Molecular Subtype-Specific Therapy in DLBCL

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Molecular classification of diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, is beginning to influence treatment selection and hopefully will improve outcomes, according to presenters at an education session.

Cell-of-origin (COO) identification by genetic analysis has enabled classification of DLBCL into 2 subtypes that have different pathologies and treatment outcomes: germinal center B-cell–like (GCB) and activated B-cell–like (ABC). The ABC subtype is associated with poorer outcomes compared with GCB. About 15% of patients with DLBCL will not fit into either subtype category.

Determining the COO holds the promise of providing predictive biomarkers for treatment, according to the session’s lead speaker, David W. Scott, MBChB, PhD, of the British Columbia Cancer Agency, Vancouver, Canada.

Initial gene expression profiling with a microarray required fresh frozen tissue, but this method has been superseded by use of formalin-fixed paraffin-embedded tissue (FFPET) biopsies. Current assays use immuno­­histochemistry and gene expression methods to analyze FFPET specimens.

Nevertheless, this method has drawbacks that prevent it from moving into routine clinical decision making: uncontrolled specimen processing and storage variables, lack of a standardized methodology, antibody performance, and interobserver variability.

Gene expression–based testing requires adequate amounts of tissue that may be difficult to obtain with core needle biopsies, particularly if the tissue is being used for several diagnostic tests. Thus, Scott recommended using excisional biopsies or core needle biopsies specifically dedicated for genetic testing.

Despite current hurdles, he believes reliable assays will be available in the near future, and cited progress in application of 2 FFPET tests in ongoing phase 3 randomized trials. For example, patients enrolled in the REMoDL-B trial are being stratified into groups of ABC and GCB DLBCL using 1 assay, and another assay is being used for patient selection in the ROBUST trail of patients with the ABC subtype.

In addition to these applications of genetic analysis tests, several other trials are studying molecular subtype-specific therapy in DLBCL, said Grzegorz S. Nowakowski, MD, The Mayo Clinic, Rochester, MN.

These studies are adding novel agents such as the proteasome inhibitor bortezomib, the Bruton’s tyrosine kinase inhibitor ibrutinib, and the immunomodulatory agent lenalidomide to standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) and are prestratifying patients according to genetic subtype (ie, ABC, GCB, non-GCB), or enriching the trial for subtype and analyzing results according to genetic subtype.

Scott said he was concerned that the approximately 15% of “unclassfied” DLBCL patients—that is, of neither the ABC or GCB subtype—will probably be excluded from clinical trials and thus “left in a therapeutic wasteland.”

“Double-Hit” DLBCL

Myron S. Czuczman, MD, Roswell Park Cancer Institute, Buffalo, NY, discussed current treatments of patients with “double-hit” lymphoma (DHL): MYC translocations and B-cell lymphoma 2 (BCL2) translocations. Despite a variety of drug combinations that have been studied in these patients, their current prognosis remains poor.

The difficult task of identifying a promising regimen that targets MYC is compounded by this factor being necessary for many functions in healthy cells.

Czuczman explained, “If we try to target MYC or the MYC protein, we are going to be in trouble, because normal cells depend on MYC for the cell cycle and maintenance.”

Nevertheless, he believes that the best chance for improving outcomes in DHL patients is with novel agents that target MYC and BCL2. Some agents that he believes have particular promise are ABT-199 (a BCL2 inhibitor), BET bromodomain inhibitors, alisertib (an aurora-kinase inhibitor), ixazomib (a proteasome inhibitor), and checkpoint inhibitors.

Since optimal therapies are lacking, clinicians should be proactive about enrolling patients in clinical trials, Czuczman told listeners. This is especially important for patients with DHL or double-expressor lymphoma as determined from biopsy specimens from all newly diagnosed DLBCL patients.

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