Examining the Role of Frontline BTKi Monotherapy in CLL - Episode 4

Unmet Needs in Frontline Treatment of CLL

March 29, 2021
Jennifer R. Brown, MD, PhD

The shortcomings physicians face in combatting CLL (chronic lymphocytic leukemia) are discussed, in addition to what the high-level updates from the ELEVATE-RR press release may reveal regarding future treatments for CLL.

Jennifer R. Brown, MD, PhD: Frontline CLL [chronic lymphocytic leukemia] treatment has become quite effective. But patients who are at high risk for early failure or Richter syndrome appear to be a subset of those who have deletion 17p or TP53 aberrancy and those with complex karyotype. Fortunately, a subset of both of those groups will do quite well, even with a single-agent BTK [Bruton tyrosine kinase] inhibitor, while another subset may develop Richter quite early. We don’t know how to figure out which is which, unfortunately.

There is a lot of interest for this population in looking at combination regimens, particularly BTK inhibitor with BCL2 inhibitor, plus or minus an anti-CD20. The idea is that if we give 2 potent agents together, the likelihood of early resistance will be reduced. Mathematically, it’s harder for the CLL to be resistant to 2 drugs rather than 1. For example, the German CLL Study Group has an ongoing study, CLL2-GiVe, looking at ibrutinib with venetoclax and obinutuzumab, monitoring for undetectable MRD [minimal residual disease], and discontinuing therapy in the study of undetectable MRD. That remains a question that clearly needs more data to address. High-risk patients benefit particularly from continuous therapy vs how we can address time-limited therapy for these patients.

The CLL14 study with time-limited therapy with venetoclax and obinutuzumab has about a 3-year progression-free survival of 60% for the 17p subgroup, whereas frontline single-agent ibrutinib in the NHLBI [National Heart, Lung, and Blood Institute] study had a 6-year progression-free survival of 60%. That has led many of us at present to use continuous BTK inhibitors for these patients. However, the idea of driving them into deeper remissions achieving undetectable MRD is appealing. The question is, can we actually stop therapy? If we do stop therapy, should we monitor for MRD and then re-treat early? Those are some key research questions. These may also be patients who, down the line, would perhaps be early candidates for CAR [chimeric antigen receptor] T-cell therapy when or if we start to see better tolerability as well as prolonged efficacy of CAR T cell. For example, a patient is on a BTK inhibitor, achieves a deep remission, still has residual disease, and then has what by then would hopefully be a safe and effective cellular therapy for consolidation, with the goal of a longer-term remission.

Ultimately, we’re all eagerly awaiting the head-to-head data comparing next-generation BTK inhibitors with ibrutinib in CLL. We did hear about a month ago by a press release that the data from the ELEVATE-RR trial will soon be available and that it did meet its primary end point of noninferiority for progression-free survival for acalabrutinib compared with ibrutinib and a decreased rate of atrial fibrillation with acalabrutinib. As a reminder, this is the head-to-head trial comparing acalabrutinib with ibrutinib in relapsed patients with deletion 17p or deletion 11q, the results of which have been eagerly awaited and should have quite mature follow-up when we see there are data, hopefully later this year. There is also an ongoing relapsed trial with zanubrutinib comparing zanubrutinib head-to-head with ibrutinib in CLL, but those data are still further off.

Transcript edited for clarity.