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Pola-R-CHP May Reverse Outlook in High-Risk Lymphoma
LUGANO, Switzerland — Patients with diffuse large B-cell lymphoma (DLBCL) in a genetic subgroup associated with worse outcomes show significantly greater responses to treatment with the standard first-line regimen of polatuzumab vedotin plus R-CHOP (Pola-R-CHP) compared with R-CHOP alone, new research showed.
'We found that newly diagnosed patients with DLBclass [classifier]-defined C5 DLBCLs derive the greatest benefit from Pola-R-CHP therapy,' said first author Eleonora Calabretta, MD, of the Dana-Farber Cancer Institute in Boston , in presenting the late-breaking findings at the 18th International Conference on Malignant Lymphoma (ICML) 2025.
'These findings support the use of DLBclass to design molecularly driven clinical trials and inform practice.'
The pivotal POLARIX trial, comparing the combination of the anti-CD79B drug polatuzumab and the long-time standard chemotherapy regimen of R-CHOP to R-CHOP alone, became the first phase 3 trial in more than 20 years to show a regimen to have greater efficacy over R-CHOP, with a 2-year progression-free survival (PFS) of 76.7% vs 70.2%, respectively, which was sustained at 5 years (66.7% vs 58.1%), placing Pola-R-CHP in position as a new standard of care in newly diagnosed patients with intermediate- to high-risk DLBCL.
However, as evidence mounts showing a multitude of genetic subsets in DLBCL that may have varying responses to therapies, Calabretta and her colleagues conducted an analysis of the POLARIX trial to look at possible differences within that trial.
For their analysis, the team's recently established DLBclass classifier, a probabilistic, neural network-based tool that categorizes patients in genetic clusters ranging from C1 through C5, was utilized.
Tumor biopsies from 407 patients in the POLARIX trial were analyzed, including 198 who were treated with R-CHOP and 209 treated with Pola-R-CHP.
Patients' baseline clinical characteristics were well balanced between treatment arms.
The results showed a substantial difference between patients in the two treatment groups who were specifically in the C5 cluster, which is associated with the poorest outcomes of the five groups, characterized by recurrent MYD88 and CD79B gain-of-function mutations and enhanced B-cell receptor signaling.
Among those patients, the 5-year PFS rate of those in the Pola-R-CHP group was 70.4% compared with just 42% in the R-CHOP arm (hazard ratio [HR], 0.38; P = .005).
'These findings are especially important if we consider that the cluster C5 patients are those with the poorest prognoses among all the subsets, suggesting that the Pola-containing regimen may abrogate the predicted poor outcomes of this particular subset,' Calabretta said.
In contrast, all of the 5-year PFS outcomes in the four other molecular clusters (C1-C4) were comparable between the two treatment arms, she added.
The improved benefit of Pola-R-CHP in the C5 group remained after a multivariate adjustment for factors including International Prognostic Index score (2 vs 3-5), age (60 years or older vs younger than 60 years), and cell of origin (activated B cell, germinal center B cell, or unclassified, unknown; HR 0.41; P = .012).
The study further showed the Pola-R-CHP benefit in C5 DLBCL was independent of patients' CD79B mutational status, which is known to be prevalent in C5 DLBCL.
While the results did not show a significant improvement in overall survival — consistent with the findings in the POLARIX primary results — Calabretta noted that there was a significant trend that was nevertheless promising.
'We do see a nonstatistically significant trend that is likely due to the fact that salvage therapies for patients that relapse have great efficacy and can rescue many patients,' she told Medscape Medical News .
'There are many novel therapies for patients that relapse, and this is quite exciting and unprecedented in DLBCL treatment history.'
The DLBclass app is free and available for download. 'It does require processed sequencing data,' Calabretta said, 'but is available for use for anyone that would like to.'
'Our work has shown that DLBclass can identify patients that respond to Pola-R-CHP, but as of now in a research setting. There is ongoing effort to make this a clinically actionable assay,' she added.
Classifiers Provide Granularity to DLBCL's High Molecular Heterogeneity
As opposed to another genetic classifier tool, LymphGen, in which approximately 40% of cases were unclassified or in a composite category, the newer DLBclass classifier, described in May in the journal Blood , assigns all patients with detectable mutations to one of the five genetic clusters, regardless of the confidence level.
Commenting on the study, Alvaro Alencar, MD, an associate professor of clinical medicine at the University of Miami Sylvester Comprehensive Cancer Center in Miami, noted the study has important 'clinical significance as it expands the understanding of the activity of Pola-R-CHP in different DLBCL subsets.'
The study supports prior exploratory subgroup analyses of POLARIX that suggest greater benefit in patients with the ABC cell-of-origin, one of two main genetic subtypes previously identified (along with the GCB subtype), Alencar noted.
'We know C5 is enriched for the ABC [molecular subset], and the greater response in this class reinforces the previous knowledge of greater activity of Pola-R-CHP in the ABC vs GCB [subgroups],' he told Medscape Medical News .
While the retrospective analysis is 'incredibly helpful, the next frontier is how to apply this on a large scale,' he noted.
'Not even the FISH [fluorescence in situ hybridization; chromosomal test) is uniformly performed in DLBCL worldwide,' he noted. 'If indeed available with fast turnaround time, [the DLBclass classifier] could help identify a subgroup that should be certainly preferably treated with Pola-R-CHP,' Alencar said.
Molecular Classification in DLBCL Hits 'Prime Time'
Discussing the DLBclass research, as well as a dizzying array of other studies at the meeting tackling the complex genetic heterogeneity of DLBCL, Martin Dreyling, MD, noted that many prior studies looking to improve upon the long-held standard of R-CHOP basically 'failed because we didn't see the whole picture.'
Due to advances such as LymphGen, the DLBclass tool, and other emerging stratifying approaches, 'we now have more granular classification, and this will give us a more detailed view of the disease,' said Dreyling, a professor of medicine and head of the lymphoma program at the Department of Medicine III, LMU Hospital Munich, Munich, Germany, in a meeting overview.
'The key question is, what are the clinical consequences? That is what we have to explore,' he emphasized, noting that in the POLARIX analysis, 'we can see that Pola-R-CHP does have a major impact in the C5 subgroup.'
The rapidly evolving research developments ultimately indicate that 'it's prime time in molecular classification,' Dreyling said.
