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      Feasible outcome of blinatumomab followed by allogeneic hematopoietic cell transplantation for adults with Philadelphia chromosome‐negative acute lymphoblastic leukemia in first salvage

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          Abstract

          In adult patients with relapsed or refractory (R/R) Philadelphia chromosome‐negative (Ph‐negative) B‐cell presursor acute lymphoblastic leukemia (BCP‐ALL), complete remission (CR) and overall survival (OS) rates are poor. We analyzed treatment outcomes and prognostic factors for 32 adult patients with R/R Ph‐negative BCP‐ALL who received blinatumomab at first salvage. Patients who achieved CR proceeded to allogeneic hematopoietic cell transplantation (allo‐HCT). At the time of blinatumomab treatment, 11 patients (34.3%) were primary refractory, 10 (31.4%) had relapsed with first CR duration (CRD1) ≥12 months, and 11 (34.3%) had relapsed with CRD1 <12 months. After the first blinatumomab cycle, 22 (68.8%) achieved CR. At the end of the second cycle, 20 of the 22 patients remained in persistent CR, and 1 patient achieved new CR. The overall minimal residual disease negativity rate was 75% among evaluable patients with persistent CR. Patients with CRD1 <12 months were associated with poorer response to blinatumomab. Twenty (62.5%) of 32 patients underwent allo‐HCT in blinatumomab‐induced CR. After a median follow‐up of 15.2 months, the 1‐year OS rates for all patients and patients receiving allo‐HCT in CR were 55.5% (median OS, 18.2 months) and 70.7%, respectively. Patients with CRD1 <12 months, extramedullary disease (EMD), and high peripheral blood blasts were associated with poorer OS. Blinatumomab is effective for achieving good quality CR and bridging to allo‐HCT for adult patients with R/R Ph‐negative BCP‐ALL in first salvage. The role of blinatumomab in patients with CRD1 <12 months, EMD, or high tumor burden should be evaluated in future trials.

          Abstract

          Blinatumomab is effective for achieving good quality CR and bridging to allo‐HCT for adult patients with R/R Ph‐negative BCP‐ALL in first salvage. The role of blinatumomab in relapsed patients with short CR duration, extramedullary disease, and high tumor burden should be cautiously considered due to poor response.

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          Immunopharmacologic response of patients with B-lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody blinatumomab.

          T cell-engaging CD19/CD3-bispecific BiTE Ab blinatumomab has shown an 80% complete molecular response rate and prolonged leukemia-free survival in patients with minimal residual B-lineage acute lymphoblastic leukemia (MRD(+) B-ALL). Here, we report that lymphocytes in all patients of a phase 2 study responded to continuous infusion of blinatumomab in a strikingly similar fashion. After start of infusion, B-cell counts dropped to < 1 B cell/μL within an average of 2 days and remained essentially undetectable for the entire treatment period. By contrast, T-cell counts in all patients declined to a nadir within < 1 day and recovered to baseline within a few days. T cells then expanded and on average more than doubled over baseline within 2-3 weeks under continued infusion of blinatumomab. A significant percentage of reappearing CD8(+) and CD4(+) T cells newly expressed activation marker CD69. Shortly after start of infusion, a transient release of cytokines dominated by IL-10, IL-6, and IFN-γ was observed, which no longer occurred on start of a second treatment cycle. The response of lymphocytes in leukemic patients to continuous infusion of blinatumomab helps to better understand the mode of action of this and other globally T cell-engaging Abs. The trial is registered with www.clinicaltrials.gov identifier NCT00560794.
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            Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome–Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study

            Purpose Few therapeutic options are available for patients with Philadelphia chromosome–positive (Ph + ) B-precursor acute lymphoblastic leukemia (ALL) who progress after failure of tyrosine kinase inhibitor (TKI) −based therapy. Here, we evaluated the efficacy and tolerability of blinatumomab in patients with relapsed or refractory Ph + ALL. Patients and Methods This open-label phase II study enrolled adults with Ph + ALL who had relapsed after or were refractory to at least one second-generation or later TKI or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib. Blinatumomab was administered in 28-day cycles by continuous intravenous infusion. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles. Major secondary end points included minimal residual disease response, rate of allogeneic hematopoietic stem-cell transplantation, relapse-free survival, overall survival, and adverse events (AEs). Results Of 45 patients, 16 (36%; 95% CI, 22% to 51%) achieved CR/CRh during the first two cycles, including four of 10 patients with the T315I mutation; 88% of CR/CRh responders achieved a complete minimal residual disease response. Seven responders (44%) proceeded to allogeneic hematopoietic stem-cell transplantation, including 55% (six of 11) of transplantation-naïve responders. Median relapse-free survival and overall survival were 6.7 and 7.1 months, respectively. The most frequent AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Three patients had cytokine release syndrome (all grade 1 or 2), and three patients had grade 3 neurologic events, one of which (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events. Conclusion Single-agent blinatumomab showed antileukemia activity in high-risk patients with Ph + ALL who had relapsed or were refractory to TKIs. AEs were consistent with previous experience in Ph – ALL.
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              Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells.

              Certain bispecific single-chain antibody constructs exhibit an extraordinary potency for polyclonal T cell engagement and target cell lysis. Here we studied the structural basis for this potency, using laser scanning confocal microscopy. Cytolytic human T cell synapses could be triggered either by addition of a specific peptide antigen or an Ep-CAM-/CD3-bispecific T cell engager (BiTE). Both kinds of synapses showed a comparable distribution of all protein markers investigated. Two other BiTEs constructed from different Ep-CAM-specific antibodies gave similar results. BiTEs could also induce lytic synapses between human T cells and a MHC class I-negative, Ep-CAM cDNA-transfected cell line resulting in potent target cell lysis. This shows that certain T cell recognition molecules on target cells are dispensable for synapse formation and BiTE activity, and suggests that BiTE-activated polyclonal T cells may ignore major immune evasion mechanisms of tumor cells in vivo, such as loss of MHC class I expression.
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                Author and article information

                Contributors
                leeseok@catholic.ac.kr
                Journal
                Cancer Med
                Cancer Med
                10.1002/(ISSN)2045-7634
                CAM4
                Cancer Medicine
                John Wiley and Sons Inc. (Hoboken )
                2045-7634
                05 November 2019
                December 2019
                : 8
                : 18 ( doiID: 10.1002/cam4.v8.18 )
                : 7650-7659
                Affiliations
                [ 1 ] Department of Hematology Catholic Hematology Hospital and Leukemia Research Institute Seoul St. Mary's Hospital College of Medicine The Catholic University of Korea Seoul Korea
                Author notes
                [*] [* ] Correspondence

                Seok Lee, Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo‐daero, Seocho‐gu, Seoul 06591, Republic of Korea.

                Email: leeseok@ 123456catholic.ac.kr

                Author information
                https://orcid.org/0000-0002-2145-9131
                https://orcid.org/0000-0002-9810-2050
                https://orcid.org/0000-0002-4524-6616
                https://orcid.org/0000-0003-2949-4166
                Article
                CAM42680
                10.1002/cam4.2680
                6912052
                31691536
                4ffc213b-9a29-4036-b11d-6d618fb249ca
                © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 June 2019
                : 24 July 2019
                : 21 October 2019
                Page count
                Figures: 3, Tables: 4, Pages: 10, Words: 6875
                Funding
                Funded by: National Research Foundation of Korea , open-funder-registry 10.13039/501100003725;
                Award ID: NRF‐2017R1D1A1B03029283
                Funded by: The Catholic University of Korea , open-funder-registry 10.13039/501100002648;
                Award ID: ZC17SISI0412
                Categories
                Original Research
                Clinical Cancer Research
                Original Research
                Custom metadata
                2.0
                December 2019
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.2 mode:remove_FC converted:16.12.2019

                Oncology & Radiotherapy
                acute lymphoblastic leukemia,allogeneic,blinatumomab,first salvage,hematopoietic cell transplantation

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