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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.

Large B-cell lymphoma (LBCL) accounts for about one-third of adult lymphoma cases. Diagnosis requires specialized hematopathology laboratories, with immunophenotypic analysis essential for confirming B-cell lineage and identifying variants. MYC and BCL2 rearrangements indicate a poor prognosis. Staging and prognosis rely on positron emission tomography computed tomography (PET-CT). The International Prognostic Index (IPI) aids risk stratification. PET-CT is critical for assessing treatment response and guiding strategies. First-line management for LBCL can be informed by interim PET to assess chemosensitivity, with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or polatuzumab vedotin rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) for advanced stages depending on IPI scores. Primary mediastinal B-cell lymphoma (PMBCL) management favors R-CHOP given every 14 days (R-CHOP14) or dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab (DA-EPOCH-R) without radiotherapy in complete responders. Elderly patients, unfit or not (≥80 years or <80 with poor fitness), need geriatric assessment to guide therapy, often R-miniCHOP or non-anthracycline regimens. Frail patients should have adapted treatments. Prephase corticosteroids improve performance status, and supportive treatment should be optimized. The value of central nervous system (CNS) prophylaxis remains uncertain. CNS-IPI scores and specific anatomical sites help identify high-risk patients; magnetic resonance imaging (MRI) and colony-stimulating factor (CSF) analysis are recommended. Approximately 30%–40% of patients with LBCL experience relapsed or refractory disease after 1L treatment. Treatment strategies vary based on the timing of relapse (<1 year or ≥1 year). For those refractory or relapsing within <1 year and fit for therapy, chimeric antigen receptor T (CART) are the gold standard in 2L. CART in CART-naïve patients and bispecific antibodies appear to be the best approach in 3L. Follow-up includes clinical examination for 2 years and management for long-term side effects, such as cardiotoxicity, osteoporosis, immune dysfunction, neurocognitive impairment, endocrine dysfunction, fatigue, neuropathy, and mental distress.

Circulating tumor cells (CTCs) have emerged as a key prognostic factor in newly diagnosed multiple myeloma (NDMM). However, it remains unclear if high CTC counts represent a mere surrogate of tumor burden or might reflect a distinct genomic or transcriptomic entity. In this study, we characterized the genomic and transcriptomic features associated with CTC burden and assessed their combined prognostic value in NDMM patients. We analyzed 540 NDMM patients from the CoMMpass dataset with available baseline CTC information and matched bone marrow transcriptomic (n = 374) and genomic (n = 460) sequencing data. We then validated the results on an external cohort of 135 NDMM patients with CTCs enumerated by next-generation flow cytometry. Higher CTC levels were significantly associated with high-risk clinical features (e.g., ISS or IMS/IMWG 2024). Furthermore, genomic analyses revealed that high CTC counts were associated with complex genomic features such as chromothripsis, APOBEC mutagenesis, and loss of key tumor suppressors, typically linked to high-risk disease. Transcriptomic analyses revealed that elevated CTCs were enriched in cell cycle and proliferation (PR) genes while presenting a reduced association with immune response. Importantly, CTCs also emerged as a surrogate for PR transcriptomic signatures and demonstrated prognostic superiority, potentially simplifying application in the clinical setting. Elevated CTC levels reflect aggressive biological features of multiple myeloma and outperform prognostic markers such as PR signatures. Integrating CTC data into genomic and transcriptomic classifiers could enhance risk stratification and provide a streamlined and powerful tool for clinical decision-making in NDMM.