The hyper CVAD regimen consists of a dose-intensive phase of therapy, consisting of eight cycles of alternating hyper CVAD and high-dose methotrexate/cytarabine followed by POMP maintenance (mercaptopurine 50 mg orally (PO) three times a day (TDS) on days 1 to 28, methotrexate 20 mg/m2 PO once a week, vincristine 2 mg intravenous (IV) monthly and prednisolone 200 mg PO once a day on days 1-5 each month). The long-term response rates to hyper CVAD need to be considered in this context, not just in the context of dose-intensive therapy alone. Additionally, therapy for documented central nervous system (CNS) disease consisted of twice weekly intrathecal (IT) therapy with methotrexate and cytarabine. Patients with cranial nerve root involvement received 24 to 30 Gy of radiation in 10 to 12 fractions directed to the base of skull or whole brain. In those without documented CNS involvement, prophylaxis was administered as methotrexate 12 mg IT on Day 2, and cytarabine 100 mg IT on day 8 for 16 treatments in high-risk patients, 4 treatments in low-risk patients and 8 treatments in unknown-risk patients.
Treatment regimens for acute lymphoblastic leukaemia (ALL) have evolved empirically into complex schemes using numerous agents in various dose combinations and schedules. Few have been subjected to randomised control trials, and it is difficult to assess the comparative merits of each regimen and hence the most important components that lead to cure. Each schedule aims to use multi-agent therapy at acceptable toxicities allowing for marrow recovery and includes the use of CNS prophylaxis and post-remission consolidation. With each regimen, complete response (CR) rates are > 80% and a median survival of 18 to 36 months. There appears to be very little difference in long-term treatment outcomes after use of any one of the commonly used ALL treatment regimens: disease-free survival (DFS) 29 to 46% at 2 to 10 years. The published results of case series are more strongly influenced by cytogenetics risk factors, white cell count (WCC) and patient age.
Hyper CVAD, as reported by Kantarjan et al., 2000, is a sequential multi-agent alternating cycles of chemotherapy approach for the management of ALL. The results of hyper CVAD reflect its use in 288 patients.r Overall a 92% CR rate was achieved, with a 5% death rate during induction chemotherapy. Estimate 5-year survival and CR rates were 38% and 38%, respectively. This is comparable to any other ALL regimen for adults.r Patients with good risk disease, as determined by age, absence of Ph-positive disease, leukocyte and platelet count, performance status and liver size, had a 62% 5-year survival.
The group at M.D. Anderson, who devised the hyper CVAD protocol, have made several modifications to the protocol since 2000,r which have been the subject of an ongoing phase II study. Progress in this study was published ahead of print in the Journal of Clinical Oncology, comparing the results of the modified hyper CVAD protocol (173 patients) compared to standard hyper CVAD (109 patients).r Modifications included:
- Rituximab, two doses with each of first 4 cycles if CD20 expression is ≥ 20%.
- Patients with low risk receive 6 IT chemotherapy treatments instead of 4.
- POMP maintenance is continued for 30 months instead of 24 months.
- Maintenance included intensifications: 2 hyper CVAD treatments are given at months 6 and 18; IV methotrexate and asparaginase (colaspase) are given at months 7 and 19.
- Note that initially, there was an anthracycline intensification in cycle 2, but this was scrapped early due to a worse outcome and has not been given since 2001.
The results of this comparison with standard hyper CVAD can be summarised as follows:
- Young patients (<60 years) with CD20 expression ≥ 20% did better with rituximab than without (3-year CR duration 70% v 38% p = < .001); overall survival (OS) 75% v 47% (p= 0.003). There was no difference in older patients.
- For CD20-negative patients, there was no difference in outcome between the modified and standard protocols.
Efficacy
Table 1: Hyper CVAD response rates acute lymphoblastic leukaemiar
Complete Response (CR) |
92% |
Estimated 5 year CR rate |
38% |
Estimated 5 year Survival |
38% |
Incidence of CNS Relapse |
4% |
CR after 1 course |
81% |
Figure 1: Hyper CVAD survival acute lymphoblastic leukaemia with the presence of none or one, two or three, or four or more adverse factors.r
© Cancer 2004
Toxicity
Table 2: Toxicity hyper CVAD acute lymphoblastic leukaemiar
Median time to recovery of granulocytes |
18 days |
Median time to recovery of platelets |
21 days |
Toxicity Grade 3 to 4 |
(%) |
Steroid related neurotoxicity |
6 |
Mucositis |
6 |
Diarrhoea |
3 |
Ileus |
2 |
Disseminated intravascular coagulation (DIC) |
2 |
Following courses - 100% myelosuppression associated side effects |
Hospitalisation for side effects - 18% of courses |
Table 3: Toxicity hyper CVAD acute lymphoblastic leukaemia part Br
Toxicity Grade 3 to 4 |
(%) |
Sepsis |
11 |
Pneumonia |
5 |
Renal and hepatic |
2 |
Neurotoxicity |
5 |
Skin rash |
5 |
Hand and foot |
3 |
Mucositis |
5 |
Diarrhoea |
1 |
Cytarabine associated fever |
6 |
Hospitalisation for side effects - 42% of courses |