The frontline management of diffuse large B-cell lymphoma (DLBCL) has long relied on rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as the standard of care.
This approach “has been very rewarding because we know that most patients can be cured with R-CHOP,” said Laurie H. Sehn, MD, MPH, chair of the Lymphoma Tumour Group at the BC Cancer Centre for Lymphoid Cancer in Vancouver, Canada in a session presented at the 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023).
However, there “clearly is a group of patients that remain refractory or resistant to R-CHOP, and we don’t have a good way of identifying those at the time of diagnosis [and] we know that as we add extra agents to R-CHOP, we’re also usually adding extra toxicity,” Dr. Sehn noted. “So, the question is, how do you balance out the need to improve outcomes while not making toxicity worse for the majority of patients that might do just as well with R-CHOP?”
In a background review, she discussed the 2 molecular subtypes of DLBCL: the activated B-cell-like (ABC) and germinal-center B-cell-like (GCB) subtypes. The ABC subtype has demonstrated worse outcomes following R-CHOP compared to the GCB subtype, with a 15%-20% difference in progression-free survival (PFS).
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Beyond ABC and GCB, Dr. Sehn described “another subgroup that we’re going to be hearing more about and we need to pay attention to. This has been termed the ‘double hit signature subgroup’ or more recently the ‘dark zone signature’ subgroup.” These patients have the poorest outcomes of all patient groups.
Multiple randomized trials investigating the addition of a novel agent to R-CHOP for the treatment of DLBCL have failed to produce positive results, although lessons have been learned to inform future trials, Dr. Sehn said. For example, secondary analyses suggest that some of the more recently recognized subtypes may have been more sensitive to the study drug in certain trials, suggesting that perhaps “we weren’t necessarily targeting the best patients.”
The latest trial in this space is the “first trial that we’ve had that has been considered positive,” Dr. Sehn said. The randomized, double-blind POLARIX trial explored the upfront addition of polatuzumab vedotin, an anti-CD79b drug conjugate, to rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) compared to R-CHOP in patients with previously untreated DLBCL and an International Prognostic Index (IPI) of 2-5.
The results showed greater improvement in PFS with pola-R-CHP vs R-CHOP (hazard ratio [HR] 0.73; 95% CI, 0.57-0.95; P <.02), with comparable safety profiles in each group. Updated results from POLARIX showed that the PFS benefit associated with pola-R-CHP was maintained at 3 years (HR, 0.76; 95% CI, 0.60–0.97).
According to Dr. Sehn, remaining questions include: Is pola-R-CHP the new standard of care in frontline DLBCL? Should it be used in all patients? Should it be the comparator in all clinical trials?
She also mentioned multiple planned and ongoing trials in upfront DLBCL and noted the need to “design trials where we really capture the appropriate patients and the high-risk patients,” including enriching for “molecular subgroups based on early phase data and validated biomarkers.”
Sehn LH. Incorporating novel agents in frontline DLBCL. 11th Annual Meeting of the Society of Hematologic Oncology (SOHO 2023). Houston, Texas. September 8, 2023.
Urata T, Naoi Y, Jiang A, et al. Distribution and clinical impact of molecular subtypes with Dark Zone signature of DLBCL in a Japanese real-world study. Blood Adv. Published online August 8, 2023. doi:10.1182/bloodadvances.2023010402
Hervé Tilly, Franck Morschhauser, Laurie H. Sehn, et al. The POLARIX study: polatuzumab vedotin with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) versus rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) therapy in patients with previously untreated diffuse large B-cell lymphoma. Blood. 2021;138(Suppl_2):LBA-1. doi:10.1182/blood-2021-154729