Long-awaited results of the Cancer and Leukemia Group B (CALGB)/Alliance 50303 trial were a disappointment to many hematologists/oncologists at the 2016 American Society of Hematology (ASH) Annual Meeting & Exposition. The study failed to show that dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [Rituxan]) was superior to the by-now old standard R-CHOP (rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone) in patients with previously untreated diffuse large B-cell lymphoma.1 Both regimens achieved similar efficacy in event-free and overall survival, but dose-adjusted EPOCH-R was more toxic.
Developed at the National Cancer Institute, dose-adjusted EPOCH-R relies on a long infusional schedule, the addition of etoposide, and use of a pharmacodynamic dose adjustment based on absolute neutrophil count nadir. It is more difficult to deliver EPOCH-R than R-CHOP and less convenient for patients because it requires 96 hours to deliver.
A phase II CALGB multicenter trial showed a progression-free survival of 81% at 4 years using dose-adjusted EPOCH-R in diffuse large B-cell lymphoma.2 These findings raised hopes that this dose-intensive regimen would be an improvement over R-CHOP. However, to date, R-CHOP retains its position as standard of care for diffuse large B-cell lymphoma.
Correlative analysis of study results according to the cell of origin as well as BCL2 and MYC protein expression and rearrangements will be presented at a later date. It is possible that these analyses will identify subgroups that derive a preferential benefit from dose-adjusted EPOCH-R. For now, dose-adjusted EPOCH-R may be a better choice than R-CHOP for mediastinal B-cell lymphoma based on phase II data, according to the experts interviewed for this article. This question cannot be answered by the phase III trial because only 28 patients with mediastinal large B-cell lymphoma participated.
CALGB/Alliance 50303 Details
Dose-adjusted EPOCH-R may have an advantage for patients with more adverse factors, although this study was not designed to answer that question...— Nancy Bartlett, MD
“The study was designed more than 13 years ago. The primary objectives were to compare event-free survival with the two regimens and to develop a molecular profiling predictor of outcome with each regimen. We had hoped to present the results of both primary objectives together, but because of data-transfer delays, the molecular-profiling data are not yet available, and we did not want to hold up presentation of the clinical data,” said lead investigator Nancy Bartlett, MD, of Siteman Cancer Center, Washington University School of Medicine, St. Louis.
CALGB/Alliance 50303 was a phase III study designed to compare dose-adjusted EPOCH-R with R-CHOP in 524 patients with newly diagnosed, previously untreated stage II or higher diffuse large B-cell lymphoma. Patients were randomized 1:1 and treated for a total of 6 cycles. About 6% of patients in each arm had primary mediastinal B-cell lymphoma, which tends to respond better to dose-adjusted EPOCH-R. Patients with high-risk features including elevated LDH and more than one extranodal site of involvement or marrow or testicular involvement received central nervous system (CNS) prophylaxis. Positron-emission tomography/computed tomography (PET/CT) was recommended but not required. No patient received radiation therapy.
In May 2016, the Data Safety Monitoring Board recommended release of clinical data from the trial, although the event rate of 167 was still below the threshold set in the study design. The efficacy analysis included 233 patients treated with R-CHOP and 232 patients treated with dose-adjusted EPOCH-R. Baseline demographics and disease characteristics were similar in each arm. About 75% of all patients had stage III or IV disease.
Dose-adjusted EPOCH-R was more toxic, with more early treatment discontinuations due to adverse events compared with R-CHOP, 6.5% vs 1.5%, respectively (P = .004). More hematologic toxicity was seen with dose-adjusted EPOCH-R: grade 4 neutropenia occurred in 90% vs 56% for R-CHOP; grade 4 thrombocytopenia occurred in 35% vs 6%, respectively; grades 3 and 4 febrile neutropenia were reported in 37% vs 19%, respectively; and there were higher rates of grade 3 sensory and motor neuropathies. There was no difference in the rate of serious infection. Five treatment-related deaths occurred in each arm.
“The hematologic toxicity was expected with the dose-adjusted EPOCH-R, because by design, dose escalations continued until patients experienced grade 4 neutropenia,” Dr. Bartlett noted.
The rate of event-free survival—the primary endpoint of the trial—was similar in both arms. The 3-year and 5-year event-free survival rates were 79% and 66%, respectively, with dose-adjusted EPOCH-R, vs 81% and 69% with R-CHOP. No difference was found in overall survival, with 85% of patients alive at 3 years in both arms.
No significant differences were observed for patients younger than age 60 vs older, although a numerical trend suggested worse outcomes for older patients. International prognostic index status was highly correlated with event-free survival, she said, and “almost identical to published results with R-CHOP but did not differentiate patients on dose-adjusted EPOCH-R as well,” she continued.
Approximately one-third of patients participated in a PET substudy and had PET scans after cycle 2 and at the end of treatment. Interim PET had a modest predictive value for event-free survival, Dr. Bartlett said. “We await the results of the correlative analysis of cell of origin, BCL2, and MYC expression and rearrangements,” she added.
“Who should continue to get dose-adjusted EPOCH-R? The phase II data are encouraging for patients with mediastinal large B-cell lymphoma, and the regimen allows you to avoid radiation therapy. Unfortunately, the current study will not help answer this question. I will continue to use it for double-hit lymphoma, but we need more data regarding both double-hit by [fluorescence in situ hybridization] and double-expressor status. The population in this study had good prognostic features, and dose-adjusted EPOCH-R may have an advantage for patients with more adverse factors, although this study was not designed to answer that question, and the number of patients in the highest risk group was small,” Dr. Bartlett noted. ■
Disclosure: Dr. Bartlett reported no potential conflicts of interest.
1. Wilson WH, Jung SH, Pitcher BN, et al: Phase III randomized study of R-CHOP versus DA-EPOCH-R and molecular analysis of untreated diffuse large B-cell lymphoma: CALGB/Alliance 50303. 2016 ASH Annual Meeting. Abstract 469. Presented December 4, 2016.
2. Wilson WH, Jung SH, Porcu P, et al: A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica 97:758-765, 2012.
Lawrence Kaplan, MD
“This study is important because R-CHOP [rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone] has been the standard of care for many years. CHOP, the chemotherapy backbone, has withstood challenges from more aggressive regimens in the past. The...!-->!-->