Expert Reviews CLL Advances Presented at ASH

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.

OncLive^®: What is the current state of CLL?

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

In an interview during the 2018 OncLive^® State of the Science Summit^TM 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.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.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.

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?

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. 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.

The advantage of adding rituximab is that patients achieve a CR rate half the time when compared with single-agent ibrutinib. That might be an option for patients who need debulking, have a large tumor burden, and need to make the symptoms better.

There was another trial that combined venetoclax and ibrutinib as a therapy to see the visibility of this approach and whether it is too toxic. Most patients tolerated it well, but we are still waiting on the long-term follow-up results from those patients. There are additional trials using venetoclax and ibrutinib or venetoclax/ibrutinib plus obinutuzumab (Gazyva), so we are waiting for the readout of those trials. We don't have much information on that.

For ibrutinib as a single agent, we have evaluated a large pool of patients from different institutions. Real-world evidence was evaluated from more than 600 patients to see how long they remain on ibrutinib. There is a significant portion of patients who discontinue ibrutinib mainly because of toxicity, which was over 30% of patients in this trial. Patients discontinued mostly because of joint pain or atrial fibrillation.

Different than what has been reported in the past, a proportion of these patients do quite well with or without ibrutinib at that point, depending on how long they remain on the drug. They can be changed to a different drug, or even a BCL-2 inhibitor with a good degree of success in recovery and response rates. The challenge with ibrutinib has been the toxicity. Thus far, it is a drug that has some off-target inhibition of other enzymes to commute to atrial fibrillation and platelet dysfunction, bruising, and bleeding.

With many novel agents emerging, what do you envision the role of chemotherapy becoming?

Newer versions of BTK inhibitors are being evaluated to minimize those toxicities, such as acalabrutinib (Calquence). It has been reported before that it has good response rates as a single agent. There are ongoing trials that have finished accruing comparing acalabrutinib with ibrutinib for relapsed disease, as well as comparing acalabrutinib alone or in combination with obinutuzumab versus obinutuzumab plus chlorambucil, which is one of the standards of care for frontline therapy. We are eagerly awaiting the readout of those trials. The interim analysis should happen by the end of 2018.Chemotherapy certainly has its role for selective patients. In general, I reserve chemotherapy for patients who have a certain cytogenetic profile. They don't have complex cytogenetics and their IGVH molecule is mutated. Those patients seem to have a much better response and a much longer PFS when receiving chemotherapy, especially younger patients who receive fludarabine, cyclophosphamide, and rituximab (FCR). The University of Texas MD Anderson Cancer Center data show that patients who have this particular combination of cytogenetics can have 12-year remissions. I reserve the chemotherapy for this subset of patients. Even for older patients who cannot tolerate FCR, BR may be an option if they meet the cytogenetic criteria.

What is the biggest unmet need in CLL that you would like to see addressed?

For everyone else, I would still do either a clinical trial as my first choice or one of the novel agents if it is a frontline treatment, such as ibrutinib. There is still a role for chemotherapy; however, it is being minimized by the advance of these newer agents. I still have to see the new combinations as they may be more effective than chemotherapy. There are FCR plus ibrutinib data showing that it is a feasible combination; chemotherapy in combination with novel agents may be an even more fruitful approach, so we have to see the long-term data for that. That is not out yet, but it may be on its way.I want CLL to be cured. The idea that CLL is an incurable disease is changing. We see long-term remissions with many patients. We have to find either the right combination of agents or the right sequence of agents to achieve that goal, but it is possible.

Seymour JF, Kipps TJ, Eichhorst BF, et al. Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/ refractory chronic lymphocytic leukemia - results from pre-planned interim analysis of the randomized phase 3 MURANO study. In: Proceedings from the 2017 ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, Georgia. Abstract LBA-2.