PHILADELPHIA (October 18, 2022)—The development of a family of drugs known as Bruton tyrosine kinase inhibitors (BTKi) was a huge step forward in treating chronic lymphocytic leukemia and non-Hodgkin lymphoma.
However, the rapid pace of basic science studies and clinical trials investigating these therapies, which include ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib, has made it hard to keep up with the latest research. Now a new review paper from clinicians and scientists at Fox Chase Cancer Center distills what’s known about BTKi in three types of lymphoma.
While BTKi have improved survival rates, resistance has been a challenge in some patients, said Shazia Nakhoda, MD, assistant professor in the Department of Hematology/Oncology at Fox Chase and lead author on the paper. Current research looks at how different types of lymphomas respond to these therapies, what causes resistance and how it can be overcome, and how the next generation of BTKi might improve outcomes.
“The landscape of lymphoma is changing every day,” Nakhoda said. “With this paper, we’re bridging the clinical and the basic science and we’re making it more digestible.”
Principal investigator Y. Lynn Wang, MD, PhD, FCAP, a professor in the Blood Cell Development and Function research program and medical director for Molecular Pathology in the Department of Pathology, said she is gratified by how well-received the paper has been.
“I think the response shows that this information is really useful for clinicians,” she said. “This field is fast moving because there is always new research and sometimes conflicting findings being published. With the aid of tables and figures, the review helps organize the most pertinent information for practitioners. This makes it easy to find resistance mechanisms under each particular clinical indication and to take a view of the landscape of treatment options.”
B-cell non-Hodgkin lymphomas and leukemias make up around 3.5% of all cancers in the United States. BTKi therapies work by targeting the B-cell receptor signaling pathway, a genetic trigger that drives malignancies in a type of white blood cell called B-cells. Ibrutinib is the most widely used of these therapeutics.
For the paper, researchers reviewed studies and clinical trials from the last five to seven years that looked at ibrutinib’s use in three common types of leukemia and lymphoma: chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and diffuse large B-cell lymphoma. They also looked at clinical trials of combination therapies and newer BTKi therapies.
“Because BTKi have favorable toxicity profiles and seem to be very effective in patients with certain high-risk features that make tumors resistant to traditional chemotherapy, we are seeing this class approved and investigated in more subtypes of lymphoma and in earlier lines of therapy,” Nakhoda said. Key clinical takeaways from the review include:
- Patients with CLL show a more durable response with ibrutinib compared to the previous standard of care, chemo-immunotherapy. However, 10% to 16% of these patients show resistance at the outset of treatment, while 10% to 18% eventually relapse.
- Mantle cell lymphoma patients who have relapsed after frontline therapy can be treated with ibrutinib; however, 30% of these patients fail to respond and 60% achieve only a partial response.
- Ibrutinib may offer some benefits to younger patients with ABC diffuse large B-cell lymphoma, a subtype of the disease with historically poor survival rates.
- Ongoing clinical trials evaluating novel combinations of BTKi with other targeted agents and chemotherapies may help overcome resistance to these agents when given together as a multipronged approach. Reducing resistance to these agents may offer patients longer duration of response.
“It’s not one-size-fits-all anymore,” Nakhoda said. “We are now seeing a shift in management of lymphoma guided by the molecular data. This can inform us what disease pathways we should be targeting based on specific genetic subtypes that can evolve over time.”
Wang added that her lab continues to work on studies to understand the mechanisms of BTKi resistance in the hope of coming up with new strategies to help patients. In 2014, the lab was the first to identify a key mutation mechanism of ibrutinib resistance.
The paper, “Resistance to Bruton Tyrosine Kinase Inhibition in Chronic Lymphocytic Leukemia and Non-Hodgkin Lymphoma,” was published in the British Journal of Haematology.