{"doi":"10.1002/ajh.25968","title":"A phase <scp>II</scp> study of ibrutinib and short‐course fludarabine in previously untreated patients with chronic lymphocytic leukemia","abstract":"To the Editor: Ibrutinib, a Bruton tyrosine kinase inhibitor, has impressive clinical efficacy in chronic lymphocytic leukemia (CLL), being able to improve progression-free survival (PFS) and overall survival (OS), compared to conventional chemoimmunotherapy in treatment-naïve patients with chronic lymphocytic leukemia (CLL).1, 2 Despite representing a major therapeutic advance, single-agent ibrutinib has limitations. While responses to ibrutinib can be durable, the depth of responses are infrequently deep, reflected in low rates of complete responses (CRs) and undetectable minimal residual disease (U-MRD).3 We hypothesized that modulation of the T-cell compartment could improve the quality of response to ibrutinib. We report results from a phase 2 study in which short-course fludarabine was added to continuous ibrutinib, with the aim to debulk CLL cells and induce rapid reductions in T cell numbers. Eligible patients had treatment-naïve CLL requiring treatment. The study was approved by the Institutional Review Board and registered at clinicaltrials.gov (NCT02514083). All patients provided written informed consent. Ibrutinib 420 mg was administered orally once daily on 28-day cycles until disease progression or intolerable side effects. Fludarabine 25 mg/m2/day was given intravenously on days 1-5 of cycle three and four (Figure 1A). The primary efficacy endpoint was the CR rate at 6 months according to IWCLL criteria.4 The primary safety endpoint was the rate of treatment discontinuation within 6 months due to intolerable side effects. Secondary endpoints included assessments of residual CLL cells and T cell phenotypes in peripheral blood using flow cytometry. Undetectable minimal residual disease was defined as <1 CLL cell in 10 000 leukocytes (<10−4). The T cells were analyzed for CD3, CD4 and CD8. Additional surface and intracellular stains were applied to assess Treg (CD127-/CD25+/FoxP3+) and T follicular helper (TFH; CXCR5+/PD-1+) cells. Sample size was determined based on the alternative hypothesis of a CR rate at 6 months ≥20% against the null hypothesis of a CR rate ≤5%, with 27 patients providing 80% power at an alpha level of 0.05. For the primary safety endpoint, the null hypothesis was the rate of treatment discontinuation being ≥30% and the alternative hypothesis was the discontinuation rate being ≤10%; 27 patients provided 81% power at an alpha level of 0.05. We used descriptive statistics to summarize findings, Kaplan-Meier method to estimate survival, Wilcoxon signed-rank test to assess changes in residual disease burden and T cell subsets over time. Statistical analyses were conducted using R version 3.6.1 and GraphPad Prism, version 7.02. Between December 2015 and April 2019, 29 patients were enrolled. Table S1 summarizes baseline characteristics. The median age was 65 years. More than half of the patients were male and had advanced Rai stages (III/IV). Fourteen (48.3%) patients had unmutated immunoglobulin heavy chain variable gene (IGHV). Three (10.3%) patients had deletion 17p by FISH. Two patients who had concurrent hairy cell leukemia at baseline were eligible for the study because; (a) neither had received prior therapy for CLL or hairy cell leukemia, (b) CLL was the dominant disease process, and (c) the study allowed enrollment of patients with second primary malignancies when their expected survival was over 2 years. With a median follow-up of 29 months (range, 7-47 months), 24 (82.8%) of 29 patients remain on study (Figure S1). Two patients discontinued study therapy due to hepatotoxicity before reaching the primary endpoint. One of these patients who did not receive any fludarabine was counted as a non-responder. The other patient who received one cycle of fludarabine was considered evaluable for response and achieved a partial response. The overall response rate at 6 months was 93.1%. The CR rates at 6, 12 and 24 months were 20.7%, 28.0% and 44.4%, respectively (Figure 1B). There was no associatio","journal":"American Journal of Hematology","year":2020,"id":111222,"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":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9616,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":262681,"name":"Xin Tian","orcid":"0000-0003-1896-2462","position":1,"is_corresponding":false},{"id":410787,"name":"Shakuntala Rampertaap","orcid":null,"position":2,"is_corresponding":false},{"id":529186,"name":"Rui Mu","orcid":null,"position":3,"is_corresponding":false},{"id":262682,"name":"Susan Soto","orcid":"0009-0003-3746-890X","position":4,"is_corresponding":false},{"id":265131,"name":"Jeanine Superata","orcid":null,"position":5,"is_corresponding":false},{"id":262683,"name":"Erika M. Gaglione","orcid":"0000-0003-4831-3105","position":6,"is_corresponding":false},{"id":262685,"name":"Clare Sun","orcid":"0000-0001-8498-4729","position":7,"is_corresponding":false},{"id":265130,"name":"Jennifer Lotter","orcid":null,"position":8,"is_corresponding":false},{"id":278258,"name":"Maryalice Stetler‐Stevenson","orcid":"0000-0003-2591-0353","position":9,"is_corresponding":false},{"id":278259,"name":"Constance M. Yuan","orcid":"0000-0002-2601-3665","position":10,"is_corresponding":false},{"id":280055,"name":"Irina Marić","orcid":null,"position":11,"is_corresponding":false},{"id":225661,"name":"Stefania Pittaluga","orcid":"0000-0001-7688-1439","position":12,"is_corresponding":false},{"id":246526,"name":"Sergio D. Rosenzweig","orcid":"0000-0002-5550-9678","position":13,"is_corresponding":false},{"id":325558,"name":"Thomas A. Fleisher","orcid":"0000-0001-8301-6929","position":14,"is_corresponding":false},{"id":233559,"name":"Adrian Wiestner","orcid":"0000-0002-3533-2924","position":15,"is_corresponding":false},{"id":233544,"name":"Inhye E. Ahn","orcid":"0000-0003-3717-287X","position":16,"is_corresponding":false},{"id":262680,"name":"Christopher Pleyer","orcid":"0000-0002-9569-9605","position":0,"is_corresponding":true}],"reference_count":6,"raw_metadata":null,"created_at":"2026-07-18T23:13:05.597252Z","pmid":"32808680","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":[]}