In Early-Stage DLBCL, One Size No Longer Fits All

SAN FRANCISCO – The treatment of early-stage diffuse large B-cell lymphoma (DLBCL) is evolving after decades of failed attempts to improve on the standard treatment of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), a hematologist-oncologist said at the Association of Veterans Affairs (VA) Hematology/Oncology regional meeting on lymphoma on March 21.

A combination therapy known as pola-R-CHP is now the preferred option for many patients but has limited additional benefit, said Solomon A. Graf, MD, of the University of Washington and VA Puget Sound Health Care System. Pola-R-CHP is a modified regimen of R-CHOP that replaced vincristine in R-CHOP with polatuzumab vedotin.

The keys to treatment, Graf said, include consideration of disease variations that can affect therapy efficacy and understanding the special needs of older patients.

Understanding DLBCL

DLBCL is the most common non-Hodgkin lymphoma in the US with about 30,000 new cases per year; the median age at diagnosis is 67 years, Graf said.

“The overall incidence of DLBCL has been relatively stable over the last decades,” he said. “But gratifyingly, the rate of death from this disease has steadily been declining since about the turn of the century.”

Pola-R-CHP: A New Standard, Significant Limitations

From 2002-2022, “many attempts to improve on first-line DLBCL therapy did not pan out,” Graf said, as more than a dozen large phase 3 trials failed to dethrone R-CHOP as the standard. Most of the trials attempted to add an agent to R-CHOP but showed no additional benefit.

Then, in 2021, the landmark POLARIX study was published. The double-blind, randomized trial on the new regime showed a progression-free survival benefit (PFS) vs R-CHOP (76.7% vs 70.2% at 2 years, respectively). Safety profiles were similar between the 2 combination therapies.

However, overall survival (OS) did not differ.

"Pola-R-CHP is now considered a preferred standard, despite no overall survival benefit and despite increased upfront cost,” Graf said. (A 2023 analysis found that pola-R-CHP is more cost-effective than R-CHOP in DLBCL.)

Pola-R-CHP or Not Pola-R-CHP?

Pola-R-CHP is not for all patients with DLBCL. In advanced cases, Graf said, genomic analyses provide important information that helps clinicians understand whether patients will fare better with R-CHOP. Cell-of-origin classifications include germinal center B-cell like (GCB), activated B-cell like (ABC), and unclassifiable.

“If it’s GCB type, there's no clear benefit for pola-R-CHP,” Graf said. “On the other hand, the ABC subtype does much better when treated with pola-R-CHP.”

Graf highlighted the recently updated VA Oncology Clinical Pathway for DLBCL, which recommends cell-of-origin testing by the Hans algorithm for certain advanced-stage patients. The guidelines suggest R-CHOP for GCB-type patients and pola-R-CHP for non–GCB-type patients. However, he cautioned that the Hans algorithm comes with an increased risk of misclassification.

Early-Stage Disease: Radiation or No Radiation?

About 25% to 30% of patients have stage I or II disease, and the landmark 1998 SWOG trial initially suggested that 3 cycles of CHOP plus radiation had superior PFS and OS compared with 8 cycles of CHOP alone, Graf said. This trial was conducted prior to the R-CHOP era. However, follow-up revealed that the benefit vanished over time and the risk of secondary cancers grew. “Both strategies are perfectly viable, but there isn’t as much of a preference anymore,” Graf said.

A pair of recent trials – a 2019 European study and a 2020 US study – support eliminating radiation and lowering the number of cycles of therapy in certain patients, he said.

Managing Older Patients

Patients with DLBCL tend to be older, Graf said, and many have comorbidities and other limitations. A standard course of 6 cycles of therapy may be too much for them, he said. Graf highlighted the Elderly Prognostic Index, a tool created by an Italian group that allows clinicians to predict outcomes based on patient fitness levels.

Graf offered additional guidance for this population:

• Consider corticosteroids in the prephase setting, which can be “very valuable” and improve a patient’s ECOG performance status, “giving you better confidence about proceeding with more standard therapy.”
• Include anthracycline-based therapies such as R-CHOP if appropriate, such as in patients who are focused on living longer, since they “are really crucial to achieving cure in patients with DLBCL.” Graf noted that he has “a low threshold to involve cardiology if there’s anthracycline use and some underlying cardiac comorbidity.”
• Adjust dosage as appropriate: “You can adjust in the middle, be rather flexible and creative about these doses and dosing levels as you get going with your patient and see just what they can tolerate,” he said. “Sometimes you can ramp it up over the course, and sometimes you have to ramp it down to respond to toxicities.”
• Be aware that older patients are at much higher risk of suffering from toxicities due to the vincristine component of R-CHOP. These include neurotoxicities and constipation.

Graf highlighted the phase 3 Polar Bear study, which may offer more insight into therapy options in patients aged ≥ 75 years who are frail or those aged ≥ 80 years. The trial is scheduled to end in early 2027.

Graf discloses relationships with Janssen, TG Therapeutics, BeOne, AstraZeneca, Genentech, Incyte, Eli Lilly, and Pfizer.