Disease relapse remains the leading cause of failure following allogeneic hematopoietic cell transplantation (HCT). As novel prophylactic strategies increasingly aim to universally eliminate all forms of graft‑versus‑host disease (GVHD), how these approaches may inadvertently sacrifice graft‑versus‑leukemia activity in the post‑transplant cyclophosphamide (PTCy) era is unclear. To evaluate the associations between time‑updated GVHD phenotypes and clinical outcomes, including relapse, non‑relapse mortality (NRM), and overall survival (OS), in patients undergoing PTCy‑based haploidentical or mismatched unrelated donor (MMUD) HCT. This was a retrospective cohort study using the Center for International Blood and Marrow Transplant Research registry. Participants included 7055 patients with hematologic malignancies who received a first haploidentical or MMUD HCT with PTCy from 2013 to 2021. Associations with relapse, NRM, and OS were evaluated using multi‑state time‑dependent Cox proportional hazards models and a multi‑state random survival forest (MS‑RSF). Time‑updated acute and chronic GVHD phenotypes included isolated Grade II acute GVHD (aGVHD), Grade III to IV aGVHD, mild chronic GVHD (cGVHD), and immunosuppressive therapy-requiring (IST‑requiring) cGVHD. IST‑requiring cGVHD without antecedent aGVHD was associated with a lower modeled relapse hazard compared with remaining GVHD‑free (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.62 to 0.89; false discovery rate-adjusted P [q] = 0.006) and lower overall mortality (HR, 0.62; 95% CI, 0.53 to 0.73; q < 0.001). In contrast, Grade III to IV aGVHD was associated with significantly higher modeled NRM (HR, 3.15; 95% CI, 2.57 to 3.84; q < 0.001). Mild cGVHD and isolated Grade II aGVHD showed intermediate patterns without consistent associations. These associations were directionally consistent across multiple analytic approaches, including standard time‑dependent Cox regression, dynamic and fixed landmark analyses, and MS‑RSF. In this large PTCy‑treated mismatched donor cohort, IST‑requiring cGVHD was the GVHD phenotype most consistently associated with lower relapse incidence, whereas severe aGVHD was associated with higher NRM. These findings highlight heterogeneity in GVHD phenotypes and suggest that strategies distinguishing toxic aGVHD from chronic alloreactivity patterns may better balance morbidity and long‑term disease control. Given that relapse remains the predominant cause of post‑transplant mortality, approaches aiming to universally eliminate all GVHD warrant careful reconsideration.

Allogeneic CAR-engineered NK cells enable scalable off-the-shelf therapy, yet donor heterogeneity remains a major barrier to consistent potency. Building on our clinical experience with cord blood-derived CAR NK cells, we identified an immature CD16-CD161- double-negative (DN) NK subset associated with poor outcomes. Following CAR engineering, DN-derived NK cells remained hypofunctional yet exhibited exaggerated trogocytosis, accumulating high levels of cognate antigen and forming an intra-product trogocytic-antigen sink (TAS) that diverted CAR engagement from tumor targets and promoted on-target off-tumor interactions within the product. Consequently, CD16+CD161+ double-positive (DP) effectors exposed to the TAS underwent sustained activation, metabolic stress, fratricide, reduced viability, programmed cell death, and progressive exhaustion, culminating in impaired persistence and tumor control. Pre-manufacturing DN depletion eliminated the TAS and restored DP antitumor activity across hematologic and solid tumor models. Together, these findings define a donor subset-driven mechanism of CAR NK dysfunction and provide a manufacturing strategy to improve antitumor potency.

Metastatic uveal melanoma (mUM) is a rare, aggressive malignancy with limited therapeutic options in the metastatic setting. Tebentafusp (IMCgp100) is an immune-mobilizing monoclonal T cell receptor against cancer (ImmTAC), targeting gp100 in HLA-A*0201+ patients. Tebentafusp has demonstrated an overall survival (OS) benefit in clinical trials, usually without marked radiographic tumor regression. We describe a mUM patient who was treated with tebentafusp for more than two years and achieved durable stable disease on imaging but passed away due to sudden cardiac death. Autopsy examination revealed extensive tumor necrosis and dense immune cell infiltration within metastatic liver lesions with minimally viable tumor, providing direct evidence of robust immune activation in the tumor microenvironment. This case highlights the potential for T cell bispecifics to induce profound anti-tumor effects that are not fully captured by conventional radiographic assessment, underscoring the need for integrated clinical, pathologic, and imaging evaluation in this setting.

The role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adults with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with B-cell-directed immunotherapies remains controversial. We analyzed 172 adults treated in first salvage with blinatumomab and/or inotuzumab ozogamicin (InO)-based regimens to determine prognostic factors and benefit from allo-HSCT after achieving remission. Relapse within 12 months of initial diagnosis (HR 2.21, 95%CI 1.28-4.16) and measurable residual disease (MRD) positivity by multiparametric flow cytometry after cycle 1 of salvage (HR 3.06, 95%CI 1.75-5.33) predicted inferior relapse-free survival (RFS) on multivariate analysis; both factors as well as older age predicted inferior overall survival (OS). Patients who achieved early flow MRD negativity and had late relapse or were primary refractory to frontline therapy did not benefit from allo-HSCT (4-year RFS 60% vs 63% without allo-HSCT, p = 0.82), while allo-HSCT improved outcomes in patients with MRD positivity and/or relapse within 12 months (4-year RFS 56% vs. 22% without allo-HSCT, p = 0.03). MRD status after cycle 1 of salvage therapy and duration of first remission can risk stratify adults with R/R B-ALL; those with early MRD negativity and late relapse or primary refractory disease may have favorable outcomes without consolidative allo-HSCT.

OBJECTIVE: This study aimed to compare the marginal and internal fit of endocrowns with cavity depths of 3 mm and 5 mm, using two printable resins fabricated by additive manufacturing within a digital workflow. MATERIALS AND METHODS: Thirty-two human mandibular molars were prepared for endocrowns with cavity depths of 3–5 mm and allocated into four groups (n = 8). Two printable resins (Biocrown Diamond and Voxel Print) were evaluated at both preparation depths. The restorations were designed using CAD software and manufactured by DLP-based additive manufacturing. Marginal and internal fit were assessed using micro-computed tomography (micro-CT) from standardized sagittal and coronal sections at predefined anatomical regions. Data were analyzed using two-way repeated-measures ANOVA followed by Tukey’s test (α = 0.05). RESULTS: Material and preparation depth influenced the marginal and internal fit of endocrown restorations, with a significant interaction with the anatomical region. The highest discrepancies were observed in the axio-occlusal angle, particularly for the 5-mm preparation groups. Significant differences between materials occurred at the axio-occlusal angle for 3-mm preparations and in the marginal gap for 5-mm preparations. No significant differences were detected in the pulpal regions. CONCLUSION: Endocrowns showed clinically acceptable marginal adaptation at both preparation depths. However, internal adaptation was region-dependent, with greater discrepancies in the axio-occlusal region. Both resins demonstrated acceptable behavior, although localized differences were observed according to preparation depth and anatomical region. CLINICAL SIGNIFICANCE: Preparation depth and printable resin type may influence the internal adaptation of additively manufactured endocrowns and should be considered during treatment planning.

Haploidentical hematopoietic cell transplantation (HCT) offers potent graft-versus-tumor effects but is historically limited by higher non-relapse mortality (NRM) compared to matched unrelated (MUD) or related donors (MRD). To algorithmically decouple the competing risks of NRM and relapse, we analyzed 1,713 adult patients (MD Anderson discovery cohort) and 6,829 patients (registry replication cohorts) using a double machine-learning framework of Causal Survival Forests to estimate individualized treatment effects, while Random Survival Forests defined absolute prognostic risk. We found biological uncoupling of relapse and NRM: relapse was driven by disease biology, while NRM was governed by physiological reserve. Specifically, cardiovascular or cerebrovascular comorbidities acted as selective amplifiers of haploidentical toxicity-a "vascular penalty" that doubled mortality risk in the bootstrapped model (sub-distribution hazard ratio 2.09, 95% confidence interval 1.26-3.35). We developed a 3-factor nomogram (recipient age, vascular comorbidity, B-leader matching status) to identify an "Optimized Haploidentical" phenotype. Exploratory multivariable modeling suggested MUD consistently maximized predicted disease-free survival across all subgroups. Among haploidentical versus MRD comparisons, B-leader mismatch appeared to favor MRD across ages, while B-leader matched haploidentical donors in older patients (≥ 60 years) modeled near-equivalent DFS to MRD, representing a hypothesis-generating "zone of equivalence" requiring prospective validation.