Large B-cell lymphoma (LBCL) patients who fail frontline therapy (R/R-LBCL) experience highly unfavorable outcomes. The development of T-cell redirecting therapies is rapidly evolving this outlook. However, costs and infrastructural challenges limit access to such innovative therapies. This study was conducted to document the shortcomings of management in the absence of regular access to T-cell redirecting therapies in a contemporary patient population and define subgroups with the most urgent need for accessing innovative treatments. The second-line management and outcomes of a large real-world LBCL cohort from Türkiye were retrospectively analyzed with the participation of nine centers from four different geographical regions. Despite the contemporary period (2012-24), there was no regular access to novel agents. The median PFS-2 was 6.9 months. Less than a quarter of patients (24.3%) received transplantation following a response to second-line therapy, the only subgroup who benefited from the standard care (2-year PFS-2: 67.8%). The remaining 295 patients (75.7% of the cohort) had a median survival of 6.1 months and a 2-year PFS-2 of 10.3%. Progression within a year from diagnosis, non-curative intent at second line, and failure of curative second-line therapy were key adverse features for a dismal prognosis, with median survival durations of 8.8, 2, and 7.4 months, respectively. The current therapeutic strategy of intensive chemoimmunotherapy followed by autologous transplantation yields a reasonable chance of survival for only a fifth of patients. The findings emphasize the urgent need for expanding access to T-cell redirecting approaches in R/R LBCL for early progressors, transplant-ineligible cases, those who fail intensive second-line regimens.

Mesenchymal stem/stromal cells (MSCs) exhibit broad differentiation capability and strong immunoregulatory potential mediated through intercellular communication and the release of diverse paracrine mediators. They represent a promising but still investigational therapeutic approach for managing complications associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). This review provides an updated synthesis of MSC biology, their bidirectional interaction with immune cells, and their functional contribution to the hematopoietic niche. It also evaluates current clinical evidence regarding the therapeutic roles of MSCs and MSC-derived extracellular vesicles (EVs) in acute and chronic graft-versus-host disease (aGVHD/cGVHD), as well as in poor graft function. Mechanistic insights encompass macrophage polarization toward an anti-inflammatory phenotype, inhibition of dendritic cell maturation, enhancement of regulatory T-cell expansion, and modulation of cytokine signaling pathways. Within the bone marrow milieu, MSCs contribute to stromal restoration and angiogenic repair. Recent phase II/III trials in steroid-refractory (SR)-aGVHD have demonstrated overall response rates ranging from 48 to 71%. Efficacy appears particularly enhanced in pediatric patients and with early MSC administration. Across studies, MSC therapy shows a favorable safety profile; however, heterogeneity in response and inconsistent survival outcomes remain notable limitations. For poor graft function, limited prospective studies indicate hematopoietic recovery following third-party MSC infusions, and combination approaches such as co-administration with thrombopoietin receptor agonists are under investigation. MSC-derived EVs emulate many immunomodulatory effects of their parental cells with a potentially safer profile, though clinical validation remains in its infancy. MSC-oriented interventions hold substantial biological and therapeutic promise, offering a favorable safety margin; however, clinical translation is hindered by product variability, suboptimal engraftment and persistence, and inconsistent efficacy across studies. Future directions should emphasize standardized manufacturing and potency assays, biomarker-driven patient and timing selection, optimized conditioning and dosing strategies, and the systematic appraisal of EV-based or genetically modified MSC products through controlled trials.

Mesenchymal stem/stromal cells (MSCs) exhibit broad differentiation capability and strong immunoregulatory potential mediated through intercellular communication and the release of diverse paracrine mediators. These features render MSCs a promising therapeutic option for managing complications associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). This review provides an updated synthesis of MSC biology, their bidirectional interaction with immune cells, and their functional contribution to the hematopoietic niche. It also evaluates current clinical evidence regarding the therapeutic roles of MSCs and MSC-derived extracellular vesicles (EVs) in acute and chronic graft-versus-host disease (aGVHD/cGVHD) as well as in poor graft function. Mechanistic insights encompass macrophage polarization toward an anti-inflammatory phenotype, inhibition of dendritic cell maturation, enhancement of regulatory T-cell expansion, and modulation of cytokine signaling pathways. Within the bone marrow milieu, MSCs contribute to stromal restoration and angiogenic repair. Data from phase II/III clinical trials and real-world cohorts in steroid-refractory aGVHD consistently confirm the safety of MSC therapy, although response rates vary—typically higher in pediatric patients and when administered early—while survival outcomes remain inconsistent. For poor graft function, limited prospective studies indicate hematopoietic recovery following third-party MSC infusions, and combination approaches such as co-administration with thrombopoietin receptor agonists are under investigation. MSC-derived EVs emulate many immunomodulatory effects of their parental cells with a potentially safer profile, though clinical validation remains in its infancy. MSC-oriented interventions hold substantial biological and therapeutic promise, offering a favorable safety margin; however, clinical translation is hindered by product variability, suboptimal engraftment and persistence, and inconsistent efficacy across studies. Future directions should emphasize standardized manufacturing and potency assays, biomarker-driven patient and timing selection, optimized conditioning and dosing strategies, and the systematic appraisal of EV-based or genetically modified MSC products through controlled trials.