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Expert Reviews CLL Advances Presented at ASH

Danielle Bucco
Published: Thursday, Apr 05, 2018

Alan Skarbnik, MD
Alan Skarbnik, MD
The 2017 ASH Annual Meeting provided physicians with numerous updates for the treatment of patients with chronic lymphocytic leukemia (CLL), leaving experts to predict what regulatory advances could take place in the near future.

“For the past several years, CLL has been an ever-changing landscape with newer and more effective drugs, so it is interesting to see where the field is headed,” said Alan Skarbnik, MD.

For example, results from the phase III MURANO trial presented at ASH showed that the combination of venetoclax (Venclexta) and rituximab (Rituxan) reduced the risk of disease progression or death by 83% versus bendamustine plus rituximab (BR) in patients with relapsed/refractory CLL (investigator-assessed HR, 0.17; 95% CI, 0.11-0.25; P <.0001). The 2-year progression-free survival (PFS) rates were 84.9% versus 36.3%, and the overall response rates were 93.3% versus 67.7% with the venetoclax regimen versus BR, respectively.

In an interview during the 2018 OncLive® State of the Science SummitTM on Hematologic Malignancies, Skarbnik, staff physician, Department of Bone Marrow Transplant, Department of Lymphoma, John Theurer Cancer Center, shared his insight on the latest updates in CLL presented at the 2017 ASH Annual Meeting.

OncLive®: What is the current state of CLL?

Skarbnik: Newer combinations are coming along improving response rates, survival rates, and PFS rates for patients. We are looking at the evidence suggesting the importance of minimal residual disease (MRD)-negativity in CLL. We can have long-term treatment-free intervals for some patients, but since the novel therapies need to be given continuously, we are looking to stop it earlier.

Can you speak to some of the combination data that were presented at ASH?

The biggest splash at the 2017 ASH Annual Meeting was the MURANO trial. It is a phase III trial for patients with relapsed CLL independent of cytogenetics and they must have had at least 1 chemotherapy-containing line of therapy to be enrolled in the trial. Patients were randomized to either BR, which is one of the standards of care for CLL, or venetoclax plus rituximab. BR was given in the usual fashion for 6 cycles; however, in the venetoclax/rituximab combination, rituximab was given for 6 months—starting after the ramp-up of venetoclax—but venetoclax had a finite therapy time of 2 years. Patients stayed on the drug for 2 years but if they progressed or had an unacceptable toxicity, they stopped sooner. This is different to how venetoclax has been approved, which is continuous until disease progression.

There was a very significant difference in response rates for this patient population. There was a 90% response rate for the venetoclax/rituximab combination versus approximately 70% for the BR arm. More importantly, there was a very significant difference in PFS. The median PFS was not reached for the venetoclax arm and was about 17 months for the BR arm with a very significant P value. In addition, a large portion of the patients receiving venetoclax and rituximab achieved MRD negativity in the peripheral blood. At a 9-month landmark analysis, about 60% of patients achieved this, whereas only 13% of the BR arm achieved MRD-negative status. 

A known, preplanned subset analysis evaluated all patients who achieved MRD-negative status. Everyone who achieved MRD negativity had a much longer PFS. That adds to the importance of achieving that status, and it shows that venetoclax/rituximab is likely a much better choice for patients with relapsed disease because rates of MRD negativity are much higher. It is something that we need to look into further in trials and it may be a goal for oncologists. 

Finally, these patients stopped therapy after 2 years and 90% of patients who were on the venetoclax/rituximab arm have not received any additional therapy at this point. It is a very telling number and it shows that patients who need to be on therapy forever may stop. That may be an attractive approach for patients because many don't want to be on a pill for the rest of their lives. 

Ibrutinib (Imbruvica) has long-term data demonstrating its efficacy. What is the future role of ibrutinib as a single agent or in combination, and which patients are best able to receive it?

One of the downfalls of ibrutinib as a single agent is that although most patients respond to the drug, they don't achieve a complete response to the drug as monotherapy. There was a trial for patients with either high-risk or relapsed disease to either use ibrutinib as a single agent or ibrutinib plus rituximab. The goal was to see improvement in PFS and, although there was a slightly higher rate of CR in the rituximab-containing arm, there was no difference in PFS for those patients. 

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