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In this large single-centre study, we report high prevalence (25%) of, small (<10%) and very small (<1%), paroxysmal nocturnal hemoglobinuria (PNH) clones by high-sensitive cytometry among 3085 patients tested. Given PNH association with bone marrow failures, we analyzed 869 myelodysplastic syndromes (MDS) and 531 aplastic anemia (AA) within the cohort. PNH clones were more frequent and larger in AA vs. MDS ( p  = 0.04). PNH clone, irrespective of size, was a good predictor of response to immunosuppressive therapy (IST) and to stem cell transplant (HSCT) (in MDS: 84% if PNH+ vs. 44.7% if PNH−, p  = 0.01 for IST, and 71% if PNH+ vs. 56.6% if PNH− for HSCT; in AA: 78 vs. 50% for IST, p  < 0.0001, and 97 vs. 77%, p  = 0.01 for HSCT). PNH positivity had a favorable impact on disease progression (0.6% vs. 4.9% IPSS-progression in MDS, p  < 0.005; and 2.1 vs. 6.9% progression to MDS in AA, p  = 0.01), leukemic evolution (6.8 vs. 12.7%, p  = 0.01 in MDS), and overall survival [73% (95% CI 68–77) vs. 51% (48–54), p  < 0.0001], with a relative HR for mortality of 2.37 (95% CI 1.8–3.1; p  < 0.0001) in PNH negative cases, both in univariate and multivariable analysis. Our data suggest systematic PNH testing in AA/MDS, as it might allow better prediction/prognostication and consequent clinical/laboratory follow-up timing.

Diagnostic criteria for hypoplastic myelodysplasic syndrome (h-MDS) have not been clearly established, making the differential diagnosis from other bone marrow failure syndromes (BMF) challenging. In this study, we aimed to delineate clinical, histopathological, and molecular features of h-MDS, based on a large and well-annotated cohort of patients with bone marrow (BM) hypocellularity. The study included 534 consecutive adult patients with hypocellular BM (278 h-MDS and 136 aplastic anemia), and 727 with normo- or hypercellular MDS (n-MDS). Comparison of clinical features of patients with h-MDS as defined by BM cellularity ≤25% (n = 204) or reduced age-adjusted cellularity (n = 74) did not reveal significant differences. We developed a diagnostic score to discriminate h-MDS from non-malignant BMF based on histological and cytological variables with the highest specificity for MDS (h-score). The information from chromosomal abnormalities and somatic mutation patterns was then integrated into a cyto-histological/genetic score (hg-score). This score was able to segregate two groups of h-MDS with a significantly different risk of blast progression (P < 0.001). The integration of cyto-histological and genetic features in adult patients with hypocellular BM facilitated segregation into two distinct groups, one with clinical and genetic features highly consistent with myeloid neoplasm, and one with features more consistent with non-malignant BMF.

Background Benign ethnic neutropenia (BEN) is the most common cause of chronic neutropenia seen in individuals of African, Middle Eastern and West Indian descent. This phenotype is broadly defined by an absolute neutrophil counts (ANC) below 1.8 × 10 9 cells/L in the absence of other causes, without an increased risk of infection. BEN has been implicated as a potential source of disparity in patients treated with clozapine, the antipsychotic of choice in treatment-resistant schizophrenia. Our main objective was to examine the current level of BEN recognition in a cohort of patients treated with clozapine and the potential impact of unidentified BEN on the initiation and maintenance of clozapine treatment. Methods This was an observational, retrospective analysis of patients registered with clozapine haematological monitoring systems in two large mental health trusts, chosen because they serve an ethnically diverse population. The first objective was to establish certified BEN prevalence in current users of clozapine. The second objective was to explore the stage of treatment at which BEN was identified. The third objective was to evaluate the extent of unrecognised BEN in patients registered on the Central Non-Rechallenge Database (CNRD), a database for patients whose haematological parameters fall below set thresholds when receiving clozapine treatment, meaning they cannot ordinarily be prescribed clozapine again. Results The study population comprised of 2020 patients on the clozapine register. 111 patients were monitored under BEN criteria. BEN was mostly identified after a below threshold haematological result or clozapine rechallenge (68%) compared to at clozapine initiation (32%). Eight of the 18 (42%) black patients registered on the CNRD were classified as BEN after assessment by a haematologist. Of these 8 patients, none would have met CNRD criteria again if monitored with BEN criteria at clozapine initiation. Conclusions Current evidence suggests that BEN remains an uncommonly recognised haematological phenotype. Improved timely identification of BEN will reduce unnecessary interruption or discontinuation of clozapine treatment. Our results suggest consideration should also be given to determining BEN status prior to initiating clozapine. Moreover, adoption of current FDA BEN monitoring criteria in the UK may further reduce clozapine discontinuation due to perceived neutropenia as drug toxicity, particularly in treatment-refractory schizophrenia patients.

Pre-emptive DLI (pDLI) is an effective strategy in lowering the risk of relapse without significantly increasing the risk of graft-versus-host disease (GVHD) in the case of T cell lineage mixed chimerism (MC) post allogeneic transplant in hematological malignancies. Many patients, however, fail to receive timely pDLI and have dismal outcomes, which are not taken into consideration. We compared long-term outcomes of 106 patients having T cell MC after day 60 and undergoing allogeneic stem cell allograft for acute leukemia from an unrelated donor (UD), with 111 patients having complete chimerism (CC). Fifty-three (56%) patients received prophylactic pDLI. Thirty-six patients (67%) had a response (RR), 17 (33%) had no response (NR), and fifty-two (54%) did not receive any pDLI (ND). OS was better in MC group as compared to CC (54% vs 43%, p = 0.04), mainly due to reduction in NRM (14% vs 25%, p = 0.05), and all grade acute and chronic GVHD. Within the MC group, response to pDLI was the only significant factor predicting OS, DFS, and relapses with NR and ND having unfavorable outcomes as compared to RR (p = 0.001). T cell MC in patients undergoing UD allografts with alemtuzumab is no longer an adverse prognostic factor, as compared to patients having CC, after timely implementation of pDLI.

ABSTRACT Objective To examine the incidence of invasive fungal disease (IFD) in patients receiving targeted agents for acute myeloid leukaemia (AML). Methods Literature for this systematic review was identified through a PubMed search in April 2024, using AML, IFD and targeted therapy terms. The following filters were applied: published in the last 10 years and published in English. Results The PubMed search yielded 54 results, of which 16 were deemed relevant for inclusion. Four additional references were identified through manual searches. The majority of publications focused on the incidence of IFD during treatment with targeted agents; the remainder focused on the efficacy of targeted treatments and reported IFD as an adverse event. Most publications were retrospective analyses. Prophylaxis use and agents differed across studies. In several studies, IFD incidence was above the 8% threshold identified for anti‐mould prophylaxis. Aspergillus was the most commonly reported pathogen, and most IFD cases occurred in the lungs. Conclusions IFD is relatively common among patients with AML receiving targeted therapies, despite the use of prophylaxis. Prospective studies with detailed IFD reporting, together with large epidemiological studies, are required to better understand the risk factors for, and incidence and nature of IFD in this patient population.

Background Acute leukaemias (AL) are life-threatening blood cancers that can be potentially cured with treatment involving myelosuppressive, multiagent, intensive chemotherapy (IC). However, such treatment is associated with a risk of serious infection, in particular invasive fungal infection (IFI) associated with prolonged neutropenia. Current practice guidelines recommend primary antifungal (AF) prophylaxis to be administered to high-risk patients to reduce IFI incidence. AFs are also used empirically to manage prolonged neutropenic fever. Current strategies lead to substantial overuse of AFs. Galactomannan (GM) and β-D-glucan (BG) biomarkers are also used to diagnose IFI. Combining both biomarkers may enhance the predictability of IFI compared to administering each test alone. Currently, no large-scale randomised controlled trial (RCT) has directly compared a biomarker-based diagnostic screening strategy without AF prophylaxis to AF prophylaxis (without systematic biomarker testing). Methods BioDriveAFS is a multicentre, parallel, two-arm RCT of 404 participants from UK NHS Haematology departments. Participants will be allocated on a 1:1 basis to receive either a biomarker-based antifungal stewardship (AFS) strategy, or a prophylactic AF strategy, which includes existing standard of care (SoC). The co-primary outcomes will be AF exposure in the 12-month post randomisation and the patient-reported EQ-5D-5L measured at 12-month post randomisation. Secondary outcomes will include total AF exposure, probable/proven IFI, survival (all-cause mortality and IFI mortality), IFI treatment outcome, AF-associated adverse effects/events/complications, resource use, episodes of neutropenic fever requiring hospital admission or outpatient management, AF resistance in fungi (non-invasive and invasive) and a Desirability of Outcome Ranking. The trial will have an internal pilot phase during the first 9 months. A mixed methods process evaluation will be integrated in parallel to the internal pilot phase and full trial, aiming to robustly assess how the intervention is delivered. Cost-effectiveness analysis will also be performed. Discussion The BioDriveAFS trial aims to further the knowledge of strategies that will safely optimise AF use through comparison of the clinical and cost-effectiveness of a biomarker-led diagnostic strategy versus prophylactic AF to prevent and manage IFI within acute leukaemia. The evidence generated from the study will help inform global clinical practice and approaches within antifungal stewardship. Trial registration ISRCTN11633399. Registered 24/06/2022.

Acute megakaryoblastic leukaemia is a rare entity with distinct immunophenotype profile and cytogenetic lesions. Herein, we report a case of acute myeloid leukaemia with myelodysplastic‐related changes with megakaryoblastic differentiation in absence of recurrent genomic lesions such as t(1;22), inv(3) and t(3;3). One of the peculiarities of this case is the positivity of CD34+ within the abnormal megakaryoblasts; CD61 immunohistochemistry highlights the heavily infiltration of bone marrow from abnormal megakaryoblasts.

Non-severe aplastic anemia is a rare bone marrow failure disorder characterized by variable degrees and combination of cytopenias, with limited data on management and outcome. We describe a large multicentric series of 259 patients, focusing on clinical and molecular features, treatment, evolution, and survival. The majority required treatment with cyclosporine (CyA) alone (N = 84) or in combination with anti-thymocyte globulin (ATG,44) or eltrombopag (20), eltrombopag alone (10), or others (25) including androgens. Similar outcomes were observed across different strategies, with a 6-month overall response rate of 73% for CyA, 74% for ATG plus CyA, 68% for CyA plus eltrombopag, 87% for eltrombopag, and 79% for others. Notably, 56 patients (39%), mainly receiving CyA plus eltrombopag, achieved a trilineage response (p = 0.02). Progression to myeloid neoplasms was limited (8%) and not related to mutational status. Hemolytic PNH developed in 10% of cases, being predicted by detection of small clones at diagnosis. Survival was negatively impacted by age, male gender, LDH, platelets/erythrocyte transfusion need, and somatic mutations by NGS, and positively by higher neutrophils at diagnosis, PNH clones, and trilineage response at 6 and 12 months. Multivariable analysis confirmed the detrimental role of age and the favorable association with PNH clone and trilineage response at 6 months.