Can Risk-Adapted EPOCH-R Replace Intensive Therapy for Burkitt Lymphoma?

Adults with Burkitt lymphoma are typically treated with dose-intensive combination chemotherapy derived from pediatric leukemia regimens, which the study investigators noted is “acutely toxic with late sequelae.” With this study, they hypothesized that risk-adapted, dose-adjusted EPOCH-R could obviate the need for highly dose-intensive chemotherapy, therefore reducing toxicity.

The phase II trial enrolled 113 patients (median age = 49 years; range = 18-86) with previously untreated Burkitt lymphoma from across 22 centers. Most participants (n=98; 87%) were considered to have high-risk disease (defined as stage ≥3 disease, an Eastern Cooperative Oncology Group performance status score ≥2, or tumors measuring ≥7 cm).

Per study protocol, patients with low-risk disease received 3 cycles of dose-adjusted EPOCH-R without central nervous system (CNS) prophylaxis, while patients with high-risk disease received 6 treatment cycles with intrathecal CNS prophylaxis. High-risk patients who had leptomeningeal involvement received extended intrathecal treatment.

“Highly dose-intensive chemotherapy is unnecessary for cure, and carefully defined low-risk patients may be treated with limited chemotherapy.”

—Mark Roschewski, MD

Of the patient population, 11 people (10%) had CSF involvement and 28 (25%) were positive for HIV.

The investigators reported efficacy results for the 13 low-risk patients who received all 3 planned cycles and 80 high-risk patients who received all 6 planned cycles. In the high-risk population, 5 patients died of adverse events early in the treatment, including 3 patients with CSF involvement.

At a median follow-up of 58.7 months, the 4-year EFS rate for all 113 patients was 84.5%, while the 4-year OS rate was 87%. The authors noted that all patients with low-risk disease are in remission and the EFS and OS rates in the high-risk population were 82.1% and 84.9%, respectively.

“Relapses in the CNS after therapy were uncommon,” they added, with only 2 relapses in the brain parenchyma among the 81 patients with high-risk disease who had no pretreatment evidence of CSF involvement.

As part of their analysis, the researchers also explored variables associated with survival, including interim PET scans in 14 low-risk and 85 high-risk patients. All scans were interpreted as negative in the low-risk group, while 60% were interpreted as negative in the high-risk group. However, the 4-year EFS rate was not significantly different between those high-risk patients with a positive or negative interim PET scan (90% vs. 79%; p=0.12).

Similarly, HIV infection, age, and International Prognostic Index score had no effect on survival. CSF involvement was the only variable that was strongly associated with survival, the authors concluded (TABLE). In the group of 11 patients who had CSF involvement at presentation, 6 experienced disease progression or died.

As expected with the lower-intensity EPOCH-R regimen used in this study, the authors reported that the treatment was “tolerable” in this patient population, across all age groups. While highly dose-intensive regimens typically lead to serious infections in 15 to 20% of patients during each cycle of therapy, “serious infections were observed in 6% of cycles in our study, despite the inclusion of patients with HIV,” they wrote.

Other hematologic adverse events observed across the 562 treatment cycles administered during the study included grade 3/4 thrombocytopenia (96 cycles; 17%) and febrile neutropenia (89 cycles; 16%). Nonhematologic toxicity included:

  • tumor lysis syndrome: 5 patients (5%)
  • grade 3/4 mucositis: 21 patients (19%)
  • grade 3/4 sensory neuropathy: 5 patients (5%)

“Most serious complications occurred early in therapy and were associated with impaired performance status,” the researchers noted. However, they added that, of 7 patients with ECOG scores of 3 or 4, 5 were alive without disease at last follow-up, suggesting that impaired performance status does not preclude successful treatment with dose-adjusted EPOCH-R.

“[Our results] suggest highly dose-intensive chemotherapy is unnecessary for cure, and carefully defined low-risk patients may be treated with limited chemotherapy,” the authors wrote, adding that the findings also support a strategy of risk-adapted intrathecal therapy (without the use of high-dose methotrexate) to prevent CNS relapses.

The findings of the study are limited by the nonrandomized design and the lack of a
head-to-head comparison between dose-adjusted EPOCH-R and highly dose-intensive regimens.

The authors report no relevant conflicts of interest. The study was sponsored by the National Cancer Institute.

Reference

Roschewski M, Dunleavy K, Abramson JS, et al. Multicenter study of risk-adapted therapy with dose-adjusted EPOCH-R in adults with untreated Burkitt lymphoma. J Clin Oncol. 2020 May 26. [Epub ahead of print]