Study Finds Standard R-CHOP Bests Dose-Adjusted EPOCH-R in DLBCL

In an update from the phase III intergroup Alliance/CALGB 50303 trial, treatment with frontline dose-adjusted (DA) EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) failed to improve survival outcomes compared with standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in patients with untreated diffuse large B-cell lymphoma (DLBCL). However, DA-EPOCH-R was associated with higher toxicity, according to the results published in the Journal of Clinical Oncology.

The study was led by Nancy L. Bartlett, MD, of the Washington University School of Medicine in St. Louis. Patients were enrolled in the trial if they had untreated DLBCL, primary mediastinal large B-cell lymphoma (PMBCL), or intravascular large B-cell lymphoma. Eligible participants also had stage II to IV DLBCL (or stage I PMBCL) and an Eastern Cooperative Oncology Group performance status of 0-2.

In the overall cohort, approximately 74% of patients had stage III or IV disease. Patients were stratified into four International Prognostic Index (IPI) risk groups, including:
  • IPI 0 to 1 (26%)
  • IPI 2 (37%)
  • IPI 3 (25%)
  • IPI 4 to 5 (12%)
Investigators obtained tumor biopsy specimens from each patient prior to enrollment. The cohort was randomized (1:1) to one of the following groups:
  • R-CHOP every 21 days for 6 cycles (n=250)
  • DA-EPOCH-R every 21 days for 6 cycles (n=241)

Patients treated with DA-EPOCH-R were required to receive Pneumocystis prophylaxis as well as filgrastim on days six to 15 or until achievement of an absolute neutrophil count (ANC) of >5,000/mL following nadir. Filgrastim or pegfilgrastim were administered in the R-CHOP group if a patient’s ANC was <500/mL or if febrile neutropenia occurred with the prior treatment cycle.

Progression-free survival (PFS) was the study’s primary endpoint and assessed using unadjusted Cox models stratified by IPI; secondary endpoints included response rate, overall survival (OS), and safety.

“In my practice, I limit the use of dose-adjusted EPOCH-R to Burkitt lymphoma, double- or triple-hit lymphoma, and PMBCL.”

—Nancy l. Bartlett, MD

After a median follow-up of 5.2 years (interquartile range = 4.8-5.4 years), the authors observed no difference in PFS between the R-CHOP and DA-EPOCH-R groups (hazard ratio [HR] = 0.93; 95% CI 0.68-1.27; p=0.65). Two-year PFS rates for the two groups also were similar: 78.9% for DA-EPOCH-R and 75.5% for R-CHOP.

In addition, there was no difference in OS rates at five years between the DA-EPOCH-R and R-CHOP groups (77.5% vs. 78.5%; HR=1.09; 95% CI 0.75-1.59; p=0.64). Again, two-year OS rates were similar (86.5% and 85.7%).

Survival outcomes remained similar with each treatment group across risk categories, the researchers added.

“The most surprising finding was the good outcome with standard R-CHOP, likely related to the favorable characteristics of the patients accrued to the study,” Dr. Bartlett told ASH Clinical News. “This study confirms what we have suspected for a long time: The highest-risk patients with DLBCL, the ones who may stand to benefit most from new approaches, are often not treated on clinical trials either because of strict inclusion/exclusion criteria or, as in our trial, the need for additional procedures that may delay the start of treatment.”

The lack of a survival benefit with DA-EPOCH-R was accompanied by an increase in grade ≥3 treatment-related adverse events (AEs). Incidence of grade ≥3 AEs with the standard R-CHOP regimen was 78.2%, compared with 98.3% in the DA-EPOCH-R group (p<0.001). Patients in the DA-EPOCH-R group had a higher incidence of both grade 3/4 hematologic AEs (97.5% vs 73.7%; p<0.001) and nonhematologic AEs (72.2% vs. 43.2%; p<0.001).

Grade 3/4 AEs that occurred more frequently in the DA-EPOCH-R group included: infection (16.9% vs. 10.7%), febrile neutropenia (35% vs. 17.7%), mucositis (8.4% vs. 2.1%), and neuropathy (18.6% vs. 3.3%). Incidence of treatment-related deaths was similar with each treatment, occurring in five patients (2.1%) in each group.

Together, the results suggest that R-CHOP should remain the standard of care in all patients with untreated DLBCL, the authors concluded.

“Unfortunately, the study was not powered to determine whether there may be an advantage to the more intensive DA-EPOCH-R regimen in the highest-risk patients (i.e., those with IPI scores of 4 or 5 or those who harbor an MYC gene rearrangement),” Dr. Bartlett noted. “In my practice, I limit the use of DA-EPOCH-R to Burkitt lymphoma, double- or triple-hit lymphoma, and PMBCL.”

Limitations of the study included its relatively small patient population. The authors also noted that “the more favorable results with R-CHOP compared with historical controls suggest a potential patient selection bias and may preclude generalizability of results to specific risk subgroups.”

According to Dr. Bartlett, “future investigations in DLBCL should explore the addition of novel agents to the R-CHOP backbone either in combination or as consolidation, allow the sickest patients to participate in trials, and strive to identify new predictive markers.”

The authors report relationships with Pfizer, Seattle Genetics, Bristol-Myers Squibb and other companies. The study was supported by the National Cancer Institute.

Reference

Bartlett NL, Wilson WH, Jung SH, et al. Dose-adjusted EPOCH-R compared with R-CHOP as frontline therapy for diffuse large b-cell lymphoma: clinical outcomes of the phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol. 2019 April 2. [Epub ahead of print]

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