Acalabrutinib Among Exciting Options Emerging in CLL

Jacqueline Claudia Barrientos, MD

Ibrutinib (Imbruvica) has significantly changed the treatment landscape for patients with chronic lymphocytic leukemia (CLL). However, researchers have hope for another BTK inhibitor, acalabrutinib (Calquence), and are investigating the regimens in a head-to-head phase III study (NCT02477696; ACE-CL-006).

This randomized trial is designed to evaluate the progression-free survival (PFS) of acalabrutinib versus ibrutinib in patients with previously treated CLL. This trial is currently recruiting patients and will expect to see results in 2019.

“We are eager to see the results from this trial because it would be practice changing for a drug to have a better response rate and remission duration than ibrutinib,” said Jacqueline Claudia Barrientos, MD.

OncLive: What is the excitement with acalabrutinib? What potential could this have for patients with CLL?

In an interview with OncLive, Barrientos, an associate professor at The Feinstein Institute for Medical Research at Northwell Health, discussed emerging treatment options in CLL.Barrientos: There was a trial that was presented at the 2016 ASH Annual Meeting for patients who no longer take ibrutinib because they have intolerance. That is one of the approaches to take with this regimen. It would be off-label because there is no current FDA approval for CLL yet. However, ibrutinib was first approved in mantle cell lymphoma (MCL), then the approval came for patients with CLL who harbored a 17p deletion, followed by a full approval for relapsed/refractory patients with CLL, and then in the frontline setting. My guess is that it will be the same for acalabrutinib.

How would you describe the impact of ibrutinib on the treatment landscape for CLL?

There is a phase III study that has completed accrual for patients with high-risk CLL. It studied acalabrutinib versus ibrutinib, which has not been done before. We are eager to see the results from this trial because it would be practice changing for a drug to have a better response rate and remission duration than ibrutinib. However, until the phase III trial data comes out, we cannot say it is the new and improved drug because we do not know. It could have a better response rate but, if the remission duration is not as good, then it is not the same. I am cautiously optimistic that it is promising. We already have 5-year long-term follow-up with ibrutinib, which will be hard to beat.It has changed the way we practice. Currently, it is the most commonly prescribed drug for patients with CLL as well as those with other [hematologic] malignancies.

What is your typical go-to approach for patients who progress on ibrutinib?

What else can be said regarding these more targeted frontline options for patients with CLL?

However, it is important to recognize that, with time, some of our patients will stop responding so there may be an issue with salvage therapy. We are investigating that. Venetoclax is one drug that we can use for patients needing salvage therapy who have stopped responding to ibrutinib. It has seen good response rates following ibrutinib failure.There are other options, but they have not been tested yet or presented in clinical trials. Many patients have responded to idelalisib (Zydelig) in my practice. There were data combined from several centers, which stated that the best outcomes were venetoclax or idelalisib for patients who stopped responding to ibrutinib because chemotherapy will not work. It reflects that many of these patients were already refractory to chemotherapy. It is possible to give chemotherapy to those patients who had never received it because they might respond. We have not tested this yet. However, for patients who are refractory to chemotherapy and then receive ibrutinib, chemotherapy will not be an option.Ibrutinib can be given in the frontline setting. It is on-label by the FDA regardless of age, especially for patients with 17p deletion.

Venetoclax can be given frontline but it would be an off-label indication. I would assume those who would receive venetoclax are patients with 17p deletion who have a history of intracranial hemorrhages since ibrutinib can put patients at high risk for that. However, it is not yet approved.

Idelalisib could not be given as a frontline therapy. Every time that it has been tested in the frontline setting, patients would see too many grade 3/4 adverse events. Investigators have stated that liver enzymes could go up to 4000 in 1 day following treatment with idelalisib in this setting. This is a significant amount as it is usually only 100 at most. This is hard to control. Idelalisib has clinical activity, but the toxicities are difficult to manage and the benefits are not worth the risks in the frontline setting.