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As discussed with previous articles highlighted in the ASCO Reading Room on diffuse large B-cell lymphoma (DLBCL), improvements upon the standard-of-care treatment for the last 20 years have been unsuccessful until very recently. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment and is expected to cure roughly 65% of patients with advanced stage disease, yet we have known for many years that certain subtypes of DLBCL do worse than others.

Such subtypes include double-hit (MYC and BCL2/BCL6 translocations) and non-germinal center B-cell classification on the basis of cell-of origin (non-GCB). Earlier this year (2022), a phase III randomized clinical trial showed that replacing vincristine in R-CHOP with the antibody-drug conjugate polatuzumab vedotin (so called R-CHP-Pola regimen) improved progression-free survival at 2 years (77% vs 70%). There was no overall survival difference at 2 years, and whether there will eventually be one remains to be seen.

This trial was performed in advanced stage DLBCL patients with an international prognostic index score of 2-5, but otherwise did not stratify based on any molecular features. If this regimen receives regulatory approval, it will likely become a new standard of care for patients who qualify.

However, despite this potential new therapeutic regimen there remain no treatments specifically designed to treat those subgroups known to respond poorly to R-CHOP. In the , investigators performed a phase II clinical trial to address the non-GCB DLBCL subtype by adding two cycles of targeted therapy upfront before adding conventional chemotherapy.

Rituximab, lenalidomide and ibrutinib (RLI) were given based on previously published studies suggesting higher responses to lenalidomide and/or ibrutinib in non-GCB DLBCL (most cases being activated B-cell subtype).

This study only included 60 patients and of those, 38 were advanced stage. Nonetheless, 100% had a response at the end of therapy with 94.5% complete responses. The 2-year progression-free survival rate was 91.3% and the overall survival rate at 2 years was 96.6%. Two deaths occurred during therapy due to infections and two deaths after 2 years were due to DLBCL progression and unrelated malignancy.

Although not clinically actionable, these results show that a pre-standard chemotherapy run-in of targeted agents is possible without compromising efficacy. This allows for future trials to follow a similar roadmap, perhaps speeding the development of new therapies for high-risk subtypes of DLBCL.

Justin Taylor, MD, is assistant professor in the Division of Hematology and a member of the Cancer Epigenetics Program at Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine.

Read the study here and an interview about it here.