Data indicate that replacement of vincristine with polatuzumab vedotin in combination with etoposide, prednisone, cyclophosphamide, doxorubicin, and rituximab should be further explored in large B-cell lymphoma.
Polatuzumab vedotin-piiq (Polivy) was tolerable and elicited responses as a substitution for vincristine in a regimen of dose-adjusted etoposide, prednisone, cyclophosphamide, doxorubicin, and rituximab (Rituxan; EPCH-R) in a small population of patients with aggressive large B-cell lymphoma (LBCL), according to findings from a phase 1 trial (NCT04231877) published in Blood Advances.
Of 18 evaluable patients, 17 (94%) completed all 6 cycles of the study therapy. Investigators reported 5 serious adverse effects (AEs), including a single death from grade 5 sepsis/typhlitis (6%), 3 events of grade 3 febrile neutropenia (17%), and a single instance of grade 3 colonic perforation in the setting of diverticulitis (6%). A total of 3 dose-limiting toxicities (DLTs) occurred, consisting of 2 asymptomatic, incidentally detected pulmonary emboli and the aforementioned death from sepsis/typhlitis. As such, the trial met its primary end point.
The most common grade 3/4 AEs included neutropenia (94%), thrombocytopenia (56%), anemia (39%), oral mucositis (22%), thromboembolic events (22%), febrile neutropenia (17%), hyperglycemia (17%), abdominal pain (11%), and hypokalemia (11%).
Grade 1 peripheral sensory neuropathy affected 8 patients (44%) but never occurred at any higher grade. Thromboembolic events affected 6 patients (33%) in total, and 2 experienced grade 2 deep vein thrombosis (DVT). Of these DVT events, 1 affected a patient with a history of prior DVT and the other was asymptomatic and discovered incidentally on a restaging scan. Grade 3 pulmonary embolism affected 3 patients, but all were similarly asymptomatic and discovered incidentally.
The best overall response rate was 100%, and the complete response (CR) rate was 76%, across the 17 evaluable patients. The 12-month event-free survival (EFS) and overall survival (OS) rates were 72% (95% CI, 54%-96%) and 94% (95% CI, 84%-100%), respectively, after a median follow-up of 12.9 months. No relapses have occurred to date in patients without detectable circulating tumor DNA at the end of treatment.
“Until now, improvements to the EPOCH-R [etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab] regimen have proven to be challenging. Recently, the addition of venetoclax [Venclexta] was associated with increased cytopenias, treatment delays, and death when compared with dose-adjusted EPOCH-R,” the investigators wrote. “With [certain] notable exceptions, the safety profile of [polatuzumab vedotin plus dose-adjusted EPCH-R] appears comparable to previously published reports of EPOCH-R and much improved over the previous effort to combine a novel agent (venetoclax) with an intensive upfront regimen.”
Enrollment on this single-center, open-label trial occurred between October 2020 and November 2021. Patients were a median of 64 years old (range, 41-74) and most had stage IV disease at diagnosis (72%). The median diagnosis-to-treatment interval in this population was 24 days (range, 10-37).
In terms of histologies, 6 patients (33%) had high-grade B-cell lymphoma (HGBCL) with MYC, BCL2, and/or BCL6 rearrangements; 4 (22%) had primary mediastinal B-cell lymphoma; and the rest had diffuse LBCL not otherwise specified (44%). Most had elevated lactate dehydrogenase (78%), an International Prognostic Index score of 3 or higher (72%), or MYC rearrangement (53%).
Half of the enrolled patients had received prephase prednisone. Additionally, 33% had a Ki-67 of 90% or more.
All patients received polatuzumab vedotin at a dose of 1.8 mg/kg on the first day of each 21-day cycle concurrently with dose-adjusted EPCH-R. The experimental agent was not escalated with the other drugs but could be reduced due to toxicity. All patients received granulocyte colony–stimulating factor support.
The primary end point was safety according to the Common Terminology Criteria for Adverse Events v5.0. The secondary end points were oriented toward efficacy and included the rates of CR, EFS, and OS.
“These safety data support the further evaluation and potential use of this approach in histologies, where the potential benefit of both an intensified regimen and [polatuzumab vedotin] may be desired,” the investigators concluded.
Lynch RC, Poh C, Ujjani CS, et al. Polatuzumab vedotin with infusional chemotherapy for untreated aggressive B-cell non-Hodgkin lymphomas. Blood Adv. 2023;7(11):2449-2458. doi:10.1182/bloodadvances.2022009145