Prognostic Biomarkers in Diffuse Large B-cell Lymphoma

Jason Yonehiro, founder and CEO of CombImmune Inc., talked about diagnostic biomarkers in lymphoma and their application in clinical utility and drug discovery, at www.bio2devicegroup.org event.

Non-Hodgkin’s Lymphoma refers to any of a large group of cancers of lymphocytes (white blood cells) and is often marked by lymph nodes that are larger than normal, accompanied by fever and weight loss.  They can be aggressive or fast growing and indolent or slow growing.  NHL is steadily growing over past few years.  While there were 115,000+ cases of NHL in 2002, worldwide, over 140,000 cases of NHL are anticipated in 2019.  NHL is more common in women.

Currently R-CHOP, a combination therapy that adds the drug Rituximab, a monoclonal antibody to standard combination called CHOP, consisting of four chemotherapy drugs, is considered a standard regimen for Diffuse Large B-Cell Lymphoma, the commonest type of NHL.  Bone marrow transplant is considered to be the second line of treatment.  Rituxan can lead to serious, including fatal, adverse effects and not all patients respond to this mode of treatment.  There is a significant unmet need for effective therapies for treatment of T-cell lymphomas, said Yonehiro.  There are several drugs in the pipeline.  Avastin failed in the trials, Revlimid is showing promise, but likely to be pushed further in treatment paradigm and Rituxan continues to remain gold standard in treatment.  Rituxan is not cheap.  A 28 day regimen with Revlimid, costs up to $10,000.  Rituxan is expected to come off patent and price may come down but its efficacy remains the same.

Thus far, it has been observed that Diffused Large B Cell Lymphoma (DLBCL) patients do poorly with the current standard of care, the R-Chop therapy.  But there do not exist any molecular diagnostic tests that predict patient outcome.  About 75% of patients respond to the standard of care but about 30-40% of patients relapse and die within 5 years.  The challenge is to identify high risk patients who might benefit from more aggressive chemotherapy.  It is important to minimize overtreatment of all patients, offer more treatment options, individualize treatment plans, identify high risk patients, make better clinical assignment, and optimize treatment.

Studies indicate that distinct patterns of chromosomnal abnormalities characterize NHL and there is need to better understand how these differences impact the response to certain therapies, said Yonehiro.  The field of personalized medicine is growing.  About $9.7B went into this area but this is expected to double by 2017.  The tool currently used is International Prognostic Index or IPI.  It is a clinical tool developed to aid in predicting the prognosis of patients with aggressive non-Hodgkin’s lymphoma.  In addition to the Ann Arbor Stage, IPI added certain other factors deemed significant, including age, elevated serum LDH, performance status, and number of extranodal sites of diseases.  However, this tool does a poor job, said Yonehiro.

CombImmune’s mission is to utilize prognostic and predictive biomarkers that enhance understanding of immune dysfunction to tumor infiltration and combine that with therapeutics that restore immune function and destruction of the tumor.  CombImmune prognostic test is based on Two Gene Score (TGS) to identify high risk patients.  TGS + IPI give a significantly more accurate patient profile, said Yonehiro.  Originally, they developed a 300 gene assay and now it is distilled down to 2 genes.  TGS has been vetted through study of 692 patients and there is an ongoing 215 patients prospective study.  TGS is based on PCR (Polymerase Chain Reaction) standardized molecular diagnostic genetic technique.

Genomic information is critical to improving management of hematologic cancers, said Yonehiro.  Two Gene Test, based on LMO2 and CD 137 expressions are robust independent prognostic determinants in DLBCL.  All studies thus far clearly indicate that TGS and IPI capture more high risk patients than IPI alone.  The clinical utility and value would be in its ability to pick out patients in need of more aggressive therapy, while others are put on “wait and watch” list.  The talk was followed by Q&A.

English: Micrograph of a diffuse large B cell lymphoma, abbreviated DLBCL. Lymph node FNA specimen. Field stain. See also Image:Large b cell lymphoma – cytology small.jpg (Photo credit: Wikipedia)