Novel Combination Advances in CLL - Episode 4

Novel-Based Combinations as Treatment for CLL

December 20, 2019

Sameer Parikh, MBBS:The CAPTIVATE study is a phase II study that is treating previously untreated patients with CLL [chronic lymphocytic leukemia] with a combination of ibrutinib and venetoclax. Ibrutinib is given for 3 months prior to starting venetoclax, and then the combination is continued for a total of 1 year.

In a study presented at the ASH [American Society of Hematology] 2019 meeting, Dr Constantine Tam showed data demonstrating] that the percentage of patients treated on this trial that achieve MRD [minimal residual disease]-negativity after 12 cycles of combined therapy is approximately 75%. These are very encouraging results because this allows us to treat patients to MRD negativity and then potentially stop treatment. There is a second randomization that’s happening after 12 months of combination therapy is completed. However, those results are not yet available.

The CAPTIVATE study design is very interesting. One of the major concerns with the use of venetoclax is the problem with tumor lysis syndrome. Many patients need hospitalization or need to be monitored very carefully with the weekly dose ramp-up of venetoclax, as we begin from 20 mg and go all the way up to 400 mg in 5 weeks. The study design of CAPTIVATE allows patients to start therapy with single-agent ibrutinib, which then mitigates the risk of tumor lysis syndrome. After 3 months of single-agent ibrutinib therapy, a number of patients experience debulking of their disease to the extent where the risk of tumor lysis syndrome with weekly ramp-up of venetoclax substantially reduces.

In the CAPTIVATE study, only 1 patient experienced laboratory tumor lysis syndrome, and no patients experienced clinical tumor lysis syndrome. This is encouraging and important because as we all begin to get comfortable treating our patients with this combination therapy, once it is approved in the outpatient setting, it will be important and useful to know that upfront therapy with ibrutinib will reduce the risk of tumor lysis syndrome and allow patients to be treated safely.

The CAPTIVATE study results are very encouraging. The combination of ibrutinib and venetoclax will lead to deep MRD-negative remissions. This combination is not yet FDA approved, and, therefore, cannot be used outside the context of a clinical trial. If and when this combination does become approved by the FDA for use, I think the biggest competition for this particular combination therapy will be with the combination of venetoclax and obinutuzumab. Both of these regimens seem to induce significant numbers of patients who can get into minimal residual disease-negative remissions.

The issues with venetoclax and obinutuzumab are that patients will need to get infusions with obinutuzumab as an outpatient; whereas the combination of ibrutinib and venetoclax is an all-oral regimen.

We also need to wait for longer-term follow up from both of these studies to see what proportion of patients who are MRD negative at the end of 12 cycles of treatment do end up staying MRD negative over time, and what the progression-free survival of these patients is going to be.

If the results are comparable, I would prefer that my patients get venetoclax and obinutuzumab as opposed to ibrutinib and venetoclax. That way, I could save ibrutinib for salvage therapy down the road, if the patients have progression of disease after upfront therapy with a venetoclax-based regimen.

Transcript edited for clarity.