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Opinion Makers is an exclusive 乌鸦传媒 video series, presenting leaders from all areas of medicine, offering their views on current topics in clinical care, research, and policy.

In this video, , executive medical director of the Huntsman Cancer Institute at the University of Utah in Salt Lake City, reviews the evidence for using gene expression profiling to guide therapy for diffuse large B-cell lymphoma (DLBCL). He concludes that a good rationale exists for distinguishing between DLBCL and choosing therapy accordingly and that data from clinical trials have been encouraging. However, randomized trials have yet to validate the early findings. No definitive conclusions can be drawn until ongoing trials of gene expression-directed therapies have been completed.

Diffuse large B-cell lymphoma can be divided into two major subtypes by gene expression profiling. There has been hope that this will lead to a new understanding of the biology of this disease which will direct us to new therapeutic approaches.

Early data showed that the activated B-cell (or ABC subtype) has a worse prognosis than the germinal center (or GCB) subtype, and further studies showed that the ABC type has some distinctive features. ABC disease is characterized by chronic B-cell receptor signaling, suggesting that molecules on this pathway could have specific activity in this type of DLBCL. In addition, the transcription factor, NF kappa-B, appears to have an important role in its pathogenisis.

These discoveries have led to clinical trials of new targeted treatments for the ABC subtype, which have shown some early promise.

Important new data has emerged in the last few months which adds to our knowledge, but also raises some questions about the true clinical utility of this new treatment paradigm for DLBCL.

I would like to discuss three aspects of this targeted approach to treating DLBCL patients

Immunohistochemical algorithms which assign cell of origin are less accurate than gene expression profiling, but are inexpensive, accessible to routine labs, and, unlike conventional molecular studies, can be performed on routinely formalin fixed, paraffin embedded tissue.

Gene expression profiling has been thought to be too costly and too slow to have clinical utility. Two important studies have challenged this.

A new technique, the Lymph 2Cx assay, is a robust 20-gene predictor of ABC versus GCB subtype. This test can be performed on paraffin-embedded tissue for about $40 per case, and the result is available in 36 hours, meaning that we could use this routinely in the clinic.

Also, a recent study from the U.K., the so-called Remodel B trial, has assessed the feasibility of using gene expression profiling in a large scale, multicenter randomized trial. Data presented at the ASH meeting in December demonstrate the utility of this approach. Early-phase studies suggested that the addition of bortezomib to R-CHOP or similar chemotherapy may improve outcome for the ABC subtype. Randomized trials have assessed whether this is true. A recent European study compared R-CHOP with a bortezomib-containing regimen, VR-CAP, for patients with non-GCB disease, showing no improvement in outcome with the addition of bortezomib.

Similarly, a large, randomized trial from the U.S., known as the Pyramid trial, was reported at ASH. Just over 180 patients with non-GCB disease were randomized to receive R-CHOP with or without bortezomib. No difference in overall or progression free survival has been observed.

Whether B-cell receptor signaling is a useful target has been addressed in a recent study in which ibrutinib, an inhibitor of Bruton's tyrosine kinase, was assessed in 80 patients with relapsed or refractory DLBCL. In this study, a response rate of 37% was seen in patients with the ABC subtype versus only 5% of those with the GCB subtype.

Although encouraging, these results require confirmation in a prospective trial -- a randomized trial of R-CHOP with or without ibrutinib is now in progress.

What can we conclude from these studies?

First, there is a good rationale for the distinction between ABC and GCB disease -- it has prognostic value and early signals suggest that these different entities may benefit from different treatments.

Second, like all other treatments, the true test of these targeted therapies is in the context of a prospective, randomized trial. So far, these have not confirmed the initial promise, but it's early days, the jury is still out, and we need to see the data from other ongoing studies.

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