What are the risks of macro hemorrhage in patients receiving donanemab (anti-amyloid antibody)

Risks of Macrohemorrhage in Patients Receiving Donanemab

Patients receiving donanemab are at risk for intraparenchymal macrohemorrhages (>10mm in diameter), which is a serious adverse event that can significantly impact morbidity and mortality, and is a contraindication for initiating treatment in patients with pre-existing macrohemorrhages. 1

Definition and Screening

• Macrohemorrhages in the context of anti-amyloid antibody therapy are defined as intraparenchymal hemorrhages >10mm in diameter, which are detectable on MRI 1
• These hemorrhages are part of the spectrum of Amyloid-Related Imaging Abnormalities with hemorrhage (ARIA-H) that can occur with anti-amyloid monoclonal antibody therapies 1
• Pre-treatment screening with MRI is mandatory within 12 months of initiating donanemab therapy to detect exclusionary findings, including existing macrohemorrhages 1

Risk Factors for Macrohemorrhage with Donanemab

• Pre-existing cerebrovascular pathology, particularly:
  • History of prior macrohemorrhages >10mm in diameter 1
  • Presence of 4 or more microhemorrhages <10mm in diameter 1
  • Superficial siderosis 1
  • Cerebral amyloid angiopathy (CAA) 1, 2
• Patient-specific risk factors:
  • Advanced age 3, 2
  • APOE ε4 carrier status, especially homozygotes 4, 5
  • Concomitant use of antiplatelet or anticoagulant medications 3, 2
  • History of prior strokes 3

Incidence and Clinical Significance

• In clinical trials, ARIA-H (including microhemorrhages and macrohemorrhages) had an incidence ranging from 15% to 20% 1
• Specifically for donanemab:
  • In the TRAILBLAZER-ALZ phase 2 and 3 trials, ARIA-E (edema) was detected in up to 26.7% of patients 1
  • Cerebral microhemorrhage events occurred in 13.0% of patients receiving donanemab in phase 1b studies 6
  • At least one fatality due to ARIA-H (hemorrhage) with donanemab has been reported 2

Monitoring Requirements

• MRI monitoring is essential for early detection of ARIA-H, including macrohemorrhages 1
• MRI must include specific sequences:
  • DWI (diffusion-weighted imaging)
  • T2 FLAIR (fluid-attenuated inversion recovery)
  • T2* GRE (gradient-echo) or SWI (susceptibility-weighted imaging) 1
• 3T MRI units provide greater sensitivity for detection of hemorrhagic abnormalities 1
• Regular monitoring at specified intervals is required during treatment 1
• Additional MRI should be performed if patients develop new neurological signs or symptoms 1, 2

Management of Macrohemorrhage Risk

• Patients with pre-existing macrohemorrhages >10mm should be excluded from donanemab therapy 1
• Management of ARIA-H depends on clinical symptoms and MRI grading severity 1
• Detection of significant ARIA-H may require:
  • Temporary suspension of treatment
  • Permanent cessation of treatment in severe cases 1, 2
• Patients requiring anticoagulation may have higher risk and should be carefully evaluated before initiating therapy 3, 2, 7

Prevention Strategies

• Thorough pre-treatment screening to exclude high-risk patients 1
• Consider APOE ε4 testing before treatment to assess ARIA risk 4, 5
• Careful management of modifiable risk factors:
  • Blood pressure control 1
  • Avoiding concomitant use of antiplatelet or anticoagulant medications when possible 3, 2
• Dose titration strategies may mitigate risk of ARIA, though specific protocols for donanemab may vary 2

Clinical Implications and Decision-Making

• Benefit-risk assessment should consider that clinical benefit may be reduced in certain patient populations 4
• The presence of lobar macrohemorrhages may suggest underlying cerebral amyloid angiopathy, which increases the risk of recurrent hemorrhage 1
• Careful patient selection and monitoring are essential, particularly for those with identified risk factors 4
• Patients and caregivers should be educated about symptoms that might indicate hemorrhagic complications 2, 7

The risk of macrohemorrhage with donanemab represents a significant concern that requires careful patient selection, thorough pre-treatment screening, and vigilant monitoring throughout the treatment course to minimize morbidity and mortality.