Highlights
– At a median follow-up of 64.1 months, pola‑R‑CHP produced a statistically significant 5‑year PFS benefit versus R‑CHOP (HR 0.77), with 5‑year PFS rates 64.9% vs 59.1%.
– Overall survival differences remain non‑significant at five years (HR 0.85); lymphoma‑related deaths were fewer with pola‑R‑CHP (46 vs 62).
– Patient‑reported outcomes showed rapid, sustained HRQoL improvements in both arms but highlighted higher symptom reporting by patients than clinicians.
– In older patients (particularly ≥70 years), exploratory analyses suggested clinically meaningful PFS gains with pola‑R‑CHP; safety was similar though febrile neutropenia rates were higher and G‑CSF prophylaxis is important.
Background and Unmet Need
Diffuse large B‑cell lymphoma (DLBCL) is the most common aggressive non‑Hodgkin lymphoma and remains curable in only a proportion of patients treated with standard immunochemotherapy. R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) has been the frontline standard for decades, yet cure rates approximate 60% in population‑based reports for intermediate‑ and high‑risk patients. New strategies to improve durable disease control without unacceptable incremental toxicity are therefore a priority.
Polatuzumab vedotin is an antibody–drug conjugate (ADC) targeting CD79b, a B‑cell receptor component broadly expressed on malignant B cells. Replacing vincristine in R‑CHOP with polatuzumab (pola‑R‑CHP) was hypothesized to intensify anti‑tumor activity while preserving the established rituximab‑anthracycline backbone.
Study Design: POLARIX Phase 3 Trial and 5‑Year Update
The POLARIX study is an international, randomized, double‑blind, placebo‑controlled phase 3 trial comparing pola‑R‑CHP (polatuzumab vedotin replacing vincristine in R‑CHP) versus standard R‑CHOP in previously untreated intermediate‑risk or high‑risk DLBCL. Adults aged 18–80 were randomized 1:1 to six cycles of pola‑R‑CHP or R‑CHOP, followed by two cycles of single‑agent rituximab. The primary endpoint was investigator‑assessed progression‑free survival (PFS); key secondary endpoints included overall survival (OS) and safety. Patient‑reported outcomes (PROs) and subgroup analyses in older patients were prespecified or conducted post hoc to evaluate tolerability and differential benefit.
The 5‑year analysis includes the global intention‑to‑treat population (N = 879) with a median follow‑up of 64.1 months. Additional exploratory and subgroup analyses were reported, including PRO versus clinician‑reported adverse event comparisons and outcomes in older age cohorts (≥60, ≥65, ≥70, ≥75 years).
Key Results
Primary endpoint: Progression‑Free Survival
At five years, pola‑R‑CHP demonstrated a statistically significant PFS advantage over R‑CHOP in the ITT population: HR 0.77 (95% CI, 0.62–0.97). Absolute 5‑year PFS rates were 64.9% (95% CI, 59.8–70.0) with pola‑R‑CHP versus 59.1% (95% CI, 53.9–64.3) with R‑CHOP. These results indicate a sustained reduction in the risk of progression, relapse, or lymphoma‑related death with the polatuzumab‑containing regimen.
Overall survival
Overall survival differences at five years were not statistically significant: HR 0.85 (95% CI, 0.63–1.15). Numerically fewer lymphoma‑related deaths occurred in the pola‑R‑CHP arm (46) than in the R‑CHOP arm (62) in the expanded population, suggesting that PFS improvement has translated into fewer disease‑specific deaths, though the trial is not yet conclusive for a definitive OS benefit.
Subgroup analyses — biology and risk strata
Exploratory analyses suggested that high‑risk subgroups derived relatively greater benefit from pola‑R‑CHP, notably patients with activated B‑cell (ABC) subtype and International Prognostic Index (IPI) scores 3–5. These findings are hypothesis‑generating and support the biological plausibility that targeted delivery of cytotoxic payloads to B‑cell receptor components may preferentially benefit certain DLBCL phenotypes.
Older patient subgroups
A post hoc analysis of older patients (median follow‑up 40 months) included 629 patients aged ≥60 years (pola‑R‑CHP n = 311; R‑CHOP n = 318). Clinically meaningful PFS improvements were observed across age strata, with a pronounced effect in patients ≥70 years: unstratified HR 0.63 (95% CI, 0.41–0.96), representing a 37% relative reduction in risk of progression/relapse/death. Overall survival among patients ≥60 years was similar (HR 0.99; 95% CI, 0.67–1.47).
Safety and tolerability
Overall long‑term tolerability was reported as similar between arms. In older patients, rates of grade 3–4 adverse events were comparable (62.7% pola‑R‑CHP vs 61.5% R‑CHOP), as were grade 3–5 infections (15.0% vs 12.9%) and grade 5 AEs (3.6% vs 3.2%). A notable safety signal was higher grade 3–4 febrile neutropenia with pola‑R‑CHP in older patients (16.3% vs 7.6%), emphasizing the value of routine granulocyte colony‑stimulating factor (G‑CSF) prophylaxis in patients at risk. No novel long‑term toxicities were reported in the five‑year update.
Patient‑reported outcomes and clinician AE reporting
An analysis comparing PROs with clinician‑reported adverse events emphasized a consistent discordance: patients reported a greater incidence and severity of symptoms than what was captured by clinician AE reporting. Both treatment arms demonstrated rapid and sustained improvements from baseline in health‑related quality of life (HRQoL) and lymphoma‑specific symptoms, with the largest gains in global health status/QoL, lymphoma symptoms, fatigue, and role/emotional/social functioning. Gastrointestinal symptoms were similar between arms and returned toward baseline after treatment completion.
Expert Commentary and Interpretation
1) Clinical significance of the PFS benefit: The 5‑year PFS improvement with pola‑R‑CHP (HR 0.77, absolute increase ~5.8% at 5 years) is clinically meaningful in a disease where durable remission equates to cure for many patients. PFS is an accepted surrogate for clinical benefit in DLBCL where post‑progression treatments remain imperfect, and fewer lymphoma‑related deaths in the pola‑R‑CHP arm reinforce the regimen’s disease‑control advantage.
2) Overall survival and follow‑up: The absence of a definitive OS advantage at five years does not negate the PFS benefit but highlights factors that can dilute OS differences, including effective salvage therapies (autologous stem cell transplant, CAR T‑cell therapy), crossover/second‑line advances, and non‑lymphoma competing mortality. Longer follow‑up and pooled analyses may better define OS impact.
3) Safety considerations: The overall similarity in tolerability is reassuring, but clinicians must anticipate higher febrile neutropenia rates in older patients receiving pola‑R‑CHP and should adopt primary G‑CSF prophylaxis. The PRO data further emphasize that clinician assessments may undercapture symptom burden; systematic use of validated PRO instruments can improve symptom management and patient‑centered care.
4) Generalizability and subgroups: Benefit signals in ABC subtype and high‑IPI patients are encouraging but exploratory. Routine molecular subtyping and careful risk stratification may help tailor frontline therapy decisions in the future, but prospective validation is needed before restricting pola‑R‑CHP to specific biological subgroups.
Limitations
– OS remains non‑significant at five years; definitive mortality benefit has not been demonstrated.
– Some subgroup analyses are post hoc or exploratory and should be interpreted cautiously.
– Cost, access to polatuzumab, and real‑world tolerability outside clinical trial populations require further evaluation.
– Discordance between PROs and clinician AEs underscores potential underreporting of symptoms in trials and routine care.
Clinical Implications and Practical Recommendations
– For previously untreated intermediate‑ or high‑risk DLBCL, pola‑R‑CHP should be considered a frontline option given its sustained PFS advantage and comparable long‑term tolerability; guideline adoption is already evolving based on these data.
– When using pola‑R‑CHP, implement routine primary G‑CSF prophylaxis in older patients and others at risk for neutropenia to mitigate febrile neutropenia rates.
– Integrate PRO instruments into clinical practice to better capture symptom burden and guide supportive care interventions.
– For patients with high‑risk biology (e.g., ABC subtype, high IPI), discuss the potential for greater benefit with pola‑R‑CHP while acknowledging exploratory nature of subgroup findings.
– Consider cost, drug availability, and patient preferences when selecting frontline regimens; multidisciplinary discussion and shared decision‑making remain essential.
Conclusion
The five‑year POLARIX update confirms that replacing vincristine with polatuzumab vedotin (pola‑R‑CHP) produces a sustained PFS advantage over R‑CHOP in patients with previously untreated intermediate‑ or high‑risk DLBCL, with comparable long‑term tolerability. While overall survival differences are not yet statistically significant, fewer lymphoma‑related deaths and durable disease control support pola‑R‑CHP as an important frontline option. Clinicians should balance the modest absolute PFS gain against cost and logistics, apply G‑CSF prophylaxis where appropriate, and routinely assess patient‑reported symptoms to optimize care.
Funding and ClinicalTrials.gov
The POLARIX trial was sponsored by the trial sponsor reported in the original publications. ClinicalTrials.gov identifier: NCT03274492 (as cited in trial reports).
References
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