Blood最新文献

Myelodysplastic syndromes/neoplasms (MDS) are a widely heterogenous group of myeloid malignancies characterized by morphologic dysplasia, a defective hematopoiesis, and recurrent genetic abnormalities. The original and revised International Prognostic Scoring Systems (IPSS) have been used to risk-stratify patients with MDS to guide treatment strategies. In higher-risk MDS, the therapeutic approach is geared toward delaying leukemic transformation and prolonging survival. For over a decade, the hypomethylating agents azacitidine and decitabine have been the standard of care and, when feasible, an allogeneic hematopoietic stem cell transplantation (AHSCT) should be considered. However, the IPSS scoring systems solely rely on clinical, morphological, and cytogenetic features and do not account for somatic mutations present in over 80% of cases. These genetic abnormalities have been shown to play a crucial role in prognostication, prompting the development of molecular IPSS, and the integration of genomic features into MDS classification systems in recent years. In this review, we delineate our approach to higher-risk MDS in the context of updated classifications and the latest prognostication tools. We employ illustrative clinical cases to support our discussion and share insights from recent clinical trials, highlighting lessons learned.

Sclerosis is a highly morbid manifestation of chronic GVHD (cGVHD), associated with distressing symptoms and significant long-term disability. A patient-reported outcome measure (PRO) for cGVHD-associated sclerosis is essential to advance therapeutic trials. We aimed to develop a PRO for adults with cGVHD-associated sclerosis and evaluate and refine its content validity. Adults age ≥18 years with cGVHD-associated sclerosis participated in semi-structured interviews to identify salient symptoms and functions. Sclerosis-relevant symptoms and functions from existing PROs were also used to prompt discussion of topics not spontaneously mentioned. Symptoms and functions (subcodes) of importance were clustered and mapped to overarching domains (codes) using inductive analysis, and candidate items were developed. Cognitive interviews were employed to evaluate content validity of the items, response options, recall period, and respondent instructions.Thirty-five open-ended interviews, conducted to saturation, revealed the breadth of the patient experience with cGVHD-associated sclerosis including 5 overarching domains: (1) skin changes, (2) symptoms, (3) emotional and social functioning, (4) mobility restrictions, and (4) activity limitations. A pool of 54 items was tested and iteratively refined through cognitive debriefing interviews (n=25). Phrasing changes were made to improve relevance and comprehension. One item was removed and two items were added to address respondent feedback, resulting in 55 items. Results support the relevance, comprehensibility, and comprehensiveness of the provisional Lee Symptom Scale-Skin Sclerosis. Concept elicitation and cognitive interviewing have informed the development of the Lee Symptom Scale-Skin Sclerosis. Psychometric testing and determination of minimal clinically important difference are underway in an external cohort to validate the PRO.

Robust genetic characterization of paediatric AML has demonstrated that fusion oncogenes are highly prevalent drivers of AML leukemogenesis in young children. Identification of fusion oncogenes associated with adverse outcomes has facilitated risk stratification of patients, although successful development of precision medicine approaches for most fusion-driven AML subtypes have been historically challenging. This knowledge gap has been in part due to difficulties in targeting structural alterations involving transcription factors and in identification of a therapeutic window for selective inhibition of the oncofusion without deleterious effects upon essential wild-type proteins. Herein, we discuss the current molecular landscape and functional characterisation of three of the most lethal childhood AML fusion-oncogene driven subtypes harbouring KMT2A, NUP98, or CBFA2T3::GLIS2 rearrangements. We further review early-phase clinical trial data of novel targeted inhibitors and immunotherapies that have demonstrated initial success specifically for children with these poor-prognosis genetic subtypes of AML and provide appreciable optimism to improve clinical outcomes in the future.

Anemia is a common consequence of myelofibrosis. The treatment of myelofibrosis-associated anemia is complicated by a multifactorial pathobiology, as well as a lack of therapies that result in normalization of the bone marrow and complete restoration of its function. Established agents that are used to treat anemia in other bone marrow failure states such as myelodysplastic syndromes and aplastic anemia, are used for the treatment of myelofibrosis-associated anemia. However, there has been rapid development of new anemia-directed therapies; some of which have garnered regulatory approval. In addition to adopting therapies from other disease states, better understating of the root causes of myelofibrosis-associated anemia has positioned the field to be on the cutting edge of new anemia treatments, spearheading the advancement of agents that work on the hepcidin pathway to improve red cell production.

BTK inhibitors (BTKi) are an established standard of care in CLL. The covalent BTKi ibrutinib, acalabrutinib and zanubrutinib bind to BTK C481 and are all susceptible to the C481S mutation. Non-covalent BTKi including pirtobrutinib overcome C481S resistance but are associated with multiple variant (non-C481) BTK mutations, including those associated with resistance to acalabrutinib and zanubrutinib (T474 codon and L528W mutations). We review the current knowledge on variant BTK mutations, discuss their clinical implications and consider their impact on clinical trials.

Natural killer (NK) cells have proven to be safe and effective immunotherapies, associated with favorable treatment responses in chronic myeloid leukemia (CML). Augmenting NK cell function with oncological drugs could improve NK cell-based immunotherapies. Here, we used a high-throughput drug screen consisting of over 500 small-molecule compounds to systematically evaluate the effects of oncological drugs on primary NK cells against CML cells. We identified SMAC mimetics as potent enhancers of NK cell cytotoxicity in both cell lines and primary patient samples. In contrast, several drug classes, including glucocorticoids and tyrosine kinase inhibitors such as dasatinib, inhibited NK cell cytotoxicity. Single-cell RNA sequencing revealed drug-induced transcriptomic changes in both NK and target CML cells. SMAC mimetics upregulated NF-κB target genes in NK cells, potentially contributing to their enhanced cytotoxicity. Inhibitory drugs dexamethasone, dasatinib, and sotrastaurin prevented NK cell transition to an activated state and suppressed the expression of IFN-γ by NK cells, thus preventing IFN-γ mediated target cell transcriptomic response. In conclusion, we discovered that SMAC mimetics sensitize cancer cells to NK cell mediated killing, with potential clinical applications especially in patients with advanced phase CML.

Differentiation of antigen-activated B cells into pro-proliferative germinal center (GC) B cells depends on the activity of the transcription factors MYC and BCL6, and the epigenetic writers DOT1L and EZH2. GCB-like Diffuse Large B Cell Lymphomas (GCB-DLBCLs) arise from GCB cells and closely resemble their cell of origin. Given the dependency of GCB cells on DOT1L and EZH2, we investigated the role of these epigenetic regulators in GCB-DLBCLs and observed that GCB-DLBCLs synergistically depend on the combined activity of DOT1L and EZH2. Mechanistically, inhibiting both enzymes led to enhanced derepression of PRC2 target genes compared to EZH2 single treatment, along with the upregulation of BCL6 target genes and suppression of MYC target genes. The sum of all these alterations results in a 'cell identity crisis', wherein GCB-DLBCLs lose their pro-proliferative GC identity and partially undergo PC differentiation, a state associated with poor survival. In support of this model, combined epi-drugging of DOT1L and EZH2 prohibited the outgrowth of human GCB-DLBCL xenografts in vivo. We conclude that the malignant behavior of GCB-DLBCLs strongly depends on DOT1L and EZH2 and that combined targeting of both epigenetic writers may provide an alternative differentiation-based treatment modality for GCB-DLBCL.

Patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have poor outcomes. Gemcitabine + oxaliplatin (GemOx) with rituximab, a standard salvage therapy, yields complete response (CR) rates of approximately 30% and median overall survival (OS) of 10-13 months. Patients with refractory disease fare worse, with a CR rate of 7% for subsequent therapies and median OS of 6 months. Epcoritamab, a CD3xCD20 bispecific antibody approved for the treatment of R/R DLBCL after ≥2 therapy lines, has shown promising safety and efficacy in various combinations. We report results from the phase 1b/2 EPCORE® NHL-2 trial evaluating epcoritamab + GemOx in patients with R/R DLBCL who were ineligible for or had failed autologous stem cell transplant (ASCT). Patients received 48-mg subcutaneous epcoritamab after 2 step-up doses until progression or unacceptable toxicity; GemOx was given Q2W for 8 doses. The primary endpoint was overall response rate (ORR). As of December 15, 2023, 103 patients were enrolled (median follow‑up, 13.2 months). Patients had a median age of 72 years and challenging-to-treat disease: ≥2 prior therapy lines, 62%; prior CAR T, 28%; primary refractory disease, 52%; refractory to last therapy, 70%. ORR/CR rates were 85%/61%. Median duration of CR and OS were 23.6 and 21.6 months. Common treatment‑emergent adverse events were cytopenias and cytokine release syndrome (CRS). CRS events had predictable timing, were primarily low grade (52% overall, 1% grade 3), and resolved without leading to discontinuation. Epcoritamab + GemOx yielded deep, durable responses and favorable long-term outcomes in ASCT‑ineligible R/R DLBCL. NCT04663347.

Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy limited by graft-versus-host disease (GVHD). In preclinical studies and early-phase clinical studies enrichment of donor regulatory T cells (Tregs) appears to prevent GVHD and promote healthy immunity.We enrolled 44 patients on an open-label, single-center, phase 2 efficacy study investigating if a precision selected and highly purified Treg cell therapy manufactured from donor mobilized peripheral blood improves one-year GVHD-free relapse free survival (GRFS) after myeloablative conditioning (trial NCT01660607). We compared this study arm to a concomitant standard of care (SOC) cohort. All donor Treg cell products were successfully manufactured and administered without cryopreservation within 72 hours. Participants had a one-year incidence of acute grade III-IV GVHD of 7%, moderate to severe chronic GVHD of 11% and non-relapse mortality rate of 4.5%. The primary endpoint of significantly improved one-year GRFS was achieved at 64% evaluated against a predicted incidence of 40% (p = 0.002) with a realized incidence of 36% in the SOC comparitor. For those trial patients whow developed grade II-IV acute GVHD, 91% responded to front-line steroid therapy wheras 50% responded in the SOC comparator group. Trial participants had a reduced incidence and burden of GVHD and improved GRFS, as compared to rates common to highly variable unmanipulated donor grafts and multi-agent immune suppression.

Abstract: Treatment outcomes for acute promyelocytic leukemia (APL) have improved with the widespread use of targeted therapy with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Our study aimed to validate these data in a large patient cohort, and to redefine prognostic factors. Leveraging the HARMONY Platform, we analyzed 1438 newly diagnosed patients with APL, diagnosed between 1999 and 2022. Patient data derived from the 2 international multicenter Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA)-APL0406 and National Cancer Research Institute (NCRI)-AML17 trials and 4 European registries: the Haemato Oncology Foundation for Adults in the Netherlands, Belgium and Luxembourg (HOVON), AML Study Group (AMLSG), Swedish AML Registry, and Study Alliance Leukemia (SAL). The study cohort included 721 males and 717 females, with a median age of 50.5 years (range, 16-94 years). Of 1309 patients starting therapy, 562 received ATRA-ATO, and 747 idarubicin-based chemotherapy (AIDA-like CHT). Early death (ED) occurred in 85 of 1438 patients (5.9%) at a median of 9 days after APL diagnosis and was independently associated with increasing age and high Sanz risk score (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.04-1.08; and OR, 4.65; 95% CI, 2.55-8.51, respectively). The median follow-up was 5.5 years (interquartile range, 3.2-7.5 years). ATRA-ATO regimen was associated with the best outcome, reaching 91% 7-year overall survival (vs 81% for AIDA-like CHT; hazard ratio [HR], 2.14; 95% CI, 1.51-3.05), 89% event-free survival (vs 71% for AIDA-like CHT; HR, 2.72; 95% CI, 2.01-3.69), and 3% relapse (vs 13% for AIDA-like CHT; HR, 4.19; 95% CI, 2.38-7.39; P < .001 for all outcomes). The survival advantage of ATRA/ATO was independent of patients' age, Sanz risk score, and treatment scenario. Our study confirms the superiority of ATRA-ATO over ATRA-chemotherapy in patients with APL. Reducing the risk of ED still represents an unmet medical need, in particular in older patients and in high-risk APL.