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: Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), leg type (PCDLBCL-LT) is a rare subset of DLBCL that exhibits genetic features shared with LBCL of immune-privileged sites (notably the MYD88L265P mutation) and is enriched in tumor-associated macrophages expressing M2 markers. Using a unique PCDLBCL-LT cell line (ARSI cell line) developed in our institute, we sought to mechanistically decipher the interplay between lymphoma cells and macrophages. We demonstrate that ARSI cells induce phenotypic, transcriptional, and functional changes in macrophages obtained from primary monocytes and THP-1 cell line. These changes do not require cell-cell contact, and proteome analysis of ARSI secretome reveals high concentration of several cytokines and chemokines known to affect macrophages, including interleukin-10 (IL-10). We then demonstrate that IL-10/Interleukin 10 receptor subunit alpha (IL-10RA) interaction blockade inhibits macrophage polarization induced by tumor cells. These findings are reproduced when macrophages are cocultured with PCDLBCL-LT cells from different patient-derived xenografts. However, among 4 other DLBCL cell lines, only the MYD88-mutated OCI-Ly3 cell line exhibits similar effects, which highlights the variability of macrophage interplays and led us to hypothesize that macrophage shaping, beyond the cutaneous localization, may rely on specific genetics of tumor cells. Finally, we reveal that macrophages enhance tumor cell proliferation and promote resistance to doxorubicin in coculture. In conclusion, these results confirm the robustness of this model to study lymphoma cell and macrophage interplays, underline the critical role of IL-10 in lymphoma microenvironment modeling, and may contribute to better defining its specificities in an era of rising microenvironment-targeted therapies.

Abstract: Sickle cell disease (SCD) is an inherited red blood cell disorder with significant complications, including vaso-occlusive crisis (VOC), the most common cause of emergency department (ED) visits and hospitalizations. Pain in children with SCD is often underestimated. We evaluated the impact of a standardized institutional nurse-initiated ED SCD pain protocol, using intranasal (IN) fentanyl (INF) as the initial agent, on hospital admission rates. We conducted a preintervention/postintervention study of patients with SCD (aged 0-21 years) presenting to a quaternary pediatric ED for uncomplicated VOC pain from June 2015 to December 2019. Overall, 162 patients accounted for 471 ED visits in the preintervention period and 80 patients accounted for 162 visits in the postintervention period. After intervention, hospitalization rates (P = .0017) and inpatient length of stay (P = .0019) decreased, but median pain scores at presentation (P = .0047) and discharge (P = .1451) remained comparable. The time to initial analgesia dose significantly improved in the postintervention (P< .0001), along with the time from physician order to initial analgesia administration (P = .0005). IV and IN analgesia use rose significantly in the postintervention (odds ratio, 4.7; P< .0001), with INF being the preferred analgesic agent (61%) and a corresponding reduction in oral analgesic use (P< .0001). In an ad hoc sustainability analysis, INF use remained high and time to first dose was sustained. Implementing a standardized ED SCD pain protocol improved timeliness and consistency in analgesia administration and decreased overall hospitalization rates. This study also highlights the role of INF as an effective initial analgesic within standardized ED protocols for pediatric VOC.