Polatuzumab vedotin with infusional chemotherapy for untreated aggressive B-cell non-Hodgkin lymphomas

Abstract

The POLARIX trial demonstrated the superiority of polatuzumab vedotin (Pola) over vincristine in the rituximab-cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) regimen for large B-cell lymphomas, but it is unknown whether Pola can be safely incorporated into intensified regimens (eg, dose-adjusted [DA]-EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab]) typically used for the highest risk histologies. This was a single-center, open-label, prospective clinical trial of 6 cycles of Pola-DA-EPCH-R (vincristine omitted) in aggressive large B-cell lymphomas. The primary end point was to estimate the safety of Pola-DA-EPCH-R as measured by the rate of dose-limiting toxicities (DLTs) in the first 2 cycles with prespecified suspension rules. Secondary and exploratory end points included efficacy and correlation with circulating tumor DNA (ctDNA) levels. We enrolled 18 patients on study, and with only 3 DLTs observed, the study met its primary end point for safety. There were 5 serious adverse events, including grade 3 febrile neutropenia (3, 17%), grade 3 colonic perforation in the setting of diverticulitis, and grade 5 sepsis/typhlitis. Among 17 evaluable patients, the best overall response rate was 100%, and the complete response rate was 76%. With a median follow-up of 12.9 months, 12-month event-free survival was 72%, and 12-month overall survival was 94%. No patient with undetectable ctDNA at the end of treatment has relapsed to date. Using Pola to replace vincristine in the DA-EPOCH-R regimen met its primary safety end point. These data support the further evaluation and use of this approach in histologies where the potential benefit of both an intensified regimen and Pola may be desired. This trial was registered at www.clinicaltrials.gov as #NCT04231877.

Graphical abstract

Figure 1.

Consort diagram.

Figure 2.

Heat map displaying each patient by histology, age, and gender with each column displaying the chemotherapy dose level achieved by cycle. ∗ indicates that patient had a platelet nadir <25 000 cells per μL requiring dose reduction to DL1. ∗∗ indicates that patient had a grade 3 colonic perforation in the setting of diverticulitis requiring interruption of chemotherapy for surgery. The subsequent cycle was delayed 12 days and dose level decreased to DL1 as discretion of investigator while maintaining the standard Pola dose. ∗∗∗ indicates that patient died of sepsis during cycle 1. F, female; M, male.

Figure 3.

(A) EFS for the overall study population for the start of therapy. (B) OS for overall study population from the start of therapy. (C) EFS stratified by interim PET results. (D) EFS stratified by EOT PET results. (E) Spider plot of ctDNA allele frequency from start of therapy through EOT stratified by patients with or without known progressive disease. (F) EFS stratified by detection of ctDNA at the EOT.

Figure 4.

Landmark analysis of EFS from time of ctDNA analysis including early molecular response (EMR) (A), major molecular response (MMR) (B), and EOT ctDNA clearance (C).