HemaSphere最新文献

Autologous stem cell transplantation (auto-SCT) is an established treatment for peripheral T-cell lymphoma (PTCL) to consolidate first remission and for patients with relapsed/refractory (r/r) disease. We aimed to examine the outcomes of patients with PTCL NOS, AITL, and ALK-negative ALCL undergoing auto-SCT between 2010 and 2022 and reported to EBMT. Adult patients with major T-cell entities who had received auto-SCT either up-front or for r/r disease were included. 2082 patients underwent up-front and 1249 salvage auto-SCT. Three-year progression-free (PFS) and overall survival (OS) after up-front auto-SCT were 55.2% and 73.1%. For r/r patients, 3-year PFS and OS were 42.6% and 59.5%. In multivariate analysis, male patients, histology other than ALK-negative ALCL, non-CR, and higher age at auto-SCT showed significantly lower PFS and OS after both, up-front and salvage auto-SCT, mostly reflecting the higher relapse incidence for these patients. Major outcomes did not significantly change when the analyses were restricted to the patients with PET-based response at auto-SCT (n = 2062). Auto-SCT demonstrated excellent outcomes when used up-front and surprisingly good results in salvage settings. Patients with ALK-negative ALCL survived significantly better than patients with PTCL NOS or AITL. Male gender, higher age, and non-CR at auto-SCT were associated with poor outcomes. Overall, auto-SCT is a valid treatment option in T-cell lymphoma where targeted therapies still play a limited role.

Bone marrow fibrosis is the most extensive matrix remodeling of the microenvironment and can include de novo formation of bone (osteosclerosis). Spatiotemporal information on the contribution of distinct bone marrow niche populations to this process is incomplete. We demonstrate that fibrosis-inducing hematopoietic cells cause profibrotic reprogramming of perivascular CXCL12-abundant reticular (CAR) progenitor cells, resulting in loss of their hematopoiesis-support and upregulation of osteogenic and pro-apoptotic programs. In turn, peritrabecular osteolineage cells (OLCs) are activated in an injury-specific, Wnt-dependent manner, comparable to skeletal repair. OLCs fuel bone marrow fibrosis through their expansion and skewed differentiation, resulting in osteosclerosis and expansion of Ly6a⁺ fibroblasts. NCAM1 expression marks peritrabecular OLCs and their expansion into the central marrow is specific for fibrosis in mice and patients. Peritrabecular stromal β-catenin expression is linked to fibrosis in patients, and inhibition of Wnt signaling reduces bone marrow fibrosis and osteosclerosis, possibly being a clinically relevant therapeutic target.

KMT2A-rearranged B-cell acute lymphoblastic leukemia (KMT2Ar B-ALL) exhibits significant heterogeneity in age of onset, developmental origins, and clinical outcomes. The interplay of individual factors influencing early treatment response within this high-risk molecular subtype remains poorly elucidated. To identify determinants of early treatment response to induction chemotherapy, we analyzed 465 KMT2Ar B-ALL cases spanning a wide age range (1 month to 89 years) by integrating transcriptomic and genomic profiling with functional drug response and measurable residual disease (MRD) kinetics. We observed a strong inverse correlation between MRD clearance with advancing age (P = 2.1E−04), proximity to early B-cell-precursor developmental state (low maturity score, P = 1.3E−03), and AFF1 as fusion partner (P = 7.0E−04). A multivariable analysis confirmed the strong impact of maturity (P = 0.02) and KMT2A fusion partner (P = 0.03) on MRD clearance, supporting the concept that the cell's developmental state defines therapy response. Gene expression analysis identified cellular traits that relate to MRD clearance (e.g., chromatin organization, immune modulation, and proliferation). This gene expression classifier grouped cases not only by MRD clearance but also by ex vivo sensitivity to induction therapy drugs. Notably, good responders to ex vivo induction drugs were characterized by a higher maturity score (P = 1.8E−03), whereas for less mature KMT2Ar B-ALL cases, response profiles suggested higher Venetoclax sensitivity. Our study provides an integrative framework linking developmental phenotype, fusion partner, and MRD kinetics across the full age spectrum of KMT2Ar B-ALL. These insights may support future risk-adapted strategies and therapeutic targeting, particularly in immature KMT2Ar B-ALL.

Advancements in the understanding of chronic lymphocytic leukemia (CLL) have transformed patient care, leading to the development of novel targeted therapies. Traditionally, patient fitness for treatment was based on the tolerability of chemoimmunotherapy such as fludarabine–cyclophosphamide–rituximab. As the CLL patient population is predominantly older, age has historically been a major factor in how a physician selects a patient's treatment. However, as a patient's fitness goes beyond age, the definition of patient fitness should also evolve. Here, we provide suggestions for the current best practice on assessing fitness for treating CLL. Considerations for treatment include assessment of polypharmacy, history of infections, cardiovascular and renal comorbidities, functional status, cognitive and psychological status, nutritional status, and social support. The flow of assessments can start with a typical clinical evaluation followed by geriatric, cardiovascular, and renal reviews, if needed, and include collecting a patient's full history to evaluate their risk of complications with specific CLL treatments. The severity of a patient's cardiovascular profile can range from low to high risk; for those at high risk, collaboration with a cardiologist is recommended. Geriatric assessment is advised to determine baseline frailty and resilience to tolerate treatments, to avoid inappropriate treatment or undertreating patients based on chronological age, and to align the patient's fitness status with the most optimal treatment. Continuous monitoring and assessment, regardless of therapy, are recommended. Patient preferences are also integral to this decision-making process. Looking beyond a patient's age and basing treatment selection on their fitness is key in the new era of treatment in CLL.

Beta-thalassemia is an inherited anemia characterized by a broad spectrum of clinical manifestations. The most severe form is transfusion-dependent β-thalassemia, in which patients need regular blood transfusions to survive, since no adequate amount of hemoglobin is produced by the bone marrow. The therapeutic landscape for this disease is constantly evolving, and new therapies have been recently approved. Luspatercept is the first and only approved drug for treating anemia in transfusion-dependent β-thalassemia. Most available information regarding its safety and efficacy is derived from clinical trials, with limited data on real-world experiences. Thus, a significant gap remains in the literature concerning patient management in everyday clinical settings, particularly in terms of assessing efficacy and the challenges that arise when managing luspatercept. Indeed, effectiveness evaluation in the real-world presents a much more complex scenario compared to clinical trials. In this paper, we present five clinical cases that drive us through the complexity of luspatercept management and highlight the following topics: (1) the role of genotype in the patient selection, (2) the importance of patient empowerment and the psychological aspects when introducing a new therapy, (3) efficacy assessment in the real-world, including improvement of iron balance, optimization of pretransfusion hemoglobin, and (4) the importance of the constant monitoring for safety and for adverse events. Emerging evidence and insights from real-world settings play a crucial role in shaping best practices for everyday clinical practice.

KMT2A-rearranged B-cell acute lymphoblastic leukemia (KMT2Ar B-ALL) exhibits significant heterogeneity in age of onset, developmental origins, and clinical outcomes. The interplay of individual factors influencing early treatment response within this high-risk molecular subtype remains poorly elucidated. To identify determinants of early treatment response to induction chemotherapy, we analyzed 465 KMT2Ar B-ALL cases spanning a wide age range (1 month to 89 years) by integrating transcriptomic and genomic profiling with functional drug response and measurable residual disease (MRD) kinetics. We observed a strong inverse correlation between MRD clearance with advancing age (P = 2.1E−04), proximity to early B-cell-precursor developmental state (low maturity score, P = 1.3E−03), and AFF1 as fusion partner (P = 7.0E−04). A multivariable analysis confirmed the strong impact of maturity (P = 0.02) and KMT2A fusion partner (P = 0.03) on MRD clearance, supporting the concept that the cell's developmental state defines therapy response. Gene expression analysis identified cellular traits that relate to MRD clearance (e.g., chromatin organization, immune modulation, and proliferation). This gene expression classifier grouped cases not only by MRD clearance but also by ex vivo sensitivity to induction therapy drugs. Notably, good responders to ex vivo induction drugs were characterized by a higher maturity score (P = 1.8E−03), whereas for less mature KMT2Ar B-ALL cases, response profiles suggested higher Venetoclax sensitivity. Our study provides an integrative framework linking developmental phenotype, fusion partner, and MRD kinetics across the full age spectrum of KMT2Ar B-ALL. These insights may support future risk-adapted strategies and therapeutic targeting, particularly in immature KMT2Ar B-ALL.

Following approval of axicabtagene ciloleucel (axi-cel) as second-line (2 L) treatment for large B-cell lymphoma (LBCL), results from real-world CAR T cohorts will be key to confirm safety and efficacy in standard practice. We present comprehensive clinical outcomes of LBCL patients intended to be treated with 2 L axi-cel through the UK National CAR T service. Of 345 patients approved for 2 L axi-cel, 302 (87.5%) were infused. The median age was 62 years (range 22–78); 21% were over 70 years. 75% of patients were approved for CAR T within 3 months from end of first-line (1 L) therapy. 42% of patients required pre-apheresis holding therapy, and 97% received bridging therapy. The best overall response rate was 86% (64% complete response). The 12-month OS was 73.9% (95% CI: 68.3–78.7) for infused patients and 1.5 months (0.9–3.0) for patients not proceeding to CAR T. The 12-month PFS was 52.4% (46.3–58.0). In multivariable analysis, advanced stage, male sex, no response to 1 L therapy, high LDH, and high CRP pre-infusion were independently associated with PFS. Grade ≥3 CRS and ICANS rates were 5% and 18%, respectively. Outcomes in patients aged ≥70 years were similar to the younger population. In this large UK real-world cohort of 2 L axi-cel in LBCL, we demonstrate efficacy and toxicity outcomes comparable to the pivotal ZUMA-7 trial, despite 42% patients requiring urgent holding therapy. Outcomes were favorable in patients aged ≥70 years, supporting the use of 2 L CAR T in older fit patients.

The clinical and biological significance of clonal hematopoiesis (CH) has not been investigated in the myeloid compartment of chronic lymphocytic leukemia (CLL). By studying 488 newly diagnosed CLL through CAPP-seq using a 28-gene panel on granulocyte genomic DNA (gDNA), CH occurred in 231 (47.3%) patients. Cell sorting of cases that never developed Richter transformation (RT) confirmed that CH mutations, including CH-related TP53 mutations, were restricted to the myelomonocytic compartment and absent in CLL cells, as also documented by single-cell DNA sequencing. CH associated with shorter overall survival (OS) (hazard ratio [HR] 1.36, 95% CI 1.04–1.77, P = 0.023); specifically, TET2 mutations independently predicted inferior OS (HR 1.62, 95% CI 1.15–2.28, P = 0.01) after adjusting for age and for CLL-related prognostic biomarkers, namely IGHV and TP53 status. Regarding therapy-related toxicities, CH correlated with a higher incidence of Grade ≥ 3 neutropenia (P = 0.004) after venetoclax-based regimens. Sequential samples (n = 57) analysis showed that Bruton tyrosine kinase (BTK) and BCL2 inhibitors do not induce CH expansion, which was instead driven by chemotherapy. CH is significantly associated with a higher risk of second hematological malignancies only in chemo-exposed patients. Single-cell RNA sequencing of seven CH+ and six CH− CLL revealed that the T-cell compartment of CH+ patients exhibits a less exhausted phenotype, documented by lower expression of TOX, the master regulator of T-cell exhaustion, and a higher pro-inflammatory profile. CH also influenced RT, since CH ASXL1 mutations independently associated with higher RT risk (HR 11.19, 95% CI 4.09–30.62, P < 0.001). Overall, CH in CLL impacts survival, therapeutic toxicity, and transformation risk while also influencing the T-cell immune compartment.