Jul 3, 2019
This JCO Podcast provides observations and commentary on the JCO article “Dose-Adjusted EPOCH-R Compared to R-CHOP as Frontline Therapy for Diffuse Large B Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial CALGB 50303 (Alliance)” by Bartlett et al. My name is Patrick Stiff, and I am Division Director of Hematology-Oncology at Loyola University Stritch School of Medicine in Maywood, Illinois. My oncologic specialty is hematologic malignancies and stem cell transplantation.
CHOP has remained the chemotherapy backbone of choice for the treatment of diffuse aggressive non-Hodgkin lymphoma since the 4 arm randomized SWOG study was performed 25 years ago1. Since then, only the addition of rituximab has improved patients' outcome2. Investigators have tried to improve outcomes by employing other strategies like increasing drug intensity, shortening the interval between cycles, adding newer agents, changing the method of administration, and adding transplantation, but none clearly demonstrated a survival advantage.
Among these strategies is an infusional one designed to increase apoptosis and inhibit BCL6 and p-glycoprotein in resistant cells. While SWOG tested infusional CHOP in 2001 and found no difference in outcomes, compared to bolus CHOP3, the NCI group has explored a modified CHOP infusional regimen known as EPOCH consisting of etoposide, vincristine, and doxorubicin given simultaneously as a continuous 4 day infusion with a bolus dose of cyclophosphamide at the end of the 4 days along with daily oral prednisone Combined with aggressive dose escalations based on nadir myelosuppression, they tested this regimen with rituximab, EPOCH-R, reporting an impressive 5 year PFS of 79% in an unselected study of 72 patients from 3 centers4. Based on this, 18 CALGB institutions treated 69 patients with dose adjusted EPOCH-R, demonstrating a similar 62 month TTP of 81%, with an impressive 100% TTP for the germinal center B cell subgroup as defined by the Hans algorithm, all seemingly superior to R-CHOP5. Equally impressive was a Phase II study in mediastinal B cell NHL with a 5-yr EFS of 93% administered without consolidative radiotherapy, added frequently to R-CHOP6. Therefore, a head-to-head comparison was the natural next step.
The trial that accompanies this podcast was designed to compare the PFS and OS at 3 years between patients treated with 6 cycles of dose adjusted EPOCH-R to the standard R-CHOP. The trial opened in 2005 and enrolled 524 patients with either DLBCL, primary mediastinal BCL or intravascular large cell NHL over an 8+ year period to its close in 2013. Seventy-four % had stage III/IV disease and 12% high IPI disease. Eighty-eight percent of the R-CHOP and 82% of the dose adjusted EPOCH-R cycles were administered with 75% of the dose adjusted EPOCH-R patients receiving initial dose escalations per protocol. At a median follow-up of 5.2 years the 5 year PFS and OS were 66 and 85% for the R-CHOP treated patients no different from the 68 and 77.5% for the dose adjusted EPOCH-R patients. Prognostic factors for PFS were age > 60, IPI, and double expressers (15.6% of the 270 with complete data) for MYC, BCL-2 and BCl-6.
There were a number of post hoc subgroup analyses performed. Of these, the PFS for the combined High and High intermediate IPI group was higher for the dose adjusted EPOCH-R group (p = 0.041) but no difference in OS was noted. In none of the other subgroups was a benefit seen for dose adjusted EPOCH-R including CNS relapses, mediastinal B cell NHL, double expressors or those with MYC positivity although percentages of these subgroups were small. There were however significantly increased grade III-IV myelotoxic and non-myelotoxic complications for the infusional regimen.
Should we take these results as the final word on the lack of a benefit of dose adjusted EPOCH-R in the treatment of DLBCL? In other words is this a case of "déjà vu all over again"?. This trial recruited slowly, 524 patients over more than 8 years, with < 5% of US eligible patient enrolled. The reasons seem obvious. Encouraging enrollment on a trial comparing a familiar outpatient regimen administered over hours, versus a 4+ day in-patient regimen was at best difficult. Recall also that this trial took place during the Great Recession, with patients/families fearful of losing their jobs dealing with an in-pt regimen. Slow accrual in and of itself should not have been impacted outcome. But these were not a unselected group as the authors concluded. First by design, all who had an ECOG PS of > 2 (20% of the phase II study5) were excluded. Second there was the requirement for submission of fresh/frozen material including a second biopsy if needed thereby likely eliminating mostly patients with rapidly progressing disease. Together possibly with some investigator bias, given the promising Phase II data, there was a decrease in High IPI enrollment of only 12% versus the 20% in the Phase II study, which extended to other high risk patients including double expressors, C-Myc positive, and mediastinal B cell disease. Combined these led to the 3 year PFS for R-CHOP of 72%, 17% better than the planned outcome. However, considering the trial exclusions, and ultimately a PFS similar to that of other recent R-CHOP experiences7,8 one could argue that the 3-yr 55% PFS endpoint for this trial was far too conservative.
While the R-CHOP PFS was 17% better than planned, the dose adjusted EPOCH-R 5-yr PFS was 7% worse than the Phase II results, which is difficult to explain considering the earlier studies, in which the more favorable patients did better5. A lower administered dose intensity compared to prior studies4,5 was not apparent with the incidence of grade III/IV febrile neutropenia and neurotoxicity similar to the Phase II trial. However 82% vs 91% of those in the Phase II study completed all dose adjusted EPOCH-R cycles with the decrease mostly due to on treatment deaths and AEs, suggesting that when used in a more 'real world setting' this regimen is more toxic than initially seen. Might those who completed therapy also have had dose reductions or delays that could also have impacted PFS? Finally, this report does not include PFS based on cell of origin(COO), which for patients with germinal center B cell of origin in the Phase II study was 100%. Perhaps the germinal B cell percentage was lower than in the Phase II studies as well.
So what can be concluded about these negative results? The authors conclude that there was a "potential patient selection bias", at least partially explainable by trial design, and that this "may preclude generalizibility….to specific subgroups". I would conclude that given the outcome and toxicity data, for the low and low intermediate IPI patient, R-CHOP remains the treatment of choice. The post hoc PFS improvement for the high risk subgroup might argue for dose adjusted EPOCH-R, but the lack of an OS advantage in this subgroup needs to be acknowledged. However, other compelling phase II studies in high risk subsets, e.g double hit, underrepresented in this trial, still makes the efficacy of dose adjusted EPOCH-R in certain circumstances an open question.
This concludes this JCO Podcast. Thank you for listening.