Can Prognostic Factors Guide the Treatment of DLBCL?

February 2013 Vol 6, No 1, Special Issue

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and is readily curable, even in the most advanced cases. Nevertheless, the treatment of DLBCL can be a challenge, according to Laurie H. Sehn, MD, MPH, FRCPC, a medical oncologist at the British Columbia Cancer Agency, Vancouver, Canada, who discussed DLBCL at ASH 2012.

Advanced Disease and Personalized Medicine
When relapse or progression occurs, high-dose chemotherapy and autologous stem-cell transplantation offer the best chance of cure for many patients, although only 50% of all patients are eligible for an intensive approach.
As the treatment options for patients with advanced disease increase, “improved prognostication will be crucial to allow for the possibility of individualized risk-adapted therapy,” she suggested.

There is a need to identify patients with advanced disease in whom the combination regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) will prove insufficient so that alternate treatment approaches, especially targeted therapies, can be considered. The question of whether reliable prognostic or predictive markers exist and should be used to guide initial treatment choice deserves consideration.

Today’s clinical tools “do not provide the necessary biologic insight to allow for tailored therapy approaches with novel targeted agents,” Dr Sehn said.

Molecular prognostic markers are emerging for patients with DLBCL who are receiving the R-CHOP regimen.

BCL2 is an antiapoptotic protein that is associated with worse survival (although rituximab may overcome its negative influence).
Myc oncogene rearrangement is identified in up to 10% of patients with typical DLBCL morphology. This may be associated with worse outcomes with R-CHOP treatment, although some studies suggest that coexpression of BCL2 is necessary for this.

“Currently, the one subgroup of patients that should be considered for alternate initial therapy outside of a clinical trial is the subset with a concurrent translocation involving BCL2 and Myc (ie, a double hit),” Dr Sehn suggested. “These patients have a remarkably poor outcome after R-CHOP, with a median survival of less than 1 year.”

Gene-expression profiling has identified molecularly distinct sub­types within patients with DLBCL, and these distinctions have prognostic implications. Gene-expression profiling is not routinely available in patient care, but immunohistochemistry
(IHC)-based algorithms have been developed to mimic the molecular designations that are obtained through gene-expression profiling.
“Unfortunately, these IHC algorithms remain an imperfect substitution for microarray-based gene-expression profiling because of their inherent oversimplification and poor reproducibility,” Dr Sehn said.

Novel Targeted Therapies
Predictive markers will become paramount in making treatment decisions,” she added.
Gene-expression profiling studies have identified potential targets, leading to the development of targeted agents for patients who are too frail for R-CHOP or have relapsed or refractory disease. Molecular profiling has also demonstrated the importance of the microenvironment in DLBCL.

Some of the novel agents and their postulated targets include bortezomib (nuclear factor [NF]-κB), fostamatinib (Syk), ibrutinib (Bruton’s tyrosine kinase), Cal-101 (PI3K), enzastaurin (protein kinase C-β), navitoclax (B-cell lymphoma 2), EZH2 inhibitors (EZH2), bevacizumab (vascular endothelial growth factor), and lenalidomide (angiogenesis, NF-κB).

“Recognition of the biologic het­erogeneity of DLBCL is of paramount importance and must be taken into consideration when investigating new therapies,” Dr Sehn concluded. n

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