Tumor control is frequently not achieved with standard immunochemotherapy in patients with primary mediastinal B-cell lymphoma, requiring consolidation with mediastinal radiotherapy. However, radiotherapy is associated with serious late adverse effects and is still associated with disease progression in approximately 20% of patients. More aggressive chemotherapy has been associated with improved outcomes.
In this context, Wyndham Wilson, MD, PhD, and colleagues from the Center for Cancer Research at the National Cancer Institute (NCI) found that dose-intense chemotherapy with dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone (DA-EPOCH) produced a favorable overall survival rate (79%) without consolidation radiotherapy in a phase II study in primary mediastinal B-cell lymphoma patients.1 They hypothesized that the addition of rituximab (Rituxan)—DA-EPOCH-R—could further improve response.
As recently reported in The New England Journal of Medicine by Kieron Dunleavy, MD, also from the Center for Cancer Research at NCI, and colleagues, a prospective phase II trial of DA-EPOCH-R and filgrastim (Neupogen) without radiotherapy performed by the NCI investigators showed high event-free and overall survival in patients with primary mediastinal B-cell lymphoma without late morbidity or cardiotoxic effects.2
Prospective NCI Study
The prospective NCI study included 51 patients with previously untreated disease. Patients had a median age of 30 years (range, 19–52 years), 59% were women, and the median tumor diameter was 11 cm. Bulky tumor with a greatest diameter of 10 cm or more was present in 65% of patients, 78% had elevated lactate dehydrogenase levels, and 29% had stage IV disease. Patients received chemotherapy plus filgrastim for 6 to 8 cycles, with disease sites being evaluated by computed tomography (CT) after cycles 4 and 6.
After treatment, residual tumor mass was measured by FDG-PET-CT (18F-fluorodeoxyglucose–positron-emission tomography-CT). Patients with a maximum standardized uptake value greater than that of the mediastinal blood pool in the residual mediastinal mass had repeat scans at approximately 6-week intervals until normalization or stabilization.
At a median follow-up of 63 months (range, 3–156 months), event-free survival was 93% (95% confidence interval [CI] = 81%–98%) and overall survival was 97% (95% CI = 81%–99%). Three patients had evidence of residual disease, two with persistent focal disease and one with disease progression. Two of the patients underwent mediastinal radiotherapy, and one was observed after excisional biopsy. All became disease-free; one later died from acute myeloid leukemia (AML) while in remission from primary mediastinal B-cell lymphoma at 49 months after treatment.
Stanford Retrospective Cohort
To provide an independent assessment of DA-EPOCH-R, the NCI investigators collaborated with investigators at Stanford University Medical Center who had begun to use DA-EPOCH-R for primary mediastinal B-cell lymphoma in 2007. Review of charts from 2007 to 2012 identified 16 previously untreated patients who had been consecutively treated with DA-EPOCH-R, with none requiring consolidation radiotherapy.
Baseline characteristics of these patients were similar to those in the prospective NCI cohort except for a significantly greater age (median, 33 vs 30 years, P = .04) and a significantly smaller proportion with extranodal disease sites (19% vs 53%, P = .02). In this retrospective cohort, 100% of patients (95% CI = 79%–100%) were alive and event-free after median follow-up of 37 months (range, 5–53 months).
The authors also assessed longer-term outcome of 18 patients in their initial phase II trial of DA-EPOCH (no rituximab). Baseline characteristics of these patients were similar to those of patients in the prospective DA-EPOCH-R trial. Over a median follow-up of 16 years, event-free survival was 67% and overall survival was 78%. Event-free survival (P = .007) and overall survival (P = .01) in the cohort receiving DA-EPOCH-R were significantly better than in the cohort receiving DA-EPOCH alone, suggesting that the addition of rituximab may account for the improved outcome.
Absence of Cardiotoxcity
In the NCI prospective cohort, 90% of patients received 6 cycles of DA-EPOCH-R and 10% received 8 cycles. More than half of the patients had a marked dose escalation (to at least dose level 4, a 73% increase over dose level 1), and 6% of patients had no dose escalation. More than half of patients received a doxorubicin dose of 69 mg/m2 for at least 1 cycle and cumulative doses of 345 to 507 mg/m2.
Left-ventricular ejection fractions were measured in 42 patients to assess cardiotoxic effects. All had normal ejection fractions for up to 10 years after treatment, and there were no significant associations between ejection fraction and length of time since treatment (P = .30) or cumulative doxorubicin dose (P = .20) and no significant interaction of ejection fraction with dose and time interval (P = .40).
The target absolute neutrophil count of less than 500 cells/µL occurred during 50% of the total of 294 cycles of DA-EPOCH-R. Thrombocytopenia occurred in 6% of cycles, and hospitalization for fever and neutropenia occurred in 13% of cycles. Nonhematologic toxicities were consistent with those reported in other studies of DA-EPOCH-R treatment.
As noted, one patient died from AML while in remission from primary mediastinal B-cell lymphoma. Given the unexpected severe neutropenia observed in this patient during treatment, the investigators sought evidence of a germline telomerase mutation associated with chemotherapy intolerance and myeloid leukemia, and found telomerase shortening and the presence of a heterozygous mutation for the telomerase reverse transcriptase gene (TERT, codon Ala1062Thr).
The investigators concluded, “The use of DA-EPOCH-R obviated the need for radiotherapy in all but 2 of 51 patients (4%) with primary mediastinal B-cell lymphoma in a prospective cohort, and no patients had recurring disease over a median follow-up of more than 5 years (maximum, > 13). Furthermore, in an independent retrospective cohort, treatment with DA-EPOCH-R … resulted in an event-free survival rate of 100%. Despite the limitations of the phase II study and the retrospective study, these findings suggest that DA-EPOCH-R is a therapeutic advance for this type of lymphoma. Our results suggest that rituximab significantly improves the outcome of chemotherapy in patients with primary mediastinal B-cell lymphoma.”
Confirmatory evidence of this approach is currently being sought in an international trial of DA-EPOCH-R in children with primary mediastinal B-cell lymphoma (ClinicalTrials.gov number NCT01516567). ■
Disclosure: The study authors reported no potential conflicts of interest.
References
1. Wilson WH, Grossbard ML, Pittaluga S, et al: Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: A pharmacodynamic approach with high efficacy. Blood 99:2685-2693, 2002.
2. Dunleavy K, Pittaluga S, Maeda LS, et al: Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med 368:1408-1416, 2013.
