HemaSphere最新文献

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.

Overall survival (OS) is widely recognized as the gold standard endpoint in oncology clinical trials, but it can be difficult to assess OS in chronic lymphocytic leukemia (CLL) due to the slow progression of the disease, resulting in extended patient survival following diagnosis.^{1, 2} Additionally, CLL primarily affects older adults, with a mean age at diagnosis of 70 years,³ further complicating survival comparisons.²

Treatment for CLL has evolved significantly in recent years, shifting from traditional chemotherapy to targeted therapies, subsequently improving life expectancy despite the disease remaining incurable.⁴ Consequently, the combination of prolonged survival and potential long-term disease control through multiple lines of therapy can make it challenging to attribute OS benefits to a specific intervention.^{1, 2}

Ibrutinib, a once-daily Bruton's tyrosine kinase inhibitor (BTKi), has played a pivotal role in this evolution of CLL treatment in either single-agent⁵ or combination therapies,^{6, 7} and more recently, in fixed-duration (time-limited) treatment.^{8, 9} Long-term follow-up data from the phase 3 RESONATE-2 study demonstrated significant improvement in progression-free survival (PFS) and sustained OS benefit with single-agent ibrutinib in older patients compared with chlorambucil.^{10, 11} Additionally, the ECOG1912 study, which assessed ibrutinib-rituximab in younger patients, demonstrated superior PFS and OS compared with fludarabine, cyclophosphamide, and rituximab.¹² The iLLUMINATE study evaluated ibrutinib-obinutuzumab in older or comorbid patients and showed sustained PFS benefit compared with chlorambucil-obinutuzumab.¹³ Long-term follow-up from the fixed-duration cohort of the phase 2 CAPTIVATE trial, which focused on patients aged 18–70 years,⁹ showed clinically meaningful PFS with ibrutinib-venetoclax, including in patients with high-risk genomic features.¹⁴ The phase 3 GLOW study demonstrated the superior efficacy of fixed-duration ibrutinib-venetoclax over chlorambucil-obinutuzumab in older or comorbid patients (≥65 years or 18–64 years with a Cumulative Illness Rating Scale score >6), with the longest reported follow-up for ibrutinib-venetoclax to date.^{8, 15-17}

A recent pooled analysis revealed that patients receiving first-line continuous ibrutinib-based regimens had OS estimates comparable with an age-matched general US population.¹⁸ Here, we extend that analysis by comparing OS estimates in patients with previously untreated CLL treated with either continuous ibrutinib-based or fixed-duration ibrutinib-venetoclax regimens with those of an age-matc

Chimeric-antigen-receptor (CAR) T-cells have rapidly become a cornerstone in the treatment of advanced hematological malignancies,¹ offering transformative outcomes for patients. Since the approval of the first two products in 2017, the number of authorized CAR T-cell therapies has steadily increased, with at least seven now approved worldwide.² This expansion has brought not only clinical progress but also growing complexity in the organizational processes required to ensure the safe and effective delivery of CAR T-cell therapies, including the conduct of post-registration studies captured through the European Society for Blood and Marrow Transplantation (EBMT)'s CAR T-cell registry.^{3, 4}

A growing challenge is not only the increasing number of new CAR T-cell products entering clinical testing^{5, 6} but also the fact that each approved product is tied to a proprietary platform, requiring distinct onboarding protocols, electronic systems, documentation procedures, and post-infusion monitoring requirements. Importantly, many of these demands are shaped by formal regulatory documents. In the United States, these include the Food and Drug Administration (FDA)'s Biologics-License-Application (BLA) letters and Risk-Evaluation-and-Mitigation-Strategies (REMS); in Europe, analogous requirements are outlined in the European Medicines Agency (EMA)'s European-Public-Assessment-Reports (EPARs), Risk-Management-Plans (RMPs), and Annex II of the marketing authorization.^{7, 8} These documents define marketing authorization holder (MAH)-specific obligations related to manufacturing, traceability, pharmacovigilance, and controlled distribution. As a result, MAHs interpret and implement regulatory expectations through their own systems, leading to significant variability in comparable clinical procedures. While the core workflow (patient selection, apheresis, shipment, conditioning, infusion, and follow-up) is broadly consistent, its implementation varies substantially by product. This divergence adds significant operational and administrative burdens to hospitals, particularly those managing multiple CAR T-cell therapies, by diverting time and resources away from direct clinical care. A major contributor to this burden is the increasing number and overlapping tenor of these inspections and audits required for the implementation and ongoing maintenance of CAR T-cell programs, with some centers facing more than nine inspections per year. These include inspections by MAHs, certification/accreditation bodies (e.g., Joint Accreditation Committee [JACIE]/Foundation for the Accreditation of Cellular Therapy [FACT]), national regulatory agencies, and internal onboarding teams with the introduction of each new product.

To better understand how the interpretation and implementation of defined regulatory requirements by MAHs translate into real-

Mantle cell lymphoma (MCL) is a relatively rare B-cell lymphoma subtype, with a higher incidence among males and a median age of 70 years at diagnosis. MCL is characterized by clinically diverse behavior, from indolent disease to extremely aggressive, related to the presence of biological risk factors such as proliferation rate and TP53 mutations. Most often, patients present with disseminated disease, necessitating systemic treatment. Immunochemotherapy has historically been the mainstay of treatment, but recent data indicate that addition of novel agents, especially covalent Bruton tyrosine kinase inhibitors (cBTKi), may substantially improve outcome in younger and older patients, although a curative approach remains to be shown. In elderly patients, the standard of care is still immuno-chemotherapy such as rituximab-bendamustine, although this may be challenged by non-chemotherapeutic options, such as rituximab plus cBTKi. For patients with relapsed or refractory disease, treatment options are developing rapidly, including CAR-T cell therapy, novel BTK targeting agents, BCL2 inhibitors, and T-cell engagers. In this clinical practice guideline, we present current evidence-based recommendations for diagnosis, staging, treatment, and follow-up of MCL.