Single-Agent Acalabrutinib Improves Survival in Relapsed/Refractory Chronic Lymphocytic Leukemia

According to results from the phase III ASCEND trial, treatment with acalabrutinib as a single agent improved progression-free survival (PFS) compared with idelalisib or bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). The second-generation tyrosine kinase inhibitor also appeared to have a better safety profile than the other regimens.

Lead author Paolo Ghia, MD, PhD, from the Vita-Salute San Raffaele University in Milan, Italy, presented the findings as a late-breaking abstract at the 24th Congress of the European Hematology Association.

“This is a very exciting period for this disease because we have a number of novel drugs – chemotherapy-free drugs – that have been approved and that are under development; however, still we are not able to cure the disease,” Dr. Ghia said during a press briefing at the meeting.

ASCEND was a randomized, multicenter, open-label study that enrolled patients who had CLL that was relapsed or refractory to at least one prior systemic therapy. A total of 310 patients were stratified by del17p status, Eastern Cooperative Group performance status, and prior lines of therapy. Patients were then randomized 1:1 to receive either:

  • acalabrutinib 100 mg twice daily (n=155)
  • rituximab plus investigator’s choice of idelalisib 150 mg twice daily (n=119) or
  • bendamustine 70 mg/m2 (n=36)

Treatment continued until disease progression or unacceptable toxicity.
Median age in the entire population was 67 years (range = 32-90 years), and the median number of prior therapies was one (range = 1-8) in the acalabrutinib group and two (range = 1-10) in the investigator’s-choice group.

At a median follow-up of 16.1 months (range not reported), 11% of acalabrutinib-treated patients discontinued treatment due to adverse events (AEs); AE rates appeared to be lower than in the other groups: In those who received the idelalisib combination, 49% of patients discontinued idelalisib and 12% discontinued rituximab; in those who received bendamustine, 11% discontinued bendamustine and 17% discontinued rituximab. P values for comparisons were not reported.

During the study, 23% of patients who were randomized to investigator’s choice of treatment eventually crossed over to the acalabrutinib arm.

Headache was the most commonly reported any-grade AE in the acalabrutinib group, affecting 22% of participants, but Dr. Ghia noted that headache was “self-resolving.”

The most common grade ≥3 AEs in each treatment group were as follows:

  • acalabrutinib: neutropenia (16%), anemia (12%), and pneumonia (5%)
  • idelalisib: neutropenia (40%) and diarrhea (24%)
  • bendamustine: neutropenia (31%), anemia (9%), and constipation (6%)

The researchers noted that AEs of interest appeared to be more common in the acalabrutinib group, as well, though p values were not provided:

  • atrial fibrillation (5.2% with acalabrutinib vs. 3.3% with investigator’s choice)
  • bleeding (including major hemorrhage; 26% vs. 7.2%)
  • second primary malignancies (6.5% vs. 2.6%)

Single-agent acalabrutinib significantly prolonged median PFS, the study’s primary endpoint, compared with idelalisib or bendamustine combinations (not reached vs. 16.5 months; p<0.0001). This represented a 69% reduction in the risk of disease progression or death (hazard ratio = 0.31; 95% CI 0.20-0.49; p<0.0001).

Rates of PFS at 12 months appeared to be higher in the acalabrutinib group (88% vs. 68%; p value not reported). Overall survival at 12 months appeared to be similar, although p values were not reported for this comparison (94% vs. 91%).

The PFS benefit with acalabrutinib was seen across subgroups, including in patients with del17p and TP53 mutations, the investigators added.

Acalabrutinib also was associated with a higher overall response rate, as well as more durable responses, than investigator’s choice of treatment (81% vs. 76%; median duration of response = not reached vs. 13.6 months; p<0.0001).

Together, these results suggest that single-agent acalabrutinib significantly improves PFS, possibly with less toxicity, compared with idelalisib or bendamustine and rituximab in this patient population. However, these results are limited by potential bias in treatment selection.

The authors report no relevant conflicts of interest.


Ghia P, Pluta A, Wach M, et al. ASCEND phase 3 study of acalabrutinib vs investigator’s choice of rituximab plus idelalisib (IDR) or bendamustine (BR) in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Abstract #LB2606. Presented at the 24th European Hematology Association Annual Congress, June 16, 2019; Amsterdam, The Netherlands.