Long-term Data: Acalabrutinib Provides Tolerable, Durable Responses in Relapsed/Refractory CLL


Long-term data from a phase Ib/II trial of the BTK inhibitor acalabrutinib were recently published. Acalabrutinib appears to evoke durable responses with good safety and efficacy.

Acalabrutinib (Calquence) continued to be generally safe and effective in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) on long-term follow-up. Additionally, the BTK inhibitor’s responses were generally durable. These are the key findings from an updated and expanded phase Ib/II trial that was published recently in Blood.1

With a median follow-up of 41 months, 134 patients with relapsed/refractory CLL or SLL received acalabrutinib 100 mg twice daily. They had received a median of 2 prior therapies, and follow-up ranged from 0.2-58 months.

Slightly more than half of patients (56%, n = 75) remained on treatment at data cutoff in January 2019. Among those who discontinued treatment, the main reasons given were progressive disease (21%) and adverse events (AEs; 11%). The median duration of response and progression-free survival (PFS) have not been reached. The estimated 45-month PFS was 62% (95% Confidence Interval [CI], 51% - 71%).

The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%. The authors noted that responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status). BTK mutation was detected in 6 of 9 patients (67%) at relapse.

“As BTK inhibition requires chronic dosing until progression, the importance of long-term tolerability cannot be overstated, especially when treating a disease that occurs in the elderly, such as CLL,” wrote the authors, led by John C. Byrd, MD, of The Ohio State University. “In addition, the favorable AE profile observed with acalabrutinib to date supports combination with other therapeutics for the treatment of CLL.”

This phase Ib/II multicenter study (#NCT02029443) was designed to determine the recommended dose, safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib in patients with R/R CLL. Its efficacy results were published in The New England Journal of Medicine in January 2016.2

Inclusion criteria included a diagnosis of R/R CLL/SLL for which the patient had received at least 1 previous therapy, ECOG performance status of 2 or less, adequate organ function, and absence of active infection. Patients with bone marrow involvement had no restrictions for cytopenia. Exclusion criteria included anticoagulation therapy, bleeding disorders, significant cardiovascular disease. Atrial fibrillation history was not exclusionary.

The median patient age was 66 years (range, 42-85 years); 20% were aged 75 years or older. Nearly half of the patients (49%) had high-risk disease, while 39% had bulky disease, with lymph nodes at least 5 cm in size. Slightly more than two-thirds of patients had cytopenia at baseline. Baseline genomic features included 73% of patients with IGHV unmutated disease, 23% with del(17)(p13.1), 18% with del(11)(q22.3), and 35% with complex karyotype.

Of 17 patients who died during the trial, 10 experienced fatal AEs. All patients reported at least 1 AE, most of which were mild to moderate in severity. The most common were diarrhea (52%), headache (51%), upper respiratory tract infection (37%), and fatigue (34%). Two-thirds of patients (n = 89, 66%) developed AEs of grade 3 or higher. The most common were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Additionally, 23% of patients developed infections of grade 3 or higher.

Among the 10 patients who experienced fatal AEs, 5 died from pneumonia and 1 each died from Candida sepsis, congestive cardiac failure, metastatic lung adenocarcinoma, metastatic prostate cancer, and respiratory failure. The authors observed that the overall frequency of grade 3 or higher events of pneumonia, diarrhea, anemia, neutropenia, and thrombocytopenia decreased the longer the patients remained on acalabrutinib therapy.

A total of 13% of patients (n = 17) discontinued acalabrutinib due to AEs. This included 4 fatal cases of pneumonia, plus 2 events each of anemia (grade 1 and grade 2), neutropenia (both grade 3), and thrombocytopenia (both grade 4); other causes of discontinuation occurred in only 1 patient apiece. Dose reductions and dose interruptions were permitted in this study; about one-fourth of patients experienced dose reductions (27%, n = 36 patients) and included those patients affected by the protocol changes to a uniform dose of 100 mg twice daily. A similar number of patients (n = 33, 25%), experienced AEs that led to treatment interruptions.

The objective response rate (ORR) of 94% (95% CI, 89% - 97%) included 6 patients (4%) with complete response (CR). An additional 112 patients (84%) experienced a partial response (PR). The median duration of response (DOR) was not reached, although the estimated 45-month DOR for PRL or better was 63% (95% CI, 52% - 72%).

The median PFS was not reached for the entire population of treated patients, although the estimated 45-month PFS was 62% (95% CI, 51% - 71%). Nor was median event-free survival (EFS) reached in the overall trial population; the estimated 45-month EFS was 58% (95% CI, 48% - 67%). ORRs by genomic status were comparable to the overall ORR: 95% for patients with IGHV unmutated disease, 95% for patients with del(11)(q22.3), 93% for patients with del(17)(p13.1), and 90% for patients with complex karyotype. Median PFS (95% CI) for patients with del(17)(p13.1) and complex karyotype was 36 months (21 to not estimable) and 33 months (17 to not estimable), respectively. Median PFS was not reached in patients with del(11)(q22.3).

“An ongoing phase 3 study that compares acalabrutinib with standard first-line treatment (NCT02475681) will address the long-term contribution of this agent to the treatment armamentarium for CLL,” Byrd et al wrote. “Several studies are also under way to assess the combination potential of acalabrutinib with other agents, including venetoclax and other targeted therapies for CLL, which ultimately may allow cessation of therapy at an appropriate treatment end point.”


  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).
  2. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323-332.
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