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      The role of FLT3 inhibitors as maintenance therapy following hematopoietic stem cell transplant

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          Abstract

          Activating mutations in FLT3 in acute myeloid leukemia (AML) portend a poor prognosis, and targeting FLT3 with a tyrosine kinase inhibitor has been an area of intense research recently. Most FLT3 mutated AML patients undergo hematopoietic stem cell transplantation (HSCT) as standard of care but a significant proportion of patients relapse. Although the use of FLT3 inhibitors in the pre-HSCT perspective is more clearly defined, its use in the post-HSCT scenario, when most relapses occur, remains unclear. In this review, we comprehensively present the data on the recent and ongoing studies evaluating the role of various FLT3 inhibitors in AML with a particular focus in the post-HSCT setting.

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          Therapeutic advances in acute myeloid leukemia.

          Alan K Burnett, Meir Wetzler, Bob Löwenberg (2011)
          The choice of treatment approach and outcome in acute myeloid leukemia (AML) depends on the age of the patient. In younger patients, arbitrarily defined as being younger than 60 years, 70% to 80% enter complete disease remission with several anthracycline-based chemotherapy combinations. Consolidation with high-dose cytarabine or stem-cell transplantation in high-risk patients will restrict overall relapse to approximately 50%. A number of demographic features can predict the outcome of treatment including cytogenetics and an increasing list of molecular features (ie, FLT3, NPM1, MLL, WT1, CEBPalpha, EVI1). These are increasingly being used to direct postinduction therapy, but they are also molecular targets for a new generation of small molecule inhibitors that are in early development; however, randomized data have yet to emerge. In older patients who comprise the majority, which will increase with demographic change, the initial clinical decision to be made is whether the patient should receive an intensive or nonintensive approach. If the same anthracycline/cytarabine-based approach is deployed, the remission rate will be around 50%, but the risk of subsequent relapse is approximately 85% at 3 years. This difference from younger patients is explained partly by the ability of patients to tolerate effective therapy, and also the aggregation of several poor risk factors compared with the young. There remains a substantial proportion of patients older than 60 years who do not receive intensive chemotherapy. Their survival is approximately 4 months, but there is considerable interest in developing new treatments for this patient group, including novel nucleoside analogs and several other agents.
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            Phase 1 clinical trial using mbIL21 ex vivo–expanded donor-derived NK cells after haploidentical transplantation

            Stefan O. Ciurea, Jolie Schafer, Roland Bassett … (2017)
            Relapse has emerged as the most important cause of treatment failure after allogeneic hematopoietic stem cell transplantation (HSCT). To test the hypothesis that natural killer (NK) cells can decrease the risk of leukemia relapse, we initiated a phase 1 dose-escalation study of membrane-bound interleukin 21 (mbIL21) expanded donor NK cells infused before and after haploidentical HSCT for high-risk myeloid malignancies. The goals were to determine the safety, feasibility, and maximum tolerated dose. Patients received a melphalan-based reduced-intensity conditioning regimen and posttransplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis. NK cells were infused on days -2, +7, and +28 posttransplant. All NK expansions achieved the required cell number, and 11 of 13 patients enrolled received all 3 planned NK-cell doses (1 × 105/kg to 1 × 108/kg per dose). No infusional reactions or dose-limiting toxicities occurred. All patients engrafted with donor cells. Seven patients (54%) developed grade 1-2 acute GVHD (aGVHD), none developed grade 3-4 aGVHD or chronic GVHD, and a low incidence of viral complications was observed. One patient died of nonrelapse mortality; 1 patient relapsed. All others were alive and in remission at last follow-up (median, 14.7 months). NK-cell reconstitution was quantitatively, phenotypically, and functionally superior compared with a similar group of patients not receiving NK cells. In conclusion, this trial demonstrated production feasibility and safety of infusing high doses of ex vivo-expanded NK cells after haploidentical HSCT without adverse effects, increased GVHD, or higher mortality, and was associated with significantly improved NK-cell number and function, lower viral infections, and low relapse rate posttransplant.
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              Azacitidine augments expansion of regulatory T cells after allogeneic stem cell transplantation in patients with acute myeloid leukemia (AML).

              C D Goodyear, Rahela Khanum, Paresh Vyas … (2012)
              Strategies that augment a GVL effect without increasing the risk of GVHD are required to improve the outcome after allogeneic stem cell transplantation (SCT). Azacitidine (AZA) up-regulates the expression of tumor Ags on leukemic blasts in vitro and expands the numbers of immunomodulatory T regulatory cells (Tregs) in animal models. Reasoning that AZA might selectively augment a GVL effect, we studied the immunologic sequelae of AZA administration after allogeneic SCT. Twenty-seven patients who had undergone a reduced intensity allogeneic transplantation for acute myeloid leukemia were treated with monthly courses of AZA, and CD8(+) T-cell responses to candidate tumor Ags and circulating Tregs were measured. AZA after transplantation was well tolerated, and its administration was associated with a low incidence of GVHD. Administration of AZA increased the number of Tregs within the first 3 months after transplantation compared with a control population (P = .0127). AZA administration also induced a cytotoxic CD8(+) T-cell response to several tumor Ags, including melanoma-associated Ag 1, B melanoma antigen 1, and Wilm tumor Ag 1. These data support the further examination of AZA after transplantation as a mechanism of augmenting a GVL effect without a concomitant increase in GVHD.
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                Author and article information

                Contributors
                George Yaghmour
                Journal
                Journal ID (nlm-ta): Leuk Res Rep
                Journal ID (iso-abbrev): Leuk Res Rep
                Title: Leukemia Research Reports
                Publisher: Elsevier
                ISSN (Electronic): 2213-0489
                Publication date PMC-release: 19 July 2018
                Publication date Collection: 2018
                Publication date (Electronic): 19 July 2018
                Volume: 10
                Pages: 26-36
                Affiliations
                [a ]Jane Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, University of Southern California, Keck School of Medicine of USC, USC Norris Comprehensive Cancer Center, Los Angeles, CA 90033, United States
                [b ]Department of Medicine, University of Southern California, Keck School of Medicine of USC, Los Angeles, CA 90033, United States
                [c ]Department of Pulmonary and Critical Care, University of Southern California, Keck School of Medicine of USC, Los Angeles, CA 90033, United States
                Author notes
                [* ]Corresponding author. George.Yaghmour@ 123456med.usc.edu
                [1]

                Both authors contribute equally to this work.

                Article
                Publisher ID: S2213-0489(18)30049-9
                DOI: 10.1016/j.lrr.2018.06.003
                PMC ID: 6092446
                SO-VID: 209091c6-12ce-442f-8ff6-d55158ea9126
                Copyright © © 2018 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 21 May 2018
                Date revision received : 25 June 2018
                Date accepted : 29 June 2018
                Categories
                Subject: Article

                Keywords: acute myeloid leukemia,flt3,hematopoietic stem cell transplant,tyrosine kinase inhibitors,multikinase inhibitors,drug resistance
                Data availability:
                Keywords: acute myeloid leukemia, flt3, hematopoietic stem cell transplant, tyrosine kinase inhibitors, multikinase inhibitors, drug resistance

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