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Summary This Good Practice Paper provides recommendations for the diagnosis and initial management of transplant‐eligible high‐risk myeloma patients. It describes recent updates to the genetic diagnostics of high‐risk myeloma and provides recommendations for treatment on the basis of recent prospective clinical trial evidence. [ABSTRACT FROM AUTHOR]

This article provides information on the diagnosis and management of smouldering myeloma, a precursor condition to multiple myeloma. It discusses various diagnostic tests and imaging techniques used to identify smouldering myeloma and emphasizes the importance of restaging if there is evidence of progression. The article also provides recommendations for screening and initial investigations for suspected myeloma. Additionally, it discusses risk stratification models and treatment options for smouldering myeloma, including the use of lenalidomide. The article concludes by highlighting ongoing clinical trials and the need for further research in the treatment of smouldering myeloma. [Extracted from the article]

The article discusses the diagnosis and investigation of patients with mantle cell lymphoma (MCL. Topics covered include the latest information on molecular pathology, the use of positron emission tomography/computed tomography (PET/CT) scanning in staging and response assessment, and biological prognostic factors of MCL.

Presents papers to be published in the periodical "British Journal of Haematology." Advances in the molecular and serological diagnosis of invasive fungal infection in hemato-oncology patients; Serum free light chains for monitoring multiple myeloma; Complex chromosomal abnormalities in utero.

Summary: For this paper, cases reported formally and anecdotally to the authors in their screening and diagnostic roles have been selected to demonstrate areas where errors have occurred, and caution should be exercised. The cases demonstrate that it is vital that the performance and limitations of the techniques used, along with the phenotypic presentation of cases where haemoglobin variants and/or thalassaemias are coinherited are understood by those performing result interpretation. Those who deliver the service as well as those who receive reports and give results and counselling should be aware of the complexity of the topic. [ABSTRACT FROM AUTHOR]

The article presents a list of papers to be published in the "British Journal of Haematology" including "Novel therapeutic strategies targeting growth factor signalling cascades in multiple myeloma," by H. Yasui and T. Hideshima, "The role of gemtuzumab ozogamicin in acute leukaemia therapy," by M. J. Keating and H. Kantarjian, "Guidelines on the diagnosis and management of multiple myeloma 2005 ," by A. Smith and F. Wisloff, "Subarachnoid haemorrhage: more than meets the eye, by E. Tse and Y. L. Kwong and "Acute lymphoblastic leukaemia presenting as vasculitis," by A. Gupta and R. Marouf.

Mutations are less frequent (<20%) in patients with indolent SM (ISM).101,102 In advanced SM, mutations in I SRSF2 i , I ASXL1 i , I RUNX1 i , I EZH2 i and I NRAS i have been associated with an adverse prognosis and thus molecular profiling is useful to guide transplant decisions.98,102-104 In ISM, high VAF (>=30%) mutations in I ASXL1 i , I RUNX1 i and/or I DNMT3A i have been associated with an adverse prognosis102 but the value of routine molecular profiling in this subtype remains to be established. Keywords: myeloproliferative neoplasms; myelodysplastic/myeloproliferative neoplasms; mastocytosis; eosinophilia; chronic myelomonocytic leukaemia EN myeloproliferative neoplasms myelodysplastic/myeloproliferative neoplasms mastocytosis eosinophilia chronic myelomonocytic leukaemia 338 351 14 11/01/21 20211101 NES 211101 Methodology This Good-Practice Paper was compiled according to the BSH process at https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf. For older patients without thrombosis, testing may be considered but results must be interpreted with caution in view of the possibility of incidental CH. Testing is not indicated in patients with normal or reactive bone marrow histology. More than half of patients with "triple-negative" PMF do harbour additional mutations when screened with comprehensive genomic assays31 and approximately a third have an abnormal karyotype.51 In patients with bone marrow histology and clinical features consistent with PMF, myeloid gene panel testing in combination with conventional karyotyping (or SNP array) is recommended. [Extracted from the article]

In this issue, the British Society for Haematology presents guidelines for the diagnosis and management of patients with smouldering multiple myeloma (SMM). The authors provide a practical, evidence‐based approach to managing these patients. Key questions remain yet unsolved. Commentary on: Hughes et al. Diagnosis and management of smouldering myeloma: A British Society for Haematology Good Practice Paper. Br J Haematol 2024;204:1193‐1206. [ABSTRACT FROM AUTHOR]

Summary: We describe the clinical/haematological characteristics of 446 patients with hereditary spherocytosis diagnosed in the last 40 years in a reference centre. The frequency of splenectomy decreased over time (44% before 1990 to 7% in 2011–2020), notwithstanding a confirmed good efficacy. Age at splenectomy progressively increased (63% in children before 1990 to 88% in patients aged ≥20 years in 2011–2020). Our real‐life experience showed that even a fraction of patients in the trait/mild categories (19/92, 21%) were splenectomised, whilst 30/78 (38%) in the moderate/severe groups were not. Overall, these data pinpoint to the increasing awareness about post‐splenectomy thromboses and infections. [ABSTRACT FROM AUTHOR]

The article offers information on antiphospholipid syndrome (APS) and APS management and investigation guidelines. It features a discussion for APS an acquired autoimmune condition which is diagnosed in thrombosis patients or with defined pregnancy morbidity. It discusses the paper published by Galli and colleagues regarding the relation of antiphospholipid antibodies (aPL) and thrombosis.

Invasive fungal infections (IFIs) continue to cause considerable morbidity and mortality in haematopoietic stem cell transplant (HSCT) recipients. This review focuses on the risks for, and diagnosis of, IFIs (candidiasis, aspergillosis and other mould infections), and factors that affect current outcomes. Diagnosis of IFI is difficult, with the sensitivity of the gold standard tests (culture and histopathology) often <50%. Therefore, physicians rely on a constellation of clinical signs, radiography, culture, histopathology and adjunctive tests to establish diagnosis. HSCT recipients often have multiple co-morbidities, and understanding the current outcomes and prognostic variables is therefore important for overall management. This paper reviews historical trends and current data. [ABSTRACT FROM AUTHOR]

The article offers information on human aplastic anaemia-derived mesenchymal stromal cells form functional haematopoietic stem cell niche in vivo. It discusses mesenchymal stromal cells has display decreased proliferation and clonogenic potential. It also mentions patients who had responded to immunosuppressive treatment such as Hematopoietic stem cell transplantation.

Summary: Acquired haemophilia A (AHA) is a rare bleeding disorder caused by acquired antibodies against coagulation factor VIII. In the Nordic countries, treatment and outcomes have not been studied in recent times. To collect retrospective data on patients diagnosed with AHA in the Nordic countries between 2006 and 2018 and compare demographic data and clinical outcomes with previously published reports, data were collected by six haemophilia centres: three Swedish, one Finnish, one Danish and one Estonian. The study included 181 patients. Median age at diagnosis was 76 (range 5–99) years, with even gender distribution. Type and severity of bleeding was comparable to that in the large European Acquired Haemophilia Registry study (EACH2). Bleedings were primarily treated with activated prothrombin complex concentrate (aPCC) with a high success rate (91%). For immunosuppressive therapy, corticosteroid monotherapy was used most frequently and this may be the cause of the overall lower clinical remission rate compared to the EACH2 study (57% vs. 72%). Survey data on 181 patients collected from four north European countries showed similar demographic and clinical features as in previous studies on AHA. aPCC was used more frequently than in the EACH2 study and the overall remission rate was lower. [ABSTRACT FROM AUTHOR]

The article focuses on diagnosing myelodysplastic syndrome according to the World Health Organization (WHO), which included a refractory cytopenia with unilineage dysplasia (RCUD) category in 2008. Topics discussed include findings of the rare occurrence of WHO 2008 refractory neutropenia (RN) and refractory thrombocytopenia (RT) diagnoses, diagnosis of single cytopenia after 2008, and AML progression in IN and IT.

The diagnosis of 'rare diseases', such as mastocytosis, remains a challenge. Despite this, the precise benefits of referral of mastocytosis patients to highly specialized reference centres are poorly defined and whether patients should be managed at non-specialized versus reference centres remains a matter of debate. To evaluate the quality and efficiency of diagnostic procedures performed at the reference centres for mastocytosis in Spain (REMA) versus other non-reference centres, we retrospectively analysed a series of 122 patients, for the overall degree of agreement obtained for the World Health Organization (WHO) diagnostic and classification criteria betwen the referring and REMA centres. Our results showed that not all WHO diagnostic criteria were frequently investigated at the referring centres. Among the five WHO diagnostic criteria, the highest degree of agreement was obtained for serum tryptase levels [median 90% (95% confidence interval 84-96%)]; in turn, the overall agreement was significantly lower for the major histopathological criterion [80% (72-89%)], and the other three minor criteria: cytomorphology [68% (56-80%)] immunophenotyping of BM mast cells [75% (62-87%)] and detection of the KIT mutation [34% (8-60%)]. Referral of patients with diagnostic suspicion of mastocytosis to a multidisciplinary reference centre improves diagnostic efficiency and quality. [ABSTRACT FROM AUTHOR]

In the middle of March 2021, clinicians became aware of a syndrome that appeared to be linked to the AstraZeneca ChAdOx1 nCOV-19 vaccine. Patients were presenting with thrombosis, thrombocytopenia and very high D-dimer levels, much higher than would normally be expected in association with a new diagnosis of venous thrombosis. Whilst clinicians do need to remain vigilant for VITT, it is important that other causes of thrombocytopenia and high d-dimers, with or without thrombosis, such as malignancy or major vessel aneurysm, are not disregarded. [Extracted from the article]

Scope: The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with Waldenström macroglobulinaemia. In individual patients, circumstances may dictate an alternative approach. Methodology: This guideline was compiled according to the British Society for Haematology (BSH) process at http://www.b‐s‐h.org.uk/guidelines/proposing‐and‐writing‐a‐new‐bsh‐guideline/. Recommendations are based on a review of the literature using Medline, Pubmed, Embase, Central, Web of Science searches from beginning of 2013 (since the publication of the previous guidelines) up to November 2021. The following search terms were used: Waldenström('s) macroglobulin(a)emia OR lymphoplasmacytic lymphoma, IgM(‐related) neuropathy OR cold h(a)emagglutinin disease OR cold agglutinin disease OR cryoglobulin(a)emia AND (for group a only) cytogenetic OR molecular OR mutation OR MYD88 OR CXCR4, management OR treatment OR transfusion OR supportive care OR plasma exchange OR plasmapheresis OR chemotherapy OR bendamustine OR bortezomib OR ibrutinib OR fludarabine OR dexamethasone OR cyclophosphamide OR rituximab OR everolimus, bone marrow transplantation OR stem cell transplantation. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee Haemato‐Oncology Task Force, the BSH Guidelines Committee and the Haemato‐Oncology sounding board of BSH. It was also on the members section of the BSH website for comment. It has also been reviewed by UK Charity WMUK; these organisations do not necessarily approve or endorse the contents. [ABSTRACT FROM AUTHOR]

The article presents a research on longitudinal evaluation of cerebral white matter hyperintensities (WMH) lesion volume in children with sickle cell disease (SCD). Topics discussed include magnetic resonance imaging (MRI) as a part of SCD clinical care; measuring of white matter lesion volume by drawing all lesions on each fluid attenuation inversion recovery (FLAIR) image; and lesion volume was increased in some patients and it remained the same in other patients.

Summary: Although synovitis is recognized as a marker of joint disease activity, its periodic assessment is not included in routine clinical surveillance of patients with haemophilia (PwH). In order to evaluate the current knowledge and to identify controversial issues, a preliminary literature search by the Musculoskeletal Committee of the Italian Association of Haemophilia Centres (AICE) has been conducted. Statements have been established and sent to the Italian AICE members to collect their level of agreement or disagreement by a Delphi process. Thirty‐seven consensus recommendations have been drafted. We found a general agreement on the indication to consider the presence of synovitis as a marker of joint disease activity in PwH. Accordingly, there was agreement on the indication to search for synovitis both in patients reporting joint pain and in asymptomatic ones, recognizing ultrasound as the most practical imaging technique to perform periodic joint screening. Interestingly, after detection of synovitis, there was agreement on the indication to modify the therapeutic approach, suggesting prophylaxis in patients treated on demand and tailoring treatment in patients already under prophylaxis. Whereas the need of an early consultation with a physiotherapist is recommended for PwH affected by chronic synovitis, the exact timing for an orthopaedic surgeon consultation is currently unknown. [ABSTRACT FROM AUTHOR]

An ageing population and the continuing expansion of clinical indications for coumadin therapy have increased pressure on hospital anticoagulant clinics. One solution is patient self-testing (PST) of the international normalized ratio (INR) using capillary blood samples on point-of-care coagulation monitors at home. We conducted a prospective study to determine whether patients can achieve accurate INR values through PST, using the CoaguChek S (Roche Diagnostics, Lewes, UK). The main outcome measurements were: comparability of INR values obtained by PST and the hospital laboratory, patient acceptability as assessed by a questionnaire and anticoagulant control. Eighty-four patients [53 men, 31 women; median age 59 years (range 26–83)], receiving long-term oral anticoagulation (warfarin), were recruited from our Anticoagulation Clinic. Patients were randomized to weekly self-testing or continuing 4-weekly hospital laboratory monitoring of INR. Comparison of INRs (n = 234) showed no significant differences between the CoaguChek (median INR 3·02) and laboratory testing (median INR 3·07). There was excellent correlation between the two methods (r = 0·95), with 85% of CoaguChek results within 0·5 INR units of the laboratory method. On four occasions, differences of>1 unit INR were obtained, but in each case the patient's anticoagulation was unstable (INR>4·5 by both methods) and the differences in INR would not have altered patient management. 87% of patients found self-testing straightforward, 87% were confident in the result they obtained and 77% preferred self-testing. We conclude that PST is a reliable alternative to hospital clinic attendance and is acceptable to the majority of suitably trained patients. [ABSTRACT FROM AUTHOR]

Summary: Lymphocyte‐variant hypereosinophilic syndrome (L‐HES) is a rare disease driven by immunophenotypically aberrant T cells producing eosinophilopoetic cytokines such as interleukin‐5 (IL‐5). Treatment is challenging because L‐HES is relatively steroid resistant and not amenable to tyrosine kinase inhibitors. We searched the literature for clinical trials and observational studies, including case reports, of patients treated for L‐HES. In all, 25 studies were selected; two were randomised controlled trials of IL‐5 blockade, which included some patients with L‐HES, and the rest were observational studies. Corticosteroids are often used as first‐line therapy, but patients with L‐HES have lower response rates than other types of HES. Treatments that reduce symptoms and steroid dependence in some patients include interferon‐alpha (IFN‐α), anti‐IL‐5 monoclonal antibodies, cyclosporine and mycophenolate. These drugs target T‐cell activation and proliferation, or IL‐5 directly. Although effective, IFN‐α and cyclosporine were commonly reported to cause side‐effects resulting in discontinuation. Alemtuzumab can induce remissions, but these are generally short lived. The anti‐IL‐5 monoclonal antibodies mepolizumab and benralizumab are effective and well tolerated, but with a high rate of relapse once withdrawn. Hydroxyurea, methotrexate, imatinib were unsuccessful in most patients studied. More prospective clinical trials are needed for patients with L‐HES. [ABSTRACT FROM AUTHOR]

Summary: Vaccine‐induced immune thrombotic thrombocytopenia (VITT) is a novel entity that emerged in March 2021 following reports of unusual thrombosis after ChAdOx1 nCoV‐19, (AstraZeneca) vaccination. Following the recognition of this syndrome, multiple consensus guidelines have been released to risk stratify patients presenting with possible symptoms after ChAdOx1 nCoV‐19 vaccination. All guidelines rapidly identify VITT in patients with the complete triad of thrombocytopenia, thrombosis and elevated D‐dimers after ChAdOx1 nCoV‐19 vaccination. However, with earlier recognition of the associated symptoms, the clinical manifestations are likely to be more heterogeneous and represent an evolving spectrum of disease. In this setting, current guidelines may lack the sensitivity to detect early cases of VITT and risk missed or delayed diagnoses. The broad clinical phenotype and challenges associated with diagnosis of VITT are highlighted in our present case series of four patients with confirmed VITT. Dependent on the guidance used, each patient could have been classified as a low probability of VITT at presentation. The present study highlights the issues associated with the recognition of VITT, the limitations of current guidance and the need for heightened clinical vigilance as our understanding of the pathophysiology of this novel condition evolves. [ABSTRACT FROM AUTHOR]

Summary: Grade 3B follicular lymphoma (G3B FL) is rare, accounting for only 5–10% of FLs. Not only has it been routinely excluded from clinical trials, but data published on diagnosis, outcomes, choice of therapies and role of imaging are conflicting. With the advent of increasingly diverse treatment options for low‐grade (G1–3A) FL, and the molecular subcategorisation of high‐grade B‐cell lymphomas, characterisation and treatment of G3B FL is ever more important as extrapolation of data becomes more difficult. New data have emerged exploring unique genetic characteristics, specific features on positron emission tomography imaging, choice of therapy, and outcomes of G3B FL in the current era. The present review will summarise and appraise these new data, and offer recommendations based on current evidence. [ABSTRACT FROM AUTHOR]

Summary: Relapse constitutes the greatest threat to event‐free survival after completion of treatment for childhood acute lymphoblastic leukaemia (ALL). However, evidence on optimal follow‐up schedules is limited. The aims of the present population‐based cohort study were to assess the value of current follow‐up schedules after completion of Nordic Society of Paediatric Haematology and Oncology ALL protocol treatment and to estimate the impact of relapse detection mode on overall survival (OS). Among 3262 patients diagnosed between 1992 and 2014 and who completed treatment, 338 developed a relapse. Relapse detection was equally distributed between extra visits (50·8%) and scheduled follow‐up visits (49·2%). All cases detected at an extra visit and 64·3% of cases detected at a scheduled visit presented with symptoms or objective findings. Neither the mode of detection {adjusted hazard ratio 0·95, [95% confidence interval (CI) 0·61–1·48] for scheduled visits} nor the duration of symptoms was an independent risk factor for OS after relapse. The estimated number of scheduled blood samples needed to diagnose one subclinical relapse during the first 5 years after treatment cessation was 1269 (95% CI 902–1637). In conclusion, based on OS data, scheduled visits after cessation of therapy seem to yield no extra benefit. These results should frame future follow‐up strategies. [ABSTRACT FROM AUTHOR]

Summary: There is an emerging body of evidence that patients with chronic myeloid leukaemia (CML) may carry not only breakpoint cluster region‐Abelson murine leukaemia viral oncogene homologue 1 (BCR‐ABL1) kinase domain mutations (BCR‐ABL1 KD mutations), but also mutations in other genes. Their occurrence is highest during progression or at failure, but their impact at diagnosis is unclear. In the present study, we prospectively screened for mutations in 18 myeloid neoplasm‐associated genes and BCR‐ABL1 KD in the following populations: bulk leucocytes, CD34+CD38+ progenitors and CD34+CD38– stem cells, at diagnosis and early follow‐up. In our cohort of chronic phase CML patients, nine of 49 patients harboured somatic mutations in the following genes: six ASXL1 mutations, one SETBP1, one TP53, one JAK2, but no BCR‐ABL1 KD mutations. In seven of the nine patients, mutations were detected in multiple hierarchical populations including bulk leucocytes at diagnosis. The mutation dynamics reflected the BCR‐ABL1 transcript decline induced by treatment in eight of the nine cases, suggesting that mutations were acquired in the Philadelphia chromosome (Ph)‐positive clone. In one patient, the JAK2 V617F mutation correlated with a concomitant Ph‐negative myeloproliferative neoplasm and persisted despite a 5‐log reduction of the BCR‐ABL1 transcript. Only two of the nine patients with mutations failed first‐line therapy. No correlation was found between the mutation status and survival or response outcomes. [ABSTRACT FROM AUTHOR]

Summary: Splenic marginal zone lymphoma (SMZL) is a rare low‐grade B‐cell lymphoma where associations with viral hepatitis and autoimmune and inflammatory diseases (AID) have been indicated. We aimed at assessing the prevalence of viral hepatitis and AID at SMZL diagnosis and outcome by treatment in a Swedish population‐based study. A total of 277 SMZL patients registered in the Swedish Lymphoma Register in 2007–2017 were included. A history of viral hepatitis was reported in five (2%) patients and AID prior to SMZL in 72/240 (30%) patients. Treatment was given up front for 207 (75%) patients. Splenectomy with or without systemic treatment was performed in 119 (57%) and was associated with statistically significantly better overall survival [hazard ratio, HR = 0·47 (95% confidence interval, CI: 0·23–0·93), P = 0·03] and progression‐free survival (HR = 0·55, 95% CI: 0·35–0·86, P = 0·008) compared to non‐splenectomised patients in multivariable analyses. The up‐front splenectomised group was younger and generally had a lower Ann Arbor stage, but also more frequently B symptoms and high lactate dehydrogenase than the non‐splenectomised group. Viral hepatitis and AID history did not affect SMZL outcome. We report high incidence of AIDs and low incidence of viral hepatitis in this population‐based study of SMZL. Splenectomy up front was associated with a favourable outcome. [ABSTRACT FROM AUTHOR]

Keywords: myelodysplastic syndromes; MDS; guideline; diagnosis EN myelodysplastic syndromes MDS guideline diagnosis 282 293 12 07/19/21 20210715 NES 210715 Scope This document represents an update of the British Society of Haematology guideline published in 2014 due to advances in understanding the biology and therapy of the myelodysplastic syndromes (MDS).1 The objective of these guidelines is to provide healthcare professionals with clear guidance on the diagnosis and evaluation of prognosis of adult patients with MDS. Trephine section histology is especially helpful for the diagnosis of hypocellular MDS and MDS/myeloproliferative neoplasms (MPN) overlap syndromes.9 Patients with MDS/MPN overlap including CMML are now considered a distinct entity by the WHO when features of both MDS and MPN are present. Patients and family members should ideally be offered genetic counselling before genetic screening if there is a high clinical suspicion.42 Recommendations Myelodysplastic Syndromes (MDS) should be suspected in patients with otherwise unexplained cytopenias(s) or macrocytosis (1A). In the context of persistent and otherwise unexplained cytopenias, a WHO-defined diagnosis of MDS requires either (i) morphological dysplasia (involving >=10% of bone marrow cells in >=1 lineage); (ii) increased myeloblasts (>=5%, but <20%); or (iii) evidence of clonality with a typical MDS-associated cytogenetic abnormality.2,4 Dysplasia is not restricted to MDS patients and can occur following a toxic insult, in reactive conditions or secondary to haematinic deficiencies. [Extracted from the article]

Summary: As the impact of targeted next‐generation sequencing (TNGS) on daily diagnosis has not been evaluated, we performed TNGS (46 genes) on lymphomas of unclear subtype following expert haematopathological review. The potential impact on patient care and modifications of final diagnosis were divided into major and minor changes according to the European Society of Medical Oncology (ESMO) guidelines. Among 229 patients [19 primary central nervous system lymphomas (PCNSL), 48 large B‐cell lymphomas (LBCLs), 89 small BCLs (SBCLs), seven Hodgkin lymphomas (HL), 66 T‐cell lymphomas], the overall concordance rate of histological and TNGS diagnosis was 89·5%. TNGS confirmed the histological diagnosis in 144 cases (62·9%), changed the diagnosis in 24 cases (10·5%) and did not help to clarify diagnosis in 61 cases (26·7%). Modifications to the final diagnosis had a clinical impact on patient care in 8·3% of cases. Diagnostic modifications occurred in all types of lymphoma except in PCNSL and HL; the modification rate was 14·6% in SBCL and 12·5% in LBCL. While comparing informative and uninformative cases, no differences were found in terms of DNA amplification, quality or depth of sequencing and biopsy type. The present study highlights that TNGS may directly contribute to a more accurate diagnosis in difficult‐to‐diagnose lymphomas, thus improving the clinical management in routine practice. [ABSTRACT FROM AUTHOR]

Summary: Patients with chronic lymphocytic leukaemia (CLL) have an increased risk of new malignancies. However, limited data have been published about the impact of CLL treatment on this risk. Here we followed a Danish population‐based cohort of CLL patients for risks of new malignancies. Patients in the Danish CLL registry (2008–2017) were included. Up to 50 CLL‐free matched comparators were identified. First‐line treatment was categorized into four groups; bendamustine, chlorambucil, fludarabine or other. Patients were followed from CLL diagnosis for individual types of malignancy. Adjusted hazard ratios (HR) for new malignancies and 95% confidence intervals (95% CI) were calculated. Overall, 4286 CLL patients and 214 150 controls developed 594 and 20 565 new malignancies respectively. Risk of new malignancies was increased for CLL patients. Chemotherapy treatment was registered for 1064 (25%) patients with CLL. Chemotherapy was associated with increased HR (1·51, 95% CI: 1·3–1·8) of any new malignancy. Specifically, fludarabine was associated with an increased risk of myelodysplastic syndrome (MDS) (HR 4·93, 95% CI: 1·2–19·8). Patients with CLL are at increased risk of other haematological and solid malignancies compared to the general population. Chemotherapy exposure is associated with increased risk of second malignancies and fludarabine is associated with increased risk of MDS. [ABSTRACT FROM AUTHOR]

Summary: The presence of a serum monoclonal component has been associated with poor outcomes in some lymphomas. However, data in follicular lymphoma (FL) are scarce. We studied 311 FL patients diagnosed at a single institution, for whom information on serum immunofixation electrophoresis (sIFE) at diagnosis was available. Baseline characteristics and outcomes were compared between patients with a positive (+sIFE) and a negative sIFE (−sIFE). sIFE was positive in 82 patients (26%). Baseline features were comparable between both groups, except for an older age and higher proportion of elevated β2‐microglobulin levels in the +sIFE group. With a median follow‐up of 4.6 years, a +sIFE was associated with a higher risk of early relapse (POD24, 27% vs. 15%, P = 0·02), shorter progression‐free survival (PFS; 42% vs. 52% at 5 years, P = 0·008), and shorter overall survival (OS; 59% vs. 77% at 10 years, P = 0·046). In patients >60 years, a +sIFE was an independent predictor of OS [hazard ratio (HR) = 2·4, 95% confidence interval (CI): 1·2–5·0; P = 0·02]. Approximately one quarter of patients with FL has a +sIFE at diagnosis, which is a predictor of poor outcome. These findings encourage further investigation of its relationship with B‐cell biology and the tumour microenvironment. [ABSTRACT FROM AUTHOR]

Summary: Disease relapse is the greatest cause of treatment failure in paediatric B‐cell acute lymphoblastic leukaemia (B‐ALL). Current risk stratifications fail to capture all patients at risk of relapse. Herein, we used a machine‐learning approach to identify B‐ALL blast‐secreted factors that are associated with poor survival outcomes. Using this approach, we identified a two‐gene expression signature (CKLF and IL1B) that allowed identification of high‐risk patients at diagnosis. This two‐gene expression signature enhances the predictive value of current at diagnosis or end‐of‐induction risk stratification suggesting the model can be applied continuously to help guide implementation of risk‐adapted therapies. [ABSTRACT FROM AUTHOR]

Summary: Skeletal survey (SS) continues to be used in the community to detect bone disease in patients with multiple myeloma (MM). While the false‐negative rate is high, the specificity of SS is less well characterised. Here, we compare the diagnostic accuracy of SS compared to 18F‐FDG‐PET/CT (positron emission tomography/computed tomography) in 79 patients referred to our tertiary centre with a diagnosis of smouldering MM. SS had a specificity of 83·1% (95% confidence interval: 72·0–90·5%). This study reinforces the importance of using more specific imaging techniques to avoid inaccurate diagnosis that could lead to the risks associated with unnecessary therapy in patients with smouldering MM. [ABSTRACT FROM AUTHOR]

Summary: Burkitt lymphoma (BL) is an aggressive B‐cell‐malignancy derived from germinal‐centre B‐cells. Curative therapy traditionally requires intensive immunochemotherapy. Recently, immuno‐oncological approaches, modulating the T‐cell tumour response, were approved for the treatment of a variety of malignancies. The architecture of the tumour‐infiltrating T‐cell receptor (TCR) repertoire in BL remains insufficiently characterized. We therefore performed a large‐scale, next‐generation sequencing study of the complimentary‐determining region (CDR)‐3 region of the TCRβ chain repertoire in a large cohort of all epidemiological subtypes of BL (n = 82) and diffuse large B‐cell lymphoma (DLBCL; n = 34). Molecular data were subsequently assessed for correlation with clinical outcome. Our investigations revealed an age‐dependent immunoprofile in BL as in DLBCL. Moreover, we found several public clonotypes in numerous patients suggestive of shared tumour neoantigen selection exclusive to BL and distinct from DLBCL regardless of Epstein–Barr virus and/or human immunodeficiency virus status. Compared with baseline, longitudinal analysis unveiled significant repertoire restrictions upon relapse (P = 0·0437) while productive TCR repertoire clonality proved to be a useful indicator of both overall and progression‐free‐survival [OS: P = 0·0001; hazard ratio (HR): 6·220; confidence interval (CI): 2·263–11·78; PFS: P = 0·0025; HR: 3·086; CI: 1·555–7·030]. Multivariate analysis confirmed its independence from established prognosticators, including age at diagnosis and comorbidities. Our findings establish the clinical relevance of the architecture and clonality of the TCR repertoire and its age‐determined dynamics in BL. [ABSTRACT FROM AUTHOR]

The article discusses issues regarding early diagnosis of bisphosphonate-related osteonecrosis of the jaw (BONJ) that occur in thalassaemia major (TM) patients with osteopenia-osteoporosis syndrome (OOS) when treated with bisphosphonates that increase bone mass. It reports that there are no guidelines for oral medical check-ups in TM with OOS treated by bisphosphonates. It also mentions that TM patients should be aware of BONJ so that prompt diagnosis can be made by oral medicine experts.

The article discusses the Surveillance Epidemiology and End Results (SEER) database survival analysis conducted on patients diagnosed with hairy cell leukaemia (HCL) in the U.S. between 1978 and 2008. It was found that the survival of patients diagnosed with HCL has improved over the last three decades with a significant benefit being seen after 1984.

Summary: Multiple myeloma is associated with significant early morbidity and mortality, with considerable end organ damage often present at diagnosis. The Tackling EArly Morbidity and Mortality in Multiple Myeloma (TEAMM) trial was used to evaluate routes to diagnosis in patients with myeloma and the relationship between diagnostic pathways, time to diagnosis and disease severity. A total of 915 participants were included in the study. Fifty‐one per cent were diagnosed by direct referral from primary care to haematology; 29% were diagnosed via acute services and 20% were referred via other secondary care specialties. Patients diagnosed via other secondary care specialties had a longer diagnostic interval (median 120 days vs. 59 days) without an increase in features of severe disease, suggesting they had a relatively indolent disease. Marked intrahospital delay suggests possible scope for improvement. A quarter of those diagnosed through acute services reported >30 days from initial hospital consultation to haematology assessment. Participants diagnosed through acute services had poorer performance status (P < 0·0001) and higher burden of end organ damage (P < 0·0001) with no difference in the overall length of diagnostic pathway compared to those diagnosed by direct referral (median 59 days). This suggests that advanced disease in patients presenting through acute services predominantly reflects disease aggression. [ABSTRACT FROM AUTHOR]

The present study assessed the criteria for initiating cytoreduction and response to conventional therapies in 1446 patients with essential thrombocythemia (ET), 267 (17%) of which were CALR‐mutated. In low risk patients, time from diagnosis to cytoreduction was shorter in CALR‐positive than in the other genotypes (2·8, 3·2, 7·4 and 12·5 years for CALR, MPL, JAK2V617F and TN, respectively, P < 0·0001). A total of 1104 (76%) patients received cytoreductive treatment with hydroxycarbamide (HC) (n = 977), anagrelide (n = 113), or others (n = 14). The estimated cumulative rates of complete haematological response (CR) at 12 months were 40 % and 67% in CALR and JAK2V617F genotypes, respectively. Median time to CR was 192 days for JAK2V617F, 343 for TN, 433 for MPL, and 705 for CALR genotypes (P < 0·0001). Duration of CR was shorter in CALR‐mutated ET than in the remaining patients (P = 0·003). In CALR‐positive patients, HC and anagrelide had similar efficacy in terms of response rates and duration. CALR‐mutated patients developed resistance/intolerance to HC more frequently (5%, 23%, 27% and 15% for JAK2V617F, CALR, MPL and TN, respectively; P < 0·0001). In conclusion, conventional cytoreductive agents are less effective in CALR‐mutated ET, highlighting the need for new treatment modalities and redefinition of haematologic targets for patients with this genotype. [ABSTRACT FROM AUTHOR]

Summary: Disseminated intravascular coagulation (DIC) is a systemic activation of the coagulation system, which results in microvascular thrombosis and, simultaneously, potentially life‐threatening haemorrhage attributed to consumption of platelets and coagulation factors. Underlying conditions, e.g. infection, cancer, or obstetrical complications are responsible for the initiation and propagation of the DIC process. This review provides insights into the epidemiology of DIC and the current understanding of its pathophysiology. It details the use of diagnostic biomarkers, current diagnostic recommendations from international medical societies, and it provides an overview of emerging diagnostic and prognostic biomarkers. Last, it provides guidance on management. It is concluded that timely and accurate diagnosis of DIC and its underlying condition is essential for the prognosis. Treatment should primarily focus on the underlying cause of DIC and supportive treatment should be individualised according to the underlying aetiology, patient's symptoms and laboratory records. [ABSTRACT FROM AUTHOR]

Summary: Next‐generation sequencing (NGS) increasingly influences diagnosis, prognosis and management of myelodysplastic syndrome (MDS). In addition to marrow morphology and flow cytometry, our institution performs cytogenetics (CG) and NGS‐based testing routinely in patients with suspected MDS. We evaluated the relative value of NGS in the assessment of patients with suspected MDS. We initially compared the diagnostic and prognostic information derived from CG and NGS in 134 patients. NGS enhanced the diagnostic yield compared to CG for clonal myeloid disorders (sensitivity 77% vs. 42·2%; specificity 90·2% vs. 78%; positive predictive value 92·8% vs. 76%; and negative predictive value 70·8% vs. 45·5%). The identification of poor prognosis mutations by NGS altered risk category in 27/39 (69·2%) patients with MDS with good/intermediate risk CG. Subsequently, we prospectively evaluated 70 patients with suspected MDS using an 'NGS‐first approach' with CG restricted to samples with morphological abnormalities. We rarely identified mutations or CG abnormalities in patients without dysplastic features. NGS has a superior diagnostic performance compared to CG in patients with suspected MDS. We estimate that by using an 'NGS‐first approach' we could reduce karyotyping by approximately 30%. [ABSTRACT FROM AUTHOR]

Summary: Nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL) is a rare entity, with limited data on the outcome in the relapsed/refractory setting. We evaluated the outcome of all patients diagnosed between 04/1979 and 01/2019 with relapsed or progressive NLPHL after initial active therapy at two institutions, refractory disease being defined as lack of response to treatment and/or relapse within three months of treatment. NLPHL patients with histological evidence of transformation at time of first relapse or progression were excluded. In total, 69 patients with recurrent NLPHL were included in the study. After a median follow‐up after initial diagnosis of 14 years (range, 0·5–46 years), median progression‐free survival after front‐line treatment (PFS‐1) was four years. Second‐line therapy included chemotherapy in 28 (41%) patients, biological therapy (rituximab, lenalidomide or brentuximab vedotin) in 14 (20%), high‐dose chemotherapy followed by autologous stem cell transplant in 14 (20%) and radiation therapy (RT) alone in 10 (15%). The five‐year PFS after second‐line therapy (PFS‐2) was 68% [95% confidence interval (CI), 54–79%] but the five‐year overall survival (OS) after second‐line therapy (OS‐2) remained excellent, at 94% (95% CI, 85–99%). Due to excellent outcome in case of recurrence, studies aimed at characterizing its biology to guide therapy de‐escalation are needed. [ABSTRACT FROM AUTHOR]

Rosai-Dorfman disease (RDD), or sinus histiocytosis with massive lymphadenopathy, is a rare disorder involving lymph nodes, respiratory tract, skin and soft tissues.1 The histiocytes of RDD (S100 SP + sp , CD68 SP + sp , CD1a SP - sp , CD14 SP + sp ) exhibit I emperipolesis i , a histological phenomenon describing engulfment of normal-appearing lymphocytes residing in cytoplasm of pathological histiocytes.1-4 Studies suggest a possible clonal origin of RDD from NRAS proto-oncogene, GTPase ( I NRAS i ), KRAS proto-oncogene, GTPase ( I KRAS i ), mitogen-activated protein kinase kinase 1 ( I MAP2K1 i ) and A-Raf proto-oncogene, serine/threonine kinase ( I ARAF i ) mutations.5 Patients are typically observed clinically; chemotherapy traditionally has not been uniformly successful in management, with variable responses to imatinib,3 cladribine4-7 and clofarabine.8 Recently, histiocytic disorders have been successfully treated with the mitogen-activated protein kinase (MEK)-inhibitor cobimetinib (COBI), suggesting pathological dependence on mitogen-activated protein kinase signalling and MEK-inhibition.9-12 The clinical spectrum of RDD overlaps with other conditions including autoimmune lymphoproliferative syndrome (ALPS) and RAS-associated autoimmune leucoproliferative disorder (RALD).5,13 RALD involves lymphadenopathy, splenomegaly, hypergammaglobulinaemia, B-cell lymphocytosis and activating mutations of I KRAS i or I NRAS i , which have also been found in ~25% of patients with juvenile myelomonocytic leukaemia (JMML).14 Despite the chronic nature of RALD, it has been hypothesised to have rare potential for transformation to myeloid malignancies resembling JMML or chronic myelomonocytic leukaemia (CMML).14 However, given the rarity of RALD there currently is no consensus criteria to define disease progression. [Extracted from the article]

SARS-CoV-2 infection anxieties and general population restrictions delay diagnosis and treatment of acute haematological malignancies Keywords: SARS-COV-2; acute haematological malignancies; social distancing measures EN SARS-COV-2 acute haematological malignancies social distancing measures e5 e8 4 07/01/20 20200701 NES 200701 Acute leukaemias remain a very serious group of diseases often associated with major complications and substantial morbidity and mortality. Although the age of two patients, at 60 and 63 years respectively (one AML and one BC-CML) makes them potentially eligible for intensive treatment, significant pre-existing co-morbidities postponed the start of treatment (still not started), and suggested a less intensive treatment regimen. [Extracted from the article]

Summary: Acquired haemophilia A (AHA) is a rare haemorrhagic disorder caused by autoantibodies directed against the functional epitopes of coagulation factor VIII (FVIII). Its management relies on prompt diagnosis, control of bleeding and eradication of the inhibitor by immunosuppression. China Acquired Hemophilia Registry (CARE), a nationwide multicentre registry, was intended to survey the status of AHA and standardize its diagnosis and therapy in China. One hundred and eighty‐seven registered patients had an average age of 52 years. Diagnosis was delayed in 46·5% patients. There was a significant delay from diagnosis to immunosuppressive therapy in 68·3% patients. Bleeding control was significantly higher in patients treated with prothrombin complex concentrate (PCC) versus FVIII replacement therapy (84·6% vs. 34·4%; P < 0·001). Inhibitor eradication with a combination of steroids and cyclophosphamide showed a higher partial remission (PR) rate (92·2% vs. 70·3%) and stable complete remission (CR) rate (82·8% vs. 48·6%) than with steroids alone. Logistic regression model showed age and malignancy were significantly related to survival at final follow‐up. The mean age for the survivors [51 years (IQR, 35–65 years)] was significantly lower than that of the non‐survivors [79 years (IQR, 67–86 years)] (P < 0·001). Overall survival was higher in non‐malignancy group than malignancy group (94·9% vs. 70%) (OR = 1·313; 95% CI, 0·913–1·889, P = 0·015). [ABSTRACT FROM AUTHOR]

Replies to comments on a study about automated malaria detection. Contribution of gametocytes and schizonts to abnormal white cell distribution profiles encountered in malaria; Incidence of malaria in South Africa.

Summary: The use of allele‐specific quantitative polymerase chain reaction to identify KIT D816V in the peripheral blood of adults with mastocytosis has been reported to have value in the diagnosis, assessment of disease burden and management of this disease. To examine the value of this assay in children with cutaneous manifestations of mastocytosis, we assessed data on 65 patients with all variants of paediatric‐onset mastocytosis, including those known to have systemic disease, to correlate KIT mutation status with clinical findings, serum tryptase levels and bone marrow histopathology. We found that KIT D816V was not identified in the peripheral blood of children known to have only cutaneous disease (specificity 100%) but was found in those known to have both cutaneous and systemic/probable systemic disease (sensitivity of 85·2%). These findings were the basis of the development of an algorithm to assist in the decision for when to perform a bone marrow biopsy in children presenting with cutaneous manifestations of mastocytosis. [ABSTRACT FROM AUTHOR]

This study aimed to estimate the diagnostic utility of biomarkers for suspected venous thromboembolism (VTE) in pregnancy and the puerperium. Research nurses/midwives collected blood samples from 310 pregnant/postpartum women with suspected pulmonary emboli (PE) and 18 with diagnosed deep vein thrombosis (DVT). VTE was diagnosed using imaging, treatment and adverse outcome data. Primary analysis was limited to women with conclusive imaging (36 with VTE, 247 without). The area under the curve (AUC) for each biomarker was: activated partial thromboplastin time 0.669 (95% confidence interval 0.570-0.768), B-type natriuretic peptide 0.549 (0.453-0.645), C-reactive protein 0.542 (0.445-0.639), Clauss fibrinogen 0.589 (0.476-0.701), D-Dimer (by enzyme-linked immunosorbent assay) 0.668 (0.561-0.776), near-patient D-Dimer 0.651 (0.545-0.758), mid-regional pro-atrial natriuretic peptide 0.524 (0.418-0.630), prothrombin fragment 1 + 2 0.562 (0.462-0.661), plasmin-antiplasmin complexes 0.639 (0.536-0.742), prothombin time 0.613 (0.508-0.718), thrombin generation lag time 0.702 (0.598-0.806), thrombin generation endogenous potential 0.559 (0.437-0.681), thrombin generation peak 0.596 (0.478-0.715), thrombin generation time to peak 0.655 (0.541-0.769), soluble tissue factor 0.531 (0.424-0.638) and serum troponin 0.597 (0.499-0.695). No diagnostically useful threshold for diagnosing or ruling out VTE was identified. In pregnancy and the puerperium, conventional and candidate biomarkers have no utility either for their negative or positive predictive value in the diagnosis of VTE. [ABSTRACT FROM AUTHOR]

The laboratory diagnosis of heparin-induced thrombocytopenia (HIT) is based on an enzyme immunoassay combined with a functional test, and serotonin release assay (SRA) is the gold standard for detecting activating HIT antibodies. However, a recent atypical history of HIT prompted us to evaluate whether addition of platelet factor 4 (PF4) during SRA could improve its ability to detect pathogenic HIT antibodies. Using 5B9, a monoclonal antibody to PF4/H with a human Fc fragment, we first defined the optimal PF4 concentration for detecting low amounts of platelet-activating IgG with SRA. Plasma samples from 50 patients with suspected HIT were then studied, and SRA was positive in 17 cases (Group SRApos), with relatively high levels of PF4-specific IgG (median optical density = 2·66). SRA was also systematically performed after adding 10 μg/ml of PF4 in the reaction mixture, and significant serotonin release was measured with samples from 9 additional patients (Group PF4-SRApos). Importantly, levels of PF4-specific IgG were similar in these samples and those from the 24 persistently SRA negative patients. Moreover, the pre-test probability of HIT was intermediate/high in all ‘SRApos’ or ‘SRA-PF4pos’ patients. In conclusion, addition of exogenous PF4 might improve the detection of pathogenic HIT antibodies by SRA. [ABSTRACT FROM AUTHOR]

Thrombocytopenia absent radii ( TAR) syndrome is clearly defined by the combination of radial aplasia and reduced platelet counts. The genetics of TAR syndrome has recently been resolved and comprises a microdeletion on Chromosome 1 including the RBM8A gene and a single nucleotide polymorphism ( SNP) either at the 5′ untranslated region (5′ UTR) or within the first intron of RBM8A. Although phenotypically readily diagnosed after birth, the genetic determination of particular SNPs in TAR syndrome harbours valuable information to evaluate disease severity and treatment decisions. Here, we present clinical data in a cohort of 38 patients and observed that platelet counts in individuals with 5′ UTR SNP are significantly lower compared to patients bearing the SNP in intron 1. Moreover, elevated haemoglobin values could only be assessed in patients with 5′ UTR SNP whereas white blood cell count is unaffected, indicating that frequently observed anaemia in TAR patients could also be SNP-dependent whereas leucocytosis does not correlate with genetic background. However, this report on a large cohort provides an overview of important haematological characteristics in TAR patients, facilitating evaluation of the various traits in this disease and indicating the importance of genetic validation for TAR syndrome. [ABSTRACT FROM AUTHOR]

The article presents case studies related to clinical application of complement biomarkers in the diagnosis and treatment of acute thrombotic microangiopathies. It reflects on case studies of three patients including a 58-year-old male with a history of hyperlipidemia, a 52-year-old female with a history of hypertension, diabetes mellitus, systemic lupus erythematosus and asthma, and a 51-year-old female, presented with fever and cough.