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
Mené dans 4 pays sur 25 patients atteints d'une leucémie lymphoïde chronique s'étant transformée en lymphome à grandes cellules B (syndrome de Richter), cet essai de phase I/II évalue la dose maximale tolérée de l'acalabrutinib en monothérapie et analyse ses caractéristiques pharmacocinétiques, puis évalue son efficacité, du point de vue du taux de réponse globale, de la durée de la réponse et de la survie sans progression
Résumé en anglais
Background : 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.
Methods : 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 CooperativeOncology Group performance status ≤2) were assigned to receive oral acalabrutinib200 mg twice daily as monotherapy until disease progression or toxicity. Patientswere 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-treatedpopulation (patients who received ≥1 dose), and activity was assessed in the all-treatedpopulation (for progression-free survival) and efficacy-evaluable population (forresponse rate; patients in the all-treated population with ≥1 response assessmentafter the first dose). This trial is registered with ClinicalTrials.gov (NCT02029443).
Findings : 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 (March1, 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 lastacalabrutinib dose; none was considered treatment-related. Acalabrutinib was rapidlyabsorbed and eliminated, with similar day 1 and day 8 exposures. The overall responserate was 40·0% (95% CI 21·1–61·3), with two (8%) of 25 patients having a completeresponse 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 overallcohort was 3·2 months (95% CI 1·8–4·0).
Interpretation : Acalabrutinib appears to be generally well tolerated, although progression-free survival was relatively poor in this cohort of patients with Richter transformation. On thebasis of these findings, the use of acalabrutinib monotherapy in this setting is limited;however, further assessment of acalabrutinib as part of combination-based regimensfor patients with Richter transformation is warranted.
