{"doi":"10.1002/hem3.70067","title":"Long‐term results of a phase 1/1b study of ibrutinib plus umbralisib for relapsed/refractory chronic lymphocytic leukemia","abstract":"Given the fundamental importance of the B-cell receptor (BCR) pathway in chronic lymphocytic leukemia (CLL) pathophysiology,1 we investigated dual BCR blockade in treating relapsed or refractory (R/R) disease. We hypothesized that combining the Bruton tyrosine kinase inhibitor (BTKi) ibrutinib, which is highly effective in R/R CLL,2, 3 with the next-generation oral phosphoinositide-3-kinase-delta isoform inhibitor (PI3Kδi) umbralisib would be an effective, well-tolerated, and convenient therapeutic approach that could lead to more durable remissions than historical results with ibrutinib alone. Unlike the approved PI3Kis idelalisib and duvelisib, umbralisib also targets casein-kinase-1-epsilon,4 which may spare regulatory T cell functioning through downregulation of WNT signaling,5 and thereby lead to less immune-mediated toxicity. A large integrated safety analysis across four early-phase umbralisib monotherapy studies demonstrated favorable long-term tolerability.6 Our initial results of this combination indeed found the combination achieved a high overall response rate (ORR; 90%) with a promising 2-year progression-free-survival (PFS) rate of 90%.7 Here, we report long-term results with a median follow-up for survivors of just under 5 years. The design of this multicenter, investigator-sponsored trial (NCT02268851) has been described previously.7 Of note, the study also included patients with R/R mantle cell lymphoma (MCL), but here we report only on long-term follow-up for the patients with CLL, as nearly all of the patients with MCL had either progressed or died soon after the data cut for the prior publication. Briefly, key inclusion criteria were R/R CLL with progression after ≥1 prior therapy, indication for treatment per iwCLL guidelines,8 and ECOG performance status ≤2. Key exclusion criteria were allogeneic transplantation within 12 months, active graft versus host disease, or central nervous system involvement. Patients received daily oral dosing of ibrutinib 420 mg and umbralisib at 3 dose levels. Study treatment was continued until progressive disease (PD) or unacceptable toxicity. Toxicity was by CTCAE 4.0 and iwCLL hematologic criteria, and response was by iwCLL criteria. Median duration on treatment was estimated by reverse Kaplan-Meier method. PFS and overall survival (OS) were estimated by Kaplan–Meier method. Statistical analyses used R version 4.3.1 (R Foundation for Statistical Computing). Twenty-one patients with CLL were enrolled; median age was 67 years (range 48–85) with full characteristics previously described.7 Patients had a median of 1 prior line of therapy (range 1–6), with 43% of patients having received ≥2 lines. Two patients had prior BTKi exposure (both treated with ibrutinib for <6 months and without disease progression), 11/19 (58%) patients evaluated had unmutated IGHV, and 7/21 (33%) patients had TP53-aberrant disease (presence of del(17p) and/or TP53-mutation). At data cutoff (September 20, 2022), median follow-up among survivors was 57.6 months (range 8.3–86.7). Six patients were still on therapy (five patients remained on both drugs; one patient on umbralisib only), and 15 patients had discontinued treatment: five due to patient/physician decision, four due to unacceptable toxicity (n = 1 arthralgias, n = 1 elevated lipase and amylase, n = 2 general intolerance), and two each due to PD, death, and intercurrent illness (n = 1 fatal lung infection [COVID-19 pneumonia], n = 1 myelodysplastic syndrome [MDS]). The recommended phase 2 dose was umbralisib 800 mg daily when given with standard dose ibrutinib. The median duration of umbralisib and ibrutinib treatment was 48.2 and 41.8 months, respectively. The safety profile remained similar to that previously reported. Table 1 lists all toxicities (any grade) that occurred in ≥20% of patients. Hypertension and atrial fibrillation occurred in 29% of patients (5% Grade 3/4) and 19% of patients (10% Grade 3/4), respectively. One major bleeding c","journal":"HemaSphere","year":2025,"id":560396,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9598,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":853443,"name":"Yue Ren","orcid":"0009-0003-4777-3342","position":1,"is_corresponding":false},{"id":66056,"name":"Svitlana Tyekucheva","orcid":"0000-0002-3119-6507","position":2,"is_corresponding":false},{"id":481408,"name":"Jon Arnason","orcid":"0000-0001-9038-7277","position":3,"is_corresponding":false},{"id":859569,"name":"Adam Boruchov","orcid":null,"position":4,"is_corresponding":false},{"id":11101,"name":"Caron A. Jacobson","orcid":"0000-0002-0180-0654","position":5,"is_corresponding":false},{"id":343821,"name":"David C. Fisher","orcid":"0000-0001-6915-8584","position":6,"is_corresponding":false},{"id":319152,"name":"Hari P. Miskin","orcid":null,"position":7,"is_corresponding":false},{"id":936418,"name":"Peter Sportelli","orcid":null,"position":8,"is_corresponding":false},{"id":3252,"name":"Jennifer R. Brown","orcid":"0000-0003-2040-4961","position":9,"is_corresponding":false},{"id":233541,"name":"Matthew S. Davids","orcid":"0000-0003-4529-2003","position":10,"is_corresponding":false},{"id":233558,"name":"Christine E. Ryan","orcid":"0000-0003-2588-1943","position":0,"is_corresponding":true}],"reference_count":14,"raw_metadata":null,"created_at":"2026-07-19T02:55:42.883572Z","pmid":"39816532","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":[]}