Precision Medicine Wrap-up: Combination Therapies in CLL

Combination therapies that target different pathways are impacting the current treatment spectrum for chronic lymphocytic leukemia (CLL).

In a Q&A with Targeted Oncology®, Philip Thompson, MB, BS, assistant professor at the University of Texas MD Anderson Cancer Center, explained that “there’s a dizzying array of studies going on” that investigate Bruton tyrosine kinase (BTK) inhibitors with other agents.

Adding a BTK inhibitor to venetoclax, for instance, increases the rate of undetectable minimal residual disease (MRD), for instance, he explained. Trials are now looking at an MRD-directed approach using BTK inhibitor combination therapies to determine if patients continue on maintenance, discontinue therapy, or continue with combination therapy.

What still isn’t known is if adding a CD20 monoclonal antibody on top of a BTK inhibitor combination therapy, such as ibrutinib plus venetoclax, provides a benefit.

“My suspicion is that a CD20 antibody is going to add very little to that combination,” Thompson said.

Read the full Q&A at Targeted Oncology®.

Data published in Blood revealed that ibrutinib plus venetoclax showed a favorable benefit-risk profile in patients with relapsed or refractory CLL. The VISION/HOVON 141 trial is an ongoing study to determine the feasibility of MRD-guided treatment cessation and reinitiation.

In the trial, a total 230 patients will receive ibrutinib until disease progression and venetoclax for 15 cycles in the first experimental arm. Patients who achieved a partial response or better were randomized 1:2 to receive either ibrutinib maintenance or observation (aka stopping therapy). The data published in Blood are a preplanned interim analysis on the first 51 eligible patients.

Of the 51 patients evaluated, 43 completed all 15 cycles of treatment. Half of the patients experienced grade 3 adverse events (AEs), and 26% experienced grade 4 AEs. Twenty-nine patients achieved complete response and 13 patients achieved a partial response. More than half (55%) reached undetectable MRD in peripheral blood at cycle 15.

Read more at Targeted Oncology®.

Finally, the FDA accepted a biologics license application (BLA) for ublituximab in combination with umbralisib to treat patients with CLL and small lymphocytic lymphoma. Ublituximab is an investigational anti-CD20 monoclonal antibody, and umbralisib is an oral phosphoinositide 3 kinase (PI3K) delta and casein kinase (CK1) epsilon inhibitor. Umbralisib (Ukoniq) is already approved in adults with relapsed or refractory marginal zone lymphoma who have received at least 1 prior anti-CD20–based regimen and in adults with relapsed or refractory follicular lymphoma who have received at least 3 prior lines of systemic therapy.

The BLA was based on the ongoing UNITY-CLL study, which has an estimated completion date of January 2024. There are 600 patients enrolled and the study is split into 4 arms:

• Arm 1: patients receive an infusion of ublituximab on days 1, 8, and 15 followed by maintenance infusions and an oral daily dose of umbralisib
• Arm 2: patients receive a combination of obinutuzumab and chlorambucil
• Arm 3: patients receive ublituximab as a monotherapy
• Arm 4: patients receive umbralisib as a monotherapy

Interim analysis data were collected from 421 patients randomized into arm 1 and arm 2. The median progression-free survival for arm 1 was 31.9 months at a median follow-up of 36.2 months compared with 17.9 months for arm 2 (HR, 0.546; 95% CI 0.413-0.720; P < .0001).

For more about the interim analysis data, visit Targeted Oncology®.