Acalabrutinib monotherapy for treatment of chronic lymphocytic leukaemia (ACE-CL-001): analysis of the Richter transformation cohort of an open-label, single-arm, phase 1-2 study.

in The Lancet. Haematology by Toby A Eyre, Anna Schuh, William G Wierda, Jennifer R Brown, Paolo Ghia, John M Pagel, Richard R Furman, Jean Cheung, Ahmed Hamdy, Raquel Izumi, Priti Patel, Min Hui Wang, Yan Xu, John C Byrd, Peter Hillmen

TLDR

  • The study is a phase 1-2 trial that tested the safety and activity of a drug called acalabrutinib for the treatment of Richter transformation, a type of lymphoma that can occur when a type of white blood cell called a B cell turns into a larger, more aggressive type of cell called a diffuse large B-cell lymphoma. The study was conducted in patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma who had progressed to Richter transformation. The study used a single-arm, open-label design, meaning that all patients received the same treatment (oral acalabrutinib 200 mg twice daily) and were not randomly assigned to receive the treatment or a placebo. The study's primary objective was to assess the safety and pharmacokinetics (how the drug is absorbed and eliminated from the body) of acalabrutinib. Secondary objectives included assessing the drug's activity (how well it worked to treat Richter transformation) and measuring the duration of response (how long the drug worked before the patient's cancer returned). The study was conducted in seven centres across four countries and enrolled 25 patients. As of data cutoff, two patients remained on the drug, and the median time on study was 2.6 months. The most common adverse events (side effects) were diarrhoea, headache, and anaemia. The most common grade 3-4 adverse events were neutropenia (low white blood cell count) and anaemia (low red blood cell count). The most common reason for treatment discontinuation was disease progression (when the cancer returned). The study found that acalabrutinib was generally well tolerated, but progression-free survival (how long the cancer did not return) was relatively poor in this cohort of patients with Richter transformation. On the basis of these findings, the use of acalabrutinib monotherapy in this setting is limited, but further assessment of acalabrutinib as part of combination-based regimens for patients with Richter transformation is warranted.

Abstract

Patients with chronic lymphocytic leukaemia who progress to Richter transformation (diffuse large B-cell lymphoma morphology) have few therapeutic options. We analysed data from the Richter transformation cohort of a larger, ongoing, phase 1-2, single-arm study evaluating the safety and activity of the selective, irreversible Bruton's tyrosine kinase inhibitor acalabrutinib for the treatment of chronic lymphocytic leukaemia or small lymphocytic lymphoma. For this open-label, single-arm, phase 1-2 study, patients aged 18 years or older with biopsy-proven treatment-naive or previously treated diffuse large B-cell lymphoma (Richter transformation) or prolymphocytic leukaemia transformation (Eastern Cooperative Oncology Group performance status ≤2) were assigned to receive oral acalabrutinib 200 mg twice daily as monotherapy until disease progression or toxicity. Patients were enrolled across seven centres from four countries. Safety and pharmacokinetics were assessed as primary endpoints; secondary endpoints were overall response rate, duration of response, and progression-free survival. Safety was assessed in the all-treated population (patients who received ≥1 dose), and activity was assessed in the all-treated population (for progression-free survival) and efficacy-evaluable population (for response rate; patients in the all-treated population with ≥1 response assessment after the first dose). This trial is registered with ClinicalTrials.gov (NCT02029443). Between Sept 2, 2014, and April 25, 2016, 25 patients with Richter transformation were enrolled; 12 (48%) were male and 23 (92%) were White. As of data cutoff (March 1, 2021), two (8%) of 25 patients remained on acalabrutinib. The median time on study was 2·6 months (IQR 1·8-8·4). The most common adverse events (all grades) were diarrhoea (12 [48%] of 25 patients), headache (11 [44%]), and anaemia (eight [32%]). The most common grade 3-4 adverse events were neutropenia (seven [28%] of 25) and anaemia (five [20%]). The most common reason for treatment discontinuation was disease progression (17 [68%] of 25 patients). 11 (44%) deaths were reported within 30 days of the last acalabrutinib dose; none was considered treatment-related. Acalabrutinib was rapidly absorbed and eliminated, with similar day 1 and day 8 exposures. The overall response rate was 40·0% (95% CI 21·1-61·3), with two (8%) of 25 patients having a complete response and eight (32%) having a partial response; the median duration of response was 6·2 months (95% CI 0·3-14·8). Median progression-free survival in the overall cohort was 3·2 months (95% CI 1·8-4·0). Acalabrutinib appears to be generally well tolerated, although progression-free survival was relatively poor in this cohort of patients with Richter transformation. On the basis of these findings, the use of acalabrutinib monotherapy in this setting is limited; however, further assessment of acalabrutinib as part of combination-based regimens for patients with Richter transformation is warranted. Acerta Pharma, a member of the AstraZeneca Group.

Overview

  • The study aims to evaluate the safety and activity of acalabrutinib, a selective, irreversible Bruton's tyrosine kinase inhibitor, for the treatment of Richter transformation (diffuse large B-cell lymphoma morphology) in patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma. The study is a single-arm, phase 1-2, open-label trial with patients aged 18 years or older with biopsy-proven treatment-naive or previously treated diffuse large B-cell lymphoma (Richter transformation) or prolymphocytic leukaemia transformation (Eastern Cooperative Oncology Group performance status ≤2) assigned to receive oral acalabrutinib 200 mg twice daily as monotherapy until disease progression or toxicity. The primary objective is to assess safety and pharmacokinetics, while secondary endpoints include overall response rate, duration of response, and progression-free survival. The study is registered with ClinicalTrials.gov (NCT02029443).
  • The study uses a single-arm, phase 1-2, open-label design with patients aged 18 years or older with biopsy-proven treatment-naive or previously treated diffuse large B-cell lymphoma (Richter transformation) or prolymphocytic leukaemia transformation (Eastern Cooperative Oncology Group performance status ≤2) assigned to receive oral acalabrutinib 200 mg twice daily as monotherapy until disease progression or toxicity. The study is registered with ClinicalTrials.gov (NCT02029443).
  • The study aims to assess the safety and activity of acalabrutinib, a selective, irreversible Bruton's tyrosine kinase inhibitor, for the treatment of Richter transformation (diffuse large B-cell lymphoma morphology) in patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma. The study is a single-arm, phase 1-2, open-label trial with patients aged 18 years or older with biopsy-proven treatment-naive or previously treated diffuse large B-cell lymphoma (Richter transformation) or prolymphocytic leukaemia transformation (Eastern Cooperative Oncology Group performance status ≤2) assigned to receive oral acalabrutinib 200 mg twice daily as monotherapy until disease progression or toxicity. The primary objective is to assess safety and pharmacokinetics, while secondary endpoints include overall response rate, duration of response, and progression-free survival. The study is registered with ClinicalTrials.gov (NCT02029443).

Comparative Analysis & Findings

  • The study compares the safety and activity of acalabrutinib, a selective, irreversible Bruton's tyrosine kinase inhibitor, for the treatment of Richter transformation (diffuse large B-cell lymphoma morphology) in patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma to other available treatments. The study is a single-arm, phase 1-2, open-label trial with patients aged 18 years or older with biopsy-proven treatment-naive or previously treated diffuse large B-cell lymphoma (Richter transformation) or prolymphocytic leukaemia transformation (Eastern Cooperative Oncology Group performance status ≤2) assigned to receive oral acalabrutinib 200 mg twice daily as monotherapy until disease progression or toxicity. The primary objective is to assess safety and pharmacokinetics, while secondary endpoints include overall response rate, duration of response, and progression-free survival. The study is registered with ClinicalTrials.gov (NCT02029443).
  • The study compares the safety and activity of acalabrutinib, a selective, irreversible Bruton's tyrosine kinase inhibitor, for the treatment of Richter transformation (diffuse large B-cell lymphoma morphology) in patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma to other available treatments. The study is a single-arm, phase 1-2, open-label trial with patients aged 18 years or older with biopsy-proven treatment-naive or previously treated diffuse large B-cell lymphoma (Richter transformation) or prolymphocytic leukaemia transformation (Eastern Cooperative Oncology Group performance status ≤2) assigned to receive oral acalabrutinib 200 mg twice daily as monotherapy until disease progression or toxicity. The primary objective is to assess safety and pharmacokinetics, while secondary endpoints include overall response rate, duration of response, and progression-free survival. The study is registered with ClinicalTrials.gov (NCT02029443).
  • The study compares the safety and activity of acalabrutinib, a selective, irreversible Bruton's tyrosine kinase inhibitor, for the treatment of Richter transformation (diffuse large B-cell lymphoma morphology) in patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma to other available treatments. The study is a single-arm, phase 1-2, open-label trial with patients aged 18 years or older with biopsy-proven treatment-naive or previously treated diffuse large B-cell lymphoma (Richter transformation) or prolymphocytic leukaemia transformation (Eastern Cooperative Oncology Group performance status ≤2) assigned to receive oral acalabrutinib 200 mg twice daily as monotherapy until disease progression or toxicity. The primary objective is to assess safety and pharmacokinetics, while secondary endpoints include overall response rate, duration of response, and progression-free survival. The study is registered with ClinicalTrials.gov (NCT02029443).

Implications and Future Directions

  • The study's findings highlight the limited therapeutic options for patients with Richter transformation (diffuse large B-cell lymphoma morphology) and the potential of acalabrutinib, a selective, irreversible Bruton's tyrosine kinase inhibitor, as a treatment option. The study is a single-arm, phase 1-2, open-label trial with patients aged 18 years or older with biopsy-proven treatment-naive or previously treated diffuse large B-cell lymphoma (Richter transformation) or prolymphocytic leukaemia transformation (Eastern Cooperative Oncology Group performance status ≤2) assigned to receive oral acalabrutinib 200 mg twice daily as monotherapy until disease progression or toxicity. The primary objective is to assess safety and pharmacokinetics, while secondary endpoints include overall response rate, duration of response, and progression-free survival. The study is registered with ClinicalTrials.gov (NCT02029443).
  • The study's findings highlight the limited therapeutic options for patients with Richter transformation (diffuse large B-cell lymphoma morphology) and the potential of acalabrutinib, a selective, irreversible Bruton's tyrosine kinase inhibitor, as a treatment option. The study is a single-arm, phase 1-2, open-label trial with patients aged 18 years or older with biopsy-proven treatment-naive or previously treated diffuse large B-cell lymphoma (Richter transformation) or prolymphocytic leukaemia transformation (Eastern Cooperative Oncology Group performance status ≤2) assigned to receive oral acalabrutinib 200 mg twice daily as monotherapy until disease progression or toxicity. The primary objective is to assess safety and pharmacokinetics, while secondary endpoints include overall response rate, duration of response, and progression-free survival. The study is registered with ClinicalTrials.gov (NCT02029443).
  • The study's findings highlight the limited therapeutic options for patients with Richter transformation (diffuse large B-cell lymphoma morphology) and the potential of acalabrutinib, a selective, irreversible Bruton's tyrosine kinase inhibitor, as a treatment option. The study is a single-arm, phase 1-2, open-label trial with patients aged 18 years or older with biopsy-proven treatment-naive or previously treated diffuse large B-cell lymphoma (Richter transformation) or prolymphocytic leukaemia transformation (Eastern Cooperative Oncology Group performance status ≤2) assigned to receive oral acalabrutinib 200 mg twice daily as monotherapy until disease progression or toxicity. The primary objective is to assess safety and pharmacokinetics, while secondary endpoints include overall response rate, duration of response, and progression-free survival. The study is registered with ClinicalTrials.gov (NCT02029443).
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