The CALGB/Alliance 50303 clinical trial failed to show that dose-adjusted treatment with the EPOCH-R (etoposide, phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride, and rituximab) regimen was superior to standard therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) in patients with diffuse large B-cell lymphoma (DLBCL). Both treatment regimens were equally effective for event-free survival and overall survival (OS), but dose-adjusted EPOCH-R was associated with a higher incidence of adverse events than R-CHOP, said lead investigator Nancy L. Bartlett, MD, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, at the 2016 American Society of Hematology meeting.
The lymphoma community was hopeful that the dose-adjusted EPOCH-R regimen would be superior to R-CHOP and provide the first new standard of care since the introduction of R-CHOP.
Although it has not yet been completed, the hope is that correlative analyses according to the cell of origin—BCL2—and MYC protein expression and rearrangements will identify subgroups of patients who may benefit from therapy with dose-adjusted EPOCH-R, but for now, R-CHOP is still the standard of care for patients with DLBCL.
“The study was designed more than 13 years ago. The primary outcome was to compare event-free survival with the 2 regimens and to develop a molecular profiling predictor of outcome with each regimen. The molecular profiling data are not yet available,” said Dr Bartlett.
The dose-adjusted EPOCH-R regimen was developed at the National Cancer Institute. Dose-adjusted EPOCH-R involves hospitalization because of a 96-hour infusion schedule, including chemotherapy with etoposide and pharmacodynamic dose-adjustment based on the absolute neutrophil count nadir. Dose-adjusted EPOCH-R is more cumbersome and less convenient for patients than the R-CHOP regimen.
Promising phase 2 clinical trial data raised hopes that dose-adjusted EPOCH-R would replace R-CHOP as the standard of care for patients with DLBCL.
The phase 3 CALGB/Alliance 50303 clinical trial randomized 524 patients with newly diagnosed, previously untreated, stage II or higher DLBCL in a 1:1 ratio to receive dose-adjusted EPOCH-R or R-CHOP for 6 cycles. All patients received central nervous system prophylaxis, and radiation therapy was not administered. Positron emission tomography–computed tomography was recommended but not required.
The Data Safety Monitoring Board recommended releasing the study results in May 2016. The efficacy analysis was based on 233 patients who received R-CHOP and 262 patients who received dose-adjusted EPOCH-R. The baseline demographics and disease characteristics were similar in both arms. Approximately 75% of patients had stage III or IV disease.
Adverse events led to early treatment discontinuation in 6.5% of patients who received dose-adjusted EPOCH-R compared with 1.5% of patients who received R-CHOP (P = .004). A higher incidence of hematologic toxicity was with dose-adjusted EPOCH-R than with R-CHOP, including grade 4 neutropenia (90% vs 56%, respectively), grade 4 thrombocytopenia (35% vs 6%, respectively), grade 3 or 4 febrile neutropenia (37% vs 19%, respectively), and as higher rates of grade 3 sensory and motor neuropathies. No differences were seen in the rate of infection between the 2 treatment arms. There were 5 treatment-related deaths in each arm.
The primary end point of event-free survival was 89% at 5 years in both arms. The event-free survival at 3 years was 79% with dose-adjusted EPOCH-R versus 81% with R-CHOP. There was no difference in the OS between the 2 treatment arms; 85% of patients in each group were alive at 5 years.
No significant differences in event-free survival were observed by age, but a numerical trend suggested worse outcomes for older patients than for younger patients.
“We await the results of the correlative analysis of cell of origin, BCL2, and MYC expression and rearrangements to determine if specific subsets benefit from dose-adjusted EPOCH-R,” Dr Bartlett said. “For now, I will probably continue to use it for double-hit double-expresser [ie, BCL2 and MYC], but we need more data. The population in this study had good prognostic features, and dose-adjusted EPOCH-R appears better for patients with adverse factors,” she added.
The next round of studies will look at biologic agents added to R-CHOP, including lenalidomide (Revlimid), ibrutinib (Imbruvica), and venetoclax (Venclexta), said Stefan K. Barta, MD, MS, MRCP, Director, T-Cell Lymphoma Program, Fox Chase Cancer Center, Philadelphia, PA.
“We have been waiting for a very long time for these results that could have been potentially practice-changing, but that turns out not to be the case. R-CHOP is still the established backbone of therapy for diffuse large B-cell lymphoma,” said Dr Barta.
“I am surprised by the results, and slightly disappointed. I hoped we would have a leap forward, but still nothing is better than R-CHOP for the majority of patients with diffuse large B-cell lymphoma. Dose-adjusted EPOCH-R may turn out to be better for ‘double-hit’ lymphoma,” he concluded.