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Modified Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (Hyper-CVAD) regimen for acute lymphoblastic leukemia (ALL) in adults[1]

Modified Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone (Hyper-CVAD) regimen for acute lymphoblastic leukemia (ALL) in adults[1]
Dose intensive phase:
The dose intensive phase consists of 8 courses of therapy administered at 21-day intervals. The drugs used in each course alternate such that Hyper-CVAD is used for courses 1, 3, 5, and 7 while high-dose methotrexate plus cytarabine is given for courses 2, 4, 6, and 8.
Hyper-CVAD (courses 1, 3, 5, and 7)
Cyclophosphamide IV 300 mg/m2 over 2 to 3 hours every 12 hours for 6 doses Days 1 to 3
Mesna IV 600 mg/m2/day administered as a continuous infusion starting with cyclophosphamide and ending 6 hours after last dose of cyclophosphamide Days 1 to 3
Vincristine IV 2 mg per day Days 4 and 11
Doxorubicin IV

if LVEF ≥50 percent: 50 mg/m2 over 24 hours

if LVEF <50 percent: 50 mg/m2 over 48 hours[1,2]

 Day 4
Dexamethasone PO or IV 40 mg per day Days 1 to 4 and days 11 to 14
High dose methotrexate plus cytarabine (courses 2, 4, 6, and 8)
Methotrexate IV 200 mg/m2 administered over first 2 hours then 800 mg/m2 administered over 24 hours (total dose per cycle of 1 gram/m2) Day 1
Leucovorin IV 50 mg IV 12 hours after end of methotrexate; then 15 mg IV every 6 hours for 8 doses or until methotrexate level ≤0.1 micromol/L. Dose modifications made based upon methotrexate levels. Day 2
Cytarabine IV

for patients <60 years old: 3 g/m2 administered over 2 hours every 12 hours for 4 doses

for patients ≥60 years old: 1 g/m2 administered over 2 hours every 12 hours for 4 doses

 Days 2 and 3
Methylprednisolone IV 50 mg twice daily Days 1 to 3
Rituximab for CD20+ ALL (courses 1, 2, 3, 4)
Rituximab IV Give only if ≥20 percent of lymphoblasts are CD20 positive: 375 mg/m2 Days 1 and 11 of Hyper-CVAD and Days 1 and 8 of high dose methotrexate plus cytarabine
CNS prophylaxis: total number of intrathecal treatments varies based upon risk factors*
Methotrexate IT 12 mg (6 mg if through Ommaya)[3,4] Day 2 of each cycle
Cytarabine IT 100 mg Day 8 of each cycle
Maintenance phase:
Therapy after the intensive phase varies depending upon ALL subtype:
• Patients with Burkitt leukemia (mature B-cell ALL) are not given maintenance
• Patients with Philadelphia chromosome positive ALL undergo allogeneic hematopoietic cell transplantation if they are candidates for this procedure and have a donor
• All other patients receive maintenance chemotherapy with POMP intensification plus intensification cycles of Hyper-CVAD and methotrexate plus L-asparaginase
Maintenance POMP: administered months 1 through 5, 8 through 17, 20 through 30
Mercaptopurine PO 50 mg three times a day on an empty stomach Days 1 to 28
Methotrexate PO 20 mg/m2 Days 1, 8, 15, and 22
Vincristine IV 2 mg Day 1
Prednisone PO 200 mg per day Days 1 to 5
Intensification Hyper-CVAD: administered months 6 and 18, plus rituximab on days 1 and 11 if CD20+
Intensification methotrexate and L-asparaginase: administered months 7 and 19
Methotrexate IV 100 mg/m2 Day 1 weekly x 4
L-asparaginase IV 20,000 units Day 2 weekly x 4
Details on dose modification, prophylactic antibiotics, growth factor support, and mediastinal irradiation can be found in the original articles. In addition, it is now standard practice to include a tyrosine kinase inhibitor for patients with Philadelphia chromosome positive ALL.
LVEF: left ventricular ejection fraction.
* Patients were given central nervous system (CNS) prophylaxis based upon risk factors as follows: Patients with a lactate dehydrogenase level >600 u/liter or with a proliferative index of 14 percent or above were considered "High risk" and received 8 intrathecal (IT) treatments. Patients with neither of these features were considered "Low risk" and received 6 IT treatments. Patients with unknown risk received 8 IT treatments[1]. Patients with cranial neuropathies or CNS involvement are given whole brain radiation therapy (24 to 30 Gy) at the time of diagnosis and receive even more frequent IT therapy.
References:
  1. Thomas DA, O'Brien S, Faderl S, et al. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol 2010; 28:3880.
  2. Thomas DA, O'Brien S, Cortes J, et al. Outcome with the hyper-CVAD regimens in lymphoblastic lymphoma. Blood 2004; 104:1624.
  3. Kantarjian HM, O'Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000; 18:547.
  4. Kantarjian HM, Thomas D, O'Brien S, et al. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer 2004; 101:2788.
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