What is the Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimen for Acute Lymphoblastic Leukemia (ALL)?

Hyper-CVAD Regimen for Acute Lymphoblastic Leukemia (ALL)

The Hyper-CVAD regimen is an effective intensive chemotherapy protocol for adult ALL that consists of alternating cycles of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) with high-dose methotrexate and cytarabine, and includes CNS prophylaxis. 1

Regimen Components and Administration

Hyper-CVAD Cycles (Odd-numbered cycles: 1,3,5,7)

• Cyclophosphamide: 300 mg/m² IV twice daily on days 1-3 (total 6 doses), hyperfractionated 1, 2
• Vincristine: 2 mg IV on days 4 and 11 2
• Doxorubicin (Adriamycin): 50 mg/m² IV on day 4 2
• Dexamethasone: 40 mg daily on days 1-4 and 11-14 2

Alternating High-Dose Methotrexate/Cytarabine Cycles (Even-numbered cycles: 2,4,6,8)

• Methotrexate: 200 mg/m² IV over 2 hours, followed by 800 mg/m² IV over 22 hours on day 1 3
• Cytarabine: 3 g/m² IV every 12 hours for 4 doses on days 2-3 3
• Methylprednisolone: 50 mg IV twice daily on days 1-3 3

CNS Prophylaxis

• Intrathecal therapy alternating methotrexate and cytarabine on days 2 and 7 of each course 4
• Systemic therapy with high-dose methotrexate and cytarabine provides additional CNS protection 1

Efficacy and Outcomes

• Complete remission (CR) rates: 91% in newly diagnosed adult ALL patients 2
• 5-year overall survival rate: approximately 38-39% 1, 2
• Low incidence of CNS relapse: approximately 4% 2
• For CD20-positive B-ALL, addition of rituximab to Hyper-CVAD improves outcomes with 3-year CR duration of 67% and OS of 61% 1

Patient Selection and Risk Stratification

• Suitable for adult patients with newly diagnosed ALL, both Ph-negative and Ph-positive (with TKI addition) 1
• Particularly effective in younger adults (<60 years) with fewer comorbidities 1, 4
• For Ph-positive ALL, tyrosine kinase inhibitors (imatinib or dasatinib) are added to the regimen 1
• For CD20-positive B-ALL, rituximab should be incorporated 1

Supportive Care Requirements

• Granulocyte colony-stimulating factor (G-CSF) support during intensive chemotherapy cycles 1
• Prophylactic antibiotics to reduce infection risk 2
• Hyperglycemia monitoring and management (hyperglycemia during induction is associated with shorter remission duration and increased mortality) 3

Special Considerations

• Higher toxicity in patients ≥60 years old with increased induction mortality (15% vs. 2% in younger patients) 1
• For older adults or those with significant comorbidities, dose modifications may be necessary 1
• Consider TPMT gene polymorphism testing for patients receiving 6-MP during maintenance phase 1

Maintenance Therapy

• After completing 8 cycles of intensive therapy, maintenance therapy is recommended for 2-3 years 1
• Maintenance consists of:
  • Weekly methotrexate
  • Daily 6-mercaptopurine (6-MP)
  • Monthly vincristine/prednisone pulses 1

Comparison with Other Regimens

• Hyper-CVAD shows comparable outcomes to other intensive regimens like MRC UKALL XII/ECOG 2993 1
• Complete remission rates and 5-year survival rates are similar between Hyper-CVAD (92% CR, 38% 5-year survival) and UKALL XII (93% CR, 41% 5-year survival) 1
• Hyper-CVAD may be less complex than some pediatric-inspired regimens while maintaining similar efficacy 1

Common Complications and Management

• Myelosuppression: Requires growth factor support and transfusions as needed 1
• Infections: Prophylactic antibiotics and prompt treatment of febrile neutropenia 2
• Hyperglycemia: Regular monitoring of blood glucose levels as hyperglycemia is associated with worse outcomes 3
• Neurotoxicity: Monitor for vincristine-related neuropathy 2
• Hepatotoxicity: Monitor liver function during high-dose methotrexate cycles 3

Hyper-CVAD has become a standard intensive chemotherapy option for adult ALL patients due to its established efficacy and manageable toxicity profile when appropriate supportive care is provided 1.