HemaSphere最新文献

Kazianka L, Pichler A, Agreiter C, et al. Comparing functional and genomic-based precision medicine in blood cancer patients. HemaSphere. 2025;9(4):e70129. doi:10.1002/hem3.70129

A funder was not acknowledged in the original article. The following statement has now been added in the Funding section: “Open Access funding provided by Medizinische Universitat Wien/KEMÖ.”

The original article has been updated. We apologize for this error.

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) in Western countries, accounting for about 10%–20% of all newly diagnosed NHLs and 70% of all indolent lymphomas.^{1, 2}

The clinical course of FL is typically indolent and is characterized by a waxing and waning course. Most patients eventually need treatment, and responses to initial chemo-immunotherapy (CIT) are usually impressive. Nevertheless, relapses occur, requiring additional therapeutic interventions that result in shorter remission duration and an increased risk of drug resistance.³ At present, progression-free survival (PFS) after CIT in advanced stage FL ranges from 73% to 86% at 3 years,^{4, 5} and overall survival (OS) at 5 years varies between 68% and 90%, depending on the patient's age group.^{6, 7}

Disease progression or relapse within 2 years from first-line CIT (POD24_1) identifies a group of FL patients with significantly inferior outcomes (12% event-free survival at 5 years)^{6, 8} and hence with an unmet medical need. Current knowledge is insufficient to identify patients with high-risk disease upfront, nor can it guide initial treatment decisions. Second-line treatments employed in patients with relapsed/refractory (R/R) FL, which differ greatly from country to country and even within single institutions, are guided by initial therapy, patient's age and fitness, and disease characteristics.^9-12

For the design of more uniform treatment guidelines, it is important to better understand which specific combinations of first- and second-line treatments result in the most favorable outcome in specific FL patient populations.

Thanks to the extraordinary commitment of Dr. Steve Ansell, the Coach of the Cantera—2018 edition, and his fantastic training ability, it took just a few days for 20 individuals (the Cantera Players) to become one single, compact group: the Lupiae team (Figure 1).

The magic blend of these young brains soon produced the Lupiae study, an observational study whose aim was to define the disease course of R/R FL after first-line CIT, report current real-life approaches in various countries, and provide a rationale for the identification of novel treatment strategies. The Cantera Headquarter and EHA LyG enthusiastically supported this project, and in March 2019, the LUPIAE registry (NCT04587388) opened enrollment.

Patients with a histologically confirmed initial diagnosis of Grades 1–3a FL who were refractory to first-line CIT or who had relapsed or transformed to aggressive lymphoma were eligible and registered at the time of the first event (documented by biopsy, imaging, or clinical evaluation). Events were defined as (1) FL progression during induction or maintenance therapy; (2) FL relapse or progression after the achievement of at least partial remission (PR); and

We read with great interest the study by Veenstra et al.¹ validating the 17 immunophenotypic core marker panel (ELN Scoring System), defined by the ELN-iMDS-Flow Working Group (ELN-iMDS).² It includes aberrancies in myeloid progenitor cells (MPCs), neutrophils, monocytes, and nucleated erythroid cells. The presence of at least three aberrancies was indicative of either myelodysplastic neoplasm (MDS) or chronic myelomonocytic leukemia (CMML). Veenstra et al. could diagnose MDS with a sensitivity of 90% compared to an integrated diagnostic approach, which was also maintained within low-risk MDS (<5% bone marrow blasts) at 87%. This is comparable to the established comprehensive Integrated Flow Score (iFS)³ (all MDS: 91%) and represents a significant improvement compared to the 4-parameter Ogata-score⁴ (all MDS: 66%). In pathological controls (i.e., non-clonal cytopenias), concordance of ELN Scoring System was achieved in 76% (41/54) of patients. Some aberrancies were restricted to MDS patients but absent in pathological controls (aberrant expression of CD5, CD7, or CD56 on MPC and abnormal expression of CD33 on neutrophils). Exclusion of four markers predominantly associated with CMML (low side scatter and aberrant CD33 expression on neutrophils, aberrant percentage and CD13 expression of monocytes) (Kern et al.²) increased specificity to 96%.

We aimed to confirm the applicability and therefore the significance of the ELN Scoring System in routine diagnostics. To do this, we analyzed a large, independent cohort of MDS (359 patients) and pathological controls (41 patients with non-clonal cytopenias, for details see legend of Figure 1). In addition to the study by Veenstra et al., samples of 38 CMML patients and 32 healthy bone marrow (HBM, hip surgery patients) were included. The antibody panel, staining, acquisition, and data analysis have been previously delineated.⁵

Applying the ELN Scoring System to our MDS cohort, the diagnosis was confirmed in 89% of all MDS cases (Figure 1A). High sensitivity was also maintained in the low-risk MDS group (<5% blasts: 84%; low-to-moderate low IPSS-M: 86%). These results were in line with those reported by Veenstra et al. Regarding false negative cases (38/359), 42% of these would have been assigned to MDS by alternative scoring systems (Ogata-score: 8%, iFS: 21%, both simultaneously: 13%). Almost all CMML samples (97%) had an ELN Score compatible with MDS/CMML, in line with the ELN-iMDS study by Kern et al.² We also confirmed the four parameters described above as significantly associated with CMML.

As determined in pathological controls, the specificity of the ELN Scoring System was notably higher in our cohort than in the Veenstra and Kern studies (98%, 75%, and 78%, respectively). However, this high sp

The Duffy null variant is caused by a single-nucleotide polymorphism in the promoter region of the ACKR1 gene, which encodes atypical chemokine receptor 1, also called the Duffy antigen receptor for chemokines (DARC). This variant leads to an absence of Duffy antigens on red blood cells. Due to impacts on neutrophil chemotaxis, the variant is also associated with a 30%–40% lower circulating neutrophil count but no increased risks of infection or decreased stress response.¹ One US cohort found 10% of Duffy null individuals had an absolute neutrophil count (ANC) less than 1.5 × 10⁹/L.² The same study reported a Duffy null-associated neutrophil count (DANC) reference interval of 1210 to 5390/μL,² which has recently been validated in an international cohort.³ This phenomenon of DANC is also known as ACKR1/DARC-associated neutropenia (ADAN).⁴

People of all genetic ancestries can have the Duffy null phenotype, but the variant is mostly prevalent in individuals of African and Middle Eastern ancestry as it confers partial protection against Plasmodium vivax which is endemic in those regions.⁵ For example, amongst individuals self-identifying as Black in the United States (US) and the United Kingdom (UK), approximately 65% and 80% are Duffy null, respectively,⁶ and prevalence amongst Saudi Arabian nationals within two different provinces of Saudi Arabia is around 50%–80%.^{7, 8}

ANC criteria are often incorporated into clinical trial eligibility criteria, but these criteria rarely take Duffy status into account. Thus, patients with DANC may be disproportionately excluded from cancer trials due to their lower baseline ANC. A recent cross-sectional study assessed 289 phase 3 clinical trials for the five most common cancer types, reporting that 77% of trials excluded individuals for ANC values that would be within the normal range for someone with the Duffy null variant.⁹

We hypothesised that restrictions excluding Duffy null individuals could also be present in clinical trials within medical haematology. Medical haematology (previously called “non-malignant” or “benign” haematology) encompasses many chronic disorders that disproportionately affect populations from minoritised ethnic groups¹⁰ who are likely to have a higher prevalence of the Duffy null variant.

To address this hypothesis, we designed a cross-sectional study with the aim of assessing the proportion of medical haematology clinical trials with exclusion criteria for ANC values within the DANC reference range. We aimed to assess both explicit exclusions (i.e., studies requiring ANC above a value within the normal range for DANC) and implicit exclusions (i.e., studies requiring ANC within normal limits, commonly

The treatment landscape for older patients with multiple myeloma (MM) has rapidly evolved with the introduction of CD38-targeting antibodies. Yet, outcomes remain highly variable and are only partially explained by frailty status. To address this, we investigated the impact of the immune system on survival outcomes of 89 newly diagnosed MM patients in the HOVON-143 trial, where frail or intermediate-fit patients received daratumumab–ixazomib–dexamethasone. Comprehensive immunophenotyping of lymphoid and myeloid subsets as relative or absolute counts in peripheral blood (PB) and bone marrow revealed comparable immune composition between frail and intermediate-fit patients at diagnosis, except for reduced naive CD4⁺ and CD8⁺ T-cells and increased effector memory CD4⁺ T-cells and CD56^bright NK-cells in frail patients. Among 36 T-cell and NK-cell subsets analyzed, 9 subsets—measured as absolute counts in PB—showed strong association with progression-free survival (PFS) and 5 with overall survival (OS). Four subsets were linked to both PFS and OS: higher absolute counts of naive CD8⁺ T-cells, CD38⁺CD4⁺ T-cells, and CD56^dimCD57⁺ NK-cells were associated with longer survival, whereas elevated EM CD8⁺ T-cell counts were linked to shorter survival. Using the most predictive immune parameters, we subsequently developed two immune risk scores—one for PFS and one for OS—which remained strongly associated with survival after adjusting for frailty status, disease stage, and cytogenetic risk. Our findings underscore the importance of a composite analysis of the immune system and demonstrate the association of baseline immune parameters with survival outcomes of first-line therapy in non-fit MM patients.

Hematotoxicity after anti-CD19 chimeric antigen receptor T-cell therapy has drawn attention for potential long-term effects, and yet, recovery of lymphocyte subsets and immunoglobulin levels beyond B-cell aplasia remains poorly understood. We retrospectively analyzed 76 consecutive axicabtagene ciloleucel (axi-cel) recipients with relapsed/refractory aggressive B-cell lymphoma between 2020 and 2024, focusing on basic immune recovery patterns and their impact on outcomes. Median CD8⁺ T and NK cells increased to >300/mm³ and >100/mm³, respectively, within 2 months after infusion. CD4⁺ T-cell recovery was slower, with 42% cumulative incidence of >200/mm³ cell count at 12 months. B-cells were detectable in 18% at 12 months. Immunoglobulin levels initially declined and then plateaued, with 51% incidence of immunoglobulin G (IgG) levels > 400 mg/dL at 12 months. Modified EASIX > 2.00 was associated with delayed kinetics of CD3⁺ T-cells, CD4⁺ T-cells, and CD8⁺ T-cells, and cumulative dexamethasone dose > 120 mg with delayed recovery of CD4⁺ T-cells, NK cells, and IgG. At 1 month post-infusion, low CD4⁺ T-cell count and high CAR-HEMATOTOX predicted worse 12-month progression-free survival (hazard ratio [HR] 2.81 and 3.34) and overall survival (HR 3.21 and 4.41), respectively. After axi-cel, CD4⁺ T-cells and IgG recovered slowly during the first year, while CD8⁺ T and NK cells increased rapidly. A higher modified EASIX score may predict slower cellular recovery, while corticosteroids may delay both cellular and humoral recovery. Lower CD4⁺ T-cell count was associated with worse outcomes.

Female-biased incidence in primary mediastinal large B-cell lymphoma (PMBCL) is enigmatic and points to a potential contribution of the X chromosome in this disease. To elucidate the postulated involvement of X-linked factor(s), we profiled the X chromosome in 48 diagnostic PMBCLs of male (21) and female (27) origin. Molecular cytogenetic analysis detected copy number gain of X/Xq in all male patients and 59.3% (16/27) of female patients. The remaining female cases revealed either a cytogenetically cryptic copy-neutral loss of heterozygosity (CNLOH) of X/Xq (14.8%) or germline XX (25.9%). Remarkably, RNAseq data of 28 cases indicated a nonrandom involvement of transcriptionally active X homolog in gain/CNLOH, validated by hXIST RNA-fluorescence in situ hybridization (FISH) in two PMBCL-derived cell lines. Further transcriptomic analysis revealed IL13RA1 (Xq24) as the target of the Xq aberrations. In agreement with this, the vast majority (32/38, 84.2%) of PMBCL cases were IL13RA1-positive by immunohistochemistry. The intriguing finding of IL13RA1 protein expression in female PMBCLs with germline XX suggests epigenetic reactivation and expression of IL13RA1 on the inactive X. Functional in vitro studies performed on Ba/F3 cells showed that overexpressed IL13RA1 is potent to transform murine pro-B cells and constitutively activate the oncogenic JAK-STAT signaling pathway. The novel pathogenic Xq24/IL13RA1 defects appeared as disease-defining aberrations driving PMBCL and contributing to the related sex disparity. Our findings indicate that female predominance in PMBCL is due to the higher risk of women of acquiring pathogenic Xq24/IL13RA1 defects by female-exclusive genetic/epigenetic mechanisms (CN-LOHX and reactivation of IL13RA1 on Xi) not operating in males.

Platelets are anucleate cells produced in the bone marrow and derived from large progenitor cells called megakaryocytes (MKs). Platelets receive RNA transcripts from their progenitorial MKs during thrombopoiesis. However, the correspondence between platelet and MK transcriptomes is poorly understood, particularly in the context of germline mutations that cause platelet formation defects or thrombocytopenia. We have studied the effects of two such mutations on MK and platelet transcriptomes. We generated immortalized MK cell line (imMKCL)-based models of Bernard–Soulier syndrome and IKZF5-related thrombocytopenia. MKs derived from imMKCLs with either a homozygous deletion of GP9 (GP9^−/−) or a heterozygous Y121F variant in IKZF5 (IKZF5^WT/Y121F) exhibited reduced proplatelet formation (reductions of 96% and 57%, respectively). Platelets from patients with either GP9^−/− or IKZF5^WT/Y121F genotypes had broad transcriptomic dysregulation, suggesting that (pro)platelet formation defects due to mutations in glycoprotein receptor and transcription factor genes such as GP9 and IKZF5 already affect the MK transcriptome. RNA-seq data from MKs at four stages of differentiation revealed widespread but distinct changes in expression over time between the GP9^−/− and the IKZF5^WT/Y121F genotypes. Dysregulated genes in GP9^−/− MKs were enriched for RNA metabolism and actin/tubulin folding pathways, whereas those in IKZF5^WT/Y121F MKs were enriched for cell cycle pathways. Most of these genes were also dysregulated in the platelets of patients with the corresponding diseases. Our results suggest that patients with inherited forms of thrombocytopenia present with specific transcriptomic changes during platelet formation.