Hyper-CVAD as Initial Treatment for ALL

Abstract & Commentary

Synopsis: The chemotherapy regimen Hyper-CVAD is increasingly used for patients with hematological malignancies. In this report from the MD Anderson Cancer Center, clinical outcomes for 288 adults who received first-line treatment with this regimen for acute lymphocytic leukemia were presented. Overall complete response rate was 92%, induction mortality was 5% and the 5-year CR duration was 38%. These results warrant additional consideration of this regimen for initial therapy by comparing it with more commonly used regimens in a large, cooperative group trial.

Source: Kantarjian H, et al. Cancer. 2004;101:2788-2801.

Intensive chemotherapy regimens have increased the response rate and long-term outcome for patients with adult acute lymphocytic leukemia (ALL). Prior to modern therapeutic approaches, a slow response to induction chemotherapy, older age, and the demonstration of either Philadelphia chromosome or T-cell markers were shown to be negative prognostic indicators.1,2 With newer regimens including Hyper-CVAD, greater than 80% of patients achieve complete responses and long-term survival rates have occurred in 30% to 40%.3 In the current report, Kantarjian and colleagues from MD Anderson report the complete remissions (CR) and long-term survival rates for a large series of adults with ALL treated with the Hyper-CVAD chemotherapy regimen.

The researchers reviewed the outcomes of 288 patients who were treated with Hyper-CVAD between 1992 and 2000 at MD Anderson. This complex regimen includes alternating cycles of cyclophosphamide, daunorubicin vincristine and dexamethasone with high-dose cytosine arabinoside and methotrexate.2 In this series, the median age was 40 years and 20% were older than age 60. The incidence of T-Cell ALL was 13% and Philadelphia chromosome was demonstrable in 17%. Complete remission was achieved in more than 90% and at 63 months there was a 30-45% overall survival rate. Prognostic factors that influenced outcome were identified as age, performance score, hepatomegaly, leukocyte and platelet counts, albumin and bilirubin levels, FAB classification, immunophenotype, karyotype and myeloid markers. After dividing participants into low risk, intermediate risk, and poor risk groups based on a multivariate analysis of these prognostic factors, 5-year CR duration rates were found to be 52%, 37%, and 10%, respectively. Overall results of the Hyper-CVAD regimen were found to be favorable and were significantly better when compared to the previous CVAD regimens.

Comment by William B. Ershler, MD

The Hyper-CVAD regimen, developed initially for the treatment of ALL, has been used with benefit for a variety of other hematological malignancies including lymphoblastic lymphoma, mantle cell lymphoma, multiple myeloma, and Richter’s transformation of chronic lymphocytic leukemia.4-7 Although the current report is that of a non-randomized population of adults with ALL treated at a single institution, the findings are remarkable because of the high response and long-term survival rate. Comparison with other published reports of front-line ALL treatment8,9 is problematic inasmuch as there was a higher percentage of older patients and patients with other negative prognostic factors in the current series. Thus, Hyper-CVAD is a very reasonable first-line approach to the management of ALL. The findings of a 92% CR rate, an induction mortality rate of 5%, a median survival of 32 months, and a 5-year survival rate of 38% is as good as has ever reported, particularly because of the inclusion of higher-risk patients. Future cooperative group trials will hopefully include this regimen to determine if these improved numbers are reproducible outside of the large cancer center from which they were generated. Furthermore, the regimen might be altered to some degree under certain circumstances, such as the inclusion of imatinib for those with Ph-positive ALL, or incorporating monoclonal antibody therapy in patient whose leukemic cells express the appropriate target (eg, rituximab if CD20 positive, alemtuzumab if CD52 positive or gemtuzumab if CD33 positive). These alterations, too, should be subjected to clinical trial before assuming the designation as standard of care.

William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC, is Editor for Clinical Oncology Alert.

References

1. Linker CA, et al. Blood. 1991;78:2814-2822.

2. Kantarjian HM, et al. J Clin Oncol. 2000;18:547-561.

3. Faderl S, et al. Cancer. 2003;98:1337-1354.

4. Thomas D, et al. Blood. 2004;104:1624-1630.

5. Romaguera JE, et al. Leuk Lymphoma. 2000;39:1-9.

6. Dimopoulos MA, et al. Am J Hematol. 1996;52:77-81.

7. Tsimberidou AM, et al. Cancer. 2003;97:1711-1720.

8. Linker CA, et al. Blood. 1991;78:2814-2822.

9. Hoelzer D, et al. Blood. 1988;71:123-131.