To date, many of the most successful checkpoint inhibitor-based therapies in cancer have targeted T-cells and adaptive immunity. However, there is an ongoing search for novel checkpoints with ...targeting innate immunity via activation of macrophage phagocytosis representing an exciting therapeutic strategy. CD47 is the dominant negative macrophage immune checkpoint expressed on cancer cells which acts as a “don't eat me signal”, preventing phagocytosis via its interaction with SIRP-α on macrophages. CD47 has been shown to be upregulated in many cancer types including myeloid malignancies with increased expression associated with inferior OS. Magrolimab, an anti-CD47 antibody, has shown proof-of-principle of efficacy in this therapeutic class with promising early results in both higher risk myelodysplastic syndromes (MDS) and TP53 mutant acute myeloid leukemia (AML). The toxicity profile to date has been shown safe and manageable with on-target anemia related to CD47 being present on aged red blood cells and without evidence of immune related toxicities. Investigation of novel agents targeting this pathway and novel combinations are ongoing. New strategies targeting macrophage checkpoints are encouraging and likely will lead a paradigm shift in the current treatment of myeloid malignancies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Novel therapies in myelodysplastic syndromes Swoboda, David M; Gesiotto, Quinto; Sallman, David A
Current opinion in hematology,
2020-March, 2020-Mar, 2020-03-00, 20200301, Volume:
27, Issue:
2
Journal Article
PURPOSE OF REVIEWCurrently, there is a rapid expansion of novel, efficacious therapies for the treatment of patients with myelodysplastic syndromes (MDS) at a rate never seen to date. In this review, ...we will outline new treatment strategies in MDS focusing on novel hypomethylating agents (HMA) and combinations in addition to targeted and immune-based therapies.
RECENT FINDINGSLarge-scale gene sequencing and immune-based research has given us a great deal of information regarding the complexity and heterogeneity of MDS. This rapid improvement in our knowledge has provided a framework for development of novel therapies with specific gene and immune-based targets. Additionally, expanding and optimizing our current HMA-based strategies has led us to potentially not only ease administration but also improve outcomes.
SUMMARYNovel therapies in MDS are greatly needed is a disease state where few options are currently available, particularly in the HMA failure setting. Fortunately, through comprehensive genetic profiling, characterization of novel underlying pathogenic drivers, and understanding of the immune microenvironment, the treatment paradigm of patients with MDS is encouraging.
The ASXL1 and SRSF2 mutations in AML are frequently found in patients with preexisting myeloid malignancies and are individually associated with poor outcomes. In this multi‐institutional ...retrospective analysis, we assessed the genetic features and clinical outcomes of 43 patients with ASXL1mutSRSF2mut AML and compared outcomes to patients with either ASXL1 (n = 57) or SRSF2 (n = 70) mutations. Twenty‐six (60%) had secondary‐AML (s‐AML). Variant allele fractions suggested that SRSF2 mutations preceded ASXL1 mutational events. Median overall survival (OS) was 7.0 months (95% CI:3.8,15.3) and was significantly longer in patients with de novo vs s‐AML (15.3 vs 6.4 months, respectively; P = .04 on adjusted analysis). Compared to ASXL1mutSRSF2wt and ASXL1wtSRSF2mut, co‐mutated patients had a 1.4 and 1.6 times increase in the probability of death, respectively (P = .049), with a trend towards inferior OS (median OS = 7.0 vs 11.5 vs 10.9 months, respectively; P = .10). Multivariable analysis suggests this difference in OS is attributable to the high proportion of s‐AML patients in the co‐mutated cohort (60% vs 32% and 23%, respectively). Although this study is limited by the retrospective data collection and the relatively small sample size, these data suggest that ASXL1mutSRSF2mut AML is a distinct subgroup of AML frequently associated with s‐AML and differs from ASXL1mutSRSF2wt/ASXL1wtSRSF2mut with respect to etiology and leukemogenesis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
A 67-year-old female came to Tampa General Hospital with Philadelphia chromosome-positive (Ph+) acute myeloid leukemia (AML) featuring an intriguing combination of mutations, including NPM1 and IDH2 ...mutations. Novel combination therapy with azacitidine, venetoclax and ponatinib allowed her to successfully achieve a complete response (CR) and undergo an allogeneic hematopoietic stem cell transplant (HSCT). This case report provides an overview of her clinical course, emphasizing the significance of integrated therapy and the challenges associated with balancing treatment for AML. It also underscores the importance of a multidisciplinary approach and careful monitoring of patients with complex hematologic conditions.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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