Debating Molecular Markers in the Treatment of DLBCL

Jonathon B. Cohen, MD, MS

Despite the current ‘one-size-fits-all’ approach to treating patients with diffuse large B-cell lymphoma (DLBCL), advances in molecular diagnostics have allowed for a greater understanding of the biology and pathology of DLBCL, leading to the identification of subgroups according to genetic lesions that may be targetable in the treatment of the disease.

Whether or not these genetic variants should be used to determine treatment options for patients with DLBCL was the subject of a debate held at the 2016 Debates and Didactics in Hematology and Oncology meeting in Sea Island, Georgia.

Two oncologists from Emory University School of Medicine faced off to determine if molecular markers should play a role in the treatment of subgroups of patients with DLBCL.

Identifying Subgroups

The standard of care for DLBCL has been rituximab, a monoclonal antibody directed against the CD20 antigen, used in combination with an anthracycline-based chemotherapy regimen consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). While R-CHOP can lead to remission and possible cure in a sizable portion of DLBCL patients, a subgroup of patients remain that will ultimately relapse, at which time their therapeutic options will be limited and prognosis is poor.¹

A substantive heterogeneity in the clinical presentation, biology, and pathology of DLBCL has been recognized though, suggesting that a more individualized approach to treatment may be warranted.

Advances in molecular diagnostic methods are beginning to unravel the complexity of DLBCL at the molecular level, lead- ing to the identification of subsets of DLBCLs based upon the patterns of genes that they express.

Genetic lesions, including somatic mutations, chromosomal rearrangements, and copy number alterations are common in DLBCL. Some of the most common genes to be impacted (>15% of cases) are KMT2D (MLL2), BCL2, TP53, MYD88, and CREBBP. Rearrangement of the MYC oncogene, which leads to aberrant growth and proliferation, is also observed in roughly 10% of DLBCLs. MYC rearrangement along with a translocation of the anti-apoptosis BCL2 gene is one example of a “double-hit” lymphoma that is observed in the minority of patients and is associated with a poor prognosis.²

In order to identify appropriate targeted therapies that may outperform R-CHOP in high-risk subgroups, such as those with double-hit lymphoma, the patients most likely to benefit from these agents need to be identified using predictive molecular biomarkers.

For and Against

Taking the ‘Pro’ stance, Jonathon B. Cohen, MD, MS, began with an overview of DLBCL subtypes, including germinal center B-cell (GCB)—like, activated B-cell (ABC)–like, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 translocations, and high-grade B-cell lymphoma not otherwise specified (NOS).³

Cohen, assistant professor in the Department of Hematology and Medical Oncology, Emory University School of Medicine, and medical director of Infusion Services, Winship Cancer Institute, emphasized that R-CHOP is not curative for all patients. In the LNH-98.5 study, for example, DLBCL patients that achieved a complete response from treatment with R-CHOP showed a long-term disease-free survival rate of only 64% at 10 years.⁴

Cohen also cited the inadequacy of R-CHOP in selected DLBCL subsets, including MYC+ and double-hit non-Hodgkin lymphomas (NHLs), ABC-like DLBCL, and those with high International Prognostic Index (IPI) scores. For example, superior progression-free survival (PFS) over R-CHOP has been noted with intensive induction regimens (eg, HyperCVAD, DA- EPOCH) in double-hit lymphoma.⁵

Christopher R. Flowers, MD, MSc

The identification of another subgroup of so-called “double-expresser” patients who are positive for both MYC and BCL2 proteins (as opposed to patients with double-hit lymphomas, who are positive for the gene rearrangements only), was facilitated by the availability of MYC immunohistochemical (IHC) staining, Cohen said. For these “double expresser” patients, Cohen suggested a more intensive therapy than R-CHOP, such as R-EPOCH, which has shown an objective response rate of 88% in “double expresser” DLBCL patients and a 3-year PFS rate of 54%.⁶

Cohen cited several areas for further research, including op- timal therapies for GCB- and ABC-like DLBCL, and the optimal intensity of therapy for double-hit NHL and double expressing DLBCL, that will continue to explore targeted therapies for subgroups of DLBCL patients based on molecular markers.

Cohen concluded that DLBCL management should not be a ‘one-size- fits-all’ approach and that several alternative ap- proaches are available based on risk and molecular signatures and more are likely to become available in the near future.

Christopher R. Flowers, MD, MSc, took the stance against the use of molecular markers when making treatment decisions for DLBCL. Flowers, an associate professor in the Department of Hematology and Medical Oncology, Emory University School of Medicine; director of the Emory Lymphoma Program; and scientific director for Winship Research Informatics, Winship Cancer Institute, provided an overview of the different DLBCL molecular subtypes and the differences in survival between these subgroups.⁷

Flowers outlined several clinical trials, including the completed CALGB 50303 trial that has not yet published its findings (NCT 00118209), that are examining various therapies instead of, or in addition to, standard R-CHOP in subgroups of patients with DLBCL.

While there is considerable heterogeneity in biology and clinical outcomes in DLBCL, and subsets can be de ned that have poor outcomes with standard therapy, Flowers noted that there is not yet a defined strategy that improves these outcomes. With many promising agents available for combination therapy, Flowers suggested that such patients be enrolled in a clinical trial that can compare the experimental regimen against the established R-CHOP regimen.

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