Zachary Braunstein

As a major cause of morbidity in systemic lupus erythematosus (SLE), the prognosis of lupus nephritis (LN) critically depends on early detection and timely intervention. However, current diagnostic approaches remain suboptimal: renal biopsy is invasive and unsuitable for longitudinal monitoring, while conventional urine tests lack sensitivity for early-stage disease. Here, we report a molecular imaging strategy designed to target the pathogenic DNA–anti-dsDNA antibody axis for non-invasive detection of LN. We engineered a gallium-68-labeled single-stranded DNA (ssDNA) probe ([ ⁶⁸ Ga]Ga-NOTA-ssDNA) and evaluated its diagnostic performance and biosafety in the spontaneous MRL/lpr lupus mouse model. The probe showed disease-associated and sustained renal accumulation in 16-week-old diseased MRL/lpr mice, with progressively increasing kidney-to-background contrast. More importantly, [ ⁶⁸ Ga]Ga-NOTA-ssDNA enabled detection of renal immune complex deposition as early as 10 weeks of age, preceding abnormalities in conventional renal function markers and positive findings in renal histology by approximately two weeks. Mechanistically, the ssDNA backbone demonstrated favorable biocompatibility, without exacerbating autoimmune phenotypes or inducing Toll-like receptor-mediated signaling pathways. In conclusion, this study establishes a robust proof-of-concept for pathology-targeted PET/CT imaging of immune complex deposition. By directly visualizing the disease-driving renal autoantibody deposition at the preclinical stage, prior to overt organ damage, this strategy shifts LN diagnosis to non-invasive, mechanism-based molecular visualization.

Large granular lymphocytic leukemia (LGLL) is an uncommon and likely under-diagnosed leukemia that causes severe neutropenia and anemia and can have profound effects on the quality of life for afflicted patients. Frequently associated with various auto-immune phenomena, LGLL is a paradigm for a highly interdisciplinary disease. Recent advances in our pathobiological understanding of LGLL, along with the development of novel agents, have stimulated a growing number of clinical trials and innovative approaches targeting this disease. Currently, the absence of uniform diagnostic and response criteria for LGLL results in significant heterogeneity in diagnosis and response assessment across studies. Furthermore, with the emergence of a variety of novel experimental therapeutics and an increasing number of clinical trials, it becomes critical to better define the key diagnostic, treatment and response parameters for this disease. The International LGLL Consortium was created to develop cross-disciplinary expert consensus on uniform diagnostic, treatment, and response criteria for LGLL suitable for both routine clinical use and interventional trials while facilitating cross-study comparisons. Utilizing an evidence-based framework, along with the international panel that comprises the LGLL Consortium, this report delineates the key criteria that will serve as a foundation for both the clinical management and future investigations in LGLL.

Clonal expansions in large granular lymphocytic leukemia (LGLL) may arise in response to immune dysregulation in the context of other hematologic malignancies. This study aimed to investigate the co-occurrence of LGLL and plasma cell dyscrasias (PCDs) to assess its prevalence, features, and potential underlying mechanisms. We conducted a cross-sectional study involving 2064 PCD cases and 534 LGLL cases. Of the 534 LGLL cases, 20% co-occurred with PCD, while LGLL was present in 2% of the 2064 PCD cases. Among 117 patients with both conditions, PCDs were predominantly associated with IgM M-protein, while LGLL patients had increased NK-cell proliferation and fewer mutations in STAT3/5B . The co-occurrence was linked to a higher incidence of autoimmune conditions, B-cell neoplasms, and more severe immune-mediated cytopenias. In symptomatic PCD/LGLL patients with low plasma-cell infiltration, B-cell-targeted therapies outperformed immunosuppression, suggesting humoral involvement. Correlation with biological parameters revealed elevated interleukin-6 and inhibitory effects of sera of symptomatic PCD/LGLL patients on hematopoietic cells. Our findings suggest an association between PCD and LGLL, characterized by distinct features that may have significant implications for clinical management. These results highlight the importance of considering hematologic co-occurrences in clinical practice and warrant further investigation into the molecular mechanisms linking these conditions.

Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been associated with serious cardiotoxicity, including atrial fibrillation (AF) and other cardiac events. In preclinical models, posttransplant clonal hematopoiesis (CH) frequently parallels or precedes clinical AF, yet whether this is seen in patients or has implications for cardiotoxic risk in long‐term follow‐up is unknown. Methods: Leveraging consecutive patients treated with alloHSCT, genotyped using deep‐amplicon sequencing to detect the presence of CH, we assessed the development of new (incident) AF, by CH status. Secondary outcomes were the occurrence of major adverse cardiac events, defined as heart failure, myocardial infarction, AF, symptomatic ventricular arrhythmias, and cardiovascular death after alloHSCT. We also assessed the relation between CH and post‐alloHSCT cancer survival outcomes. Observed incident AF rates were compared with Framingham heart predicted rates. Multivariable regression and survival analyses were used to define the relation between CH and incident AF, major adverse cardiac events, progression‐free survival, and overall survival. We also explored these relationship by specific mutation and by varying variant allele frequency. Results: Overall, 201 patients with deep sequencing after alloHSCT were identified (median age, 59 years; 46.3% with hypertension; and 42.3% with CH, including 29.5% with ≥2 mutations). Over a median follow‐up of 35 months, 11.5% of patients developed incident AF, and 29.9% experienced major adverse cardiac events. In those without prior AF, the weighted‐average incidence was 407 per 10 000 person‐years compared with the Framingham‐predicted 63 per 10 000 person‐years (risk ratio, 6.4; P P =0.03), cancer‐progression (HR, 2.6 [95% CI, 1.3–5.2]; P =0.006), and death (HR, 2.1 [95% CI, 1.0–4.3]; P =0.047). There was no difference in non‐AF major adverse cardiac events. Conclusions: Collectively, these data suggest among patients treated with alloHSCT, the presence of CH appears to portend increased AF risk, though validation in larger prospective studies is needed.

Aggressive T-cell lymphomas (TCL) account for 10-15% of non-Hodgkin lymphomas (NHL) with weaker responses and shorter durations to chemotherapy than other types of NHL. Current therapies for patients with relapsed/refractory Cutaneous T-cell lymphoma (CTCL) have limited efficacy, and short durations of response. Gemcitabine and liposomal doxorubicin have shown single-agent activity in TCL and combined have activity in relapsed B-cell lymphomas. We evaluated outcomes of 18 patients with relapsed/refractory aggressive TCL (13 CTCL, 5 PTCL) treated with a gemcitabine plus liposomal doxorubicin (GemDox) combination and evaluated outcomes with a specific focus on CTCL patients. Significant responses were observed in CTCL patients with an overall response rate of over 80%. In all patients, objective responses were seen in eight patients (50%), with six patients (5 CTCL) able to proceed to allogeneic stem cell transplant. Given limited treatment options for r/r CTCL, GemDox should be considered a therapeutic option in relapsed/refractory CTCL.

Peripheral T-cell lymphomas (PTCLs) are a group of heterogeneous lymphomas with poor overall prognosis, particularly in the setting of relapsed/refractory PTCL. Given the limited efficacy of current therapies, several different novel therapies encompassing multiple different mechanisms of action have been evaluated for relapsed and refractory PTCLs. In this review, we explore the current standard of care for relapsed/refractory PTCL, and evaluate in depth novel and emerging therapies, their scientific basis, and current trials for relapsed/refractory PTCL.

Extranodal natural killer/T(NK/T)-cell lymphoma (ENKTL) is a rare subtype of non-Hodgkin lymphoma that typically presents with an isolated nasal mass, but a sizeable minority present with advanced stage disease and have a significantly poorer prognosis. Those with limited disease are standardly treated with chemotherapy and radiation while those with advanced stage disease are treated with L-asparaginase containing chemotherapy regimens. The addition of modern radiation therapy techniques and the incorporation of L-asparaginase into chemotherapy regimens have significantly improved outcomes in this disease, but relapses and death from relapsed disease remain frequent. Given the high rate of relapse, several novel therapies have been evaluated for the treatment of this disease. In this review, we explore the current standard of care for ENKTL as well as novel therapies that have been evaluated for its treatment and the biologic understanding behind these therapies.