Acalabrutinib Monotherapy in Patients with Richter Transformation from the Phase 1/2 ACE-CL-001 Clinical Study

Background: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world, with an annual incidence of 4.7 per 100,000 adults. Approximately 5% to 10% of CLL patients develop Richter Transformation (RT), in which CLL transforms into an aggressive lymphoma, most often diffuse large B-cell lymphoma (DLBCL). Prognosis for patients with RT is poor, with median progression-free survival (PFS) of approximately 6 months and median overall survival (OS) of 8 to 10 months (Eyre TA, Br J Haematol 2016). B-cell receptor signaling through Bruton tyrosine kinase (BTK) is one of the essential growth pathways for CLL. Acalabrutinib is a highly selective, potent BTK inhibitor in clinical development for the treatment of hematologic malignancies. Acalabrutinib monotherapy is being evaluated in a Phase 1/2 ACE-CL-001 clinical trial (NCT02029443). Preliminary results are reported for a cohort of patients with RT who were enrolled in ACE-CL-001.

Methods: Eligibility criteria for the RT cohort included biopsy-proven RT, Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2 and age ≥18 years; prior ibrutinib therapy was not an exclusion criterion. Patients with central nervous system involvement of lymphoma were excluded. Patients with RT were treated with acalabrutinib 200 mg twice per day. The primary objective of the study was safety, which was assessed by frequency, severity and attribution of adverse events (AEs). The secondary objective was to determine response rate by investigator assessment. Overall response rate (ORR), PFS, and duration of response (DOR) were calculated. Patients were defined as evaluable for response if they received at least one response assessment after the first dose of study drug and according to established Lugano criteria (Cheson 2014).

Results: A heterogeneous group of 29 patients with RT were enrolled. Results are presented through 01 June 2016. The median age was 66 years (range, 43 to 82), including 18 (62%) patients who were ≥60 years. Six (21%) patients had ECOG PS 2. Median time from initial CLL diagnosis was 5.4 years. Baseline disease characteristics included 4 (14%) patients with presence of B symptom(s), 2 of 24 (8%) with bulky lymph nodes ≥10 cm, and 5 of 24 (21%) with 17p deletion. The median number of prior systemic therapies for RT was 4 (range, 0-9). Twelve (41%) patients had received prior treatment with ibrutinib. The median time on treatment (n=29) was 2.1 months (range, 0 to 10.9), with 8 patients (28%) continuing on treatment at the time of data cutoff. The most common adverse events (AEs) (≥15% of patients) were headache [45%, all Grade (Gr) ≤2], diarrhea (28%, all Gr 1), anemia (24%), fatigue (21%), arthralgia (17%) and back pain (17%). Serious AEs (SAEs) occurred in 15 (52%) patients, with hypercalcemia (10%), fatigue (7%), and acute kidney injury (7%) as SAEs that occurred in ≥2 patients. Grade ≥3 AEs occurred in 59%, with Grade 3/4 AEs that occurred in ≥2 patients being neutropenia, anemia, back pain, hypercalcemia (n=3 each), fatigue, asthenia, and acute kidney injury (n=2 each). There were 10 deaths: 6 due to disease progression, 2 due to AEs (a Grade 5 cerebral abscess and a Grade 5 sepsis- both unrelated to study drug), and 2 of unknown cause. Treatment discontinuations occurred in 21 (72%) patients; causes of discontinuation included progressive disease in 15 (52%), withdrawal by patient in 1 (3%), physician decision in 2 (7%), and death due to progressive disease in 3 (10%). In the efficacy evaluable population (n=21), ORR including partial response (PR) or better was 38%, including complete response (CR) in 3 (14%) and PR in 5 (24%) patients. Among 8 responders (PR or better) the median DOR was 5.7 months (95% CI, 0.3 to 7.5). Two patients had a response of CR and went on to transplant. Among 6 efficacy evaluable patients who previously received ibrutinib, 3 responded (PR or better) to acalabrutinib. Median time to PR or better was 1.8 months (95% CI, 1.4 to 2.1). Stable disease was achieved in 5 (24%) patients. Median PFS was 3.2 months (95% CI, 1.8 to 4.0).

Conclusions: These preliminary data demonstrate that acalabrutinib has promising single-agent activity in RT patients. These results warrant further investigation of acalabrutinib either as monotherapy or in combination with other targeted therapies in this difficult-to-treat patient population.