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      Immunotherapy and Allogeneic Bone Marrow Transplantation in B Acute Lymphoblastic Leukemia: How to Sequence?

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          Abstract

          Long-term disease control is achieved in 80–90% of patients with acute lymphoblastic leukemia of B origin (B-ALL). About half of adult and 10% of pediatric patients develop refractory or relapsed disease, whereas survival after relapse accounts about 10% in adults and 30–50% in children. Allogeneic bone marrow transplantation offers remarkable benefit in cases with unfavorable outcome. Nevertheless, novel immunotherapeutic options have been approved for patients with adverse prognosis. Immunotherapeutic agents, nowadays, are preferred over standard chemotherapy for patients with relapsed or refractory B-ALL The mode of action, efficacy and safety data of immunotherapeutic agents released, indications and sequence of those therapies over the course of treatment, are herein reviewed.

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          Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

          Shannon Maude, Theodore Laetsch, Jochen Buechner … (2018)
          In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).
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            Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia

            Jae H. Park, Isabelle Rivière, Mithat Gonen … (2018)
            BACKGROUND CD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients. METHODS We conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19–28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics. RESULTS A total of 53 adults received 19–28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden. CONCLUSIONS In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19–28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, [Related object:] NCT01044069.)
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              Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia

              Hagop Kantarjian, Anthony Stein, Nicola Gökbuget … (2017)
              Background Blinatumomab, a bispecific monoclonal antibody construct that enables CD3-positive T cells to recognize and eliminate CD19-positive acute lymphoblastic leukemia (ALL) blasts, was approved for use in patients with relapsed or refractory B-cell precursor ALL on the basis of single-group trials that showed efficacy and manageable toxic effects. Methods In this multi-institutional phase 3 trial, we randomly assigned adults with heavily pretreated B-cell precursor ALL, in a 2:1 ratio, to receive either blinatumomab or standard-of-care chemotherapy. The primary end point was overall survival. Results Of the 405 patients who were randomly assigned to receive blinatumomab (271 patients) or chemotherapy (134 patients), 376 patients received at least one dose. Overall survival was significantly longer in the blinatumomab group than in the chemotherapy group. The median overall survival was 7.7 months in the blinatumomab group and 4.0 months in the chemotherapy group (hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55 to 0.93; P=0.01). Remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the chemotherapy group, both with respect to complete remission with full hematologic recovery (34% vs. 16%, P<0.001) and with respect to complete remission with full, partial, or incomplete hematologic recovery (44% vs. 25%, P<0.001). Treatment with blinatumomab resulted in a higher rate of event-free survival than that with chemotherapy (6-month estimates, 31% vs. 12%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery, or death, 0.55; 95% CI, 0.43 to 0.71; P<0.001), as well as a longer median duration of remission (7.3 vs. 4.6 months). A total of 24% of the patients in each treatment group underwent allogeneic stem-cell transplantation. Adverse events of grade 3 or higher were reported in 87% of the patients in the blinatumomab group and in 92% of the patients in the chemotherapy group. Conclusions Treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy among adult patients with relapsed or refractory B-cell precursor ALL. (Funded by Amgen; TOWER ClinicalTrials.gov number, NCT02013167 .).
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                Author and article information

                Contributors
                Anna Komitopoulou:
                ORCID: http://orcid.org/0000-0001-9112-580X
                annakom@yahoo.com
                Journal
                Journal ID (nlm-ta): Clin Hematol Int
                Journal ID (iso-abbrev): Clin Hematol Int
                Title: Clinical Hematology International
                Publisher: Springer Netherlands (Dordrecht )
                ISSN (Electronic): 2590-0048
                Publication date (Electronic): 11 May 2022
                Publication date PMC-release: 11 May 2022
                Publication date Collection: June 2022
                Volume: 4
                Issue: 1-2
                Pages: 11-20
                Affiliations
                [1 ]GRID grid.413408.a, ISNI 0000 0004 0576 4085, Stem Cell Transplant Unit, , “Agia Sofia Children’s Hospital”, ; Mikras Asias 46 and Levadias 8, 11527 Athens, Greece
                [2 ]GRID grid.414655.7, ISNI 0000 0004 4670 4329, Department of Haematology and Bone Marrow Transplantation Unit, , Evangelismos Hospital, ; Athens, Greece
                Author information
                http://orcid.org/0000-0001-9112-580X
                Article
                Publisher ID: 6
                DOI: 10.1007/s44228-022-00006-6
                PMC ID: 9358786
                PubMed ID: 35950202
                SO-VID: 9b86cf9d-f799-43bb-b002-72da51c104fb
                Copyright © © The Author(s) 2022
                License:

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 23 December 2021
                Date accepted : 10 March 2022
                Categories
                Subject: Review Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2022

                Keywords: immunotherapy,b-all,therapeutic choice
                Data availability:
                Keywords: immunotherapy, b-all, therapeutic choice

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