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      Research Progress of B-Cell Lymphoma/Leukemia-2 Inhibitor Combined with Azacytidine in the Targeted Therapy of Acute Myeloid Leukemia

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          Abstract

          Objective

          To investigate the efficacy and safety of azacytidine and B-cell lymphoma/leukemia-2 inhibitors in the treatment of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

          Methods

          The clinical data of 31 patients with AML/MDS who were clearly diagnosed with AML/MDS were analyzed from 2018.10 to 2021.02, and the total amount of azacyclonol and B-cell lymphoma/leukemia-2 inhibitor was used for single or combined chemotherapy, with a total amount of 75 mg/m 2 7 d, divided into 7-10 days of continuous subcutaneous injection, every 28-30 days for a course of treatment. Overall response rate (ORR), median survival, poor response, and genetic mutations were observed.

          Results

          A total of 104 courses of treatment were completed in 31 patients, the median course was 3 (1–12), and 6 patients who did not complete 2 courses of treatment were not counted in the statistics. After 2 courses, ORR was 72.0%, CRES was 2 (8.0%), mCR was 16 (64.0%), disease stable was 5 (20.0%), treatment failures were 2 (8.0%), mortality was 40.0%, and median survival time was >5 months. Single-agent and combined ORR was 64.3% and 81.8%, respectively, with median survival of 7.25 and 9 months; ORR for MDS and AML was 66.7% and 76.9%, respectively, median survival of 8 and 11 months was 66.7% and 80.0% of ORRs at 260 and V60 years, respectively, and median survival of 7 and 11.5 months; MDS-EB-1. The ORR of MDS-EB-2 was 75.0% and 62.5%, respectively, with median survival times of 11.5 and 6.5 months. During 2 courses and 4 courses, the rate of transfusion dependence was 64.0% and 55.5%, respectively. Fifteen cases were detected by second-generation sequencing, and the results were 14 cases of combined gene mutations.

          Conclusion

          Azacytidine and B-cell lymphoma/leukemia-2 inhibitors have good efficacy and high safety in the treatment of AML and MDS, and the combined treatment is better than that of monotherapy, but the side effects of combination therapy are large.

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          Most cited references25

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          Tailored tyrosine kinase inhibitor (TKI) treatment of chronic myeloid leukemia (CML) based on current evidence.

          Philadelphia (Ph*)/BCR-ABL1-positive chronic myeloid leukemia (CML) is a neoplastic hematologic disorder, which is a functionally curable chronic disease via using tyrosine kinase inhibitor (TKI) drugs. The life expectancy for the vast majority of chronic phase-CML patients is "normal", thanks to the unique effectiveness of the ABL-targeted TKIs of CML. The patients with CML receiving TKI could be expected to have a survival and 'quality of life' of the age- and sex-matched healthy people. Several TKI pathways may be selected for the first line CML treatment, including first-generation original/generic imatinib or second-generation TKIs, such as bosutinib, nilotinib, and dasatinib. Individual characteristics of the CML patients, TKI drug compliance, lifestyle preferences, comorbidities, distinct toxicity profile of the TKI drug, and physician-clinical center experience are among the critical factors to be taken into account while deciding on the proper first line TKI in the newly diagnosed CML patients. Identifying CML patients at a higher risk for the disease progression or TKI resistance is essential and could influence the choice of primary TKI. The optimized integrations of the best available evidence, individual patient characteristics, and physician clinical experience are required in order to select best TKI for the CML management. Pathobiological basis depending upon the prospective in vivo research data is also crucial during the follow-up as well.
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            LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation

            The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation, and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for remaining apoptotic debris in regulating the immunologic response to and growth of solid tumors. Here, we investigated the role of macrophage LC3–associated phagocytosis (LAP) within the BM microenvironment of AML. Depletion of BM macrophages (BMMs) increased AML growth in vivo. We show that LAP is the predominate method of BMM phagocytosis of dead and dying cells in the AML microenvironment. Targeted inhibition of LAP led to the accumulation of apoptotic cells (ACs) and apoptotic bodies (ABs), resulting in accelerated leukemia growth. Mechanistically, LAP of AML-derived ABs by BMMs resulted in stimulator of IFN genes (STING) pathway activation. We found that AML-derived mitochondrial damage–associated molecular patterns were processed by BMMs via LAP. Moreover, depletion of mitochondrial DNA (mtDNA) in AML-derived ABs showed that it was this mtDNA that was responsible for the induction of STING signaling in BMMs. Phenotypically, we found that STING activation suppressed AML growth through a mechanism related to increased phagocytosis. In summary, we report that macrophage LAP of apoptotic debris in the AML BM microenvironment suppressed tumor growth.
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              Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors.

              Gilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3-mutation (FLT3mut+ ). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi  + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen-activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.
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                Author and article information

                Contributors
                Journal
                Comput Math Methods Med
                Comput Math Methods Med
                cmmm
                Computational and Mathematical Methods in Medicine
                Hindawi
                1748-670X
                1748-6718
                2022
                8 October 2022
                : 2022
                : 3992224
                Affiliations
                Department of Oncology and Hematology, People's Hospital of Leshan, Leshan 614000, Sichuan Province, China
                Author notes

                Academic Editor: Plácido R. Pinheiro

                Author information
                https://orcid.org/0000-0001-8104-036X
                Article
                10.1155/2022/3992224
                9569197
                36254240
                50214bd3-9eb4-420a-97a9-586a8ca0c39c
                Copyright © 2022 Yanyu Wang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 8 July 2022
                : 5 September 2022
                : 22 September 2022
                Categories
                Research Article

                Applied mathematics
                Applied mathematics

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