British Journal of Haematology

Extreme thrombocytosis (ET, platelet count >1000 x 103/ul) is an uncommon clinical finding 1. Primary ET is associated with myeloproliferative disorders, such as essential thrombocythemia 2. Secondary ET is more common and occurs in reaction to infection, inflammation, or iron deficiency. Bleeding and thrombotic complications more frequently arise in primary ET cases 1, but have been reported with secondary ET in adults 3. Etiologies and complications associated with ET in children are less well-defined, as prior pediatric studies have been relatively small or restricted to specialized patient populations 4,5. We aimed to characterize ET in a large, single-center pediatric cohort.

BackgroundAnti-Platelet Factor 4 (PF4) IgG antibodies that activate platelets via Fc{gamma}RIIa have been shown to be an important part of the pathophysiology of vaccine-induced immune thrombocytopenia and thrombosis (VITT). There is now extensive literature on its presentation and initial management. There is no literature however on what happens to these patients following discharge. MethodsWe collected clinical data and samples from seven patients presenting with VITT and followed them up for 82-145 days. We also collected clinical samples from them at last follow-up. Testing for anti-PF4/heparin antibodies was done using an anti-PF4/heparin enzymatic immunoassay. Flow Cytometry was used to look at Fc{gamma}RIIa levels on patient platelets. Light Transmission Aggregometry with patient serum and healthy donor / patient platelets was used to analyse platelet responsiveness, in the presence and absence of PF4. FindingsAll patients were discharged on direct oral anticoagulants. Two patients remain completely symptom free, three have ongoing headaches, two have residual neurological deficits. Two patients developed mild thrombocytopenia and worsening headache (but without cerebral venous sinus thrombosis) and were retreated, one of these with rituximab. All patients, except the one treated with rituximab, had similar anti-PF4 antibody titres at 80-120 days to their levels at diagnosis. Platelets from patients at follow-up had normal levels of Fc{gamma}RIIa and had normal responses to thrombin and collagen-related-peptide. Patient serum from diagnosis strongly activated healthy donor platelets in the presence of PF4. Serum from follow-up was much weaker at stimulating platelets, even in the presence of PF4. InterpretationThis study shows that despite similar PF4 antibody titres at diagnosis and during follow-up, there are further differences in patient serum, that are not apparent from currently used testing, that result in lower levels of platelet activation during the follow-up period. Further understanding of these factors are important in order to assess duration of anticoagulation for these patients. FundingThis work was supported by an Accelerator Grant (AA/18/2/34218) from the British Heart Foundation (BHF) and by a National Institute for Health Research (NIHR) grant. Key pointsO_LIPF4 antibody titres do not reduce up to 4-months post ChAdOx1 nCoV-19 in patients with VITT C_LIO_LIDespite similar PF4 antibody titres, diagnostic serum is more potent at activating platelets in the presence of PF4 than follow-up serum. C_LI

Fanconi anemia (FA) is an inherited disorder classically characterized by childhood-onset bone marrow dysfunction and lifelong cancer predisposition. FA is caused by pathogenic variants in any one of 23 genes identified so far. Of these, FANCA is the most frequently mutated and accounts for disease in two-thirds of all patients with FA. The spectrum of FANCA pathogenic variants (mutations) is broad, and genotype-phenotype correlation is often unclear. Here we describe the natural history of cytopenias associated with FANCA pathogenic variants in 139 individuals diagnosed in 1995 or later. We followed blood cell counts over time and correlated these with the classification of patient mutation subtypes. Most participants experienced age-related declines in hematologic parameters beginning in early childhood. Platelets underwent the earliest decline, reaching platelet count below 50K/l at a median age of 8.2 years. The erythrocyte lineage was the most stable with hemoglobin below 8 g/dl identified at a median age of 10.7 years. Androgen therapy delayed the blood count decline. The presence of at least one predicted hypomorphic pathogenic variant in the FANCA gene significantly slowed the progression of the hematologic abnormalities. This study sheds light on the importance of mutation type in predicting the severity of hematological manifestations in FA. Furthermore, it serves as a historical comparative cohort for emerging therapies aimed at altering hematological disease progression in FANCA-deficient FA patients. Key PointsO_LIThrombocytopenia and neutropenia are the earliest and most reliable indicators of hematologic decline in FANCA-deficient patients C_LIO_LIPresence of two FANCA variants with predicted complete loss of function leads to earlier onset and faster progression of disease C_LI

Platelets are key players in hemostasis and thrombosis. Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) in which the JAK2 V617F, MPL W515K/L, and CALR mutations determine differences in clinical phenotype, in particular the thrombotic risk and the risk of myelofibrosis. Here, we examined the proteome of platelets in ET by mass spectrometry (MS) in combination with functional assays to gain insights into platelet activation in ET. MS analysis revealed a different proteome in ET platelets with stoichiometric differences in mitochondrial proteins compared with normal platelets. The tricarboxylic acid cycle enzymes (TCA) were in general downregulated in ET platelets while glycolysis enzymes were upregulated changing modes in energy production. Acetyl salicylic acid (ASA) treatment increased levels of TCA enzymes in controls and restored them only partially in JAK2 V617F platelets. Interestingly, membrane CD36 was higher in CALR Type1 implicating lipid transport and fatty acid oxidation in platelet lifespan. Aggregation levels specifically in JAK2 V617F platelets were similar or lower to healthy controls while activation markers i.e. CD62P were higher in untreated CALR Type2 than controls and the rest of ET. In summary, analysis of platelet proteome in ET implicates mitochondrial activity in platelet activation and also identified differences between JAK2 V617F and CALR patients. Our study suggests that metabolic finetuning can be critical in the control of platelet reactivity. Key pointsO_LITCA cycle enzymes are downregulated in ET platelets. ASA treatment leads to a partial correction in JAK2 V617F platelets. C_LIO_LICD62P expression and aggregation levels of untreated CALR Type2 are higher than JAK2 V617F platelets. C_LI Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/25323560v1_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@1e2e8ccorg.highwire.dtl.DTLVardef@21c3b0org.highwire.dtl.DTLVardef@b69467org.highwire.dtl.DTLVardef@c907ff_HPS_FORMAT_FIGEXP M_FIG C_FIG

Thrombosis remains the leading cause of morbidity and mortality for patients (pts) with polycythemia vera (PV), yet PV clinical trials are not powered to identify interventions that improve thrombosis-free survival (TFS). Such trials are infeasible in a contemporary PV cohort, even when selecting "high-risk" pts based on Age >60 and thrombosis history, because thousands of patients would be required for a short-term study to meet TFS endpoint. To address this problem, we used artificial intelligence and machine learning (ML) to dynamically predict near-term (1-year) thrombosis risk in PV pts with high sensitivity and positive predictive value (PPV) to enhance pts selection. Our automation-driven data extraction methods yielded more than 16 million data elements across 1,448 unique variables (parameters) from 11,123 clinical visits for 470 pts. Using the AutoGluon framework, the Random Forest ML classification algorithm was selected as the top performer. The full (309-parameter) model performed very well (F1=0.91, AUC=0.84) when compared with the current ELN gold-standard for thrombosis risk stratification in PV (F1=0.1, AUC=0.39). Parameter engineering, guided by Gini feature importance identified the 21 parameters (top-21) most important for accurate prediction. The top-21 parameters included known, suspected and previously unappreciated thrombosis risk factors. To identify the minimum number of parameters required for the accurate ML prediction, we tested the performance of every possible combination of 3-9 parameters from top-21 (>1.6M combinations). High-performing models (F1> 0.8) most frequently included age (continuous), time since dx, time since thrombosis, complete blood count parameters, blood type, body mass index, and JAK2 mutant allele frequency. Having trained at tested over 1.6M practical ML models with a feasible number of parameters (3-9 parameters in top-21 most predictive), it is clear that study cohorts of patients with PV at high near-term thrombosis risk can be identified with high enough sensitivity and PPV to power a clinical trial for TFS. Further validation with external, multicenter cohorts is ongoing to establish a universal ML model for PV thrombosis that would facilitate clinical trials aimed at improving TFS.

A growing understanding of the complexities of hematopoietic malignancies necessitates the existence of clinical recommendations that are sufficiently comprehensive. Although hereditary hematopoietic malignancies (HHMs) are increasingly recognized for conferring risk of myeloid malignancy, frequently utilized clinical recommendations have never been appraised for the ability to reliably guide HHM evaluation. We assessed established society-level clinical guidelines for inclusion of critical HHM genes and graded the strength of testing recommendations. We uncovered a substantial lack of consistency of recommendations guiding HHM evaluation. Such heterogeneity in guidelines likely contributes to refusal by payers to support HHM testing, leading to underdiagnoses and lost opportunities for clinical surveillance.

Infections are increasingly recognized as a common complication of chimeric antigen receptor (CAR) T-cell therapy. The incidence of clinically-defined infection after CD19.CAR T-cell therapy for relapsed/refractory lymphoma ranges from 60-90% in the first year after CAR T-cell therapy and is the most common cause for non-relapse mortality. However, infectious risk after CAR T-cell therapy targeting other malignancies is not well understood. Herein, we report for the first time, infectious complications after CD30.CAR T-cell treatment for patients with Hodgkins lymphoma and peripheral T-cell lymphoma. Since CD30 is only expressed on a subset of activated T and B-cells, we hypothesized that CD30.CAR T-cell patients would have reduced incidence and severity of infections after infusion compared to CD19.CAR T-cell patients. We retrospectively evaluated all 64 patients who received CD30.CAR T-cells at a single institution between 2016-2021, and assessed infections within one year after cell infusion, comparing these data to a contemporary cohort of 50 patients who received CD19.CAR T-cells at the same institution between 2018-2021. 23 CD30.CAR T-cell patients (36%) and 18 CD19.CAR T-cell patients (36%) developed a microbiologically confirmed infection. Infection severity and bacterial infections were higher in the CD19.CAR T-cell group compared to CD30.CAR T-cell recipients who more commonly had grade 1 respiratory viral infections. Our data reflect expected outcomes for severity and infection type in CD19.CAR T-cell patients and provide a benchmark for comparison with the novel CD30.CAR T-cell product. Although our findings require replication in a larger cohort, they have implications for antimicrobial prophylaxis guidelines after CD30.CAR T-cell therapy. KEY POINTS1) The incidence of infections within the first year after CD30.CAR T-cell therapy was equivalent to that following CD19.CAR T-cell therapy 2) Viral infections were more common after CD30.CAR T-cell therapy but bacterial infections predominated after CD19.CAR T-cell therapy.

Sickle cell disease (SCD) is a systemic hematological disease. Various genotypes of the disease exist; however, the two most common include hemoglobin SS (Hgb SS) and hemoglobin SC (Hgb SC) disease. Hgb SC is typically considered a less severe genotype; however, some patients with SC disease still have significant complications. Ektacytometry is utilized to measure red blood cell deformability in sickle cell patients and may help identify patients at risk for severe disease. We described a patient with genotype hemoglobin SC with a more severe phenotype, who we show to have very rigid red blood cells via ektacytometry.

ImportanceIn patients with hematologic malignancies, the immunogenicity of the standard 2-dose mRNA-1273 coronavirus disease 19 (COVID-19) vaccination schedule is often insufficient due to underlying disease and current or recent therapy. ObjectiveTo determine whether a 3rd mRNA-1273 vaccination raises antibody concentrations in immunocompromised hematology patients to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. DesignProspective observational cohort study. SettingFour academic hospitals in the Netherlands. Participants584 evaluable immunocompromised hematology patients, all grouped in predefined cohorts spanning the spectrum of hematologic malignancies. ExposureOne additional vaccination with mRNA-1273 5 months after completion of the standard 2-dose mRNA-1273 vaccination schedule. Main Outcomes and MeasuresSerum IgG antibodies to spike subunit 1 (S1) antigens prior to and 4 weeks after each vaccination, and pseudovirus neutralization of wildtype, delta and omicron variants in a subgroup of patients. ResultsIn immunocompromised hematology patients, a 3rd mRNA-1273 vaccination led to median S1 IgG concentrations comparable to concentrations obtained by healthy individuals after the 2-dose mRNA-1273 schedule. The rise in S1 IgG concentration after the 3rd vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. Specifically, patients with myeloid malignancies or multiple myeloma, and recipients of autologous or allogeneic hematopoietic cell transplantation (HCT) reached median S1 IgG concentrations similar to those obtained by healthy individuals after a 2-dose schedule. Patients on or shortly after rituximab therapy, CD19-directed chimeric antigen receptor T cell therapy recipients, and chronic lymphocytic leukemia patients on ibrutinib were less or unresponsive to the 3rd vaccination. In the 27 patients who received cell therapy between the 2nd and 3rd vaccination, S1 antibodies were preserved, but a 3rd mRNA-1273 vaccination did not significantly enhance S1 IgG concentrations except for multiple myeloma patients receiving autologous HCT. A 3rd vaccination significantly improved neutralization capacity per antibody. Conclusions and RelevanceThe primary schedule for immunocompromised patients with hematologic malignancies should be supplemented with a delayed 3rd vaccination. B cell lymphoma patients and allogeneic HCT recipients need to be revaccinated after treatment or transplantation. Trial RegistrationEudraCT 2021-001072-41 Key pointsO_ST_ABSQuestionC_ST_ABSCan a 3rd mRNA-1273 vaccination improve COVID-19 antibody concentrations in immunocompromised hematology patients to levels similar to healthy adults after the standard 2-dose mRNA-1273 schedule? FindingsIn this prospective observational cohort study that included 584 immunocompromised hematology patients, a 3rd mRNA-1273 vaccination significantly improved SARS-CoV-2 antibody concentrations to levels not significantly different from those obtained by healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule. Pseudovirus neutralization capacity per antibody of wild type virus and variants of concern also significantly improved. MeaningThe primary COVID-19 vaccination schedule for immunocompromised patients with hematologic malignancies should be supplemented with a delayed 3rd vaccination.

Patients with hematologic malignancies are a high priority for SARS-CoV-2 vaccination, yet the benefit they will derive is uncertain. We investigated the humoral response to vaccination in 53 non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), or CLL patients. Peripheral blood was obtained 2 weeks after first vaccination and 6 weeks after second vaccination for antibody profiling using the multiplex bead-binding assay. Serum IgG, IgA, and IgM antibody levels to the spike specific receptor binding domain (RBD) were evaluated as a measure of response. Subsequently, antibody-positive serum were assayed for neutralization capacity against authentic SARS-CoV-2. Histology was 68% lymphoma and 32% CLL; groups were: patients receiving anti-CD20-based therapy (45%), monitored with disease (28%), receiving BTK inhibitors (19%), or chemotherapy (all HL) (8%). SARS-CoV-2 specific RBD IgG antibody response was decreased across all NHL and CLL groups: 25%, 73%, and 40%, respectively. Antibody IgG titers were significantly reduced (p < 0.001) for CD20 treated and targeted therapy patients, and (p = 0.003) for monitored patients. In 94% of patients evaluated after first and second vaccination, antibody titers did not significantly boost after second vaccination. Only 13% of CD20 treated and 13% of monitored patients generated neutralizing antibodies to SARS-CoV-2 with ICD50s 135 to 1767, and 445 and > 10240. This data has profound implications given the current guidance relaxing masking restrictions and for timing of vaccinations. Unless immunity is confirmed with laboratory testing, these patients should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals. Statement of Translational RelevanceNon Hodgkin lymphoma (NHL) and Chronic Lymphocytic leukemia (CLL) patients who are treated with anti-CD20 antibody therapy, BTK inhibitor therapy, or who are monitored with active disease, have decreased antibody response to SARS-CoV-2 vaccination and decreased antibody titers compared to healthy controls. Antibody titers do not boost following second vaccination, and very few patients generate neutralizing antibodies against SARS-CoV-2. This data is of particular importance, given the recent guidance from the CDC that vaccinated patients no longer need to be masked indoors as well as outdoors. Patients with NHL or CLL who fall into these categories should not consider their immunity from vaccination to be assured. If infected with SARS-CoV-2, they should be a high priority for monoclonal antibody directed therapy. Unless immune response to vaccination is confirmed with laboratory testing, they should continue to mask, socially distance, and to avoid close contact with non-vaccinated individuals.

BackgroundImmunocompromised patients, including those with haematological malignancies, are among the high-risk group to develop severe coronavirus disease 2019 (COVID-19) complications. The effectiveness of passive immunotherapy with convalescent plasma (CP) on such patients diagnosed with COVID-19 has not been reviewed. Therefore, the aim of this review was to systematically appraise the current evidence for the efficacy of this therapy in haematological malignancies patients with COVID-19 infection. MethodsA comprehensive search was conducted up-to October 2021, using four databases: PubMed, Web of Science, Science Direct, and Scopus. Two reviewers independently assessed the quality of the included studies. Data collection analysis were performed using Microsoft Excel 365 and GraphPad Prism software. Results17 studies met the inclusion criteria; these records included 258 COVID-19 patients with haematological malignancies and treated with CP therapy (CPT). The main findings from the reviewed data suggests CPT may be associated with improved clinical outcomes including (a) higher survival rate, (b) improved SARS-CoV-2 clearance and presence of detectable anti-SARS-CoV-2 antibodies post CP transfusion, (c) improved hospital discharge time, and recovery after 1 month of CP therapy. Furthermore, treatment with convalescent plasma was not associated with development of adverse events. ConclusionOwing to its safety and beneficial effects in improving clinical outcomes, CPT appears to be an effective supportive therapeutic option for haematological malignancy patients infected with COVID-19.

BackgroundHaemophagocytic lymphohistiocytosis (HLH) is rare, results in high mortality and is increasingly being diagnosed. Little is known about what is driving the apparent rise in the incidence of this disease. MethodsUsing national linked electronic health data from hospital admissions and death certification cases of HLH that were diagnosed in England between 1/1/2003 and 31/12/2018 were identified using a previously validated approach. We calculated incidence rates of diagnosed HLH per million population using mid-year population estimates by calendar year, age group, sex and associated comorbidity (haematological malignancy, inflammatory rheumatological or bowel diseases (IBD)) associated with the diagnosis of HLH. We modelled trends in incidence and the interactions between calendar year, age and associated comorbidity using Poisson regression. FindingsThere were 1674 people with HLH diagnosed in England between 2003 and 2018. The incidence rate quadrupled (Incidence Rate Ratio (IRR) 2018 compared to 2003: 3.88 95% Confidence Interval (CI) 2.91 to 5.28), increasing 11% annually (adjusted IRR 1.11 95% CI 1.09 to 1.12). There was a rising trend in all age groups except those aged less than 5 years. There was a transition across the age groups with greater increases in those aged 5 to 14 years of HLH associated with rheumatological disease/IBD compared to HLH associated with haematological malignancy, with similar increases in HLH associated with both co-morbidities for those 15-54, and greater increases in associated haematological malignancies for those 55 years and older. InterpretationThe incidence of HLH in England has quadrupled between 2003 and 2018, increasing 11% annually. Substantial variation in the incidence occurred by age group and by HLH associated comorbidities with inflammatory rheumatological diseases or IBD associated HLH increasing more among the young and middle age groups, whereas in older age groups the largest increase was seen with haematological malignancy-associated HLH. Evidence before this studyThere is a paucity of population-based data on the epidemiology of HLH worldwide. The available evidence relies mostly upon a collection of cases series published in The Lancet in 2014 which described 2197 cases of HLH in adults reported in the literature to that point. Almost all of these were from tertiary referral specialist centres and/or described in small case series. The incidence of HLH has only been described in a few reports - and mainly this has focused on children with primary HLH. No previous studies have been large enough to examine trends in incidence by age, sex, underlying risk factors and calendar time. Added value of this studyThis study quantifies the incidence of diagnosed HLH for the first time in a nationwide manner for all age groups. It reports on 1674 patients with HLH from England and shows that there is substantial variation in the incidence by age group, associated disease and calendar time. The results imply reasons for the increase in HLH could be related to the increasing occurrence of haematological cancer, inflammatory rheumatological or bowel diseases and the treatments given for these conditions. This study has been carried out in partnership with the National Congenital Anomalies and Rare Diseases Registration Service and the methodology described can in future be applied to many rare diseases that as yet lack a way of quantifying crucial epidemiological metrics. Implications of all the available evidenceThe incidence of HLH is rising rapidly in people older than 5 years of age. This could be due to an increase in the biologic, immunomodulation or immunosuppressive therapy being used in people with haematological cancer and inflammatory rheumatological and bowel diseases. Further work should focus on how to minimise the risk of HLH occurring, or to improve treatment of this often fatal disease among those who need treatment for an associated comorbidity.

BackgroundGermline RUNX1 haplodeficiency (RHD) is associated with thrombocytopenia, platelet dysfunction and predisposition to myeloid malignancies. Platelet expression profiling of a RHD patient showed decreased F13A1, encoding for the A subunit of factor XIII, a transglutaminase that cross-links fibrin and induces clot stabilization. FXIII-A is synthesized by hematopoietic cells, megakaryocytes and monocytes. AimsTo understand RUNX1 regulation of F13A1 expression in platelet/megakaryocyte and the mechanisms and consequences of decreased F13A1 in RHD. MethodsWe performed studies in platelets, HEL cells and human CD34+ cell-derived megakaryocytes including on clot contraction in cells following small inhibitor (si)RNA knockdown (KD) of RUNX1 or F13A1. ResultsPlatelet F13A1 mRNA and protein were decreased in our index patient and in two siblings from an unrelated family with RHD. Platelet-driven clot contraction was decreased in the patient and affected daughter. Promoter studies in HEL cells showed that RUNX1 regulates F13A1 transcription; RUNX1 overexpression increased and (si)RNA RUNX1 KD reduced F13A1 promoter activity and protein. Following RUNX1 or F13A1 KD clot contraction by HEL cells was decreased as were FXIII-A surface expression, myosin light chain phosphorylation and PAC1 binding upon activation. F13A1 expression and clot contraction were impaired on RUNX1 downregulation in human megakaryocytes. ConclusionsRUNX1 regulates platelet-megakaryocyte F13A1 expression, which is decreased in RHD, reflecting regulation of a coagulation protein by a hematopoietic transcription factor. Platelet and megakaryocyte clot contraction is decreased in RHD, related to multiple impaired mechanisms including F13A1 expression, myosin phosphorylation and IIb{beta}3 activation. Scientific category - Platelets and thrombopoiesis EssentialsO_LIRUNX1 regulates expression of FXIII-A chain (F13A1) in megakaryocytes (MK) and platelets. C_LIO_LIPlatelet and MK F13A1 expression and clot contraction are decreased in RUNX1 deficiency. C_LIO_LIMK clot contraction, myosin phosphorylation and PAC1-binding are impaired in F13A1 deficiency. C_LIO_LIDefective clot contraction in RHD arises from defects in multiple platelet-MK mechanisms. C_LI

PurposeChronic inflammation is integral to Myeloproliferative Neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among MPN patients. Experimental DesignWe randomly assigned participants to either a Mediterranean diet or standard US Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four time points during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. ResultsThe Mediterranean diet was as easy to follow for MPN patients as the standard USDA diet. Over 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of [&ge;]8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of [&ge;]8 at any time point. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. ConclusionsWith dietician counseling and written education MPN patients can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially even be incorporated into the management of other chronic clonal hematologic conditions. STATEMENT OF TRANSLATIONAL RELEVANCEChronic clonal hematologic disorders, such as myeloproliferative neoplasm (MPN), lie at the intersection between malignancy and chronic inflammatory disease. Chronic inflammation is responsible for many of the clinical consequences of MPN. Diet is a central tenant of management of chronic conditions characterized by subclinical inflammation, such as cardiovascular disease, but has not entered the treatment algorithm for clonal hematologic disorders. Here, we establish that a Mediterranean diet intervention is feasible in the MPN patient population and can improve symptom burden. These findings warrant large dietary interventions in patients with clonal hematologic disorders to test the utility of diet in improvement of clinical outcomes.

IntroductionImmune thrombocytopenic purpura (ITP) is characterized by a decrease in platelet counts and can be triggered by various factors, such as viral infections and vaccinations. Concerns have emerged regarding potential links between the vaccines for COVID-19 and the worsening of ITP. This systematic review aims to comprehensively assess the impact of COVID-19 vaccines on patients with ITP, including associated risks and outcomes. Methods and AnalysisA thorough search will be conducted across multiple electronic databases, including PubMed, Web of Science, EMBASE, Cochrane Library, CNKI, Wan Fang, VIP, and CBM, to identify pertinent studies. This study will encompass randomized controlled trials, cohort studies, case-control studies, and case series that assess the effects of COVID-19 vaccines on individuals with ITP. The primary outcome will center on alterations in platelet count, while secondary outcomes will encompass the occurrence of thromboembolic events, bleeding complications, recurrence rate of ITP, impact of ITP exacerbation, and adverse events. The data will be synthesized and subjected to meta-analysis using Review Manager Software (RevMan) V.5.3. Additionally, subgroup analyses will be conducted to investigate potential sources of heterogeneity. Ethics and disseminationSince this study involves the analysis of previously published data, ethical approval is not required. The findings will be disseminated through publication in a peer-reviewed journal and presentation at relevant scientific conferences. PROSPERO registration number CRD42023471315. Strengths and limitations of this studyO_LIAssessing the overall impact of COVID-19 vaccines on patients with ITP C_LIO_LIIncorporating a variety of study types to perform a thorough analysis C_LIO_LIImplementing a standardized methodology to evaluate and mitigate bias in the studies included C_LIO_LIPossible restrictions in data accessibility and variations in heterogeneity among the studies considered C_LIO_LIThe effects of different types of COVID-19 vaccines on patients with ITP may differ, leading to potential disparities in the outcomes. C_LI

AimsTo evaluate the association between platelet indices and platelet count severity in patients with primary immune thrombocytopenia during routine post-treatment follow-up. MethodsThis retrospective observational study included patients with primary immune thrombocytopenia followed at a single tertiary care center between 2011 and 2025. Demographic and laboratory data were obtained from medical records. Platelet count severity was categorized as less than 30 x 10^9/L, 30 to 100 x 10^9/L, and greater than 100 x 10^9/L. Platelet indices, including mean platelet volume (MPV) and platelet distribution width (PDW), were analyzed using the most recent complete blood count obtained during routine follow-up after treatment initiation. Continuous variables were summarized as median and interquartile range. Comparisons across platelet count categories were performed using the Kruskal-Wallis test with post hoc Mann-Whitney U testing. Correlation analysis and simple linear regression were also conducted. ResultsA total of 243 patients were identified, of whom 232 met the inclusion criteria. Platelet distribution width differed significantly across platelet count severity categories (Kruskal-Wallis p < 0.001) and demonstrated a strong inverse association with platelet count. Mean platelet volume also showed a statistically significant difference across platelet count groups (Kruskal-Wallis p = 0.007), although the association was weaker and less consistent compared with PDW. Regression analysis confirmed a significant association between platelet count and PDW. ConclusionPlatelet distribution width is more closely associated with platelet count severity than mean platelet volume in patients with primary immune thrombocytopenia during routine post-treatment follow-up. PDW may represent a useful adjunctive laboratory parameter when interpreted alongside platelet count in routine clinical practice.

Rarely, recipients of adenoviral vector-based vaccines experience a severe thrombotic thrombocytopenic condition referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). VITT is a transient prothrombotic process, although recent data suggests that VITT anti-platelet factor 4 (PF4) antibodies are more persistent than antibodies seen in heparin-induced thrombocytopenia. Whether anti-PF4 antibody persistence in VITT is related to the continued persistence of antibody clones from the acute phase or the development of novel antibodies is unclear. To study this, acute and follow-up samples were obtained from six Ad26.COV2.S-associated VITT patients, with a median time to follow-up of 244 days from acute presentation (Range, 114-664 days). Upon affinity-enrichment of antibodies, mono/oligoclonal PF4/heparin-reactive anti-PF4 antibodies were observed despite negative results in serum protein electrophoresis and the more sensitive "Mass-Fix" technique. This finding distinguishes VITT from monoclonal gammopathy of thrombotic significance where monoclonal antibodies are observed in native sera. Anti-PF4 antibody abundance decreased over time, with no evidence of novel anti-PF4 antibody production after acute presentation. Although previous studies indicate a stereotypical pairing of VITT antibodies with lambda light chains, one VITT patient produced anti-PF4 antibodies with a kappa light chain, suggesting immunological heterogeneity. While none of these six antibodies caused long-term thrombocytopenia or thrombosis, platelet-activating anti-PF4 antibodies were seen four years after the acute event in an additional ChAdOx1 nCoV-19-associated VITT patient. These antibodies continued to cause chronic low-grade thrombocytopenia, highlighting the potential for long-term sequelae in what is generally viewed as a transient thrombotic thrombocytopenic syndrome.

BackgroundChronic lymphocytic leukemia (CLL) is a common adult blood cancer. There is no cure, but a third of people never require treatment and new targeted drugs have improved outcome. Understanding the experience of living with CLL is important for clinicians, health care providers and researchers. MethodsThis was an open internet-based survey of people with CLL, conducted by people with CLL. It was advertised via email and social media. Findings1,009 people completed the survey. Respondents were more likely to be women (526, 52% female; 482, 48% male) and were younger at diagnosis (574, 57% <71 years) than the general CLL population. For one third of respondents diagnosis was in the last five years. For 617 (61%) diagnosis was at a GP visit for another heath condition. 40% (406) reported no other health conditions. 558 (55%) respondents were currently on active monitoring, 261 (26%) were receiving treatment, and 190 (19%) in remission. Satisfaction with the speed of diagnosis, explanation of their CLL diagnosis and of the next steps in treatment was high. A quarter of respondents reported no current signs and symptoms of CLL, or side effects of treatment. Fatigue was reported by 578 (57%), three quarters of whom experienced this daily. Fatigue was reported to have a high impact on day-to-day life. Other common problems were bleeding and bruising more than normal (263, 26%) and getting infections often (228, 23%). From an emotional and a physical perspective, respondents reported their CLL had a higher impact on quality of life now than before the COVID-19 pandemic. Most respondents (829, 82%) received their treatment or monitoring at a hospital, for 253 (31%) contact was mostly/all remote. ConclusionsFatigue is a key problem for people with CLL. CLL impacts on the physical and emotional aspects of quality of life.

BACKGROUNDPatients with refractory thrombocytopenia (RT) are not sensitive to conventional therapies, such as platelet transfusions and thrombopoietin receptor agonists (TPO-RAs). The persistently high risk of life-threatening hemorrhage in this population highlights the urgent need for novel therapeutic strategies. Megakaryocyte (MK)-based therapies have emerged as a promising alternative, as MKs are the natural precursor cells responsible for platelet production. However, whether allogeneic MK therapy can improve platelet counts and function in patients with RT remains unclear. METHODSWe evaluated HLA-mismatched allogeneic MK therapy in 10 patients with RT following allogeneic hematopoietic stem-cell transplantation (allo-HSCT). All patients exhibited no response after at least one month of continuous treatment with TPO-RAs or other thrombopoiesis promoting therapies. MKs were expanded ex vivo and administered in a single infusion at one of three doses (1x106, 5x106, or 1x107 MKs per kilogram of body weight). Safety and efficacy were closely monitored. RESULTSMK infusion had minimal impact on inflammatory cytokine levels and coagulation parameters of patients. Among the 10 patients treated, 8 (80%) demonstrated a clinical response; including 3 complete response, and 5 partial response. Clinical improvement was observed within 28 days after infusion across all dose levels. CONCLUSIONSAmong 10 patients with RT, 8 responded to MK therapy without experiencing major toxic effects. (ClinicalTrials.gov number, NCT06534255.)

Patients with BRCA1/2-mutated ovarian, breast, prostate, or pancreatic tumors can be treated with poly ADP-ribose polymerase (PARP) inhibitors. PARP inhibitors, however, are known to cause therapy-related myeloid neoplasms (t-MN) in a subset of patients. Predisposing factors to t-MN development in the context of PARP inhibitor exposure are not well described. To determine the frequency of t-MN in these patients, an institutional cohort of 265 patients with exposure to PARP inhibitors was identified. A subset of these patients with PARP inhibitor-related cytopenias underwent bone marrow biopsies. Among 265 patients, 17 (6.4%) underwent a bone marrow biopsy, which yielded a therapy-related hematologic diagnosis in 47% (8/17). Breast cancer metastasis to the marrow was found in one patient, and hemophagocytic lymphohistiocytosis was found in another. We analyzed the molecular characteristics of t-MNs in 13 PARP inhibitor-exposed patients, including five additional PARP inhibitor-exposed patients diagnosed with t-MNs in community practices. Among patients with t-MNs, five had acute therapy-related myeloid leukemia (t-AML), six were diagnosed with therapy-related myelodysplastic syndrome (t-MDS), and two had therapy-related clonal cytopenias of uncertain significance (t-CCUS). Complex karyotypes were found in four of seven patients who underwent karyotyping (57%). Next-generation sequencing identified TP53 mutations in 7 of 9 patients analyzed (78%). Among patients with germline testing, four (40%) did not have a germline mutation identified, four (40%) had a BRCA1 pathogenic/likely pathogenic (P/LP) variant, and two (20%) had a BRCA2 P/LP variant. Four patients received supportive care and/or observation after blood cancer diagnosis, and six received t-MN-directed therapy. The median survival for patients who received t-MN-directed treatment was 148 days. While cytopenias, particularly anemia, are known to occur with PARP inhibitor therapy, a subset of patients develop chronic cytopenias requiring bone marrow biopsy to evaluate for t-MN. Our study informs the expected findings of such biopsies.