Therapeutic Sequencing Strategies in Relapsed/Refractory CLL

Paolo Ghia, MD, PhD: In the area of immunochemotherapy, it depends which therapy you applied first. If you applied sCR [stringent complete response], then you couldn’t reapply sCR as the second treatment. Luckily the era of immunochemotherapy is past. Nowadays, if a patient receives a first-line immunochemotherapy regimen, in the second line very likely he or she will get novel therapy. Here the choice is between a continuous therapy with a BTK [Bruton tyrosine kinase] inhibitor or a fixed-duration therapy with venetoclax plus rituximab for 2 years. In this case, the decision will be based not on efficacy directly, because those agents are effective, but on the patient preference: for example, fixed duration vs a continuous treatment.

On the other side, all the comorbidities of the patient that might suggest 1 treatment better is than the other for the specific patient. The patient has been treated with a novel therapy in the first line and then the decision for the second line is consequential. For example, if you had a BTK inhibitor, then you must move to BCL2 inhibitor if the patient relapsed under the therapy. If a patient instead was intolerant to whatever BTK inhibitor you used, you may always try to switch to a second or, in the future, even a third BTK inhibitor before changing class of drug. If the patient has been treated with a venetoclax-based treatment in the first line, then upon relapse the option of a treatment might still be available in case the patient had longer progression-free survival for a long time from the end of the therapy to the progression. We don’t have a lot of data about re-treatment after failing venetoclax. We have mostly re-treatment in patients who relapsed shortly after failing venetoclax. We need longer follow-up to add more data. Now we know that these patients can be recused effectively, virtually 100% with a BTK inhibitor after failing venetoclax-based therapy.

Anna Schuh, MD, PhD: The risk of high-risk molecular features in relapsed/refractory CLL [chronic lymphocytic leukemia] is still important, so we know what that risk is because those patients might be eligible for clinical trials in the future. They might be eligible for cellular therapy. Identifying those patients and managing them accordingly is important, even if the immediate treatment choice might not change. If you have a patient who has had chemoimmunotherapy in the front line, has developed TP53 abnormality or complex karyotype, and is then needing further treatment, I’d use continuous therapy with a BTK and not used a fixed-duration regimen. Because in the United Kingdom, at least, when patients relapse after a fixed duration, it’s not easy to get access to fixed-duration again. You can give the same regimen only once. But with continuous therapy, your progression-free survival might be a bit longer. When patients relapse, you’ve got the option of switching them to venetoclax-rituximab treatment fixed duration or to the venetoclax monotherapy regimen.

Transcript Edited for Clarity