Citations

7094 Background: Waldenström Macroglobulinemia (WM) remains incurable with current available therapeutic options. Treatment options for relapsed/refractory pts are limited and often continuous, underscoring the need for new agents with novel mechanisms of action and pt-centered, fixed duration therapy. Iopofosine I 131 is a novel radiopharmaceutical compound composed of a lipid raft-targeting phospholipid ether covalently bound to 131 I, a beta emitting radioisotope. Here, we report preliminary sub-group results of the CLOVER-WaM study [NCT02952508] in WM pts treated with a Bruton’s Tyrosine Kinase inhibitor (BTKi) immediately prior to iopofosine. Methods: Eligible WM pts had received >2 prior therapies and had symptomatic disease requiring therapy according to consensus recommendations for WM. Treatment consisted of 2 cycles of iopofosine I 131 administered at 15 mCi/m 2 on days 1 and 15 of each 57-day cycle. The primary efficacy endpoint was major response rate (MRR; partial response or better, as determined by the modified IWWM-VI). Secondary and exploratory endpoints included overall response rate (ORR), treatment-free survival (TFS), progression free survival (PFS), duration of response (DOR), and clinical benefit rate (CBR; stable disease or better). Herein, efficacy endpoints were assessed in the modified intent-to-treat (mITT) population (all pts who received ≥60 mCi total administered dose of iopofosine I 131), and whose treatment regimen prior to iopofosine included a BTKi. Safety was evaluated using CTCAE v4.03 in pts who received ≥1 dose of iopofosine. Data cut off for this analysis was Jan. 16, 2026. Results: As previously reported, 65 pts were dosed and 55 are included in the mITT population. Of those, 22 (40%) had received a BTKi containing regimen immediately prior to iopofosine; and 11 who previously received at least 2 regimens utilizing BTKis and 12 who were refractory to rituximab. In this subgroup, median age was 70.5 (range 55-88), 17 (77%) were male, and 5 (23%) were female. The median number of prior therapies was 3 (range 2-7), 15/22 (68%) were MYD88 mutated and 18/22 (82%) were TP53 wildtype. The MRR was 15/22 (68.2%), ORR was 19/22 (86.4%) and CBR was 100%, median PFS was 12 months (range 1.6 to 28.0) and median TFS was 19.1 months (range 2.5-34.4). Grade ≥ 3, related treatment emergent adverse events (TEAE) occurring in > 10% of pts included anemia (41%), leukopenia (41%), neutropenia (58%), and thrombocytopenia (86%). Conclusions: Iopofosine I 131 demonstrated significant efficacy; 100% CBR, 86.4% ORR and 68.2% MRR with a median PFS of 12 months (range: 1.6 – 28.0 months) in a pt population with no current standard of care therapy. The treatment was well-tolerated with a manageable toxicity profile with cytopenias as the only Grade 3 or greater TEAE. Based on the results of this pivotal trial, iopofosine I 131 could be a promising novel treatment for WM pts after BTKi therapy. Clinical trial information: NCT02952508 .

Lactococcosis has emerged as an economically and ecologically significant disease in aquatic animals worldwide. This study employed multilocus sequence typing (MLST) to investigate the genetic diversity of Lactococcus spp. strains from Brazilian fish species and evaluate their phylogenetic relationships with global isolates to elucidate potential epidemiological connections involving multiple host species and distinct geographic regions. A total of 55 isolates from different laboratories had their DNA extracted, followed by the amplification and sequencing of the internal fragments of seven housekeeping genes (als, atpA, tuf, gapC, gyrB, rpoC and galP). Sequence types (STs) and clonal complexes (CCs) were defined. An unrooted neighbor-joining phylogenetic tree was generated using allele profiles from this study and those previously reported from other aquatic animal species. The isolates comprised 29 STs (11 previously reported, 18 novel ones), which were grouped into species-specific CCs: CC5 (L. formosensis); CC4, CC17, CC62 (L. garvieae); CC24, CC29, CC97 (L. petauri). Considerable genetic divergence was observed, with L. formosensis and L. garvieae forming heterogeneous populations, while L. petauri was more homogeneous. These findings describe the MLST structure of the sampled isolates and should be interpreted as hypothesis-generating rather than population-level estimates of genotype prevalence. Phylogenetics confirmed groupings within the CCs and revealed additional phylogenetic clustering patterns. In conclusion, the Brazilian Lactococcus spp. strains analyzed in this study constitute a genetically diverse population based on their STs. MLST and phylogenetic analysis demonstrated genetic relatedness between the L. garvieae and L. formosensis isolates from this study and those from other aquatic animal species. In contrast, all the STs identified for L. petauri in this study were unrelated to the MLST lineages responsible for outbreaks in Brazilian Nile tilapia (Oreochromis niloticus) and North American rainbow trout (Oncorhynchus mykiss). This suggests that piscine L. petauri populations in the Americas evolved from distinct ancestral origins.

ABSTRACT Disease Overview Plasmablastic lymphoma (PBL) is a rare CD20‐negative aggressive lymphoma with poor prognosis when treated with standard treatment options. Although PBL is associated with HIV infection and other immunosuppressed states, it can also affect immunocompetent individuals. Diagnosis The diagnosis of PBL requires a high clinical suspicion and pathological confirmation. EBV‐encoded RNA (EBER) expression and MYC gene rearrangements are frequently detected in the malignant cells. The differential diagnosis includes EBV+ diffuse large B‐cell lymphoma (DLBCL), extracavitary primary effusion lymphoma, ALK+ DLBCL, and HHV8+ large B‐cell lymphoma, among others. Risk Stratification Age ≥ 60 years, advanced clinical stage, and high International Prognostic Index scores are associated with worse survival. Management Combination chemotherapy regimens, such as infusional EPOCH, are recommended. The addition of bortezomib or daratumumab might improve outcomes. B‐cell maturation antigen‐targeted therapies have shown early efficacy. The participation of patients with PBL in prospective clinical trials is warranted.

The persistent shortage of allogenic donor organs has driven the exploration of xenotransplantation as a viable alternative for patients with end-stage liver disease. This review investigates the progress and challenges in liver xenotransplantation, focusing on the use of genetically engineered animals, particularly pigs, as potential organ donors. This narrative review discusses various sources of xenografts, highlighting their advantages and limitations, and provides a historical overview of liver xenotransplantation, encompassing both clinical and experimental experiences. Key obstacles, such as immunological rejection, coagulation dysfunction, and the risk of zoonotic infections, are analyzed, with emphasis on how these challenges have been addressed through genetic modifications and adjunctive therapies. Recent clinical trials are also reviewed, offering insights into the outcomes and lessons learned from these pioneering efforts. We also explored the regulatory, legal, and ethical considerations critical to advancing liver xenotransplantation into clinical practice, along with future perspectives on the field’s evolution. This comprehensive overview aims to provide a clear understanding of the current state of liver xenotransplantation and the strategies being developed to overcome existing barriers, paving the way for future clinical applications.

Abstract Objectives: Community-acquired intra-abdominal infections (CA-IAIs) are a leading cause of US hospitalizations. Piperacillin-tazobactam is often used to empirically treat CA-IAIs, despite national guidelines recommending narrower-spectrum antibiotics for these infections. The overuse of broad-spectrum agents such as piperacillin-tazobactam contributes to antibiotic resistance, which poses serious public health challenges. This resident-led quality improvement initiative aimed to reduce unnecessary piperacillin-tazobactam use for treating CA-IAIs measured as DOT/1,000 patient-days by 10% without adversely affecting hospital length of stay (LOS). Methods: Using the DMAIC (define, measure, analyze, improve, control) framework, we identified barriers to appropriate antibiotic use and developed a treatment algorithm for CA-IAIs that included clear guidelines and exclusion criteria. This algorithm was disseminated to internal medicine residents and emergency department physicians along with educational sessions to highlight updated CA-IAI treatment recommendations, antibiotic resistance, and appropriate antibiotic ordering via the electronic health record. Antimicrobial stewardship pharmacists provided overnight support to assist with de-escalation. Data were collected over a 10-month period spanning 2 intervention phases. The primary outcome was piperacillin-tazobactam use, measured as days of therapy (DOT) per 1,000 patient-days and DOT per patient LOS. Mean LOS served as the balancing measure. Results: Piperacillin-tazobactam use was significantly reduced ( P < .001) after the interventions without increasing the mean LOS. Conclusion: This project raised awareness of antibiotic resistance and led to lasting improvements in reducing the inappropriate use of piperacillin-tazobactam to treat CA-IAIs, without affecting the mean LOS. This was attributed to the strong collaboration among a multidisciplinary team of infectious disease physicians, antimicrobial stewardship team members, residents, emergency department physicians, and faculty.

Abstract Objectives Diagnosing adult T-cell leukemia/lymphoma (ATLL) remains challenging due to its clinical and histopathologic heterogeneity. While HTLV-1 serology is a key diagnostic criterion, it is often unavailable at the time of diagnosis and does not confirm viral integration in tumor cells. The HTLV-1–encoded HBZ RNA is a reliable diagnostic biomarker for ATLL. We evaluated the diagnostic performance of RNAscope in situ hybridization (ISH) for HBZ RNA in formalin-fixed, paraffin-embedded (FFPE) tissues to distinguish ATLL from other T-cell lymphomas. Methods HBZ ISH was evaluated in 72 cases, including 52 ATLLs and 20 non-ATLL T-cell lymphomas, to determine diagnostic sensitivity and specificity, interobserver agreement, interlaboratory reproducibility, and comparison with digital gene expression. Results This assay demonstrated 86.5% sensitivity and 100% specificity, with sensitivity improving to 97% when excluding bone marrow clot sections and FFPE blocks older than 5 years. Interobserver agreement among 3 pathologists was excellent (κ = 0.92, percent agreement: 94%). Interlaboratory reproducibility of HBZ ISH was high, with 93% to 95% concordance across these Clinical Laboratory Improvement Amendments–certified laboratories. HBZ RNA ISH–positive cases demonstrated significantly higher HBZ gene expression levels by digital gene expression profiling. Conclusions We established HBZ ISH as a reliable tissue-based surrogate for HTLV-1 infection in ATLL. This assay will enhance diagnostic accuracy, expedite definitive diagnosis, and improve patient selection for targeted therapies and clinical trials, particularly in regions with a high prevalence of HTLV-1.

46 Background: Primary results from the randomized, multicenter, open-label, phase 3 TRITON3 (NCT02975934) study demonstrated that rucaparib significantly improved radiographic progression-free survival (rPFS) vs physician’s choice of DTX or an ARPI. ECOG PS is used as a predictor of prostate cancer survival. In this post hoc analysis, we report results from the BRCA1/2 subgroup of pts stratified by ECOG PS. Methods: Pts with disease progression after 1 prior second-generation ARPI in any setting were randomized 2:1 to rucaparib 600 mg BID or physician’s choice of DTX or ARPI (abiraterone acetate or enzalutamide). Primary endpoint was rPFS by independent radiology review (IRR). Objective response rate (ORR) for pts with measurable disease and overall survival (OS) were key secondary endpoints. Crossover from physician’s choice to rucaparib was allowed after radiographic progression was confirmed by IRR. Data cutoff was August 25, 2022. Results: Of 302 pts in the BRCA1/2 population, 147 had an ECOG status of 0 (97 rucaparib; 50 physician’s choice) and 155 had ECOG 1 (104 rucaparib; 51 physician’s choice). Baseline characteristics and demographics were generally similar between arms for pts in the ECOG 0 and ECOG 1 groups. Median rPFS favored rucaparib vs physician’s choice for pts with ECOG 0 (11.4 vs 8.2 months; HR, 0.48 [95% CI, 0.30-0.76]) and ECOG 1 (10.9 vs 6.1 months; HR, 0.48 [95% CI, 0.31-0.74]) (Table). Additionally, rPFS favored rucaparib for ECOG 0 and ECOG 1 including those whose prespecified physician’s choice was ARPI or docetaxel (Table). The confirmed ORR (95% CI) of rucaparib vs physician’s choice for ECOG 0 was 54% (37%–69%) vs 16% (3%–40%); the ORR for ECOG 1 was 37% (22%–53%) vs 18% (5%–40%), respectively. Median OS was similar between arms for rucaparib or physician’s choice; median OS was 23.7 vs 21.7 months (HR, 0.91 [95% CI, 0.61–1.37]) for ECOG 0 and 21.8 vs 20.4 months (HR, 0.85 [95% CI, 0.58–1.24]) for ECOG 1. Conclusions: Rucaparib improved rPFS and ORR in pts with BRCA-mutated prostate cancer with an ECOG PS of 0 or 1. OS was similar for these groups in both arms. These data support rucaparib as a treatment option for pts with BRCA-mutated mCRPC, whether ECOG 0 or 1. Clinical trial information: NCT02975934 . Median rPFS in patients in the ECOG 0 and ECOG 1 groups. Rucaparib, n Physician’s choice, n rPFS Rucaparib, median months rPFS Physician’s choice, median months HR (95% CI) rPFS, ECOG 0 97 50 11.4 8.2 0.48 (0.30–0.76) rPFS, ECOG 1 104 51 10.9 6.1 0.48 (0.31–0.74) rPFS, physician’s choice ARPI, ECOG 0 51 24 11.2 5.6 0.42 (0.22–0.78) rPFS, physician’s choice docetaxel, ECOG 0 46 26 11.5 8.8 0.49 (0.24–0.98) rPFS, physician’s choice ARPI, ECOG 1 52 17 11.2 4.5 0.33 (0.16–0.68) rPFS, physician’s choice docetaxel, ECOG 1 52 34 10.7 7.1 0.59 (0.34–1.01)