British Journal of Haematology最新文献

Immune effector cell-associated hematotoxicity (ICAHT) is a common toxicity associated with an important morbidity after chimeric antigen receptor (CAR)-T-cell therapy. Multiple factors seem to be involved in the development of severe ICAHT, making its management difficult. Here, we report three cases of severe ICAHT after axicabtagene-ciloleucel (axi-cel) for diffuse large B-cell lymphoma showing an expansion of large granular lymphocyte in the bone marrow with a CD3/CD57-positive non-CAR-T immunophenotype. We show that it is possible to treat them with low-dose steroids, obtaining a striking resolution of cytopenias with no deleterious impact on the underlying malignancy.

The prognosis for patients with relapsed/refractory or measurable (minimal) residual disease-positive Philadelphia chromosome (Ph)-positive acute lymphoblastic leukaemia (ALL) is poor. Currently, ponatinib is the only approved tyrosine kinase inhibitor (TKI) that is effective for Ph-positive ALL with the T315I mutation. Although the report by Liu et al. is a retrospective observational study, it offers prospects for the efficacy of chemotherapy combined with the novel third-generation TKI, olverembatinib, in these conditions, which may be validated in future prospective clinical trials. Commentary on: Liu et al. Efficacy and safety of olverembatinib in adult BCR::ABL1-positive ALL with T315I mutation or relapsed/refractory disease. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19804.

A 41-year-old female patient was admitted to our endocrinology department with the symptoms of worsening malaise, difficulty in walking and numbness in her limbs. Blood tests revealed a red blood cell count of 3.11 × 10¹²/L, haemoglobin level of 97 g/L, urinary Igκ at 1.11 g/L, Igλ at 0.05 g/L, resulting in a κ/λ ratio of 22.20. Additional findings included urinary beta-microglobulin levels exceeding 2500 μg/L, urinary immunoglobulin at 23 mg/L, urinary albumin levels above 50 mg/L and serum beta-microglobulin at 5.36 μg/L. Bone marrow aspiration showed that 9% of the total cells were plasma cells, with 7% containing acicular crystalline inclusion bodies. These plasma cells varied in size, exhibited abundant cytoplasm and displayed eccentrically located nuclei. Some cells were binucleated, with the cytoplasm containing varying numbers of acicular crystalline inclusion bodies (Wright staining, 100× objective; images, upper left, middle, and right panels). Flow cytometry analysis revealed that 3.61% of the aberrant monoclonal plasma cells expressed CD45, CD38, CD138, CD81, CD117, CD27 and CD28dim, with kappa light chain restriction (images, lower left, middle and right panels). Based on these findings, a diagnosis of multiple myeloma, kappa light chain type, was established. The presence of crystalline immunoglobulin inclusions in this case is an uncommon occurrence. The presence of crystalline inclusions of immunoglobulin in this case is a rare finding. Crystallisation is thought to occur on the surface of the rough endoplasmic reticulum, where the biochemical properties of the particular monoclonal protein produced in that case of myeloma favour its condensation into a crystal structure (Miyoshi I, Daibata M, Saito T, Ohtsuki Y, Taguchi H. Bence Jones myeloma cells with crystalline inclusions. Intern Med 2006;45(5):337–8).

This study is supported by the Scientific and Technological Research Program of Chongqing Municipal Education Commission (KJQN202000443).

Ethical review and approval were waived for this study due to the retrospective description of a few cases without identifiable patient data.

Consent for publication, both in print and electronically, has been obtained from the patient.

The Hodgkin lymphoma International Study for Individual Care (HoLISTIC) Consortium's A-HIPI model, developed in 2022 for advanced-stage classical Hodgkin lymphoma (cHL), predicts survival within 5 years amongst newly diagnosed patients. This study validates its performance in the Brazilian Hodgkin lymphoma registry. By 2022, the Brazilian HL registry included 1357 cHL patients, with a median 5-year follow-up. Probabilities for 5-year progression-free survival (PFS) and overall survival (OS) were calculated using A-HIPI-model equations. Discrimination (Harrell C-statistic/Uno C-statistic) and calibration measures assessed external validation and calibration. Lab values beyond the allowed range were excluded, mirroring the initial A-HIPI analysis. A total of 694 advanced-stage cHL patients met the original inclusion criteria (age 18-65 years, Stage IIB-IV). Median age was 31 years; 46.3% were females. Stage distribution was IIB (33.1%), III (27.4%), IV (39.5%). Bulky disease in 32.6%. Five-year PFS and OS were 68.4% and 86.0%, respectively. Harrell C-statistics were 0.60 for PFS and 0.69 for OS, and Uno C-statistics were 0.63 for PFS and 0.72 for OS. Calibration plots demonstrated well-calibrated predictions with calibration slopes of 0.91 and 1.03 for 5-year OS and PFS, respectively. Despite differing patient, clinical characteristics, and socioeconomic factors, the baseline prediction tool performed well in the Brazilian cohort, demonstrating adequate discrimination and calibration. This supports its reliability in diverse settings.

Neonatal and adult megakaryocytes differ in proliferative capacity and ploidy levels, and neonatal and adult platelets differ in function, gene expression, and protein content. The mechanisms underlying these differences are incompletely understood. CDK8 and CDK19 are transcriptional kinases part of the CDK-mediator complex, which regulates gene transcription in a cell-specific manner. We discovered that cortistatin A, a potent highly selective inhibitor of CDK8/CDK19, significantly reduced cell expansion and increased ploidy in cord blood-derived megakaryocytes. These phenotypic changes were associated with gene expression changes that partially overlapped developmentally regulated genes. These findings might have relevance for the management of developmental megakaryocyte disorders.

The choice between thrombopoietin receptor agonists (TPO-RAs) and anti-CD20 as the preferred second-line therapies for immune thrombocytopenia remains in the eye of the beholders. Each has major advantages and certain weaknesses. Stolz et al. describe a single-centre experience that whets our appetite for a large randomized controlled trial comparing a TPO agonist and an anti-CD20 agent.

Commentary on: Stolz et al. Efficacy of thrombopoietin receptor agonists versus rituximab in non-responsive immune thrombocytopenia – A single center retrospective analysis. Br J Haematol 2024; 205:1121-1125.

Imbalanced nicotinamide adenine dinucleotide (NAD⁺) homeostasis has been reported in multiple autoimmune diseases and supplementation with NAD⁺ precursors has consistently demonstrated positive therapeutic benefits for these conditions. Immune thrombocytopenia (ITP) is an acquired autoimmune disease, in which the decreased number and impaired function of regulatory T cells (Tregs) contribute to the main pathogenesis. Here we found NAD⁺ level was decreased in the plasma and CD4⁺ T cells of ITP patients. Supplementation with NAD⁺ precursor nicotinamide (NAM), but not nicotinamide mononucleotide (NMN), increased Treg frequency and ameliorated thrombocytopenia in an ITP murine model. Moreover, whilst both NAM and NMN restored cytosolic NAD⁺ level in the CD4⁺ T cells from ITP patients, only NAM promoted Treg differentiation. Mechanistically, Sirtuin1 (Sirt1), a major consumer of NAD⁺, was highly expressed in the CD4⁺ T cells of ITP patients, potentially contributing to the low level of NAD⁺. NAM, which could act as Sirt1 inhibitor, promoted Foxp3 acetylation and stability in induced Tregs derived from naïve CD4⁺ T cells of ITP patients. These findings suggest that NAM holds promise as a novel therapeutic strategy for restoring immune balance in ITP.

HbSC disease is a common form of sickle cell disease with significant morbidity and early mortality. Whether hydroxyurea is beneficial for HbSC disease is unknown. Prospective Identification of Variables as Outcomes for Treatment (PIVOT, Trial ID PACTR202108893981080) is a double-blind, randomised, placebo-controlled phase II trial of hydroxyurea for people with HbSC, age 5-50 years, in Ghana. After screening, participants were randomised to placebo (standard of care) or hydroxyurea. The primary outcome is the cumulative incidence of haematological toxicities during 12 months of blinded treatment; secondary outcomes include multiple laboratory and clinical assessments. Between April 2022 and June 2023, 112 children and 102 adults were randomised, including 44% females and average age 21.6 ± 14.5 years. Participants had substantial morbidity including previous hospitalisations (93%), vaso-occlusive events (86%), malaria (79%), often received transfusions (20%), with baseline haemoglobin 11.0 ± 1.2 g/dL and foetal haemoglobin 1.8% ± 1.5%. The spleen was palpable in six children and one adult, and ultrasonographic volumes were collected. Proliferative sickle retinopathy was common (30% children, 75% adults), but proteinuria was less common (3% children, 8% adults). Whole blood viscosity, ektacytometry, point-of-sickling, transcranial Doppler, near-infrared spectrometry (NIRS), 6-minute walk, and quality of life were also measured. Now fully enrolled, PIVOT will document the safety and potential benefits of hydroxyurea on clinical and laboratory outcomes in HbSC disease.

Jayne et al. provide a molecular characterization of the t(1;6)(p35.3;p25.2) chromosomal translocation in patients with chronic lymphocytic leukaemia. They indicate that this translocation involves the gene encoding interferon regulatory factor 4 (IRF4) on chromosome 6p25.2 with the regulator of chromosome condensation 1 (RCC1) gene on chromosome 1p35.3. This translocations may have important prognostic value. Commentary on: Jayne et al. The chromosomal translocation t(1;6)(p35.3;p25.2), recurrent in chronic lymphocytic leukaemia leads to RCC1::IRF4 fusion. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19790.