Molecular Targeted Therapy in Myelodysplastic Syndromes: New Options for Tailored Treatments

Pagliuca, Simona; Gurnari, Carmelo; Visconte, Valeria

doi:10.3390/cancers13040784

Cited by 15 publications

(17 citation statements)

References 156 publications

(172 reference statements)

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“…31 32 MDS carries inherent limitation due to heterogeneous nature of the disease; however, laboratory advances have identified genetic mutations and their therapeutic targets and is being translated into personalized medicine in clinical practice. 33 Sequencing studies are increasingly used in diagnostic practice, validation, and standardization as per the established guidelines increase the reproducibility of the test results. 34 35 Conducting large multicentric studies with participation of many countries could help in overcoming the racial heterogeneity and the generated high quality sequencing results will help in recognizing significant mutations that can be incorporated into specific risk categories in the prognostic scoring.…”

Section: Discussionmentioning

confidence: 99%

Should We Look beyond Revised International Prognostic Scoring System: A Retrospective Observational Study of Progression of Myelodysplastic Syndrome to Acute Leukemia

Nagarjun

Kalaharaghini

Sawhney

et al. 2021

Indian J Med Paediatr Oncol

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Introduction Myelodysplastic syndrome (MDS) is a clonal stem cell disorder and heterogeneous condition resulting in peripheral cytopenias with marrow dysplasia due to ineffective hematopoiesis. The revised International Prognostic Scoring System (IPSS-R) predicts the risk of progression to acute leukemia (AL). Indian data on MDS and its progression to AL are limited. Additionally, the cytogenetic findings are dictated by patients' racial background. Study intended to analyze the cytogenetic profile of the patients with MDS. Objectives This study aimed to (1) evaluate the clinicohematologic and morphologic spectrum of newly diagnosed MDS cases, (2) evaluate the cytogenetic profile of these cases, and (3) study the cases progressed to AL. Materials and Methods MDS cases diagnosed and followed-up during a 5-year study period, from January 2015 to December 2019, were included in the study and the study was conducted at regional cancer center in Western India. De novo diagnosed MDS cases with complete workup were considered and MDS due to secondary causes were excluded. Baseline clinical, hematologic findings were tabulated along with cytogenetics and risk stratified as per IPSS-R, and their progression was studied. Results A total of 63 cases of de novo MDS were diagnosed over a period of 5 years with 45 cases on follow-up and 15 cases (33.3%) progressed to AL. Maximum number of cases belonged to MDS-excess blast (EB) category accounting to 48 cases (76.1%). Apparently normal karyotyping was the commonest cytogenetic finding in 33 MDS cases (61.2%) and in 8 cases that progressed to AL (53.4%). Conclusion MDS cases diagnosed at relatively early age were at higher risk of progression to AL. Majority of the cases that progressed to AL were risk stratified in high and very high risk groups and 10 cases which progressed to AL belonged to good category, interestingly apparent normal karyotyping was the commonest cytogenetic finding in more than 50% of the cases progressed to AL. Molecular mutations could only explain this progression and studies integrating molecular mutations with present IPSS-R scoring system should be conducted, as it could translate into better risk stratification and help in early identification and better management of cases at risk in progression to AL.

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Section: Discussionmentioning

confidence: 99%

Should We Look beyond Revised International Prognostic Scoring System: A Retrospective Observational Study of Progression of Myelodysplastic Syndrome to Acute Leukemia

Nagarjun

Kalaharaghini

Sawhney

et al. 2021

Indian J Med Paediatr Oncol

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“…The latest effort to define precise estimation of patients’ stratification highlights two of the most important goals in medicine: preventing treatment complications and selecting the most effective therapies for patients [ 74 ]. Novel approaches fueled by the incorporation of genetic features in prognostic scoring systems and powered by ML-based algorithms are the next steps to improve risk stratification [ 6 , 74 ].…”

Section: Future Endeavors and Perspectivementioning

confidence: 99%

Personalized Risk Schemes and Machine Learning to Empower Genomic Prognostication Models in Myelodysplastic Syndromes

Awada

Gurnari

Durmaz

et al. 2022

IJMS

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Myelodysplastic syndromes (MDS) are characterized by variable clinical manifestations and outcomes. Several prognostic systems relying on clinical factors and cytogenetic abnormalities have been developed to help stratify MDS patients into different risk categories of distinct prognoses and therapeutic implications. The current abundance of molecular information poses the challenges of precisely defining patients’ molecular profiles and their incorporation in clinically established diagnostic and prognostic schemes. Perhaps the prognostic power of the current systems can be boosted by incorporating molecular features. Machine learning (ML) algorithms can be helpful in developing more precise prognostication models that integrate complex genomic interactions at a higher dimensional level. These techniques can potentially generate automated diagnostic and prognostic models and assist in advancing personalized therapies. This review highlights the current prognostication models used in MDS while shedding light on the latest achievements in ML-based research.

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“…Venetoclax, approved by the FDA, is a BCL-2 inhibitor that can be used in combination with HMAs in HR-MDS patients and has been reported to have a good therapeutic response in a case study as a monotherapy (ClinicalTrials.gov (accessed on 21 September 2021) Identifier: NCT02966782) [ 204 ]. It acts as a BH3 mimetic that impedes the binding of BH3 proteins to BCL-2, hence releasing pro-apoptotic BAK and BAX proteins [ 205 , 206 ]. This results in mitochondrial outer membrane permeabilization (MOMP) with the release of cytochrome C into the cytoplasm, leading to the formation of cytosolic apoptosome complex, caspase activation, and subsequent cellular apoptosis [ 207 ].…”

Section: Treatment Of Mdsmentioning

confidence: 99%

Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome

Lee

Yim

Yung

et al. 2021

IJMS

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Myelodysplastic syndrome (MDS) is a heterogeneous, clonal hematological disorder characterized by ineffective hematopoiesis, cytopenia, morphologic dysplasia, and predisposition to acute myeloid leukemia (AML). Stem cell genomic instability, microenvironmental aberrations, and somatic mutations contribute to leukemic transformation. The hypomethylating agents (HMAs), azacitidine and decitabine are the standard of care for patients with higher-risk MDS. Although these agents induce responses in up to 40–60% of patients, primary or secondary drug resistance is relatively common. To improve the treatment outcome, combinational therapies comprising HMA with targeted therapy or immunotherapy are being evaluated and are under continuous development. This review provides a comprehensive update of the molecular pathogenesis and immune-dysregulations involved in MDS, mechanisms of resistance to HMA, and strategies to overcome HMA resistance.

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Molecular Targeted Therapy in Myelodysplastic Syndromes: New Options for Tailored Treatments

Cited by 15 publications

References 156 publications

Should We Look beyond Revised International Prognostic Scoring System: A Retrospective Observational Study of Progression of Myelodysplastic Syndrome to Acute Leukemia

Should We Look beyond Revised International Prognostic Scoring System: A Retrospective Observational Study of Progression of Myelodysplastic Syndrome to Acute Leukemia

Personalized Risk Schemes and Machine Learning to Empower Genomic Prognostication Models in Myelodysplastic Syndromes

Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome

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