HemaSphere最新文献

Chimeric antigen receptor (CAR)-T-cell therapy has improved response rates in relapsed/refractory multiple myeloma (RRMM), yet long-term disease control remains limited, with only 20% of patients remaining progression-free at 5 years. Therefore, identifying early predictors of treatment success is critical. Here, we used next-generation flow cytometry to analyze T-cell populations in blood at leukapheresis, before infusion, and post-anti-BCMA CAR-T infusion, together with CAR-T-cell kinetics and phenotypes before, during, and after the expansion peak, in 53 RRMM patients. Anti-BCMA CAR-T cells peaked at Day +14 (72%), comprising >65 distinct populations, predominantly central memory (CM) T-helper (Th) 1 and Th1/2 CAR-TCD4⁺ and CM CAR-TCD8⁺ cells. Multivariate analyses revealed that higher frequencies of TCD4⁺ naive and Th22 transitional memory (TM) cells at leukapheresis, together with circulating tumor plasma cells (CTPCs) before infusion, but none of the specific CAR-T-cell populations, were predictors of progression-free survival (PFS). Based on these variables, we built a risk score that together with disease stage (International Staging System-Revised [ISS-R]) independently predicted, before CAR-T-cell infusion, which RRMM patients were most likely to benefit from anti-BCMA CAR-T therapy. These findings suggest that long-term PFS is primarily influenced by the patient's immune landscape and the tumor burden rather than anti-BCMA CAR-T-cell properties.

Thieblemont C, Gomes Da Silva M, Leppä S, et al. Large B-cell lymphoma (LBCL): EHA Clinical Practice Guidelines for diagnosis, treatment, and follow-up. HemaSphere. 2025;9(9):e70207. doi:10.1002/hem3.70207.

The abbreviation CSF was incorrectly defined as “colony-stimulating factor” in the Abstract and Table 2. The correct definition is “cerebrospinal fluid.”

Additionally, in the author listing of the manuscript, the name of an author was incorrectly listed as Marie-José Kersten. The correct name is Marie José Kersten.

The original article has been updated. We apologize for these errors.

Health-related quality of life (HRQoL) of patients with myeloproliferative neoplasms (MPNs) may be impaired across several domains. In this multicenter observational study, we evaluated HRQoL and symptoms in a cohort of MPN patients with validated measures, including the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS), and the Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-Fatigue) questionnaire. The primary objective was to compare the HRQoL profile of patients, by disease subtype, with that of the general population according to the EORTC QLQ-C30. A total of 572 patients with essential thrombocythemia (ET, n = 228), polycythemia vera (PV, n = 207), and myelofibrosis (MF, n = 137) were assessed. Worse statistically and clinically significant differences were observed for role functioning (ET: ∆ = 8.9, P < 0.001; PV: ∆ = 11, P < 0.001; MF: ∆ = 16.7, P < 0.001) and fatigue (ET: ∆ = 5, P < 0.001; PV: ∆ = 8.3, P < 0.001; MF: ∆ = 11.5, P < 0.001) in all three diagnostic groups. However, patients with MF also reported impairments in other important health domains. Fatigue was the most frequently reported and burdensome symptom, with greater severity correlating with a broader and more complex array of associated symptoms. Our analysis also revealed a substantial underestimation of symptoms by treating hematologists in paired physician–patient reports. Current findings may help to disentangle specific HRQoL limitations and symptomatology experienced by patients with MPNs, and underscore the importance of incorporating patient-reported outcomes into routine practice to better reflect the patient's perspective of the disease and treatment-related burden.

The T-cell Leukemia Homeobox 1 (TLX1) oncogene is frequently deregulated in T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL). In most instances, TLX1 overexpression results from its juxtaposition with a T-cell receptor (TCR) locus caused by interchromosomal translocations. However, in the subset of non-TCR-translocated TLX1-positive (non-TCR TLX1+) T-ALL cases, the underlying mechanisms driving TLX1 overexpression and their clinico-biological implications remain unclear. By integrating high-resolution data from next-generation sequencing, fluorescence in situ hybridization, karyotyping, optical genome mapping, and long-read whole-genome sequencing across a cohort of 1122 adult and pediatric T-ALL/T-LBL cases, we identified TLX1 overexpression in 11% of T-ALL/T-LBL cases, with an unexpected 14% incidence of non-TCR TLX1+ cases among TLX1+ cases. Non-TCR TLX1 + T-ALL cases show distinct clinico-biological features, including a lower frequency of cortical phenotype compared to the TCR-translocated TLX1+ (TCR TLX1+) subgroup, regardless of TLX1 expression levels. In non-TCR TLX1⁺ cases, TLX1 deregulation results mostly (83%) from the hijacking of the ANKRD1 and PCGF5 enhancer at 10q23.31 through various chromosomal aberrations. Genomic analyses revealed that these aberrations juxtapose the ANKRD1 and PCGF5 enhancer with TLX1, driving its overexpression. Importantly, survival analysis revealed that non-TCR TLX1+ patients had significantly poorer outcomes compared to their TCR TLX1⁺ counterparts (3y-OS: 55% vs. 90%, P < 0.001 and 3y-DFS: 45% vs. 75%, P = 0.02). These findings, consistent with our previous observations in TAL1-driven T-ALL, confirm that the clinico-biological impact of an oncogene is influenced by the specific mechanism underlying its deregulation.

The emergence of next-generation sequencing techniques has led to the genetic characterization of numerous congenital erythroid disorders, emphasizing crucial pathways in both normal and pathological erythropoiesis. In this study, whole exome sequencing of a single patient with atypical congenital pure red cell aplasia revealed a mutation in the CDAN1 gene, typically associated with congenital dyserythropoietic anemia type 1 (CDAI), together with a previously unreported mutation in the MMS22L gene. Combined mms22l and cdan1 haploinsufficiency results in severe anemia in a zebrafish model. In human erythroid progenitors, loss of MMS22L leads to proliferation and differentiation arrest associated with activation of the p53 pathway and global epigenetic alterations, showing that MMS22L plays an indispensable role in erythropoiesis. Furthermore, MMS22L and CDAN1 are involved in the same protein complex whose nuclear import is mediated by the importin 4 (IPO4) protein, and MMS22L nuclear import is impaired in CDAI patients due to a defective interaction between CDAN1 and IPO4. Overall, through the genetic description of a single case characterized by digenic inheritance, we identified MMS22L as a novel key factor in erythropoiesis and brought new insights into normal erythropoiesis regulation and CDAI pathophysiology.

Atypical chronic myeloid leukemia (aCML) is a rare form of myelodysplastic (MDS)/myeloproliferative neoplasm (MPN) overlap disorder characterized by neutrophilic leukocytosis with circulating immature myeloid cells (IMC), frequent hepatosplenomegaly, and poor prognosis with high rates of leukemic transformation. In the 2022 World Health Organization (WHO) classification, aCML was therefore renamed to “MDS/MPN with neutrophilia.” Diagnostic criteria for aCML include leukocytosis ≥ 13 × 10⁹/L, circulating IMC ≥ 10%, dysgranulopoiesis, and at least one cytopenia for MDS-thresholds (per International Consensus Classification [ICC]). Bone marrow is hypercellular due to granulocytic proliferation, associated with dysplasia in granulocytes ± other cell lines. Mutations can be used to support the diagnosis in both classifications, that is, SETBP1 and ASXL1 or SETBP1 and/or ETNK1. Absence of monocytosis, basophilia, or eosinophilia, <20% blasts, and exclusion of other MPN, MDS/MPN, and tyrosine kinase fusions are mandatory. Cytogenetic abnormalities are identified in roughly 20%–40% of aCML patients, along with a complex genomic context with high rates of recurrent somatic mutations in ASXL1, SETBP1, SRSF2, TET2, EZH2, and, less frequently, in NRAS/KRAS, CBL, CSF3R, JAK2, and ETNK1. Unfortunately, effective risk stratification systems for identifying prognostic subgroups of aCML patients are lacking, resulting in the absence of a standard of care for its management. The most used agents include hydroxyurea, interferon, hypomethylating agents, and JAK inhibitors, although none of them are disease-modifying. Allogeneic hematopoietic stem cell transplant remains the only potentially curative approach and should be considered in all eligible patients. Actionable mutations (CSF3R, NRAS/KRAS, and KIT) have also been identified, supporting the development of new agents targeting the involved pathways.

Clonal hematopoiesis (CH), a prevalent and premalignant state in the elderly, has been detected in young individuals under selective pressures such as hematopoietic cell transplantation (HCT). However, the origin of CH and mutational processes underlying CH driver mutations in young blood systems remain unclear. Here, we used genome-wide somatic mutation profiles to retrospectively trace the origin of DNMT3A-mutant CH in three individuals, 14–41 years after childhood HCT. Both the rate and spectrum of somatic mutations in individuals with posttransplant CH were consistent with normal age-associated mutagenesis. Phylogenetic analysis revealed that DNMT3A-mutant HSPCs were present in the donor before 6.8 years of age, including during fetal development, despite being undetectable with a limit of detection of variant allele frequency of 0.001 at the time of transplantation. These findings were validated by comparing the observed mutations to expected age-dependent mutational signatures. Our results reveal that undetectable DNMT3A-mutant clones in young donors can expand into significant CH clones within decades upon transplantation. The rapid expansion of these clones in this context indicates that specific environmental pressures, rather than solely mutation acquisition, drive the development of CH.