Blood Cancer Discovery最新文献

Models of tumor drug response have illuminated important concepts in oncology, but there remains a need for theory that combines intra-tumor and inter-patient heterogeneity to explain patient outcomes, especially for curative treatments. We present a mathematical model of multi-drug therapy that describes both cell-to-cell and patient-to-patient heterogeneity as distributions of drug sensitivity, and apply it to simulate curative combination therapies for Diffuse Large B-Cell Lymphoma (DLBCL). Simulated trials reproduced Progression-Free Survival and changes in circulating tumor DNA observed under standard therapy, and accurately predicted success or failure of nine randomized trials of first-line combinations based on drugs' efficacies in relapsed/refractory DLBCL. Finally, we used the model to explore how drug synergies, biomarkers, and subtype-specific endpoints could improve the chance of success of targeted combination therapies. This study offers a quantitative model of curative drug combinations and suggests that predictive simulations could aid the design of new regimens with curative intent.

Despite the curative potential of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML), its efficacy is limited by intrinsic resistance of cancer cells to donor-derived T-cell cytotoxicity. Using a genome-wide CRISPR screen, we identified the SOCS1-JAK1-STAT1 pathway as a mediator of AML susceptibility to T cells. SOCS1 knockdown in AML cells sensitized them to killing by allogeneic T cells, whereas SOCS1 overexpression in AML cells induced resistance to T-cell anti-leukemic activity. Mechanistically, SOCS1 protected AML cells from T-cell killing by antagonizing IFNγ-JAK1-induced ICAM-1 expression. Furthermore, primary AML cells with lower SOCS1 expression correlated with better overall survival in patients, especially those with a lower exhausted CD8+ T-cell score. Thus, this study reveals SOCS1 and its downstream mediators as a potential targetable pathway to enhance T cell-based immunotherapy for AML.

Genetic alterations of chronic active B-cell receptor signaling often occur in primary central nervous system lymphoma (PCNSL). We conducted a phase-II trial of high-dose methotrexate plus ibrutinib and temozolomide (MIT) in the treatment of newly diagnosed PCNSL. A total of 35 patients were enrolled, with 33 patients included in the analysis. The best overall response rate was 93.9% and complete response rate was 72.7% for induction therapy. The 2-year progression-free survival (PFS) and overall survival were 57.6% (95%CI: 49.0-66.2) and 84.8% (95%CI: 78.6-91.0). The incidence of grade ≧ 3 adverse events was 27.3% (10/33). Mutations in PIM1, MYD88, BTG2, and CD79B were most frequent among 475 genes tested by targeted sequencing of tumor and CSF samples at baseline. The consistency of ctDNA clearance from CSF/plasma and complete response on imaging were observed. Patients with clearance of ctDNA from CSF after two cycles achieved longer PFS (p = 0.044).

Brexucabtagene autoleucel (brexu-cel) and allogeneic hematopoietic cell transplantation (alloHCT) are effective treatments for relapsed or refractory mantle cell lymphoma (r/r MCL), but the optimal choice remains unclear. We conducted an analysis of 64 r/r MCL patients aged ≥50 years treated with brexu-cel in the ZUMA-2 study, matching them 1:1 by propensity score to 64 (out of 272) r/r MCL patients who underwent alloHCT using data from the EBMT registry. Median follow-up time was 36.5 and 34.1 months for the brexu-cel and matched alloHCT cohort, respectively. Brexu-cel patients had a significantly higher overall survival (OS, 81.3% vs 59.2%, HR: 0.39, p=0.004) and lower non-relapse mortality (3.6% vs 21.2%, p=0.015) one year after treatment. Chronic graft-vs-host disease occurred in 26.9% of alloHCT patients within the first year. However, long-term progression-free survival and OS remain comparable. Despite limitations of this non-randomized study, it indicates a superior safety profile for brexu-cel in r/r MCL.

Significance: This review underscores our shared responsibility to champion multidimensional strategies rooted in basic and translational science, community involvement, and societal responsiveness for a meaningful impact. Unifying themes include the need to enhance collaborative infrastructure to engage laboratory researchers, epidemiologists, data scientists, clinicians, patients, community leaders, and policymakers; patient-level support services; outreach, education, and navigation for patients at the community level; recruitment and retention of underrepresented groups in the healthcare and research workforce; and funding for these efforts.

In pediatric hematopoietic cell transplantation (HCT) recipients, transplanted donor cells may need to function far beyond normal human lifespan. Here, we investigated the risk of clonal hematopoiesis (CH) in 144 pediatric long-term HCT survivors and 258 non-transplanted controls. CH was detected in 16% of HCT recipients and 8% of controls, at variant allele frequencies (VAFs) of 0.01-0.31. Mutations were predominantly in DNMT3A (80%) and TET2 (20%). Older hematopoietic age (odds ratio: 1.07, p<0.001) and the HCT procedure (odds ratio: 2.53, p=0.02) independently increased the risk of CH, indicating both aging- and transplantation-induced effects. Large clones (VAF >0.10) were found exclusively in HCT recipients. Notably, CH was also detected within 15 years after a cord blood HCT. Inflammatory processes around graft infusion were associated with CH presence. Future studies are required to track the evolution of post-transplant CH and its impact on future cardiovascular disease, second malignancies and overall survival.

Significance: In recent years, there has been tremendous interest surrounding the integration of venetoclax into both non-intensive and intensive chemotherapy regimens for AML. However, with this increasing utilization of venetoclax, considerable questions surrounding key issues such as dosing strategies and the practicality of venetoclax administration have arisen. This review highlights the evolution of venetoclax-based regimens in AML and provides a commentary on notable practical considerations when utilizing this agent.

Among patients with poly-refractory myeloma, autologous chimeric antigen receptor T-cell therapy offers exceptional promise. With the availability of bispecific antibodies, a total immunotherapeutic strategy in combination with chimeric antigen receptor T-cell therapy is now feasible. See related article by Fandrei et al., p. 38.

Significance: The acceptance of MRD-negative complete response as an endpoint that is reasonably likely to predict clinical benefit will allow for the design of streamlined clinical trials for accelerated approval, enabling significantly faster patient access to novel therapies. Cooperative efforts were required to obtain and analyze clinical trial data from multiple sponsors and to determine the best approach to analysis with a relatively limited number of available datasets. The process to evaluate MRD as an intermediate endpoint, undertaken jointly by myeloma researchers and industry, with feedback from the FDA, serves as a roadmap for other areas of oncology to develop intermediate endpoints.

Significance: Our study demonstrates the use of "IF-THEN" SynNotch-gated CAR-T cells targeting CD33 and CD123 in AML reduces off-tumor toxicity. This strategy enhances T-cell phenotype, improves expansion, preserves HSPCs, and mitigates cytokine release syndrome-addressing critical limitations of existing AML CAR-T therapies.