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Cytopenias in myelodysplastic syndromes are associated with differentiation block and ineffective hematopoiesis. Although initially considered to be an effect of bone marrow precursor apoptosis, more recent research has evaluated the role of inflammatory forms of cell death in myelodysplastic syndromes. Ferroptosis, a form of iron-dependent non-apoptotic cell death, is one of such forms of inflammatory cell death. A recent study by Lv et al, evaluating ferroptosis regulation in MDS cell lines and primary patient samples also identified that decitabine may elicit its cytotoxic effect in MDS through induction of ferroptosis. In this study, the inhibitory effects of decitabine on cell growth were partially reversed with concurrent use of deferrioxamine, an iron-chelating agent, or ferrostatin-1 both in MDS cell lines, murine models or in MDS patient samples. Ferrostatin was also capable of partially reversing the reduced cell viability of bone marrow mononuclear cells of iron overload mice. Use of inducers of ferroptosis such as erastin in combination with decitabine induced higher reactive oxygen species levels and cytotoxicity and reduced further the levels of glutathione suggesting increased oxidative stress. Although it still remains unclear if ferroptosis might account for a frequent mechanisms of cell death in all genomic MDS subtypes or cellular subpopulations, this data supports exploring further the potential role of this and other forms of inflammatory cell death in MDS pathogenesis in order to develop novel molecules targeting or inhibiting these processes.
The current COVID-19 pandemic has afflicted over 44 million individuals across the planet and been responsible for over 1 million deaths, particularly in high-risk populations. As a result of the overall advanced age, frailty and pre-existing comorbidities of patients with MDS, SARS-Cov2 was feared to be particularly dangerous in this patient population. A recent study by Mossuto et al describes the outcomes of patients with MDS with SARS-CoV-2 infection during the Coronavirus outbreak in Italy. Among a total of 5326 patients with MDS followed during the study period, 63 (1.18%) had confirmed SARS-CoV-2 infection. With a median age of 73 years, the mortality rate among these patients was 52% compared to that of the non-MDS population (24%), and was particularly high on male MDS patients (73% of total deaths). Respiratory failure was the cause of death in all the MDS patients with ARDS in 50% of deceased patients, and with majority of patients who were able to recover having lower risk IPSS-R categories. Interestingly, no differences in mortality or severity of infection were observed based on the type of therapy received for their MDS. These findings are not surprising given the underlying inflammation and immunosuppression in patients with MDS. Until the development of COVID-19 vaccines has been completed, identification of high-risk populations and specific guidelines for the management of SARS-CoV-2 infection in patients with MDS remains of paramount importance.
Clonal hematopoiesis is a known cardiovascular risk factor which has been associated with increased risk of cardiac and cerebrovascular events. Recent studies have also associated MDS with higher than expected cardiovascular comorbidities and cardiovascular-related deaths. In accordance to prior publications by Naqvi et al, a recent study by Faber et al retrospectively evaluated 236 MDS patients and studied the associations of somatic mutations with cardiovascular risk. Overall, the authors observed that 27% of patients in their study population developed vascular event, and that ASXL1 mutations were predictive of vascular disease by multivariate analysis (with an odds ratio of 4.2). This data further supports the biological connection between comorbidities and hematopoietic clonal disorders, the role of inflammaging and the need to maximize cardiovascular risk factor care in patients with MDS and develop specific therapies targeting both the disease biology and the underlying mechanisms leading to increased cardiovascular risk.
Guillermo Montalban Bravo, MD
Assistant Professor, Department of Leukemia, Division of Cancer Medicine
MD Anderson Cancer Center, Houston, TX
Cytopenias in myelodysplastic syndromes are associated with differentiation block and ineffective hematopoiesis. Although initially considered to be an effect of bone marrow precursor apoptosis, more recent research has evaluated the role of inflammatory forms of cell death in myelodysplastic syndromes. Ferroptosis, a form of iron-dependent non-apoptotic cell death, is one of such forms of inflammatory cell death. A recent study by Lv et al, evaluating ferroptosis regulation in MDS cell lines and primary patient samples also identified that decitabine may elicit its cytotoxic effect in MDS through induction of ferroptosis. In this study, the inhibitory effects of decitabine on cell growth were partially reversed with concurrent use of deferrioxamine, an iron-chelating agent, or ferrostatin-1 both in MDS cell lines, murine models or in MDS patient samples. Ferrostatin was also capable of partially reversing the reduced cell viability of bone marrow mononuclear cells of iron overload mice. Use of inducers of ferroptosis such as erastin in combination with decitabine induced higher reactive oxygen species levels and cytotoxicity and reduced further the levels of glutathione suggesting increased oxidative stress. Although it still remains unclear if ferroptosis might account for a frequent mechanisms of cell death in all genomic MDS subtypes or cellular subpopulations, this data supports exploring further the potential role of this and other forms of inflammatory cell death in MDS pathogenesis in order to develop novel molecules targeting or inhibiting these processes.
The current COVID-19 pandemic has afflicted over 44 million individuals across the planet and been responsible for over 1 million deaths, particularly in high-risk populations. As a result of the overall advanced age, frailty and pre-existing comorbidities of patients with MDS, SARS-Cov2 was feared to be particularly dangerous in this patient population. A recent study by Mossuto et al describes the outcomes of patients with MDS with SARS-CoV-2 infection during the Coronavirus outbreak in Italy. Among a total of 5326 patients with MDS followed during the study period, 63 (1.18%) had confirmed SARS-CoV-2 infection. With a median age of 73 years, the mortality rate among these patients was 52% compared to that of the non-MDS population (24%), and was particularly high on male MDS patients (73% of total deaths). Respiratory failure was the cause of death in all the MDS patients with ARDS in 50% of deceased patients, and with majority of patients who were able to recover having lower risk IPSS-R categories. Interestingly, no differences in mortality or severity of infection were observed based on the type of therapy received for their MDS. These findings are not surprising given the underlying inflammation and immunosuppression in patients with MDS. Until the development of COVID-19 vaccines has been completed, identification of high-risk populations and specific guidelines for the management of SARS-CoV-2 infection in patients with MDS remains of paramount importance.
Clonal hematopoiesis is a known cardiovascular risk factor which has been associated with increased risk of cardiac and cerebrovascular events. Recent studies have also associated MDS with higher than expected cardiovascular comorbidities and cardiovascular-related deaths. In accordance to prior publications by Naqvi et al, a recent study by Faber et al retrospectively evaluated 236 MDS patients and studied the associations of somatic mutations with cardiovascular risk. Overall, the authors observed that 27% of patients in their study population developed vascular event, and that ASXL1 mutations were predictive of vascular disease by multivariate analysis (with an odds ratio of 4.2). This data further supports the biological connection between comorbidities and hematopoietic clonal disorders, the role of inflammaging and the need to maximize cardiovascular risk factor care in patients with MDS and develop specific therapies targeting both the disease biology and the underlying mechanisms leading to increased cardiovascular risk.
Guillermo Montalban Bravo, MD
Assistant Professor, Department of Leukemia, Division of Cancer Medicine
MD Anderson Cancer Center, Houston, TX
Cytopenias in myelodysplastic syndromes are associated with differentiation block and ineffective hematopoiesis. Although initially considered to be an effect of bone marrow precursor apoptosis, more recent research has evaluated the role of inflammatory forms of cell death in myelodysplastic syndromes. Ferroptosis, a form of iron-dependent non-apoptotic cell death, is one of such forms of inflammatory cell death. A recent study by Lv et al, evaluating ferroptosis regulation in MDS cell lines and primary patient samples also identified that decitabine may elicit its cytotoxic effect in MDS through induction of ferroptosis. In this study, the inhibitory effects of decitabine on cell growth were partially reversed with concurrent use of deferrioxamine, an iron-chelating agent, or ferrostatin-1 both in MDS cell lines, murine models or in MDS patient samples. Ferrostatin was also capable of partially reversing the reduced cell viability of bone marrow mononuclear cells of iron overload mice. Use of inducers of ferroptosis such as erastin in combination with decitabine induced higher reactive oxygen species levels and cytotoxicity and reduced further the levels of glutathione suggesting increased oxidative stress. Although it still remains unclear if ferroptosis might account for a frequent mechanisms of cell death in all genomic MDS subtypes or cellular subpopulations, this data supports exploring further the potential role of this and other forms of inflammatory cell death in MDS pathogenesis in order to develop novel molecules targeting or inhibiting these processes.
The current COVID-19 pandemic has afflicted over 44 million individuals across the planet and been responsible for over 1 million deaths, particularly in high-risk populations. As a result of the overall advanced age, frailty and pre-existing comorbidities of patients with MDS, SARS-Cov2 was feared to be particularly dangerous in this patient population. A recent study by Mossuto et al describes the outcomes of patients with MDS with SARS-CoV-2 infection during the Coronavirus outbreak in Italy. Among a total of 5326 patients with MDS followed during the study period, 63 (1.18%) had confirmed SARS-CoV-2 infection. With a median age of 73 years, the mortality rate among these patients was 52% compared to that of the non-MDS population (24%), and was particularly high on male MDS patients (73% of total deaths). Respiratory failure was the cause of death in all the MDS patients with ARDS in 50% of deceased patients, and with majority of patients who were able to recover having lower risk IPSS-R categories. Interestingly, no differences in mortality or severity of infection were observed based on the type of therapy received for their MDS. These findings are not surprising given the underlying inflammation and immunosuppression in patients with MDS. Until the development of COVID-19 vaccines has been completed, identification of high-risk populations and specific guidelines for the management of SARS-CoV-2 infection in patients with MDS remains of paramount importance.
Clonal hematopoiesis is a known cardiovascular risk factor which has been associated with increased risk of cardiac and cerebrovascular events. Recent studies have also associated MDS with higher than expected cardiovascular comorbidities and cardiovascular-related deaths. In accordance to prior publications by Naqvi et al, a recent study by Faber et al retrospectively evaluated 236 MDS patients and studied the associations of somatic mutations with cardiovascular risk. Overall, the authors observed that 27% of patients in their study population developed vascular event, and that ASXL1 mutations were predictive of vascular disease by multivariate analysis (with an odds ratio of 4.2). This data further supports the biological connection between comorbidities and hematopoietic clonal disorders, the role of inflammaging and the need to maximize cardiovascular risk factor care in patients with MDS and develop specific therapies targeting both the disease biology and the underlying mechanisms leading to increased cardiovascular risk.