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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.

Venetoclax has been combined with intensive chemotherapy regimens in the treatment of acute myeloid leukemia (AML). We aimed to investigate the safety and efficacy of venetoclax combined with full-dose CPX-351 (CPX + VEN) in newly diagnosed (ND) AML. Seventeen patients with a median age of 59 years (range, 43–69) were treated; 71% had secondary AML, 47% had prior hypomethylating agent (HMA) exposure, 59% had myelodysplastic syndrome (MDS)-related (MR) mutations, 47% had complex karyotype, and 29% were TP53 mutated. The overall response rate (ORR) was 82% (95% CI, 57–96) with a composite complete remission rate (CRc) of 71% (95% CI, 50–93). Patients with MR mutations had an ORR of 100% (95% CI, 69–100), including a CRc of 90% (95% CI, 55–100). Patients with prior HMA exposure had a CRc of 63% (95% CI, 24–91). With a median follow-up time of 11.8 months, the median overall survival (OS) was 12.8 months (95% CI, 5–NE) with a 2-year OS of 34% (95% CI, 10–61). Patients with MR mutations had a median OS of 17.9 months versus 5.1 months in patients without MR mutations (P = 0.039). Twelve (86%) of 14 responding patients proceeded to stem cell transplant (SCT); the median recurrence-free survival and OS landmarked from date of SCT were 14.7 months (95% CI, 1–32) and 14.7 months (95% CI, 4–25), respectively. The 4-week mortality was 0% and the 8-week mortality was 17%. The most common adverse events were related to myelosuppression. CPX + VEN resulted in high remission rates and enabled progression to allogenic SCT for the majority of a highly adverse group of ND AML patients.

Anti-CD19 CAR NK cells may provide a promising non-HLA-restricted immune cell product and have been clinically studied primarily on low-grade B-cell lymphoma patients. We used retroviral gene transfer to generate aCD19 CAR NK cells from the peripheral blood of healthy volunteers. We evaluated their efficacy in B-lineage acute lymphoblastic leukemia (BCP-ALL) using patient-derived xenograft (PDX) cells in vitro and in vivo. aCD19 CAR NK cells showed potent specific cytotoxicity against eleven BCP-ALL PDX models in vitro. When used as monotherapy in vivo, they provided a survival benefit, albeit complete remissions were not achieved. Due to the low accumulation of aCD19 CAR NK cells in the bone marrow, we used targeted pharmacotherapy based on venetoclax, dexamethasone, and dasatinib to induce remission in BCR-ABL-positive ALL and combined it with aCD19 NK cell therapy for consolidation. Overlapping therapy enhanced aCD19 CAR NK cell cytotoxicity in vitro and significantly prolonged survival in two high-risk BCP-ALL PDX models with individual long-term remissions. Relapse cells showed no signs of therapy-induced evolution as CD19 expression, sensitivity to venetoclax, and aCD19 CAR cell cytotoxicity remained unchanged. These data demonstrate the potential of aCD19 CAR NK cells as a component of combinatorial therapy for BCP-ALL, which should be further evaluated in clinical trials.