Acalabrutinib Shows More Promise in High-Risk CLL

Acalabrutinib monotherapy continues to yield high response rates and durable remissions in patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including those with high-risk disease, according to a new study.

Targeted inhibition of Bruton tyrosine kinase (BTK) has greatly improved the clinical outcomes of CLL patients. Acalabrutinib, a second-generation, highly selective, potent, covalent BTK inhibitor, showed a promising safety and efficacy profile in patients with relapsed/refractory CLL/SLL, including those with high-risk disease, in an ongoing phase I/II study.

John C. Byrd, MD, of the Ohio State University Comprehensive Cancer Center in Columbus, presented an updated analysis of this fully enrolled cohort of 134 patients at the American Society of Hematology (ASH) Annual Meeting & Exposition (abstract 498).

The 134 patients (132 CLL, 2 SLL), with a median age of 66 years, received oral acalabrutinib in 28-day cycles at 100 to 400 mg daily or 100 to 200 mg twice daily in the dose-escalation phase of the study, and 100 mg twice daily or 200 mg daily (later switched to 100 mg twice daily) in the expansion phase of the study. All patients were treated until progressive disease or unacceptable toxicity.

About three-quarters of the patients were IgVH-unmutated. The median number of prior therapies was two. The median time on study and follow-up were 19.8 months.

The overall response rate (ORR) was 87%, and the ORR including partial response with lymphocytosis was 93%; 3% of patients achieved complete response. ORRs were consistent across high-risk subgroups.

The median time to response was 4.7 months. The median duration of response was not reached; the 18-month duration of response rate was 85%.

The median progression-free survival (PFS) has not yet been reached, and the 18-month PFS rate is 88% and “above 80% in all subgroups,” said Byrd.

The most common adverse events of any grade were headache (46%), diarrhea (43%), upper respiratory tract infection (28%), fatigue (27%), nausea (27%), arthralgia and pyrexia (each 23%), contusion (22%), petechiae (21%), and weight increase (21%). Grade 3/4 adverse events were infrequent, and included neutropenia (11%) and pneumonia (10%). Other adverse events of interest (any grade/grade ≥ 3) included hypertension (11%/3%) and atrial fibrillation (3%/2%). No grade 3 or higher bleeding events occurred.

Most patients (78%) remain on treatment. The primary reasons for treatment discontinuation were adverse events (8%), progressive disease (6%), and death (2%).

Richter transformation occurred in 3 patients at 2, 16, and 16 months, respectively. The most common adverse events leading to discontinuation were pneumonia, anemia, neutropenia, and thrombocytopenia.

In conclusion, Byrd said, “In this updated analysis, treatment with acalabrutinib continues to be associated with high response rates and durable remissions in patients with relapsed/refractory CLL/SLL, including those with high-risk disease. With a median response of 24.5 months, median PFS was not reached, including in patients with del(17p) and del(11q). Reported adverse events with acalabrutinib indicated a tolerable safety profile, including a relatively low rate of grade 3 or higher bleeding and cardiac events.”

Treatment with acalabrutinib is being investigated in patients with treatment-naive and relapsed/refractory CLL in three ongoing phase III studies.