AMSTERDAM — A new drug is making its mark in the treatment of chronic lymphocytic leukemia (CLL) — acalabrutinib (Calquence, AstraZeneca).

At present, this drug is approved for use in mantle cell lymphoma, but new clinical data for CLL pave the way for a new indication.

Late-breaking results from the phase 3 ASCEND trial show that acalabrutinib as monotherapy yields significant improvement in tolerability as well as in progression-free survival when compared to standard treatment regimens.

"The ASCEND study demonstrated that acalabrutinib can provide a more effective and tolerable treatment option for patients with relapsed/refractory CLL compared to the standard combination therapies, including chemo-free approaches such as idelalisib plus rituximab," first author Paolo Ghia, MD, a professor of medical oncology at the Università Vita-Salute San Raffaele, Milan, Italy, told Medscape Medical News.

"These data may change the current practice of how we treat patients with relapsed or refractory disease," he said.

The findings were presented here at the European Hematology Association (EHA) 2019 Annual Meeting.

Despite high response rates to the effective chemo-free regimens that are currently available for CLL, nearly all patients eventually experience relapse and require additional treatment, Ghia noted.

Two standard therapy regimens for relapsed/refractory CLL — bendamustine plus rituximab and idelalisib plus rituximab — have overall response rates of 45% to 84%; however, median progression-free survival rates range from 14 to 19 months.

Acalabrutinib, a second-generation Bruton tyrosine kinase (BTK) inhibitor, has unique properties that may help improve upon those rates, Ghia noted.

"Acalabrutinib is more selective for Bruton tyrosine kinase, with less off-target inhibition compared with ibrutinib in vitro," he said. He noted that an ongoing study is comparing acalabrutinib and ibrutinib head to head, with each agent given as monotherapy.

Encouraging Data

Approached for comment, Kanti Rai, MD, director of the CLL Research Program and professor of medicine and molecular medicine, Hofstra North Shore–LIJ School of Medicine, Hempstead, New York, said the study is encouraging.

"I think it's a very good, prospective study and an appropriate comparison. It is quite clear that these early results are in favor of the new drug in the treatment of CLL," he told Medscape Medical News.

"The investigators' primary goal was to improve the progression-free survival, and that is where these data convincingly demonstrate superiority of the new drug compared to the comparator arm."

Key developments to be watched include the longer-term results, Rai added.

"The caveat is that whether in the longer follow-up, these results will also translate into survival advantage, because the study allowed a crossover from one arm to acalabrutinib arm; therefore, the survival advantage may never be convincingly provable," he noted.

"Nevertheless, in my opinion, the investigators have demonstrated that, toxicity-wise, this drug is better than the comparators," he said.

Rai said that in treating patients with acalabrutinib, he has found that the occurrence of headache, which is the primary side effect with acalabrutinib, is usually not serious.

"In my own experience with other patients in clinical practice, I find that headache is complained about by many patients when we start this drug, but it is very minor, and acetaminophen types of treatment successfully improve it, and with continued use, the headache eventually is no longer a problem.

"So I think that overall, this is an encouraging step forward," he said.

Study Details

The ASCEND trial is the first randomized study to compare a BTK inhibitor as monotherapy with either standard chemoimmunotherapy (bendamustine with rituximab) or the chemotherapy-free combination of idelalisib plus rituximab.

For the study, 310 patients with relapsed/refractory CLL were randomly assigned in a 1:1 ratio to receive treatment with either 100-mg oral acalabrutinib twice daily until disease progression (n = 155), or the physician's choice of either idelalisib (150 mg orally twice daily in combination with up to eight IV infusions of rituximab) (n= 119) or bendamustine (70 mg/m2 IV on days 1 and 2 of each cycle combined with rituximab on day 1 of each 28-day cycle for up to six cycles) (n = 36).

The median age of the patients was 67 years (range, 32 – 90 years); 16% had del(17p) status, 27% had del(11q) status, and 42% had Rai stage III/IV CLL.

Those in the acalabrutinib group had received a median of one prior therapy (range, one to eight). Patients in the idelalisib/bendamustine groups had received a median of two prior therapies (range, two to 10).

With regard to tolerability, 11% of the patients who received acalabrutinib discontinued the study because of adverse events, compared to 49% of patients who received idelalisib, 12% of patients who received rituximab with idelalisib, 11% of those who received bendamustine, and 17% of those who received rituximab with bendamustine.

Progression-free survival, which was an endpoint for the study, was significantly improved for the patients who received acalabrutinib compared to the patients in the idelalisib/bendamustine groups (hazard ratio, 0.31; P < .0001). There was a 69% improvement in the risk for progression or death. The median follow-up was 16.1 months.

The progression-free survival rates at 12 months were 88% with acalabrutinib, compared to 68% with idelalisib/bendamustine. The improvement was seen across subgroups, including patients with higher-risk disease stage and mutation status.

"After 1 year, the difference with acalabrutinib was already quite obvious," Ghia said.

The overall response rates between the acalabrutinib group and the idelalisib/bendamustine groups were not significantly different (81% vs 75%, respectively; P < .22). Mean 12-month overall survival rates were also similar (94% and 91%, with 15 and 18 deaths, respectively, for acalabrutinib and idelalisib/bendamustine).

Of patients randomly assigned to receive idelalisib/bendamustine, 51% who had documented disease progression subsequently crossed over to receive acalabrutinib monotherapy.

The most common adverse event with acalabrutinib was headache (22%), which occurred in 6% of the patients who received idelalisib and none of the patients given bendamustine.

"Headache is a side effect, but it's usually very transient, and patients don't even need anything to treat it," Ghia said.

Rates of atrial fibrillation were not significantly different in the treatment arms, Ghia noted. Atrial fibrillation occurred in 5.2% of the patients who received acalabrutinib, vs 3.3% of those in the idelalisib/bendamustine arms. Atrial fibrillation of grade 3 or higher occurred in 1% of acalabrutinib patients (n = 1), 1% of idelalisib patients, and 3% of bendamustine patients.

Neutropenia was less common, occurring in 19% of acalabrutinib patients, compared to 45% of idelalisib and 34% of bendamustine patients. Diarrhea occurred in 18% of acalabrutinib patients, vs 47% of idelalisib patients and 14% of bendamustine patients.

Anemia occurred in 15% of those receiving acalabrutinib, 9% of those given idelalisib, and 6% of bendamustine patients.

"We were very happy to see a safety profile from this study that compares very favorably with similar studies in relapsed/refractory CLL in terms of bleeding, atrial fibrillation, arthralgia/myalgia, neutropenia, fatigue, and diarrhea," Ghia told Medscape Medical News.

The study was sponsored by Acerta Pharma. Ghia is a consultant/advisor for and has received honoraria from AbbVie, AstraZeneca, BeiGene, Celgene, Gilead Sciences, Janssen R&D and Sunesis Pharmaceuticals. Rai has disclosed no relevant financial relationships.

European Hematology Association (EHA) 2019 Annual Meeting: Abstract LB2606. Presented June 16, 2019.

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