Introduction: Aplastic anemia (AA) is a life-threatening disorder characterized by pancytopenia a... more Introduction: Aplastic anemia (AA) is a life-threatening disorder characterized by pancytopenia and a hypocellular bone marrow. Pure red cell aplasia (PRCA) is a similar disorder with primary reduction in the red blood cell population and virtual absence of erythroid precursors in the bone marrow. While the etiology of immune mediated marrow failure is multifactorial, preceding viral infections have been associated with the disease; these include parvovirus B19, cytomegalovirus, and Epstein-Barr virus. We present four cases of immune mediated marrow failure with either preceding or simultaneous SARS-CoV-2 infection. Methods: The medical records of patients treated for AA or PRCA at the University of Texas Southwestern Medical Center, Parkland Hospital, and the National Institutes of Health (NIH) were reviewed for SARS-CoV-2 infection. Four patients without prior hematological diseases were identified who had SARS-CoV-2 infection prior to or with simultaneous the diagnosis of AA or PRCA. Results: Patient #1 was a 22-year-old white female who was diagnosed with asymptomatic COVID-19 10 days prior to her pancytopenia and AA diagnosis was confirmed by bone marrow biopsy (5% cellularity; Table 1). Her extensive work-up including HIV, hepatitis panel, immunoglobulins, B12 and folate was negative, and she underwent HLA-matched family donor hematopoietic stem cell transplant. Patient #2 was a 69-year-old Asian female who presented to her primary care physician with symptoms of fatigue and was found to be pancytopenic. CBC from a few months prior was completely normal. Further work-up was positive for COVID-19 and negative for HIV, nutritional deficiency, or hemolysis. She did not have respiratory symptoms, was eventually diagnosed with pRBC and platelet transfusion-dependent severe AA (5-10% cellularity on bone marrow), and underwent treatment with cyclosporine, equine antithymocyte globulin, and eltrombopag. She has had a partial response to this therapy. Both patients had bone marrow specimens stained for SARS-CoV-2 by immunohistochemistry that were negative. Patient #3 was a 76-year-old white male who was diagnosed with COVID-19 4 months prior to presenting with a non-ST segment myocardial infarction and found to be profoundly anemic, requiring pRBC transfusion. He re-presented with chest pain one week later and was found to be anemic again, and required transfusion. A trial of darbepoetin alfa was unsuccessful. Extensive work-up for malignancy, infection, and autoimmune etiologies were negative. He was diagnosed with PRCA based on the bone marrow biopsy and initiated treatment with cyclosporine. Patient # 4 was diagnosed with severe AA (presenting as pancytopenia) and COVID-19 infection. He had fatigue for one month and fever, chills and sore throat one-week prior seeking medical care. Testing for hepatitis, HIV, EBV, and CMV was negative. He was treated on a clinical trial (NCT04304820) at NIH with cyclosporine and eltrombopag until SARS-CoV-2 PCR was negative then received equine anti-thymocyte globulin. He has achieved a complete hematologic response at 6 months and remains well at last follow-up. Conclusion: The four patients described had minimal respiratory COVID-19 symptoms, but they presented with cytopenia and were eventually diagnosed with bone marrow failure. It is possible that this is co-incidental due to the high prevalence of SARS-CoV-2. However, there is emerging evidence that COVID-19 pneumonia is a hyperinflammatory and immune dysregulated state improved by dexamethasone therapy. Other immune mediated hematologic conditions, such as autoimmune hemolytic anemia and immune thrombocytopenia, have been reported. The onset from infection to cytopenia appears rapid, although patients often presented with symptoms for many days prior to diagnosis and thus testing may have been delayed from the onset of infection. This case series does not provide a mechanistic link between SARS-CoV-2 infection and bone marrow failure, but it raises the possibility that SARS-CoV-2 may mediate an immunologic response that contributes to marrow failure. Patients appear to respond well to standard immunosuppressive treatment. Further cases and studies are needed to determine if this is directly linked to SARS-CoV-2 and whether the natural history and response to standard therapy is different than idiopathic cases. Figure 1 Figure 1. Disclosures Young: Novartis: Research Funding.
Background: The risk of severe COVID-19 is increased in patients (pts) with hematologic malignanc... more Background: The risk of severe COVID-19 is increased in patients (pts) with hematologic malignancies, with a reported risk of death of 34% (Vijenthira et al, 2020). The ASH-ASTCT COVID-19 vaccine guidelines indicate that certain immunocompromised patient populations could have an attenuated response to the SARS-CoV-2 vaccine. However, most SARS-CoV-2 vaccine trials required pts to be off immune suppression to be eligible and therefore excluded most pts with hematologic malignancies. Little is known about the efficacy of SARS-CoV-2 vaccines in pts with hematologic malignancies. In this study, we aimed to evaluate the serological response of Pfizer and Moderna vaccination after two doses given in pts with hematologic malignancies with a focus on pts with myeloid malignancies. Methods: Patients with a history of hematologic malignancies treated at the University of Texas Southwestern Medical Center and received two doses of vaccination with quantitative measurement of SARS-CoV-2 IgG Sp...
Background: TP53 mutations (TP53MT) occur in diverse genomic configurations. Particularly, bialle... more Background: TP53 mutations (TP53MT) occur in diverse genomic configurations. Particularly, biallelic inactivation is associated with poor overall survival in cancer. Lesions affecting only one allele might not be directly leukemogenic, questioning the presence of cryptic biallelic subclones in cases with dismal prognosis. Methods: We have collected clinical and molecular data of 7400 patients with myeloid neoplasms and applied a novel model to properly resolve the allelic configuration of TP53MT and assess prognosis more precisely. Results: Overall, TP53MT were found in 1010 patients. Following the traditional criteria, 36% of cases were classified as single hits while 64% exhibited double hits genomic configuration. Using a newly developed molecular algorithm, we found that 579 (57%) patients had unequivocally biallelic, 239 (24%) likely contained biallelic, and 192 (19%) had most likely monoallelic TP53MT. Such classification was further substantiated by a survival-based model bui...
Importance Early prognostication of patients hospitalized with COVID-19 who may require mechanica... more Importance Early prognostication of patients hospitalized with COVID-19 who may require mechanical ventilation and have worse outcomes within 30 days of admission is useful for delivering appropriate clinical care and optimizing resource allocation. Objective To develop machine learning models to predict COVID-19 severity at the time of the hospital admission based on a single institution data. Design, setting, and participants We established a retrospective cohort of patients with COVID-19 from University of Texas Southwestern Medical Center from May 2020 to March 2022. Easily accessible objective markers including basic laboratory variables and initial respiratory status were assessed using Random Forest’s feature importance score to create a predictive risk score. Twenty-five significant variables were identified to be used in classification models. The best predictive models were selected with repeated tenfold cross-validation methods. Main outcomes and measures Among patients w...
Acquired pure red cell aplasia is a rare bone marrow failure disorder characterized by many under... more Acquired pure red cell aplasia is a rare bone marrow failure disorder characterized by many underlying etiologies. The hallmark bone marrow feature is the near absence of erythroid precursors that otherwise exhibit normal cellularity, which has been attributed to both immune- and cellular-mediated mechanisms. Besides being merely speculative and considering the rarity of the disorder, the description of acquired pure red cell aplasia clinical associations represents a unique occasion to improve our current clinical knowledge of the disease, reveal clues on its pathogenesis, and guide therapeutic decisions. The varied clinical scenarios and common acquired pure red cell aplasia associated conditions (i.e., thymoma, T cell/NK-cell large granular lymphocyte leukemia, B cell dyscrasia) suggest a heterogeneity of pathogenic routes. Viral etiologies must always be considered and worked up in the initial assessment of newly diagnosed acquired pure red cell aplasia patients. In this report,...
Biomarkers for Thrombosis in COVID-19: A Role for High Sensitivity Troponin-I and Immature Platel... more Biomarkers for Thrombosis in COVID-19: A Role for High Sensitivity Troponin-I and Immature Platelet Fraction? Introduction Coronavirus disease 2019 (COVID-19) is associated with increased risk of thrombosis with both venous and arterial thromboembolism observed. While d-dimer elevation has been shown to be associated with thrombosis, this elevation is present in over 50% of COVID-19 infections demonstrating a clear need for more specific biomarkers of thrombosis in this population. While there are a variety of theories to explain the increased risk for thrombosis: all center on Virchow's triad, specifically hypercoagulability and inflammation. Platelets play a significant role in hypercoagulability. Immature platelets, which are thought to be hyper-reactive, may specifically be associated with thrombosis in COVID-19. It would thus be reasonable to expect immature platelet fraction (IPF) and immature platelet count (IPC) to be predictive biomarkers of thrombosis in this populatio...
Introduction: COVID-19 has killed more than four million people worldwide and resulted in straine... more Introduction: COVID-19 has killed more than four million people worldwide and resulted in strained health resources globally(Dong Lancet ID 2020). There is a critical need for prognostic biomarkers to predict severity and outcomes in COVID-19 patients to allow more efficient resource allocation. Studies using pre-vaccination hospitalized patient data have demonstrated that elevated initial and peak immature platelet fraction (IPF), as well as related platelet indices, were associated with progression to severe COVID-19 outcomes (Welder Br J Haem 2021). This suggests the potential role of immature platelets as a cost-effective biomarker. The underlying pathophysiology of immature platelets in COVID-19 is unclear but these results support the hypothesis of higher inflammatory response, leading to thrombopoiesis mediated by pro-inflammatory cytokines and platelet hyper-reactivity in this population (Manne Blood 2021). It is unclear if this holds true in patients vaccinated against COVI...
Background: Anemia is a nearly universal complication of End Stage Renal Disease (ESRD). Erythrop... more Background: Anemia is a nearly universal complication of End Stage Renal Disease (ESRD). Erythropoiesis-stimulating agents (ESAs) have greatly decreased transfusion dependence in the anemia of ESRD. In some cases, ESAs are not effective, indicating ESA-resistance. ESA-resistant anemia is not well characterized and can be difficult to manage. Among the most frequent causes of ESA-resistant anemia is secondary hyperparathyroidism (SHP), which can induce bone marrow remodeling and fibrosis. Treatment protocols in SHP are centered on goal calcium, phosphorus and parathyroid hormone (PTH) levels and not the biologic consequences of high PTH. The hematologic insults secondary to SHP are rarely addressed. Instead, it is common to simply increase ESA dosing, rather than address the cause of ESA-resistance. In this retrospective review, we describe a cohort of patients with ESRD and SHP and highlight in detail one patient with reversible bone marrow changes and transfusion-dependent anemia, ...
4897 Much is known regarding the location, cellular composition, signaling pathways, and function... more 4897 Much is known regarding the location, cellular composition, signaling pathways, and functional role of the normal hematopoietic stem cell (HSC) niche in the bone marrow microenvironment. Microenvironmental cells including osteoblasts, other specialized mesenchymal cells, and vascular endothelial cells exert control over HSC self-renewal, differentiation, and engraftment. Niche occupancy appears to be competitive and limiting in terms of controlling the number of HSCs per organism. Leukemia stem cells (LSCs), through their inherent properties of quiescence and resistance to chemotherapeutic agents, are thought to be one of the principal mechanisms underlying disease relapse in patients. Much less is known regarding the interaction of LSCs and the marrow microenvironment. It is not clear whether LSCs localize to the same niches as HSCs, compete with HSCs for niche occupancy, or share dependence on niche signals, and whether those signals affect tumor responses to chemotherapy. Us...
Introduction: Aplastic anemia (AA) is a life-threatening disorder characterized by pancytopenia a... more Introduction: Aplastic anemia (AA) is a life-threatening disorder characterized by pancytopenia and a hypocellular bone marrow. Pure red cell aplasia (PRCA) is a similar disorder with primary reduction in the red blood cell population and virtual absence of erythroid precursors in the bone marrow. While the etiology of immune mediated marrow failure is multifactorial, preceding viral infections have been associated with the disease; these include parvovirus B19, cytomegalovirus, and Epstein-Barr virus. We present four cases of immune mediated marrow failure with either preceding or simultaneous SARS-CoV-2 infection. Methods: The medical records of patients treated for AA or PRCA at the University of Texas Southwestern Medical Center, Parkland Hospital, and the National Institutes of Health (NIH) were reviewed for SARS-CoV-2 infection. Four patients without prior hematological diseases were identified who had SARS-CoV-2 infection prior to or with simultaneous the diagnosis of AA or PRCA. Results: Patient #1 was a 22-year-old white female who was diagnosed with asymptomatic COVID-19 10 days prior to her pancytopenia and AA diagnosis was confirmed by bone marrow biopsy (5% cellularity; Table 1). Her extensive work-up including HIV, hepatitis panel, immunoglobulins, B12 and folate was negative, and she underwent HLA-matched family donor hematopoietic stem cell transplant. Patient #2 was a 69-year-old Asian female who presented to her primary care physician with symptoms of fatigue and was found to be pancytopenic. CBC from a few months prior was completely normal. Further work-up was positive for COVID-19 and negative for HIV, nutritional deficiency, or hemolysis. She did not have respiratory symptoms, was eventually diagnosed with pRBC and platelet transfusion-dependent severe AA (5-10% cellularity on bone marrow), and underwent treatment with cyclosporine, equine antithymocyte globulin, and eltrombopag. She has had a partial response to this therapy. Both patients had bone marrow specimens stained for SARS-CoV-2 by immunohistochemistry that were negative. Patient #3 was a 76-year-old white male who was diagnosed with COVID-19 4 months prior to presenting with a non-ST segment myocardial infarction and found to be profoundly anemic, requiring pRBC transfusion. He re-presented with chest pain one week later and was found to be anemic again, and required transfusion. A trial of darbepoetin alfa was unsuccessful. Extensive work-up for malignancy, infection, and autoimmune etiologies were negative. He was diagnosed with PRCA based on the bone marrow biopsy and initiated treatment with cyclosporine. Patient # 4 was diagnosed with severe AA (presenting as pancytopenia) and COVID-19 infection. He had fatigue for one month and fever, chills and sore throat one-week prior seeking medical care. Testing for hepatitis, HIV, EBV, and CMV was negative. He was treated on a clinical trial (NCT04304820) at NIH with cyclosporine and eltrombopag until SARS-CoV-2 PCR was negative then received equine anti-thymocyte globulin. He has achieved a complete hematologic response at 6 months and remains well at last follow-up. Conclusion: The four patients described had minimal respiratory COVID-19 symptoms, but they presented with cytopenia and were eventually diagnosed with bone marrow failure. It is possible that this is co-incidental due to the high prevalence of SARS-CoV-2. However, there is emerging evidence that COVID-19 pneumonia is a hyperinflammatory and immune dysregulated state improved by dexamethasone therapy. Other immune mediated hematologic conditions, such as autoimmune hemolytic anemia and immune thrombocytopenia, have been reported. The onset from infection to cytopenia appears rapid, although patients often presented with symptoms for many days prior to diagnosis and thus testing may have been delayed from the onset of infection. This case series does not provide a mechanistic link between SARS-CoV-2 infection and bone marrow failure, but it raises the possibility that SARS-CoV-2 may mediate an immunologic response that contributes to marrow failure. Patients appear to respond well to standard immunosuppressive treatment. Further cases and studies are needed to determine if this is directly linked to SARS-CoV-2 and whether the natural history and response to standard therapy is different than idiopathic cases. Figure 1 Figure 1. Disclosures Young: Novartis: Research Funding.
Background: The risk of severe COVID-19 is increased in patients (pts) with hematologic malignanc... more Background: The risk of severe COVID-19 is increased in patients (pts) with hematologic malignancies, with a reported risk of death of 34% (Vijenthira et al, 2020). The ASH-ASTCT COVID-19 vaccine guidelines indicate that certain immunocompromised patient populations could have an attenuated response to the SARS-CoV-2 vaccine. However, most SARS-CoV-2 vaccine trials required pts to be off immune suppression to be eligible and therefore excluded most pts with hematologic malignancies. Little is known about the efficacy of SARS-CoV-2 vaccines in pts with hematologic malignancies. In this study, we aimed to evaluate the serological response of Pfizer and Moderna vaccination after two doses given in pts with hematologic malignancies with a focus on pts with myeloid malignancies. Methods: Patients with a history of hematologic malignancies treated at the University of Texas Southwestern Medical Center and received two doses of vaccination with quantitative measurement of SARS-CoV-2 IgG Sp...
Background: TP53 mutations (TP53MT) occur in diverse genomic configurations. Particularly, bialle... more Background: TP53 mutations (TP53MT) occur in diverse genomic configurations. Particularly, biallelic inactivation is associated with poor overall survival in cancer. Lesions affecting only one allele might not be directly leukemogenic, questioning the presence of cryptic biallelic subclones in cases with dismal prognosis. Methods: We have collected clinical and molecular data of 7400 patients with myeloid neoplasms and applied a novel model to properly resolve the allelic configuration of TP53MT and assess prognosis more precisely. Results: Overall, TP53MT were found in 1010 patients. Following the traditional criteria, 36% of cases were classified as single hits while 64% exhibited double hits genomic configuration. Using a newly developed molecular algorithm, we found that 579 (57%) patients had unequivocally biallelic, 239 (24%) likely contained biallelic, and 192 (19%) had most likely monoallelic TP53MT. Such classification was further substantiated by a survival-based model bui...
Importance Early prognostication of patients hospitalized with COVID-19 who may require mechanica... more Importance Early prognostication of patients hospitalized with COVID-19 who may require mechanical ventilation and have worse outcomes within 30 days of admission is useful for delivering appropriate clinical care and optimizing resource allocation. Objective To develop machine learning models to predict COVID-19 severity at the time of the hospital admission based on a single institution data. Design, setting, and participants We established a retrospective cohort of patients with COVID-19 from University of Texas Southwestern Medical Center from May 2020 to March 2022. Easily accessible objective markers including basic laboratory variables and initial respiratory status were assessed using Random Forest’s feature importance score to create a predictive risk score. Twenty-five significant variables were identified to be used in classification models. The best predictive models were selected with repeated tenfold cross-validation methods. Main outcomes and measures Among patients w...
Acquired pure red cell aplasia is a rare bone marrow failure disorder characterized by many under... more Acquired pure red cell aplasia is a rare bone marrow failure disorder characterized by many underlying etiologies. The hallmark bone marrow feature is the near absence of erythroid precursors that otherwise exhibit normal cellularity, which has been attributed to both immune- and cellular-mediated mechanisms. Besides being merely speculative and considering the rarity of the disorder, the description of acquired pure red cell aplasia clinical associations represents a unique occasion to improve our current clinical knowledge of the disease, reveal clues on its pathogenesis, and guide therapeutic decisions. The varied clinical scenarios and common acquired pure red cell aplasia associated conditions (i.e., thymoma, T cell/NK-cell large granular lymphocyte leukemia, B cell dyscrasia) suggest a heterogeneity of pathogenic routes. Viral etiologies must always be considered and worked up in the initial assessment of newly diagnosed acquired pure red cell aplasia patients. In this report,...
Biomarkers for Thrombosis in COVID-19: A Role for High Sensitivity Troponin-I and Immature Platel... more Biomarkers for Thrombosis in COVID-19: A Role for High Sensitivity Troponin-I and Immature Platelet Fraction? Introduction Coronavirus disease 2019 (COVID-19) is associated with increased risk of thrombosis with both venous and arterial thromboembolism observed. While d-dimer elevation has been shown to be associated with thrombosis, this elevation is present in over 50% of COVID-19 infections demonstrating a clear need for more specific biomarkers of thrombosis in this population. While there are a variety of theories to explain the increased risk for thrombosis: all center on Virchow's triad, specifically hypercoagulability and inflammation. Platelets play a significant role in hypercoagulability. Immature platelets, which are thought to be hyper-reactive, may specifically be associated with thrombosis in COVID-19. It would thus be reasonable to expect immature platelet fraction (IPF) and immature platelet count (IPC) to be predictive biomarkers of thrombosis in this populatio...
Introduction: COVID-19 has killed more than four million people worldwide and resulted in straine... more Introduction: COVID-19 has killed more than four million people worldwide and resulted in strained health resources globally(Dong Lancet ID 2020). There is a critical need for prognostic biomarkers to predict severity and outcomes in COVID-19 patients to allow more efficient resource allocation. Studies using pre-vaccination hospitalized patient data have demonstrated that elevated initial and peak immature platelet fraction (IPF), as well as related platelet indices, were associated with progression to severe COVID-19 outcomes (Welder Br J Haem 2021). This suggests the potential role of immature platelets as a cost-effective biomarker. The underlying pathophysiology of immature platelets in COVID-19 is unclear but these results support the hypothesis of higher inflammatory response, leading to thrombopoiesis mediated by pro-inflammatory cytokines and platelet hyper-reactivity in this population (Manne Blood 2021). It is unclear if this holds true in patients vaccinated against COVI...
Background: Anemia is a nearly universal complication of End Stage Renal Disease (ESRD). Erythrop... more Background: Anemia is a nearly universal complication of End Stage Renal Disease (ESRD). Erythropoiesis-stimulating agents (ESAs) have greatly decreased transfusion dependence in the anemia of ESRD. In some cases, ESAs are not effective, indicating ESA-resistance. ESA-resistant anemia is not well characterized and can be difficult to manage. Among the most frequent causes of ESA-resistant anemia is secondary hyperparathyroidism (SHP), which can induce bone marrow remodeling and fibrosis. Treatment protocols in SHP are centered on goal calcium, phosphorus and parathyroid hormone (PTH) levels and not the biologic consequences of high PTH. The hematologic insults secondary to SHP are rarely addressed. Instead, it is common to simply increase ESA dosing, rather than address the cause of ESA-resistance. In this retrospective review, we describe a cohort of patients with ESRD and SHP and highlight in detail one patient with reversible bone marrow changes and transfusion-dependent anemia, ...
4897 Much is known regarding the location, cellular composition, signaling pathways, and function... more 4897 Much is known regarding the location, cellular composition, signaling pathways, and functional role of the normal hematopoietic stem cell (HSC) niche in the bone marrow microenvironment. Microenvironmental cells including osteoblasts, other specialized mesenchymal cells, and vascular endothelial cells exert control over HSC self-renewal, differentiation, and engraftment. Niche occupancy appears to be competitive and limiting in terms of controlling the number of HSCs per organism. Leukemia stem cells (LSCs), through their inherent properties of quiescence and resistance to chemotherapeutic agents, are thought to be one of the principal mechanisms underlying disease relapse in patients. Much less is known regarding the interaction of LSCs and the marrow microenvironment. It is not clear whether LSCs localize to the same niches as HSCs, compete with HSCs for niche occupancy, or share dependence on niche signals, and whether those signals affect tumor responses to chemotherapy. Us...
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