CAR T Related Pharmacotherapy Concepts

Chimeric antigen receptor T-cell therapy uses a patient's own T cells, engineered to recognise a tumour antigen (CD19 in B-cell cancers; BCMA in myeloma), expanded and re-infused after lymphodepleting chemotherapy. The pharmacotherapy around it covers lymphodepletion, management of cytokine release syndrome and immune effector cell-associated neurotoxicity, infection prevention, and supportive care. It is delivered only in specialist transplant centres.

Classification. Lymphodepleting chemotherapy; interleukin-6 blockers (tocilizumab, siltuximab); corticosteroids (dexamethasone, methylprednisolone); interleukin-1 blockade (anakinra); antiseizure drugs; antimicrobial prophylaxis; immunoglobulin replacement.

Pharmacokinetics. CAR T cells expand in the body within 1 to 2 weeks and may persist for months to years.

• Lymphodepletion: fludarabine 25 to 30 mg/m2 and cyclophosphamide 250 to 500 mg/m2 daily on days minus 5 to minus 3 before infusion (doses reduced for kidney impairment).
• Tocilizumab 8 mg/kg intravenously over 1 hour (12 mg/kg if under 30 kg; maximum 800 mg a dose); repeat after 8 hours if no response; maximum 3 doses in 24 hours and 4 in total.
• Dexamethasone 10 mg intravenously every 6 hours for severe cytokine release syndrome or neurotoxicity; methylprednisolone 1 g daily for 3 days for life-threatening toxicity.
• Anakinra 100 mg subcutaneously or intravenously every 6 to 12 hours for refractory toxicity; siltuximab 11 mg/kg for tocilizumab-refractory syndrome.
• Levetiracetam 500 to 750 mg twice daily for seizure prophylaxis in selected high-risk patients.

Differences. Cytokine release syndrome usually appears 1 to 14 days after infusion with fever, hypotension and hypoxia; neurotoxicity appears later (days 3 to 28) with confusion, aphasia, seizures or cerebral oedema. Early treatment of cytokine release syndrome with tocilizumab does not appear to reduce efficacy.

• Indications for cellular therapy: relapsed or refractory large B-cell lymphoma, acute lymphoblastic leukaemia in younger patients, mantle cell lymphoma, follicular lymphoma, and multiple myeloma; chosen by the transplant team.
• Monitoring after infusion: admission or daily review for at least 7 to 14 days and stay near the treating centre for 4 weeks; temperature, blood pressure, oxygen saturation, orientation and handwriting (neurotoxicity assessed daily using a validated score).
• Fever after infusion: assume infection and cytokine release syndrome together: blood cultures and broad-spectrum antibiotics immediately.
• Management by grade: grade 1 (fever only): supportive care and antipyretics; grade 2 (hypotension or hypoxia needing low-flow oxygen): tocilizumab; grade 3 to 4: tocilizumab with dexamethasone 10 mg every 6 hours and intensive care.
• Neurotoxicity: dexamethasone 10 mg every 6 hours (grade 2 or more); tocilizumab when concurrent cytokine release syndrome (tocilizumab does not cross the blood-brain barrier and may not help neurotoxicity alone); anakinra or methylprednisolone for severe cases.
• Prophylaxis: aciclovir, an antifungal and co-trimoxazole (pneumocystis) from lymphodepletion until immune recovery, intravenous immunoglobulin for IgG under 4 g/L with infections, and irradiated blood products.
• Haematological recovery: G-CSF after cytokine release syndrome has resolved.
• Regional: not available in most of East Africa; patients are referred abroad or to a few centres; local teams need to know the signs and give early steroids and antimicrobials in returning patients.

Selection. Decided by a specialist team, with early involvement of intensive care and neurology.

Contraindications. Active uncontrolled infection; active graft-versus-host disease; severe organ dysfunction; pregnancy.

Adverse effects. Cytokine release syndrome, neurotoxicity, prolonged cytopenias, B-cell aplasia and hypogammaglobulinaemia, infections, tumour lysis syndrome, haemophagocytic lymphohistiocytosis, parkinsonism-like movement disorder (BCMA products), and secondary T-cell malignancy.

Interactions. Avoid corticosteroids before infusion unless essential; live vaccines are contraindicated for at least 6 weeks before lymphodepletion and 12 months after; avoid driving for 8 weeks after infusion.

Special groups.

• Pregnancy: contraindicated; effective contraception.
• Children and young adults: acute lymphoblastic leukaemia indications, with dose by weight band.
• Older adults: higher neurotoxicity.
• Kidney impairment: reduce fludarabine; tocilizumab needs no change.
• Liver impairment: caution.

Monitoring. Full blood count, ferritin, C-reactive protein, fibrinogen, liver function, creatinine, immunoglobulins, B-cell counts, and infection surveillance.

Referral and escalation. All patients return to the treating centre for fever, confusion, seizures, hypotension or hypoxia; these are emergencies.