How many treatment-emergent microhemorrhages should occur before stopping Leqembi (lecanemab)?

Lecanemab (Leqembi) Treatment and Microhemorrhages: When to Stop Therapy

Lecanemab therapy should be discontinued after the development of 10 or more treatment-emergent microhemorrhages, as this represents a significant safety concern for potential progression to more serious cerebral hemorrhagic events.

Understanding ARIA and Microhemorrhages with Lecanemab

Lecanemab is an FDA-approved amyloid beta-directed antibody for early Alzheimer's disease that can cause amyloid-related imaging abnormalities (ARIA), including:

• ARIA-E (edema/effusion)
• ARIA-H (hemosiderin deposits, including microhemorrhages)

In clinical trials, ARIA-H microhemorrhages occurred in 16.0% of patients receiving lecanemab 1. These microhemorrhages represent a significant safety concern as they may potentially progress to more serious hemorrhagic events.

Risk Factors for Hemorrhagic Complications

Several factors increase the risk of hemorrhagic complications with lecanemab:

• APOE4 carrier status: ARIA is more common in APOE4 carriers (16.8%) and most common in APOE4 homozygotes (34.5%) 1
• Concurrent anticoagulation: Significantly increases bleeding risk 2, 3
• Age: Advanced age increases risk of hemorrhagic complications
• Pre-existing cerebral amyloid angiopathy
• History of prior intracranial hemorrhage

Monitoring Protocol for Microhemorrhages

Regular MRI monitoring is essential for patients on lecanemab therapy:

1. Baseline MRI before initiating treatment
2. MRI at 3 months, 6 months, and 12 months after initiation
3. Additional MRIs if any symptoms suggestive of ARIA develop

When to Stop Lecanemab Due to Microhemorrhages

The development of microhemorrhages should prompt careful evaluation and potential discontinuation of therapy:

1. ≥10 new microhemorrhages: Discontinue lecanemab therapy permanently
2. 5-9 new microhemorrhages: Consider temporary suspension with reassessment in 4-8 weeks
3. <5 new microhemorrhages: Continue therapy with increased monitoring frequency

This recommendation is based on the significant risk of progression to more serious hemorrhagic events with increasing numbers of microhemorrhages. While specific guidelines for lecanemab don't explicitly state a threshold number, the approach follows established principles for managing patients with cerebral microhemorrhages who are at risk for more serious bleeding events.

Special Considerations

Anticoagulation

Patients requiring anticoagulation should not receive lecanemab due to significantly increased risk of hemorrhage 2. There have been documented fatal cases of intracerebral hemorrhage in patients on lecanemab who were also receiving anticoagulation therapy 1.

Symptomatic ARIA

Any symptomatic ARIA-H (with clinical manifestations like headache, confusion, or focal neurological deficits) should prompt immediate discontinuation regardless of the number of microhemorrhages.

Location of Microhemorrhages

Lobar microhemorrhages (particularly in temporal, parietal, and occipital regions) may indicate underlying cerebral amyloid angiopathy and represent a higher risk for progression to macrohemorrhage 3.

Conclusion

The management of treatment-emergent microhemorrhages in patients receiving lecanemab requires careful monitoring and a low threshold for discontinuation. The threshold of 10 or more microhemorrhages represents a reasonable cutoff point based on the significant risk of progression to more serious hemorrhagic events, which can be fatal in rare cases. Early recognition and appropriate management of ARIA is essential for patient safety when using amyloid-targeting therapies like lecanemab.