| Abstract: |
Background: Richter transformation usually presents as an aggressive diffuse large B-cell lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukaemia, has no approved therapies, and is associated with a poor prognosis. Pirtobrutinib has shown promising efficacy and tolerability in patients with relapsed or refractory B-cell malignancies, including those who progress on covalent Bruton tyrosine kinase (BTK) inhibitors. This study aims to report the safety and activity of pirtobrutinib monotherapy in a subgroup of patients with Richter transformation from the multicentre, open-label, phase 1/2 BRUIN study. Methods: This analysis included adult patients (aged ≥18 years) with histologically confirmed Richter transformation, an Eastern Cooperative Oncology Group performance status score of 0–2, and no limit of previous therapies, with patients receiving first-line treatment added in a protocol amendment (version 9.0, Dec 15, 2021). Pirtobrutinib 200 mg was administered orally once a day in 28-day cycles. The primary endpoint of phase 1 of the BRUIN trial as a whole, which has been previously reported, was to establish the recommended phase 2 dose for pirtobrutinib monotherapy and the phase 2 primary endpoint was overall response rate. Safety and activity were measured in all patients who received at least one dose of pirtobrutinib monotherapy. This BRUIN phase 1/2 trial was registered with ClinicalTrials.gov and is closed to enrolment (NCT03740529). Findings: Between Dec 26, 2019, and July 22, 2022, 82 patients were enrolled, of whom five were enrolled during phase 1 and 77 during phase 2. All but one patient received a starting dose of 200 mg pirtobrutinib once a day as the recommended phase 2 dose. The remaining patient received 150 mg pirtobrutinib once a day, which was not escalated to 200 mg. The median age of patients was 67 years (IQR 59–72). 55 (67%) of 82 patients were male and 27 (33%) were female. Most patients were White (65 [79%] of 82). 74 (90%) of 82 patients received at least one previous Richter transformation-directed therapy. Most patients (61 [74%] of 82) had received previous covalent BTK inhibitor therapy for chronic lymphocytic leukaemia or Richter transformation. The overall response rate was 50·0% (95% CI 38·7–61·3). 11 (13%) of 82 patients had a complete response and 30 (37%) of 82 patients had a partial response. Eight patients with ongoing response electively discontinued pirtobrutinib to undergo stem-cell transplantation. The most common grade 3 or worse adverse event was neutropenia (n=19). There were no treatment-related deaths. Interpretation: Pirtobrutinib shows promising safety and activity among patients with Richter transformation, most of whom received previous Richter transformation-directed therapy, including covalent BTK inhibitors. These data suggest that further investigation is warranted of pirtobrutinib as a treatment option for patients with relapsed or refractory Richter transformation after treatment with a covalent BTK inhibitor. Funding: Loxo Oncology. © 2024 Elsevier Ltd |
| Keywords: |
adult; treatment outcome; aged; aged, 80 and over; middle aged; overall survival; clinical trial; constipation; fatigue; neutropenia; diarrhea; hypertension; monotherapy; progression free survival; infection; phase 2 clinical trial; anemia; basal cell carcinoma; protein kinase inhibitor; bleeding; nausea; thrombocytopenia; stem cell transplantation; pathology; pyrimidines; b lymphocyte; abdominal pain; arthralgia; asthenia; coughing; dyspnea; rash; protein kinase inhibitors; hypoxia; acute kidney failure; dysphagia; heart failure; heart infarction; multicenter study; pancreatitis; pancytopenia; headache; lymphoma, large b-cell, diffuse; blood cell count; phase 1 clinical trial; drug therapy; toxicity; pyrimidine derivative; gastrointestinal disease; atrial fibrillation; disease exacerbation; leukemia, lymphocytic, chronic, b-cell; respiratory failure; sinus bradycardia; bowen disease; lymphocytosis; diffuse large b cell lymphoma; contusion; bruton tyrosine kinase; richter syndrome; very elderly; humans; human; male; female; article; agammaglobulinaemia tyrosine kinase; positron emission tomography-computed tomography; b cell chronic lymphocytic leukemia; bruton tyrosine kinase inhibitor; pirtobrutinib; btk protein, human; b cell malignancy
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