What is the treatment for relapsed or refractory Acute Myeloid Leukemia (AML) with gemtuzumab ozogamicin?

Gemtuzumab Ozogamicin for Relapsed/Refractory AML

Gemtuzumab ozogamicin (GO) is the recommended treatment for relapsed or refractory CD33-positive AML in adults and pediatric patients 2 years and older, with a dose of 9 mg/m² administered intravenously on days 1 and 14. 1

Patient Selection and Eligibility

• Verify CD33 expression in ≥30% of leukemic blasts before administering GO 2
• Ensure patient is appropriate for GO therapy:
  • FDA-approved for relapsed/refractory CD33+ AML in adults and children ≥2 years 1
  • Particularly effective in patients with favorable or intermediate-risk cytogenetics 3
  • Consider alternative therapies for patients with adverse cytogenetics

Treatment Protocol

Dosing and Administration

• Standard dose: 9 mg/m² IV infused over 4 hours on day 1, repeated on day 14 1
• Premedication required to prevent infusion reactions:
  • Adults: acetaminophen 650 mg PO, diphenhydramine 50 mg PO/IV 1 hour before GO, and methylprednisolone 1 mg/kg within 30 minutes before infusion 1
  • Pediatric patients: acetaminophen 15 mg/kg (max 650 mg), diphenhydramine 1 mg/kg (max 50 mg), and methylprednisolone 1 mg/kg 1

Special Considerations

• For patients with hyperleukocytosis (WBC ≥30 Gi/L), cytoreduction is recommended prior to GO administration to prevent tumor lysis syndrome and ARDS 1, 4
• Lower doses (3 mg/m²) may be safer with comparable efficacy compared to higher doses 3

Response Assessment and Follow-up Therapy

• After GO therapy, approximately 30% of patients achieve overall response (16% complete remission, 14% complete remission with incomplete platelet recovery) 4
• In recent studies, overall response rates of 54.1% have been reported with GO in r/r AML 5
• For patients achieving remission, consider consolidation options:
  • Additional cycles of ATO with or without ATRA/standard chemotherapy 6
  • Hematopoietic stem cell transplantation (HSCT) 6

HSCT Considerations

• Wait at least 2 months between the last dose of GO and HSCT conditioning to reduce risk of VOD/SOS 2
• Autologous HSCT is preferred for patients without detectable minimal residual disease and prolonged (>1 year) first CR 6
• Allogeneic HSCT should be considered for patients failing to achieve second molecular remission and those with short first CR duration 6

Monitoring and Management of Adverse Effects

Hepatotoxicity

• Monitor frequently for signs and symptoms of hepatic veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) 1
• Liver function tests should be monitored regularly during treatment
• 37.5% of patients may experience elevated liver function tests 5

Hematologic Toxicity

• Myelosuppression is common, especially neutropenia and thrombocytopenia 4
• Monitor for febrile neutropenia (occurs in approximately 25% of patients) 5
• Consider prophylactic antimicrobials when GO is given in combination or at high doses 2

Infusion-Related Reactions

• Acute infusion-related symptoms are usually transient and respond to standard care 5
• Be prepared to repeat corticosteroid dose for any sign of infusion reaction during or within 4 hours after infusion 1

Other Common Adverse Events

• Nausea/vomiting (79.2% of patients) 5
• Headache (62.5% of patients) 5
• Bleeding (25% of patients) 5
• Infections (most common cause of death is septic shock) 5

Mechanism of Action and Rationale

GO is a humanized anti-CD33 monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic that causes DNA damage and apoptosis 4. It targets CD33, which is expressed on monocytes, granulocytes, mast cells, and myeloid progenitors 6.

GO has been shown to eliminate leukemic initiating cells (LICs) when combined with induction chemotherapy, which may explain its efficacy in relapsed/refractory disease 7.

Clinical Pearls and Pitfalls

• GO was withdrawn from the market in 2010 but reapproved by the FDA in 2017 with modified dosing recommendations 8
• GO shows greater benefit in patients with favorable or intermediate-risk cytogenetics 3
• The risk of VOD/SOS is increased in patients who proceed to HSCT shortly after GO therapy 1
• Tumor lysis and ARDS have been reported in patients with leukocytes above 30,000/ml treated with GO; reduction of leukocyte counts before treatment is recommended 4
• No specific risk of infection is associated with GO monotherapy, but standard antimicrobial prophylaxis should be considered when given in combination with other agents 6

GO represents an important targeted therapy option for relapsed/refractory AML patients with CD33-positive disease, offering meaningful response rates and potential survival benefits when used appropriately.