BTK-Targeted Therapy for CLL


Jennifer R. Brown, MD, PhD: Hello, and thank you for joining this Targeted Oncology™ presentation titled, “Expanding Options for Treatment of Chronic Lymphocytic Leukemia Using BTK Inhibitors.” In recent years, treatment for chronic lymphocytic leukemia [CLL] has evolved from standard chemoimmunotherapy approaches to strategies based on novel targeted agents. Today we’re going to talk about the expanding role of Bruton tyrosine kinase [BTK] inhibitors, which are now central to the treatment of CLL.

I am Dr Jennifer Brown, the director of the Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute, in Boston, Massachusetts. I am also a professor of medicine at Harvard Medical School. Joining me today is Dr Alan Skarbnik, the director of the lymphoproliferative disorders program at Novant Health, in Charlotte, North Carolina.

Thank you so much for joining us. Let’s begin.

Alan Skarbnik, MD: Dr Brown, thank you so much for having me. It’s a pleasure to be here, and I’m excited to discuss the role of BTK inhibition in CLL treatment.

Jennifer R. Brown, MD, PhD: Great. Why don’t we start? Let’s begin by discussing the rationale for BTK inhibition in B-cell lymphomas. Do you want to start us off there, Alan? What does BTK inhibition achieve?

Alan Skarbnik, MD: Sure, Jennifer. BTK, or Bruton tyrosine kinase, is an enzyme that serves as a single transducer from the B-cell receptor to the nucleus. B cells, in many lymphoproliferative disorders, are addicted to the B-cell receptor pathway and require BTK transduction for survival, homing, and proliferation. Inhibiting this enzyme leads us to decrease proliferation of malignant B cells and decrease their survival, and also dislocate them from the lymph node compartment, allowing them to die in the peripheral blood, in general. So it’s a very interesting target to have in B-cell malignancies.

BTK is found not only in B cells. Other cells in the hematopoietic environment are dependent on BTK for their survival, particularly myeloid cells. BTK has a small role in activating RANKL in osteoclasts as well. But largely, nonhematopoietic cells don’t carry BTK and don’t express BTK, so it’s an interesting target to minimize nontargeted toxicities as well.

Jennifer R. Brown, MD, PhD: We also know from the genetic disease, where BTK is knocked out, that virtually the only problem that those patients have is related to B-cell immunodeficiency and hypogammaglobulinemia.

Alan Skarbnik, MD: Correct.

Jennifer R. Brown, MD, PhD: That’s really part of how the rationale developed. Prior to the availability of BTK-targeted therapies, the treatment approach for patients with CLL was largely based on chemotherapy. And then chemoimmunotherapy represented a significant improvement. When rituximab was added to chemotherapy, it did improve overall survival, as seen in the case of FCR [fludarabine, cyclophosphamide, rituximab]. But as we’ll talk about, patients with higher-risk markers, in particular, derived significant benefit from BTK-targeted therapies.

Alan Skarbnik, MD: Yes, that’s correct. Not only that, but as we know, patients with CLL are, in general, older. The average age of diagnosis is 71 years. It can become challenging to give chemoimmunotherapy to older patients who have additional comorbidities, particular FCR. Bendamustine and rituximab has been the regimen that’s been widely used, but again, it seems that the patients with higher-risk abnormalities don’t fare as well in terms of long-term outcomes with this regimen.

Jennifer R. Brown, MD, PhD: Right. As we’ll discuss, comorbidities still come into play, even with our targeted agents.

Transcript edited for clarity.

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