HemaSphere最新文献

Hairy-cell leukemia (HCL) is a rare, chronic mature B-cell neoplasm, usually presenting with cytopenias and splenomegaly at a median age of 55–60 years with a marked male predominance (male-to-female ratio ~ 4:1).^{1, 2} Standard front-line chemotherapy with purine analogs (PNAs; cladribine or pentostatin) produces durable complete remissions (CRs) in ~80%–85% of cases and a median relapse-free survival > 10 years, yet up to 58% of patients eventually relapse and become progressively less sensitive to these myelotoxic and immune-suppressive drugs.^{1, 3-5}

Discovery of the activating BRAF-V600E kinase mutation as the founding genetic lesion in >95% of HCL cases,⁶ and of other genetic lesions of BRAF or MAP2K1 in the rare cases negative for BRAF-V600E,^{7, 8} provides both a useful diagnostic marker and a therapeutic target tractable with oral BRAF or MAP2K1 inhibitors.^{7, 9-19} In particular, clinical trials of vemurafenib or dabrafenib treatment for a short and fixed duration in HCL relapsed after, or refractory to, PNAs (R/R-HCL) produced ~90% overall response and ~35% CR rates.^{11, 17, 18, 10} However, all CRs were positive for minimal residual disease (MRD), and relapse of cytopenias usually occurred relatively early (median ≤ 1.5 years) after treatment cessation.

A subsequent academic single-center Phase 2 trial (HCL-PG03) on 30R/R-HCL patients with a median of 3 prior therapies tested vemurafenib (960 mg b.i.d. for a total of 8 weeks, with a 2-week interval of drug holiday after the first 4 weeks) in combination with rituximab/MabThera (a monoclonal antibody against CD20, which is highly expressed by HCL) given intravenously for eight doses (375 mg/mq every 2 weeks; four doses concomitant to vemurafenib and four sequential). Such a very short chemotherapy-free regimen led to dramatically improved results: 87% CR rate, 60% MRD-negativity rate, and a progression-free survival (PFS) of 78% at a median follow-up of 37 months, with relatively limited and manageable toxicities.¹⁸

Here, to validate the HCL-PG03 single-center trial results in the real world of routine clinical care, we performed a multicenter retrospective study (HCL-PG03R) on 54 patients with BRAF-V600E + HCL (R/R, n = 52; newly diagnosed, n = 2) who were homogenously treated, at 22 Italian centers between June 2019 and April 2025, with 8 continuous weeks of vemurafenib (960 mg b.i.d.) plus four concomitant and four sequential doses of rituximab (mostly biosimilar: n = 50/54 patients, 93%; 375 mg/m² intravenously every 2 weeks), with follow-up until June 2025.

Patients (Table 1 and Table S1) had a median of two prior treatments (range 0–11), including cladribine in 47/54 (87%) of cases, pentostatin in 17/54 (31%), interferon in 15/28 (28%), rituximab in 16/54 (30%)

Immune surveillance is increasingly recognized as a key determinant of cancer treatment outcomes. However, the impact of Human Leukocyte Antigen (HLA) diversity in chronic myeloid leukemia (CML) remains poorly understood and has been scarcely investigated. We retrospectively analyzed 367 CML patients with high-resolution HLA typing to investigate the impact of HLA allele distribution and HLA evolutionary divergence (HED) on disease susceptibility, molecular response, and treatment-free remission (TFR). Compared to 2832 healthy donors, CML patients exhibited significantly lower HED scores for all class I loci (A, B, C) and HLA-DQB1 (FDR < 0.001), suggesting a narrower immunopeptidome repertoire at diagnosis. Specific alleles, such as HLA-A*30:01 (OR [95% CI] = 2.08 [1.26–3.25]) and B*14:02 (OR = 1.90 [1.26–2.79]), were associated with increased CML risk (FDR < 0.01). Among 289 patients with clinical follow-up, HLA-DQB1*06:04 (aHR [95% CI] = 3.71 [1.57–8.77]) and DRB1*13:02 (aHR = 3.95 [1.77–8.81]) were associated with faster MR4 achievement in imatinib-treated patients (FDR < 0.01), while B*44:02 (aHR = 4.83 [1.62–14.41]) predicted favorable response to dasatinib (FDR < 0.05). In the TFR cohort (n = 105), alleles A*26:01 (aHR = 3.47 [1.44–8.38]), A32:01 (aHR = 3.28 [1.52–7.09], FDR < 0.05), and B18:01 (aHR = 12.96 [3.59–46.77], FDR < 0.001) were significantly associated with increased relapse risk. Conversely, a higher HED score for HLA-C was associated with improved TFR in dasatinib-treated patients (P = 0.0067). These findings suggest that HLA genotype and class-specific HED may influence CML susceptibility and outcomes and could inform TKI selection and discontinuation strategies.

Hemoglobinopathies, such as sickle cell disease and thalassemias, impose a substantial global burden, particularly in endemic regions. Current diagnostic methods, such as high-performance liquid chromatography (HPLC), capillary electrophoresis, and genetic testing, can be time-consuming, expensive, or limited in detecting all variants. This study introduces a novel diagnostic framework that combines high-throughput proteomics with machine learning to address these challenges. We processed red blood cells, whole blood, and plasma samples from 82 individuals (development cohort) and 45 individuals (validation cohort) with structural hemoglobin variants (hemoglobin S, hemoglobin C, hemoglobin D, and hemoglobin E) or β-thalassemia trait, as confirmed by standard clinical testing. Tryptic peptides were analyzed using data-independent acquisition mass spectrometry, and random forest classifiers were trained to identify structural variants or β-thalassemia trait. Model performance was evaluated across 100 Monte Carlo cross-validations. For structural variants, the classifier achieved an area under the receiver-operating characteristic curve (AUC) of 1.000 and 99.9% prediction accuracy in the validation cohort, when comparing our proteomics-based diagnostics to standard testing with HPLC and Sanger sequencing (gold standard). For β-thalassemia trait, the mean AUC was 1.000, and the prediction accuracy was 96.9% in the validation cohort, and a single peptide alone yielded 92% accuracy in a simple decision tree. This high-throughput proteomics approach offers a rapid, scalable, and potentially cost-effective alternative to existing diagnostic workflows, requiring minimal sample preparation while reducing manual interpretation. By combining peptide-level data with machine learning, it enables precise classification of hemoglobinopathies and demonstrates a compelling path for routine clinical evaluation of hereditary anemias.

Relapse following CD19-targeting chimeric antigen receptor T-cell therapy (CD19-CAR) remains a major barrier to long-term cure in relapsed/refractory B-cell acute lymphoblastic leukemia, with nearly 50% of patients relapsing within 6 months. Early B-cell recovery (BCR), as detected by the re-emergence of CD19-positive cells, has been strongly associated with relapse risk and serves as a surrogate marker for loss of CAR T-cell persistence. However, clinical use of BCR is hindered by variability in monitoring practices, including inconsistent definitions, timing, and measurement across institutions. To address this gap, we convened an international working group of pediatric cellular therapy experts to establish a consensus definition for BCR. Our collaborative effort outlines standardized criteria for BCR assessment aimed at improving comparability across studies and guiding post-CAR T-cell surveillance strategies.

Stamatopoulos K, Pavlova S, Al-Sawaf O, et al. Realizing precision medicine in chronic lymphocytic leukemia: remaining challenges and potential opportunities. HemaSphere. 2024;8(7):e113. doi:10.1002/hem3.113

A funder was incorrectly acknowledged in the original article. In the funding section, the sentence ‘…by the Italian Ministry of Health, grant PNRR-MAD-2022-12376441 (Paolo Ghia) “Leukemic cell and microenvironment interactions as the culprit of chronicity in CLL” and grant PNRR-MAD-2022-12375673 (Gianluca Gaidano) (Next Generation EU, M6/C2_CALL2022)…’ should have read ‘…by the European Union—Next Generation EU—NRRP M6C2—Investment 2.1 Enhancement and strengthening of biomedical research in the NHS—grant PNRR-MAD-2022-12376441 (Paolo Ghia) cup master C43C22001280007 and grant PNRR-MAD-2022-12375673 (Gianluca Gaidano) cup master J53C22004080001….’

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

Infant acute myeloid leukemia (AML), particularly in those under 3 years of age, presents poor prognostic outcomes and distinct biological characteristics that require age-specific risk assessment. This study, utilizing data from four pediatric AML (pAML) trials conducted by the Children's Oncology Group, aimed to develop a simple RNA expression-based prognostic model to refine risk stratification for infant AML. Expression data from 213 infant AML patients were analyzed using machine-learning algorithms to develop the infant-prognostic-score (IPSscore), or IPSgroup when categorized. To validate the stability of the model, internal validation was conducted on a set of 127 cases, and external validation was performed using a separate set of 63 patients from a different ethnic background. Furthermore, we compared its prognostic prediction capability with that of other AML models and explored its potential clinical decision-making value for infant AML patients. The IPSgroup independently and specifically predicted outcomes in infant AML, outperforming several previously published RNA expression-based models. Infant patients categorized into the high-risk group based on IPSgroup may benefit from hematopoietic stem cell transplantation (HSCT), while those in the low-risk group are not suitable for HSCT. Additionally, when combined with the current pAML stratification system used in clinical trials, the IPSgroup enabled re-stratification of 43% of infant AML patients into more accurate risk groups, highlighting the advantage of incorporating gene expression analysis into clinical decision-making. Infant AML demonstrates significant heterogeneity at clinical, molecular, and prognostic levels. The newly proposed model surpasses existing AML stratifications, offering a valuable tool for clinical decision-making and treatment strategies.

Waldenström's macroglobulinemia (WM) is a rare, indolent lymphoproliferative disorder, genetically characterized by the presence of the L265P mutation in the MYD88 gene in almost all cases, resulting in constitutive activation of NF-kappa B (NF-κB). Despite its slow progression, WM remains incurable due to the lack of specific treatments. The efficacy of therapies capable of reactivating the antitumor response of T-cells is well documented in various solid tumors. Apart from Hodgkin's lymphoma, these therapies have very mixed effects on B-cell lymphomas, especially those with NF-κB activation. Here, we used the published Myd88^L252P mouse model, which develops a WM-like disease close to human WM. By focusing on T-cell exhaustion and regulatory T-cell expansion, we show how T-cells located near WM-like tumors in mice are disrupted, while Myd88^L252P tumor B-cells adopt an immunoregulatory phenotype evoking regulatory B-cells. We also demonstrate, for the first time in the context of WM, the dual effect of Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK), able to decrease B-cell activation and expansion and to partially reverse T-cell depletion in Myd88^L252P mice. With Ibrutinib as an example, this work provides new perspectives for the development of therapeutic combinations targeting tumor B-cells while reactivating antitumor T-cells.

Children with relapsed acute leukemia have a poor prognosis; current relapse treatments are toxic, and novel treatments are needed. The anti-CD38 antibody isatuximab is approved for relapsed-refractory multiple myeloma in adults. We present results of the ISAKIDS study (NCT03860844) investigating isatuximab in children with relapsed-refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). This Phase 2, single-arm, multicenter, open-label study enrolled children aged 28 days to <18 years. Patients received isatuximab 20 mg/kg induction on Day 1, then weekly for 5 weeks (ALL) or 3 weeks (AML). Standard salvage chemotherapy was added on Day 8. Participants showing possible response could receive consolidation with every-other-week isatuximab (two doses) plus chemotherapy (T-ALL, B-ALL) or optional second induction (AML). The primary endpoint was the complete response (CR) rate (proportion with CR or CR with incomplete peripheral recovery [CRi]). CR/CRi was observed for 32/59 (54%) evaluable patients (B-ALL, 13/25 [52%]; T-ALL, 5/11 [45%]; and AML, 14/23 [61%]). Secondary endpoints included minimal residual disease (MRD) status and safety. Based on local and central analysis, 56% (18/32) of CR/CRi patients reached MRD negativity using 10⁻⁴ sensitivity threshold for ALL and 10⁻³ sensitivity threshold for AML. One event of fatal cytokine release syndrome was reported in a patient with a high baseline white blood cell count, leading to trial adaptation. The toxicity of isatuximab with chemotherapy was otherwise manageable. Despite initial evidence of efficacy of isatuximab combined with intensive chemotherapy, CR/CRi rates did not meet stringent prespecified criteria to proceed to ISAKIDS Stage 2 (≥60% [T-ALL] and ≥70% [B-ALL and AML]).

Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy characterized by the clonal proliferation of undifferentiated myeloid precursors in the bone marrow. Although standard induction regimens based on anthracyclines often achieve initial remission, up to 25% of patients exhibit primary refractory disease and nearly 50% relapse, underscoring the urgent need to overcome therapy resistance. Aldehyde dehydrogenase 1 (ALDH1) contributes to leukemic cell survival by maintaining stemness, proliferation, and chemoresistance through aldehyde detoxification and retinoic acid synthesis. Here, we identify two enhancer elements, ALDH1A1-E3 and ALDH1A2-E1-A, that mediate transcriptional activation of ALDH1A1 and ALDH1A2 in response to the anthracycline daunorubicin. These enhancers are regulated by STAT3 and FOS/JUN transcription factors, which cooperatively link drug response to ALDH1 induction. Functional validation in AML cell lines, primary samples, and xenograft models shows that ALDH1 upregulation is part of an adaptive stress response and may contribute to reduced anthracycline sensitivity. Co-treatment with the ALDH1A1/1A2 inhibitor DIMATE synergistically enhances daunorubicin efficacy across in vitro and in vivo resistant models. Consistently, high ALDH1 expression is associated with adverse genetic risk, prior anthracycline exposure, and inferior OS, particularly in relapsed/refractory AML. These findings uncover a novel enhancer-mediated mechanism of ALDH1 induction in the context of anthracycline exposure and support the rationale for future clinical trials combining standard treatments with ALDH1-targeted approaches, including the clinical-stage inhibitor DIMATE.