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Patients treated with antineoplastic therapy often develop thrombocytopenia requiring platelet transfusion, which has potential to exacerbate pulmonary injury. This study tested the hypothesis that amotosalen-UVA pathogen-reduced platelet components (PRPCs) do not potentiate pulmonary dysfunction compared with conventional platelet components (CPCs). A prospective, multicenter, open-label, sequential cohort study evaluated the incidence of treatment-emergent assisted mechanical ventilation initiated for pulmonary dysfunction (TEAMV-PD). The first cohort received CPC. After the CPC cohort, each site enrolled a second cohort transfused with PRPC. Other outcomes included clinically significant pulmonary adverse events (CSPAE) and the incidence of treatment-emergent acute respiratory distress syndrome (TEARDS) diagnosed by blinded expert adjudication. The incidence of TEAMV-PD in all patients (1068 PRPC and 1223 CPC) was less for PRPC (1.7 %) than CPC (3.1%) with a treatment difference of -1.5% (95% confidence interval [CI], -2.7 to -0.2). In patients requiring ≥2 PCs, the incidence of TEAMV-PD was reduced for PRPC recipients compared with CPC recipients (treatment difference, -2.4%; 95% CI, -4.2 to -0.6). CSPAE increased with increasing PC exposure but were not significantly different between the cohorts. For patients receiving ≥2 platelet transfusions, TEARDS occurred in 1.3% PRPC and 2.6% CPC recipients (P = .086). Bayesian analysis demonstrated PRPC may be superior in reducing TEAMV-PD and TEARDS for platelet transfusion recipients compared with CPC recipients, with 99.2% and 88.8% probability, respectively. In this study, PRPC compared with CPC demonstrated high probability of reduced severe pulmonary injury requiring assisted mechanical ventilation in patients with hematology disorders dependent on platelet transfusion. This trial was registered at www.ClinicalTrials.gov as #NCT02549222.

Objective: To investigate the quality of life (QoL) and the impact of caregiving in family caregivers of hematological cancer patients and its association with patient symptom burden. Methods: A cross-sectional study including Danish patients (n = 375) and caregivers (n = 140). Caregivers completed scales for anxiety and depression using the Hospital Anxiety and Depression Scale, sleep quality using the Pittsburgh Sleep Quality Index, health related QoL using the 12-item Short-Form Health Survey, and caregiver roles using the Caregiver Roles and Responsibilities Scale. Patients reported symptoms using the MD Anderson Symptom Inventory. Analysis of covariance was used to examine associations between patient symptom burden and caregivers' QoL outcomes. Results: The results show that caregivers experience sleep difficulties, moderate anxiety, and reduced QoL. Patient symptom burden was significantly associated with caregiver anxiety (p = 0.009), and mental well-being (p = 0.002), while patient treatment status was a significant factor associated with caregiver anxiety (p = 0.016), depression (p = 0.009), emotional well-being (p = 0.002), and sleep (p = 0.01). Conclusion: Caregivers of patients with hematological cancers undergoing active treatment face a high symptom burden, which significantly impacts their QoL, including sleep, psychological well-being, and emotional health. Patients reported a high symptom burden, and patient symptom burden was significantly associated with caregiver QoL. Adequate patient and caregiver support is needed to promote their well-being and mitigate adverse health effects in caregivers, and this should be acknowledged in the context of caring for patients with hematological cancer.

Objective: To investigate the quality of life (QoL) and the impact of caregiving in family caregivers of hematological cancer patients and its association with patient symptom burden. Methods: A cross-sectional study including Danish patients (n = 375) and caregivers (n = 140). Caregivers completed scales for anxiety and depression using the Hospital Anxiety and Depression Scale, sleep quality using the Pittsburgh Sleep Quality Index, health related QoL using the 12-item Short-Form Health Survey, and caregiver roles using the Caregiver Roles and Responsibilities Scale. Patients reported symptoms using the MD Anderson Symptom Inventory. Analysis of covariance was used to examine associations between patient symptom burden and caregivers' QoL outcomes. Results: The results show that caregivers experience sleep difficulties, moderate anxiety, and reduced QoL. Patient symptom burden was significantly associated with caregiver anxiety (p = 0.009), and mental well-being (p = 0.002), while patient treatment status was a significant factor associated with caregiver anxiety (p = 0.016), depression (p = 0.009), emotional well-being (p = 0.002), and sleep (p = 0.01). Conclusion: Caregivers of patients with hematological cancers undergoing active treatment face a high symptom burden, which significantly impacts their QoL, including sleep, psychological well-being, and emotional health. Patients reported a high symptom burden, and patient symptom burden was significantly associated with caregiver QoL. Adequate patient and caregiver support is needed to promote their well-being and mitigate adverse health effects in caregivers, and this should be acknowledged in the context of caring for patients with hematological cancer.

BackgroundKDM6A is a demethylase encoded by a gene with female-biased expression due to escape from X inactivation. Its main role is to facilitate gene expression through removal of the repressive H3K27me3 mark, with evidence of some additional histone demethylase-independent functions. KDM6A mutations have been implicated in congenital disorders such as Kabuki Syndrome, as well as in sex differences in cancer.MethodsKdm6a was knocked out using CRISPR/Cas9 gene editing in F1 male and female mouse embryonic stem cells (ES) derived from reciprocal crosses between C57BL6 x Mus castaneus. Diploid and allelic RNA-seq analyses were done to compare gene expression between wild-type and Kdm6a knockout (KO) clones. The effects of Kdm6a KO on sex-biased gene expression were investigated by comparing gene expression between male and female ES cells. Changes in H3K27me3 enrichment and chromatin accessibility at promoter regions of genes with expression changes were characterized by ChIP-seq and ATAC-seq followed by diploid and allelic analyses.ResultsWe report that Kdm6a KO in male and female embryonic stem (ES) cells derived from F1 hybrid mice cause extensive gene dysregulation, disruption of sex biases, and specific parental allele effects. Among the dysregulated genes are candidate genes that may explain abnormal developmental features of Kabuki syndrome caused by KDM6A mutations in human. Strikingly, Kdm6a knockouts result in a decrease in sex-biased expression and in preferential downregulation of the maternal alleles of a number of genes. Most promoters of dysregulated genes show concordant epigenetic changes including gain of H3K27me3 and loss of chromatin accessibility, but there was less concordance when considering allelic changes.ConclusionsOur study reveals new sex-related roles of KDM6A in the regulation of developmental genes, the maintenance of sex-biased gene expression, and the differential expression of parental alleles.

BackgroundKDM6A is a demethylase encoded by a gene with female-biased expression due to escape from X inactivation. Its main role is to facilitate gene expression through removal of the repressive H3K27me3 mark, with evidence of some additional histone demethylase-independent functions. KDM6A mutations have been implicated in congenital disorders such as Kabuki Syndrome, as well as in sex differences in cancer.MethodsKdm6a was knocked out using CRISPR/Cas9 gene editing in F1 male and female mouse embryonic stem cells (ES) derived from reciprocal crosses between C57BL6 x Mus castaneus. Diploid and allelic RNA-seq analyses were done to compare gene expression between wild-type and Kdm6a knockout (KO) clones. The effects of Kdm6a KO on sex-biased gene expression were investigated by comparing gene expression between male and female ES cells. Changes in H3K27me3 enrichment and chromatin accessibility at promoter regions of genes with expression changes were characterized by ChIP-seq and ATAC-seq followed by diploid and allelic analyses.ResultsWe report that Kdm6a KO in male and female embryonic stem (ES) cells derived from F1 hybrid mice cause extensive gene dysregulation, disruption of sex biases, and specific parental allele effects. Among the dysregulated genes are candidate genes that may explain abnormal developmental features of Kabuki syndrome caused by KDM6A mutations in human. Strikingly, Kdm6a knockouts result in a decrease in sex-biased expression and in preferential downregulation of the maternal alleles of a number of genes. Most promoters of dysregulated genes show concordant epigenetic changes including gain of H3K27me3 and loss of chromatin accessibility, but there was less concordance when considering allelic changes.ConclusionsOur study reveals new sex-related roles of KDM6A in the regulation of developmental genes, the maintenance of sex-biased gene expression, and the differential expression of parental alleles.

Hyperviscosity syndrome (HVS) is a rare complication of newly diagnosed multiple myeloma (NDMM) related to high tumour burden. Studies about the prognosis of HVS in modern-era therapy for NDMM are missing. We investigated a retrospective cohort study of NDMM with HVS between 2011-2021. Thirty-nine NDMM patients with HVS were included. HVS presentation was heterogeneous, with asymptomatic, mild, and neurological forms in 23%, 59%, and 18% of cases, respectively. No thrombosis or major bleeding was observed. Therapeutic plasma exchanges were used in 92% of patients, which were effective and well tolerated. No rebound effect was observed. All patients except one had at least one CRAB criterion. Most of the patients received bortezomib and high-dose steroids (95%) associated with an immunomodulatory drug (43%) or alkylating agents (42%). HVS in NDMM patients had dismal overall survival matched to multiple myeloma patient controls (without HVS) in our center (median: 3.6 vs. 7.7 years, p=0.01), as confirmed by multivariate analysis. Early deaths (in the first two months) occurred in 21% of older patients (>65 years). HVS in NDMM patients is a rare but life-threatening complication associated with high lethality in older patients and be a potential dismal prognosis factor in the modern treatment era.

Background: Canine immune thrombocytopenia (ITP) ranges from a mild to severe bleeding disorder, and platelet counts do not reliably predict clinical disease course. The detection of platelet autoantibodies may further define the disease phenotype, but variability in assay configurations and a lack of well-characterized controls limit the diagnostic utility of anti-platelet antibody assays. Objectives: We aimed to develop control reagents to facilitate the characterization of canine platelet surface-associated immunoglobulin (PSAIg) in flow cytometric assays. Methods: Silica microspheres were coated with canine IgG and IgM to assess the reactivity of goat and rabbit origin anti-canine immunoglobulin reagents. They were also used as positive controls in the PSAIg assay. Preliminary assay evaluation and determination of sample stability used PRP isolated from seven healthy dogs and 26 dogs newly diagnosed with thrombocytopenia. Results: Blood sample stability was established for up to a 48-hour storage time. The conjugated positive control microspheres demonstrated stable fluorescent labeling over a 2-year observation period. Rabbit and goat origin anti-dog IgM fluorescent antibody labels reacted nonspecifically with canine IgG. Rabbit origin anti-dog IgG antibody demonstrated greater class specificity for canine IgG than a goat origin antibody. Thrombocytopenic dogs had a broad range of membrane-bound immunoglobulin. Median PSAIgG for dogs with primary or secondary ITP (18.4%, 34.1%, respectively) were significantly higher than controls (3.8%, P <.05). Conclusions: The described assay reagents and procedures provide positive controls and allow consistent thresholding to define a positive test result, suitable for any flow cytometer. A rabbit anti-dog IgG fluorescent label demonstrated specificity for canine IgG and was useful for the detection of PSAIgG in thrombocytopenic dogs.

Most eukaryotes harbor two distinct pre-mRNA splicing machineries: the major spliceosome, which removes >99% of introns, and the minor spliceosome, which removes rare, evolutionarily conserved introns. Although hypothesized to serve important regulatory functions, physiologic roles of the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations, yet functional connections among minor introns, hematopoiesis and cancers are unclear. Here, we identify that impaired minor intron excision via ZRSR2 loss enhances hematopoietic stem cell self-renewal. CRISPR screens mimicking nonsense-mediated decay of minor intron-containing mRNA species converged on LZTR1, a regulator of RAS-related GTPases. LZTR1 minor intron retention was also discovered in the RASopathy Noonan syndrome, due to intronic mutations disrupting splicing and diverse solid tumors. These data uncover minor intron recognition as a regulator of hematopoiesis, noncoding mutations within minor introns as potential cancer drivers and links among ZRSR2 mutations, LZTR1 regulation and leukemias.

Most eukaryotes harbor two distinct pre-mRNA splicing machineries: the major spliceosome, which removes >99% of introns, and the minor spliceosome, which removes rare, evolutionarily conserved introns. Although hypothesized to serve important regulatory functions, physiologic roles of the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations, yet functional connections among minor introns, hematopoiesis and cancers are unclear. Here, we identify that impaired minor intron excision via ZRSR2 loss enhances hematopoietic stem cell self-renewal. CRISPR screens mimicking nonsense-mediated decay of minor intron-containing mRNA species converged on LZTR1, a regulator of RAS-related GTPases. LZTR1 minor intron retention was also discovered in the RASopathy Noonan syndrome, due to intronic mutations disrupting splicing and diverse solid tumors. These data uncover minor intron recognition as a regulator of hematopoiesis, noncoding mutations within minor introns as potential cancer drivers and links among ZRSR2 mutations, LZTR1 regulation and leukemias.

Antimicrobial stewardship programs (ASPs) in hematological patients are especially relevant. However, information about ASPs in this population is scarce. For 11 years, we quarterly assessed antimicrobial consumption and incidence and death rates of multidrug-resistant (MDR) bloodstream infections (BSI) in the hematology Department. Healthcare activity indicators were also monitored yearly. We performed an interrupted time-series analysis. Antimicrobials showed a sustained reduction with a relative effect of −62.3% (95% CI −84.5 to −40.1) nine years after the inception of the ASP, being especially relevant for antifungals (relative effect −80.4%, −90.9 to −69.9), quinolones (relative effect −85.0%, −102.0 to −68.1), and carbapenems (relative effect −68.8%, −126.0 to −10.6). Incidence density of MDR BSI remained low and stable (mean 1.10 vs. 0.82 episodes per 1000 occupied bed days for the pre-intervention and the ASP period, respectively) with a quarterly percentage of change of −0.3% (95% CI −2.0 to 1.4). Early and late mortality of MDR BSI presented a steady trend (quarterly percentage of change −0.7%, 95% CI −1.7 to 0.3 and −0.6%, 95% CI −1.5 to 0.3, respectively). Volume and complexity of healthcare activity increased over the years. The ASP effectively achieved long-term reductions in antimicrobial consumption and improvements in the prescription profile, without increasing the mortality of MDR BSI

American Society of Hematology conducts an annual meeting, where investigators from around the globe presented ground-breaking research in the fields of malignant and non-malignant hematology. We provide a summary of non-malignant hematology abstracts from the 2020 meeting. Topics included range from those related to thrombosis, including thrombotic complications of COVID-19, bleeding and novel therapies such as gene therapies. Readers are encouraged to access meeting materials for a more detailed coverage of the event.

Antimicrobial stewardship programs (ASPs) in hematological patients are especially relevant. However, information about ASPs in this population is scarce. For 11 years, we quarterly assessed antimicrobial consumption and incidence and death rates of multidrug-resistant (MDR) bloodstream infections (BSI) in the hematology Department. Healthcare activity indicators were also monitored yearly. We performed an interrupted time-series analysis. Antimicrobials showed a sustained reduction with a relative effect of −62.3% (95% CI −84.5 to −40.1) nine years after the inception of the ASP, being especially relevant for antifungals (relative effect −80.4%, −90.9 to −69.9), quinolones (relative effect −85.0%, −102.0 to −68.1), and carbapenems (relative effect −68.8%, −126.0 to −10.6). Incidence density of MDR BSI remained low and stable (mean 1.10 vs. 0.82 episodes per 1000 occupied bed days for the pre-intervention and the ASP period, respectively) with a quarterly percentage of change of −0.3% (95% CI −2.0 to 1.4). Early and late mortality of MDR BSI presented a steady trend (quarterly percentage of change −0.7%, 95% CI −1.7 to 0.3 and −0.6%, 95% CI −1.5 to 0.3, respectively). Volume and complexity of healthcare activity increased over the years. The ASP effectively achieved long-term reductions in antimicrobial consumption and improvements in the prescription profile, without increasing the mortality of MDR BSI

Antimicrobial stewardship programs (ASPs) in hematological patients are especially relevant. However, information about ASPs in this population is scarce. For 11 years, we quarterly assessed antimicrobial consumption and incidence and death rates of multidrug-resistant (MDR) bloodstream infections (BSI) in the hematology Department. Healthcare activity indicators were also monitored yearly. We performed an interrupted time-series analysis. Antimicrobials showed a sustained reduction with a relative effect of −62.3% (95% CI −84.5 to −40.1) nine years after the inception of the ASP, being especially relevant for antifungals (relative effect −80.4%, −90.9 to −69.9), quinolones (relative effect −85.0%, −102.0 to −68.1), and carbapenems (relative effect −68.8%, −126.0 to −10.6). Incidence density of MDR BSI remained low and stable (mean 1.10 vs. 0.82 episodes per 1000 occupied bed days for the pre-intervention and the ASP period, respectively) with a quarterly percentage of change of −0.3% (95% CI −2.0 to 1.4). Early and late mortality of MDR BSI presented a steady trend (quarterly percentage of change −0.7%, 95% CI −1.7 to 0.3 and −0.6%, 95% CI −1.5 to 0.3, respectively). Volume and complexity of healthcare activity increased over the years. The ASP effectively achieved long-term reductions in antimicrobial consumption and improvements in the prescription profile, without increasing the mortality of MDR BSI

The ability to predict invasive fungal infections (IFI) in patients with hematological malignancies is fundamental for successful therapy. Although gut dysbiosis is known to occur in hematological patients, whether airway dysbiosis also contributes to the risk of IFI has not been investigated. Nasal and oropharyngeal swabs were collected for functional microbiota characterization in 173 patients with hematological malignancies recruited in a multicenter, prospective, observational study and stratified according to the risk of developing IFI. A lower microbial richness and evenness were found in the pharyngeal microbiota of high-risk patients that were associated with a distinct taxonomic and metabolic profile. A murine model of IFI provided biologic plausibility for the finding that loss of protective anaerobes, such as Clostridiales and Bacteroidetes, along with an apparent restricted availability of tryptophan, is causally linked to the risk of IFI in hematologic patients and indicates avenues for antimicrobial stewardship and metabolic reequilibrium in IFI.

This retrospective study assessed the effectiveness of eltrombopag (EPAG), a thrombopoietin receptor agonist, in the treatment of poor graft function (PGF) following an allogeneic haemopoietic stem cell transplantation (HSCT). Complete response was defined as normalization of blood counts, whereas partial response was defined as transfusion independence. A total of 48 patients with full donor chimerism after HSCT, received EPAG for a median of 120 days (range 10–591). Patients with uni- bi- or tri-lineage cytopenia started treatment at a median of 95 days (range 17–877) after HSCT. The overall response rate was 75%: 24 patients had a complete response and 12 had a partial response. Positive predictors of response were an HLA-matched donor, a CD34+ dose at transplant > 4 × 106/kg, and starting EPAG treatment at least 90 days after HSCT. Patients with more than one positive predictor had a response rate of 92% for the overall patient cohort and 94% for patients with tri-lineage cytopenia. One-year survival was 89% for complete responders, 60% for partial responders and 20% for non-responders (p = 0.0004). EPAG improves peripheral blood counts in patients with poor graft function following HSCT. Response to EPAG can be predicted and has a significant impact on survival.

Somatic KRAS mutations are highly prevalent in many cancers. In addition, a distinct spectrum of germline KRAS mutations causes developmental disorders called RASopathies. The mutant proteins encoded by these germline KRAS mutations are less biochemically and functionally activated than those in cancer. We generated mice harboring conditional KrasLSL-P34Rand KrasLSL-T58I knock-in alleles and characterized the consequences of each mutation in vivo. Embryonic expression of KrasT58I resulted in craniofacial abnormalities reminiscent of those seen in RASopathy disorders, and these mice exhibited hyperplastic growth of multiple organs, modest alterations in cardiac valvulogenesis, myocardial hypertrophy, and myeloproliferation. By contrast, embryonic KrasP34R expression resulted in early perinatal lethality from respiratory failure due to defective lung sacculation, which was associated with aberrant ERK activity in lung epithelial cells. Somatic Mx1-Cre-mediated activation in the hematopoietic compartment showed that KrasP34R and KrasT58I expression had distinct signaling effects, despite causing a similar spectrum of hematologic diseases. These potentially novel strains are robust models for investigating the consequences of expressing endogenous levels of hyperactive K-Ras in different developing and adult tissues, for comparing how oncogenic and germline K-Ras proteins perturb signaling networks and cell fate decisions, and for performing preclinical therapeutic trials.

Myelosuppression is one of the most common and severe adverse events associated with anti-cancer therapies and can be a source of drug attrition. Current mathematical modeling methods for assessing cytopenia risk rely on indirect measurements of drug effects and primarily focus on single lineage responses to drugs. However, anti-cancer therapies have diverse mechanisms with varying degrees of effect across hematopoietic lineages. To improve predictive understanding of drug-induced myelosuppression, we developed a quantitative systems pharmacology (QSP) model of hematopoiesis in vitro for quantifying the effects of anti-cancer agents on multiple hematopoietic cell lineages. We calibrated the system parameters of the model to cell kinetics data without treatment and then validated the model by showing that the inferred mechanisms of anti-proliferation and/or cell-killing are consistent with the published mechanisms for three classes of drugs with different mechanisms of action. Using a set of compounds as a reference set, we then analyzed novel compounds to predict their mechanisms and magnitude of myelosuppression. Further, these quantitative mechanisms are valuable for the development of translational in vivo models to predict clinical cytopenia effects.

BACKGROUND: To study etiologies of anemia using an extensive laboratory analysis in general practices. METHOD: An extensive laboratory analysis was performed in blood of newly diagnosed anemia patients aged ≥50 years from the general population in the city of Dordrecht area, the Netherlands. Eight laboratory-orientated etiologies of anemia were defined. Patients were assigned one or more of these etiologies on the basis of their test results. RESULTS: Blood of 4152 patients (median age 75 years; 49% male) was analyzed. The anemia etiology was unclear in 20%; a single etiology was established in 59%; and multiple etiologies in 22% of the patients. The most common etiologies were anemia of chronic disease (ACD) (54.5%), iron deficiency anemia (IDA) (19.1%) and renal anemia (13.8%). The most common single etiologies were IDA (82%) and ACD (68%), while the multiple etiologies most commonly included folic acid deficiency (94%) and suspected bone marrow disease (88%). Older age was associated with a lower incidence of IDA and a higher incidence of renal anemia. Mild anemia was more often associated with ACD and uncertain anemia, while severe anemia was mainly seen in patients with IDA. CONCLUSION: Extensive laboratory analysis in anemic patients from the general population helped clarify the etiology of anemia and revealed many various combinations of etiologies in a significant proportion of patients. Age, sex and the severity of anemia are predictive of the underlying etiology.

Myelosuppression is one of the most common and severe adverse events associated with anti-cancer therapies and can be a source of drug attrition. Current mathematical modeling methods for assessing cytopenia risk rely on indirect measurements of drug effects and primarily focus on single lineage responses to drugs. However, anti-cancer therapies have diverse mechanisms with varying degrees of effect across hematopoietic lineages. To improve predictive understanding of drug-induced myelosuppression, we developed a quantitative systems pharmacology (QSP) model of hematopoiesis in vitro for quantifying the effects of anti-cancer agents on multiple hematopoietic cell lineages. We calibrated the system parameters of the model to cell kinetics data without treatment and then validated the model by showing that the inferred mechanisms of anti-proliferation and/or cell-killing are consistent with the published mechanisms for three classes of drugs with different mechanisms of action. Using a set of compounds as a reference set, we then analyzed novel compounds to predict their mechanisms and magnitude of myelosuppression. Further, these quantitative mechanisms are valuable for the development of translational in vivo models to predict clinical cytopenia effects.

Somatic KRAS mutations are highly prevalent in many cancers. In addition, a distinct spectrum of germline KRAS mutations causes developmental disorders called RASopathies. The mutant proteins encoded by these germline KRAS mutations are less biochemically and functionally activated than those in cancer. We generated mice harboring conditional KrasLSL-P34Rand KrasLSL-T58I knock-in alleles and characterized the consequences of each mutation in vivo. Embryonic expression of KrasT58I resulted in craniofacial abnormalities reminiscent of those seen in RASopathy disorders, and these mice exhibited hyperplastic growth of multiple organs, modest alterations in cardiac valvulogenesis, myocardial hypertrophy, and myeloproliferation. By contrast, embryonic KrasP34R expression resulted in early perinatal lethality from respiratory failure due to defective lung sacculation, which was associated with aberrant ERK activity in lung epithelial cells. Somatic Mx1-Cre-mediated activation in the hematopoietic compartment showed that KrasP34R and KrasT58I expression had distinct signaling effects, despite causing a similar spectrum of hematologic diseases. These potentially novel strains are robust models for investigating the consequences of expressing endogenous levels of hyperactive K-Ras in different developing and adult tissues, for comparing how oncogenic and germline K-Ras proteins perturb signaling networks and cell fate decisions, and for performing preclinical therapeutic trials.

Sickle cell disease (SCD) is the most common inherited blood disorder in the United States. It is a medically and socially complex, multisystem illness that affects individuals throughout the lifespan. Given improvements in care, most children with SCD survive into adulthood. However, access to adult sickle cell care is poor in many parts of the United States, resulting in increased acute care utilization, disjointed care delivery, and early mortality for patients. A dearth of nonmalignant hematology providers, the lack of a national SCD registry, and the absence of a centralized infrastructure to facilitate comparative quality assessment compounds these issues. As part of a workshop designed to train health care professionals in the skills necessary to establish clinical centers focused on the management of adults living with SCD, we defined an SCD center, elucidated required elements of a comprehensive adult SCD center, and discussed different models of care. There are also important economic impacts of these centers at an institutional and health system level. As more clinicians are trained in providing adult-focused SCD care, center designation will enhance the ability to undertake quality improvement and compare outcomes between SCD centers. Activities will include an assessment of the clinical effectiveness of expanded access to care, the implementation of SCD guidelines, and the efficacy of newly approved targeted medications. Details of this effort are provided.

Purpose of reviewRas pathway mutations are one of the most common type of alterations in pediatric hematologic malignancies and are frequently associated with adverse outcomes. Despite ongoing efforts to use targeted treatments, there remain no Food and Drug Administration (FDA)-approved medications specifically for children with Ras pathway-mutated leukemia. This review will summarize the role of Ras pathway mutations in pediatric leukemia, discuss the current state of Ras pathway inhibitors and highlight the most promising agents currently being evaluated in clinical trials.Recent findingsEfficacy using RAF and MEK inhibitors has been demonstrated across multiple solid and brain tumors, and these are now considered standard-of-care for certain tumor types in adults and children. Clinical trials are now testing these medications for the first time in pediatric hematologic disorders, such as acute lymphoblastic leukemia, juvenile myelomonocytic leukemia, and histiocytic disorders. Novel inhibitors of the Ras pathway, including direct RAS inhibitors, are also being tested in clinical trials across a spectrum of pediatric and adult malignancies.SummaryActivation of the Ras pathway is a common finding in pediatric hematologic neoplasms. Implementation of precision medicine with a goal of improving outcomes for these patients will require testing of Ras pathway inhibitors in combination with other drugs in the context of current and future clinical trials.

Immune checkpoint inhibitors have improved outcomes for patients with numerous hematological and solid cancers. Hematologic toxicities have been described, but the spectrum, timing, and clinical presentation of these complications are not well understood. We used the World Health Organizations pharmacovigilance database of individual-case-safety-reports (ICSRs) of adverse drug reactions, VigiBase, to identify cases of hematologic toxicities complicating immune checkpoint inhibitor therapy. We identified 168 ICSRs of immune thrombocytopenic purpura (ITP), hemolytic anemia (HA), hemophagocytic lymphohistiocytosis, aplastic anemia, and pure red cell aplasia in 164 ICSRs. ITP (n = 68) and HA (n = 57) were the most common of these toxicities and occurred concomitantly in four patients. These events occurred early on treatment (median 40 days) and were associated with fatal outcome in 12% of cases. Ipilimumab-based therapy (monotherapy or combination with anti-programmed death-1 [PD-1]) was associated with earlier onset (median 23 vs. 47.5 days, p = .006) than anti-PD-1/programmed death ligand-1 monotherapy. Reporting of hematologic toxicities has increased over the past 2 years (98 cases between January 2017 and March 2018 vs. 70 cases before 2017), possibly because of increased use of checkpoint inhibitors and improved recognition of toxicities. Future studies should evaluate incidence of hematologic toxicities, elucidate risk factors, and determine the most effective treatment algorithms. KEY POINTS: Immune-mediated hematologic toxicities are a potential side effect of immune checkpoint inhibitors (ICIs).Providers should monitor complete blood counts during treatment with ICIs.Corticosteroids are the mainstay of treatment for immune-mediated hematologic toxicities.Further research is needed to define patient-specific risk factors and optimal management strategies for hematologic toxicities.

Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707).

Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707).

Nutritional deficiencies, including deficiencies of vitamin B12, copper, and vitamin C, may result in cytopenias and hematologic symptoms. Early recognition of these deficiencies is imperative for prompt treatment and improvement in hematologic and other manifestations. We describe 5 cases which illustrate the hematologic manifestations of nutritional deficiencies and challenges to initial diagnosis and management. Supplementation of the deficient vitamin or micronutrient in all of these cases resulted in rapid resolution of cytopenias, hemorrhage, and other associated hematologic symptoms. We also review other nutritional deficiencies that manifest with hematologic symptoms and compile recommendations on treatment and expected time to response.

BACKGROUND: Laparoscopic splenectomy (LS) is considered the treatment of choice for benign hematologic diseases of the spleen. However, the role of LS in malignancies is still controversial. Technical difficulties, hemorrhagic risk, the need of pathological characterization of malignant disease, may be considered contraindications to LS in malignancies. This study aims to verify the efficacy and feasibility of LS for hematologic malignancies. METHODS: One hundred and forty-five patients underwent LS for hematologic disease and were retrospectively shared in two groups: Group A (N.=83) patients with preoperative diagnosis of benign hematologic disease and Group B (N.=62) with malignancies. Bipolar spleen diameter, mean operative time, conversion rate and causes, complications and need of transfusion were evaluated. RESULTS: Median splenic diameter was greater in Group B than in Group A with a statistically significant difference (P<0.005), and the number of accessory mini-laparotomies (P<0.005) and the conversion rate (P=0.024) in the group of patients with a diagnosis of malignancy were also higher. The mean operative time was 117.6 minutes in group A and 148.1 minutes in Group B (P<0.005). Besides, there were no significant differences relative to intraoperative and postoperative transfusions and the incidence of postoperative complications. No perioperative mortality occurred. CONCLUSIONS: The analysis of our data highlights that LS for hematologic malignancies is effective and feasible even if it associated with higher conversion rate due to splenomegaly and difficult hilum dissection. Besides, no differences in the patient outcome were highlighted. LS may be considered a safe procedure in the treatment of haematological malignancies of the spleen.

Recent years have seen important advances in the diagnosis of invasive pulmonary aspergillosis (IPA), complemented by the introduction of new therapies. Despite this, IPA remains a major cause of infection-related mortality in patients with haematological diseases. There are two main reasons for this. First, diagnosis of IPA remains a challenge, since risk factors and the clinical, radiological and mycological presentations vary not only by fungal disease stage, but also by patient group (eg neutropenic vs non-neutropenic patients). Diagnosis is particularly challenging in patients receiving mould-active prophylactic or empirical treatment, which reduces the sensitivity of all diagnostic tests for IPA. Second, treatment of IPA is complex due to unpredictable pharmacokinetic profiles of antifungal agents, small therapeutic window in terms of exposure and adverse events, and multiple drug-drug interactions through the CYP450 system. Here we report a case of a 23-year-old male with severe aplastic anaemia and subpleural nodules. Diagnostic tests for IPA obtained during ongoing mould-active empirical treatment were negative. Intravenous voriconazole was stopped after visual disturbances and hallucinations. The patient then had an anaphylactic reaction to liposomal amphotericin B and was switched to intravenous posaconazole, which had to be discontinued due to a significant increase in transaminase levels. He was treated with oral isavuconazole with reduced dosage, triggered by increasing transaminases under the standard dosage. Even under reduced dosage, blood concentrations of isavuconazole were high and treatment was successful. The case illustrates real-world challenges and unmet needs in the diagnosis and treatment of IPA in patients with haematological diseases.

The impact of underlying immune-mediated inflammatory diseases (IMID) in patients undergoing hematopoietic stem cell transplant (HSCT) is unclear. Hematopoietic cell transplantation co-morbidity index (HCT-CI) is gaining acceptance as a reliable clinical method to score pre-transplant co-morbidities. Higher HCT-CI from a co-morbid IMID implies higher NRM. However, HCT-CI integrates many IMIDs with different pathogenesis and treatment together which may lead to spurious results. We performed a cross-sectional study using Nationwide Inpatient Sample dataset from 1998 to 2011 to compare the outcomes of HSCT in patients with different co-morbid IMIDs with patients without any co-morbid IMIDs. In both our multivariate and stringent matched-pair analysis, ulcerative colitis (UC) was associated with increased mortality while rheumatoid arthritis and psoriasis were associated with lower mortality as compared to no IMID group. Furthermore, in allogeneic HSCT subgroup, UC was associated with higher mortality and psoriasis was associated with lower mortality. In conclusion, we found that depending on the type of HSCT, each IMID has a different impact on outcomes of HSCT. Furthermore, UC patients had increased mortality if they had primary sclerosing cholangitis and had a higher risk of opportunistic infections like tuberculosis and cytomegalovirus suggesting the need for increased vigilance in this cohort.

This randomized, open-label, phase 2b study (NCT01565668) evaluated the efficacy and safety of 2 dosing regimens of quizartinib monotherapy in patients with relapsed/refractory (R/R) FLT3-internal tandem duplication (ITD)-mutated acute myeloid leukemia (AML) who previously underwent transplant or 1 second-line salvage therapy. Patients (N = 76) were randomly assigned to 30- or 60-mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral quizartinib dihydrochloride. Allelic frequency of at least 10% was defined as FLT3-ITD-mutated disease. Coprimary endpoints were composite complete remission (CRc) rates and incidence of QT interval corrected by Fridericia's formula (QTcF) of more than 480 ms (grade 2 or greater). Secondary endpoints included overall survival (OS), duration of CRc, bridge to transplant, and safety. CRc rates were 47% in both groups, similar to earlier reports with higher quizartinib doses. Incidence of QTcF above 480 ms was 11% and 17%, and QTcF above 500 ms was 5% and 3% in the 30- and 60-mg groups, respectively, which is less than earlier reports with higher doses of quizartinib. Median OS (20.9 and 27.3 weeks), duration of CRc (4.2 and 9.1 weeks), and bridge to transplant rates (32% and 42%) were higher in the 60-mg groups than in the 30-mg group. Dose escalation occurred in 61% and 14% of patients in the 30- and 60-mg groups, respectively. This high clinical activity of quizartinib at the evaluated doses is consistent with previous reports with an improved safety profile. Need to dose-escalate more than half of patients who received quizartinib 30 mg also supports further investigation of treatment with quizartinib 60 mg/day.

Recent years have seen important advances in the diagnosis of invasive pulmonary aspergillosis (IPA), complemented by the introduction of new therapies. Despite this, IPA remains a major cause of infection-related mortality in patients with haematological diseases. There are two main reasons for this. First, diagnosis of IPA remains a challenge, since risk factors and the clinical, radiological and mycological presentations vary not only by fungal disease stage, but also by patient group (eg neutropenic vs non-neutropenic patients). Diagnosis is particularly challenging in patients receiving mould-active prophylactic or empirical treatment, which reduces the sensitivity of all diagnostic tests for IPA. Second, treatment of IPA is complex due to unpredictable pharmacokinetic profiles of antifungal agents, small therapeutic window in terms of exposure and adverse events, and multiple drug-drug interactions through the CYP450 system. Here we report a case of a 23-year-old male with severe aplastic anaemia and subpleural nodules. Diagnostic tests for IPA obtained during ongoing mould-active empirical treatment were negative. Intravenous voriconazole was stopped after visual disturbances and hallucinations. The patient then had an anaphylactic reaction to liposomal amphotericin B and was switched to intravenous posaconazole, which had to be discontinued due to a significant increase in transaminase levels. He was treated with oral isavuconazole with reduced dosage, triggered by increasing transaminases under the standard dosage. Even under reduced dosage, blood concentrations of isavuconazole were high and treatment was successful. The case illustrates real-world challenges and unmet needs in the diagnosis and treatment of IPA in patients with haematological diseases.

This randomized, open-label, phase 2b study (NCT01565668) evaluated the efficacy and safety of 2 dosing regimens of quizartinib monotherapy in patients with relapsed/refractory (R/R) FLT3-internal tandem duplication (ITD)-mutated acute myeloid leukemia (AML) who previously underwent transplant or 1 second-line salvage therapy. Patients (N = 76) were randomly assigned to 30- or 60-mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral quizartinib dihydrochloride. Allelic frequency of at least 10% was defined as FLT3-ITD-mutated disease. Coprimary endpoints were composite complete remission (CRc) rates and incidence of QT interval corrected by Fridericia's formula (QTcF) of more than 480 ms (grade 2 or greater). Secondary endpoints included overall survival (OS), duration of CRc, bridge to transplant, and safety. CRc rates were 47% in both groups, similar to earlier reports with higher quizartinib doses. Incidence of QTcF above 480 ms was 11% and 17%, and QTcF above 500 ms was 5% and 3% in the 30- and 60-mg groups, respectively, which is less than earlier reports with higher doses of quizartinib. Median OS (20.9 and 27.3 weeks), duration of CRc (4.2 and 9.1 weeks), and bridge to transplant rates (32% and 42%) were higher in the 60-mg groups than in the 30-mg group. Dose escalation occurred in 61% and 14% of patients in the 30- and 60-mg groups, respectively. This high clinical activity of quizartinib at the evaluated doses is consistent with previous reports with an improved safety profile. Need to dose-escalate more than half of patients who received quizartinib 30 mg also supports further investigation of treatment with quizartinib 60 mg/day.

The impact of underlying immune-mediated inflammatory diseases (IMID) in patients undergoing hematopoietic stem cell transplant (HSCT) is unclear. Hematopoietic cell transplantation co-morbidity index (HCT-CI) is gaining acceptance as a reliable clinical method to score pre-transplant co-morbidities. Higher HCT-CI from a co-morbid IMID implies higher NRM. However, HCT-CI integrates many IMIDs with different pathogenesis and treatment together which may lead to spurious results. We performed a cross-sectional study using Nationwide Inpatient Sample dataset from 1998 to 2011 to compare the outcomes of HSCT in patients with different co-morbid IMIDs with patients without any co-morbid IMIDs. In both our multivariate and stringent matched-pair analysis, ulcerative colitis (UC) was associated with increased mortality while rheumatoid arthritis and psoriasis were associated with lower mortality as compared to no IMID group. Furthermore, in allogeneic HSCT subgroup, UC was associated with higher mortality and psoriasis was associated with lower mortality. In conclusion, we found that depending on the type of HSCT, each IMID has a different impact on outcomes of HSCT. Furthermore, UC patients had increased mortality if they had primary sclerosing cholangitis and had a higher risk of opportunistic infections like tuberculosis and cytomegalovirus suggesting the need for increased vigilance in this cohort.

BackgroundMedication prior authorization (PA) is a commonly occurring requirement, particularly for medications used for rare conditions. Based on standard definitions, cancer and many blood disorders affecting children are rare. The study aims were to describe the relative frequency of PA requests and their association with payers and medications in order to identify opportunities to improve system efficiency.ProcedureRequests for medication PA were logged prospectively for patients seen at a single institution over a 7-month period. Period prevalence was used to estimate the relative frequency of PA requests. Descriptive statistics summarized the relationship among payers, medications, and approvals relative to the frequency of PA requests.ResultsFor the study duration of 150 clinic days, there were 5,583 patient visits. A total of 142 medication PA requests were received resulting in a period prevalence rate of 2.5% patient visits. Of the 137 medication PA requests with available outcome data, 135 (98.5%) were ultimately approved with additional provider efforts. The median clinic staff time spent per request was 46 min with an interquartile range of 25-80 min. There was striking process heterogeneity among different payers.ConclusionVirtually no medication PA request in pediatric hematology and oncology (PHO) leads to alterations in care. Medication utilization management strategies in PHO fail to provide benefits reported in other areas of medicine and have unmeasured negative effects on timeliness of care and parenteral psychological/emotional health. There is opportunity for increasing efficiency through payer and provider collaboration on the creation of prescribing standards for PHO patients.

Patients with germline mutations in PIK3CD, immunodeficiency, lymphoproliferation, and autoimmunity show a distinct pattern of abnormal B-cell maturation in the bone marrow.

Medication prior authorization (PA) is a commonly occurring requirement, particularly for medications used for rare conditions. Based on standard definitions, cancer and many blood disorders affecting children are rare. The study aims were to describe the relative frequency of PA requests and their association with payers and medications in order to identify opportunities to improve system efficiency. Requests for medication PA were logged prospectively for patients seen at a single institution over a 7-month period. Period prevalence was used to estimate the relative frequency of PA requests. Descriptive statistics summarized the relationship among payers, medications, and approvals relative to the frequency of PA requests. For the study duration of 150 clinic days, there were 5,583 patient visits. A total of 142 medication PA requests were received resulting in a period prevalence rate of 2.5% patient visits. Of the 137 medication PA requests with available outcome data, 135 (98.5%) were ultimately approved with additional provider efforts. The median clinic staff time spent per request was 46 min with an interquartile range of 25-80 min. There was striking process heterogeneity among different payers. Virtually no medication PA request in pediatric hematology and oncology (PHO) leads to alterations in care. Medication utilization management strategies in PHO fail to provide benefits reported in other areas of medicine and have unmeasured negative effects on timeliness of care and parenteral psychological/emotional health. There is opportunity for increasing efficiency through payer and provider collaboration on the creation of prescribing standards for PHO patients.

The National Heart, Lung, and Blood Institute (NHLBI) AIDS Program's goal is to provide direction and support for research and training programs in areas of HIV-related heart, lung, blood, and sleep (HLBS) diseases. To better define NHLBI current HIV-related scientific priorities and with the goal of identifying new scientific priorities and gaps in HIV-related HLBS research, a wide group of investigators gathered for a scientific NHLBI HIV Working Group on December 14-15, 2015, in Bethesda, MD. The core objectives of the Working Group included discussions on: (1) HIV-related HLBS comorbidities in the antiretroviral era; (2) HIV cure; (3) HIV prevention; and (4) mechanisms to implement new scientific discoveries in an efficient and timely manner so as to have the most impact on people living with HIV. The 2015 Working Group represented an opportunity for the NHLBI to obtain expert advice on HIV/AIDS scientific priorities and approaches over the next decade.

Purple Thrombocytopenia Idiopathic (PTI) is a blood disorder caused due to a hematological disorder characterized by a decrease in the number of circulating platelets in the blood. The aim of this study is to guide the dentist with care regarding the treatment of patients with PTI. A literature review was performed using the databases: PubMed and SciELO. In the buccal cavity it can cause petechiae, ecchymosis in the mucosa, spontaneous gingival bleeding, bleeding of superficial lesions and cuts, and may be spontaneous or caused by minor trauma. The dentist must understand and take care of the treatment of these patients, being important to carry out preventive actions and working with the philosophy of minimal intervention., A Púrpura Trombocitopênica Idiopática (PTI) é uma doença sanguínea causada devido a um distúrbio hematológico caracterizado por uma diminuição do número de plaquetas circulantes no sangue. O objetivo deste trabalho é orientar o cirurgião-dentista com os cuidados referentes ao tratamento de pacientes com PTI. Foi realizada uma revisão da literatura utilizando as bases de dado: PubMed e SciELO. Na cavidade bucal a PTI pode provocar petéquias, equimoses na mucosa, sangramento gengival espontâneo, sangramento de lesões superficiais e de cortes, podendo ser espontânea ou causada por pequenos traumas. O cirurgião-dentista deve compreender e ter os cuidados para o tratamento desses pacientes, sendo importante a realização de medidas preventivas e realizando procedimentos com a filosofia da mínima intervenção.

The French-Speaking Cellular Haematology Group (GFHC) recently published criteria for microscopic analysis of a blood smears when a hemogram is requested. In order to evaluate and improve these recommendations using an XN (Sysmex) analyzer, we assessed 31,836 samples categorized into two sub-groups of patients either receiving or not receiving care in the clinical hematology/oncology departments of two university hospitals. By combining the manufacturer's recommendations and the GFHC recommendations, 21.3% of samples had a positive review flag in phase 1 of our study (17,991 samples). In phase 2 (13,845 samples), increasing the immature granulocytes (IG) percentage from 5-10% as a review trigger threshold, and ignoring slides with isolated flags 'PLT HIGH' (thrombocytosis) or 'MCV LOW' (microcytosis) or 'Blast/Abn Lymph and Atypical Lymph' (blast cells/abnormal lymphocytes and atypical lymphocytes) (in the absence of abnormal cells on a previous blood smear within 72 h), enabled us to significantly reduce the number of slides reviewed from 21.3-15.0% (p < 0.0001), without loss of clinical value. This decrease occurred in both sub-groups (hematology 48.7-38.0%, non-hematology 18.3-11.7%, p < 0.0001). In conclusion, the application of the GFHC criteria adapted to XN analyzers has enabled us to optimize the hematology laboratory processes, and thus reduce the production costs and the turnaround time of hemogram results.

Nephropathy due to BK virus (BKV) infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation (HSCT). We hypothesized that BKV infection was a marker of kidney function decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic HSCT at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the Chronic Kidney Disease Epidemiology equation. Cox proportional hazard regression was used to model the cause-specific hazard of kidney function decline, and the Fine-Gray method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic HSCT, BK viruria was detected in 25% (n = 629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft-versus-host disease (GVHD), chronic GVHD, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (p < 0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. After allogeneic HSCT, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT.

Nephropathy due to BK virus (BKV) infection is an evolving challenge in patients undergoing hematopoietic stem cell transplantation (HSCT). We hypothesized that BKV infection was a marker of kidney function decline and a poor prognostic factor in HSCT recipients who experience this complication. In this retrospective study, we analyzed all patients who underwent their first allogeneic HSCT at our institution between 2004 and 2012. We evaluated the incidence of persistent kidney function decline, which was defined as a confirmed reduction in estimated glomerular filtration rate of at least 25% from baseline using the Chronic Kidney Disease Epidemiology equation. Cox proportional hazard regression was used to model the cause-specific hazard of kidney function decline, and the Fine-Gray method was used to account for the competing risks of death. Among 2477 recipients of a first allogeneic HSCT, BK viruria was detected in 25% (n = 629) and kidney function decline in 944 (38.1%). On multivariate analysis, after adjusting for age, sex, acute graft-versus-host disease (GVHD), chronic GVHD, preparative conditioning regimen, and graft source, BK viruria remained a significant risk factor for kidney function decline (p < 0.001). In addition, patients with BKV infection and kidney function decline experienced worse overall survival. After allogeneic HSCT, BKV infection was strongly and independently associated with subsequent kidney function decline and worse patient survival after HSCT.

UVOD: Citopenija je jedna od glavnih karakteristika mnogih hematoloških bolesti. U rutinskoj transfuziološkoj upotrebi su metode detekcije prisustva antitela u serumu ili na eritrocitima bolesnika. Primena direktnog testa utroška antihumanog globulina predstavlja efikasan način da se stekne kompletan uvid u imunološka zbivanja na svim krvnim lozama, prati dinamika razvoja antitela i toka bolesti. MATERIJAL I METODE: Svim pacijentima su se iz uzoraka periferne krvi vršile sledeće analize krvi: 1) direktni antiglobulinski test mikrometodom aglutinacije u gel karticama (LISS)/ Coombs ID. Dobijeni rezultat aglutinacije mikrometodom na gelu moţe biti negativan ili pozitivan i 2) direktni test utroška antihumanog globulina metodom aglutinacije u epruveti. Očitavanje se vršilo određivanjem razlike u titru antihumanog globuli na i očitavanjem postojeće reakcije aglutinacije dobijene u uzorcima pacijenta u odnosu na rezultate reakcije aglutinacije dobijene sa uzorcima zdrave kontrolne osobe. Test se smatra o pozitivnim ukoliko se dobijala razlika u titru AHG - a za bar dva razređen ja sa pacijentovim ćelijama u odnosu na ćelije zdrave kontrolne osobe. Statistička značajnost je analizirana t - testom, Spirmanovim koeficijentom korelacije REZULTATI: Analizirano je 100 pacijenata sa dijagnozom anemije, leukopenije, limfoproliferativnih bolesti, trombocitopenije, trombotične trombocitopenijske purpure, idiopatske trombocitopenične purpure, mijelodisplastičnog sindroma, miastenije gravis i sistemskog eritematoznog lupusa pre i nakon primljene terapije. Direktni antiglobulinski test je biopozitivan u 20% slučajeva dok je direktni test utroška antihumanog globulina bio u 51%, odnosno za 31% više. Nakon primljene terapije direktni antiglobulinski test je ostao pozitivan u 18% slučajeva a direktni test utroška antihumanog globulina u 46% što je za 28% više. Utvrđivanjem povezanosti između citopenije i stepena utroška antihumanog globulina dokazano je da svi praćeni parame, INTRODUCTION: Cytopenia is one of the main characteristics of many hematologic diseases. In routine use are methods of detecting the presence of antibodies in the serum or on red blood cells of patients. The application of direct consumption test of antihuman globulin is an efficient way to gain complete insight into the immunological events at all bloodlines, monitor the dynamics of the development of antibodies and disease progression. MATERIALS AND METHODS: All patients samples were tested for: 1) direct antiglobulin test by micro agglutination method in the gel card (LISS) / Coombs ID. The result obtained by micro agglutination gel can be negative or positive, 2) direct consumption test of antihuman globulin in a test tube. Interpretation is performed by determining differences in titer of antihuman globulin by reading existing reactions of agglutination in samples of the patient and compare it to the results obtained with the samples of the healthy control persons. The test is considered positive if the difference in titres obtained AHG differs for at least two dilutions of a patient's cells compared to cells of healthy control persons. Statistical significance was analyzed by t-test, Spearman correlation coefficient. RESULTS: A total of 100 patients diagnosed withanemia, leukopenia, lymphoproliferative disease, thrombocytopenia, thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, myelodysplastic syndrome, myasthenia gravis and systemic lupus erythematosus were analyzed before and after receiving treatment. Direct antiglobulin test was positive in 20% cases, while the direct consumption test of anti-human globulin was 51%, that is the difference of 31%. After treatment direct antiglobulin test remained positive in 18% of cases and direct consumption test of antihuman globulin was in 46%, which is 28% higher. Determining the relationship between the degree of cytopenia and consumption of anti-human globulin showed that all monitored paramet

PURPOSE: Secondary and therapy-related acute myeloid leukemia (sAML and tAML, respectively) remain therapeutic challenges. Still, it is unclear whether their inferior outcome compared with de novo acute myeloid leukemia (AML) varies as a result of previous hematologic disease or can be explained by differences in karyotype and/or age.PATIENTS AND METHODS: In a Danish national population-based study of 3,055 unselected patients with AML diagnosed from 2000 to 2013, we compared the frequencies and characteristics of tAML, myelodysplastic syndrome (MDS) -sAML, and non-MDS-sAML (chronic myelomonocytic leukemia and myeloproliferative neoplasia) versus de novo AML. Limited to intensive therapy patients, we compared chance of complete remission by logistic regression analysis and used a pseudo-value approach to compare relative risk (RR) of death at 90 days, 1 year, and 3 years, overall and stratified by age and karyotype. Results were given crude and adjusted with 95% CIs.RESULTS: Overall, frequencies of sAML and tAML were 19.8% and 6.6%, respectively. sAML, but not tAML, was associated with low likelihood of receiving intensive treatment. Among intensive therapy patients (n = 1,567), antecedent myeloid disorder or prior cytotoxic exposure was associated with decreased complete remission rates and inferior survival (3-year adjusted RR for MDS-sAML, non-MDS-sAML, and tAML: RR, 1.14; 95% CI, 1.02 to 1.32; RR, 1.27; 95% CI, 1.16 to 1.34; and RR, 1.16; 95% CI, 1.03 to 1.32, respectively) compared with de novo AML. Among patients ≥ 60 years old and patients with adverse karyotype, previous MDS or tAML did not impact overall outcomes, whereas non-MDS-sAML was associated with inferior survival across age and cytogenetic risk groups (adverse risk cytogenetics: 1-year adjusted RR, 1.47; 95% CI, 1.23 to 1.76; patients ≥ 60 years old: 1-year adjusted RR, 1.31; 95% CI, 1.06 to 1.61).CONCLUSION: Our results support that de novo AML, sAML, and tAML are biologica

BACKGROUND AND OBJECTIVES: Transfusion of red blood cells (RBC) is beneficial for the patient but can also be harmful, as randomized trials have demonstrated increased infection rates, bleeding and mortality. The study aim was to investigate the response of the vascular system (the haemostatic function and the endothelium) to RBC transfusion.MATERIALS AND METHODS: Blood was sampled from patients with various transfusion-dependent haematologic diseases before 1 and 24 h after RBC transfusion. Primary and secondary haemostasis was evaluated by whole-blood impedance aggregometry (Multiplate) and by thromboelastography (TEG). Samples were analysed by ELISA for biomarkers reflecting endothelial activation and damage (sICAM-1, syndecan-1, sThrombomodulin (sTM), sVE-Cadherin), platelet activation (sCD40L) and inflammation (hsCRP).RESULTS: A total of 58 patients were enrolled in the study. Median age was 71 years. Compared to before transfusion, patients had slightly reduced coagulability 1 h after RBC transfusion, assessed by TEG. However, transfusion of older RBC products (>14 days) was associated with increased coagulability (all P < 0·05). The level of syndecan-1 increased slightly 24 h after transfusion (median 12·4 (IQR 9-23) vs. 13·2 (9-25) ng/ml, P < 0·01), indicating increased glycocalyx degradation.CONCLUSION: Overall, RBC transfusion was associated with reduced coagulability and endothelial glycocalyx degradation. Transfusion of older RBCs was however associated with increased coagulability. The changes observed were small to moderate and the clinical relevance of these findings should be investigated in larger studies.

Objetivos. Evaluar las tres series celulares sanguíneas e identificar la presencia de hipocromía, macrocitosis, leucopenia, linfocitopenia y trombocitopenia en un grupo de trabajadores expuestos a la mezcla de benceno-tolueno-xileno (BTX). Materiales y métodos. Estudio transversal donde se incluyó a 97 trabajadores de una empresa de pinturas de México a los que se les realizó una biometría hemática convencional y les fue estimada la exposición a través de la dosis diaria potencial acumulada para vapores de BTX. Resultados. Del total de trabajadores, 19,6%, mostró macrocitosis, 18,6%, linfocitopenia, 10,3% hipocromía, 7,2% trombocitopenia y 5,2% leucopenia. La asociación cruda de macrocitosis con exposición a dosis alta de mezcla de BTX fue la única significativa (OR:3,6; IC95%: 1,08 - 13,9; p=0,02) y en la que se estructuró un modelo de regresión logística (OR:6,7; IC95%: 1,33 - 13,55; p:0,02) ajustada por edad, consumo de alcohol y tabaquismo. Conclusiones. Todos los componentes citohemáticos analizados mostraron cambios leves; que podrían estar asociados con la exposición a la mezcla de BTX. De ellos, la macrocitosis podría constituirse en una manifestación precoz que merece ser vigilada., Objectives. Evaluate the three blood cell series and identify the presence of hypochromia, macrocytosis, leucopenia, lymphopenia, and thrombocytopenia in a group of workers exposed to the mixture of benzene-toluene-xylene (BTX). Materials and methods. A cross-sectional study which included 97 workers from a paint factory in Mexico. The participants underwent conventional blood count and tests for potential cumulative daily dose of BTX fumes, to estimate exposure. Results. From the total of workers, 19.6% showed macrocytosis, 18.6%, lymphopenia, hypochromia 10.3%, 7.2% and 5.2% thrombocytopenia leukopenia. The crude association of macrocytosis with exposure to high doses of BTX mixture was the only with statistical significance (OR: 3.6, 95% CI 1.08 to 13.9, P = 0.02), and the base for a logistic regression model (OR: 6.7, 95% CI 1.33 to 13.55, P = 0.02) adjusted for age, alcohol consumption, and smoking. Conclusions. All blood cytological components analyzed demonstrated mild changes, potentially associated with exposure to the mixture of BTX. Macrocytosis could constitute an early manifestation worthy for surveillance., Revisión por pares.

Objetivos. Evaluar las tres series celulares sanguíneas e identificar la presencia de hipocromía, macrocitosis, leucopenia, linfocitopenia y trombocitopenia en un grupo de trabajadores expuestos a la mezcla de benceno-tolueno-xileno (BTX). Materiales y métodos. Estudio transversal donde se incluyó a 97 trabajadores de una empresa de pinturas de México a los que se les realizó una biometría hemática convencional y les fue estimada la exposición a través de la dosis diaria potencial acumulada para vapores de BTX. Resultados. Del total de trabajadores, 19,6%, mostró macrocitosis, 18,6%, linfocitopenia, 10,3% hipocromía, 7,2% trombocitopenia y 5,2% leucopenia. La asociación cruda de macrocitosis con exposición a dosis alta de mezcla de BTX fue la única significativa (OR:3,6; IC95%: 1,08 - 13,9; p=0,02) y en la que se estructuró un modelo de regresión logística (OR:6,7; IC95%: 1,33 - 13,55; p:0,02) ajustada por edad, consumo de alcohol y tabaquismo. Conclusiones. Todos los componentes citohemáticos analizados mostraron cambios leves; que podrían estar asociados con la exposición a la mezcla de BTX. De ellos, la macrocitosis podría constituirse en una manifestación precoz que merece ser vigilada., Objectives. Evaluate the three blood cell series and identify the presence of hypochromia, macrocytosis, leucopenia, lymphopenia, and thrombocytopenia in a group of workers exposed to the mixture of benzene-toluene-xylene (BTX). Materials and methods. A cross-sectional study which included 97 workers from a paint factory in Mexico. The participants underwent conventional blood count and tests for potential cumulative daily dose of BTX fumes, to estimate exposure. Results. From the total of workers, 19.6% showed macrocytosis, 18.6%, lymphopenia, hypochromia 10.3%, 7.2% and 5.2% thrombocytopenia leukopenia. The crude association of macrocytosis with exposure to high doses of BTX mixture was the only with statistical significance (OR: 3.6, 95% CI 1.08 to 13.9, P = 0.02), and the base for a logistic regression model (OR: 6.7, 95% CI 1.33 to 13.55, P = 0.02) adjusted for age, alcohol consumption, and smoking. Conclusions. All blood cytological components analyzed demonstrated mild changes, potentially associated with exposure to the mixture of BTX. Macrocytosis could constitute an early manifestation worthy for surveillance., Revisión por pares.

Objetivos. Evaluar las tres series celulares sanguíneas e identificar la presencia de hipocromía, macrocitosis, leucopenia, linfocitopenia y trombocitopenia en un grupo de trabajadores expuestos a la mezcla de benceno-tolueno-xileno (BTX). Materiales y métodos. Estudio transversal donde se incluyó a 97 trabajadores de una empresa de pinturas de México a los que se les realizó una biometría hemática convencional y les fue estimada la exposición a través de la dosis diaria potencial acumulada para vapores de BTX. Resultados. Del total de trabajadores, 19,6%, mostró macrocitosis, 18,6%, linfocitopenia, 10,3% hipocromía, 7,2% trombocitopenia y 5,2% leucopenia. La asociación cruda de macrocitosis con exposición a dosis alta de mezcla de BTX fue la única significativa (OR:3,6; IC95%: 1,08 - 13,9; p=0,02) y en la que se estructuró un modelo de regresión logística (OR:6,7; IC95%: 1,33 - 13,55; p:0,02) ajustada por edad, consumo de alcohol y tabaquismo. Conclusiones. Todos los componentes citohemáticos analizados mostraron cambios leves; que podrían estar asociados con la exposición a la mezcla de BTX. De ellos, la macrocitosis podría constituirse en una manifestación precoz que merece ser vigilada., Objectives. Evaluate the three blood cell series and identify the presence of hypochromia, macrocytosis, leucopenia, lymphopenia, and thrombocytopenia in a group of workers exposed to the mixture of benzene-toluene-xylene (BTX). Materials and methods. A cross-sectional study which included 97 workers from a paint factory in Mexico. The participants underwent conventional blood count and tests for potential cumulative daily dose of BTX fumes, to estimate exposure. Results. From the total of workers, 19.6% showed macrocytosis, 18.6%, lymphopenia, hypochromia 10.3%, 7.2% and 5.2% thrombocytopenia leukopenia. The crude association of macrocytosis with exposure to high doses of BTX mixture was the only with statistical significance (OR: 3.6, 95% CI 1.08 to 13.9, P = 0.02), and the base for a logistic regression model (OR: 6.7, 95% CI 1.33 to 13.55, P = 0.02) adjusted for age, alcohol consumption, and smoking. Conclusions. All blood cytological components analyzed demonstrated mild changes, potentially associated with exposure to the mixture of BTX. Macrocytosis could constitute an early manifestation worthy for surveillance., Revisión por pares.

Novel agents in combination with melphalan and prednisone (MP) significantly improved progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). Randomized trials comparing MP plus bortezomib (VMP) versus MP plus thalidomide (MPT) are lacking. Nine hundred and fifty-six elderly (>65 years) newly diagnosed MM patients from six European randomized trials were retrospectively analyzed and matched for age, albumin, and beta2-microglobulin at diagnosis, 296 patients were selected from the VMP groups, and 294 from MPT. Complete response rate was 21% in the VMP patients and 13% in the MPT patients (P = 0.007). After a median follow-up of 34 months (range, 1-92), VMP significantly prolonged both PFS (median 32.5 vs. 22.9 months, HR 0.65; 95% CI 0.52-0.82; P < 0.001) and OS (median 79.7 vs. 45.1 months, HR 0.44; 95% CI 0.32-0.59; P < 0.001) in comparison with MPT. The benefit in terms of OS of the VMP group was quite similar among patients with different risk factors defined by sex, ISS, ECOG performance status, or serum creatinine but not among patients ≥ 75 years. Multivariate analysis confirmed that VMP was an independent predictor of longer PFS and OS. In a control-case matched analysis, PFS and OS were prolonged in patients who received VMP in comparison with those treated with MPT.

Novel agents in combination with melphalan and prednisone (MP) significantly improved progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). Randomized trials comparing MP plus bortezomib (VMP) versus MP plus thalidomide (MPT) are lacking. Nine hundred and fifty-six elderly (>65 years) newly diagnosed MM patients from six European randomized trials were retrospectively analyzed and matched for age, albumin, and beta2-microglobulin at diagnosis, 296 patients were selected from the VMP groups, and 294 from MPT. Complete response rate was 21% in the VMP patients and 13% in the MPT patients (P = 0.007). After a median follow-up of 34 months (range, 1-92), VMP significantly prolonged both PFS (median 32.5 vs. 22.9 months, HR 0.65; 95% CI 0.52-0.82; P < 0.001) and OS (median 79.7 vs. 45.1 months, HR 0.44; 95% CI 0.32-0.59; P < 0.001) in comparison with MPT. The benefit in terms of OS of the VMP group was quite similar among patients with different risk factors defined by sex, ISS, ECOG performance status, or serum creatinine but not among patients ≥ 75 years. Multivariate analysis confirmed that VMP was an independent predictor of longer PFS and OS. In a control-case matched analysis, PFS and OS were prolonged in patients who received VMP in comparison with those treated with MPT.