The following evidence pertains to the use of hyper CVAD in mantle cell lymphoma (MCL). Specific evidence is not cited for use in other aggressive lymphomas, and use of hyper CVAD will be at the physician's discretion in most cases.
Hyper CVAD alternating with methotrexate and cytarabine is an aggressive chemotherapy regimen that has proven effective in treating patients with aggressive histopathological variants of MCL. The evidence for this regimen in the treatment of MCL comes from three prospective trials:
- Khouri et al.r reported a prospective phase II trial that included 45 patients aged 65 years or younger, with newly diagnosed or previously treated MCL evaluating hyper CVAD followed by autologous or allogeneic stem cell transplant (SCT). Complete response (CR) after four cycles of hyper CVAD was reported at 38%, while partial response (PR) was reported at 55.5%.
- Romaguera et al.rr reported a prospective open-label phase II trial of six cycles of hyper CVAD plus rituximab in newly diagnosed MCL. Of the 97 assessable patients (aged 41-80 years; median age 61 years), 87% achieved CR or unconfirmed CR. No patients went on to receive SCT. At a median follow-up of 40 months, three-year failure-free survival was 64%, and overall survival (OS) was 82%. In a subsequently published Short Report in 2010, at 10 years of follow-up (median of 8 years), the median OS for all patients had not been reached, and the time to treatment failure was 4.6 years. On subset analysis, patients 65 years or younger had significantly higher OS rates at eight years (68 versus 33%) than older patients.
- Merli et al. r reported a prospective, multicentre trial of 8 cycles of hyper CVAD plus rituximab in 63 patients with newly diagnosed MCL. The overall response and complete response rates were 83% and 72%, respectively. After a median follow-up of 46 months, the estimated 5 years OS and progression-free survival (PFS) rates were 73% and 61%, respectively. However, this study reported significant toxicity; only 37% of patients completed the full 8 cycles and 3 died during therapy.
Source |
Study & Year Published |
Supports Use
Yes/No/NA |
Is the dose and regimen consistent with the protocol?
Yes/No |
Comments |
Phase II trials |
Khouri et al.1998r |
Yes |
No |
Doxorubicin dose in Part A is given over 2 days. |
Cycles 1, 3, 5, 7
Cyclophosphamide 300 mg/m2 IV every 12 hrs for six doses D1-3
Doxorubicin 50 mg/m2 IVI over 48 hrs D4-5
Vincristine 2 mg/m2 IV (maximum 2 mg) D4 & D11
Dexamethasone 40 mg IV or PO D1-5 and D11-14 |
Cycles 2, 4, 6, 8
Methotrexate 200 mg/m2 IV bolus D1
Methotrexate 800 mg/m2 continuous IVI over 24 hrs D1
Cytarabine 3,000 mg/m2 IV over 2 hrs every 12 hrs for four doses D2-3 |
Romaguera et al.2005r |
Yes |
No |
Continuous doxorubicin infusion in Part A, rituximab on day 1 of each cycle of Part A and B. |
Cycles 1, 3, 5, 7
Rituximab 375 mg/m2 D1
Cyclophosphamide 300 mg/m2 IV over 3 hrs every 12 hrs for six doses D2-4
Doxorubicin 16.6 mg/m2/day continuous IVI over 72 hrs D5-7
Vincristine 1.4 mg/m2 IV (maximum 2 mg) D5 & D12
Dexamethasone 40 mg IV or PO D2-5 and D12-15 |
Cycles 2, 4, 6, 8
Rituximab 375 mg/m2 D1
Methotrexate 200 mg/m2 IV over 2 hrs D2
Methotrexate 800 mg/m2 continuous IVI over 22 hrs D2
Cytarabine 3,000 mg/m2 IV over 2 hrs every 12 hrs for four doses D3-4 |
Merli et al. 2012r |
Yes |
No |
Rituximab 375 mg/m2 on day 1 of each cycle. Additional dose of doxorubicin 50 mg/m2 on day 5 of part A. |
Cycles 1, 3, 5, 7
Rituximab 375 mg/m2 D1
Cyclophosphamide 300 mg/m2 IV every 12 hrs for six doses D1-3
Doxorubicin 50 mg/m2 IV D4-5
Vincristine 1.4 mg/m2 IV (maximum 2 mg) D4 & D11
Dexamethasone 40 mg IV or PO D1-5 and D11-14 |
Cycles 2, 4, 6, 8
Rituximab 375 mg/m2 D1
Methotrexate 200 mg/m2 IV bolus D1
Methotrexate 800 mg/m2 continuous IVI over 24 hrs D1
Cytarabine 3,000 mg/m2 IV D2-3 |
Guidelines |
Date published/revised |
Supports Use
Yes/No/NA |
Is the dose and regimen consistent with the protocol?
Yes/No |
Comments |
NCCN |
June 2022 |
Yes |
No |
Includes rituximab 375 mg/m2 on day 1 of each cycle |
CCO |
April 2022 |
Yes |
No |
Vincristine 1.4 mg/m2 IV (maximum 2 mg) D4 & D11 |
BCCA |
N/A |
N/A |
N/A |
- |
Abbreviations: IV - intravenous; hrs - hours; D - day(s); IVI - intravenous continuous infusion; PO - per oral
The addition of rituximab to chemotherapy has shown to be beneficial, with a 2007 meta-analysisr of rituximab plus chemotherapy for patients with indolent non-Hodgkin lymphoma (NHL) or MCL finding those treated with rituximab plus chemotherapy had superior OS, response and disease control than those that were treated with chemotherapy alone. However, only three small studies for MCL were available for inclusion in the meta-analysis. Consideration should be given to the addition of rituximab to each cycle of hyper CVAD.
Efficacy
Figure 1: Failure-free and overall survivalr
© Journal of Clinical Oncology 2005
Toxicity
Figure 2: Haematological toxicityr
© Journal of Clinical Oncology 2005
Figure 3: Non-haematological toxicityr
© Journal of Clinical Oncology 2005