An Exploration of Evidence for Cell of Origin Biomarker in DLBCL

Findings from the phase 3 POLARIX trial (NCT03274492)¹ have led to the first new FDA-approved treatment for frontline diffuse large B-cell lymphoma (DLBCL) since rituximab (Rituxan), cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).² Although the results conveyed a modest benefit, they revealed important biological heterogeneity, opening the door for future research and direction, according to Ash A. Alizadeh, MD, PhD. Alizadeh explored the effectiveness of using the regimen in the front line during the National Comprehensive Cancer Network (NCCN) 2025 Annual Congress: Hematologic Malignancies meeting.³

Investigators modified the R-CHOP regimen, substituting polatuzumab vedotin (Polivy) for vincristine. Overall, 879 patients were randomly assigned to the pola-R-CHP group (n = 440) or the R-CHOP group (n = 439). After a median follow-up of 28.2 months, progression-free survival (PFS) was 76.7% for the treatment group compared with 70.2% for the control group (HR, 0.73; 95% CI, 65.8%-74.6%; P =.02). However, the overall survival (OS) rate at 2 years did not differ significantly between the groups, which was 88.7% for the pola-R-CHP group (95% CI, 85.7%-91.6%) and 88.6% (95% CI, 85.6%-91.6%) in the R-CHOP group (HR, 0.94; 95% CI, 0.65-1.37; P =.75).

“The overall benefit of this study is worth reflecting on…. The overall modest benefit [observed] is because of biological heterogeneity that can be unmasked,” Alizadeh, the Moghadam Family Professor of Medicine, Divisions of Oncology & Hematology, Stanford University School of Medicine, Stanford Cancer Institute, in California, said.

The 5-year outcomes for POLARIX have been reported.⁴ The PFS for patients treated with the pola-R-CHP regimen was 64.9% vs 59.1% for patients treated with R-CHOP. While a statistically significant OS benefit was not observed, the data showed a trend toward improved OS, with fewer lymphoma-related deaths in the pola-R-CHP arm.⁴

“If we think about this in clinical practice, this translates into the number [of patients] needed to [have a balanced risk to benefit] ratio. That’s about 15 to 20 patients,” Alizadeh said. “And that gives some people pause. In fact, health authorities from around the world have variably reflected on these data in decisions surrounding reimbursement or approval.” Alizadeh then turned to methods to identify populations who might benefit from this frontline approach.

Molecular Variants

A closer look at the molecular variants of patients enrolled in POLARIX identified 2 molecularly defined subgroups—the activated B-cell (ABC) subtype and the germinal center B-cell (GCB) subtype. “POLARIX had some preplanned analysis of the cell of origin [COO] with therapeutic efficacy,” Alazideh said. “In the historical era of CHOP-based therapy, this had prognostic value beyond what we could measure using the international prognostic index,” he continued.

These 2 subtypes have different pathophysiology and outcomes, and the assessment of these is now considered a mandated or essential component of World Health Organization classification and NCCN diagnostic evaluations.⁵

Alizadeh noted that patients with the ABC subtype demonstrated a dramatic benefit (HR, 0.38; 95% CI, 0.24-0.59) compared with the GCB subtype (HR, 1.07; 95% CI, 7.4-1.56). “There were a number of interpretations explored—is this a chance association or is it really a significant interaction, and are the clinical effect sizes meaningfully different?” Alizadeh asked.

Findings from a meta-analysis of preclinical and clinical data show differential polatuzumab efficacy by COO, with a greater benefit observed in the ABC subtype vs the GCB subtype across multiple trials.⁶

Further analysis explored the number of patients that need to be treated to show cost-effectiveness. According to Alizadeh, 4 patients needed to be treated in the ABC subtype to be highly cost-effective compared with 57 patients with the GCB subtype.

“Population-level analysis would likely show that this COO-guided approach would prevent more events by treating fewer patients with a more effective therapy,” Alizadeh said.

Although POLARIX was not powered for subgroup analysis, Alizadeh noted that the trial and other research data showed selective benefit. However, definitive evidence is lacking at this time.

“I think time should tell us that we don’t have those methods available to us today, but we still have patients to treat each and every day, so our precision medicine imperative as oncologists is to use the best therapy that’s safest and most effective, and biomarkers are an important part of that decision-making,” Alizadeh said. “I hope to convince you that COO is such a biomarker of utility.”

At Alizadeh’s institution, the current approach is to determine COO. “We strongly recommend to our patients to receive the [pola]-R-CHP regimen if they have the ABC subtype. For patients with GCB, we recommend the R-CHOP standard,” Alizadeh said. If a patient has an unclassified subtype, the treatment varies depending on clinical judgment and institutional preference.

“I hope to have convinced you that cell of origin is statistically robust and a clinically meaningful biomarker that can inform our first-line decisions in large cell lymphoma and patients with the ABC subtype deriving the most benefit and patients with the GBC subtype not deriving that benefit and experiencing more toxicities,” Alizadeh concluded.

REFERENCES

1. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma. N Engl J Med. 2022;386(4):351-363. doi:10.1056/NEJMoa2115304
2. FDA approves polatuzumab vedotin-piiq for previously untreated diffuse large B-cell lymphoma, not otherwise specified, and high-grade B-cell lymphoma. FDA. Updated April 20, 2023. Accessed October 15, 2025. https://tinyurl.com/4u88w5ha
3. Alizadeh AA. Optimizing first-line therapy for diffuse large B-cell lymphoma. Presented at: NCCN 2025 Annual Congress: Hematologic Malignancies. October 10-11, 2025; San Diego, CA. Accessed October 13, 2025. https://tinyurl.com/mnun3tax
4. Morschhauser F, Salles G, Sehn LH, et al. Five-year outcomes of the POLARIX study comparing Pola-R-CHP and R-CHOP in patients with diffuse large B-cell lymphoma. J Clin Oncol. Published online September 24, 2025. doi:10.1200/JCO-25-00925
5. NCCN. Clinical Practice Guidelines in Oncology. B-cell lymphomas, version 3.2025. Accessed October 15, 2025. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
6. Palmer AC, Kurtz DM, Alizadeh AA. Cell-of-origin subtypes and therapeutic benefit from polatuzumab vedotin. N Engl J Med. 2023;389(8):764-766. doi:10.1056/NEJMc2306105