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In recent years, advances in biomedicine have revealed an important role for post-transcriptional mechanisms of gene expression regulation in pathologic conditions. In cancer in general and leukaemia specifically, RNA binding proteins have emerged as important regulator of RNA homoeostasis that are often dysregulated in the disease state. Having established the importance of these pathogenetic mechanisms, there have been a number of efforts to target RNA binding proteins using oligonucleotide-based strategies, as well as with small organic molecules. The field is at an exciting inflection point with the convergence of biomedical knowledge, small molecule screening strategies and improved chemical methods for synthesis and construction of sophisticated small molecules. Here, we review the mechanisms of post-transcriptional gene regulation, specifically in leukaemia, current small-molecule based efforts to target RNA binding proteins, and future prospects.

Summary In recent years, large‐scale sequencing efforts have identified targetable driver mutations in haematopoietic stem cells. These efforts have led to the development and approval of nine novel agents for relapsed or refractory acute myelogenous leukaemia (R/R AML). However, despite an expansion in targeted therapies, achieving a durable remission in AML and high‐risk myelodysplastic syndrome (HR‐MDS) remains a significant challenge, and there is an urgent need for new effective treatments. Modulation of aberrant RNA splicing has emerged as a novel therapeutic approach in myeloid diseases. Aberrant splicing drives dysregulated gene expression that promotes tumourigenesis through increased proliferation and metastatic potential, immune evasion, decreased apoptosis, and chemotherapy resistance. Mutations in spliceosomal components have been identified in numerous cancer subtypes, with mutations in RNA binding proteins SF3B1, SRSF2, U2AF1, and ZRSR2 occurring frequently in AML and in up to 60% of patients with MDS, as well as in chronic myelomonocytic leukaemia and in 10% of patients with chronic lymphocytic leukaemia. In this review, we explore therapeutic strategies targeting aberrant splicing and the potential of these approaches to drive clinical responses. [ABSTRACT FROM AUTHOR]

Summary Early‐phase trials of venetoclax in children and teenagers/young adults with leukaemia have yielded promising results, but there remains a paucity of real‐world data. To address this, we report a cohort of 41 children treated with venetoclax for a range of haematological malignancies, demonstrating complete remission in 43.6%, with most achieving minimal residual disease (MRD) negativity. Venetoclax was particularly effective as a bridge to transplant, with bridging successful in 75% of patients. Patients with MRD <1% at initiation of venetoclax were more likely to achieve MRD negativity (81.8% vs. 34.5%, p = 0.007) and had improved overall survival (54.5% vs. 17.9%, p = 0.004). [ABSTRACT FROM AUTHOR]

Summary Philadelphia chromosome (Ph)‐like acute lymphoblastic leukaemia (ALL) is a high‐risk subtype with a gene expression profile similar to Ph‐positive ALL, due to activation of tyrosine kinase signalling. To understand the clinical implications of Ph‐like ALL, this single‐centre retrospective study evaluates outcomes in 268 adults, largely Hispanic ALL patients treated between 2013 and 2024, with a subgroup analysis of 139 haematopoietic stem cell transplantation (HSCT) patients. ALL subtypes included 68 (25.4%) Ph‐like, 89 (33.2%) Ph‐positive, and 111 (41.4%) Ph‐negative. Ph‐like patients were the youngest age at diagnosis (p = 0.007), most likely to have refractory disease (p < 0.001), and least likely to achieve minimal residual disease (MRD) negativity after induction (p = 0.031). Relative to Ph‐negative ALL, Ph‐like achieved worse event‐free survival (EFS) (HR = 1.66; 95% CI 1.12–2.46; p = 0.012), whereas Ph‐positive had improved EFS (HR = 0.60; 95% CI 0.38–0.93; p = 0.024) and cumulative incidence of relapse (CIR) (HR = 0.59; 95% CI 0.35–0.99; p = 0.046). Within the transplant subgroup, Ph status did not impact disease‐free survival (DFS), CIR, or overall survival (OS). However, patients who received blinatumomab within 1‐year pre‐HSCT had improved DFS (HR = 0.43; 95% CI 0.20–0.94; p = 0.034) and CIR (HR = 0.26; 95% CI 0.09–0.75; p = 0.13). In conclusion, our data suggest that Ph‐like is less likely to respond to standard induction therapy and HSCT may result in similar survival outcomes to Ph‐negative ALL. [ABSTRACT FROM AUTHOR]

Summary Acute lymphoblastic leukaemia (ALL) in 20%–30% of adult patients contains the Philadelphia (Ph+) chromosome. Historically, Ph+ ALL denoted a markedly inferior outcome and long‐term survival in the absence of an allograft was uncommon. However, the advent of targeted therapy directed against the BCR::ABL1 fusion protein with various tyrosine kinase inhibitors (TKIs) has markedly improved the prognosis, resulting in a number of treatment controversies in allograft‐eligible patients. Which is the best TKI to use in induction? What is the clinical relevance of the subdivision of Ph+ ALL into multilineage vs lymphoid types? Do all patients in first morphological complete remission (CR1) after induction and consolidation with chemotherapy/TKI require an allograft? If not, what risk factors predict a poor outcome without an allograft? Can chemotherapy‐free approaches, such as blinatumomab in conjunction with more potent TKIs, obviate the need for an allograft in high‐risk patients? What is the best strategy to deal with persistent or emerging minimal residual disease both pre‐ and post‐transplant? Is maintenance TKI indicated in all patients post allograft? Can salvage therapy and a subsequent allograft cure patients who relapse after not being transplanted in CR1? This manuscript reviews the latest data influencing contemporary management and discusses these controversies. [ABSTRACT FROM AUTHOR]

Summary Addition of molecular data to prognostic models has improved risk stratification of myelodysplastic neoplasms (MDS). However, the role of molecular lesions, particularly in the group of low‐risk disease (LR‐MDS), is uncertain. We evaluated a set of 227 patients with LR‐MDS. Overall survival (OS) and probability of leukaemic progression were the main endpoints. RUNX1 was associated with lower OS and SF3B1 with a reduced risk of death (HR: 1.7, 95% CI, 1.1–2.9; p = 0.05; and HR: 0.23, 95% CI 0.1–0.5; p < 0.001; respectively). TP53 and RUNX1 mutations were predictive covariates for the probability of leukaemic progression (p < 0.001). Blast percentage, neither analysed as categorical (<5% vs. 5%–9%; HR: 1.3, 95% CI, 0.7–2.9; p = 0.2) nor as a continuous variable (HR: 1.07, 95% CI, 0.9–1.1; p = 0.07), had impact on survival or probability of progression (sHR: 1.05, 95% CI, 0.9–1.1; p = 0.2). These results retained statistical significance when analysis was restricted to the definition of LR‐MDS according to the WHO 2022 and ICC classifications (<5% blasts). Thus, with the incorporation of molecular data, blast percentage happens to lose clinical significance both for survival and probability of progression in the group of patients with LR‐MDS. [ABSTRACT FROM AUTHOR]

Background: Bleeding is a primary outcome for many transfusion‐related trials in acute leukaemia (AL) patients, typically graded using the World Health Organisation (WHO) bleeding scale (clinically significant bleed (CSB) is ≥grade 2). This composite outcome fails to differentiate minor bleeds that may not be significant, poorly represents the total burden of bleeding and lacks input from healthcare providers (HCPs) and patients. As part of a multi‐step project to create a better bleeding tool for trials, our objective was to identify HCPs' perspectives on the components of CSB in AL patients. Study Design and Methods: Using qualitative description, we interviewed 19 physicians and nurses who care for AL patients undergoing induction chemotherapy. Participants were recruited from professional organisations, networks and social media. An inductive approach to conventional content analysis was used. Results: HCPs identified features of CSB as the anatomical site of bleeding, amount of bleeding, need for intervention and changes in vital signs. Using these characteristics, bleeding events were categorised into three groups: clinically significant, could evolve into a CSB and not clinically significant. HCPs considered the patient's condition, bleeding history and clinical intuitions when deciding whether a bleed could escalate into serious bleeding. Discussion: Using data from HCPs, we categorised bleeds as clinically significant, could evolve into a CSB, and not significant. A study of patients' perspectives on the importance of different kinds of bleeding is the next step to creating a bleeding definition that is informed by evidence, clinicians and patients. [ABSTRACT FROM AUTHOR]

Abstract Introduction Relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) remains a therapeutic challenge. Preclinical data in both B‐ and T‐ALL suggests synergy of venetoclax (VEN) with vincristine (VCR). We designed a phase I/II trial (EA9152) of the combination of L‐VCR and VEN for patients with r/r B‐or T‐cell ALL or LL. Here, we report the safety and efficacy outcomes of the phase I portion of this trial (NCT03504644). Methods In a 3+3 dose escalation design, r/r ALL subjects were given single‐agent VEN doses reaching 400, 600, or 800 mg for the three respective dose levels. Weekly L‐VCR at 2.25 mg/m2 IV was started on D15 of cycle 1. The primary phase I objective was to determine the maximum tolerated dose (MTD) of the combination. Results Among the 18 patients in phase I, grade ≥ 3 treatment‐related adverse events were reported in 89% of treated patients. Two patients (two of three) at dose level 3 experienced dose‐limiting toxicities. Therefore, the MTD of the combination was determined to be dose level 2 (VEN 600 mg). Twenty‐two percent of evaluable patients (N = 4) achieved a complete response, with two of them showing no evidence of measurable residual disease (MRD). Conclusion The combination of VEN and L‐VCR was found to be safe for patients with r/r ALL and encouraging preliminary efficacy, including MRD negative responses. With the removal of L‐VCR from the US market, the phase 2 portion of this trial is actively enrolling with vincristine sulfate.

ABSTRACTIn recent years, advances in biomedicine have revealed an important role for post-transcriptional mechanisms of gene expression regulation in pathologic conditions. In cancer in general and leukaemia specifically, RNA binding proteins have emerged as important regulator of RNA homoeostasis that are often dysregulated in the disease state. Having established the importance of these pathogenetic mechanisms, there have been a number of efforts to target RNA binding proteins using oligonucleotide-based strategies, as well as with small organic molecules. The field is at an exciting inflection point with the convergence of biomedical knowledge, small molecule screening strategies and improved chemical methods for synthesis and construction of sophisticated small molecules. Here, we review the mechanisms of post-transcriptional gene regulation, specifically in leukaemia, current small-molecule based efforts to target RNA binding proteins, and future prospects.

Abstract 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.

Summary: European LeukemiaNet refined their risk classification of acute myeloid leukaemia (AML) in 2022 (ELN 2022) according to the two new myeloid classifications published the same year. We have retrospectively assessed the prognostic value of the ELN 2022 in 120 AML patients undergoing allogeneic haematopoietic cell transplantation (allo‐HCT), including 99 in first complete response (CR1) from 2011 to 2021 in our centre. Adverse risk patients (Adv) presented inferior outcome in terms of overall survival (OS) and leukaemia‐free survival (LFS) (OS [p = 0.003], LFS [p = 0.02]), confirmed in multivariate analysis (hazard ratio [HR] for OS = 2.00, p = 0.037). These results were also seen in patients allografted in CR1. Further analysis identified a subgroup named adverse‐plus (AdvP), including complex karyotype, MECOM(EVI1) rearrangements and TP53 mutations, with worse outcomes than the rest of groups of patients, including the Adv (HR for OS: 3.14, p < 0.001, HR for LFS: 3.36, p < 0.001), with higher 2‐year cumulative incidence of relapse (p < 0.001). Notably, within this analysis, the outcome of Adv and intermediate patients were similar. These findings highlight the prognostic value of ELN 2022 in patients undergoing allo‐HCT, which can be improved by the recognition of a poor genetic subset (AdvP) within the Adv risk group. [ABSTRACT FROM AUTHOR]

Summary: Therapy‐related acute lymphoblastic leukaemia (tr‐ALL) is a disease entity attributed to previous exposure to chemotherapy and/or radiation for antecedent malignancy. There is observed female predominance for tr‐ALL, likely due to high prevalence and excellent curable rate for non‐metastatic breast cancer as well as the frequent use of carcinogenic agents as part of adjuvant therapy. Here, we reviewed 37 women with diagnosis of ALL following breast cancer treatment with focus on cytogenetic categorization. Philadelphia chromosome positivity (Ph+), KMT2A alterations and other cytogenetic change groups were observed in 32%, 22% and 46% of patients respectively. Median overall survival (OS) and relapse‐free survival (RFS) were 19.4 and 12.9 months, overall while both OS and RFS were superior in tr‐ALL with Ph+ disease compared to KMT2Ar and other cytogenetics respectively. Seventeen (45.9%) patients underwent consolidative allogeneic haematopoietic cell transplantation (alloHCT) in CR1 out of which 4 (24%) relapsed following transplant. Both OS and RFS were superior in the KMT2Ar cytogenetics group following alloHCT. Ph chromosome represents the largest genetic entity of tr‐ALL following breast cancer therapy, and it may be associated with superior survival outcomes while KMT2Ar may be associated with poorer outcomes that can perhaps be mitigated by alloHSCT. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: Despite advancements in utilizing genetic markers to enhance acute myeloid leukaemia (AML) outcome prediction, significant disease heterogeneity persists, hindering clinical management. To refine survival predictions, we assessed the transcriptome of non‐acute promyelocytic leukaemia chemotherapy‐treated AML patients from five cohorts (n = 975). This led to the identification of a 4‐gene prognostic index (4‐PI) comprising CYP2E1, DHCR7, IL2RA and SQLE. The 4‐PI effectively stratified patients into risk categories, with the high 4‐PI group exhibiting TP53 mutations and cholesterol biosynthesis signatures. Single‐cell RNA sequencing revealed enrichment for leukaemia stem cell signatures in high 4‐PI cells. Validation across three cohorts (n = 671), including one with childhood AML, demonstrated the reproducibility and clinical utility of the 4‐PI, even using cost‐effective techniques like real‐time quantitative polymerase chain reaction. Comparative analysis with 56 established prognostic indexes revealed the superior performance of the 4‐PI, highlighting its potential to enhance AML risk stratification. Finally, the 4‐PI demonstrated to be potential marker to reclassified patients from the intermediate ELN2017 category to the adverse category. In conclusion, the 4‐PI emerges as a robust and straightforward prognostic tool to improve survival prediction in AML patients. [ABSTRACT FROM AUTHOR]

Summary: Physiologically based pharmacokinetic (PBPK) modelling is an alternative modelling technique that is increasingly used in pharmacokinetics. Due to its nature, it can be complementarily employed to population pharmacokinetics, especially when it comes to small population size. Here, we report the proof of concept of its application to accurately describe the pharmacokinetics of a recombinant L‐asparaginase in paediatric patients with acute lymphoblastic leukaemia. Data from two randomized, double‐blind, phase II/III clinical studies (MC‐ASP.4/ALL; MC‐ASP.5/ALL) were included to setup and evaluate the final model, respectively. Final population values for basic pharmacokinetic parameters were calculated (clearance: 0.0569 L/h/19.5 kg, volume of distribution: 1.251 L, half‐life: 18.5 h, trough concentration: 140.9 IU/L). Pharmacokinetic parameter prediction as well as predictive performance of the model proofed to be comparable to a separately developed population pharmacokinetic model with 13% deviation in predicted median L‐asparaginase trough levels. To the best of our knowledge, this is the first whole‐body PBPK model of a non‐antibody therapeutic protein. [ABSTRACT FROM AUTHOR]

Summary Secondary primary malignancies (SPM) have been reported after anti‐BCMA or anti‐CD19 chimeric antigen receptor (CAR)‐T‐cell therapies. While the cytotoxic effect of antecedent therapies, including chemotherapy and radiotherapy, has been well established, few data are available on risk related to CAR‐T immunotherapies. The study aimed to analyse the incidence of SPM in 651 patients enrolled in the Italian prospective observational CART‐SIE study. SPMs were documented in 4.3% (28/651), and the most frequent SPMs were haematological malignancies. In conclusion, the frequency of SPMs in our cohort of heavily pretreated patients receiving CAR‐T was relatively low and consistent with previous studies. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to assess the prognostic significance of various morphological markers of chromosomal instability (CI). Design: This is a cross-sectional analytical study. Setting: Single centre study from the Department of Pathology of a tertiary care centre in India. Participants: The study included samples of bone marrow aspirates (BMA) and biopsies of patients with acute leukaemia (AL) and myelodysplastic syndrome (MDS) performed between June 2019 and June 2021. Inadequate samples were excluded. We included 178 samples from 80 cases. Interventions: BMA and biopsies slides examined for CI markers like chromatin bridges, multipolar mitosis, nuclear budding, micronuclei, laggards, chromatin string (CS) and nuclear heterogeneity (NH). CI markers were correlated with the type, severity and prognosis of acute leukaemia and MDS. Main outcome measures: Evaluation of CI markers as prognostic markers in AL and MDS. Results: We included B-cell ALL (35), AML (11), MDS (04), relapse of AL (12), and remission of AL (116). All CI markers were significantly increased in AL and MDS compared to the remission group. All CI markers were significantly higher in non-responders to therapy than in responders. In regression analysis, the median (IQR) values of CS and NH were significantly higher among non-survivors than survivors. Conclusion: CI markers of morphology are significantly associated with poor prognosis, including Non-survival of the disease. These markers are easy to identify and cost-effective. We recommend incorporating morphological markers of CI in routine reporting of haematological malignancies to assist in prognostication before reports from sophisticated techniques are available. [ABSTRACT FROM AUTHOR]

Aims: To report the clinicopathological features of Kikuchi disease in patients with acute leukaemia, emphasising similarities among cases. Methods and results: In a cohort of 454 Kikuchi disease patients, we identified three cases of concurrent acute leukaemia. These patients shared similar clinical traits, with Kikuchi disease emerging approximately a month after induction chemotherapy onset, featuring neck‐region lymphadenopathy. Notably, two patients were middle‐aged, deviating from the typical age distribution of Kikuchi disease. Histologically, these cases aligned with typical Kikuchi disease. Negative immunohistochemical stains (CD34, CD117, ERG, TdT) indicated the absence of extramedullary leukaemic infiltration. Herpes simplex virus immunohistochemical staining was also negative. Significantly, a human leucocyte antigen (HLA) association was observed in these three cases. HLA‐B*15:01, C*04:01, and DRB1*04:06 were more prevalent in these patients compared to the general population (compared with three independent control cohorts: Taiwanese Han Chinese (n = 504), Tzu Chi Taiwanese bone marrow donors (n = 364) and Hong Kong Chinese (n = 5266)). Conclusions: Our study underscores the unique link between Kikuchi disease and acute leukaemia, characterised by specific features and HLA associations. This underlines Kikuchi disease as a possible differential diagnosis in pertinent clinical scenarios. Furthermore, this syndrome offers insights into postchemotherapy immunology in acute leukaemia, enhancing comprehension. [ABSTRACT FROM AUTHOR]

In their paper, using zebrafish models, Gioacchino et al. have demonstrated the GATA2 haploinsufficiency, the genetic hallmark of GATA2 deficiency syndrome, promotes erythroid and myeloid cytopenia, and have discovered a self‐regulatory mechanism to compensate GATA2 levels and protein function. Commentary on: Gioacchino et al. GATA2 heterozygosity causes an epigenetic feedback mechanism resulting in myeloid and erythroid dysplasia. Br J Haematol 2024;205:580‐593. [ABSTRACT FROM AUTHOR]

Summary: We have conducted a retrospective, single‐centre analysis of 20 patients with relapsed or refractory FLT3‐mutated acute myeloid leukaemia (FLT3m AML) who received a salvage quadruplet regimen consisting of gilteritinib, venetoclax, low‐dose cytarabine and actinomycin D (G‐ACTIVE). G‐ACTIVE resulted in a 95% (19/20) overall response rate and 75% (15/20) complete remission and complete remission with an incomplete platelet recovery (CR + CRp) rate. Out of 13 transplant‐eligible patients, 11 (86%) proceeded to an allogeneic stem cell transplantation. The median overall survival and relapse‐free survival after G‐ACTIVE were 32 and 12.9 months respectively. The Day 60 mortality rate was 15%. [ABSTRACT FROM AUTHOR]

This article discusses the use of long-read sequencing, specifically nanopore sequencing, for the identification and analysis of atypical structural variations (SVs) in haematological neoplasms. SVs are common in these conditions, but their diagnosis can be challenging. The article presents a case study where nanopore sequencing was used to characterize a novel inv(16) in acute myeloid leukaemia (AML). The findings highlight the potential of long-read sequencing for the comprehensive analysis of atypical SVs. The study describes the use of long-read sequencing to characterize a new atypical inversion in a patient with AML, and suggests that a complete characterization of driver defects in hematological neoplasms could lead to improved disease monitoring and patient management. [Extracted from the article]

Introduction: Acute leukaemias are complicated with numerous disease and treatment related medical complications. Infection is one of the major complications and is related to chemotherapy associated-neutropaenia. This study aims to identify medical complications in acute leukaemia patients during the induction chemotherapy period. Results: Medical complications were observed in patients receiving induction chemotherapy N=50. Infections and electrolyte disturbances were the most frequently observed complications (74% each) followed by chemotherapy induced neutropaenia (38%), alteration of liver functions (32%), steroid induced hyperglycaemia (28%) and bleeding (16%). Thrombosis and tumour lysis were detected at lesser frequencies (4% each). Among infections, the majority showed evidence of blood stream infection (27%) followed by pulmonary infections (24.3%). Gram negative organisms were the most frequently identified pathogen. Among the electrolyte disturbances, hypokalaemia (48%), hyponatraemia (48%), and hypocalcaemia (44%) were more prevalent. Mean duration from initiation of chemotherapy to neutrophil nadir was 10.05 days. Conclusions: Patients with acute leukaemia encounter a multitude of disease and treatment related medical complications during induction chemotherapy. Infection is the most common complication with higher rates of bacteraemia and gram-negative sepsis. This is likely to be a result of treatment related neutropaenia. However, further focused studies on neutropaenic sepsis during induction chemotherapy are recommended. Clinical vigilance, strict and improved infection control strategies are necessary to improve the outcome of these patients.

Introduction: Cryoprecipitate is a slushy product derived from Fresh Frozen Plasma (FFP) through centrifugation at specific temperatures and speeds. It is rich in factor VIII or antihaemorrhagic factor, fibrinogen, and minor amounts of other clotting factors. Cryoprecipitate is primarily used to correct hypofibrinogenaemia or replenish depleted fibrinogen levels. Aim: To examine the appropriate clinical utilisation of cryoprecipitate (cryo) by various departments in the Institute and evaluate the improvement in patients through laboratory tests. Materials and Methods: A single group quasi-experimental study was conducted in the Department of Immunohaematology and Transfusion Medicine (IHBT) at Nizam’s Institute of Medical Sciences (NIMS), Hyderabad, Telangana, India. The duration of the study was over a period of six years, from May 2016 to April 2022. A total of 486 cases where cryoprecipitate was requested were included in the present study. The results were analysed using Prothrombin Time (PT) and International Normalised Ratio (INR). Percentages and means were used to assess various parameters in this study. All statistical analyses were performed using Statistical Package for Social Sciences (SPSS) version 25.0. Results: The mean age of the study participants was 52.7 years. A total of 486 cases were included over a period of six years, with 3375 cryoprecipitate transfusions performed. The youngest patient was a 9-year-old male, the oldest patient was an 83-year-old male. Most of the cryoprecipitate was appropriately utilised by the Medical Oncology Department (995 cases, 995 units, 20-25 mL per unit-29.48%), while the Cardiology Department had the lowest utilisation (12 cases, 12 units-0.35%). Utilisation by other departments ranged between 45 and 564 cases or units (1.33% to 16.71% per department). The majority of cryoprecipitate units were issued for multiple myeloma and acute leukaemias (new cases and relapse)-28.38% (958 units), while the least were issued for minor surgery and medical cases (29 cases or 29 units-0.85%). Conclusion: Cryoprecipitate should be used appropriately to achieve desired results and avoid unnecessary transmission. Clinicians, residents, and surgeons should adhere to comprehensive regulatory guidelines for the appropriate usage of cryoprecipitate or any other blood products, as outlined by their hospital transfusion committee.

Abstract UBTF tandem duplications are recurrent in adult and paediatric acute myeloid leukaemia and have been reported to be associated with a poor prognosis. Co‐mutations in WT1 and FLT3 are common while morphological dysplasia is frequent. The role of UBTF‐TDs in leukemogenesis is yet to be elucidated; however they have been proposed as early initiating events, making them attractive for assessment of MRD and a potential therapeutic target. We present two cases where the UBTF‐TD was observed in remission and discuss the implications of these findings in the clinicobiological understanding of this emerging entity.

Aims: Azathioprine (AZA) and 6‐mercaptopurine are prescribed in acute lymphoblastic leukaemia (ALL) and inflammatory bowel diseases (IBD). Metabolism to active 6‐thioguanine (6TGN) and 6‐methylmercaptopurine nucleotides (6MMPN) is variable but therapeutic drug monitoring (TDM) remains debatable. This study reports on factors impacting on red blood cell (RBC) metabolites concentrations in children to facilitate TDM interpretation. Methods: The first paediatric TDM samples received during year 2021 were analysed, whatever indication and thiopurine drug. Target concentration ranges were 200–500, <6000 pmol/8 × 108 RBC for 6TGN and 6MMPN. Results: Children (n = 492) had IBD (64.8%), ALL (22.6%) or another autoimmune disease (12.6%): mean ages at TDM were 7.5 in ALL and 13.7 years in IBD (P <.0001). ALL received 6‐mercaptopurine (mean dose 1.7 mg/kg/d with methotrexate), IBD received AZA (1.9 mg/kg/d with anti‐inflammatory drugs and/or monoclonal antibodies). Median 6TGN and 6MMPN concentrations were 213.7 [interquartile range: 142.5; 309.6] and 1144.6 [419.4; 3574.3] pmol/8 × 108 RBC, 38.8% of patients were in the recommended therapeutic range for both compounds. Aminotransferases and blood tests were abnormal in 57/260 patients: 8.1% patients had high alanine aminotransaminase, 3.4% of patients had abnormal blood count. Factors associated with increased 6TGN were age at TDM and thiopurine methyltransferase genotype in ALL and AZA dose in IBD. The impact of associated treatment in IBD patients was also significant. Conclusion: TDM allowed identification of children who do not reach target levels or remain over treated. Including TDM in follow‐up may help physicians to adjust dosage with the aim of reducing adverse effects and improve treatment outcome. [ABSTRACT FROM AUTHOR]

Invasive fungal diseases (IFDs) still represent a relevant cause of mortality in patients affected by hematological malignancies, especially acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) undergoing remission induction chemotherapy, and in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Mold-active antifungal prophylaxis (MAP) has been established as a standard of care. However, breakthrough IFDs (b-IFDs) have emerged as a significant issue, particularly invasive aspergillosis and non-Aspergillus invasive mold diseases. Here, we perform a narrative review, discussing the major advances of the last decade on prophylaxis, the diagnosis of and the treatment of IFDs in patients with high-risk neutropenic fever undergoing remission induction chemotherapy for AML/MDS and allo-HSCT. Then, we present our single-center retrospective experience on b-IFDs in 184 AML/MDS patients undergoing high-dose chemotherapy while receiving posaconazole (n = 153 induction treatments, n = 126 consolidation treatments, n = 60 salvage treatments). Six cases of probable/proven b-IFDs were recorded in six patients, with an overall incidence rate of 1.7% (6/339), which is in line with the literature focused on MAP with azoles. The incidence rates (IRs) of b-IFDs (95% confidence interval (95% CI), per 100 person years follow-up (PYFU)) were 5.04 (0.47, 14.45) in induction (n = 2), 3.25 (0.0013, 12.76) in consolidation (n = 1) and 18.38 (3.46, 45.06) in salvage chemotherapy (n = 3). Finally, we highlight the current challenges in the field of b-IFDs; these include the improvement of diagnoses, the expanding treatment landscape of AML with molecular targeted drugs (and related drug–drug interactions with azoles), evolving transplantation techniques (and their related impacts on IFDs' risk stratification), and new antifungals and their features (rezafungin and olorofim). [ABSTRACT FROM AUTHOR]

Aim and Objectives: To identify the main concern of patients with acute leukaemia and their family caregivers in the process of coping with the disease and to determine how patients and their family caregivers address these concerns on an ongoing basis. Background: Acute leukaemia is a progressive disease that may lead to physical problems and mental stress in patients. It also affects the psychological well‐being and quality of life of family caregivers. Nevertheless, few studies explore the behavioural pattern across the trajectories of illness in Chinese patients with acute leukaemia and their family caregivers. Design: Grounded theory. Methods: Theoretical sampling was performed to collect 14 sets of secondary data from Bilibili platform, literature, articles from WeChat official account, press releases and documentary. A total of 29 participants were selected to participate in semistructured interviews from the haematology department of a tertiary care hospital in Fuzhou, Fujian Province from January 2021 to November 2021. Data collection and analysis were conducted in a synchronous iterative manner until theoretical saturation was reached. Data analysis included open coding, selective coding and constant comparison, et al. The CCOREQ checklist was utilised. Results: This study discovered the main concern (i.e. seeking survival) and main behavioural pattern of how patients with acute leukaemia and their family caregivers addressed this issue. Three decision‐making strategies, 'responding' 'accommodating' and 'resisting' also emerged. Conclusions: This study explored the behavioural pattern of patients with acute leukaemia and their family caregivers in the process of coping with disease. The study found that the main concern of patients with acute leukaemia and their family caregivers, and provided a theoretical basis for disease management and nursing interventions for them in the future. Relevance to Clinical Practice: The findings of this study contribute to nursing knowledge, practice in the field of patients' participation in decision‐making. Patient or Public Contribution: Due to the characteristics of grounded theory (no presupposition of research questions), the interviews in this study mainly focus on theory generation. Participants were not asked to assess the burden of the intervention and the time required to participate in the study, as interviews were conducted for theory generation. This study may assist patients and family caregivers in obtaining better understand and adapt to changes across the trajectory of illness, as well as to promote public destigmatisation of acute leukaemia and reforms in family‐hospital‐community diversified care. [ABSTRACT FROM AUTHOR]

Acute leukaemia (AL) is a heterogeneous neoplastic disease that occurs by the growth of abnormal lymphoid and myeloid cells in the bone marrow and blood leading to acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL). Conventional cytogenetics is a characteristic technique to hunch chromosomal abnormalities, it helps in the diagnosis and therapeutic approach of the disease by the molecular cytogenetics technique of fluorescence in situ hybridization (FISH). Chromosomal abnormalities in AL are performed by karyotyping to confirm specific chromosomal abnormalities using FISH. The descriptive study included 42 clinically diagnosed AL patients. Karyotyping analysis was performed using the standard Giemsa banding procedure. To confirm specific chromosomal abnormalities and all culture failure (CF) cases, FISH was done. Among 42 cases, 29 (69.4%) males and 13 (30.9%) females, AML comprised 22 (52.38%) cases, ALL 14 (33.33%) cases, and AL 6 (14.2%) cases. Normal karyotype was found in 18 (42.85%), abnormal karyotype in 16 (39.09%), and 8 (19.09%) were CF. Specific abnormalities of t(15;17), hyperdiploidy; t(3;3) with monosomy 7 in; del(9q22); del(2p); del(17p); del(Xq); 1~2 dmin; der(3); +11, +13 and composite karyotype. Hypodiploidy was strongly associated with AL, which signifies the loss of chromosomes causing potential risk. Composite karyotype, rare t(3;3) double minutes, +11,+13, del(9q), and del(Xq) were the novel findings reported in the South Canara region of Karnataka. Despite other molecular techniques, conventional cytogenetics remains the baseline in the diagnosis of malignancies.

Abstract Background Published epidemiological studies of haematological cancers are few. Hereby we present a 20-year epidemiological data of haematological cancers in Sarawak from a population-based cancer registry. Methods Haematological cancer cases with ICD-10 coded C81-C96 and ICD-O coded /3 diagnosed from 1996 to 2015 were retrieved from Sarawak Cancer Registry. Adult was defined as those 15 years and above. Incidence rate (IR) was calculated based on yearly Sarawak citizen population stratified to age, gender, and ethnic groups. Age-standardised IR (ASR) was calculated using Segi World Standard Population. Results A total of 3,947 cases were retrieved and analysed. ASR was 10 and male predominance (IR ratio 1.32, 95%CI 1.24,1.41). Haematological cancers generally had a U-shaped distribution with lowest IR at age 10–14 years and exponential increment from age 40 years onwards, except acute lymphoblastic leukaemia (ALL) with highest IR in paediatric 2.8 versus adult 0.5. There was a significant difference in ethnic and specific categories of haematological cancers, of which, in general, Bidayuh (IR ratio 1.13, 95%CI 1.00, 1.27) and Melanau (IR ratio 0.54, 95%CI 0.45, 0.65) had the highest and lowest ethnic-specific IR, respectively, in comparison to Malay. The ASR (non-Hodgkin lymphoma, acute myeloid leukaemia, ALL, chronic myeloid leukaemia, and plasma cell neoplasm) showed a decreasing trend over the 20 years, -2.09 in general, while Hodgkin lymphoma showed an increasing trend of + 2.80. There was crude rate difference between the 11 administrative divisions of Sarawak. Conclusions This study provided the IR and ASR of haematological cancers in Sarawak for comparison to other regions of the world. Ethnic diversity in Sarawak resulted in significant differences in IR and ASR.

Granulocytic sarcoma is a myeloid neoplasm that can occur in isolation or in association with acute leukaemia. The temporal bone represents a sanctuary site for myeloid progenitors: granulocytic sarcoma may develop in this location before or concomitantly with the onset of acute leukaemia. This atypical presentation with clinical and radiological data that closely mimic those of cholesteatoma often delays an accurate diagnosis. We here describe the clinical case of a 28-year-old male with granulocytic sarcoma of the external auditory canal that preceded the relapse of promyelocytic leukaemia. [ABSTRACT FROM AUTHOR]

Purpose: To longitudinally investigate choroidal and choriocapillaris perfusion metrics and the number of choroidal hyperreflective foci (HRF) in patients with acute leukaemia (AL) before and after disease remission and to correlate these metrics with systemic parameters during active disease. Methods: Prospective, longitudinal study of 26 eyes of 14 AL patients. All patients underwent optical coherence tomography (OCT) and OCT‐angiography (OCTA) in the acute phase. Subfoveal choroidal thickness (CT), total, luminal and stromal choroidal area (TCA, LCA, SCA), choroidal vascularity index (CVI), choriocapillaris flow deficits (cFD) density, and choroidal HRF number were computed. In a subset, the measurements were repeated after AL remission. Age‐ and gender‐matched 26 healthy controls were recruited for cross‐sectional comparisons. Results: Patient's mean age was 59 ± 12 years. The TCA, LCA, SCA and choroidal HRF number were significantly higher in patients than controls (p = 0.028, p = 0.044, p = 0.024 and p = 0.001, respectively). Lower haemoglobin levels were associated with lower CT (r = 0.58, p = 0.008). Higher D‐dimer values were associated with lower TCA (r = −0.52, p = 0.008), lower LCA (r = −0.50, p = 0.006), higher cFD density (r = 0.41, p = 0.044) and higher choroidal HRF number (r = 0.47, p = 0.008). The CT, TCA, SCA and choroidal HRF number significantly reduced after AL remission (p = 0.001, p = 0.047, p = 0.007 and p = 0.002 respectively). The CVI increased significantly compared to the active phase (p = 0.013). Conclusion: The study demonstrates a subclinical choroidal involvement in patients with AL, with relative stromal thickening in the acute phase, and normalization after disease remission. Choroidal HRF were identified as a biomarker of leukaemic choroidopathy. Choriocapillaris and choroidal vascularity were inversely correlated with a systemic pro‐coagulant state. [ABSTRACT FROM AUTHOR]

Abstract With modern treatment most children with acute lymphoblastic leukemia (ALL) survive without relapse. However, for children who relapse the prognosis is still poor, especially in children with T‐cell phenotype (T‐ALL) and remains the major cause of death. The exact mechanism of relapse is currently not known. While contribution of RNA processing alteration has been linked to other hematological malignancies, its contribution in pediatric T‐ALL may provide new insights. Almost all human genes express more than one alternative splice isoform. Thus, gene modulation producing a diverse repertoire of the transcriptome and proteome have become a significant molecular marker of cancer and a potential therapeutic vulnerability. To study this, we performed RNA‐sequencing analysis on patient‐derived samples followed by splice isoform‐specific PCR. We uncovered a distinct RNA splice isoform expression pattern characteristic for relapse samples compared to the leukemia samples from the time of diagnosis. We also identified deregulated splicing and apoptosis pathways specific for relapse T‐ALL. Moreover, patients with T‐ALL displayed pro‐survival splice isoform switching favoring pro‐survival isoforms compared to normal healthy stem cells. Cumulatively, pro‐survival isoform switching and DFFB isoform regulation of SOX2 and MYCN may play a role in T‐ALL proliferation and survival, thus serving as a potential therapeutic option.

Purpose: Knowledge about oral health-related quality of life (OHRQoL) in adult patients with leukaemia is still limited. Accordingly, aim of this cross-sectional study was to assess OHRQoL and its associations to different parameters in adult patients with newly diagnosed acute leukaemia.Materials and Methods: Participants with first diagnosis of acute leukaemia were consecutively recruited in the Clinic of Hematology and Oncology of the University Medical Center Goettingen. OHRQoL was assessed using the German short form of oral health impact profile (OHIP-G14). Presence of oral initial symptoms, dental health (decayed- [D-T], missing- [M-T] and filled-teeth index [DMF-T]), dental behaviour and periodontal disease severity were assessed. For comparison, a healthy control group (HC) was recruited.Results: Thirty-nine patients with leukaemia and 38 HC were included. In the leukaemia group, a statistically significant and clinically relevant higher OHIP-sum score compared to HC was found (6.13 [3; 0-7] vs 0.87 [0; 0-2], p <0.01). The different subaspects of OHRQoL (patterns) 'oral function' and 'orofacial appearance' were statistically significantly worse in the leukaemia group (p <0.01). Time since diagnosis showed a clinically relevant association to the pattern 'psychosocial impact' (p = 0.06). Patients with oral initial symptoms had a statistically significantly worse OHIP-sum score (p <0.04, V = 0.775). DMF-T (p = 0.03, r = 0.242) and M-T (p = 0.03, r = 0.252) showed an association to OHIP sum score. Moreover, D-T (p = 0.03, r = 0.253) and M-T (p = 0.01, r = 0.296) were associated to orofacial appearance. Additionally, M-T showed an association to pattern 'oral function' (p = 0.01, r = 0.277).Conclusion: Patients with newly diagnosed acute leukaemia show a reduced OHRQoL. This might be particularly caused by oral health situation, especially oral initial symptoms as well as missing teeth. [ABSTRACT FROM AUTHOR]

Introduction: Leukaemia is characterised by widespread proliferation of leucocytes and their precursors in the body tissues and is usually associated with qualitative and quantitative changes in circulating white blood cells. The global burden of leukaemia is increasing. Aim: To study the morphology of leukaemia from Peripheral Blood Smears (PBS) and/or bone marrow smears and evaluate the clinical and haematological profile of leukaemia patients. Materials and Methods: This prospective observational study was conducted in a Tertiary Care Centre of the Vindhya region, in the Department of Pathology at Shyam Shah Medical College, Rewa, Madhya Pradesh, India. The study was carried out over a period of one year, from June 2019 to June 2020. A total of 90 newly diagnosed cases of all types of leukaemia during the study period. Detailed history, physical examination, complete blood counts, and bone marrow examinations were performed to confirm the diagnosis. Cytochemistry was used for the diagnosis and classification of acute leukaemia according to the French-American-British (FAB) classification. The data was compiled and analysed using appropriate statistical methods, and the mean was described with Standard Deviation (SD). Statistical significance was assessed using Analysis of Variance (ANOVA) test conducted with Statistical Package for Social Sciences (SPSS) version 22.0. Results: The study included 90 cases of all types of leukaemia, with a mean age of 36.5±22.5 years. There was a male preponderance in the study, with 65 (72.2%) males and 25 (27.8%) females, resulting in a male-to-female ratio of 2.6:1. Chronic Myeloid Leukaemia (CML) was the most common malignancy, accounting for total 40 (44.4%) cases. Non specific symptoms such as fever in 50 (55.6%), weight loss 49 (54.4%), and loss of appetite 42 (46.7%) cases were the most common symptoms across all types of leukaemia. Acute leukaemia also presented with leukopenia and normal leucocyte counts, while chronic leukaemia mostly showed markedly elevated Total Leucocyte Count (TLC) with a mean count of 1,30,912±63,792 per mm3. Conclusion: Light microscopic features of peripheral smear and bone marrow examination still play an important role in the diagnosis of leukaemia, especially in resource-poor health centres lacking immunotyping and cytogenetics.

Summary: HAX1‐related congenital neutropenia (HAX1‐CN) is a rare autosomal recessive disorder caused by pathogenic variants in the HAX1 gene. HAX1‐CN patients suffer from bone marrow failure as assessed by a maturation arrest of the myelopoiesis revealing persistent severe neutropenia from birth. The disorder is strongly associated with severe bacterial infections and a high risk of developing myelodysplastic syndrome or acute myeloid leukaemia. This study aimed to describe the long‐term course of the disease, the treatment, outcome and quality of life in patients with homozygous HAX1 mutations reported to the European branch of the Severe Chronic Neutropenia International Registry. We have analysed a total of 72 patients with different types of homozygous (n = 68), compound heterozygous (n = 3), and digenic (n = 1) HAX1 mutations. The cohort includes 56 paediatric (<18 years) and 16 adult patients. All patients were initially treated with G‐CSF with a sufficient increase in absolute neutrophil counts. Twelve patients required haematopoietic stem cell transplantation for leukaemia (n = 8) and non‐leukaemic indications (n = 4). While previous genotype–phenotype reports documented a striking correlation between two main transcript variants and clinical neurological phenotypes, our current analysis reveals novel mutation subtypes and clinical overlaps between all genotypes including severe secondary manifestations, e.g., high incidence of secondary ovarian insufficiency. [ABSTRACT FROM AUTHOR]

Background Hyperleukocytosis is a high-mortality emergency that must be diagnosed and treated promptly. The treatment options are low-dose cytosine arabinoside, hydroxyurea, steroids and leukapheresis. The risks and benefits of leukapheresis and leukapheresis with cytoreductive drugs in hyperleukocytosis are unclear. Therefore, we aimed to evaluate the efficacy of leukapheresis and the effect of adding cytoreductive drugs to leukapheresis in reducing leukocyte count and mortality in our patients. Material and Methods Thirty-four adult patients with acute leukaemia who underwent leukapheresis were included in this retrospective study. Results The median age was 66.5 years old, and 88.2% of the patients were acute myeloid leukaemia. The total number of leukapheresis was 69 cycles, and the median number of the procedure was 2. The most common symptoms were associated with the pulmonary system (67.6%). The median follow-up was 17.5 days. The mean reduction of leukocyte count was 69,112/mm3, and the efficacy of leukapheresis was 40.9%. The decrease in leukocyte and platelet counts was statistically significant when compared before and after leukapheresis. The mortality rate was 76.5% during hospitalization. While 24 patients received concomitant cytoreductive drugs with leukapheresis, ten did not. There was no statistically significant difference between these groups regarding reducing leukocyte count, efficiency of leukapheresis and mortality (p values 0.857, 0.562 and 0.553). Conclusions In our study, we showed the efficacy of leukapheresis in hyperleukocytosis but failed to show any difference in leukocyte reduction or mortality with additional cytoreductive drugs. Leukapheresis with concomitant cytoreduction does not abolish or increase mortality. [ABSTRACT FROM AUTHOR]

Background: Published epidemiological studies of haematological cancers are few. Hereby we present a 20-year epidemiological data of haematological cancers in Sarawak from a population-based cancer registry. Methods: Haematological cancer cases with ICD-10 coded C81-C96 and ICD-O coded /3 diagnosed from 1996 to 2015 were retrieved from Sarawak Cancer Registry. Adult was defined as those 15 years and above. Incidence rate (IR) was calculated based on yearly Sarawak citizen population stratified to age, gender, and ethnic groups. Age-standardised IR (ASR) was calculated using Segi World Standard Population. Results: A total of 3,947 cases were retrieved and analysed. ASR was 10 and male predominance (IR ratio 1.32, 95%CI 1.24,1.41). Haematological cancers generally had a U-shaped distribution with lowest IR at age 10–14 years and exponential increment from age 40 years onwards, except acute lymphoblastic leukaemia (ALL) with highest IR in paediatric 2.8 versus adult 0.5. There was a significant difference in ethnic and specific categories of haematological cancers, of which, in general, Bidayuh (IR ratio 1.13, 95%CI 1.00, 1.27) and Melanau (IR ratio 0.54, 95%CI 0.45, 0.65) had the highest and lowest ethnic-specific IR, respectively, in comparison to Malay. The ASR (non-Hodgkin lymphoma, acute myeloid leukaemia, ALL, chronic myeloid leukaemia, and plasma cell neoplasm) showed a decreasing trend over the 20 years, -2.09 in general, while Hodgkin lymphoma showed an increasing trend of + 2.80. There was crude rate difference between the 11 administrative divisions of Sarawak. Conclusions: This study provided the IR and ASR of haematological cancers in Sarawak for comparison to other regions of the world. Ethnic diversity in Sarawak resulted in significant differences in IR and ASR. [ABSTRACT FROM AUTHOR]

Summary: Oral azacitidine (Oral‐AZA) maintenance therapy improved relapse‐free (RFS) and overall survival (OS) significantly versus placebo for AML patients in remission after intensive chemotherapy (IC) in the phase 3 QUAZAR AML‐001 study. Immune profiling was performed on the bone marrow (BM) at remission and on‐treatment in a subset of patients with the aim of identifying prognostic immune features and evaluating associations of on‐treatment immune effects by Oral‐AZA with clinical outcomes. Post‐IC, increased levels of lymphocytes, monocytes, T cells and CD34 + CD117+ BM cells were prognostically favourable for RFS. CD3+ T‐cell counts were significantly prognostic for RFS in both treatment arms. At baseline, high expression of the PD‐L1 checkpoint marker was identified on a subset of CD34 + CD117+ BM cells; many of which were PD‐L2+. High co‐expression of T‐cell exhaustion markers PD‐1 and TIM‐3 was associated with inferior outcomes. Oral‐AZA augmented T‐cell numbers during early treatment, increased CD4+:CD8+ ratios and reversed T‐cell exhaustion. Unsupervised clustering analysis identified two patient subsets defined by T‐cell content and expression of T‐cell exhaustion markers that were enriched for MRD negativity. These results indicate that Oral‐AZA modulates T‐cell activity in the maintenance setting of AML, and these immune‐mediated responses are associated with clinical outcomes. [ABSTRACT FROM AUTHOR]

Background: To reduce the risk of invasive aspergillosis (IA), air purification by high‐efficiency particulate air filtration and laminar air flow (HEPA/LAF) is standard of care in allogeneic blood stem cell transplantation. Its use in non‐transplant haematological patients is inconsistent. Objectives: We sought to assess the incidence and outcome of pulmonary IA in non‐transplant patients with life‐threatening neutropenia by comparing an ambient air hospitalisation period (2008–2011) with a subsequent HEPA/LAF hospitalisation period (2012–2014). Patients and Methods: We compared 204 consecutive patients with acute myeloid leukaemia, acute lymphoblastic leukaemia or aplastic anaemia completing 534 neutropenia‐related hospitalisations under ambient air conditions with 126 such patients completing 437 neutropenia‐related hospitalisations under HEPA/LAF conditions. IA was defined using the 2008 EORTC/MSG criteria. Results: Within a 7‐year study period, we observed one 'proven', three 'probable' and 73 'possible' IAs, most often during acute leukaemia remission induction. Their frequency rose with increasing duration of life‐threatening neutropenia (1–10 days, 1.8%; >40 days, 35.2%) and concomitant severe anaemia (0 days, 3.2%; >20 days, 31.0%). Multiple logistic regression revealed a strong correlation between IA incidence and hospitalisation under HEPA/LAF conditions (odds ratio [OR], 0.368 [95% confidence interval, 0.207–0.654]; p <.001) and duration of neutropenia (OR, 1.043 [1.023–1.062] per day; p <.001) and anaemia (OR, 1.044 [1.008–1.081] per day; p =.016). IA‐associated fatal outcomes were non‐significantly reduced under HEPA/LAF (OR, 0.077 [0.005–1.151]; p =.063). The protective effect of HEPA/LAF was not seen under posaconazole prophylaxis (OR, 0.856 [0.376–1.950]; p =.711). Conclusions: Implementation of HEPA/LAF was associated with a significant reduction in neutropenia‐related IA in non‐transplant haematological patients. [ABSTRACT FROM AUTHOR]

Bacterial infections are common during induction therapy in children and adolescents with acute leukaemia and may cause infection-related mortality. To determine the efficacy and safety of prophylactic antibiotics in paediatric patients with acute leukaemia receiving induction chemotherapy. From three English databases and four Chinese databases, we searched for randomized controlled trials (RCTs) and cohort studies that compared prophylactic antibiotics to placebo, no prophylaxis, or that compared one antibiotic versus another in paediatric patients with acute leukaemia undergoing induction chemotherapy. Two reviewers independently screened the studies, extracted data, and assessed the risk of bias using Cochrane Risk of Bias 2 tool and Newcastle–Ottawa Scale, and the certainty of evidence using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Two RCTs and ten cohort studies were finally included. For children with acute lymphoblastic leukaemia, antibiotic prophylaxis, including levofloxacin, sulfamethoxazole–trimethoprim, or other antibiotics, probably reduced bacteraemia (risk ratio (RR): 0.44; 95% confidence interval (CI): 0.33–0.60; moderate certainty) without significantly increasing Clostridioides difficile infection (CDI) or invasive fungal infection. Levofloxacin reduced the CDI rate (RR: 0.08; 95% CI: 0.01–0.62; high certainty). Ciprofloxacin prophylaxis probably reduced infection-related mortality (RR: 0.12; 95% CI: 0.01–0.97; moderate certainty). In children with acute myeloid leukaemia, ciprofloxacin plus vancomycin may reduce febrile neutropenia (RR: 0.79; 95% CI: 0.66–0.94; low certainty). Individual studies indicated that prophylaxis increased antibiotic exposure but reduced non-preventive antibiotic exposure. In children with acute leukaemia undergoing induction therapy, antibiotic prophylaxis may improve the bacterial infection and mortality. [ABSTRACT FROM AUTHOR]

Abstract A 17‐gene stemness (LSC17) score determines risk in acute myeloid leukaemia patients treated with standard chemotherapy regimens. The present study further analysed the impact of the LSC17 score at diagnosis on outcomes following allogeneic haematopoietic cell transplantation (HCT). Out of 452 patients with available LSC17 score, 123 patients received allogeneic HCT. Transplant outcomes, including overall (OS), leukaemia‐free survival (LFS), relapse incidence (RI) and non‐relapse mortality (NRM), were compared according to the LSC17 scored group. The patients with a low LSC17 score had higher OS (56.2%) and LFS (54.4%) at 2 years compared to patients with high LSC17 score (47.2%, p = 0.0237 for OS and 46.0%, p = 0.0181 for LFS). The low LSC17 score group also had a lower relapse rate at 2 years (12.7%) compared to 25.3% in the high LSC17 score group (p = 0.017), but no difference in NRM (p = 0.674). Worse outcomes in the high LSC17 score group for OS, LFS and relapse were consistently observed across all stratified sub‐groups. The use of more intensive conditioning did not improve outcomes for either group. In contrast, chronic graft‐versus‐host‐disease was associated with more favourable outcomes in both groups. The 17‐gene stemness score is highly prognostic for survival and relapse risk following allogeneic HCT.

Abstract The effect of higher FOXP3 mRNA expression by recipient pre‐transplant CD4+ T cells on leukaemia relapse was analysed in a series of 106 patients who received allogeneic haematopoietic stem cell transplantation after myeloablative conditioning with or without antithymocyte globulin (ATG) due to acute leukaemia in 1st or 2nd complete remission. FOXP3 mRNA was measured by qPCR in purified CD4+ T cells from blood obtained before conditioning. Higher FOXP3 mRNA expression was associated with an increased relapse risk when conditioning included ATG (n = 43, hazard ratio [HR] 11.0 [2.50–48.4], p = 0.00001). No effect was observed in patients not receiving ATG (HR 0.95 [0.53–1.81]).

Abstract Cerebral sinovenous thrombosis (CSVT) is a serious complication during asparaginase therapy in patients with acute lymphoblastic leukaemia (ALL). We identified 46 patients with CSVT among 2651 patients (1‒45 years) treated according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between 2008 and 2018. CSVT cases were prospectively registered in the NOPHO database with retrospective updates. We examined the frequency of asparaginase re‐exposure after CSVT, potential factors associated with asparaginase truncation, and sequelae after CSVT. This work was supported by the Danish Cancer Society and the Danish Childhood Cancer Foundation. The 2.5‐year cumulative incidence of CSVT was 1.9% (95% confidence interval 1.4%–2.5%). The majority of patients (74%, n = 31) were re‐exposed to asparaginase (with low‐molecular‐weight heparin coverage), one of whom had a second CSVT, without neurological sequelae. Patients re‐exposed to asparaginase were earlier in ALL treatment and lacked more asparaginase doses than non‐re‐exposed patients at CSVT diagnosis (median 50 vs. 81 days, p = 0.03; mean 11.2 vs. 8.4 asparaginase doses, p = 0.04). No other examined factors had an impact on asparaginase re‐exposure. At the last follow‐up (median 4.5 years after CSVT), 61% of patients had normal neurological status, and 57% had complete recanalisation of CSVT, with no significant difference between patients re‐exposed and non‐re‐exposed to asparaginase. Our results indicate that re‐exposure to asparaginase is safe after CSVT during anticoagulation.

Acute leukaemia (AL) is a heterogeneous neoplastic disease that occurs by the growth of abnormal lymphoid and myeloid cells in the bone marrow and blood leading to acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL). Conventional cytogenetics is a characteristic technique to hunch chromosomal abnormalities, it helps in the diagnosis and therapeutic approach of the disease by the molecular cytogenetics technique of fluorescence in situ hybridization (FISH). Chromosomal abnormalities in AL are performed by karyotyping to confirm specific chromosomal abnormalities using FISH. The descriptive study included 42 clinically diagnosed AL patients. Karyotyping analysis was performed using the standard Giemsa banding procedure. To confirm specific chromosomal abnormalities and all culture failure (CF) cases, FISH was done. Among 42 cases, 29 (69.4%) males and 13 (30.9%) females, AML comprised 22 (52.38%) cases, ALL 14 (33.33%) cases, and AL 6 (14.2%) cases. Normal karyotype was found in 18 (42.85%), abnormal karyotype in 16 (39.09%), and 8 (19.09%) were CF. Specific abnormalities of t(15;17), hyperdiploidy; t(3;3) with monosomy 7 in; del(9q22); del(2p); del(17p); del(Xq); 1~2 dmin; der(3); +11, +13 and composite karyotype. Hypodiploidy was strongly associated with AL, which signifies the loss of chromosomes causing potential risk. Composite karyotype, rare t(3;3) double minutes, +11,+13, del(9q), and del(Xq) were the novel findings reported in the South Canara region of Karnataka. Despite other molecular techniques, conventional cytogenetics remains the baseline in the diagnosis of malignancies. [ABSTRACT FROM AUTHOR]

Summary: Since the early 1970s, the treatment of acute myeloid leukaemia (AML) has undergone a major transformation. Initially based on only two drugs, an anthracycline and cytosine arabinoside, the aim of therapy was to achieve a haematological response allowing patients to recover and go home. Back in those early days, cure was not a realistic expectation. Treatment was analogous to a heart attack; upon recovery and a short respite, recurrence and death inevitably followed. Over the subsequent decades, slow but remarkable progress was made such that a subgroup of young adults could become long‐term survivors. This astonishing feat was achieved initially without the use of new drugs. Supportive care played a major role with the widespread availability of platelet transfusions and improved antimicrobial therapy, particularly antifungal. No less important was the better use of existing drugs and the development of allogeneic haematopoietic cell transplantation. While initially the focus was on maximal tolerated therapy, an understanding of the immunologic role of allogeneic transplantation, better genetic characterization of the biology of the disease, advanced tools for detection of minimal disease as well as the recent development of new drugs changed the focus to a more refined approach targeting patients who are more likely to respond. Clearly, the historical paradigm where the term AML was generic and applicable to all patients requires a rethinking from the traditional therapeutic demarcations of therapy into phases of induction, consolidation and maintenance. These evolving new concepts and paradigm will be herein considered. [ABSTRACT FROM AUTHOR]

Invasive fungal diseases (IFDs) still represent a relevant cause of mortality in patients affected by hematological malignancies, especially acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) undergoing remission induction chemotherapy, and in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Mold-active antifungal prophylaxis (MAP) has been established as a standard of care. However, breakthrough IFDs (b-IFDs) have emerged as a significant issue, particularly invasive aspergillosis and non-Aspergillus invasive mold diseases. Here, we perform a narrative review, discussing the major advances of the last decade on prophylaxis, the diagnosis of and the treatment of IFDs in patients with high-risk neutropenic fever undergoing remission induction chemotherapy for AML/MDS and allo-HSCT. Then, we present our single-center retrospective experience on b-IFDs in 184 AML/MDS patients undergoing high-dose chemotherapy while receiving posaconazole (n = 153 induction treatments, n = 126 consolidation treatments, n = 60 salvage treatments). Six cases of probable/proven b-IFDs were recorded in six patients, with an overall incidence rate of 1.7% (6/339), which is in line with the literature focused on MAP with azoles. The incidence rates (IRs) of b-IFDs (95% confidence interval (95% CI), per 100 person years follow-up (PYFU)) were 5.04 (0.47, 14.45) in induction (n = 2), 3.25 (0.0013, 12.76) in consolidation (n = 1) and 18.38 (3.46, 45.06) in salvage chemotherapy (n = 3). Finally, we highlight the current challenges in the field of b-IFDs; these include the improvement of diagnoses, the expanding treatment landscape of AML with molecular targeted drugs (and related drug–drug interactions with azoles), evolving transplantation techniques (and their related impacts on IFDs’ risk stratification), and new antifungals and their features (rezafungin and olorofim).

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematologic neoplasm and classified under acute myeloid leukemia. Here, we describe the clinicopathological features of three cases of BPDCN: two with classical and one uncommon immunophenotype. A-35-year-old female (case 1) presented with complaint of nasal mass and generalized lymphadenopathy. Biopsy from axillary lymph node showed infiltration by cells with scant cytoplasm which were immunopositive for LCA, CD4, CD43, and ALK1. Flowcytometry showed positivity for CD45, CD4, CD33, and CD123 while negative for rest all markers. The other two cases have classical immunophenotype. In clinical practice, nasal mass with lymphadenopathy suggests natural killer T-cell/peripheral T-cell lymphoma. Again immunohistochemical positivity for CD4, CD43, and ALK while negativity for CD3 suggests anaplastic large cell lymphoma. In this case, morphology and extensive bone marrow involvement raise the suspicion. Fowcytometry positivity for HLADR, CD123, and CD33 helps in making diagnosis. [ABSTRACT FROM AUTHOR]

Purpose: The treatment and side effects of chemotherapy for acute leukaemia (AL) may cause both physical and psychological symptoms in patients. This study evaluated the effects of a WeChat-based multimodal psychoeducational intervention (ICARE programme) on fatigue, distress, anxiety, depression, and quality of life (QoL) among adult AL patients. Methods: In total, 72 participants were randomly assigned either to an intervention or control group (n = 36), respectively, from two large tertiary hospitals in Fuzhou, China (from April to December 2019). Data were collected at baseline, post-intervention, and after a 4-week follow-up using the Brief Fatigue Inventory, Distress Thermometer, Hospital Anxiety and Depression Scale, and Functional Assessment of Cancer Therapy-leukaemia. Descriptive statistics was used to summarise the sociodemographic and clinical characteristics of the participants and a linear mixed model was used to analyse the score changes. Results: Between the two groups, there were statistically significant improvements in fatigue, distress, anxiety, depression, physical well-being, social/family well-being, emotional well-being, functional well-being (all p < 0.001), and leukaemia-specific subscale (p = 0.001). The difference over time was significant for leukaemia-specific subscale and fatigue, both (p < 0.001), anxiety (p = 0.001), and social/family well-being (p = 0.005). The interaction effects were significant for fatigue, distress, anxiety, physical well-being, social/family well-being, and emotional well-being, all (p < 0.001), depression (p = 0.019), leukaemia-specific subscale (p = 0.008), and total QoL score (p = 0.004). Conclusion: WeChat-based multimodal psychoeducational intervention demonstrated a significant effect in reducing fatigue, distress, anxiety, depression, and QoL in AL patients. This ICARE programme contributed to continuing care to support AL patients. Implications for Cancer Survivors: The ICARE programme can improve the mental health and QoL of AL patients. The application of WeChat-based psychoeducational interventions have significant potential to benefit cancer patients due to their reach and can be an added value to routine care. [ABSTRACT FROM AUTHOR]