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Background:There is an unmet need for a minimally invasive clinical test using samples collected by medical staff or by self-collection to screen persons for Alzheimer's disease (AD), Parkinson's Disease (PD) and other dementias and diseases. AD is underdiagnosed today, particularly in underserved populations where it is high incidence (non-Hispanic black and Hispanic) and in rural populations. Even in populations with access to health care, diagnosis is often delayed by years, even though the most recently approved therapies are most efficacious when given early in the progression of disease. While dementias are diseases of the brain, many publications link the underpinning inflammatory aspects to circulating neutrophils, macrophages, and lymphocytes. Thus, there is an opportunity to exploit the hematologic aspects of AD and PD in its diagnosis and potentially, therapeutically. AD gene expression signatures using RNA extracted from venipuncture whole blood have been reported. FDA-cleared tests based on circulating biomarkers are in use today but are not definitive tests for AD. We developed a direct, extraction-free TempO-Seq® assay of gene expression using blood from a finger prick spotted on filter paper, providing a simple and minimally invasive method of obtaining a blood sample and performing a test that can potentially be used to identify a host of diseases and disease risk. We then implemented a test that classified patients as having AD or PD.

Children and young adults with sickle cell disease (SCD) require complex health care services to screen for early signs of disease-related complications and to initiate and monitor disease-modifying therapies. Care coordination is challenging as it involves multiple team members across multiple subspecialties. Evidence-based clinical protocols and quality metrics are essential for SCD programs to deliver high-quality care. Systems to track this care delivery are crucial to ensure equitable, accessible care is consistently provided.

1. Paper electrophoresis of abnormal hemoglobins is a simple and convenient technic for the study of the hereditary hemoglobinopathies. 2. A semiquantitative paper electrophoretic technic is described, which allows rather accurate quantitation of the various hemoglobin components by inspection alone. 3. For exact results, the more elaborate technics of elution or photoelectric scanning may be employed. The accuracy of these quantitative technics is illustrated by artificial mixture experiments. 4. The clinical applications of the method in the study of sickle cell disease and hemoglobin C abnormalities are discussed. Apart from the more common hemoglobin abnormalities (such as sickle cell trait, sickle cell anemia, C trait, sickle cell-hemoglobin C disease), a patient with 100 per cent hemoglobin C (homozygous hemoglobin C disease) and a Negro patient with sickle cell-thalassemia disease were discovered. Normal adult hemoglobin (hemoglobin A) was found in all other hereditary and acquired anemias studied. Slightly increased amounts of fetal hemoglobin were detected in cases of hereditary nonspherocytic hemolytic disease and aregenerative anemia. 5. This technic may be used for red cell life span determinations by serially following the disappearance of a certain hemoglobin type transfused into a patient with a different hemoglobin variety. Further applications of the technic are suggested. 6. The combination of the technics of paper electrophoresis and alkali denaturation offer an adequate, simple, and practical tool for diagnosis and investigation of hereditary hemoglobinopathies. 7. Identical apparatus and buffer may be used for serum protein electrophoresis.

Two-dimensional paper chromatography was used to partition the acid-soluble phosphates in the erythrocytes of normal newborn infants, infants with erythroblastosis fetalis and adults. The inorganic phosphate concentration was higher in the fresh red cells of normal and erythroblastotic infants and rose more during incubation for four hours than in the cells of adults. The amount of erythrocyte adenosine-5’-triphosphate in the adults exceeded the quantities found in the cells of the two groups of babies. The 2,3-diphosphoglycerate level was greater in the erythrocytes of adults and infants with erythroblastosis than it was in the normal infants and incubation for four hours resulted in a sharper decrease of this compound in cells of the normal and erythroblastotic infants than in the adults.

Introduction: Global health research is hampered by the lack of inexpensive and reliable assays to annotate clinical study cohorts for geographically localized endemic genetic disorders. The most prevalent modifier in Africa is sickle cell disease (SCD, HbSS). In SCD, sickling of erythrocytes by polymerization of hemoglobin S (HbS) causes vaso-occlusion and hemolysis, leading to significant morbidity/mortality and constituting a major healthcare and economic burden. The inhomogeneity bias introduced into the clinical data of patient cohorts by the changes associated to undiagnosed SCD is a significant challenge. Thus, our aims were to: a) optimize a paper-based screening test for SCD for its application in suboptimal and resource-limited conditions, b) demonstrate the feasibility of retrospective SCD annotation of a large cohort of children enrolled in a global health research study, and c) extract novel evidence on potential differences in clinical presentation between febrile children with and without SCD enrolled in this cohort.

No relevant conflicts of interest to declare.

Piety: Halcyon Biomedical: Patents & Royalties: Mr. Piety is a co-inventor on a utility PCT application, "Paper-based diagnostic test" (PCT/US2012/064856, 11/13/2012), claiming priority benefit of U.S. 61/692,994 (8/24/2012) and U.S. 61/558,009 (11/10/2011). . Shevkoplyas:Halcyon Biomedical: Equity Ownership, Patents & Royalties: Co-inventor on a utility PCT application, "Paper-based diagnostic test" (PCT/US2012/064856, 11/13/2012), claiming priority benefit of U.S. 61/692,994 (8/24/2012) and U.S. 61/558,009 (11/10/2011). Part-owner of Halcyon Biomedical Inc.,.

No relevant conflicts of interest to declare.

Introduction:Sickle cell disease (SCD) is a common inherited blood disorder caused by sickle hemoglobin (HbS) which, unlike normal adult hemoglobin (HbA), becomes insoluble and polymerizes under hypoxic conditions. Patients with SCD experience chronic hemolytic anemia, episodic pain crises and abnormal blood flow to critical organs that cumulatively result in significant illness and shortened lifespans for many. The severity of SCD varies significantly between patients, but for individuals the rate of adverse events is strongly correlated with intraerythrocytic concentration of HbS (%HbS). High per test costs and long turnaround times make conventional laboratory methods (e.g. Hb electrophoresis, HPLC, IEF) impractical for quantifying %HbS in real-time (e.g. during transfusion therapy). The objective of this study was to demonstrate that %HbS in blood could be quantified using our recently developed rapid, low-cost paper-based SCD assay [1].

Sickle cell disease (SCD) is the most common inherited blood disorder caused by a mutation in the beta-globin chain of the hemoglobin (Hb) molecule. The result of this mutation, Hb S, polymerizes when deoxygenated, giving the red blood cells a characteristic, sickled shape. This polymerization causes in vivo vaso-occlusion and disrupts the vascular endothelium causing multi-organ complications in affected individuals. Nearly 70% of all affected births occur in Africa, where conservative estimates of SCD prevalence suggest a 10.68/1000 rate at birth (compared to 0.49/1000 in the U.S.). Although SCD causes significant morbidity and premature mortality, most affected persons born in the U.S. are able to survive into adulthood (primarily due to the implementation of universal newborn screening). In contrast, most affected individuals born in low-income countries die before the age of 5 years due to lack of early intervention. Current technology for diagnosing SCD relies on hemoglobin electrophoresis, isoelectric focusing or high performance liquid chromatography. This type of testing remains prohibitively expensive to low-income countries, where SCD is most prevalent and newborn screening is unavailable. Thus, many affected individuals are not diagnosed before severe complications or death can occur. The urgent need to develop a low-cost diagnostic test for SCD has been recently recognized as a priority by the World Health Organization. In this study, we describe the implementation of a paper-based hemoglobin solubility assay as a simple, low-cost and rapid test for definitive diagnosis of SCD.Normal human venous blood (Hb AA) was collected and compared to blood from patients with SCD (Hb SS) and SCT (Hb AS). To perform the test, a 20uL droplet of whole blood mixed with the components of the Hb solubility assay (SickleDex™, Streck) was deposited onto a paper-fluidic device fabricated using a previously published method. Polymerized deoxy-Hb S remained in the center of the blood stain entrapped by the paper substrate, while other forms of Hb remained soluble and were transported laterally to the periphery of the stain by capillary action. The resulting blood stain was digitized with a portable scanner and analyzed automatically. The red color intensity profiles were normalized by the total area under the curve to account for the differences in hematocrit among subjects. The SCD index was defined as the normalized color intensity 5 mm from the center of the blood stain. Data were presented as results of individual experiments and as mean ± SD. The values of the SCD index for samples from each Hb genotype were compared using a paired two-tailed t-test.The entanglement of polymerized deoxy-Hb S by the fibers of the paper substrate resulted in the formation of a dark red spot in the center of the blood stain, while the wicking of the soluble forms of Hb from the center produced a pink ring on the periphery of the stain. The patterns of the blood stains produced on paper by normal (Hb AA), SCT (Hb AS) and SCD (Hb SS) samples were significantly different (Fig. A). The tight clustering of the normalized color intensity profiles for different subjects with the same Hb genotype enabled the use of the SCD index as a quantitative metric for distinguishing between the three types of samples (Fig. B). The difference between the SCD index measured for Hb AA, Hb AS and Hb SS samples was highly significant, with p<0.001 (Fig. C). Unlike the conventional, commercially available Hb solubility tests (e.g. SickleDex), the paper-based Hb solubility assay can conclusively differentiate between SCT and SCD samples using the characteristic blood stain patterns produced by each sample on the paper substrate.This proof-of-concept study demonstrated the feasibility of using the paper-based Hb solubility assay as a simple, low-cost, point-of-care diagnostic test for SCD. The ability to diagnose SCD quickly and inexpensively will be particularly useful for universal SCD screening in resource-limited settings, such as Africa. This test will also be very useful in the emergency room setting in high-income countries to enable healthcare professionals to objectively confirm suspected SCD at the bedside.No relevant conflicts of interest to declare.

ELISA assays have been proposed as a complement to the Bethesda assay for detection and follow-up of factor VIII (FVIII) antibodies in subjects with hemophilia. The Bethesda assay has several drawbacks. Most importantly, the Bethesda assay would not detect non-inhibitory antibodies, even though these could be responsible for low in vivo recovery of FVIII and /or a pharmacokinetic pattern suggestive of rapid clearance of FVIII. ELISA assays for detecting antibodies to FVIII are not routinely performed in most hospital laboratories and as such, specimens need to be transported to specialized laboratories for processing. Transportation of plasma specimens frozen on dry ice, however, is both costly and cumbersome. Room temperature storage of whole blood and serum specimens adsorbed and dried onto filter paper has been shown to be a convenient and reliable alternative to frozen whole blood and serum samples for various analyses. This study was undertaken to assess whether FVIII antibodies from haemophilic plasma would display similar stability when stored adsorbed onto filter paper at room temperature for 1 month or on plasma specimens stored frozen. Stability was assessed by comparing results of ELISA assays.two hundred and thirteen frozen (at -80°C) plasma samples from patients with or without known FVIII inhibitors were tested. Samples came from 97 congenital haemophilic subjects and 5 subjects with acquired haemophilia. The samples were tested with a previously reported ELISA assay (Haemophilia 2009; 15: 374-6) with minor modifications. The coating antigens were two therapeutic preparations of recombinant FVIII: the full length FVIII preparation Helixate® FS, and the B-domain deleted FVIII Xyntha®. Five dilutions of plasma from a subject with congenital severe hemophilia A known to have a high Bethesda titer was put on all plates as positive control. Six normal plasmas were used on all plates as negative controls. Mean and standard deviation of optical densities were calculated for negative controls. Mean was subtracted from optical density of each test plasma. The resulting value was divided by the value of one standard deviation of negative controls to generate the number of standard deviations for test plasmas. All plasmas were assayed in duplicate. The numbers of standard deviations were compared between frozen samples and samples dried on filter papers.The correlation between the numbers of standard deviations obtained with frozen specimens and with specimens dried on filter paper was excellent for both therapeutic preparations of recombinant FVIII, going from R= 0.91 to R= 0.99.FVIII antibodies tested by ELISA using plasma dried on filter paper for one month at room temperature or plasma stored at -80°C give comparable results.No relevant conflicts of interest to declare.

Background

No relevant conflicts of interest to declare.

Piety: Tulane University: PCT/US2012/064856 Patents & Royalties. Yang:Tulane University: PCT/US2012/064856 Patents & Royalties. Shevkoplyas:Tulane University: PCT/US2012/064856 Patents & Royalties; Halcyon Biomedical Incorporated: Equity Ownership.

Abstract 245This icon denotes a clinically relevant abstract

Abstract 3479

With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

Patients with hematologic malignancies and recipients of hematopoietic cell transplantation (HCT) are more likely to experience severe coronavirus disease 2019 (COVID-19) and have a higher risk of morbidity and mortality after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Compared with the general population, these patients have suboptimal humoral responses to COVID-19 vaccines and subsequently increased risk for breakthrough infections, underscoring the need for additional therapies, including pre- and postexposure prophylaxis, to attenuate clinical progression to severe COVID-19. Therapies for COVID-19 are mostly available for adults and in the inpatient and outpatient settings. Selection and administration of the best treatment options are based on host factors; virus factors, including circulating SARS-CoV-2 variants; and therapeutic considerations, including the clinical efficacy, availability, and practicality of treatment and its associated side effects, including drug-drug interactions. In this paper, we discuss how we approach managing COVID-19 in patients with hematologic malignancies and recipients of HCT and cell therapy.

The Editors of Bloodretract the 1 March 2005 paper cited above. Concerns regarding the duplication of several outlying data points in Figure 4 were brought to the journal’s attention. A search for original source data was unsuccessful. As a result, the data underlying this figure cannot be validated, and the paper has been retracted.

Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2 study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute graft-versus-host disease (GVHD) grades 2 to 4 and 3 to 4 were 33% and 5%, respectively; 2 cases of mild (10%) and 1 case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) rates were 85%, 71%, and 0%, respectively. In a matched analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab’s efficacy. Correlative studies of baseline and posttreatment samples identified patients with specific T-cell profiles as “responders” or “nonresponders” to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Nonresponders were T-cell deficient and expressed more inhibitory checkpoint molecules, including T-cell immunoglobulin and mucin domain 3 (TIM3). We found that blinatumomab postallogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment. This paper is posted on ClinicalTrials.gov, study ID: NCT02807883.

This year we celebrate Blood's 70th year of publication. Created from the partnership of the book publisher Henry M. Stratton and the prominent hematologist Dr William Dameshek of Tufts School of Medicine, Blood has published many papers describing major advances in the science and clinical practice of hematology. Blood's founding antedated that of the American Society of Hematology (ASH) by more than 11 years and Stratton and Dameshek helped galvanize support for the creation of ASH. In this review, I place the birth of Blood in the context of the history of hematology before 1946, emphasizing the American experience from which it emerged, and focusing on research conducted during World War II. I also provide a few milestones along Blood's 70 years of publication, including: the growth in Blood's publications, the evolution of its appearance, the countries of submission of Blood papers, current subscriptions to Blood, and the evolution of topics reported in Blood's papers. The latter provides a snapshot of the evolution of hematology as a scientific and clinical discipline and the introduction of new technology to study blood and bone marrow. Detailed descriptions of the landmark discoveries reported in Blood will appear in later papers celebrating Blood's birthday authored by past Editors-in-Chief.

This year we celebrate Blood's 70th year of publication. Created from the partnership of the book publisher Henry M. Stratton and the prominent hematologist Dr William Dameshek of Tufts School of Medicine, Bloodhas published many papers describing major advances in the science and clinical practice of hematology. Blood's founding antedated that of the American Society of Hematology (ASH) by more than 11 years and Stratton and Dameshek helped galvanize support for the creation of ASH. In this review, I place the birth of Bloodin the context of the history of hematology before 1946, emphasizing the American experience from which it emerged, and focusing on research conducted during World War II. I also provide a few milestones along Blood's 70 years of publication, including: the growth in Blood's publications, the evolution of its appearance, the countries of submission of Bloodpapers, current subscriptions to Blood, and the evolution of topics reported in Blood's papers. The latter provides a snapshot of the evolution of hematology as a scientific and clinical discipline and the introduction of new technology to study blood and bone marrow. Detailed descriptions of the landmark discoveries reported in Bloodwill appear in later papers celebrating Blood's birthday authored by past Editors-in-Chief.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.govas #NCT02152956.

Within the myelodysplastic syndrome (MDS) work package of the European LeukemiaNet, an Expert Panel was selected according to the framework elements of the National Institutes of Health Consensus Development Program. A systematic review of the literature was performed that included indexed original papers, indexed reviews and educational papers, and abstracts of conference proceedings. Guidelines were developed on the basis of a list of patient- and therapy-oriented questions, and recommendations were formulated and ranked according to the supporting level of evidence. MDSs should be classified according to the 2008 World Health Organization criteria. An accurate risk assessment requires the evaluation of not only disease-related factors but also of those related to extrahematologic comorbidity. The assessment of individual risk enables the identification of fit patients with a poor prognosis who are candidates for up-front intensive treatments, primarily allogeneic stem cell transplantation. A high proportion of MDS patients are not eligible for potentially curative treatment because of advanced age and/or clinically relevant comorbidities and poor performance status. In these patients, the therapeutic intervention is aimed at preventing cytopenia-related morbidity and preserving quality of life. A number of new agents are being developed for which the available evidence is not sufficient to recommend routine use. The inclusion of patients into prospective clinical trials is strongly recommended.

Within the myelodysplastic syndrome (MDS) work package of the European LeukemiaNet, an Expert Panel was selected according to the framework elements of the National Institutes of Health Consensus Development Program. A systematic review of the literature was performed that included indexed original papers, indexed reviews and educational papers, and abstracts of conference proceedings. Guidelines were developed on the basis of a list of patient- and therapy-oriented questions, and recommendations were formulated and ranked according to the supporting level of evidence. MDSs should be classified according to the 2008 World Health Organization criteria. An accurate risk assessment requires the evaluation of not only disease-related factors but also of those related to extrahematologic comorbidity. The assessment of individual risk enables the identification of fit patients with a poor prognosis who are candidates for up-front intensive treatments, primarily allogeneic stem cell transplantation. A high proportion of MDS patients are not eligible for potentially curative treatment because of advanced age and/or clinically relevant comorbidities and poor performance status. In these patients, the therapeutic intervention is aimed at preventing cytopenia-related morbidity and preserving quality of life. A number of new agents are being developed for which the available evidence is not sufficient to recommend routine use. The inclusion of patients into prospective clinical trials is strongly recommended.

Previous studies have demonstrated that sickle cell disease (SCD) can be corrected in mouse models by transduction of hematopoietic stem cells with lentiviral vectors containing antisickling globin genes followed by transplantation of these cells into syngeneic recipients. Although self-inactivating (SIN) lentiviral vectors with or without insulator elements should provide a safe and effective treatment in humans, some concerns about insertional mutagenesis persist. An ideal correction would involve replacement of the sickle globin gene (βS) with a normal copy of the gene (βA). We recently derived embryonic stem (ES) cells from a novel knock-in mouse model of SCD and tested a protocol for correcting the sickle mutation by homologous recombination. In this paper, we demonstrate the replacement of the human βS-globin gene with a human βA-globin gene and the derivation of mice from these cells. The animals produce high levels of normal human hemoglobin (HbA) and the pathology associated with SCD is corrected. Hematologic values are restored to normal levels and organ pathology is ameliorated. These experiments provide a foundation for similar studies in human ES cells derived from sickle cell patients. Although efficient methods for production of human ES cells by somatic nuclear transfer must be developed, the data in this paper demonstrate that sickle cell disease can be corrected without the risk of insertional mutagenesis.

Previous studies have demonstrated that sickle cell disease (SCD) can be corrected in mouse models by transduction of hematopoietic stem cells with lentiviral vectors containing antisickling globin genes followed by transplantation of these cells into syngeneic recipients. Although self-inactivating (SIN) lentiviral vectors with or without insulator elements should provide a safe and effective treatment in humans, some concerns about insertional mutagenesis persist. An ideal correction would involve replacement of the sickle globin gene (βS) with a normal copy of the gene (βA). We recently derived embryonic stem (ES) cells from a novel knock-in mouse model of SCD and tested a protocol for correcting the sickle mutation by homologous recombination. In this paper, we demonstrate the replacement of the human βS-globin gene with a human βA-globin gene and the derivation of mice from these cells. The animals produce high levels of normal human hemoglobin (HbA) and the pathology associated with SCD is corrected. Hematologic values are restored to normal levels and organ pathology is ameliorated. These experiments provide a foundation for similar studies in human ES cells derived from sickle cell patients. Although efficient methods for production of human ES cells by somatic nuclear transfer must be developed, the data in this paper demonstrate that sickle cell disease can be corrected without the risk of insertional mutagenesis.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

Breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) is a recently described form of T-cell non-Hodgkin lymphoma now formally recognized by the World Health Organization classification of lymphoid neoplasms. The disease most often presents with a delayed seroma around the breast implant, almost exclusively with a textured surface, and manifests with breast pain, swelling or asymmetry, capsular contracture, but can also present with a breast mass, and lymph node involvement. The prognosis of BIA-ALCL is favorable compared with many other subtypes of systemic T-cell lymphoma; however, unlike other non-Hodgkin lymphomas, complete surgical excision for localized disease is an important part of the management of these patients. In this paper, we share our recommendations for a multidisciplinary team approach to the diagnosis, workup, and treatment of BIA-ALCL in line with consensus guidelines by the National Comprehensive Cancer Network.

Breast implant–associated anaplastic large cell lymphoma (BIA-ALCL) is a recently described form of T-cell non-Hodgkin lymphoma now formally recognized by the World Health Organization classification of lymphoid neoplasms. The disease most often presents with a delayed seroma around the breast implant, almost exclusively with a textured surface, and manifests with breast pain, swelling or asymmetry, capsular contracture, but can also present with a breast mass, and lymph node involvement. The prognosis of BIA-ALCL is favorable compared with many other subtypes of systemic T-cell lymphoma; however, unlike other non-Hodgkin lymphomas, complete surgical excision for localized disease is an important part of the management of these patients. In this paper, we share our recommendations for a multidisciplinary team approach to the diagnosis, workup, and treatment of BIA-ALCL in line with consensus guidelines by the National Comprehensive Cancer Network.

OBJECTIVE:The presence of transient abnormal protein banding (i.e. M-protein immune reconstitution) in serum immunofixation electrophoresis after autologous hematopoietic stem cell transplantation in patients with multiple myeloma has been reported, and patients with high-risk cytogenetics tend to have poor prognosis; the purpose of this paper is to investigate the impact of post-transplant M-protein immune reconstitution on the prognosis of patients with high-risk cytogenetic multiple myeloma;

The BCR::ABL1fusion gene is a hallmark of chronic myeloid leukemia (CML) but is also found in patients with acute lymphoblastic leukemia (ALL). There are two main breakpoint clusters in BCR- “minor” (between exons 1-2, resulting in p190 fusion protein, prevalent in ALL and scarce in CML) and “Major” (between exons 13-15, resulting in p210 protein). On the ABL1side, the breakpoints are mostly localized between exons 1-3. Due to large intronic areas where the breakpoints occur, only a few papers have been published focusing on the structure of BCR::ABL1fusions. Moreover, with a single exception, these studies included only the Major- BCR::ABL1patients. Here, we focused on the analysis of BCR::ABL1breakpoints involving CML and ALL, children and adults, and Major and minor forms of fusion. To our knowledge, we present data on the largest cohort of patients with BCR::ABL1fusion identified at the DNA level described to date.

The Florida Department of Health's Division of Children's Medical Services administers, with facilitation service from the National Institute for Children's Health Quality, a Statewide Network of Access and Quality program composed of five pediatric hematology-oncology organizations throughout Florida. Recognizing the importance of an adequate transition process to minimize morbidity and even mortality among youth with sickle cell disease (SCD), we have worked together for three years in several projects related to transition including educating medical providers and our own practices about SCD, transition, and GotTransition™ Six Core Elements ®. In June 2022, we began a new project with the aim statement that by December 2023, 80% or higher of the sickle cell patients ages 14-21 years attending clinic at the five hematology centers would have a readiness assessment and a transition plan updated at least once during the previous 12 months as assessed on monthly chart audits. At onset, 486 patients met criteria to be on a transition program due to age and cognitive ability. Two programs had previously participated in The Sickle Cell Trevor Thompson Transition Project (ST3P Up) (NCT 03593395), a Patient-Centered Outcomes Research Institute (PCORI) sponsored sickle cell transition study and learned to implement the GotTransition Six Core Elements. Three programs did not have transition programs implemented. The change ideas were either collective or implemented in a particular program depending on the program decision. The collective change ideas consisted of educating the clinical staff about GotTransition and quality improvement strategies, identifying eligible patients through patient roster, and implementing either monthly audits of ten random charts or reviewing charts of all patients who came the previous month for missed opportunities. The program-specific change ideas consisted of prospective review of patients who were scheduled to come to clinic within the week, staff huddles to discuss patients on transition, conversion of paper-based ASH or TIP-RFT sickle cell readiness assessment into electronic medical record (EMR) version, the use of smart phrases to document the readiness assessment and plan, and sharing ownership of the process with different members of the staff for sustainability. Data and learning from improvement strategies were reviewed twice a month with all group members in virtual one-hour meetings. Two quality improvement consultants encouraged and coached sites.