Improved Responses Seen in Aggressive B-cell Lymphomas With Dose-Adjusted EPOCH-R Regimen

The dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [Rituxan]) chemotherapy regimen induced either a complete or partial response (CR/PR) in 87% of patients with aggressive B-cell lymphomas with anMYCrearrangement, a population that has had historically poor prognoses with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment.¹

Roughly 10% of patients with diffuse large B-cell lymphoma (DLBCL) express anMYC8q24 rearrangement that is sometimes accompanied by a translocation inBCL2,BCL6, or both. The poor outcomes typically seen in this patient population have prompted the use of intensive treatments, such as those used in patients with Burkitt lymphoma and stem cell transplantation.

In a prospective, nonrandomized, phase II study, 53 patients with untreated aggressive B-cell lymphomas with de-novoMYCrearrangements—which included high-grade double-hit B-cell lymphoma, high-grade B-cell lymphoma, high-grade B-cell lymphoma not otherwise specified, DLBCL, and plasmablastic lymphoma—were treated with a dose-adjusted regimen of EPOCH-R.

Primary study outcomes were event-free survival (EFS), defined as being the same as progression-free survival by study investigators, and overall survival (OS) with analysis in single- and double-hit patients.

Eligibility for the trial included confirmation ofMYCrearrangement by fluorescence in situ hybridization using breakapart probes or conventional cytogenetics. Histology results included high-grade double- or triple-hit B-cell lymphoma in 24 patients (45%), high-grade B-cell lymphoma not otherwise specified in 10 (19%), and DLBCL in 18 (34%).

Patients at all disease stages and performance statuses and those with central nervous system leptomeningeal involvement or HIV infection could be included in the cohort. Participants had a median age of 61 years (range, 29-80), 75% were male, and 81% had stage III or IV disease.

EPOCH-R was administered for six 21-day cycles with starting doses of 50 mg/m²per day of etoposide, 10 mg/m²per day of doxorubicin, and 0.4 mg/m²per day of vincristine, infused on days 1 through 5; 750 mg/m²of cyclophosphamide given intravenously on day 5; 60 mg/m²of prednisone orally twice daily on days 1 through 5; 375 mg/m²of rituximab given intravenously on day 1; and 5 mg/kg filgrastim subcutaneously daily starting on day 6 and continuing until absolute neutrophil counts were >5000 per μL past the nadir.

Thirty-nine patients in the cohort achieved a CR and 7 achieved a PR, for a total of 46 out of 53 patients responding to the trial regimen. Five patients, 4 with CRs and 1 with a PR, went on to either autologous (n = 4) or allogeneic (n = 1) bone marrow transplantation and 2 patients with CRs received consolidation radiotherapy following dose-adjusted EPOCH-R.

For all patients, the rate of EFS was 71.0% (95% CI, 56.5%-81.4%) and the rate of OS was 76.7% (95% CI, 62.6%-86.1%) at 48 months. In 32 patients with confirmed single- versus double-hit lymphoma (n = 32), the 48-month EFS rate was 62.7% (95% CI, 37.2%-80.2%) versus 73.4% (95% CI, 50.1%-87.1%), respectively (P= .40). For both groups, the rate of OS was 63.2% (95% CI, 38%-80.4%) for single-hit versus 82.0% (95% CI, 58.8%-92.8%) for double-hit at 48 months (P= .12).

When 24 double-hit patients were stratified by international prognostic index (IPI) score, those with low or low-intermediate IPI (score 0-2) versus those with high or high-intermediate IPI (score 3-5) had a 48-month EFS rate of 91.7% (95% CI, 53.9%-98.8%) and 54.5% (95% CI, 22.9%-78%), respectively (P= .049). The OS rate at 48 months for both groups was 90.9% (95% CI, 50.8%-98.7%) in low-risk patients and 72.2% (95% CI, 37.1%-90.3%) in high-risk patients (P= .25), indicating that the latter group can achieve durable remissions with this regimen.  

Additional analyses were conducted to assess whether or not age influenced the efficacy of EPOCH-R in this patient population; no difference was found demonstrating that this regimen could be effective in elderly patients.

“The absence of an age effect in our study suggests that [dose-adjusted] EPOCH-R could be effective in elderly patients and, unlike more intensive so-called Burkitt-like regimens, has acceptable tolerance,” the trial investigators said.

Stratifying patients by tumor histology—DLBCL versus high-grade double-hit B-cell lymphoma or disease not otherwise specified—also found no differences in outcomes.

A preplanned analysis using 18^F-fluorodeoxyglucose PET scan was performed to assess whether patients at increased risk of treatment failure could be identified. Patients with a negative scan, or those with a Deauville score ≤3, had 48-month EFS and OS rates of 87.4% (95% CI, 58.1%-96.7%) and 87.5% (95% CI, 58.6%-96.7%), respectively. Patients with a Deauville score of 4 to 5 were considered to have positive scans and had a 64.5% (95% CI, 45.2%-78.5%;P= .057) rate of EFS and a 74.2% (95% CI, 55%-86.2%;P= .23) rate of OS at 48 months.

There were 45 patients who received all 6 cycles of treatment, 3 who received 5 cycles due to concerns about tolerance, and 5 who did not complete their treatment. Of those, 3 patients died during the study, 1 had progressive disease, and 1 withdrew from the study.

Grade 4 neutropenia and thrombocytopenia occurred in 160 cycles of therapy (53%) and 40 cycles (13%), respectively, out of a total 301 cycles assessed for toxicity. Fever and neutropenia of any grade occurred in 56 cycles (19%). Three treatment-related deaths occurred because of infections.

Favorable outcomes and the relative tolerability of dose-adjusted EPOCH-R has made it an accepted standard regimen outlined by the National Comprehensive Cancer Network Guidelines for high-grade B-cell lymphomas with translocation ofMYC.²

“The results from this study suggest that [dose-adjusted] EPOCH-R could improve on the outcome of R-CHOP in this patient population,” trial investigators said.

In an effort to further improve outcomes, a phase I trial of EPOCH-R plus venetoclax (Venclexta; NCT03036904) in patients withMYC-rearranged aggressive B-cell lymphomas, including DLBCL, is recruiting to assess the maximum tolerated dose and safety of the regimen.

References:

1. Dunleavy K, Fanale MA, Abramson JS, et al. Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) in untreated aggressive diffuse large B-cell lymphoma with MYC rearrangement: a prospective, multicentre, single-arm phase 2 study.Lancet Haematol. 2018;5(12):e609-e617. doi: 10.1016/S2352-3026(18)30177-7.
2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): B-cell Lymphomas Version 1.2019. NCCN website. nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Published November 30, 2018. Accessed January 16, 2019.