Time-Limited Triplet Emerges as a Potential Standard in Relapsed/Refractory CLL

Paul M. Barr, MD

The time-limited triplet of umbralisib, ublituximab, and venetoclax (Venclexta) could potentially become a standard of care for patients with relapsed/refractory chronic lymphocytic leukemia (CLL) who have progressed on frontline BTK inhibition, according to Paul M. Barr, MD.

In a phase 1/2 dose-escalation trial, the regimen led to a high rate of undetectable minimal residual disease (uMRD) and complete responses (CRs) in patients with relapsed/refractory CLL.

Results showed that the objective response rate (ORR) was 100%, and the CR rate was 44% at the end of 1 year of treatment. All patients had uMRD in the peripheral blood, and 78% had MRD negativity in the bone marrow. At a median follow-up of 6.4 months (range, 0.7-19.0+), no patients had progressed.

In terms of safety, there were no cases of clinical or laboratory tumor lysis syndrome (TLS) because patients had been adequately debulked with a lead-in of ublituximab and umbralisib. The most common grade 3/4 adverse events (AEs) included neutropenia (19%), leukopenia (15%), and infusion reaction (7%).

“We hope this regimen could help us build on venetoclax in the relapsed/refractory setting. If we see lasting MRD-undetectable remissions in a larger number of patients, the regimen could become a standard of care for patients who have progressed through BTK inhibitors,” Barr said.

To that end, study investigators have expanded the trial to include patients with Richter’s transformation and mantle cell lymphoma (MCL; NCT03379051), and launched the phase 2 ULTRA-V trial (NCT03801525), which will evaluate the safety and efficacy of the triplet regimen in patients with treatment-naïve and relapsed/refractory CLL.

In an interview with OncLive, Barr, an associate professor and medical director, Cancer Center Clinical Trials Office, Department of Medicine, Wilmot Cancer Institute, University of Rochester, discussed the findings from the phase 1/2 trial and the evolution toward triplet therapies in CLL.

OncLive: Could you provide a rationale for the study?

Barr: This study was developed in light of the responses we had seen early on with venetoclax. [Venetoclax] is an oral agent that provides very deep remissions compared with a lot of the other single agents we’re using. We wanted to evaluate whether we could build on those responses [with triplet therapy]. We also wanted to determine whether we could do so with a novel class of drugs that don’t get a whole lot of use—–the PI3K inhibitors. Umbralisib is a PI3K-delta inhibitor that seems to be better tolerated than others in its class.

We used umbralisib and its partner anti-CD20 antibody, ublituximab, to debulk patients to protect them from venetoclax-associated tumor lysis. When we added venetoclax, we hypothesized that a relatively short duration of this 3-drug regimen would provide deep MRD undetectable remissions.

How was the trial designed and what methods were used?

Patients received 3 cycles of induction with umbralisib/ublituximab. They underwent tumor lysis evaluations before and after that. Venetoclax was ramped up in the typical fashion. Patients received 9 additional cycles of venetoclax and umbralisib for a total of 12 cycles for just under 1 year. [Once patients completed treatment], we did full response assessments, including CT scans, bone marrow biopsy, and MRD testing.

What did the results show?

We focused on the 9 patients that completed 12 months of treatment in the phase 1 cohort and presented preliminary data on patients in the phase 2 cohort. Overall, the regimen is very well tolerated. There are, as there are with most treatments, some AEs. However, they were of relatively low grade. The gastrointestinal effects were low grade and the cytopenias were mild for the most part. We didn’t see any tumor lysis events; no TLS or laboratory tumor lysis [was found] because patients had been adequately debulked.

We were very encouraged by the early efficacy. The first 9 patients completed the 12 cycles of therapy. At the end of therapy, 4 of these patients were in a CR. The MRD testing in the peripheral blood showed that all 9 patients had undetectable MRD, and 7 had undetectable MRD in the bone marrow. We’re encouraged, and we’re continuing to treat and enroll patients with CLL. We have expanded the study to test the regimen in patients with Richter’s transformation, as well as MCL.

What are the next steps?

We still need to follow patients further. Further discussion will help dictate where this regimen should be tested further, whether that’s in the first-line setting remains to be seen. At the very least, the data look very promising for use in this specific population with relapsed/refractory disease.

As venetoclax is becoming a standard part of the treatment algorithm and based on other data, we expect that ublituximab/umbralisib will be approved in the months or year to come. This combination could warrant further use, depending on what the long-term outcomes look like. A larger study will be investigating the 3-drug triplet in the national ULTRA-V study; that trial is open and is accruing. There are a lot more data to come with this regimen.

What is the role of MRD testing in CLL?

We still have a lot of work to do with MRD. I primarily consider it a research tool at this point. It’s not something we want to use across the board outside of a clinical trial setting. In this study, we used the European Research Consortium standard flow cytometry with a sensitivity of 10^-4. For most studies, that’s the technique where we get the most data. Nonetheless, next-generation sequencing is very promising and provides a deeper level of sensitivity. This is a first look at what this regimen can do using the standard flow cytometry-based assay. Certainly, more work needs to be done before this is an accepted standard.

Could you speak to the emergence of triplet therapies in CLL?

We are certainly seeing an abundance of combinations with all these new agents, and rightfully so. We’re seeing the largest amount of data with some of the same strategies we used in our study with BCR signaling inhibition, BCL-2 inhibition, and [sometimes in combination with] a CD20-directed antibody.

There are a variety of regimens. There are trials investigating ibrutinib (Imbruvica) with venetoclax, and a CD20-directed antibody, such as obinutuzumab (Gazyva). We also started to see data with acalabrutinib (Calquence), venetoclax, and obinutuzumab. To date, we have seen responses and MRD results at the end of the treatment.

Some of these studies have a defined treatment period, and some studies are asking whether MRD can be used to direct therapy. Thus far, we are seeing a high level of CRs and MRD undetectable disease. The question is, “What is the progression-free survival? What’s the duration of disease control?” It’s too early to say right now, but as these studies mature, we’re going to get a better idea of which of these doublets or triplets will change practice as well as which patients are going to be best served with these combination therapies. Right now, it’s early, but given the responses we’re seeing, it’s very encouraging.

Is the CLL paradigm headed in a similar direction as multiple myeloma, in that there are multidrug combinations being explored?

I think that’s a fair analogy. In the old days, multiple myeloma was treated heavily with chemotherapy. Now, there are novel agents that have certainly demonstrated better tolerability and better efficacy. Now, there’s an abundance of novel agents that are being combined in different ways.

We’re making a similar transition in CLL. However, chemotherapy worked pretty well [in CLL]. It’s still fair to say that patients were served well with fludarabine/cyclophosphamide/rituximab (Rituxan) and bendamustine/rituximab. However, based on recent randomized studies, we’re seeing better outcomes in terms of tolerability, disease control, and even overall survival with the novel agents. Building novel combinations similar to myeloma is kind of like starting from scratch.

Barr P, Hill BT, Ma S, et al. A phase 1/2 study of umbralisib ublituximab and venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia. Blood. 2019;134(suppl_1; abstr 360). doi:10.1182/blood-2019-123404