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Trial Shows Molecular Subtypes of Diffuse Large B-Cell Lymphoma React Differently to Ibrutinib

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Key Points

  • Tumor responses were seen in 25% of patients overall, including 8 patients with complete responses and 12 with partial responses.
  • Ibrutinib produced complete or partial responses in 37% of patients with activated B-cell–like diffuse large B-cell lymphoma but in only 5% of patients with germinal center B-cell–like diffuse large B-cell lymphoma.
  • A new clinical trial will test whether the addition of ibrutinib to standard chemotherapy can increase the cure rate of patients with activated B-cell–like diffuse large B-cell lymphoma.

A clinical trial has shown that patients with a specific molecular subtype of diffuse large B-cell lymphoma are more likely to respond to ibrutinib (Imbruvica) than patients with another molecular subtype of the disease. The study was published by Wilson et al in Nature Medicine.

In this phase II trial, patients with the activated B-cell–like subtype of diffuse large B-cell lymphoma were more likely to respond to ibrutinib than patients with the germinal center B-cell–like subtype of diffuse large B-cell lymphoma. The trial was jointly conducted by the National Cancer Institute (NCI) and Pharmacyclics.

Study Background

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, NCI scientists 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 that targeted treatments could be developed for each subtype.

Building on this work, the trial enrolled 80 patients with diffuse large B-cell lymphoma who had relapsed or had not responded to prior treatment.

Study Findings

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 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 activated B-cell–like diffuse large B-cell lymphoma but in only 5% (1 of 20) of patients with germinal center B-cell–like diffuse large B-cell lymphoma. Based on these results, the researchers concluded that, for future clinical trials involving ibrutinib, the activated B-cell–like diffuse large B-cell lymphoma 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 activated B-cell–like tumors may produce abnormal B-cell receptor signals that promote the survival of cancer cells by activating BTK, thereby accounting for the sensitivity of activated B-cell–like tumors to ibrutinib.

“Clinical trials such as this are critical for translating basic molecular findings into effective therapies,” said Louis Staudt, MD, PhD, of the NCI Center for Cancer Genomics, who co-led the study and discovered the role of B-cell receptor signaling in activated B-cell–like diffuse large B-cell lymphoma. Study co-leader Wyndham Wilson, MD, PhD, of the NCI Center for Cancer Research, added, “This is the first clinical study to demonstrate the importance of precision medicine in lymphomas.”

New Trial

Based on this study's results, an international phase III trial of standard chemotherapy with or without ibrutinib in patients with diffuse large B-cell lymphoma, excluding the germinal center B-cell–like subtype, is being conducted by Janssen Pharmaceuticals in collaboration with Drs. Wilson and Staudt (ClinicalTrials.gov NCT01855750). This is the first time a phase III trial has been designed to selectively enroll patients with a particular molecular subtype of diffuse large B-cell lymphoma. The study's objective is to determine whether the addition of ibrutinib to standard chemotherapy can increase the cure rate of patients with activated B-cell–like diffuse large B-cell lymphoma.

Ibrutinib has been approved by the U.S. Food and Drug Administration for the treatment of certain patients with several other cancers, including mantle cell lymphoma, chronic lymphocytic leukemia, and Waldenström’s macroglobulinemia.

Dr. Staudt is the corresponding author of the Nature Medicine article.

For full disclosures of the study authors, visit www.nature.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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