Improved Outcome of Allogeneic Transplantation in Older Patients Treated for Myeloid Malignancies Using Post-Transplantation Cyclophosphamide and Reduced Duration of Immune Suppression.

Allogeneic stem cell transplantation (alloSCT) offers curative potential for older patients with myeloid malignancies. We evaluated the efficacy and safety of alloSCT using post-transplantation cyclophosphamide (PTCy) in combination with a very short duration of immune suppression (IS) in this population. We retrospectively analyzed 92 consecutive patients aged 65 years and older who underwent an alloSCT for myeloid malignancies between February 2018 and December 2022 at our institution. Data on patient characteristics, treatment modalities, and outcomes were collected. Ninety-two patients received an alloSCT with PTCy-based graft versus host disease (GVHD) prophylaxis. The majority had minimal comorbidities and were diagnosed with acute myeloid leukemia. Patients mostly received conditioning regimens with low to intermediate transplant conditioning intensity scores. In 43% of patients, IS could be permanently stopped at day +90, resulting in a median time of IS of 2.93 months in high-risk patients. At a median follow-up of 21.3 months, the 1- and 2-year overall survival rates were 89% and 87%, respectively. Relapse-free survival rates were 88% and 84% at 1 and 2 years, respectively. The 1- and 2-year cumulative incidences of relapse were 8% and 13%, while treatment-related mortality (TRM) estimates were 9% at both time points. Acute GVHD grade 3 to 4 occurred in 7% within the first 180 days and severe chronic GVHD in 6% of patients. This all resulted in a 1- and 2-year graft versus host and relapse-free survival of 74% and 70%, respectively. AlloSCT using PTCy in combination with a short duration of IS in older patients with myeloid malignancies demonstrates favorable survival outcomes due to low relapse rates and a low TRM. The low incidence of relapse and acceptable rates of graft-versus-host disease suggest the efficacy and safety of this approach. Further studies are warranted to validate these findings and optimize transplant strategies for older patients with myeloid malignancies.

[Stridor due to a subglottic hemangioma compressing the trachea]. / L'image du mois. Stridor secondaire à un hémangiome sous-glottique comprimant la trachée.

Subglottic haemangioma can cause stridor in young children, and sometimes be life-threatening. Larynx ultrasound is a useful, non-irradiating screening test, but the diagnosis must be confirmed by bronchial fibroscopy and injected chest CT scan. Nowadays propranolol is the first-line treatment. If treated early, the prognosis is excellent.

L'hémangiome sous-glottique peut être responsable d'un stridor chez le jeune enfant et, parfois, menacer le pronostic vital. L'échographie du larynx est un examen utile et non irradiant pour le dépistage, mais le diagnostic sera confirmé par une fibroscopie bronchique et un scanner thoracique avec injection de produit de contraste. Le traitement en première intention est le propranolol. Lors d'une prise en charge précoce, le pronostic est excellent.

Hereditary Alpha Tryptasemia: Validation of a Single-Well Multiplex Digital Droplet PCR Assay in a Cohort of Symptomatic Patients.

BACKGROUND: Hereditary alpha tryptasemia (HαT) has significant prevalence and potential morbidity in the general population. However, it remains largely undiagnosed in routine clinical diagnostics due to low availability of efficient assessment methods. To address this issue, we developed a reliable and efficient single-well multiplex digital droplet PCR assay. METHODS: The assay was based on the reconstruction of the TPSAB1 gene through quantification of the ratio of α- and ß-tryptase copy number variants (CNV) in a single-well measurement. We performed analytical validation by determining CNV measurement clustering around the expected copy numbers in 281 cases and determined the diagnostic accuracy of basal serum tryptase (BST) to predict HαT and HαT subtypes in 141 symptomatic patients. RESULTS: The assay determined α- and ß-tryptase CNVs with an overall accuracy, expressed as a 99% prediction interval, of 0.03 ± 0.27 copy numbers. The optimal BST cutoff level to predict HαT in symptomatic patients, who had no other explanation for relatively high tryptase levels (i.e., no diagnosis of systemic mastocytosis, myeloid neoplasm, or end-stage renal failure), was 9.2 ng/mL (sensitivity: 98.1%; specificity: 96.6%). HαT showed a linear gene-dose effect, with an average gene-dose increase of 7.5 ng/mL per extra α-tryptase gene. CONCLUSION: Our single-well multiplex digital droplet PCR assay accurately determined HαT and could be implemented as a state-of-the-art routine diagnostic test. The assay demonstrated a strong correlation with BST and the optimal threshold for identifying HαT in symptomatic patients with unexplained high tryptase concentrations was at a BST level of 9.2 ng/mL.

[How I treat vitamin D intoxication in a child with cystic fibrosis]. / Comment je traite une intoxication à la vitamine D chez un enfant atteint de mucoviscidose.

At least 80 % of persons with cystic fibrosis are pancreatic insufficient and benefit from daily supplementation with fat-soluble vitamins (ADEK). Magistral formulations offer ideal flexibility for prescriptions tailored to vitamin A, D and E blood levels. However, they expose to human errors, mainly leading to vitamin D intoxication whose clinical features are related to hypercalcaemia. Symptoms are mostly digestive (vomiting, constipation, abdominal pain …) and, less frequently, renal (nycturia …) complaints. When symptoms and/or serum calcium levels ≥ 14 mg/100 ml are present, prompt management is required. Besides interruption of supplementation, rapid intravenous hyperhydration (saline) is essential. Once hydration has been restored, and still under close biological supervision, a loop diuretic (furosemide) may be used but the drug of choice to achieve rapid normalization of blood calcium levels will often be intravenous pamidronate. Normalization of serum vitamin 25(OH)-D levels may take several months but the prognosis is very good. In Belgium, the very late reimbursement of a fixed combination of fat-soluble vitamins (Dekas®) meeting the standards of the pharmaceutical industry is expected to reduce the incidence of these intoxications, at the price, however, of less flexible prescription.

Au moins 80 % des patients atteints de mucoviscidose présentent une insuffisance pancréatique exocrine et bénéficient quotidiennement d'une supplémentation en vitamines liposolubles (ADEK). Une préparation magistrale offre alors une souplesse idéale de prescription. Elle expose cependant à des erreurs humaines, qui mènent surtout à des intoxications à la vitamine D. Les symptômes, souvent surtout digestifs (vomissements, constipation, douleurs abdominales …), voire rénaux (nycturie …), sont liés à l'hypercalcémie. En cas de symptômes et/ou de calcémie ≥ 14 mg/100 ml, une prise en charge immédiate est nécessaire. Outre l'interruption de la supplémentation, elle inclut d'abord une hyperhydratation rapide, par voie intraveineuse (sérum physiologique). Une fois l'hydratation restaurée, et toujours sous contrôles biologiques rapprochés, un diurétique de l'anse (furosémide) peut être utilisé, mais c'est souvent une administration intraveineuse de pamidronate qui permettra la normalisation rapide de la calcémie. Le taux sérique de vitamine 25(OH)-D peut mettre plusieurs mois à se normaliser, mais le pronostic est très bon. Remboursée tardivement en Belgique, une combinaison fixe de vitamines liposolubles (Dekas®), répondant aux normes de l'industrie pharmaceutique, devrait limiter le nombre de ces intoxications au prix, toutefois, d'une moindre souplesse de prescription.

Rapid Whole Genome Sequencing Diagnoses and Guides Treatment in Critically Ill Children in Belgium in Less than 40 Hours.

Rapid Whole Genome Sequencing (rWGS) represents a valuable exploration in critically ill pediatric patients. Early diagnosis allows care to be adjusted. We evaluated the feasibility, turnaround time (TAT), yield, and utility of rWGS in Belgium. Twenty-one unrelated critically ill patients were recruited from the neonatal intensive care units, the pediatric intensive care unit, and the neuropediatric unit, and offered rWGS as a first tier test. Libraries were prepared in the laboratory of human genetics of the University of Liège using Illumina DNA PCR-free protocol. Sequencing was performed on a NovaSeq 6000 in trio for 19 and in duo for two probands. The TAT was calculated from the sample reception to the validation of results. Clinical utility data were provided by treating physicians. A definite diagnosis was reached in twelve (57.5%) patients in 39.80 h on average (range: 37.05-43.7). An unsuspected diagnosis was identified in seven patients. rWGS guided care adjustments in diagnosed patients, including a gene therapy, an off-label drug trial and two condition-specific treatments. We successfully implemented the fastest rWGS platform in Europe and obtained one of the highest rWGS yields. This study establishes the path for a nationwide semi-centered rWGS network in Belgium.

Clonal hematopoiesis in patients with stem cell mobilization failure: a nested case-control study.

Inadequate mobilization of peripheral blood progenitor cells (PBPCs) is a limiting factor to proceeding with autologous hematopoietic cell transplantation (auto-HCT). To assess the impact of clonal hematopoiesis (CH) on mobilization failure of PBPC for auto-HCT, we investigated the characteristics of poor mobilizers (with a total PBPC collection <2 × 106 CD34+ cells per kg) in a consecutive single-center cohort of 776 patients. Targeted error-corrected next-generation sequencing of 28 genes was performed in a nested case-control cohort of 90 poor mobilizers and 89 matched controls. CH was detected in 48 out of 179 patients (27%), with most patients carrying a single mutation. The presence of CH (detected at variant allele frequency [VAF] ≥ 1%) did not associate with poor mobilization potential (31% vs 22% in controls, odds ratio, 1.55; 95% confidence interval, 0.76-3.23; P = .238). PPM1D mutations were detected more often in poor mobilizers (P = .005). In addition, TP53 mutations in this cohort were detected exclusively in patients with poor mobilization potential (P = .06). The incidence of therapy-related myeloid neoplasms (t-MN) was higher among patients with mobilization failure (P = .014). Although poor mobilizers experienced worse overall survival (P = .019), this was not affected by the presence of CH. We conclude that CH at low VAF (1%-10%) is common at the time of stem cell mobilization. TP53 mutations and PPM1D mutations are associated with poor mobilization potential and their role in subsequent development of t-MN in these individuals should be established.

Detection of clonal mast cell disease in wasp venom allergic patients with normal tryptase.

Background: Clonal mast cell disease (CMD) is an underlying aggravating condition in wasp venom allergy (WVA) which requires a different treatment strategy. CMD is increasingly recognized in patients with normal basal serum tryptase (bsT). However, methods to identify at risk patients have not yet been assessed in large cohorts of WVA patients with normal bsT. Methods: This retrospective study evaluated the reliability of the REMA score in detecting CMD in a cohort of grade IV WVA patients with normal bsT and assessed the added value of other clinical parameters, KIT D816V mutation analysis in peripheral blood (PB) and the diagnosis of hereditary alpha tryptasemia (HAT). All patients had a conclusive bone marrow evaluation that demonstrated or excluded underlying CMD. Results: In total 35 CMD and 96 non-CMD patients were included. REMA score had a sensitivity of 72% (95% CI 56%-88%) and specificity of 79% (95% CI 70%-87%) in this cohort. Loss of consciousness during systemic reaction and bsT between 6.3 and 11.4 ng/ml were additional parameters independently associated with CMD. Sensitivity of KIT in PB was relatively low, 56% (95% CI 36%-75%), but had added value as screening method in patients with a low REMA score due to 100% specificity. Conclusion: The REMA score is a relatively reliable method to detect patients at risk of CMD among WVA patients with normal bsT. KIT mutation analysis in PB could serve as additional screening method in patients with low REMA scores.

From fact to meaning: Care practitioners' hermeneutic competence development in residential care for persons with dementia.

In long-term care for people with dementia, person-centred care (PCC) is widely promoted as an approach that contributes to the well-being of persons in psycho-geriatric care. The goal of PCC is to acknowledge the personhood of residents and to indicate the responsibility of others to ensure the personhood of persons with dementia. In 2016 and 2018, qualitative empirical research was conducted with the purpose to enhance PCC and meaningful care. Five Dutch nursing homes and a total of eight communities of practice participated in the research project 'People and their Stories'. The aim of this project was to strengthen the hermeneutic competence of care practitioners, with a focus on informal everyday interpersonal interactions between residents and care professionals. This article highlights how care professionals, by enhancing their hermeneutical competence, can do justice to the unique personhood of residents in everyday care practice. Three distinguished features for strengthening the hermeneutic competence of care professionals were formulated: respectful curiosity as a prerequisite, being able to differentiate between fact and meaning, and the awareness of own perspectives and assumptions.

Outbreak of invasive meningococcal disease caused by a meningococcus serogroup B in a nursery school, Wallonia, Belgium, 2018.

Although most invasive meningococcal disease (IMD) cases are sporadic without identified transmission links, outbreaks can occur. We report three cases caused by meningococcus B (MenB) at a Belgian nursery school over 9 months. The first two cases of IMD occurred in spring and summer 2018 in healthy children (aged 3-5 years) attending the same classroom. Chemoprophylaxis was given to close contacts of both cases following regional guidelines. The third case, a healthy child of similar age in the same class as a sibling of one case, developed disease in late 2018. Microbiological analyses revealed MenB with identical finetype clonal complex 269 for Case 1 and 3 (unavailable for Case 2). Antimicrobial susceptibility testing revealed no antibiotic resistance. Following Case 3, after multidisciplinary discussion, chemoprophylaxis and 4CMenB (Bexsero) vaccination were offered to close contacts. In the 12-month follow-up of Case 3, no additional cases were reported by the school. IMD outbreaks are difficult to manage and generate public anxiety, particularly in the case of an ongoing cluster, despite contact tracing and management. This outbreak resulted in the addition of MenB vaccination to close contacts in Wallonian regional guidelines, highlighting the potential need and added value of vaccination in outbreak management.

Management of parapneumonic pleural effusion in children: Is there a role for corticosteroids when conventional nonsurgical management fails? A single-center 15-year experience.

OBJECTIVE: Description of the use of corticosteroids for the management of parapneumonic pleural effusion in children. METHODS: Retrospective single-center observational study of all children hospitalized with a diagnosis of parapneumonic pleural effusion during a 15-year period. RESULTS: We documented 97 cases of parapneumonic effusion during the study period, with a median age (interquartile range [IQR]) of 43 (33-61) months. Most of the children benefited from an evacuation of the pleural effusion (89/97, 91.8%): 21 patients (21.6%) were treated with needle thoracocentesis only, while a chest tube was inserted in 68 children (70.1%). Thirty-two patients (33%) were treated with intrapleural fibrinolysis. Fifty-five children (56.7%) received corticosteroids for persistent fever. The median time (IQR) between hospital admission and initiation of corticosteroids was 5.5 (4-7) days. When corticosteroids were initiated, children had been febrile for 9 (IQR: 8-11) days. The fever ceased in a median (IQR) of 0 (0-1) day after corticosteroids initiation. Only one patient required a video-assisted thoracoscopy that was necessary for morphological reasons (morbid obesity). No children treated with corticosteroids required surgery. All children were discharged from hospital. The median (IQR) hospital length of stay was 11 (8-14) days, with no difference between children with and those without corticosteroids. CONCLUSION: Our findings indicate that corticosteroids may be a part of the therapeutic armamentarium for children with parapneumonic effusion when conventional nonsurgical management fails.

Can Video Assistance Improve the Quality of Pediatric Dispatcher-Assisted Cardiopulmonary Resuscitation?

OBJECTIVES: This study aimed to evaluate the impact of adding video conferencing to dispatcher-assisted telephone cardiopulmonary resuscitation (CPR) on pediatric bystander CPR quality. METHODS: We conducted a prospective, randomized manikin study among volunteers with no CPR training and among bachelor nurses. Volunteers randomly received either video or audio assistance in a 6-minute pediatric cardiac arrest scenario. The main outcome measures were the results of the Cardiff Test to assess compression and ventilation performance. RESULTS: Of 255 candidates assessed for eligibility, 120 subjects were randomly assigned to 1 of the 4 following groups: untrained telephone-guided (U-T; n = 30) or video-guided (U-V; n = 30) groups and trained telephone-guided (T-T; n = 30) or video-guided (T-V; n = 30) groups. Cardiac arrest was appropriately identified in 86.7% of the U-T group and in 100% in the other groups (P = 0.0061). Hand positioning was adequate in 76.7% of T-T, 80% of T-V, and 60% of U-V, as compared with 23.4% of the U-T group (P = 0.0001). Fewer volunteers managed to deliver 2 rescue breaths/cycle (P = 0.0001) in the U-T (16.7%) compared with the U-V (43.3%), the T-T (56.7%), and the T-V groups (60%).Subjects in the video groups had a lower fraction of minute to ventilate as compared with the telephone groups (P = 0.0005). CONCLUSIONS: In dispatcher-instructed children CPR simulation, using video assistance improves cardiac arrest recognition and CPR quality with more appropriate chest compression technique and ventilation delivering. The long interruptions in chest compression combined with the mixed success rate to deliver proper ventilation raise question about ventilation quality and its effectiveness.

CombiFlow: combinatorial AML-specific plasma membrane expression profiles allow longitudinal tracking of clones.

Acute myeloid leukemia (AML) often presents as an oligoclonal disease whereby multiple genetically distinct subclones can coexist within patients. Differences in signaling and drug sensitivity of such subclones complicate treatment and warrant tools to identify them and track disease progression. We previously identified >50 AML-specific plasma membrane (PM) proteins, and 7 of these (CD82, CD97, FLT3, IL1RAP, TIM3, CD25, and CD123) were implemented in routine diagnostics in patients with AML (n = 256) and myelodysplastic syndrome (n = 33). We developed a pipeline termed CombiFlow in which expression data of multiple PM markers is merged, allowing a principal component-based analysis to identify distinctive marker expression profiles and to generate single-cell t-distributed stochastic neighbor embedding landscapes to longitudinally track clonal evolution. Positivity for one or more of the markers after 2 courses of intensive chemotherapy predicted a shorter relapse-free survival, supporting a role for these markers in measurable residual disease (MRD) detection. CombiFlow also allowed the tracking of clonal evolution in paired diagnosis and relapse samples. Extending the panel to 36 AML-specific markers further refined the CombiFlow pipeline. In conclusion, CombiFlow provides a valuable tool in the diagnosis, MRD detection, clonal tracking, and understanding of clonal heterogeneity in AML.

Assessment of droplet digital polymerase chain reaction for measuring BCR-ABL1 in chronic myeloid leukaemia in an international interlaboratory study.

Measurement of BCR activator of RhoGEF and GTPase -ABL proto-oncogene 1, non-receptor tyrosine kinase (BCR-ABL1) mRNA levels by reverse transcription quantitative polymerase chain reaction (RTqPCR) has been critical to treatment protocols and clinical trials in chronic myeloid leukaemia; however, interlaboratory variation remains a significant issue. Reverse transcriptase droplet digital PCR (RTddPCR) has shown potential to improve testing but a large-scale interlaboratory study is required to definitively establish this. In the present study, 10 BCR-ABL1-positive samples with levels ranging from molecular response (MR)1·0 -MR5·0 were tested by 23 laboratories using RTddPCR with the QXDX BCR-ABL %IS kit. A subset of participants tested the samples using RTqPCR. All 23 participants using RTddPCR detected BCR-ABL1 in all samples to MR4·0 . Detection rates for deep-response samples were 95·7% at MR4·5 , 78·3% at MR4·7 and 87·0% at MR5·0 . Interlaboratory coefficient of variation was indirectly proportional to BCR-ABL1 level ranging from 29·3% to 69·0%. Linearity ranged from 0·9330 to 1·000 (average 0·9936). When results were compared for the 11 participants who performed both RTddPCR and RTqPCR, RTddPCR showed a similar limit of detection to RTqPCR with reduced interlaboratory variation and better assay linearity. The ability to detect deep responses with RTddPCR, matched with an improved linearity and reduced interlaboratory variation will allow improved patient management, and is of particular importance for future clinical trials focussed on achieving and maintaining treatment-free remission.

Low relapse risk in poor risk AML after conditioning with 10-day decitabine, fludarabine and 2 Gray TBI prior to allogeneic hematopoietic cell transplantation.

Patients with poor risk acute myeloid leukemia (AML) have a dismal outcome. We hypothesized that combining decitabine with a standard non-myeloablative (NMA) conditioning regimen prior to allogeneic hematopoietic cell transplantation (allo HCT), might decrease the relapse incidence. We conducted a multicenter prospective phase II study (NCT02252107) with 10-day decitabine (20 mg/m2/day) integrated in a standard non-myeloablative conditioning regimen (3 days fludarabine 30 mg/m2 with 2 Gray total body irradiation (TBI)). Patients with AML ≥ 18 years in 1st (in)complete remission (CR/CRi) with a poor or very poor risk profile, as defined by the HOVON-132 protocol, were eligible. Results: Forty-six patients (median age 60; range 23-74) were included. Median follow up time was 44 months (range 31-65 months). The cumulative 1-year incidence of relapse and NRM were respectively 23% and 11%. Incidence of grade III-IV acute graft-vs-host-disease (GVHD) and severe chronic GVHD were 13% and 20%, respectively. One-year OS was 70%. Application of ELN 2017 risk classification to the study cohort revealed a cumulative one-year relapse rate of respectively 31% and 13% for the adverse and intermediate risk patients. To conclude, the 10-day DEC/FLU/TBI conditioning regimen prior to allo HCT in poor risk AML patients is effective and feasible.

Pretransplantation MRD in Older Patients With AML After Treatment With Decitabine or Conventional Chemotherapy.

The predictive value of measurable residual disease (MRD) for survival in acute myeloid leukemia (AML) has been firmly established in younger patients treated with intensive chemotherapy. The value of MRD after treatment with decitabine in older patients is unknown. This retrospective analysis included patients ≥60 years of age with AML who received an allogeneic hematopoietic cell transplantation (alloHCT) after treatment with decitabine or intensive chemotherapy. Of the 133 consecutively transplanted patients, 109 had available pretransplantation MRD analyses (by flowcytometry [threshold 0.1%]). Forty patients received decitabine treatment (10-day schedule), and 69 patients received intensive chemotherapy (7 + 3 regimen). Patients who received decitabine were older (median 67 versus 64 years) and more often had MRD (70% versus 38%). OS after alloHCT was comparable in both groups. In the chemotherapy group, MRD-positive patients had a significantly higher relapse probability (subdistribution hazard ratio [sHR] 4.81; P= .0031) and risk of death (HR 2.8; P= .02) compared to MRD-negative patients. In the decitabine group there was no significant association between the presence of MRD and relapse (sHR 0.85; P= .83) or death (HR 0.72; P= .60). Pretransplantation MRD in patients receiving decitabine treatment does not have similar predictive value for relapse or survival in older AML patients receiving an alloHCT, compared to patients receiving intensive chemotherapy.

The IL1-IL1RAP axis plays an important role in the inflammatory leukemic niche that favors acute myeloid leukemia proliferation over normal hematopoiesis

Upregulation of the plasma membrane receptor IL1RAP in Acute Myeloid Leukemia (AML) has been reported but its role in the context of the leukemic bone marrow niche is unclear. Here, we studied the signaling events downstream of IL1RAP in relation to leukemogenesis and normal hematopoiesis. High IL1RAP expression was associated with a leukemic GMP-like state, and knockdown of IL1RAP in AML reduced colony-forming capacity. Stimulation with IL1ß resulted in the induction of multiple chemokines and an inflammatory secretome via the p38 MAPK and NFκB signaling pathways in IL1RAP-expressing AML cells, but IL1ß-induced signaling was dispensable for AML cell proliferation and NFκB-driven survival. IL1RAP was also expressed in stromal cells where IL1ß induced expression of inflammatory chemokines and cytokines as well. Intriguingly, the IL1ß-induced inflammatory secretome of IL1RAPexpressing AML cells grown on a stromal layer of mesenchymal stem cells affected normal hematopoiesis including hematopoietic stem/progenitor cells while AML cell proliferation was not affected. The addition of Anakinra, an FDA-approved IL1 receptor antagonist, could reverse this effect. Therefore, blocking the IL1-IL1RAP signaling axis might be a good therapeutic approach to reduce inflammation in the bone marrow niche and thereby promote normal hematopoietic recovery over AML proliferation after chemotherapy.

Erythrocytosis in the general population: clinical characteristics and association with clonal hematopoiesis.

Erythrocytosis is a common reason for referral to hematology services and is usually secondary in origin. The aim of this study was to assess clinical characteristics and clonal hematopoiesis (CH) in individuals with erythrocytosis in the population-based Lifelines cohort (n = 147 167). Erythrocytosis was defined using strict (World Health Organization [WHO] 2008/British Committee for Standards in Hematology) and wide (WHO 2016) criteria. Individuals with erythrocytosis (strict criteria) and concurrent leukocytosis and/or thrombocytosis were 1:2 matched with individuals with isolated erythrocytosis and analyzed for somatic mutations indicative of CH (≥5% variant allele frequency). One hundred eighty five males (0.3%) and 223 females (0.3%) met the strict criteria, whereas 4868 males (7.6%) and 309 females (0.4%) met the wide criteria. Erythrocytosis, only when defined using strict criteria, was associated with cardiovascular morbidity (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.2-2.6), cardiovascular mortality (hazard ratio [HR], 2.2; 95% CI, 1.0-4.6), and all-cause mortality (HR, 1.7; 95% CI, 1.2-2.6), independent of conventional risk factors. Mutations were detected in 51 of 133 (38%) evaluable individuals, with comparable frequencies between individuals with and without concurrent cytosis. The JAK2 V617F mutation was observed in 7 of 133 (5.3%) individuals, all having concurrent cytosis. The prevalence of mutations in BCOR/BCORL1 (16%) was high, suggesting aberrant epigenetic regulation. Erythrocytosis with CH was associated with cardiovascular morbidity (OR, 9.1; 95% CI, 1.2-68.4) in a multivariable model. Our data indicate that only when defined using strict criteria erythrocytosis is associated with cardiovascular morbidity (especially in the presence of CH), cardiovascular mortality, and all-cause mortality.