Penn Medicine researchers have discovered a biomarker that identifies patients with aggressive activated B cell diffuse large B cell lymphoma (ABC-DLBCL) who will not respond to ibrutinib precision medicine therapy.
DLBCL is the most common subtype of adult lymphomas. Each year, around 25,000 new cases are diagnosed in the United States, with ABC-DLBCL being one of the most aggressive forms of the cancer. Ibrutinib has been shown to be an effective treatment, but not for all patients.
Ibrutinib is a type of precision medicine therapy that works by blocking the protein Bruton’s tyrosine kinase (BTK), which is part of a pathway that helps B cells thrive. When BTK activity is blocked, cancerous B cells will die or will stop dividing. While the drug has been shown to benefit some patients with refractory forms of lymphomas and leukemias, not all patients respond to the treatment.
Determining which patients will benefit from ibrutinib is important, as if the treatment is unlikely to be effective, other forms of treatment will need to be prioritized. The biomarker will help physicians decide on the best treatment for ABC-DLBCL patients.
The researchers found that ABC-DLBCL patients who have mutations in the BCL10 gene will likely have resistance to ibrutinib, as the mutations allow cells to circumvent the blockade of BTK by the drug. The normal version of BCL10 binds to two proteins – CARD11 and MALT1 – triggering NF-kB signalling, which is essential for normal B cell function.
The researchers believed the mutated BCL10 could be joining forces with other cellular catalysts to accelerate lymphoma growth, although they were unsure which cellular culprits were involved. Through an advanced analysis, the researchers identified the protein complexes and showed how the B cells were resisting treatment with ibrutinib through auxiliary signaling.
The researchers explained the process using a relay race analogy. Without the mutation, ibrutinib knocked the baton out of the first runner’s hand to end the race – or in this case, kill the cancer cells. With the mutation, while the baton is knocked out of the first runner’s hand by the drug, a runner from another team hands the runner a different baton and the race can be finished – the treatment will not be effective.
The biomarker will allow physicians to determine whether Ibrutinib will likely be an effective treatment, helping to ensure that patients receive the best treatment as early as possible to maximize the chance of a positive outcome.
“Precision medicine is the goal, where individualized therapy, based on genetics and other factors, lets us treats patients with the right drug for the right disease at the right dose and at the right time,” said Kojo Elenitoba-Johnson, MD, the Peter C. Nowell, MD, Professor in the Perelman School of Medicine at the University of Pennsylvania, Director of the Center for Personalized Diagnostics, and co-author of the study. “Identifying these new mechanisms strengthens that approach for patients with this type of lymphoma.”
The findings were presented at the plenary scientific session at the 62nd American Society of Hematology Annual Meeting & Exposition on Dec. 6, and will also be presented by Min Xi, PhD of the Melnick lab at Penn Medicine at Weill Cornell Medical College in New York.