Blood advances最新文献

Abstract: Chimeric antigen receptor T-cell (CART) therapy has transformed the management of relapsed and refractory large B-cell lymphoma (LBCL), but real-world outcomes data is needed to confirm the benefits seen in clinical trial settings. We performed a multicenter retrospective analysis evaluating CART therapy outcomes according to line of therapy, specifically second line (2L) vs third line (3L) vs fourth line (4L) and beyond (4L+). We included patients who received CD19-directed CART therapy for de novo diffuse LBCL or transformed follicular lymphoma. Overall (N = 466), 21% (n = 98) of patients received CART as 2L, 41% (n = 192) as 3L, and 38% (n = 176) as 4L+. Median follow-up from CART infusion was 35 months. Overall response rate and complete response rate were similar for 2L vs 3L vs 4L+. From CART infusion, median progression-free survival (mPFS) and median overall survival (mOS) were similar for 2L vs 3L, but shorter in patients receiving CART as 4L+ (mPFS, 11.6 vs 12.7 vs 5.7 months, P< .001; mOS, not reached vs 69.4 vs 21.9 months, P< .001). In patients with double-hit or triple-hit lymphoma (DHL/THL), receiving CART in 2L vs 3L significantly improved 3-year OS (63% [2L] vs 32% [3L], P = .01). Patients with disease that required bridging therapy were also at increased risk of progression or death. Overall, our findings inform real-world practice wherein CART therapy as 2L vs 3L yields similar survival outcomes in unselected patients. However, patients specifically with DHL/THL should be considered for CART therapy in the 2L outside of the primary refractory disease (PRD) or early relapsed setting.

Abstract: Chronic myelomonocytic leukemia (CMML) is characterized by monocytosis in blood and bone marrow and natural progression to acute myeloid leukemia (AML) in ≤30% of patients. The mutation landscape of CMML has been reported, and animal models that recapitulate its clinicopathologic features and progression are needed. We report a CMML zebrafish model based on transgenic SRSF2P95H expression that closely resembled the human disease. Hematological assessment of the transgenic animals showed myelodysplasia, monocytosis, and leukemia transformation. Transcriptomic analysis confirmed global splicing alterations and identified inflammatory phenotypes associated with activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. DNA damage, R-loop formation, and double-strand DNA accumulation were evident. Inhibition of R-loop formation or cGAS-STING axis significantly reduced gene expression associated with inflammation and immune activation and mitigated the leukemia phenotype. The inflammatory effects and their response to treatment were recapitulated in human hematopoietic stem and progenitor cells. Collectively, our findings show a pathogenetic link between SRSF2P95H and cGAS-STING activation in CMML and its vulnerability to therapeutic intervention.

Abstract: Ineffective erythropoiesis and the resulting anemia are the main characteristics of myelodysplastic syndromes (MDS). Drugs designed to promote erythropoiesis in patients with MDS include erythropoiesis-stimulating agents, such as recombinant human erythropoietin, and transforming growth factor β inhibitors, such as luspatercept, which is approved for the treatment of anemia associated with MDS or β-thalassemia. However, these types of drugs are ineffective in some patients and fail to elicit durable responses in others, underscoring the need for additional therapeutic targets. Here, we sought to define the role of ubiquitin-conjugating enzyme E2O (UBE2O), which remodels the proteome during late erythroid differentiation, in the pathogenesis of ineffective erythropoiesis in the setting of MDS and investigate its potential as a therapeutic target for improving erythropoiesis. UBE2O expression was analyzed in K562 leukemic cells and bone marrow samples from patients with MDS before and after treatment with erythropoietin and luspatercept. Bioinformatic analysis identified a GATA1 binding motif on the UBE2O promoter region, and chromatin immunoprecipitation validated the interaction. Our findings demonstrate that GATA1 binds to the UBE2O promoter, thereby regulating UBE2O transcription and expression. Although further studies are needed to explore the implications of UBE2O in MDS treatment, our work provides potential strategies for novel therapeutic approaches in MDS.

Multicolor flow cytometry (MFC) is widely used for measurable residual disease (MRD) detection in acute myeloid leukemia (AML), currently recommended to perform on bone marrow (BM) aspirate only. However, BM aspiration is invasive and sometimes inadequate, whereas peripheral blood (PB) offers a patient-friendly practical alternative. We first analyzed 53 paired PB and BM samples (30 MRD-negative, 23 MRD-positive) and observed 100% concordance with strong correlation (r=0.945, p<0.001). The assay was then prospectively evaluated in 118 patients, including 63 newly diagnosed AML in post-induction (24 intensive and 30 less intensive) remission with results corroborated by molecular, cytogenetic, and follow-up data. PB MRD was positive in 26, negative in 86, and inadequate in 6, yielding 95% adequacy and 98% concordance with BM. Using BM as reference, PB testing showed 96% sensitivity, 99% specificity, 96% positive predictive value, and 99% negative predictive value. Although PB MRD levels were lower than BM (median 0.17% vs 0.84%, p=0.002), correlation was significant (r=0.6, p=0.003). Importantly, PB MRD positivity predicted relapse-free and overall survival in the full cohort (p<0.01 for both) and also post-induction subgroup (p=0.0708 and p=0.0021 respectively). These findings demonstrate that PB MFC-MRD testing is feasible, robust, and clinically informative, supporting PB as a promising complementary specimen for MRD assessment.

Graft-versus-host disease (GVHD), an often-fatal complication of allogeneic hematopoietic stem cell transplantation (HCT), is driven by inflammatory injury that damages target organs of gastrointestinal (GI) tract, skin and liver. Effective therapies must not only suppress GVHD reactivity of donor lymphocytes but permit regeneration of the damaged epithelium, particularly in the GI tract. Systemic corticosteroids are the standard first-line treatment for GVHD due to their powerful immunosuppressive and anti-inflammatory properties but may retard epithelial repair. Ruxolitinib, a selective JAK1/2 inhibitor, is an approved therapy for steroid-refractory GVHD, although its direct effects on epithelial repair are unknown. Intestinal stem cells (ISCs) that are critical for maintaining gut integrity and barrier function are key cellular targets of GVHD. We employed both ileal and colonic organoid cultures to study the direct effects of methylprednisolone and ruxolitinib under conditions that controlled the strength of the GVH reaction. Ruxolitinib prevented inflammatory apoptosis in both human and murine organoids and preserved ISC function and proliferation, while corticosteroids offered no protection and in fact suppressed proliferation. This study highlights the importance of GVHD therapies that facilitate epithelial repair and regeneration, protect target tissues and suppress alloreactivity of donor T cells.