EJHaem最新文献

To the Editors,

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare plasma cell disorder where the diagnostic criteria include the presence of monoclonal plasma cells and polyneuropathy and at least one major (sclerotic bone lesions, elevated vascular endothelial growth factor [VEGF], or Castleman disease), and one minor (volume overload, organomegaly, endocrinopathy, skin changes, polycythemia, or thrombocytosis) criteria [1]. Due to the heterogeneity of manifestations, POEMS syndrome is a challenging diagnosis for clinicians to make with a median delay to diagnosis of 12 months [2]. Here we report a patient with a classic presentation for POEMS syndrome but unexpectedly normal plasma VEGF level due to intravitreal aflibercept which later markedly increased with clearance of aflibercept, in order to raise awareness of this previously unknown phenomenon for clinicians who see patients with suspected POEMS syndrome.

A 65-year-old male was found to have new left optic disc edema during surveillance of macular edema following retinal vein occlusion (MEfRVO) that was previously managed with intravitreal aflibercept in the right eye. On further questioning, he reported several months of unexplained fatigue, weight loss, leg weakness and paresthesias, lower extremity edema, along with recent diagnoses of hypothyroidism and hypogonadism. Further evaluation of the new optic disc edema led to brain magnetic resonance imaging demonstrating pachymeningeal enhancement. Chest, abdomen, and pelvic computed tomography (CT) imaging revealed diffuse lymphadenopathy, splenomegaly, and innumerable sclerotic bone lesions, some of which were intensely fludeoxyglucose-18 avid on positron emission tomography CT. Serum immunofixation showed 0.09 g/dL immunoglobulin A lambda monoclonal protein. Supraclavicular lymph node biopsy showed a plasma cell variant of Castleman disease, and bone marrow biopsy showed multiple lymphoplasmacytic aggregates. These findings clinically established POEMS syndrome as the diagnosis. However, plasma VEGF was unexpectedly normal at 8.7 pg/mL (normal, ≤96.2 pg/mL).

VEGF measurement is an important test for POEMS syndrome as a sensitive and specific marker, and VEGF levels correlate with disease activity [1, 3]. It is striking that this patient's VEGF level was normal despite fulfilling the criteria for POEMS syndrome. The recent treatment with intravitreal aflibercept proved noteworthy (Figure 1). Aflibercept is a decoy receptor that binds VEGF-A, VEGF-B, and placental growth factor and is approved for treating colorectal cancer (given intravenously) and exudative macular degeneration, diabetic macular edema, and MEfRVO (given intravitreally) [4]. Intravitreal aflibercept is known to markedly decrease systemic levels of VEGF [5]. In this patient, five weeks after injection and with clearance of af

BCR::ABL1 fusion is found in < 1% of de novo acute myeloid leukemia (AML) cases and confers a poor prognosis. This Japanese nationwide survey analyzed patients with AML (n = 22) and mixed phenotype acute leukemia (MPAL) (n = 10) with t(9;22) or BCR::ABL1 who underwent allogeneic hematopoietic cell transplantation (allo-HCT) between 2002 and 2018. The 3-year overall survival (OS) rates were 81.3% and 56.0%, respectively (p = 0.15), and leukemia-free survival (LFS) rates were 76.2% and 42.0%, respectively (p = 0.10) in patients with AML and MPAL. The relapse rates were 9.5% and 14.0% (p = 0.93), and the non-relapse mortality (NRM) rates were 14.3% and 44.0%, respectively (p = 0.10) in patients with AML and MPAL. One in 17 patients with AML, with pre-transplant tyrosine kinase inhibitors (TKI), and three in five patients with AML, without pre-transplant TKI, did not achieve complete remission (CR) before allo-HCT (p = 0.024). Among the 20 patients with known disease status after allo-HCT, 95.0% were in hematological or molecular CR. None of the four patients who received post-transplant TKI for prophylaxis or measurable residual disease relapse experienced hematological relapse. In conclusion, our results suggest that pre-transplant TKI could improve disease status before allo-HCT. Moreover, allo-HCT resulted in high OS, high LFS, low relapse, and low NRM rates in patients with AML with BCR::ABL1.

Sickle cell disease (SCD) patients are at higher risk of developing silent cerebral infarcts and overt stroke, which may reflect cognitive impairment, functional limitations, and worse quality of life. The cognitive function of Brazilian adult SCD patients (n = 124; 19–70 years; 56 men; 79 SS, 28 SC, 10 S/β⁰, 7 S/β⁺) was screened through Montreal Cognitive Assessment (MoCA) and correlated the results with possible predictive factors for test performance, including sociocultural, clinical, laboratory data and brain imaging. The Median MoCA score was 23 (8–30); 70% had a 25-or-less score, suggesting some level of cognitive impairment. There were no significant associations between MoCA results and any clinical or laboratory data in SS and SC patients; however, a significant correlation (P = 0.03) with stroke was found in HbS/β-thalassemic patients. Correlations were further detected according to sociodemographic conditions, such as age (r = −0.316; P < 0.001), age at first job (r = 0.221; P = 0.018), personal (r = 0.23; P = 0.012) and per capita familiar incomes (r = 0.303; P = 0.001), personal (r = 0.61; P = 0), maternal (r = 0.536; P = 0), and paternal educational status (r = 0.441; P = 0). We further sought independent predictors of performance using multivariable regressions and increased education was an independent predictor of better scores in MoCA (0.8099, 95% confidence interval [CI]: 0.509–1.111). Brain imaging analysis showed significant and progressive atrophy in important cerebral areas related to memory, learning, and executive function. These data point to the high prevalence and impact of cognitive decline in adult SCD patients, mirrored in brain atrophic areas. It is also possible to observe the influence of sociodemographic conditions on patients’ cognitive performances and the need for creating focused therapeutic plans that address these deficiencies. Moreover, the absence of a significant correlation of MoCA values with stroke in the SS and SC groups may be related to the worst sociocultural and economic conditions of the Brazilian African descent population, in which the impact of low educational stimulation on cognitive function can outweigh even the anatomical damage caused by the disease.

Lenalidomide maintenance (LM) has shown benefit in progression-free survival (PFS) and overall survival (OS) in clinical trials. LM is the recommended standard of care in patients with newly diagnosed multiple myeloma (MM) after high-dose melphalan and autologous stem cell transplantation (HDM-ASCT). In Denmark, LM has been approved and publicly funded for all patients treated with HDM-ASCT since June 2019. Patients with newly diagnosed MM treated with their first HDM-ASCT between June 2019 and March 2022 were included and followed until data cut-off in June 2023. To compare outcomes, a historical pre-LM cohort from the Danish MM Registry, consisting of 364 MM patients treated with HDM-ASCT between June 2015 and June 2019, was used. Among 364 patients treated with HDM-ASCT after June 2019, 22.3% received consolidation therapy and 3.7% underwent tandem HDM-ASCT. During follow-up, 297 patients (81.6%) initiated maintenance therapy, with 277 (76.1%) receiving LM. Overall, 145 patients (52.3%) discontinued LM most commonly due to toxicity 75 (51.7%), with fatigue (30.7%), cytopenia (25.3%), and neuropathy (17.3%) being the main reasons. In a 6-month landmark analysis, early discontinuation did not negatively impact PFS or OS. The LM cohort had similar PFS, and OS compared to the pre-LM cohort. The 3-year PFS and OS rates in the LM cohort were 61% and 86%, respectively, while the pre-LM cohort had a 3-year PFS of 55% and a 3-year OS of 89%. In conclusion, the introduction of LM as a nationwide treatment option in Denmark did not lead to improved clinical outcomes.

Smouldering myeloma (SMM) is a heterogeneous, precursor condition to multiple myeloma (MM). SMM patients have either a serum M-protein ≥30 g/L or clonal bone marrow (BM) plasma cells of 10–59% but the absence of myeloma-defining events¹. The current standard of care for SMM is observation. The risk of progression to MM is 10% / year for the first 5 years after diagnosis. However, those with high-risk disease have > 50% chance of progression within 2 years based on the International Myeloma Working Group (IMWG) risk model [1]. Two clinical trials using lenalidomide showed a significant delay in MM progression and end-organ damage [2, 3]. However, there are several challenges when designing interventional SMM trials (Figure 1).

Firstly, there is a need for more accurate risk stratification to ascertain benefit over risk. Several SMM risk models have been developed, including the Mayo 20-2-20 model, IMWG model, PETHEMA model and PANGEA model [1, 4–6]. Whilst these models identify those at higher risk of progression, they were derived from retrospective data and are discordant [7]. SMM is a heterogenous, evolving condition and future models may require dynamic clinical, imaging or genomic biomarkers. Several genetic aberrations (e.g., NRAS, KRAS, MYC and APOBEC) have been identified to be associated with a higher risk of MM progression and could be used to improve current stratification models [8, 9]. To better understand this condition, the UK COSMOS trial (NCT05047107) is an ongoing multi-centre, prospective, observational trial collecting clinical information, peripheral blood and BM samples from SMM patients longitudinally to determine the features of tumour genome and BM microenvironment, and to identify key drivers of MM progression.

Secondly, it is unclear what treatment regimen and duration is optimal for treating high-risk SMM. Some trials utilise intensive therapy to eradicate MM clones, aiming for a cure. For example, the GEM-CESAR trial uses carfilzomib, lenalidomide and dexamethasone as the induction regimen for autologous stem cell transplant, followed by consolidation and maintenance therapy. At 4 years post-transplant, 23% of patients were negative for minimal residual disease (MRD) [10]. Other trials take a preventative approach by using immunotherapies, which may be more effective in an immune system that is less altered in SMM compared with MM. A study showed significant progression-free survival (PFS) benefits using lenalidomide monotherapy compared to control despite a relatively low overall response rate (ORR) [3]. In the ongoing Immuno-PRISM trial, all evaluable SMM patients receiving teclistamab, a bispecific T cell engager, achieved MRD negativity [11]. Other examples are shown in Table S1. Many of these trials lack a control arm, making it difficult to make meaningful comparisons o

Aplastic anaemia (AA) is a rare, life-threatening, haematological disease [1, 2]. In almost all cases, the cause is idiopathic [1]. AA has an incidence of 2–3/million, with a bimodal peak (teenagers and older adults), and a similar prevalence in males and females [2]. Incidence is up to five times higher in Asia than in Europe [1, 3, 4]. Treatment includes haematopoietic stem cell transplant and immunosuppressive therapy [5, 6].

There is a need to evaluate the specific UK incidence data on AA. In this study, instead of a registry, we used hospital admission data from the Hospital Episode Statistics (HES) database* to understand the population of newly hospitalised AA patients in England. We identified people admitted to the hospital between 1 April 2017 and 31 March 2022 with an International Classification of Diseases version 10 (ICD-10) code of D61 (‘Other AAs’). See the Supporting Information Materials for methodology.

The most frequent diagnosis was ‘AA, unspecified’ (D619) (Table 1). A diagnosis of ‘constitutional AA’ (D610) was given to 12–13% of the cohort each year. The number of admissions for constitutional AA in 2017/2018 was higher than in subsequent years of the survey (60 versus 10–15), likely explained by the use of a defined five-year window to collect data on the first instance of a diagnosis. In years 2–5 (i.e., 18/19-21/22) of the study we had access to historical data to determine that any presentation was indeed a first presentation. Over these 4 years (18/19-21/22), 715 new AA diagnoses were identified, Year 1 (17/18) was excluded due to the likely overestimate of the total patients admitted to the hospital in that year. There was an average of approximately 180 new cases per year over years 2–5, based on rounded annual values.

The highest incidences of AA were in central southern England and the north of England (Figure S1).

Patients’ ages at first hospitalisation ranged from 0 to 100, with the majority aged over 40 (Figure 1). In the constitutional AA group, the majority were aged under 40. The proportions of males and females in 5-year age bands up to age 50 were similar.

Overall, 74% of patients were white. The ethnicity with the highest incidence rate was ‘Any other Asian background’ (i.e. those without Indian, Pakistani, Bangladeshi, or Chinese background) at 27 patients per 1,000,000 population (see Table S1].

Sixty-five patients (7%) underwent a haematopoietic stem cell transplant – an average of 15 per year. The mean time from diagnosis to transplant was 163 days. Ninety-two percent of allogeneic transplants had peripheral blood as stem cell source, whilst the remainder were bone marrow-derived stem cell transplants. Among those who received transplants, 69% of recipients were aged under 40. Most patients aged under 40 (81%) did not receive a transplant. 3% of patients aged over 40 received a transplant. The frequ

A literature review does not provide information about the safety of autologous hematopoietic stem cell transplantation (HSCT) in a recipient who has previously received allogeneic HSCT. We treated a 69-year-old woman with diffuse large B cell lymphoma. The patient received autologous stem cell transplantation (ASCT) in the second complete remission of malignant lymphoma. The patient had undergone allogeneic hematopoietic SCT (allo-HSCT) for chronic myeloid leukemia 20 years ago. Chronic myeloid leukemia had been in complete remission for the previous 20 years. Thus, the patient received autologous and allogenic HSCT 20 years apart. ASCT involves the patient receiving “self” hematopoietic cells from an allogeneic donor. In other words, this is immunologically the second allo-HSCT. The allo-HSCT 20 years ago was undergone by a related healthy brother, a human leukocyte antigen (HLA) 8/8 full matched donor. The conditioning regimen was reduced-intensity consisting of fludarabine and busulfan. The patient did not experience acute or chronic graft-versus-host disease (GVHD) after allo-HSCT. The second transplantation, ASCT was performed to the MEAM conditioning regimen. Engraftment was uneventful, and complete donor chimerism had been achieved even after ASCT. She suffered from an acute gastric mucosal lesion 52 days after ASCT. Pathological finding of gastric mucosa was nonspecific acute gastritis with significant neutrophil infiltration. Sex chromosome analysis of gastric mucosa demonstrated that mucosal cells had XX signals, whereas infiltrating neutrophils had XY signals. We speculated the patient onset of an acute gastric GVHD in this recipient after the second transplantation. This case remarked infiltration of neutrophils triggered GVHD reaction by resetting allogeneic immune reaction after the second transplantation. We describe a rare occurrence of GVHD reaction in a recipient of ASCT following allo-HSCT.

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder caused by autoantibodies against FVIII. Severe AHA is life-threatening. Currently, licensed hemostatic agents for the treatment of severe AHA have short half-lives and require intravenous administration, leading to a need for hospitalization, higher costs, and negative effects on quality of life. We present two cases of severe AHA with high inhibitor titers where emicizumab was safely and effectively used with intensive immunosuppression. These reports suggest in vivo efficacy even in high inhibitor environments. The optimal dosing regimen (accelerated vs. standard loading, maintenance frequency) is unknown and we discuss the current approaches.

Artificial Intelligence has the potential to reshape the landscape of clinical trials through innovative applications, with a notable advancement being the emergence of synthetic patient generation. This process involves simulating cohorts of virtual patients that can either replace or supplement real individuals within trial settings. By leveraging synthetic patients, it becomes possible to eliminate the need for obtaining patient consent and creating control groups that mimic patients in active treatment arms. This method not only streamlines trial processes, reducing time and costs but also fortifies the protection of sensitive participant data. Furthermore, integrating synthetic patients amplifies trial efficiency by expanding the sample size. These straightforward and cost-effective methods also enable the development of personalized subject-specific models, enabling predictions of patient responses to interventions. Synthetic data holds great promise for generating real-world evidence in clinical trials while upholding rigorous confidentiality standards throughout the process. Therefore, this study aims to demonstrate the applicability and performance of these methods in the context of onco-hematological research, breaking through the theoretical and practical barriers associated with the implementation of artificial intelligence in medical trials.

ETV6::RUNX1 is the most common fusion gene in childhood acute lymphoblastic leukaemia (ALL) and is associated with favorable outcomes, especially in low-risk children. However, as many as 10% of children relapse within 3 years, and such early relapses have poor survival. Identifying children at risk for early relapse is an important challenge. We interrogated data from 87 children with low-risk ETV6::RUNX1-positive B-cell ALL and with available preserved bone marrow samples (discovery cohort). We profiled somatic point mutations in a panel of 559 genes and genome-wide transcriptome and single-nucleotide variants. We found high TIMD4 expression (> 85th-percentile value) at diagnosis was the most important independent prognostic factor of early relapse (hazard ratio [HR] = 5.07 [1.76, 14.62]; p = 0.03). In an independent validation cohort of low-risk ETV6::RUNX1-positive B-cell ALL (N = 68) high TIMD4 expression at diagnosis had an HR = 4.78 [1.07, 21.36] (p = 0.04) for early relapse. In another validation cohort including 78 children with low-risk ETV6::RUNX1-negative B-cell ALL, high TIMD4 expression at diagnosis had an HR = 3.93 [1.31, 11.79] (p = 0.01). Our results suggest high TIMD4 expression at diagnosis in low-risk B-cell ALL in children might be associated with high risk for early relapse.