CODOX-M and CODOX-M Alternating with IVAC in Adult Burkitt’s Lymphoma

Abstract & Commentary

Synopsis: Burkitt’s lymphoma is a rapidly progressive form of B-cell non-Hodgkin’s lymphoma. Cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate (CODOX-M)/ifosfamide, etoposide and high-dose cytarabine (IVAC) is a highly effective alternating non-cross-resistant regimen developed by Magrath and colleagues at the National Cancer Institute.1 The aim of this paper was to confirm these results in a larger, international, multi-center study using International Prognostic Index-based criteria to assign prognostic groups, while slightly simplifying the protocol. This study confirms high cure rates with this CODOX-M/IVAC approach and the benefit of stratifying patients into low and high-risk groups.

Source: Mead G, et al. Ann Oncol. 2002;13:1264-1274.

It has been known for more than 2 decades that standard lymphoma therapy, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)2 is inadequate for this highly aggressive lesion. The CODOX-M/IVAC regimen was developed at the National Cancer Institute and the results were published in 1996.1 The regimen for high-risk patients consists of alternating cycles of regimen A (cyclophosphamide, adriamycin, vincristine and methotrexate [CODOX-M]) and B (ifosfamide, etoposide, high-dose cytarabine [IVAC]) for 4 cycles (ABAB). It showed a 92% 2-year event-free survival rate. The study was in children (median age, 12 yrs) and adults (median age, 25 yrs). This current study was to confirm these results in a large well-defined patient population.

Patients were accrued from 45 consultants at 39 centers. Fifty-two patients were reported whose pathology was confirmed by central pathologic review. The 2-year event-free survival (EFS) was 64.6% and 2 year overall survival was 72.8%. For low-risk patients, the 2-year EFS was 83.3% and overall survival 81.5%. For high-risk patients the 2-year EFS was 59.5% and overall survival was 69.9%. Toxicity was severe with World Health Organization (WHO) grade three quarters leucopenia and neutropenia in nearly all patients.

Comment by Stuart M. Lichtman, MD

Burkitt’s lymphoma is a rare and highly aggressive and rapidly progressive form of B-cell non-Hodgkin’s lymphoma. It can occur at any age but tends to present most commonly in males during childhood and young adult life and in patients with HIV infection. It has a distinct pathological appearance associated with an 8:14 translocation which results in overexpression of c-myc; these changes promote mitosis such that virtually 100% of cells are in cycle. There is occasional confusion regarding the classification of this disorder. Historically, Burkitt’s lymphoma and Burkitt-like lymphoma have been treated together as diffuse noncleaved lymphoma according to the Working Formulation Classification. The current lymphoma classification, the WHO Classification of Neoplasms of the Lymphoid System, has Burkitt-like lymphoma a subtype of Burkitt’s lymphoma and should be treated identically.

The literature relating to the treatment of adult Burkitt’s lymphoma is scant and has developed over a long period of time with changing practice patterns and supportive care modalities. This has resulted in difficulty in interpretation of the data. Also, many studies have primarily involved children and young adults and are often not applicable to the patients seen by medical oncologists primarily treating adults. In addition, there has been a difficulty in diagnoses exacerbated by the changing lymphoma classification schemes. It is imperative that the diagnosis be considered in patients with clinically aggressive lymphomas, but it should also be kept in mind that a substantial number of patients will present with localized, low-risk disease. The diagnostic criteria should include 100% Ki-67 staining and studies to confirm either the 8;14 or 14;18 translocations. This can be performed with fresh tissue or paraffin blocks with fluorescence in situ hybridization (FISH). The study of Macgrath and associates emphasized the curability of this disease with an aggressive regimen. Other regimens have been reported in the literature.3-5 The current study confirms Macrath et al’s data, showing the high efficacy of this treatment with cure possible in this older population (median age, 35 yrs). It also confirmed the classification of low- and high-risk patients. Prognostic factor analysis was limited but there was a trend to a worsening EFS with increasing age and bone marrow involvement.

Clinicians now have a proven regimen that can cure this aggressive lesion. The long-term benefit of this therapy rests on the proper identification of patients with appropriate histologic and laboratory investigation of pathologic tissue. Supportive measures should be performed scrupulously and are imperative with this highly aggressive therapy.

Dr. Lichtman is Associate Professor of Medicine, NYU School of Medicine Division of Oncology, Manhasset, NY.

References

1. Magrath I, et al. J Clin Oncol. 1996;14(3):925-934.

2. Fisher RI, et al. N Engl J Med. 1993;328:1002-1006.

3. Hoelzer D, et al. Blood. 1996;87(2):495-508.

4. Lee EJ, et al. J Clin Oncol. 2001;19(20):4014-4022.

5. Soussain C, et al. Blood. 1995;85(3):664-674.