Chimeric antigen receptor (CAR)-natural killer (NK)-cell therapy has emerged as a promising strategy in the treatment of haematological malignancies and solid cancers. Leveraging the innate immune properties of NK cells, CAR-NK-cell therapies offer potential advantages for cell therapy, including safety of use in the allogeneic setting and reduced risk of toxicity. This Nutshell provides an overview of the latest advancements in CAR-NK-cell therapy and the challenges that remain.

Cancer patients with haematological malignancies are at risk for chronic hepatitis E virus infection following chimeric antigen receptor (CAR) T-cell therapy. Strong clinical suspicion is essential for the early diagnosis and prompt treatment of this difficult-to-treat type of viral hepatitis. Commentary on: Schwarz et al. Chronic hepatitis E in a patient after CAR-T cell treatment for diffuse large B-cell lymphoma and rapid progression towards decompensated liver cirrhosis. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19892.

For patients with acute myeloid leukaemia (AML) who achieve complete remission (CR) after induction therapy, subsequent allogeneic haematopoietic stem cell transplantation (allo-HSCT) reduces the risk of relapse. However, not all patients are eligible, warranting effective alternative maintenance strategies. Oral azacitidine is the only non-targeted therapy approved by both the United States (US) Food and Drug Administration and the European Medicines Agency for the maintenance or continued treatment of allo-HSCT-ineligible patients with AML achieving CR or CR with incomplete haematological recovery following induction chemotherapy. Midostaurin and histamine dihydrochloride are approved in Europe as maintenance therapy for AML in remission, and quizartinib is approved in the United States and Europe for the treatment and maintenance of patients with newly diagnosed FLT3-ITD AML. Barriers to maintenance treatment include limited clinical trial data informing appropriate patient and treatment selection, patient preference, financial burden and paucity of real-world data. This article discusses current maintenance treatment guidelines for patients with AML in remission but not proceeding to allo-HSCT and reviews clinical trial data for agents approved for use in remission. Ongoing studies of interest and considerations for future efforts are also discussed.

Alloimmunization to minor red blood cell antigens has been linked to patient morbidity and mortality, especially among people living with sickle cell disease and transfusion-dependent thalassaemia. Prophylactic antigen matching is commonly used to prevent alloimmunization, but the evidence supporting this common practice is very limited. The report by Wolf et al. summarizes the latest literature on this topic and importantly finds that there is insufficient evidence to recommend prophylactic extended antigen matching (beyond ABO, RhD, RhCcEe and K). In an era of chronic blood shortages, this approach may help to assure patient access to elective surgery and cellular therapies, while preserving the supply of extensively antigen-matched red cells for patients with specific needs. Commentary on: Wolf et al. Red cell specifications for blood group matching in patients with haemoglobinopathies: An updated systematic review and clinical practice guideline from the International Collaboration for Transfusion Medicine Guidelines. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19837.

Diabetes insipidus (DI) in patients with acute myeloid leukaemia (AML) and chromosome 3q alterations (EVI1/PRDM3/MECOM overexpression) constitutes a poorly understood paraneoplasia. A 44-year-old patient presented with clinical and morphological features of this syndrome but, surprisingly, disclosed the rare translocation t(1;2)(p36;p21), with massive PRDM16 overexpression. WGS and RNA sequencing suggest enhancer hijacking of the ZFP36L2 enhancer region as underlying mechanism. Methylome alterations were similar to those in EVI1/PRDM3/MECOM AML, indicating converging pathways. The patient was successfully allografted, she is in complete remission 14 months later. We conclude that t(1;2)(p36;p21), with massive PRDM16 overexpression, can result in a faithful genocopy of EVI1/PRDM3/MECOM AML, including DI.

Chronic eosinophilia leukaemia-not otherwise specified (CEL-NOS) is a rare myeloproliferative neoplasm characterized by persistent clonal hypereosinophilia. Recent advances in genetics have refined diagnostic criteria, leading to the identification of CEL subtypes with specific cytogenetic and molecular abnormalities now classified as myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions, which may benefit from targeted therapies. In contrast, CEL-NOS lacks specific genetic drivers and intervention points to halt leukemogenesis. Molecular techniques have also enabled the definition of clonality in a considerable percentage of cases otherwise classified as idiopathic hypereosinophilic syndrome. CEL-NOS poses a significant therapeutic challenge due to limited treatment options, poor prognosis and the risk of progression to acute leukaemia. Patients, often elderly and with comorbidities, face restricted access to transplantation, the only potentially curative treatment. Unfortunately, the prognosis remains poor even post-transplant, with a 5-year survival rate of only one-third of patients. Other therapies, including steroids, cytoreductive and immunomodulatory treatments, offer limited and temporary responses with significant side effects. This review aims to consolidate current knowledge on CEL-NOS, covering diagnostic approaches, genetic advancements and therapeutic challenges. It seeks to provide a comprehensive overview and highlight critical areas for future research.

The distribution of trial site locations may lead to disparities in geographic access and affect patient representativeness in clinical trials. We utilised trial data covering 1993-2022 from the National Institute for Health and Care Research (NIHR) Open Data Platform, 2011 and 2021 English Census and geographic data and English individual-patient cancer registry data for patients diagnosed with lymphoma between 1997 and 2017. To assess representation, we compared patient age and sex between trial participants and the incident population. We mapped the distance and travel times of English lower layer super output areas (LSOAs) to their nearest research active NHS Trusts and assessed associations between distance and travel times and the geographic and sociodemographic characteristics of the LSOAs. Trial participants were younger than the incident population and more likely to be male. The closest NHS Trust to more than half of English LSOAs was not research active. Greater LSOA mean age, male percent, White British percent, rurality and coastal/border status were positively associated with distance and travel time (at prespecified p < 0.05 level), while greater deprivation was negatively associated. Female and older lymphoma patients in England are underrepresented in trials, with the latter facing a higher burden of geographic barriers.

Paediatric regimens which incorporate asparaginase have improved outcomes of adolescents and younger adults with acute lymphoblastic leukaemia but are limited by toxicity. This retrospective report by Tinajero and Xu suggests that delaying the timing of asparaginase administration during ALL induction may reduce risk of hepatotoxicity. Commentary on: Tinajero et al. Delaying pegaspargase during induction in adults with acute lymphoblastic leukaemia is associated with lower risk of high-grade hepatotoxicity without adversely impacting outcomes. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19880.

Avascular necrosis (AVN) is a bone disease caused by a temporary or definitive loss of the blood supply to bone resulting in cellular death. In people with sickle cell disease (SCD), AVN is one of the most common causes of severe chronic pain. Currently, there are very few treatment options for AVN and the current study by Casale et al. demonstrates how the use of patient-reported outcomes can bring us one step closer to identifying optimal treatments for this debilitating condition in SCD. Commentary on: Casale et al. Long-term outcomes of Avascular Necrosis in Sickle Cell Disease using joint-specific patient-reported outcome measures: Results from a multicentre study. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19802.

An inclusive clinical trial ecosystem is essential to obtain scientific results that can be generalized to a broad patient population. When possible, all efforts should be made to remove geographic, demographic, cultural and ethnic barriers for enrolment in clinical trials. However, to do this effectively, we need more knowledge about factors influencing clinical trial participation and practical frameworks to enhance diversity in clinical trials. Commentary on: Jones et al. Inequalities in geographic barriers and patient representation in lymphoma clinical trials across England. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19907.

In 2014, the International Myeloma Working Group (IMWG) updated the criteria for diagnosing myeloma and added three additional criteria to the traditional Calcium elevation, Renal impairment, Anemia, Bone disease (CRAB) criteria, called the Sixty % marrow plama cells, Light chain ratio >60, Mri demonstates lytic lesions (SLiM) criteria (clonal bone marrow plasma cells ≥60%, involved to uninvolved free light chain ratio (FLCr) ≥100 and >1 focal lesion on magnetic resonance imaging (MRI)). We report on the outcomes of 30 patients who underwent autologous stem cell transplantation (ASCT) where therapy was initiated solely based on SLiM criteria and compared them to a matched cohort of 60 patients whose myeloma-defining event was CRAB. The SLiM cohort had a shorter median time to neutrophil (15 vs. 16 days, p = 0.049) and platelet (15 vs. 17 days, p = 0.0004) engraftment. The 36-month overall survival (OS) was 100% in the SLiM group and 93.27% in the control group (95% CI 83.06%-97.42%), with a trend towards longer OS in the SLiM cohort (p = 0.065). The 36-month progression-free survival (PFS) was 91.61% in the SLiM (95% CI 69.93%-97.87%) and 65.95% in the control group (95% CI 52.31%-76.53%). There was no difference in the PFS between the cohorts (p = 0.414). ASCT is efficacious and safe in MM patients transplanted only due to SLIM criteria. Early intervention in this asymptomatic cohort did not appear to result in deeper responses or better PFS compared to outcomes in symptomatic patients.

HIF-2α, encoded by EPAS1, plays a dominant role in regulating erythropoietin (EPO) production, maintaining the dynamic balance of erythropoiesis. Gain-of-function mutations in EPAS1 cause erythrocytosis. However, anaemia caused by EPAS1 loss-of-function mutations has been confined to only one case report, and the underlying mechanism remains unclear. Herein, the reanalysis of high-throughput sequencing data from 311 patients with anaemia identified three monoallelic EPAS1 variants from three unrelated families in a paediatric anaemia cohort. The probands showed highly consistent clinical phenotypes with normocytic and normochromic anaemia, reticulocytopenia and relative deficiency of serum EPO, characterised as congenital hypoplastic anaemia. In vitro studies suggested that defects in steady-state protein abundance, nuclear localisation and binding with co-activator in EPAS1 variants lead to impaired EPO transcriptional activation. Therefore, loss-of-function mutations in EPAS1 can cause erythroid hypoplasia in an EPO-dependent manner. This study identified a new causative gene for congenital hypoplastic anaemia and clarified the molecular aetiology of loss-of-function EPAS1 mutations.

Traditionally, patients with asymptomatic, advanced-stage follicular lymphoma were managed with a watchful-waiting approach until disease progression. The 'Watch and Wait' Phase-3 randomised international trial examined whether rituximab could delay the need for treatment and the effect on quality of life (QoL). In this article, we present the long-term results of the QoL aspect of the trial. Patients were randomised to watchful-waiting (Arm A), rituximab induction (Arm B) or rituximab induction followed by maintenance (Arm C). We present the QoL outcomes from 180 patients (Arm A), 188 patients (Arm C) and an exploratory analysis of 82 (Arm B) compared to 81 and 84 patients concurrently randomised to arms A and C. Arm C reported greater improvement in emotional well-being overtime (Month 37, p = 0.0078) and were significantly more likely to feel in control of their situation than watchful-waiting patients (Month 25, p = 0.0004; Month 37, p = 0.0476). Watchful-waiting patients were significantly more likely to avoid thinking about their illness, did not find learning about their illness helped them and were more likely to attach unpleasant connotations to clinic visits (Month 7, p = 0.0032; Month 13, p = 0.0015; Month 25, p = 0.0104). These results demonstrate improved QoL scores in the induction and maintenance rituximab arm, indicating that rituximab was not detrimental to QoL and resulted in an improved QoL in some domains.

Resazurin, a phenoxazine used in cell viability assays, acts in vitro as an anti-leukaemic compound through the production of cellular reactive oxygen species (ROS) resulting in mitochondrial dysfunction and cell death. However, the in vivo tolerance and efficacy of resazurin in cancer are unknown. In this study, we investigated the in vitro and in vivo effects of resazurin in acute myeloid leukaemia (AML). Resazurininduced cell death in a dose-dependent manner in AML cell lines and reduced proliferation and colony formation in ex vivo treated patient-derived AML cells. Cells treated with a reduced dose of resazurin for 72 h acquired a more mature immunophenotype suggesting cell differentiation as a mechanism contributing to the anti-leukaemic effect. In vivo optical imaging in healthy mice demonstrated a reduction of resazurin to resorufin within 30 min and non-detectable after 2 h, supporting dosing twice daily as optimal. In subcutaneous and orthotopic models of MV4-11 AML in NOD/SCID IL2rγ mice, anti-tumour effects and an increased survival were found at a dose level of 75 mg/kg twice daily without observed toxicity. Our results suggest that resazurin represents a novel experimental therapeutic for the treatment of AML.

This multicentre phase II study Fondazione Italiana Linfomi (FIL)-bortezomib plus rituximab plus bendamustine (BRB) tested a combination of bendamustine (90 mg/m on days 1-2), rituximab (375 mg/m intravenously on day 1) and bortezomib (1.3 mg/m sc on days 1, 8, 15, 22) every 28 days for six cycles in 38 symptomatic patients with relapsed/refractory Waldenstrom macroglobulinaemia (RR-WM). Moreover, MYD88 and CXCR4 mutations were tested by droplet digital polymerase chain reaction (ddPCR) both at baseline and at the end of treatment in 21 patients. Overall response rate at the end of therapy was 84.6%, including 4 (11%) complete remission, 15 (39%) very good partial response, 12 (32%) partial responses according to IWWM response criteria. At 18, 24 and 30 months, progression-free survival was 84.2% (95% CI 68.2%-92.6%), 81.5% (95%CI 65.1-90.7) and 78.8% (95%CI 62.0-88.8) respectively. At 18 months, the Overall survival was 92.1% (95%CI 77.5%-97.4%). Overall, 19 patients (50%) experienced grade 3-4 haematological toxicity, mainly thrombocytopenia, and grade 1-3 neuropathy rate was about 10% and required bortezomib dose reduction but did not result in treatment interruption. Moreover, BRB treatment induced the high rates of undetectable molecular minimal residual disease (MRD) at the end of the therapy. BRB regimen used as second line is an effective and well-tolerated salvage treatment for relapsed refractory Waldenstrom macroglobulinaemia patients. MRD monitoring showed promising efficacy in clearing the residual disease.

Therapies such as corticosteroids, thrombopoietin receptor agonists and immunomodulators have been consistently under the spotlight in the search for a better treatment for immune thrombocytopenia (ITP). However, none of them has been widely embraced as a new standard. In this pilot study, we investigated feasibility, safety and preliminary efficacy of romiplostim, low-dose rituximab and high-dose dexamethasone for newly diagnosed ITP. We conducted a single-centre single-arm pilot. One-month treatment adherence was 100%. The 1-month overall response rate was 92.3%. Complete response occurred in 11 (84.6%) patients. Median duration of response was 4.13 monts (range 0.2-25). No serious adverse events presented.

Navigating choice of JAK inhibitor (JAKi) therapy for patients with myelofibrosis who are JAKi-naïve and for those who have previously been treated with a JAKi.