Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results

Abstract

Therapeutic targeting of Bruton tyrosine kinase (BTK) has dramatically improved survival outcomes for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Acalabrutinib is an oral, highly selective BTK inhibitor that allows for twice-daily dosing due to its selectivity. In this phase 1b/2 study, 134 patients with relapsed/refractory CLL or SLL (median age, 66 years [range, 42-85 years]; median prior therapies, 2 [range, 1-13]) received acalabrutinib 100 mg twice daily for a median of 41 months (range, 0.2-58 months). Median trough BTK occupancy at steady state was 97%. Most adverse events (AEs) were mild or moderate, and were most commonly diarrhea (52%) and headache (51%). Grade ≥3 AEs (occurring in ≥5% of patients) were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; 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). Median duration of response and progression-free survival (PFS) have not been reached; the estimated 45-month PFS was 62% (95% confidence interval, 51% to 71%). BTK mutation was detected in 6 of 9 patients (67%) at relapse. This updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.

Acalabrutinib plus Obinutuzumab in Treatment-Naïve and Relapsed/Refractory Chronic Lymphocytic Leukemia

“…The reported outcomes in patients with CLL are promising, with an ORR of 93% [including partial response with lymphocytosis (PRL)] and an 18-month PFS rate of 90% (95% CI, 83%-94%; ref. 18). The high selectivity of acalabrutinib may reduce the likelihood of off-target effects leading to toxicity.…”

“…The high selectivity of acalabrutinib may reduce the likelihood of off-target effects leading to toxicity. Although the results of a comparative trial between acalabrutinib and ibrutinib are not yet available, single-agent studies of acalabrutinib have shown lower rates of atrial fibrillation, hypertension, and arthralgias than similar studies with ibrutinib (18,19). In addition, the greater selectivity of acalabrutinib leads to less interference with antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC), as IL2-associated tyrosine kinase (ITK) is not inhibited.…”

Treating Leukemia in the Time of COVID-19

“…Several novel oral targeted therapies are now available, including ibrutinib, acalabrutinib, and venetoclax. The choice of targeted therapy depends on several patient-and disease-related factors [45][46][47][48][49][50]. Ibrutinib and acalabrutinib generally require fewer clinic/laboratory visits at the time of treatment initiation compared with the venetoclax + obinutuzumab regimen.…”

Overcoming Ibrutinib Resistance in Chronic Lymphocytic Leukemia

“…Acalabrutinib (ACP-196) is an oral, highly selective, irreversible and covalent BTK inhibitor which has been proven to inhibit off-target kinases, such as EGFR and ITK, to a lesser extent than ibrutinib [103,104]. In the phase I/II ACE-CL-001 trial (#NCT02029443), acalabrutinib was administered to 134 RR-CLL patients after at least one prior treatment regimen [105]. The ORR reached 85%, and inclusion of partial responses with lymphocytisis (PR-L) increased it to 93%, while the median PFS was not reached.…”