Expanding Options for Treatment of CLL Using BTK Inhibitors - Episode 4

Selecting Frontline Therapy for CLL

Alan Skarbnik, MD: Jennifer, we now have a number of different therapies approved for frontline treatment of CLL [chronic lymphocytic leukemia]. We have the BTK [Bruton tyrosine kinase] inhibitors. We have the BCL2 inhibitor venetoclax, in combination with rituximab or obinutuzumab, based on the CLL14 trial. And there’s chemoimmunotherapy. How do you choose among those 3 options when treating patients in the front line?

Jennifer R. Brown, MD, PhD: There’s still a significant effect of age and comorbidities, as well as TP53 mutation up front. For patients with a TP53 mutation, I favor a BTK inhibitor.

Venetoclax-obinutuzumab would also be a possibility based on the CLL14 trial. But I did notice that at the ASH [American Society of Hematology Annual Meeting] update last year, there was only about a 60% 3-year progression-free survival [PFS] in the subgroup of patients with 17p deletions. I am concerned that they may relapse earlier when we stop the drugs. The data were very incomplete. They didn’t tell us about the rates of undetectable MRD [minimal residual disease] versus with the patients who had MRD positivity or not. But with the relatively short follow-up and incomplete data with venetoclax-obinutuzumab in 17p patients, I am going toward a BTK inhibitor, or even a clinical trial of dual agents if such is available—for example, BTK and BCL2.

For patients who don’t have either a 17p deletion or TP53 mutation, the IGVH mutation status significantly comes into play. For patients who are very young and fit and have a mutated IGVH without 17p, I still consider FCR [fludarabine, cyclophosphamide, rituximab] to be an important standard of care for them. This is based on the fact that there are 3 reports of long-term, ongoing remissions in those patients. We’ve seen about a 55% progression-free survival of 12 years in patients with mutated IGVH who were treated at [The University of Texas] MD Anderson Cancer Center, and similar data in the German CLL Study Group. Furthermore, in the ECOG-E1912 study, which did not stratify the randomization by IGVH, in the mutated group the PFS was not statistically different between IR [ibrutinib, rituximab] and FCR [fludarabine, cyclophosphamide, rituximab]. And then there’s likely, at longer times, going to be ongoing relapses with the ibrutinib, whereas we know FCR [fludarabine, cyclophosphamide, rituximab] plateaus. So I think that data are still too immature to really address this question. I often will suggest that to patients, and I find patients are actually quite interested in getting a therapy that will offer them 10, 12-plus years of potential remission.

The unmutated patients, even if they’re very young and fit, will have a continuous relapse with FCR [fludarabine, cyclophosphamide, rituximab]—with a median PFS of about 4 to 5 years. In that type of unmutated patient, that’s where most of the benefit was seen with the ibrutinib-rituximab in the ECOG-E1912 study. So BTK inhibitors are a reasonable option for those patients, but venetoclax-obinutuzumab is also a very reasonable option. I do find that many younger patients, in particular, do like time-limited therapy. Venetoclax-obinutuzumab is a 1-year time-limited regimen, so that seems to be particularly appealing to them, and they don’t necessarily mind that you have to come in for more visits in the first month or 2 as you get started on the obinutuzumab and get ramped up on the venetoclax.

Older patients can’t tolerate FCR [fludarabine, cyclophosphamide, rituximab]. In regard to the mutated patients, the chemoimmunotherapies they can tolerate have less benefit. Although in the ALLIANCE trial, for example, there was actually not a difference in the PFS in the mutated subgroup with the 2½- to 3-year follow-up as reported. Now that may change with longer follow-up, but it also depends on the tolerability of ibrutinib. In that study, about 7% of patients actually died of ibrutinib-related toxicity in both the ibrutinib arms. This was also seen in iLLUMINATE, in the ibrutinib-obinutuzumab arm. So that’s a consideration. But the benefits of chemoimmunotherapy are much less in general in these older patients. There’s not a potential plateau. In general, we’re choosing between a BTK inhibitor and venetoclax-obinutuzumab.

Transcript edited for clarity.