Blood advances最新文献

Malignancy is a risk factor for splanchnic vein thrombosis (SpVT). Data on the natural history of cancer-associated SpVT are limited. This was a single-center retrospective cohort study of 581 adult patients with cancer and SpVT. We aimed to characterize the impact of thrombocytopenia on major bleeding and progression or recurrence of SpVT within one year of initial cancer-associated SpVT diagnosis. Baseline thrombocytopenia (platelet < 100,000/uL within 15 days of SpVT diagnosis) was present in 39.5% of patients. A total of 39.2% of patients received therapeutic anticoagulation within two weeks of SpVT diagnosis. The cumulative once-year incidence of major bleeding was 10.7% (95% CI: 8.2-13.2), and for SpVT recurrence/progression was 16.2% (95% CI: 13.2-19.2). In multivariable regression analysis, therapeutic anticoagulation was associated with increased major bleeding (aRR: 1.74, 95% CI: 1.08-2.81) and decreased progression/recurrence of SpVT (aRR: 0.55, 95% CI: 0.35-0.86). Baseline thrombocytopenia was not independently associated with either major bleeding (aRR: 0.76, 95% CI: 0.43-1.34) or progression/recurrence of SpVT (aRR: 1.14, 95% CI: 0.73-1.78). A secondary analysis using inverse probability of treatment weighting with propensity scores for baseline thrombocytopenia corroborated that patients with thrombocytopenia did not have increased bleeding risk (aHR: 0.81, 95% CI: 0.48-1.39). Multivariable analysis treating platelets as a time varying covariate also did not reveal an association with major bleeding (aHR: 0.89, 95% CI: 0.55-1.45). Bleeding and thrombosis progression were frequent in patients with cancer-associated SpVT. Anticoagulation was associated with increased major bleeding and decreased thrombotic progression; thrombocytopenia did not impact outcomes.

Gene addition and editing strategies for transfusion-dependent β-thalassemia have gained momentum as potentially curative treatment options, with studies showcasing their efficacy and safety. We report the first real-world application of betibeglogene autotemcel (beti-cel; ZYNTEGLO™) during its period of active license in Europe from January 2020 to March 2022 for patients aged ≥ 12 years without a β0/β0 genotype and without a human leukocyte antigen (HLA)-matched sibling donor, before beti-cel marketing authorization was withdrawn by its holder due to non-safety reasons. Among 15 screened patients, 4 opted out for fertility and safety concerns, 2 were excluded because of marked hepatic siderosis, and 1 had apheresis collection failure. Eight patients received beti-cel post busulfan myeloablative conditioning, all achieving transfusion independence within 8 to 59 days with posttreatment hemoglobin levels ranging from 11.3 to 19.3 g/dL. No deaths occurred, but acute toxicity mirrored busulfan's known effects. Posttreatment platelet management faced challenges due to HLA-antibodies in 3 patients. Monitoring up to Month 24 revealed pituitary-gonadal endocrine dysfunction in all 3 female and in 2 of 5 male patients. Additionally, we observed unexpected posttreatment sequelae: 1 patient developed polycythemia that could not be explained by known genetic or acquired mechanisms, 1 patient developed posttreatment depression and anxiety prohibiting her from returning to work, and 1 patient developed fatigue severely compromising both quality of life and work capacity. This real-world experience corroborates beti-cel's efficacy and safety and provides information on adverse events observed during real-world use of the therapy.

Over the past decade, T-cell directed therapies, including chimeric antigen receptor T-cell (CAR-T) and bispecific T-cell engager (BTE) therapy have reshaped the treatment of an expanding number of hematologic malignancies, while tumor infiltrating lymphocytes (TILs), a recently approved cellular therapy, targets solid tumor malignancies. Emerging data suggests that these therapies may be associated with a high incidence of serious cardiotoxicities, including atrial fibrillation, heart failure, ventricular arrhythmias, and other cardiovascular toxicities. The development of these events is a major limitation to long-term survival following these treatments. This review examines the current state of evidence, including reported incidence rates, risk factors, mechanisms, and management strategies of cardiovascular toxicities following treatment with these novel therapies. We specifically focus on CAR-T, BTE, and their relation to arrhythmias, heart failure, myocarditis, bleeding, and other major cardiovascular events. Beyond the relationship between cytokine release syndrome and cardiotoxicity, we describe other potential mechanisms and highlight key unanswered questions and future directions of research.

We analyzed access barriers to anti-CD19+ chimeric antigen receptor T-cells (CART) for non-Hodgkin lymphoma (NHL) within a community-based transplant and cell therapy network registry. 357 intended recipients of FDA-approved anti-CD19+ CART were identified in the study period (2018 to 2022). Results showed that the median age at referral was 61 years, referral year was 2018 (4%), 2019 (14%), 2020 (18%), 2021 (26%), and 2022 (38%). Diagnoses were diffuse large B-cell (69%), follicular (13%), follicular/large (7%), mantle cell (4%), or other (7%). CART products infused were Axi-cel (62%), Tisa-cel (16%), Brexu-cel (13%) and Liso-cel (9%). 182 patients were infused with CART. The median durations between referral to consultation, consultation to apheresis, and collection to infusion were 11, 107, and 32 days, respectively. The median duration from consultation to CART infusion declined steadily from 207 days in 2019 to 108 days in 2022. [P <0.0001] 124 patients (41%) did not receive CART mostly for disease progression (34%) or poor health (15%). Multivariable logistic regression showed no significant differences in demographic, financial, or social determinants compared to those receiving CART. Notably, the proportion of ineligible patients declined from 53% in 2018-2020 to 34% by 2021-2022 [P=0.001]. In conclusion, 41% of community patients were unable to access timely CART therapy for NHL, mostly related to attrition from disease-related causes while overall time to infusion exceeded four months. Time to infusion as well as the proportion receiving CART improved over time. Reducing time to apheresis, early referral, and careful attention to salvage/bridging strategies are necessary.

Preclinical data suggest a rationale for combining CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine, with venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor. This phase 1b study evaluated lower-intensity CPX-351 combined with venetoclax in adults with acute myeloid leukemia (AML) considered unfit/ineligible for intensive chemotherapy. In a dose-exploration phase using a 3+3 design, patients received stepwise dosing of CPX‑351 intravenously on days 1 and 3 plus venetoclax 400 mg orally on days 2-21 per cycle to determine the recommended phase 2 dose (RP2D) for this combination. During the expansion phase, additional patients received CPX-351 plus venetoclax at the identified RP2D. The primary endpoints were the RP2D and safety of CPX‑351 combined with venetoclax. Secondary endpoints included preliminary efficacy and pharmacokinetics. Overall, 35 patients were enrolled in the study. A RP2D of CPX-351 30 units/m2 (daunorubicin 13.2 mg/m2 and cytarabine 30 mg/m2) plus venetoclax 400 mg was established. The safety profile of the combination was consistent with the known safety profiles of CPX-351 and venetoclax. Complete remission (CR)/CR with incomplete hematologic recovery (CRi) was achieved by 17/35 (49%) patients, all after cycle 1; of these, 14 were negative for measurable residual disease. CR was achieved by 1/8 (13%) patients with a mutation in TP53, and CR/CRi was achieved by 15/26 (58%) patients with wild-type TP53. This study highlights that lower-intensity therapy of CPX-351 plus venetoclax as induction therapy provides a well-tolerated treatment option in adults with AML deemed unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT04038437.

Patients with hemophilia A can develop anti-factor antibodies to factor VIII. The incidence is ~30% and such patients suffer worse morbidity and mortality. The only proven method to eradicate these inhibitors is via immune tolerance induction therapy which consists of infusing factor VIII concentrates at a regular intervals. This approach is effective ~65% of the time leaving at least a third of patients who develop inhibitors with this lifelong problem. Although emicizumab has greatly improved the quality of life of inhibitor patients, eradicating the inhibitor remains an important treatment goal. Animal models have shown the potential for gene therapy to induce tolerance. A recent abstract describing a study in humans demonstrated the potential for successful tolerance induction. This article will describe the rationale for utilizing gene therapy to induce tolerance and provide this author's viewpoint on the importance and possible historic significance of attempting to eradicate inhibitors with this approach.

Despite the use of midostaurin (MIDO) with intensive chemotherapy (ICT) as the front-line treatment for FLT3-mutated acute myeloid leukemia (AML), complete remission rates are close to 60-70%, and relapses occur in over 40% of cases. Here we studied the molecular mechanisms underlying refractory/relapsed (R/R) situation in FLT3-mutated AML patients. We conducted a retrospective and multicenter study involving 150 patients with R/R AML harboring FLT3-ITD (n=130) and/or FLT3-TKD (n=26) at diagnosis assessed by standard methods. Patients were treated in front-line with ICT + MIDO (n=54) or ICT alone (n=96) according to the diagnosis date and label of MIDO. The evolution of FLT3 clones and co-mutations was analyzed in paired diagnosis-R/R samples by targeted high-throughput sequencing. Using a dedicated algorithm for FLT3-ITD detection, 189 FLT3-ITD microclones (allelic ratio [AR] < 0.05) and 225 macroclones (AR ≥ 0.05) were detected at both time points. At R/R disease, the rate of FLT3-ITD persistence was lower in patients treated with ICT + MIDO compared with patients not receiving MIDO (68% vs. 87.5%, P=0.011). In patients receiving ICT + MIDO, detection of multiple FLT3-ITD clones (referred to as "clonal interference") was associated with a higher FLT3-ITD persistence rate at R/R disease (multiple clones: 88% vs. single clones: 57%, P=0.049). Considering both treatment groups, if only 24% of FLT3-ITD microclones detected at diagnosis were retained at relapse, 43% of them became macroclones. Together, these results identify parameters influencing the fitness of FLT3-ITD clones and highlight the importance of using sensitive techniques for FLT3--ITD screening in clinical practice.

Mutations commonly associated with acute myeloid leukemia (AML), such as CEBPA, FLT3, IDH1/2 and NPM1 are rarely found in chronic myelomonocytic leukemia (CMML) and their prognostic significance in CMML has not been clearly identified. In 127 CMML patients, we have retrospectively analyzed next-generation sequencing and PCR data from analyses of bone marrow samples performed at diagnosis of CMML. Seven patients harbored CEBPA mutations, eight FLT3 mutations, 12 IDH1 mutations, 26 IDH2 mutations and 11 NPM1 mutations. CMML patients harboring CEBPA, FLT3, and/or NPM1 mutations (mutCFN)were more frequently associated with the myeloproliferative subtype (MP-CMML) , a high prevalence of severe cytopenia, and elevated blast counts. Regardless of their CPSS-Mol classification, mutCFN CMML patients had a poor prognosis, and the multivariate analysis identified mutCFN as an independent marker of overall survival. The genetic profile of these mutCFN CMML patients closely resembled that of AML, with higher-risk clinical characteristics. Our findings lead us to suggest including the assessment of these mutations in CMML prognostic models and treating these patients with AML-type therapies, including intensive chemotherapy and allogeneic stem cell transplantation, whenever feasible, and consider certain targeted therapies approved for use in AML.

Abstract: Platelet factor XIII-A (FXIII-A) is a major cytoplasmic protein (∼3% of total), representing ∼50% of total circulating FXIII. However, mobilization of FXIII-A during platelet activation is not well defined. To determine mechanisms mediating the retention vs release of platelet FXIII-A, platelets from healthy humans and mice (F13a1-/-, Fga-/-, Plg-/-, Stim1fl/flPf4-Cre, and respective controls) were stimulated with thrombin, convulxin plus thrombin, or calcium ionophore (A23187), in the absence or presence of inhibitors of transglutaminase activity, messenger RNA (mRNA) translation, microtubule rearrangement, calpain, and Rho GTPase. Platelet releasates and pellets were separated by (ultra)centrifugation. FXIII-A was detected by immunoblotting and immunofluorescence microscopy. Even after strong dual agonist (convulxin plus thrombin) stimulation of human platelets, >80% platelet FXIII-A remained associated with the platelet pellet. In contrast, essentially all tissue factor pathway inhibitor, another cytoplasmic protein in platelets, was released to the supernatant. Pellet-associated FXIII-A was not due to de novo synthesis via platelet F13A1 mRNA. The proportion of platelet FXIII-A retained by vs released from activated platelets was partly dependent on STIM1 signaling, microtubule rearrangement, calpain, and RhoA activation but did not depend on the presence of fibrinogen or plasminogen. Immunofluorescence microscopy confirmed the presence of considerable FXIII-A within the activated platelets. Although released FXIII-A was cleaved to FXIII-A∗ and could be degraded by plasmin, platelet-associated FXIII-A remained uncleaved. Retention of substantial platelet-derived FXIII-A by activated platelets and its reduced susceptibility to thrombin- and plasmin-mediated proteolysis suggest platelet FXIII-A is a protected pool with biological role(s) that differs from plasma FXIII.