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Activated B-cell-like subtype of diffuse large B-cell lymphoma responds to Ibrutinib, a BTK inhibitor


A clinical trial has shown that patients with a specific molecular subtype of diffuse large B-cell lymphoma ( DLBCL ) are more likely to respond to the drug Ibrutinib ( Imbruvica ) than patients with another molecular subtype of the disease.

The study is published in Nature Medicine.

In this phase II trial, patients with the activated B-cell-like ( ABC ) subtype of DLBCL were more likely to respond to Ibrutinib than patients with the germinal center B-cell-like ( GCB ) subtype of DLBCL.

Lymphomas are caused by an abnormal proliferation of white blood cells and can occur at any age. Diffuse large B-cell lymphoma is an aggressive form of lymphoma that grows rapidly but is potentially curable.
The disease accounts for approximately 30% of newly diagnosed lymphomas in the United States.

Several years ago, National Cancer Institute ( NCI ) researchers identified the two primary subtypes of diffuse large B-cell lymphoma based on characteristic patterns of gene activity within the lymphoma cells.
The discovery of these subtypes suggested to the researchers that targeted treatments could be developed for each subtype.

Building on this work, the trial enrolled 80 patients with diffuse large B-cell lymphoma that had relapsed or had not responded to prior treatment. All patients received Ibrutinib.
Tumor responses were seen in 25% of patients overall, including 8 patients with complete responses and 12 with partial responses.

For the study population as a whole, after a median follow-up of 11.5 months, the median progression-free survival ( the time until the disease worsened ) and overall survival were 1.6 months and 6.4 months, respectively.

An analysis based on disease subtype showed that Ibrutinib produced complete or partial responses in 37% ( 14 of 38 ) of patients with ABC DLBCL but only 5% ( 1 of 20 ) of patients with GCB DLBCL.

Based on these results, the researchers concluded that, for future clinical trials involving Ibrutinib, the ABC DLBCL gene signature could be used to identify patients who would be more likely to respond to the drug.

Diffuse large B-cell lymphoma originates from B cells, which play a crucial role in the body’s immune response.
The target for Ibrutinib, an enzyme called Bruton’s tyrosine kinase ( BTK ), is a key component of B-cell receptor signaling.
The new study provides the first clinical evidence that ABC but not GBC tumors may produce abnormal B-cell receptor signals that promote the survival of cancer cells by activating BTK, thereby accounting for the sensitivity of ABC tumors to Ibrutinib.

Ibrutinib has been approved for the treatment of certain patients with several other cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström macroglobulinemia. ( Xagena )

Source: National Cancer Institute ( NCI ), 2015

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