Conference Correspondent

Acalabrutinib Monotherapy in Patients with Relapsed/Refractory CLL: Updated Results from the Phase 1/2 ACE-CL-001 Study

Conference Correspondent - ASH 2017 - CLL

Targeted inhibition of Bruton’s tyrosine kinase (BTK) has greatly improved the clinical outcomes of patients with chronic lymphocytic leukemia (CLL). Although the only approved BTK inhibitor, ibrutinib, is highly effective in CLL, off-target kinase activity may contribute to adverse effects, which are the most common reason for discontinuation in clinical practice.1 Acalabrutinib (ACP-196) is a highly selective, potent, covalent BTK inhibitor in development for hematologic malignancies. A promising safety and efficacy profile was previously reported for acalabrutinib in patients with relapsed/refractory (R/R) CLL/small lymphocytic lymphoma (SLL), including those with high-risk disease, in the ongoing phase 1/2 ACE-CL-001 study.2 At ASH 2017, the authors presented an updated analysis of safety and efficacy in this cohort, which is now fully enrolled.3

Patients with confirmed CLL/SLL who had relapsed after or were refractory to ≥1 prior treatments were treated with oral acalabrutinib in 28-day cycles at 100 mg twice daily until progressive disease or unacceptable toxicity. The primary end point was safety. Secondary end points included investigator-assessed overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Time to response (TTR) was analyzed as an ad hoc end point. A total of 134 patients (132 with CLL and 2 with SLL) received treatment. Baseline characteristics included Eastern Cooperative Oncology Group performance status ≤1 (97%), bulky lymph nodes ≥5 cm (39%), del(17) (23%), del(11) (18%), unmutated IGHV (73%), and beta-2 microglobulin >3.5 mg/L (75%). The median time on study and follow-up was 24.5 months.

ORR (complete response [CR] + partial response [PR]) was 87%, and ORR including PR with lymphocytosis was 93%; 3% of patients achieved CR. The median TTR was 5.3 months. The median DOR was not reached; the 18-month DOR rate was 88%. The median PFS was also not reached, and the 18-month PFS rate was 90%.

ORRs were consistent across high-risk subgroups of del(17) (24/27 [89%]), del(11) (19/21 [90%]), and unmutated IGHV (73/81 [90%]). In patients with del(17) or del(11), median DOR and PFS were not reached, and the 18-month PFS rates were 80% and 100%, respectively.

The most common adverse events (AEs; ≥20%) of any grade were diarrhea, headache, upper respiratory tract infection, fatigue, nausea, cough, arthralgia, pyrexia, contusion, weight increase, petechiae, and constipation. Grade 3/4 AEs (≥5% of patients) were infrequent, and included neutropenia and pneumonia. Other AEs of interest (any grade/grade ≥3) included hypertension and atrial fibrillation, as well as 1 grade ≥3 bleeding event (epistaxis). Seven patients died on treatment secondary to pneumonia, candida sepsis, congestive heart failure, and plasmablastic lymphoma. Richter’s transformation occurred in 4 patients (3%). Most patients (78%) remain on treatment.

In this analysis, the authors concluded that treatment with acalabrutinib results in high response rates and durable remissions in patients with R/R CLL/SLL, including those with high-risk disease. Reported AEs indicate a tolerable safety profile. Treatment with acalabrutinib is being investigated in patients with R/R CLL in 3 ongoing phase 3 studies.


  1. Mato AR, et al. Ann Oncol. 2017;28:1050-1056.
  2. Byrd JC, et al. N Engl J Med. 2016;374:323-332.
  3. Byrd JC, et al. ASH 2017. Abstract 498.
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