{"doi":"10.1111/bjh.18558","title":"Cardiac toxicity in a pilot study of duvelisib and ibrutinib combination therapy for chronic lymphocytic leukaemia","abstract":"Bruton tyrosine kinase inhibitor (BTKi), ibrutinib, and B-cell lymphoma 2 inhibitor, venetoclax, have revolutionized the treatment of chronic lymphocytic leukaemia (CLL). Compared to prior chemoimmunotherapy regimens, ibrutinib improved progression-free survival (PFS) and overall survival (OS) in both treatment-naïve and relapsed/refractory (R/R) settings.1 Similarly, venetoclax in combination with anti-CD20 monoclonal antibodies has shown excellent PFS outcomes.1 While the phase 3 MURANO trial showed an overall response rate (ORR) of 92.3% to venetoclax–rituximab in patients with R/R CLL, almost no participants had previously received a BTKi.2 A study of venetoclax in patients previously treated with ibrutinib showed a more modest ORR of 65%.3 To address the need for alternative therapy in relapsed CLL after BTKi, we performed an investigator-initiated, single-centre, open-label phase 2 study of duvelisib, a dual-inhibitor of PI3Kδ and PI3Kγ, in patients with progressive disease (PD) or BTK or PLCG2 mutations on ibrutinib. This study was designed with a lead-in period of combined therapy with duvelisib and ibrutinib to minimize the risk of tumour flare syndrome, commonly seen upon discontinuation of BTKi,4 and to assess the efficacy and safety of the combination. Duvelisib 15 mg twice daily was given in 28-day cycles. Ibrutinib was continued at the patient's dose prior to study entry for the first six cycles, followed by duvelisib monotherapy until progression or intolerance. Additional protocol details are provided in the Supporting Information . The primary end-point of the study was ORR. Secondary objectives included the safety of duvelisib–ibrutinib combination therapy and of duvelisib monotherapy. The study was approved by the NIH intramural institutional review board (IRB) (ClinicalTrials.gov NCT04209621). All patients provided written informed consent. A total of three patients enrolled between 31 July 2020 and 28 August 2020 (Table 1). Shortly after beginning enrolment, the study was stopped due to a sudden death and development of significant burden of ventricular ectopy in a second patient. These events are described herein. Patient #1 was a 68-year-old male with CLL PD after treatment with ibrutinib for three years. Baseline electrocardiogram (EKG) and echocardiogram were normal. After completing cycle 1 of duvelisib–ibrutinib, he reported nighttime palpitations. Subsequent EKG showed sinus bradycardia (heart rate of 58 beats per minute) and premature atrial complexes, at which time ambulatory EKG was planned. Prior to completion of the prescribed monitoring, the patient was found unresponsive in bed on cycle 2 day 16. He was pronounced dead by emergency medical services. Patient #2 was a 58-year-old male with CLL PD after three years on ibrutinib. After the first patient's sudden death, EKG, ambulatory EKG, exercise stress test, and echocardiogram were obtained. The number of ventricular ectopic beats (VEs) in 48 hours increased from 750 on ibrutinib monotherapy to 4315 (1.84% of total beats) on duvelisib–ibrutinib. Ventricular trigeminy was noted. Although the patient was asymptomatic, ibrutinib was discontinued as a precaution. Repeat ambulatory EKG on duvelisib monotherapy showed 5525 VEs (2.19% of total beats) in 48 hours. The patient developed PD and was transitioned to venetoclax. Ambulatory EKG on venetoclax monotherapy showed 11 VEs in 48 hours. After review by the Data and Safety Monitoring Board and IRB, patient #3, who had a history of atrial fibrillation (AF) and tachycardia/bradycardia syndrome with pacemaker placement, discontinued duvelisib and ibrutinib after cycle 1. Since duvelisib is a moderate CYP3A4 inhibitor, the possibility of elevated ibrutinib exposure was investigated. In stored specimens from patient #1, random serum ibrutinib concentrations were 278 ng/ml and 72.6 ng/ml in samples collected two weeks and one day prior to initiation of duvelisib, respectively. As reference, the average s","journal":"British Journal of Haematology","year":2022,"id":292197,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9509,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":290485,"name":"Douglas R. Rosing","orcid":null,"position":1,"is_corresponding":false},{"id":314245,"name":"Mark C. Haigney","orcid":"0000-0001-6449-4386","position":2,"is_corresponding":false},{"id":109199,"name":"Cody J. Peer","orcid":"0000-0001-9395-3473","position":3,"is_corresponding":false},{"id":109200,"name":"William D. Figg","orcid":"0000-0003-2428-5613","position":4,"is_corresponding":false},{"id":233559,"name":"Adrian Wiestner","orcid":"0000-0002-3533-2924","position":5,"is_corresponding":false},{"id":262685,"name":"Clare Sun","orcid":"0000-0001-8498-4729","position":6,"is_corresponding":false},{"id":975879,"name":"Shira Paul","orcid":"0000-0002-7191-2141","position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":null,"created_at":"2026-07-19T00:30:42.221508Z","pmid":"36366824","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}