.
- Binding & Internalization: The antibody binds CD33 → receptor‑mediated endocytosis.
- Linker Cleavage: Inside the lysosome, a hydrazine‑based linker is cleaved.
- Drug Release: The small‑molecule cytotoxic auristatin G is released, inhibiting microtubule polymerization.
- Cell Death: Disruption of microtubules → mitotic arrest → apoptosis of the leukemic cell.
This targeted delivery preserves normal marrow cells while maximizing cytotoxicity to AML blasts.
Pharmacokinetics
| Parameter | Typical Value (Adult) | Notes |
| Absorption | Intravenous infusion; complete bioavailability | No oral formulation |
| Volume of Distribution | 60–120 mL/kg | Reflects antibody component |
| Metabolism | Proteolytic catabolism → amino acids | No hepatic CYP involvement |
| Elimination | Renal & biliary excretion of metabolites | Elimination half‑life of the intact drug ~8–12 h; active metabolite longer |
| Clearance | ~0.7 mL/min/kg | Reduced in renal impairment |
| Protein Binding | 70–80 % | Mostly to serum albumin and Fc receptors |
> Clinical Tip: No dose adjustment required for mild–moderate renal impairment; avoid in severe renal failure (CrCl < 30 mL/min) pending further data.
Indications
- Acute myeloid leukemia (AML) –
- Newly diagnosed, unfit for intensive chemotherapy or as salvage therapy.
- First‑line in combination with cytarabine ± anthracycline (e.g., 7 + 3).
- Post‑remission consolidation in high‑risk cytogenetic AML (except t(15;17)).
> Off‑label: Consider in relapsed/refractory AML where no standard options remain.
Contraindications
- Contraindicated in patients with:
- Known hypersensitivity to gemtuzumab‑ozogamicin or murine proteins.
- Active infections precluding immunosuppression.
- Warnings:
- Veno‑occlusive disease (VOD)—especially post‑bone‑marrow transplant.
- Immune‑mediated cytokine release syndrome (CRS)—may mimic sepsis.
- Hepatotoxicity & transaminitis.
- Toxic epidermal necrolysis / Stevens–Johnson syndrome in severe reactions.
- Precautions:
- Avoid in pregnancy and lactation (category X).
- Use with caution in patients with pre‑existing liver disease or ongoing drug interactions that may affect albumin levels.
Dosing
| Regimen | Dose | Infusion Rate | Cycle |
| Initial Dose | 3 mg/m² (max 150 mg) | 1 h | 1st cycle |
| Subsequent Dose | 1.5 mg/m² (max 75 mg) | 1–2 h | 2nd–6th cycles |
| Total Cycles | 6 | – | 6–8 weeks |
• Pre‑medication: Antipyretic (acetaminophen) ± antihistamine 30 min before infusion.
• Monitoring: Baseline CBC, CMP, bilirubin; repeat CBC ≥ daily for 14 days, CMP weekly.
• Infusion Duration: 90 min for first dose; 60 min for subsequent.
> Important: Do not exceed 6 cumulative cycles; dose escalation beyond 6 is not FDA‑approved.
Adverse Effects
- Common (≥10 %)
- Neutropenia, thrombocytopenia
- Fever, chills, infusion‑related reactions
- Nausea, vomiting, constipation
- Fatigue, anorexia
- Serious (≤10 %)
- Veno‑occlusive disease of the liver (VOD) – 5–10 %
- Cytokine release syndrome (CRS) – 3–5 %
- Severe hepatotoxicity (ALT/AST ↑ >5× ULN) – 2–3 %
- Drug reaction with eosinophilia and systemic symptoms (DRESS) – < 1 %
- Cardiac arrhythmias (rare)
- Late‑onset
- Secondary malignancies (e.g., acute lymphoblastic leukemia) Management:
>
• Administer tocilizumab or steroids for CRS.
>
• Treat VOD with defibrotide if early signs appear.
>
• Supportive care for cytopenias.
Monitoring
| Parameter | Frequency | Rationale |
| CBC (WBC, ANC, platelets) | Daily first 10 days, then weekly | Tracks cytopenias, risk of infection |
| CMP (AST, ALT, bilirubin, creatinine) | Weekly | Detect hepatotoxicity, VOD |
| Liver Ultrasound (if VOD suspected) | As needed | Visualize hepatic blood flow |
| BP & HR (CRS monitoring) | Pre‑infusion, every 15 min during infusion, then 4 h post | Detect cytokine‑mediated hemodynamic changes |
| Temperature | Pre‑infusion and 24 h post | Monitor fever, infection risk |
| Pregnancy test | Women of childbearing potential | Avoid teratogenic exposure |
> Alert: Patients with baseline bilirubin > 2 mg/dL are at increased VOD risk; consider dose reduction or defer therapy.
Clinical Pearls
- Infusion Speed Matters: Faster infusions (>45 min) increase CRS risk; slow the rate to ≤2 h.
- Bilirubin Check: A pre‑infusion bilirubin > 2 mg/dL is a red flag; consider switching to alternative AML regimens.
- Post‑Transplant VOD: Avoid Mylotarg within 30 days pre‑ or post‑stem cell transplant unless absolutely required.
- Combination with Idarubicin: Studies suggest synergistic benefit, but vigilance for overlapping cardiotoxicity.
- Adjuvant Therapy: Pairing Mylotarg with low‑dose cytarabine extends overall survival in older adults (≥60 y).
- Patient Education: Emphasize signs of VOD (painful hepatomegaly, weight gain, jaundice) and CRS (fever, hypotension).
- Drug–Drug Interactions: Minimal CYP involvement; watch for drugs affecting albumin levels that may alter free drug fraction.
> These pearls help tailor Mylotarg therapy safely to the most vulnerable AML patients while minimizing life‑threatening complications.