HemaSphere最新文献

Corticosteroids are commonly used to manage cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) following chimeric antigen receptor (CAR) T-cell therapy, and yet, their dose-specific impact on outcomes remains uncertain. We retrospectively evaluated 276 adults with large B-cell lymphoma (LBCL) treated with CD19-directed CAR-T therapy (axi-cel, tisa-cel, or liso-cel) between 2016 and 2023 at a single institution. Cumulative corticosteroid dose was defined as the total dose administered within 21 days of infusion. Corticosteroids were administered to 105 patients (38%), initiated at a median of 5 days post-infusion (interquartile range [IQR] 3–7) for CRS (38%), ICANS (15%), or both (47%). Use was more frequent with axi-cel (P < 0.001), although the cumulative dose and duration were similar across products. To assess the impact of corticosteroid exposure, we carried out a 21-day landmark analysis. Corticosteroid exposure, modeled as a time-dependent covariate, was not significantly associated with infection risk, non-relapse mortality, or inferior overall survival (OS) or progression-free survival (PFS). However, in a landmark analysis, patients receiving above-median cumulative corticosteroid doses had a significantly higher risk of infection compared to those receiving below-median corticosteroid doses or no corticosteroids (P = 0.042). In a landmark multivariable analysis, corticosteroid cumulative dose was associated with increased late hematologic toxicity (adjusted hazard ratio [HR] 1.02, 95% CI 1.02–1.03). Finally, in a sensitivity analysis excluding patients with Grade ≥4 CRS/ICANS, corticosteroid cumulative dose remained unassociated with OS or relapse, but was linked to shorter PFS (adjusted HR 1.04, 95% CI 1.01–1.06). These findings support the safe yet judicious use of corticosteroids to manage CAR-T toxicities in LBCL.

Advancements in the rapidity, cost efficacy, and sensitivity of next-generation sequencing (NGS) have facilitated molecular risk stratification and precision medicine-based treatment for pediatric leukemia. The benefit of uniform cytomolecular analyses for clinical trial risk assignment is clear. However, the clinical impact of comprehensive NGS for pediatric leukemias at an institutional level is not well described. We report the genomic spectrum of one of the largest cohorts of pediatric and adolescent/young adult (AYA) acute leukemias examined to date (n = 1442) via institutional NGS testing from our large tertiary care center. We evaluated the clinical utility of genomic results for informing prognosis and treatment. We identified high utility of the comprehensive DNA-based mutational panel and RNA-fusion panel, which detected leukemia-associated variants in 99% of specimens. We observed 65% of B-cell acute lymphoblastic leukemia cases and 69% of patients with acute myeloid leukemia harbored a prognostic molecular alteration. In total, 325 of 1134 patients (29%) harbored potentially targetable molecular biomarkers, and 23% of cases with follow-up data received precision medicine-based therapy. Paired diagnostic and relapsed leukemia samples aided in differentiation between treatment-related leukemia versus lineage drift/switch. These findings demonstrate the broad utility of comprehensive molecular sequencing for pediatric/AYA leukemia at an institutional level to improve outcomes.

The treatment landscape of heavily pretreated relapsed/refractory MM has changed considerably in recent years with the introduction of novel BCMA- and GPRC5D-directed immunotherapies, including CAR T-cell therapy, bispecific antibodies (BsAbs), and antibody-drug conjugates (ADCs). Treatment selection and sequencing become increasingly complex with the broad range of therapeutic options. In this review, the European Myeloma Network provides recommendations on how to best incorporate these novel therapies into the present treatment landscape using current evidence. The optimal treatment sequence depends on various patient- and tumor-related features, but also reimbursement and availability issues. In addition, mechanisms underlying relapse (e.g., antigen loss, reduced T-cell fitness, or outgrowth of T-cell resistant clones) dictate the efficacy of sequential BCMA- or GPRC5D-directed immunotherapy. BCMA-targeting BsAbs and ADCs should preferably be avoided prior to CAR T-cell therapy, as some studies have shown that these agents negatively influence clinical outcomes after CAR T-cell therapy. Therefore, we recommend the selection of CAR T-cell therapy first, and BsAbs and/or belamaf later in the disease course, if patients are eligible for CAR T-cell therapy and in case CAR T-cell therapy is available within a short time frame. However, bridging therapy with GPRC5D-directed BsAbs (initiation after apheresis) can be considered to significantly reduce tumor burden, because this was shown to improve the efficacy of consecutive BCMA-directed CAR T-cell therapy. Sequential treatment with agents targeting the same antigen, but with different modes of action, is feasible, but several studies have demonstrated that target switch is a more effective strategy. In addition, there is increasing evidence indicating that the efficacy of sequential use of BsAbs can be improved by creating a BsAb-free interval.

Overdiagnosis describes situations where ‘people are labelled with or treated for a disease that would never cause them harm’.¹ We believe the current diagnostic paradigm for chronic lymphocytic leukaemia (CLL) constitutes overdiagnosis, imposing a diagnosis which can cause significant distress to patients without benefit. In this article, we begin with the personal experience of one of the authors (Peter Allen), which powerfully depicts the harms of a CLL label. We then consider the historical context of current CLL diagnostic criteria and question their suitability. Finally, we consider other possible approaches to CLL diagnosis, including intentional non-investigation and de-diagnosis.

Peter Johnstone: Conceptualisation; writing—original draft; writing—review and editing; project administration. Peter Allen: Writing—review and editing; writing—original draft. Pinky Jimenez-Agrawal: Writing—review and editing. Samir Agrawal: Writing—review and editing. Stephen P. Hibbs: Conceptualization; writing—original draft; project administration; writing—review and editing.

Pinky Jimenez-Agrawal reports speaker engagements with AstraZeneca, BeOne (formerly BeiGene) and Eli Lilly. Samir Agrawal reports speaker engagements with AbbVie, BeOne (formerly BeiGene) and AstraZeneca.

The remaining authors (P.J., P.A. and S.P.H.) have no relevant conflicts of interest to declare.

S.P.H. is supported by a HARP doctoral research fellowship, funded by the Wellcome Trust (Grant number 223500/Z/21/Z).

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.

The treatment landscape of relapsed and refractory (R/R) diffuse large B-cell lymphoma (DLBCL) has significantly improved with the development of CD19-directed chimeric antigen receptor T-cell therapy (CAR T).^{1, 2} Even so, approximately 50%–60% of patients treated with CAR T will ultimately experience disease progression.³

Tafasitamab (tafa) and loncastuximab tesirine (lonca) both target CD19 and are approved for the treatment of R/R DLBCL. Following the approval of CAR T in the second-line setting,^{4, 5} these agents may be used to treat DLBCL after CAR T failure. Notably, the L-MIND study of tafa with lenalidomide (tafa/len) excluded patients with prior CAR T, while the LOTIS-2 study for lonca enrolled only 13 post–CAR T patients.^{6, 7}

Prior reports, including our own, have shown poor outcomes with CD19-directed therapies following CAR T, though it remains unclear whether this reflects the effects of prior CAR T itself or underlying high-risk disease features.^{8, 9}

We aimed to evaluate the impact of prior CD19-directed therapy on subsequent CD19-based treatment, focusing on the impact of prior CD19 CAR T on tafa/len efficacy. We compared CAR T-exposed versus CAR T-naïve patients receiving tafa/len, and used propensity score matching to address baseline imbalances between CAR-exposed and CAR-naïve cohorts. We also explored CD19 expression patterns and outcomes with other CD19-directed sequences, including lonca and CAR T.

This multicenter, retrospective cohort study included adults (≥18 years) with R/R DLBCL treated with tafa between August 2020 and August 2022 across 11 institutions. Eligible histologies included DLBCL-not otherwise specified (NOS), high-grade B-cell lymphoma (HGBCL), transformed indolent lymphomas, T-cell/histiocyte-rich large B-cell lymphoma, and primary mediastinal B-cell lymphoma. Responses to therapy were evaluated by each site using routine imaging and assessments. CD19 expression was locally assessed by immunohistochemistry or flow cytometry and defined as positive by local center criteria.

We previously reported the overall outcomes of tafa/len.⁸ Subsequently, additional data were collected on the outcomes of other CD19-directed therapies aside from tafa. This study was approved by the institutional review boards of all participating institutions.

Patients were categorized into CAR T-naïve and CAR T-exposed cohorts based on treatment exposure at the time of tafa/len initiation. Patients who had received prior CD19-directed therapy other than CAR T before tafa/len were excluded. Descriptive statistics were reported by cohort. Fisher's exact and Wilcoxon rank-sum tests were used to assess differences by cohort for categorical and continuous variables, respectively.

The primary outcome was progression-free survival (PFS) from tafa initiation

In a recent Editorial in HemaSphere, an important aspect of advanced therapy medicinal products (ATMPs) produced and used in therapy under the hospital exemption (HE) status is raised by Domanovic et al.¹ The European Blood Alliance, together with scientific societies and professional organizations, strongly supports maintaining and strengthening the HE scheme provided that specific criteria are approved by Regulatory Authorities, European and National.

As the authors mark, a working system for monitoring outcomes in patients treated with ATMP/HE is lacking in the EU with public reporting, despite the clinical importance of this therapeutic modality. However, we also note that although important scientific and technological advancements were experienced since the establishment of ARMP Regulation in the European Union,² the scientific community in general is not yet in a position to evaluate the whole results of chimeric antigen receptor T (CAR-T) cell therapies as applied with the commercial products available in the EU. This is mainly due to the lack of any active system gathering cumulative data regarding the short- and long-term outcomes of ATMPs. The data individually kept by each medical center or by marketed CAR-T cell suppliers cannot provide a global insight to this mode of treatment. Besides several parameters involved in evaluating the results (population group applied, disease, age, sex, management history, comorbidities, etc.) before a final argument on the efficacy of this treatment is achieved, the variability of commercial products has also to be accounted for. Different particular products produced by different protocols may also turn to have different therapeutic effects or untoward effects. Therefore, treatment trials with particular commercial products may be non-comparable as far as the outcome is concerned. It is only a cumulative analysis that can permit such a conclusion.

It seems that it is now the proper time for establishing a monitoring system for the outcomes in cases treated with ATMPs/CAR-T cell approved centrally by commercial products or via the HE mode in Europe. The authorization of these products was in principle a “conditional” one; the regulatory authorities and scientists must insist on consistent quality, safety, and efficacy standards.

Kostas Konstantopoulos: Conceptualization; writing—original draft; writing—review and editing.

The author declares no conflicts of interest.

This research received no funding.

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.