Burkitt's Yields to Longer-Duration, Lower-Dose Chemo

Neil Osterweil

November 18, 2013

Aggressive malignancies respond best to aggressive dose-intense therapies; oncologists hold this truth to be self-evident.

However, in adults with the extremely aggressive Burkitt's lymphoma, a regimen that favors longer exposure to chemotherapy over lower doses was associated with overall survival rates that were comparable to, or better than, those seen with shorter-course high-intensity regimens, and with substantially less toxicity.

This finding comes from a study of the longer-duration, less-intense chemotherapy regimen conducted by a team of researchers from the National Cancer Institute, headed by Wyndham Wilson, MD, PhD, from the Lymphoid Malignancy Branch. The results were published in the November 14 issue of the New England Journal of Medicine.

For 19 adults with sporadic Burkitt's lymphoma, a dose-adjusted version of the EPOCH-R (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab) regimen was associated with 95% progression-free survival and 100% overall survival at a median follow-up of 86 months.

For 11 adults with immunodeficiency-associated Burkitt's lymphoma treated with a lower-dose, short-course version of EPOCH-R in which the rituximab dose is doubled, progression-free survival was 100% and overall survival was 90%, the team reported.

"Low-intensity EPOCH-R-based therapy appears to obviate the need for high-intensity treatment and markedly reduces treatment toxicity while achieving high rates of durable response," they conclude.

Rapidly Progressive

Burkitt's lymphoma is a highly proliferative B-cell lymphoma with a high growth fraction and short cell-doubling (between 24 and 48 hours). The HIV-associated variant of Burkitt's lymphoma requires treatment with less-toxic chemotherapy regimens, the researchers explain.

Typically, the sporadic variant of the disease is treated with intensive, short-cycle chemotherapy, and cure rates in children approach 90% in Western nations. Adults with Burkitt's lymphoma are typically treated with high-intensity regimens that contain methotrexate and are delivered intrathecally.

The researchers note that previous efforts "to substantially lower the treatment intensity while maintaining efficacy have not been very successful in adults, although risk-adapted treatment has reduced toxicity in children."

Dr. Wilson told Medscape Medical News that the standard high-dose regimen for adults with Burkitt's lymphoma is based on clinical experience with B-cell acute lymphoblastic leukemia, with which it shares some key biologic features.

"Nobody has ever wondered why we needed such high-dose therapy. It simply came from the leukemia literature, where standard lower-dose therapies didn't work, and they were always given over very short time periods. We started doing this in the setting of HIV, where patients couldn't tolerate the higher-dose therapy, and the results were remarkable," he explained.

In a previous study, Dr. Wilson's team showed that in patients with HIV-related lymphoma, dose-adjusted EPOCH without rituximab was associated with complete remission in 74% of patients. In addition, at a median follow-up of 53 months, disease-free survival was 92% and overall survival was 60% (Blood. 2003;101:4653-4659).

On the basis of these encouraging results, the researchers decided to cautiously extend a similar regimen to adults with Burkitt's lymphoma.

Longer Duration, Lower Doses

They hypothesized that "the exquisite sensitivity of Burkitt's lymphoma cells to genotoxic stress makes prolonged exposure time, not increased dose, the important therapeutic strategy for maximizing the killing of tumor cells."

Nineteen HIV-negative adults with previously untreated Burkitt's lymphoma (including 2 with primary immunodeficiency syndrome) were treated with dose-adjusted EPOCH-R, delivered in 6 to 8 cycles of 96 hours. The doses were adjusted on the basis of the patient's neutrophilic nadir.

Patients with HIV-associated immunodeficiency were treated with short-course EPOCH-R, with rituximab given twice in each cycle, for 3 to 6 cycles. In this regimen, the median cumulative doses of doxorubicin and etoposide were 47% lower than in the dose-adjusted regimen, and the cyclophosphamide dose was 57% lower. This regimen was not dose-adjusted.

The primary toxicities were fever and neutropenia, which occurred in 22% of the dose-adjusted cycles and in 10% of the short-course cycles. There was 1 case of tumor lysis syndrome in a patient on short-course therapy, and there were no treatment-related deaths.

Results Are Encouraging

"The results couldn't be more encouraging, but it's a small study with a lot of lower-risk Burkitt's patients. Before it becomes a reasonable standard of care in younger patients with Burkitt's, we need a multicenter clinical trial in a broader population of patients with Burkitt's," said Jeremy S. Abramson, MD, clinical director of the Center for Lymphoma at Massachusetts General Hospital in Boston.

He noted that the patients in this study were generally young (median age, 33 years), and many had low-risk features. For example, 12 of the 19 patients in the dose-adjusted group had normal serum lactate dehydrogenase levels, suggesting a lower disease burden than is commonly seen in patients with Burkitt's lymphoma, Dr. Abramson told Medscape Medical News.

In addition, only 1 patient in the study had central nervous system (CNS) involvement. He noted that some clinicians are concerned about using the EPOCH regimen in patients with Burkitt's lymphoma because it does not contain either high-dose methotrexate or cytarabine, both of which are used in regimens for patients with disease involving the CNS.

The EPOCH-R protocol contains an intrathecal component for treatment of disease in the CNS, but the therapy works on the leptomeninges, not the brain parenchyma, and intrathecal therapy has an uneven distribution throughout the neural axis, Dr. Abramson added.

Ann LaCasce, MD, assistant professor of medicine at Harvard Medical School and a hematologist-oncologist at the Dana-Farber Cancer Institute in Boston, agrees that EPOCH-R appears to be a good therapeutic option for older patients and for some, but not all, younger adults with Burkitt's lymphoma.

"I think for selected younger patients, it's a very good option, but for patients who have a lot of bone marrow involvement or very high-risk disease, I don't know that we would yet consider changing from our current more-intensive multiagent chemo regimen," she said in an interview with Medscape Medical News.

Dr. Abramson, Dr. LaCasce, and colleagues are currently participating in confirmatory clinical trials of risk-stratified treatment using EPOCH-R regimens.

The study was supported by the National Cancer Institute. Dr. Wilson is an NCI employee. Dr. Abramson and Dr. LaCasce have disclosed no relevant financial relationships.

N Engl J Med. 2013;369:1915-1925. Abstract

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