Updated Safety Information: Pegylated Liposomal Doxorubicin

The product information for pegylated liposomal doxorubicin (Caelyx®) has been updated. The adverse effects section now includes advice that renal-limited thrombotic microangiopathy (TMA) has been reported in association with high cumulative exposure.

Pegylated liposomal doxorubicin (PLD) is a specialised formulation of the anthracycline chemotherapeutic, doxorubicin. Encapsulation of doxorubicin in polyethylene-glycol (PEG)-coated liposomes prolongs its circulation time, enhances tumour targeting, and may reduce key toxicities such as cardiotoxicity and myelosuppression. These properties have made PLD a valuable option in the treatment of a range of malignancies, including Kaposi sarcoma, ovarian cancer, and breast cancer.

While pegylation reduces some toxicities, this formulation is associated with higher rates of palmar-plantar erythrodysesthesia. More recently, rare reports have emerged of renal-limited TMA.

What is renal-limited thrombotic microangiopathy?

Thrombotic microangiopathy refers to a group of conditions characterised by:

• Endothelial injury in microvessels;
• Microvascular thrombosis; and
• Organ dysfunction.

The condition is often drug-induced, although other causes include autoimmune diseases, malignant hypertension, and infections.

When TMA affects the kidneys without systemic haemolysis or thrombocytopaenia, it is classified as renal-limited TMA. While not a common finding, renal-limited TMA has a poor prognosis. One recent study demonstrated that 30% of these patients will progress to end-stage kidney disease.

Case reports

Renal‑limited TMA has previously been reported in association with PLD, although many early cases involved patients also taking other medications known to cause TMA. More recently, the American Journal of Kidney Diseases published a case report of two patients who developed this condition in association with PLD without exposure to other TMA-causing drugs.

Case details include:

• High cumulative PLD doses (760mg/m² and 1240mg/m²)
• Proteinuria and rising serum creatinine
• Kidney biopsy consistent with chronic TMA
• No exposure to other drugs known to cause TMA
• Stabilisation or improvement occurred once PLD was ceased. Neither patient required dialysis.

Additional clinical reports:

• Renal-limited TMA was reported in an 80-year old man after extended PLD monotherapy for metastatic Kaposi sarcoma. Acute kidney injury resulted and the patient required haemodialysis. The patient’s clinical history, laboratory, and kidney biopsy data all support PLD as the primary aetiologic factor.
• A case was reported in a kidney transplant recipient with Kaposi sarcoma in remission following treatment with PLD. This patient developed a slowly progressive renal-limited TMA that was proven on biopsy. Kidney function improved following discontinuation of PLD. The patient presented with Kaposi sarcoma recurrence and, due to poor tolerance to alternative therapies, was restarted on PLD. Kidney function started to deteriorate again three months after resuming PLD therapy.

Across case reports, high cumulative PLD exposure (often >700-800mg/m²) is a common factor. However, one report occurred at a lower cumulative dose (~300mg/m²) in a patient with preexisting chronic kidney disease (CKD) and hypertension. This highlights the potential for patient-specific susceptibilities.

Clinical features

Renal-limited TMA linked to PLD tends to present with:

• Gradual rise in serum creatinine;
• Proteinuria;
• Hypertension; and
• Little or no evidence of systemic haemolysis or thrombocytopaenia.

The mechanism for how PLD may cause this condition is not understood. However, processes implicated in other drug-induced cases of TMA include:

• Endothelial cell injury due to oxidative stress;
• Platelet aggregation triggered by damaged microvascular endothelium; and
• Impaired microcirculatory blood flow in glomeruli.

Management and monitoring

Early recognition is critical to minimise renal impairment. Increases in creatinine, new proteinuria or hypertension in patients on PLD may warrant evaluation for renal-limited TMA. Renal biopsy is required for definitive diagnosis.

Management of renal-limited TMA includes removal of the causative agent along with supportive care. Cessation of the causative agent often stabilises or improves kidney function if implemented early.

A wide range of medications have been associated with drug‑induced TMA, with chemotherapeutics and quinine most commonly implicated. However, establishing causal relationships with drugs is challenging and the condition is thought to be under-recognised. Some medications linked with TMA are shown in Table 1.

Table 1. Drugs associated with TMA (adapted from Mazzierli 2023)

*Cases of TMA secondary to the intravenous use of the sustained-release product intended for oral use. This is suspected to be related to the polyethylene oxide coating on these tablets which may be directly toxic to endothelial cells. Other excipients may also play a role.    

Conclusion

Pegylated liposomal doxorubicin has some potential advantages over conventional doxorubicin in terms of reduced cardiotoxicity and enhanced pharmacokinetics. However, it may be associated with renal-limited TMA. While this adverse event is rare, the clinical outcome is often poor.

Awareness of this association, along with active monitoring of renal function and early investigation of kidney injury are vital. These steps can prevent irreversible kidney damage and preserve renal function in affected patients.