Hyper-CVAD Treatment Protocol
Regimen Overview
Hyper-CVAD consists of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Cycle A) alternating with high-dose methotrexate and cytarabine (Cycle B), administered for a total of 8 cycles with mandatory CNS prophylaxis. 1
Treatment Structure
Cycle A: Hyper-CVAD
- Cyclophosphamide: 300 mg/m² IV over 3 hours every 12 hours for 6 doses (days 1-3) 2
- Vincristine: 2 mg IV on days 4 and 11 1
- Doxorubicin: 50 mg/m² IV continuous infusion over 24 hours on day 4 2
- Dexamethasone: 40 mg PO or IV daily on days 1-4 and 11-14 1
Cycle B: High-Dose Methotrexate/Cytarabine
- Methotrexate: 1 g/m² IV over 24 hours on day 1 1
- Cytarabine: 3 g/m² IV over 2 hours every 12 hours for 4 doses (days 2-3) 1, 2
- Leucovorin rescue: Required following methotrexate 1
Cycle Schedule
- Cycles alternate: A-B-A-B-A-B-A-B for total of 8 cycles 1
- Cycle frequency: Every 21 days with G-CSF support 1
- Total duration: Approximately 6 months for intensive phase 2
CNS Prophylaxis (Mandatory)
All patients require CNS-directed therapy throughout treatment: 1
- Intrathecal therapy: Methotrexate 12 mg and/or cytarabine 100 mg on day 2 of each cycle 1
- Alternative: Triple intrathecal therapy (methotrexate, cytarabine, hydrocortisone) 1
- Frequency: Minimum 4-8 doses during induction/consolidation 1
- Cranial irradiation: Reserved for patients with CNS disease at diagnosis 1
Rituximab Addition for CD20-Positive Disease
For CD20-positive B-cell malignancies (>20% expression), add rituximab 375 mg/m² IV on days 1 and 11 of each Cycle A and day 2 of each Cycle B. 1
- This modification improves 3-year complete remission duration to 67% and overall survival to 61% in Ph-negative B-ALL 1
- Rituximab is standard for Burkitt lymphoma and mantle cell lymphoma 1
Maintenance Therapy (Post-Induction)
Following completion of 8 cycles, continue maintenance for 24-36 months: 1
- Methotrexate: 10 mg/m² PO weekly 1
- 6-Mercaptopurine: 50 mg PO three times daily 1
- Vincristine/Prednisone pulses: Monthly (vincristine 2 mg IV + prednisone 200 mg PO × 5 days) 1
- TPMT testing: Consider before starting 6-mercaptopurine to avoid severe neutropenia 1
Disease-Specific Modifications
Ph-Positive ALL
- Add tyrosine kinase inhibitor: Imatinib 600 mg daily or dasatinib 140 mg daily starting day 1 of cycle 1 1
- Continue TKI throughout maintenance phase 1
Salvage/Relapsed Disease
- Augmented hyper-CVAD: Intensified vincristine (2 mg on days 4,11,18), intensified dexamethasone (40 mg days 1-4,11-14,21-24), plus L-asparaginase 20,000 units/m² on days 5-7 1
Elderly Patients (≥60 years)
- Dose reductions required: 25-33% reduction in cyclophosphamide and doxorubicin doses 1
- Induction mortality: 15% in elderly vs 2% in younger patients 1
- Consider alternative: Moderate-intensity regimens may be more appropriate given high death-in-remission rates (34%) 1
Supportive Care Requirements
Growth Factor Support
- G-CSF: 5 mcg/kg SC daily starting 24 hours after chemotherapy completion until ANC >1,000/μL 1
- G-CSF significantly reduces neutropenia duration and infectious complications 1
Hepatitis B Screening
- Mandatory testing: HBsAg and anti-HBc before treatment initiation 1
- Prophylaxis: Antiviral therapy required for HBV-positive patients throughout treatment 1
- This is particularly critical in Asian populations with higher HBV prevalence 1
Cardiac Monitoring
- Baseline MUGA or echocardiogram: Required before anthracycline administration 1
- Monitor for cumulative doxorubicin cardiotoxicity (total dose 400 mg/m² over 4 cycles) 2
Response Assessment
Complete Remission Criteria
- Bone marrow: <5% blasts with trilineage hematopoiesis 1
- Blood counts: ANC >1,000/μL, platelets >100,000/μL 1
- Extramedullary disease: Complete resolution of lymphadenopathy, organomegaly, CNS involvement 1
- Duration: No recurrence for minimum 4 weeks 1
Common Pitfalls
Myelosuppression Management
- Universal myelosuppression expected: Nadir typically days 10-14 3
- Infectious prophylaxis: Consider antibacterial, antifungal, and antiviral prophylaxis during neutropenic periods 3
- Dose delays: May be necessary but attempt to maintain dose intensity 4
Methotrexate Toxicity
- Leucovorin rescue critical: Begin 24 hours after methotrexate completion 1
- Hydration: Aggressive IV hydration and urine alkalinization required 2
- Methotrexate levels: Monitor and continue leucovorin until level <0.05 μmol/L 2
Treatment Completion
- Only 65-81% complete all planned cycles due to toxicity 5
- Unplanned hospitalizations: Occur in approximately 81% of patients 5
- Early identification of high-risk patients for dose modification is essential 5
Expected Outcomes
Acute Lymphoblastic Leukemia
- Complete remission rate: 81-92% 1, 4, 3
- 5-year overall survival: 38-52% 1, 4
- Median overall survival: 32 months 1