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      Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis

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          Abstract

          Clinical trials that led to ibrutinib’s approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.

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          Most cited references 18

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          BTK(C481S)-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia.

          Purpose Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.
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            Survival probabilities (the Kaplan-Meier method).

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              Complex karyotype is a stronger predictor than del(17p) for an inferior outcome in relapsed or refractory chronic lymphocytic leukemia patients treated with ibrutinib-based regimens.

              Ibrutinib is active in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). In patients treated with ibrutinib for R/R CLL, del(17p), identified by interphase fluorescence in situ hybridization (FISH), is associated with inferior progression-free survival despite equivalent initial response rates. Del(17p) is frequently associated with a complex metaphase karyotype (CKT); the prognostic significance of CKT in ibrutinib-treated patients has not been reported.
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                Author and article information

                Journal
                Haematologica
                Haematologica
                haematol
                Haematologica
                Haematologica
                Ferrata Storti Foundation
                0390-6078
                1592-8721
                May 2018
                01 February 2018
                : 103
                : 5
                : 874-879
                Affiliations
                [1 ]Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, USA
                [2 ]Cardinal Health, Dublin, OH, USA
                [3 ]Hematology/Oncology, Presbyterian/Columbia University Medical Center, New York, NY, USA
                [4 ]Hematology/Oncology, Duke University, Durham, NC, USA
                [5 ]Hematology and Medical Oncology, Cleveland Clinic, OH, USA
                [6 ]Pharmacy, Ernest Mario School of Pharmacy, New Brunswick, NY, USA
                [7 ]Hematology/Oncology, John Theurer Cancer Center, Hackensack, NY, USA
                [8 ]Hematology/Oncology, Georgetown University Hospital, Washington DC, USA
                [9 ]Hematology/Oncology, University of Rochester Medical Center, NY, USA
                [10 ]Hematology/Oncology, Penn State Milton S Hershey Medical Center, PA, USA
                [11 ]Lymphoma, Celgene Corp, Summit, NY, USA
                [12 ]Hematology/Oncology, Lankenau Hospital, Wynnewood, PA, USA
                [13 ]Division of Hematology and Oncology, University of Rochester, NY, USA
                Author notes
                Correspondence: amato@ 123456mskcc.org
                [*]

                Indicates shared last authorship

                Article
                1030874
                10.3324/haematol.2017.182907
                5927982
                29419429
                Copyright © 2018 Ferrata Storti Foundation

                Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions:

                https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions:

                https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.

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                Chronic Lymphocytic Leukemia

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