Tag Archives: #ibrutinib

Ibrutinib Effective Treatment For Difficult To Treat Forms of Hairy Cell Leukemia (Medicine)

The oral targeted therapy drug ibrutinib is an effective treatment option for high-risk hairy cell leukemia, according to a new study conducted by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).

Hairy cell leukemia is a rare form of B-cell blood cancer that is diagnosed in 600 to 800 people annually in the United States. Researchers note that while the disease generally has a good prognosis for the majority of people affected, a small group of patients with variants of the disease do not respond well to existing U.S. Food and Drug Administration (FDA) approved therapies or cannot tolerate the side effects of established therapies.

“There is a critical unmet need for therapy options in this subset of patients to achieve long-term cancer control,” said Kerry Rogers, MD, principal investigator of the clinical trial and a hematologist/scientist at the OSUCCC – James. “Our study shows that ibrutinib (pronounced eye-broo-ti-nib) is a safe, effective and well-tolerated option for patients with relapsed or variant forms of hairy cell leukemia. It is a very important discovery for patients facing this diagnosis.”

For this phase 2 clinical trial, a multi-institutional team led by the OSUCCC – James recruited 44 patients with high-risk hairy cell leukemia to test the effectiveness of the drug ibrutinib, 15 of whom were treated in Columbus, Ohio, at the OSUCCC – James.

All study participants had either classic hairy cell leukemia and had received other treatments previously or the variant form of the disease where it is not likely that the standard therapies — the chemotherapy drugs cladribine (pronounced KLAD-rih-been) and pentostatin (pronounced PEN-toh-STA-tin) — would be effective.

Researchers reported their findings in the June 24 issue of Blood.

Ibrutinib is an oral therapy in a class of drugs known as Bruton’s tyrosine kinase (BTK) inhibitors. These drugs block specific chemical reactions in the body that are involved in cellular processes. Use of the drug for this study was considered experimental; however, ibrutinib is FDA approved for the treatment of certain cancers, including mantle cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma and others.

“The underlying cellular biology of these diseases is similar, so we wanted to determine if this FDA-approved drug that is used to treat other forms of blood cancer could also serve as an effective treatment for this small segment of hairy cell leukemia patients who did not respond to traditional therapies,” said Rogers, who is an assistant professor in Ohio State’s College of Medicine.

“Even though hairy cell leukemia is a disease with a generally good prognosis, there is a small group of patients for whom current therapies are inadequate for cancer control,” Rogers added. “This is an effective, well-tolerated new treatment option for patients impacted by the highest-risk forms of hairy cell leukemia. It’s a very exciting development that could transform survivorship for this subset of patients from months and years, to years and decades.”

This study was sponsored by the Cancer Therapy Evaluation Program at the National Cancer Institute and grants from the National Cancer Institute/National Institutes of Health and conducted at the OSUCCC – James; the NCI clinical trials center, Karmanos; Mayo Clinic and MD Anderson Cancer Center. The study began in 2013 and is closed to patient accrual.

Featured image: Hairy cell leukemia slide © OSU

Reference: Kerry A. Rogers, Leslie A. Andritsos, Lai Wei, Eric M. McLaughlin, Amy S. Ruppert, Mirela Anghelina, James S. Blachly, Timothy Call, Dai Chihara, Anees Dauki, Ling Guo, S. Percy Ivy, Lacey R. James, Daniel Jones, Robert J. Kreitman, Gerard Lozanski, David M. Lucas, Apollinaire Ngankeu, Mitch Phelps, Farhad Ravandi, Charles A. Schiffer, William E. Carson, Jeffrey A. Jones, Michael R. Grever; Phase 2 study of ibrutinib in classic and variant hairy cell leukemia. Blood 2021; 137 (25): 3473–3483. doi: https://doi.org/10.1182/blood.2020009688

Provided by OSU

New Biomarker Identifies Patients with Aggressive Lymphoma Who Don’t Respond to Precision Therapy (Medicine)

Penn Medicine researchers help isolate pathways of resistance to ibrutinib.

A new biomarker discovered by a team that includes researchers from Penn Medicine identifies patients with an aggressive form of lymphoma unlikely to respond to the targeted treatment ibrutinib. It’s a clinically actionable finding that will help guide physicians toward the right treatment for patients with activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) who harbor these newly exposed mutations in the BCL10 gene.

The findings were presented during the plenary scientific session at the 62ndAmerican Society of Hematology Annual Meeting & Exposition on Dec. 6 (abstract #3). Kojo S. J. Elenitoba-Johnson, MD, the Peter C. Nowell, MD, Professor in the Perelman School of Medicine at the University of Pennsylvania and Director of the Center for Personalized Diagnostics, serves as a co-author.

“This is a mechanism of resistance that was previously underappreciated,” Elenitoba-Johnson said. “Ibrutinib would have been a candidate for such patients, but if they have these BCL10 mutations, another route for treatment should be prioritized.”

Ibrutinib is a targeted therapy that blocks a protein called “Bruton’s tyrosine kinase,” which is part of a pathway that helps B cells thrive. Blocking BTK can make B cells, including cancerous B cells, die or prevent them from dividing. The drug has been shown to be useful in the treatment of relapsed and refractory forms of lymphomas and leukemias, but not all.

Mutations in BCL10, the researchers found, promote abnormal signaling pathways that allow cells to circumvent the drug’s blockade.

The normal BCL10 binds to two other proteins known as CARD11 and MALT1 to trigger NF-kB signaling, which is important in normal B cell function. However, mutations in BCL10 subvert this pathway, and the mechanisms by which this is achieved are not well understood. The researchers discovered using a number of sophisticated techniques, including cyroelectron microscopy, that mutated BCL10 could be joining forces with other cellular culprits to drive lymphoma growth and resistance to treatment, but it wasn’t clear what those were.

That’s where Penn Medicine researchers came in, with their deep expertise in a technology known as mass spectrometry-based proteomic analyses, which drills down even further into the nuances of protein complexes. They identified new interactors—including NF-κB2 and TAB1—that showed how cells are capable of evading the drug through auxiliary signaling. If the process were a relay race, in a “normal” patient, the drug would knock the baton out of the first runner’s hand to thwart cancer. But with these mutations, a runner from another team swoops in with a new baton to help finish.

“Cutting off the signaling up top would be immaterial because this protein has now acquired a new capability that subverts the mechanism by which the drug could effectively act as an inhibitor in lymphomas harboring these mutations,” Elenitoba-Johnson said.

The findings add to the growing list of genetic drivers of cancers that continue to help inform treatment plans for lymphoma patients. DLBCL is the most common subtype of adult lymphomas, with more than 25,000 new cases a year in the United States. ABC-DLBCL is one of its most aggressive forms.

“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,” Elenitoba-Johnson said. “Identifying these new mechanisms strengthens that approach for patients with this type of lymphoma.” 

Penn co-authors include Ozlem Onder, PhD in the Elenitoba-Johnson Lab. The findings will be presented by Min Xi, from the Melnick lab at Weill Cornell Medical College in New York. Other co-authors include, Liron David, PhD, of Boston Children’s Hospital, and Matthew Teater, PhD, Lorena Fontan, PhD, Hao Wu, PhD, and Ari Melnick, MD, of Weill Cornell Medical College in New York.

Provided by Penn Medicine

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Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $8.6 billion enterprise.

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