Abstract
Background: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma, which is curable in approximately 50% of the cases. The combination of polatuzumab with bendamustine and rituximab (Pola-BR) received an FDA approval based on the GO29365 study in relapsed and refractory DLBCL (R/R DLBCL), where it demonstrated 40% CR rate compare with 18% of BR alone. Given the limited role of Bendamustine in the management of R/R DLBCL, we questioned how the combination of Polatuzumab with Rituximab (Pola-R) performs compared to Pola-BR and its associated safety profile.
Methods: For the systematic research two independent authors performed a systematic search and data extraction using the MESH term: “Non-Hodgkin lymphoma”, “Lymphoma”, “DLBCL”, “Relapsed” OR “Refractory” as population, and “Polatuzumab” AND “Bendamustine” and “rituximab” as an intervention in the following databases: Medline (PubMed), EMBASE, COCHRANE, Scopus, ClinicalTrials.gov, Google scholar and gray literature (LILACS). Primary outcome was complete response (CR) and secondary outcomes were progression free survival (PFS) and overall survival (OS). Our systematic search adhered to PRISMA guidelines. Fifteen studies were reviewed qualitatively, of which 3 were randomized clinical trials. Four studies were included in a double-arm meta-analysis comparing Pola-R and Pola-BR complete response rates, progression free survival and overall survival.
Results: The pooled analysis of 585 patients with R/R DLBCL treated with Pola-BR showed a complete response (CR) rate of 29% with 95% confidence interval (CI) [24, 33] and significant heterogeneity (I2=62.83%) on a random effects model. The CR rate of 103 patients (17.6%) in randomized clinical trials (RCT) was 37% with CI [22, 51]. Median PFS (mPFS) ranged from 3.8 months to 9.5 months, while median OS (mOS) ranged from 5 to 12.4 months. The meta-analysis comparing CR rates of Pola-BR (24.6% [17, 32]) vs Pola-R (26.8% [16, 37]) included 199 patients and showed no significant difference (OR 0.94, 95% CI [0.45, 2.00]). Notably, one study reported similar mean PFS of 5.5 to 5.1 months for Pola-BR and Pola-R respectively (Argnani et al. Hemasphere 2022). Regarding the adverse events between the two treatment programs, there was a significant increase in the odds of anemia (OR of 3.84 [1.19, 12.43]) and thrombocytopenia (OR 4.25 [1.65, 10.95]) for patients treated with Pola-BR, but no differences in neutropenia OR 1.40 [0.52, 3.75]. Literature search had low risk of publication bias given symmetrical results in funnel plot.
Discussion: Our study demonstrates that the CR rates among patients treated with Pola-BR and Pola-R are similar without any statistically significant difference. Notably, Pola-BR was characterized by 4 four times higher hematologic toxicity of anemia and thrombocytopenia compared with Pola-R. These results support the emerging evidence that the addition of bendamustine to Pola-R needs to be reevaluated for the treatment of R/R DLBCL. Furthermore, the overall CR rate of Pola-BR, the median PFS and median OS were lower compared with those data from the pivotal RCT that led to the FDA approval of the Pola-BR program (Sehn et al. Journal of Clinical Oncology 2019). One limitation of our study could be that most of the patients came from observational non-randomized studies. Additional real-world data studies, comparing the efficacy and safety profile of Pola-BR vs Pola-Rituximab are needed to provide stronger evidence of the bendamustine-free Pola-R program in the management of R/R DLBCL.
Pongas:Mevox ltd: Current equity holder in private company; Amgen, Eli Lilly,. Crispr Therapeutics: Current equity holder in publicly-traded company.