Tag: diffuse large B-cell lymphoma

Novel Weill Cornell Drug Displays Promise in Treating DLBCL

Following up on an earlier breakthrough confirming the feasibility of shutting down the Bcl6 protein — an important master regulatory transcription factor that is the key to survival for diffuse large-B cell lymphoma and other aggressive B-cell lymphomas– Weill Cornell’s Dr. Ari Melnick and other researchers recently completed a study where five doses of the experimental drug eradicated human lymphoma in mice.

Published online in the journal Cell the researchers described specifically how Bcl6 promotes the survival of DLBCL, before detailing how the Weill Cornell developed Bcl6 inhibitor effectively gums up the protein. Initially developed by Dr. Melnick nine years ago, the interim period has seen him working to improve the design for use by DLBCL and other lymphoma patients, collaborating with other world class researchers to understand how both Bcl6 and its inhibitor functions.

The researchers found that Bcl6 has two independent functions required for the survival of DLBCL. Dr. Melnick described how the first function, “builds a huge shopping mall-style complex”. This complex rests on top of a stretch of the genome. Through this binding Bcl6 deactivates the DNA, prohibiting genes from producing RNA and proteins. As Dr. Melnick noted, “Bcl6 acts like a barcode reader. When it sees that barcode — the DNA sequence — it attaches there”.

He went on, “Normally, the protein complex goes away after an immune reaction has been successfully mounted against the pathogen. But when it doesn’t, and remains stuck to the genes, DLBCL can result. That’s because Bcl6 is inhibiting genes that stop cells from dividing and that sense damage to the genome. We now know the genes that Bcl6 is repressing and how that helps lymphoma develop and survive.”

According to Dr. Melnick the second function, “acts like a switch on railroad track that routes a train in one direction or another. One track is needed when antibodies are required for an immune response, while the other keeps B cells in a constant state of division.”

Importantly the researchers were surprised to find that both the complex and the train switch attach to the Bcl6 protein at the same site. “They fit into the same keyholes on Bcl6,” Dr. Melnick said. “There are two identical binding sites on the protein surface.”

As Dr. Melnick exclaimed, “This is wonderfully serendipitous — our drug just happens to be able to overcome both of the biological mechanisms that are key to survival of aggressive lymphoma,” before adding that the inhibitor completely eradicated DLBCL in mice in a short time, with no detectable side effects.

The team is conducting additional research toward an investigational new drug application from the federal Food and Drug Admission.

ASCO 2013: Effectiveness of Entecavir and Lamivudine in Preventing Reactivation of Hepatitis B in HBsAg-Positive Patients with Untreated DLBCL

peter martin photo

By Peter Martin, MD

Patients with DLBCL and a history of hepatitis B are at increased risk from the reactivation of a viral infection following treatment with R-CHOP. Many guidelines recommend that patients at risk of hepatitis B reactivation receive anti-viral prophylaxis while receiving R-CHOP, but do not specify which drug should be used. At the recent annual meeting of the American Society of Clinical Oncology in Chicago, Dr. He Huang from Sun Yatsen University Cancer Center presented the results of a trial comparing two of the most commonly used drugs: entecavir and lamivudine.

Study subjects included patients receiving R-CHOP for previously untreated DLBCL and evidence of active infection (HBsAg-positive). Of the 121 HBsAg-positive patients, 61 were randomly assigned to entecavir and 60 to lamivudine. The primary endpoint was the incidence of HBV-related hepatitis; the secondary endpoint was chemotherapy disruption due to hepatitis.

The entecavir group had significantly lower rates of hepatitis, hepatitis B reactivation, and disruption of chemotherapy. The study concluded that for HBsAg-positive DLBCL patients receiving R-CHOP, entecavir was more effective in preventing hepatitis B reactivation, and should be considered the standard for primary preventive therapy in advanced stages of the disease.

ASCO 2013: Impact of Interval Between Diagnoses and Initiation of Curative Chemotherapy on Survival of Patients with Diffuse Large B-cell Lymphoma

peter martin photoBy Peter Martin, MD

A common question arising among patients with newly diagnosed DLBCL is how soon to begin treatment. While it is generally considered more appropriate to start chemotherapy sooner rather than later after diagnosis, the exact impact of this time interval on treatment outcomes is unknown. At the recent Annual Meeting of the American Society of Clinical Oncology in Chicago, Dr. Kevin A. Hay from the University of British Columbia presented the results of a retrospective study evaluating the association of patient outcomes with time to initiation of treatment.

Dr. Hay retrospectively divided 793 patients with DLBCL and at least one cycle of R-CHOP into four groups based on the amount of time between initial diagnosis and beginning of therapy. A total of 25% of respondents received R-CHOP within 2 weeks of diagnosis, 31% in 2-4 weeks, 37% in 5-8 weeks, and 7% at longer than 8 weeks. Interestingly, there was no statistically significant difference in survival between the groups. The authors concluded that the timing of chemotherapy initiation appeared to be related to clinical factors (i.e., sicker patients were treated sooner) rather than medical system or socioeconomic barriers. While detrimental outcomes were lacking in those patients who began treatment after 8 weeks, they recommended beginning chemotherapy as soon as possible after an initial diagnosis of DLBCL.