Impact of Targeted Therapy in CLL

Expert insight on the impact that targeted therapies have had on the frontline treatment landscape of chronic lymphocytic leukemia.

John C. Byrd, MD: We’ve been blessed in the field of CLL [chronic lymphocytic leukemia] over the last decade having very impactful targeted drugs toward BTK [Bruton tyrosine kinase] and BCL2 enter the clinic. A really neat SEER [Surveillance, Epidemiology, and End Results]–based data study was done by the College of Pharmacy investigators at University of Arizona that looked at how CLL impact has been changed with this. SEER data don’t take into account therapies and other things, and they look at survival from your initial diagnosis. What’s amazing is that over the past decade, we’ve seen a hazard ratio improvement in survival of somewhere around 0.55 to 0.65 until you get to your mid-80s. At age 82, there tends to be a drop-off, which is probably reflective of patients in their 80s, who are going to have a lot of competing risk. And changing a disease that has a long natural history is not going to have a big impact on your overall survival extension.

There are other studies that have looked at some of the up-front studies of BTK inhibitors, particularly from the initial studies, that compared these to age- and sex-matched populations without CLL, and they come very close. It’s very much like the story of CML [chronic myeloid leukemia]: before imatinib we saw most patients dying of CML. Now with extended follow-up, their survival comes very close to matching patients who don’t have that disease. Many can expect to live a normal survival without the disease.

Paolo Ghia, MD, PhD: The presence of new inhibitors in new therapies and novel therapies—targeted therapies, as we call it in chronic lymphocytic leukemia—changes the perspectives of our patients and my patients. Before commenting on the outcome, in terms of overall survival and progression-free survival, the first immediate benefit has been in the quality of life of our patients. They don’t have the need to go through 6 months of adverse events—potential neutrophil decrease, use of growth factors—when they apply in the immunochemotherapy. With the novice therapists, the patient experiences a benefit almost immediately, a few days after starting the therapy, and that’s the main advantage. The quality of life improves rather immediately and then is maintained throughout the therapy. From the studies but also from the experience, we also know that patients will relapse much later with immunochemotherapy. In our clinical practice experience, we have patients who maintain the responses for years to come. That’s something that we had never experienced before.

Anna Schuh, MD, PhD: The targeted agents have made a huge difference to our patients because when FCR [fludarabine, cyclophosphamide, rituximab] came along in 2010, it was the first combination that showed that the addition of rituximab to the chemotherapy backbone improved progression-free survival and overall survival of patients with CLL. However, we know that FCR [fludarabine, cyclophosphamide, rituximab] and other chemoimmunotherapy agents are associated with a significant morbidity and up to 25% risk of hospital admissions for infections. The median progression-free survival of FCR [fludarabine, cyclophosphamide, rituximab] is around 57 months. When the targeted agents came along, we had a very well-tolerated non-chemotherapy-based regimen. That clearly changed the outcome for patients in many ways. In FCR [fludarabine, cyclophosphamide, rituximab], as the name says, there’s rituximab that’s given intravenously. Compared with ibrutinib, for example, the first-generation BTK inhibitor, it’s a purely oral agent.

For the progression-free survival in the frontline studies in patients with comorbidities, the longer-term RESONATE-2 data show that over 60% of patients are still on ibrutinib 7 years down the line. These are very impressive data when you’re comparing it with chemoimmunotherapy for patients—not just for fit patients but also for those who have significant comorbidities, such as the ones who were recruited into RESONATE-2. Clearly, 1 of the flip sides of the targeted agents is the fact that you’re giving them continuously—the BTK inhibitors—so the arrival of fixed-duration combination therapy with venetoclax-obinutuzumab has also had a big impact because it allows patients to be on a fixed-duration regimen that goes on in the frontline setting for just 1 year and is extremely well tolerated. This has had a mega impact in terms of tolerability of treatments, progression-free survival of treatments, the number of hospital visits patients have to undergo, and the number of hospital admissions.

Transcript Edited for Clarity

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