Paul M. Barr, MD, an associate professor of medicine and director of the Clinical Trials Office at the Wilmot Cancer Institute of the University of Rochester Medical Center, discusses the clinical implications of the long-term results of the phase 3 RESONATE-2 trial (NCT01722487) in chronic lymphocytic leukemia (CLL).

During the 2021 ASCO Annual Meeting, updated findings from the RESONATE-2 trial were presented. The results demonstrated sustained progression-free survival (PFS) and overall survival benefit with frontline ibrutinib (Imbruvica) at a follow-up of up to 7 years in patients with CLL. 

These findings represent the longest follow-up to date from a phase 3 study of first-line BTK inhibitor therapy in CLL , says Barr. Notably, although patients are not yet being cured of their CLL, the long-term disease control that ibrutinib can provide without cumulative or late-onset toxicities is a significant advance in the treatment of patients with this disease, concludes Barr.

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Paul M. Barr, MD, discusses the clinical implications of the long-term results of the phase 3 RESONATE-2 trial in chronic lymphocytic leukemia.



Dr. Barr on the Implications of the Long-Term Results of the RESONATE-2 Trial in CLL 

Paul M. Barr, MD, an associate professor of medicine and director of the Clinical Trials Office at the Wilmot Cancer Institute of the University of Rochester Medical Center, discusses the rationale for the long-term analysis of the phase 3 RESONATE-2 trial (NCT01722487) in chronic lymphocytic leukemia (CLL). 

Initial findings from the RESONATE-2 trial demonstrated superior progression-free survival with ibrutinib (Imbruvica) compared with chlorambucil in patients with previously untreated CLL, says Barr. These findings served as the basis for the March 2016 FDA approval of frontline ibrutinib in this patient population, Barr explains. 

During the 2021 ASCO Annual Meeting, updated findings from the study showed that 47% of patients treated with ibrutinib remained on study treatment at a follow-up of up to 7 years. The primary reasons for treatment discontinuation included unacceptable toxicity in 23% of patients and progressive disease in 12% of patients, concludes Barr. 

Paul M. Barr, MD, discusses the rationale for the long-term analysis of the phase 3 RESONATE-2 trial in chronic lymphocytic leukemia. 


Dr. Barr on the Rationale for the Long-Term Evaluation of the RESONATE-2 Trial in CLL 

Paul M. Barr, MD, an associate professor of medicine and director of the Clinical Trials Office at the Wilmot Cancer Institute of the University of Rochester Medical Center, discusses the next steps of the phase 3 RESONATE-2 trial (NCT01722487) in chronic lymphocytic leukemia (CLL).

During the 2021 ASCO Annual Meeting, updated long-terms findings from the RESONATE-2 trial were presented virtually, demonstrating sustained progression-free survival (PFS) and overall survival benefit with frontline ibrutinib (Imbruvica) in patients with CLL, including those with high-risk genomic features.

Further follow-up of the study is warranted and planned because single-agent ibrutinib is a widely utilized standard of care for the frontline treatment of patients with CLL and the median PFS has not yet been reached, says Barr. 

Additionally, a number of combination studies with ibrutinib plus BCL-2 inhibitors, CD20-directed antibodies, and Akt inhibitors are underway with the hope of achieving deeper remissions in this patient population, Barr explains. Moreover, the goals of combination therapy are to limit the duration of therapy, improve the risk of adverse effects, and prevent resistance to BTK inhibitors, Barr adds. Early data have demonstrated high rates of response, undetectable minimal residual disease, and disease control, concludes Barr.

Paul M. Barr, MD, discusses the next steps of the phase 3 RESONATE-2 trial in chronic lymphocytic leukemia.  



Dr. Barr on the Next Steps of the RESONATE-2 Trial in CLL 

Paul M. Barr, MD, an associate professor of medicine and director of the Clinical Trials Office at the Wilmot Cancer Institute of the University of Rochester Medical Center, discusses the next steps with the combination of umbralisib (Ukoniq), ublituximab, and venetoclax (Venclexta) in chronic lymphocytic leukemia (CLL).

During the 2020 ASH Annual Meeting and Exposition, findings from a phase 1/2 study demonstrated a 100% objective response rate with umbralisib/ublituximab/venetoclax in 27 patients with relapsed/refractory CLL at cycle 12. 

The trial gave rise to the ongoing phase 2 ULTRA-V trial (NCT03801525), which is evaluating the same regimen in patients with CLL but will be administered over 2 years vs 1 year, says Barr. Additionally, patients are not required to have received prior therapy for CLL, Barr explains. 

Taken collectively, the data from these studies will shed light on the utility of 1- and 2-year courses of the triplet regimen with regard to efficacy and safety, concludes Barr. 

Paul M. Barr, MD, discusses the next steps with the combination of umbralisib, ublituximab, and venetoclax in chronic lymphocytic leukemia.   



Dr. Barr on the Next Steps With Umbralisib/Ublituximab/Venetoclax in CLL 

Paul M. Barr, MD, an associate professor of medicine and director of the Clinical Trials Office at the Wilmot Cancer Institute of the University of Rochester Medical Center, discusses the safety profile of umbralisib (Ukoniq) plus ublituximab and venetoclax (Venclexta) in chronic lymphocytic leukemia (CLL).

It was expected that the risk of cytopenias would be high with a combination that consists of a PI3K inhibitor and venetoclax, says Barr. Findings from a phase 1/2 trial showed consistent rates of cytopenias with what was anticipated with the triplet, Barr explains. Additionally, gastrointestinal (GI) adverse effects (AEs) are known toxicities of all 3 agents; however, dose-limiting GI AEs were rare, Barr says. Immune-related AEs, such as colitis and diarrhea, were consistent with the expected toxicities associated with umbralisib, Barr explains. In these cases, holding umbralisib and integrating steroids was helpful for patients, Barr adds.

Notably, no pneumonitis or grade 3 liver function test elevations were observed with the triplet, says Barr. Ultimately, the safety profile of umbralisib/ublituximab/venetoclax was consistent with what is expected from each agent as monotherapy, concludes Barr.

Paul M. Barr, MD, discusses the safety profile of umbralisib plus ublituximab and venetoclax in chronic lymphocytic leukemia.  



Dr. Barr on the Safety Profile of Umbralisib/Ublituximab/Venetoclax in CLL

Paul M. Barr, MD, an associate professor of medicine and director of the Clinical Trials Office at the Wilmot Cancer Institute of the University of Rochester Medical Center, discusses the need to develop novel therapies in chronic lymphocytic leukemia (CLL). 

CLL has welcomed a wealth of novel treatment options into the paradigm in recent years, explains Barr. However, like all therapies, these agents have limitations and can cause significant toxicity for patients with this disease. Additionally, no curative options are currently available for these patients, says Barr. As such, some patients with CLL require the development of additional agents to sufficiently treat and manage their disease. 

At the 2020 ASH Annual Meeting, Barr presented findings from a phase 1/2 trial of umbralisib, ublituximab, and venetoclax (Venclexta) in patients with relapsed/refractory CLL. According to the virtual poster presentation, the regimen was well tolerated and demonstrated encouraging efficacy for patients, including those who were refractory to BTK inhibitors. 

Paul M. Barr, MD, discusses the need to develop novel therapies in chronic lymphocytic leukemia.  



Dr. Barr on the Need to Develop Novel Therapies in CLL 

Paul M. Barr, MD, Wilmot Cancer Institute, University of Rochester, discusses novel combination strategies in chronic lymphocytic leukemia (CLL).

An influx of novel combinations is poised to enter the treatment paradigm of CLL, explains Barr. Specifically, data with BCR signaling inhibitors, BCL-2 inhibitors, and CD20-directed monoclonal antibodies appear promising.

Ongoing clinical trials are investigating potential strategies, such as the combination of ibrutinib (Imbruvica) or acalabrutinib (Calquence) with venetoclax (Venclexta) and a CD20-directed antibody like obinutuzumab (Gazyva), explains Barr.

While some studies have defined treatment periods, others are aiming to determine whether minimal residual disease (MRD) status can be used to direct treatment decisions, says Barr.

Though high complete response and MRD-negative rates with these combinations appear promising, more mature data are needed in order to determine which regimens will change practice, concludes Barr.

Dr. Barr on Novel Combination Strategies in CLL

Paul M. Barr, MD, Wilmot Cancer Institute, University of Rochester, discusses the results of a phase I/II study evaluating the combination of umbralisib, ublituximab, and venetoclax (Venclexta) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL).

At the 2019 ASH Annual Meeting, data from this phase I/II trial were presented. In the phase I portion, 9 patients completed 1 year of treatment. Taken collectively with preliminary data from the phase II portion, investigators found that the regimen was well tolerated. Most of the adverse events were low-grade, says Barr. The majority of cytopenias were mild, and there weren’t any tumor lysis events.

Findings from the phase I portion showed that 4 of 9 patients achieved a complete response after completing 1 year of treatment. All 9 patients achieved undetectable minimal residual disease (MRD) in the peripheral blood, says Barr. Additionally, 7 of 9 patients had undetectable MRD in the bone marrow.

At the time of data cutoff, no patients had progressed. Given the early promise of the regimen, investigators have expanded the study to patients with Richter’s transformation, as well as mantle cell lymphoma.

Paul M. Barr, MD

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