Acalabrutinib Long-Term Benefit in CLL Captured in Published Data

The benefit of single-agent acalabrutinib continued well over 3 years after treatment initiation in patients with relapsed/refractory chronic lymphocytic leukemia.

The benefit of single-agent acalabrutinib (Calquence) continued well over 3 years after treatment initiation in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to data now published in the journal Blood.1

The long-term follow-up data from the phase I/II ACE-CL-001 study (NCT02029443) showed that median values had yet to be reached for duration of response, event-free survival (EFS), or progression-free survival (PFS) in a 134-patient cohort. The estimated 45-month EFS and PFS were 58% and 62%, respectively. Patients with high-risk characteristics also obtained long-term benefits: del(17p), median PFS of 36 months; complex karyotypes, 33 months; del(11)(q22.3), not yet reached.

Objective responses with the BTK inhibitor occurred in over 90% of patients. Adverse event (AE) rates decreased in frequency over time, and no long-term safety issues emerged.

The FDA approved acalabrutinib in November 2019 for the treatment of adult patients with CLL or small lymphocytic lymphoma, based on data from the phase III ELEVATE-TN and ASCEND trials.

The most recent data from the ELEVATE-TN trial showed that at a median follow-up of 28.3 months, acalabrutinib used in combination with obinutuzumab (Gazyva) led to a 90% reduction in the risk of disease progression or death compared with obinutuzumab plus chlorambucil in treatment-naïve patients with CLL (HR, 0.10; 95% CI, 0.06-0.17; P <.0001).2 The trial also showed that single-agent acalabrutinib also led to a statistically significant benefit in PFS versus obinutuzumab/chlorambucil (HR, 0.20; 95% CI, 0.13-0.30; P <.0001).

In the first-in-human ACE-CL-001 trial of acalabrutinib in patients with relapsed/refractory CLL, eligible patients had received at least 1 prior regimen for CLL. Patients with an increased risk of clotting or bleeding disorders were excluded, as well as those with major cardiovascular disease or advanced heart failure.

During the dose-finding component of the trial, patients received acalabrutinib doses of 100 to 400 mg daily. During the phase II component, patients received 100 mg twice daily. Treatment continued until disease progression or unacceptable toxicity.

The primary objective of the long-term follow-up analysis was to evaluate the durability of response and tolerability of acalabrutinib.

The data showed a median treatment duration of 41 months, and 56% of the patients remained on treatment at data cutoff. The principal reasons for discontinuation were progressive disease (21%), AEs (11%), death (4.5%), and physician decision (4.5%).

The study population had a median age of 66, and men accounted for 74% of the total. Almost half of the patients had bulky disease (39% ≥5 cm; 8% ≥10 cm). The median number of prior therapies was 2 (range, 1-13).

All patients reported at least 1 AE, the most common ones being diarrhea (52%), headache (51%), and upper respiratory tract infection (37%). Grade ≥3 AEs occurred in 66% of patients, the most common being neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%).

Additionally, 13 episodes of atrial fibrillation (AF) occurred in 10 patients, 7 of whom had at least 1 risk factor for AF. Major bleeding occurred in 5% of patients and was grade ≥3 in 3%.

The objective response rate for the 134 patients was 94% with the inclusion of partial response with lymphocytosis (PRL). When response was limited to complete or partial, the overall response rate was 88%. Response rates (including PRL) for high-risk groups ranged between 90% and 95%.

The presence of high-risk characteristics had a variable effect on estimated 42- and 45-month PFS. Patients with del(17p) had a 45-month PFS of 30% versus 74% for those without. Complex karyotype was associated with a 42-month PFS of 45% versus 75% for patients without. PFS did not differ substantially between patients with or without del(11q), at 60% versus 65%, or for patients with or without IGHV mutation (69% vs 58%).

Beyond CLL, acalabrutinib is also approved for the treatment of adult patients with mantle cell lymphoma who have received at least 1 prior therapy.

AstraZeneca, the developer of acalabrutinib, recently announced that the BTK inhibitor is being explored in the CALAVI trial as a treatment for cytokine storm in patients with COVID-19.

Cytokine storm, a type of severe immune overreaction that has presented in severely ill patients with COVID-19, can cause life-threatening respiratory complications. AstraZeneca, the developer of acalabrutinib, explained in a press release3 that clinical data have shown the BTK pathway has a role in the production of inflammatory cytokines, and early clinical results with acalabrutinib suggest that reducing inflammation through BTK inhibition alleviates the severity of respiratory distress caused by COVID-19.

The CALAVI trial is a large, multicenter, international study comprising a 2-part design. In part 1 of the trial patients hospitalized with respiratory complications of COVID-19 who are not on assisted ventilation and not in the ICU will be randomized in a 2:1 ratio to acalabrutinib plus best supportive care (BSC) versus BSC alone. The randomization will be the same in Part 2, but this segment will comprise a cohort of patients in the ICU with more severe respiratory complications. The primary outcome measures are mortality and the need for assisted ventilation.


  1. Byrd JC, Wierda WG, Schuh A, et al. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results. Blood. 2020;135(15):1204-1213. doi: 10.1182/blood.2018884940
  2. Sharman JP, Banerji V, Fogliatto LM, et al. Phase 3 study of acalabrutinib combined with obinutuzumab or alone versus obinutuzumab plus chlorambucil in patients with treatment-naïve chronic lymphocytic leukemia: results from ELEVATE-TN. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, Florida. Abstract 31.
  3. AstraZeneca initiates CALAVI clinical trial with Calquence against COVID-19. Published April 14, 2020. Accessed April 14, 2020.