Pola-R-CHP or R-CHOEP for first-line therapy of younger patients with high-risk diffuse large B-cell lymphoma: a retrospective comparison of two randomized phase 3 trials

Study design, patient eligibility, randomization, endpoints, and statistical analyses of the two prospective, randomized phase 3 studies R-MegaCHOEP and POLARIX have been reported previously [ 7 , 12 ]. POLARIX was an international, double-blind, placebo-controlled study, whereas R-MegaCHOEP was an open label study performed in Germany. Full inclusion and exclusion criteria of both studies were published previously [ 7 , 12 ]. The current analysis compared outcomes of younger DLBCL patients (18–60 years) with age adjusted IPI (aaIPI) 2 or 3 treated with R-CHOEP on the R-MegaCHOEP study and patients treated with Pola-R-CHP on the POLARIX study. Protocol details are provided in Supplementary Data. The current analysis limited the comparison to PFS and OS as the definition of event-free survival is variable. While positron-emission tomography in combination with computed tomography (PET/CT) was used to determine the response at end of treatment for patients treated in the POLARIX study, the response of patients treated with R-MegaCHOEP was determined by CT scan only. The incidence of adverse events occurring in both studies were also compared. The study included 113 patients treated with Pola-R-CHP from the POLARIX study and 89 patients treated with R-CHOEP from the R-MegaCHOEP study. The majority of patients were male, with median ages of 52 and 51 for Pola-R-CHP and R-CHOEP groups, respectively. Major patient characteristics were similar across groups, including IPI factors and aaIPI (Table 1 ). MYC and BCL2 rearrangements were available for 79.6% and 84.1% of Pola-R-CHP patients, and 42.7% and 48.3% of R-CHOEP patients. Translocation percentages were 8.9% and 17.9% in Pola-R-CHP, and 7.9% and 20.9% in R-CHOEP. Data on cell of origin were available for 87 Pola-R-CHP and 39 R-CHOEP patients (Table 1 ). Median dose intensities of key drugs exceeded 98% in both groups (Supplementary Table 1 ). Radiotherapy was administered to 8 Pola-R-CHP and 21 R-CHOEP patients as part of the treatment protocol. Follow-up periods differed significantly, with a median of 28.1 months for Pola-R-CHP and 42.0 months for R-CHOEP. Two-year PFS was 74.8% for Pola-R-CHP and 72.4% for R-CHOEP, while OS was 88.3% for Pola-R-CHP and 81.7% for R-CHOEP (Fig. 1 ). Differences in efficacy were not significant. Separate evaluations for aaIPI 2 and 3 patients showed no significant differences in PFS and OS between the two treatments (Supplementary Figs. 1 , 2 ). Kaplan–Meier estimates of PFS ( A ) and OS ( B ). PFS at 2 years was 72.4% (95.0% CI 62.9%–81.8%) after R-CHOEP and 74.8% (95.0% CI 66.5%–83.0%) after Pola-R-CHP, respectively. The OS at 2 years was 81.7% (95.0% CI 73.6%–89.8%) after R-CHOEP and 88.3% (95.0% CI 82.3%–94.3%) after Pola-R-CHP. CI confidence interval, OS overall survival, PFS progression-free survival. PFS and OS were also analyzed for activated B-cell-like (ABC)- and germinal center B-cell (GCB)-subtypes of DLBCL. ABC-type patients treated with Pola-R-CHP showed higher 2-year PFS and OS rates compared with those treated with R-CHOEP (Supplementary Fig. 3 ). In GCB-type DLBCL, efficacy was similar between treatments. R-CHOEP was associated with higher rates of leukocytopenia, infections, anemia, thrombocytopenia, and severe neuropathy compared to Pola-R-CHP. Low-grade toxicities affecting quality of life were also more frequent with R-CHOEP (Supplementary Table 2 ). Mortality rates up to two years post-randomization were 13 for Pola-R-CHP and 16 for R-CHOEP. Disease progression or relapse was the main cause of death. Non-relapse mortality occurred in two Pola-R-CHP and three R-CHOEP patients. CNS relapses were noted in two Pola-R-CHP and three R-CHOEP patients.

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