Treating Chronic Lymphocytic Leukemia

Transcript:Jennifer R. Brown, MD, PhD: The treatment of CLL has had a marked evolution over the last couple of decades, starting originally with oral alkylating therapy—which would control the disease for really pretty short periods of time—advancing then to multi-agent chemo-immunotherapy, like FCR (fludarabine/cyclophosphamide/rituximab), which is actually profoundly effective in a subset of patients. A subset of patients actually have prolonged progression-free survival and may even be cured by FCR.

But many patients get significant bone marrow suppression from multiple rounds of this chemo-immunotherapy, and that makes them harder to treat in relapse. Recently, of course, we’ve had the approval of a number of different targeted agents which cause less long-term side effects in terms of bone marrow damage. They each have their own side-effect profile which needs to be managed, but, in general, they’re oral agents that are better tolerated. However, they’re certainly not curing CLL as single agents, and we’re interested in developing combinations of novel agents with traditional chemo-immunotherapies to potentially move toward a cure in CLL.

It is still a topic of great study how and why the different targeted agents work in particular patients or not. And we know that, for example, patients who relapse on ibrutinib, who’ve been pretreated, often have quite resistant disease. In that context, we do know that patients who relapse with CLL on ibrutinib have acquired certain mutations. Some have acquired a mutation in the target BTK (Bruton's tyrosine kinase) residue, a cysteine mutation that abrogates the ability of ibrutinib to bind to that location and reduces its efficacy. Others have actually acquired a downstream mutation—the immediate target of BTK—a protein called PLC (phospholipase C) gamma, and those mutations are activating.

There are two reports that suggest that those mutations may represent about 70% to 80% of patients relapsing with CLL on ibrutinib. But there’s also a very recent study in which only two out of five patients carried such mutations, and certain other abnormalities were found in those patients. So, there’s still a lot to learn about patients relapsing on BTK inhibitors, even with CLL, but especially also with Richter’s Transformation. And we really are just in the infancy of setting resistance to PI3 kinase inhibitors and to BCL-2 (b-cell leukemia/lymphoma 2) inhibitors.

The biggest unmet need in CLL is still curing CLL. So, I would consider that many of the patients still have an unmet need. Certainly the highest-risk patients—17p-deleted or complex-karyotype patients—have a limited progression-free survival with the agents that we have, and we need better combinations, more effective combinations for them, especially if we want to obviate a need for transplant down the line.

We also know that the current agents are not tolerated by all patients. For example, patients on anticoagulation may not be able to tolerate ibrutinib, patients with heart problems may not be able to tolerate ibrutinib, and patients with liver problems may not tolerate idelalisib. So, there are categories of patients who just don’t tolerate these novel agents, and we need other drugs for them, or we may even have to go back to chemo-immunotherapy for some of them.

Transcript Edited for Clarity