Acalabrutinib Demonstrates Promising Response Rates in CLL

The BTK inhibitor acalabrutinib demonstrated promising reponse rates in patients with newly diagnosed or relapsed/refractory chronic lymphocytic leukemia, according to results from an open-label phase II trial.

Clare Sun, MD

The BTK inhibitor acalabrutinib (Calquence) demonstrated promising reponse rates in patients with newly diagnosed or relapsed/refractory chronic lymphocytic leukemia (CLL), according to results from an open-label phase II trial.

Among 45 efficacy-evaluable patients, responses were seen in 7 treatment-naïve patients who received acalabrutinib at 100 mg BID, as well as 14 of 15 patients with relapsed/refractory disease. Among 23 patients who received 200 mg QD, responses were seen in 7 of 9 treatment-naïve patients and 12 of 14 patients with relapsed/refractory disease.

Both dosages had acceptable toxicity, as no patient required dose delays or modification, and 3 of 48 safety-evaluable patients discontinued treatment because of adverse events (AEs), as reported at the 2018 ASH Annual Meeting.

“The study was not designed to detect a statistically significant difference in clinical outcomes between the dosing groups. Near-complete target coverage (BTK occupancy) was more rapidly achieved with 100 mg BID than 200 mg QD dosing in the lymph node and peripheral blood,” Clare Sun, MD, of the National Heart, Lung, and Blood Institute, and colleagues concluded in a poster presentation.”

“These results support further study of acalabrutinib for the treatment of patients with relapsed/refractory and high-risk treatment-naïve CLL, as well as ongoing trials with the 100 mg BID dose of acalabrutinib,” added Sun.

BTK has a critical role in B-cell receptor signaling and represents a validated treatment target for CLL. Preliminary clinical studies demonstrated promising efficacy and safety for the selective covalent BTK inhibitor acalabrutinib in patients with CLL, including those with high-risk disease. Sun and colleagues reported findings from an ongoing phase II evaluation of acalabrutinib in patients with relapsed/refractory CLL and those with high-risk untreated disease.

The study involved a total of 48 patients, 16 with high-risk previously untreated CLL and 32 with relapsed/refractory disease. The patients were randomized to the 2 different dosing schedules, administered on 28-day cycles, and followed until disease progression or development of unacceptable toxicity.

Investigators defined “high risk” as CLL associated with del(17p) or mutations inTP53orNOTCH. Patients with diagnoses of CLL or small lymphocytic lymphoma were eligible.

The primary endpoint was investigator-assessed overall response rate, including complete response, partial response, and partial response with lymphocytosis. Disease status was assessed at baseline and then day 28 of cycles 2, 6, 12, 24, and 36. Secondary endpoints included safety; BTK occupancy in peripheral cells, lymph nodes, and bone marrow; duration of response; progression-free survival (PFS); and overall survival (OS).

The study population had a median age of 64 (range 45-83), and men accounted for about 70% of the total patient population. Eighteen patients each had bulky lymph nodes and Rai stage III/IV disease, and 20 had β2 microglobulin >3.5 mg/L. All but 2 of the patients had CLL. Assessment of genomic status showed that 35 patients had unmutatedIGHV, 8 had del(17p), 9 hadTP53mutation, and 19 hadNOTCH1mutation.

Treatment with acalabrutinib led to an overall response rate of 89% in the 45 evaluable patients (85% in all 48 enrolled patients), including 96% with the 100 mg BID dosage and 83% with 200 mg QD.

The median duration of response, median PFS, and median OS had yet to be reached. The 18-month duration of response was 95% in the 100 mg BID cohort and 100% in the 200 mg QD group. The 18-month PFS rate was 91% and 94% with the 100 mg BID and 200 mg QD dosage groups, respectively, and 18-month OS rate was 100% among patients who received acalabrutinib at 100 mg BID and 94% for the 200-mg QD group.

The type, frequency, and severity of AEs were similar between the dosage groups. The most common AEs (all grades) were headache (67% in both groups), confusion (63% 100 mg BID, 50% 200 mg QD), diarrhea (42%, 46%, respectively), upper respiratory infection (42% each), maculopapular rash (17%, 46%), cough (33%, all 100 mg BID), arthralgia (30%, 38%), myalgia (29%, 33%), influenza-like illness (25%, 33%), dizziness (25%, 21%), fatigue (25%, 17%), nausea (21%, 33%), petechiae (21%, 29%), nasal congestion (17%, 25%), pyrexia (21% both groups), and peripheral edema (21%, all 200 mg QD).

The only grade 3 AEs were maculopapular rash in 4% of the 200 mg QD cohort and lung infection in 8% of the 100 mg BID group. No grade 4 events occurred in either group.

Serious AEs occurred in 18 (38%) of 48 patients, including grade ≥3 in 13 (27%) patients. AEs leading to discontinuation consisted of one case each of hepatocellular injury, lung adenocarcinoma, and myelodysplastic syndrome.


Sun CC, Nierman P, Ahn IE, et al. Acalabrutinib in patients with relapsed/refractory (R/R) and high-risk, treatment-naive (TN) chronic lymphocytic leukemia (CLL). Presented at: ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, California. Abstract 4424.