The prognostic implications of TP53 alterations in patients with relapsed or refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL) treated with chimeric antigen receptor (CAR) T-cell therapy remain inadequately characterized, particularly with respect to long-term outcomes. We report extended follow-up (median: 77.77 months) of 122 patients with r/r B-NHL who received either dual-targeted CD19/CD22 CAR-T-cell therapy alone (cohort A, n = 65) or following sequential autologous stem cell transplantation (ASCT; cohort B, n = 57). TP53 alterations were identified in 59 patients (48.4%). Within both cohorts, overall survival (OS) and progression-free survival (PFS) did not significantly differ between the TP53-altered subgroup and the wild-type subgroup (P >0.05). Notably, compared with CAR-T-cell monotherapy, the sequential ASCT-CAR-T-cell approach (cohort B) was associated with improved 5-year OS (70.2% vs. 40.0%) and PFS (64.9% vs. 35.4%). The 5-year cumulative incidence of nonrelapse mortality was 10.7% overall (9.2% in cohort A vs. 12.3% in cohort B). Secondary malignancies occurred in 2.5% of patients, whereas serious infection-related events beyond 3 months post-infusion were observed in 13.6%, supporting a favorable long-term safety profile. Multivariate analysis identified treatment options and the presence of bulky disease as independent adverse prognostic factors for OS and PFS. These findings suggest that dual-target CD19/CD22 CAR-T-cell therapy, particularly when integrated with ASCT, may mitigate the adverse prognostic influence of TP53 alterations, offering sustained clinical benefit with manageable long-term toxicity in r/r aggressive B-NHL.

Oncolytic viruses (OVs) display tumor-suppressing capacity through direct oncolysis and induction of anti-tumor immunity. Orf virus (ORFV) has shown considerable properties in inducing tumor cell pyroptosis and inflamed tumor microenvironment (TME). However, the mechanism by which ORFV reshapes tumor immune microenvironment (TIME) remains unclear. We administered a single intratumoral injection of ORFV to B16 melanoma-bearing mice and harvested tumor-infiltrating immune cells for single-cell RNA sequencing. Here, we characterized dynamic changes of TIME following ORFV challenge. Our research reveals that ORFV promotes the enrichment of activate natural killer (NK) cells and effector CD8⁺ T cells, as well as upregulates genes encoding key cytolytic factors, including Gzma, Gzmb, and Prf1. Notably, ORFV depletes lipid-metabolizing macrophages, a change that significantly correlates with the activation of cytotoxic T cells. The decrease in lipid-metabolizing macrophages, which specifically express Trem2, impairs APOE-TREM2 axis signaling between macrophages and T cells. Accordingly, specific blockade of TREM2 using the inhibitor IA9 recapitulated the therapeutic efficacy of ORFV in melanoma. Collectively, these data indicate that ORFV remodels the immunosuppressive TIME by amplifying cytotoxic lymphocyte activity and inhibiting the APOE-TREM2 signaling pathway between macrophages and T cells, thus providing a novel perspective on its anti-tumor mechanism.

Objective To evaluate the efficacy and safety of reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) for a salvage therapy of patients with myelofibrosis (MF). Methods We conducted a retrospective study of 17 MF patients with poor performance status, refractory disease, or progressive disease who underwent RIC-allo-HSCT. Overall survival (OS), progression-free survival (PFS), hematopoietic reconstitution, the cumulative incidence of relapse and improvements in myelofibrosis and splenomegaly were analyzed. Results All 17 patients received RIC regimens. The neutrophil and platelet engraftment rates were 94.1% and 88.2%, respectively, with median engraftment times of 16 days (range, 11-22 days) and 22 days (range, 10-148 days). The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) within 100 days post-transplant was 41.2%, and that of grade III-IV aGVHD was 17.6%. The overall incidence of chronic GVHD (cGVHD) was 35.3%. The reactivation rates of Epstein-Barr virus (EBV) and cytomegalovirus (CMV) were 47.1% and 29.4%, respectively. Before transplantation, there were 10 patients (58.8%) with MF-3 and splenomegaly. At six months after transplantation, the proportion of MF-3 decreased to 26.7%, MF-0 increased to 40.0%, and the proportion of splenomegaly decreased to 53.3%. As of the follow-up date, the proportion of MF-3 had decreased to 21.4%, MF-0 had increased to 57.1%, and all eight remaining patients with splenomegaly had shown varying degrees of spleen size reduction. The estimated 1-year OS and PFS were 88.2% (95% CI, 60.6%-96.9%) and 81.9% (95% CI, 53.8%-93.8%), and the estimated 3-year OS and PFS were 70.6% (95% CI, 26.0%-91.4%) and 65.5% (95% CI, 25.7%-87.7%), respectively. Conclusion RIC-allo-HSCT is a feasible and effective alternative for salvage therapy in MF patients.

Subgroup analysis of the best ORR (CR + PR) in patients in the Trial A.

Clinical characteristics of Trial A and B after PSM.

CRS, ICANS and cytopenias happened in Trial A and B.

The precise impact of febrile neutropenia (FN) during chemomobilization on the collection of CD34+ peripheral blood stem cells and post-transplant infection(s) in patients with multiple myeloma (MM) and lymphoma undergoing autologous stem cell transplantation (ASCT) remains insufficiently characterized. Real-world records of 148 patients diagnosed with MM and 130 with lymphoma, who underwent ASCT between October 2010 and January 2024, were retrospectively analyzed. All patients underwent chemotherapy with granulocyte colony-stimulating factors (G-CSF) for stem cell mobilization. Statistical analysis was performed using GraphPad Prism 9 (p < 0.050). FN was associated with poorer estimated 5-year overall survival in patients with MM (61.0% vs 84.4%; p = 0.002). Patients with MM and FN required greater G-CSF stimulation (p < .001), longer apheresis (p = 0.007), and had lower CD34+ cell yield (p < .001). They also exhibited lower optimal-mobilization rates (p < .001), and delayed neutrophil (p = 0.006) and platelet (p = 0.028) engraftment. In patients with lymphoma, FN was associated with prolonged apheresis (p = .001), delayed platelet engraftment (p = 0.017), and an increased risk for pre-engraftment infection (p = 0.034). FN during chemomobilization was associated with worse long-term survival and impaired stem cell mobilization in patients with MM, along with a heightened risk for pre-engraftment infection(s) in those with lymphoma.

Multivariate analysis of prognostic factors for PFS after PSM and IPTW.

Background: Chronic active Epstein-Barr virus disease (CAEBVD) faces a challenging prognosis due to its inflammatory and tumorigenic nature and lack of standard treatment. The outcomes of adults are more disheartening. We aim to elucidate the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adult CAEBVD, while clarifying whether the combination of antithymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy) can improve survival and reduce transplant-related complications. Methods: We conducted a retrospective study analyzing adult CAEBVD patients who underwent allo-HSCT sequentially in the Department of Hematology at Tongji Hospital, Huazhong University of Science and Technology, from June 2015 to January 2022. Results: Of 20 patients included. The median age at diagnosis was 30.5 years, and the median follow-up time post-transplantation was 26.9 months. The 5-year overall survival (OS), progression-free survival (PFS), GVHD-free and relapse-free survival (GRFS), and non-relapse mortality (NRM) rates were 54.5%, 39.4%, 44.4%, and 37.4%, respectively. These data were similar in ATG alone (50.0%, 33.3%, 33.3%, and 40.0%) and ATG+PTCy (56.3%, 41.7%, 49.0%, and 37.5%). On multivariable Cox regression, pretransplant hemophagocytic syndrome (25.0% vs. 75.0%, P=0.029) and higher EBV copies (25% vs. 61.9%, P=0.048) reduced the OS. On multivariable logistic regression, ATG+PTCy showed a lower incidence of grade II-IV acute GVHD (14.3% vs. 66.7%, P=0.037) and chronic GVHD (14.3% vs. 66.7%, P=0.037). Additionally, faster EBV clearance (P=0.002) and lower EBV reactivation (P=0.018) were observed in ATG+PTCy. Conclusion: Allo-HSCT can facilitate long-term survival in approximately half of adult CAEBVD. ATG+PTCy regimen did not improve survival but demonstrated advantages over ATG alone in reducing GVHD, eliminating EBV, and decreasing EBV reactivation.

Cellular kinetics of CD19 and CD22 CAR transgenes in peripheral blood and B cell aplasia

This retrospective study evaluated 75 patients with chronic active Epstein-Barr virus infection (CAEBV) to compare the efficacy and survival outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) and programmed death-1 (PD-1) blockade therapy. Patients were classified into HSCT and non-HSCT groups. The primary endpoints were overall response rate (ORR), overall survival (OS), and event-free survival (EFS). HSCT significantly improved ORR, 3-year OS, and 3-year EFS compared to non-HSCT treatment. Subgroup analysis showed that PD-1 blockade achieved outcomes comparable to HSCT in a subset of patients; however, HSCT remained superior, overall, particularly in patients without hemophagocytic lymphohistiocytosis (HLH). The presence of HLH was identified as an independent risk factor for inferior survival. In conclusion, allogeneic HSCT remains the preferred curative strategy for CAEBV, whereas PD-1 blockade represents a promising alternative for carefully selected patients. Early recognition and management of HLH are crucial for improving prognosis.

Subgroup analysis of the best ORR (CR + PR) in patients in all patients.

Allogeneic haematopoietic stem cell transplantation is a critical treatment for acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL), yet the risk of treatment failure still persists. Chimerism analysis serves as a potential tool for predicting disease recurrence and survival rates, but its specific role has not yet been clearly defined. This study aimed to explore the role of decreased T-cell and bone marrow (BM) chimerism in predicting post-transplant relapse and survival in patients with acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). The study subjects were 305 AML and ALL patients who underwent allogeneic haematopoietic stem cell transplantation at Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, from January 1, 2018, to September 1, 2023. We monitored the chimerism rate at monthly intervals after transplantation until either patient relapse or the end of follow-up. T-cell and BM chimerism were tested at the same time points. Relapse probabilities were estimated by the Kaplan-Meier method and compared with the log-rank test. Gehan-Breslow-Wilcoxon test was used to assess the impact of T-cell and BM chimerism levels on survival probabilities. In AML patients, our analysis revealed no significant correlation between the presence of initial mixed chimerism (at Day +30 post-transplantation) and the relapse rate. Among patients with ALL, the number with initial mixed chimerism was insufficient for statistical analysis. In AML patients whose bone marrow chimerism rate decreased first (n = 13) had a higher relapse rate and a lower survival rate than those whose T-cell chimerism rate decreased first (n = 11) (p < 0.01). In patients with ALL, there was no significant difference in the relapse or survival rates between patients whose bone marrow chimerism rate decreased first (n = 12) and those whose T-cell chimerism rate decreased first (n = 15) (p > 0.05). While a decrease in bone marrow chimerism effectively predicts AML relapse, T-cell chimerism demonstrates lower predictive efficacy. Further research is necessary to identify reliable predictors for relapse in ALL patients. The integration of chimerism analysis with other prognostic indicators, along with early monitoring and preemptive intervention, may enhance patient survival and quality of life.

This study compared the efficacy and safety of dasatinib 70 mg/day versus the standard 100 mg/day dose in newly diagnosed chronic phase chronic myeloid leukemia (CP-CML) patients from Hubei Province, China. In this prospective, randomized, multicenter trial, 91 patients were assigned to receive dasatinib 70 mg/day (n = 47) or 100 mg/day (n = 44). The primary objective was to compare the rates of optimal response, complete cytogenetic response (CCyR), major molecular response (MMR) and molecular response 4.0(MR4.0) at 3, 6, and 12 months. Safety was assessed via adverse event (AE) monitoring. No significant differences were observed in optimal response, CCyR,, MMR or MR4.0 rates between the two groups at any time point (all P > 0.05). By 12 months, CCyR rates were 100% in both groups. The overall incidence of AEs was similar, except for elevated lactate dehydrogenase (P < 0.05). However, the proportion of patients requiring treatment interruption or dose reduction due to AEs was significantly lower in the 70 mg/day group (4.1% vs. 14.7%, P < 0.05). Dasatinib 70 mg/day demonstrated comparable efficacy to the 100 mg/day dose over 12 months, with a potential trend towards better tolerability, suggesting it is a viable first-line treatment option for CP-CML patients.

Survivals of patients with Trial A and Trial B after IPTW

Prognostic impact of risk factors in patients with R/R DLBCL.

Abstract Purpose: This report presents long-term outcomes of third-generation anti-CD30 chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed/refractory (r/r) CD30+ lymphoma. Patients and Methods: In this single-arm, multicenter, phase I/II trial, patients received a lymphodepletion regimen comprising fludarabine and cyclophosphamide, followed by infusion of anti-CD30 CAR T cells. Primary endpoints included safety and overall response rate (ORR), whereas secondary endpoints were progression-free survival (PFS) and overall survival (OS). Results: Forty-four patients were enrolled, including 33 cases of Hodgkin lymphoma. Of 44 patients, 23 achieved complete response (CR) to CAR T, and 19 achieved PR, resulting in a CR rate of 52.3% and an ORR of 95.5%. The most frequent toxicities were hematologic adverse events of grade 3 or higher (68.2% of neutropenia). Cytokine release syndrome occurred in 18 (40.9%) patients, with 2 (4.5%) cases being ≥ grade 3. In the follow-up period, 24 patients underwent autologous hematopoietic stem cell transplantation (auto-HSCT) after CAR T within a median of 3 months. The best ORR was 95.5%, with 27 (61.4%) patients achieving CR. The best CR rate was higher in patients receiving CAR T followed by auto-HSCT compared with those receiving CAR T alone (75% vs. 45%). Three-year OS and PFS rates for all patients were 79% [95% confidence interval (CI), 66.1%–91.9%] and 74.2% (95% CI, 60.3% –88.1%), respectively. Patients receiving consolidated auto-HSCT following CAR T exhibited significantly longer OS and PFS compared with those treated with CAR T alone. Conclusions: Third-generation anti-CD30 CAR T demonstrates high efficacy and a favorable safety profile in patients with r/r CD30+ lymphoma. Addition of auto-HSCT following CAR T-cell therapy improves depth of remission and potentially enhances OS and PFS.

BackgroundThe mobilization of peripheral blood stem cells(PBSC) needs daily injection of granulocyte colony stimulating factor (G-CSF), which brings inconvenience to healthy donors. Can pegylated granulocyte colony-stimulating factor (Peg-G-CSF) solve this problem by single dose injection?MethodsThis multicenter, randomized controlled study was conducted from May 2018 to April 2019. Eligible donors were randomly selected to received treatment with 12 mg Peg-G-CSF on day 1 or 10 µg/kg/d G-CSF consecutively from day 1. PBSC apheresis of the donors was conducted on day 5. The primary endpoint was the percentage of donors who collected ≥4×106 CD34+cells/kg recipient weight after single apheresis.ResultsEighty (83.3%) of 96 donors in the Peg-G-SCF group and 76 (79.2%) of 96 donors in the G-CSF group collected ≥4×106 CD34+cells/kg recipient weight. The peak value of circulating CD34+ cell count occurred on day 5 in both groups. The median yield of CD34+ cell collected in the Peg-G-CSF group was comparable to that in the G-CSF group by a single apheresis procedure. Moreover, the incidence of side effects in both groups was similarly, no significant difference was observed in engraftment, graft-versus-host disease (GVHD) or survival between the two groups of recipients. By multivariate analysis, The CD34+ cell count on the fifth day was the variable that may have significantly affected the CD34+ yield.ConclusionMobilization via a single injection of Peg-G-CSF can match traditional G-CSF mobilization in terms of efficacy and safety and is expected to provide a better alternative to traditional G-CSF mobilization.Clinical Trial Registrationwww.chictr.org.cn, identifier ChiCTR1800015716

The lymphocyte subsets of the peripheral blood of Trial A and B.