Citations

Importance Lichen planus is a chronic, highly pruritic, inflammatory disease that affects the skin and other tissues. Objective To evaluate the efficacy and safety of ruxolitinib, 1.5%, cream in patients with cutaneous lichen planus. Design, Setting, and Participants This phase 2, 16-week, randomized, double-blind, vehicle-controlled trial with a 16-week open-label extension was conducted from November 2022 to February 2024. Patients were enrolled from 19 sites in the US and Canada. The trial included adults with predominantly cutaneous lichen planus, an Investigator’s Global Assessment (IGA) score of 3 or 4, an Itch Numerical Rating Scale score of 4 or greater, and an affected body surface area of 20% or less were enrolled. Data were analyzed from February to August 2024. Interventions Patients were randomized 1:1 to ruxolitinib, 1.5%, twice daily cream or vehicle cream for 16 weeks, after which eligible patients applied ruxolitinib cream twice daily as needed in a 16-week, open-label extension. Main Outcomes and Measures The primary end point was IGA treatment success (IGA score of 0 or 1 [clear/almost clear skin] with a ≥2-grade improvement from baseline) at week 16. Results Among 64 randomized patients, 46 (72%) were female, 18 (28%) were male, 18 (28%) were African American/Black, 4 (6%) were Asian, 40 (63%) were White, and the median (range) age was 57.0 (18-78) years. Significantly more patients who applied ruxolitinib, 1.5%, cream vs vehicle achieved IGA treatment success (50.0% [95% CI, 31.9%-68.1%] vs 21.9% [95% CI, 9.3%-40.0%], respectively; response rate difference, 29.4% [95% CI, 7.6%-51.3%]; P = .01; primary end point) at week 16, with further improvement to week 32. Similar results were observed in the proportion of patients who achieved a 4 or greater–point improvement from baseline in Itch Numerical Rating Scale score (week 16, 48.4% [95% CI, 30.2%-66.9%] vs 16.1% [95% CI, 5.5%-33.7%]; response rate difference, 33.5%; 95% CI, 12.2%-54.9%; P = .004; secondary end point). No serious treatment-emergent adverse events or discontinuations due to an adverse event were observed with ruxolitinib cream. Conclusions and Relevance The results of this randomized clinical trial suggest that ruxolitinib cream significantly reduced lesions and itch in patients with lichen planus. Therefore, ruxolitinib cream represents a potential treatment option for patients with cutaneous lichen planus. Trial Registration ClinicalTrials.gov Identifier: NCT05593432

Abstract Background: The Multiple Myeloma Research Foundation (MMRF) and its partners launched the MyDRUG platform clinical trial (NCT03732703) to evaluate the safety and efficacy of genomically-guided treatments for functional high-risk relapsed/refractory myeloma patients (fHRMM). fHRMM patients with no discernible activating mutations and who had received 1-3 prior therapies (exposed to at least one proteasome inhibitor and an IMiD) were given a combination of daratumumab (D), ixazomib (I), pomalidomide (P) and dexamethasone (d) (D-IPd) quadruplet therapy. The goal of this study is to evaluate the immunomodulatory effects of daratumumab-(anti-CD38)-based therapy on fHRMM patients enrolled in the MMRF-sponsored MyDRUG umbrella clinical trial over the duration of therapy and to correlate immune changes with patient response immediately following the first two cycles of therapy. Methods Bone marrow (BM) aspirates were collected at baseline (BL) prior to therapy, at the end of 2 cycles (EOC2), 4 cycles (EOC4) of the quadruplet therapy and at the end of treatment (EOT) or progressive disease (PD). CD138-negative bone marrow mononuclear cells were isolated for profiling the immune microenvironment using scRNAseq, scTCRseq and CyTOF. Results Single-cell RNA and TCR profiles were generated from ~90,000 cells across 41 samples from 16 subjects. scRNAseq identified CD3+ T cells, NK cells, classical and non-classical monocytes and B cells. CD8+ T cells were further resolved into their subsets including precursor (TPEX) and terminally exhausted T cells (TEX) within the bone marrow microenvironment. Within the CD8+ T cell compartment, an expansion of the effector memory (TEM) cell population was observed following 2-cycles of therapy (EOC2). However, this TEM expansion was not sustained at timepoint EOC4. Towards the end of therapy, enrichment of precursors to putative exhausted and terminal dysfunctional effector memory cells (TEMRA) was observed. Subjects with partial (PR), very good partial (VGPR) and complete (CR) best overall responses showed an initial increase in TEM cells followed by a slow expansion of TEX and TEMRAcells over time. One patient with progressive disease (PD) maintained the highest LAG3 expression across the cohort among CD8 T cell subsets (TEMRA, EM) and CD4 Tregs at baseline while observing a significant upregulation of PDCD1 in CD4 Tregs and CD8 Naive cells by EOC2. Cell-cell communication network analysis identified secreted ligands between responders (CR/VGPR) and partial responders (PR) at EOC2. Samples with PR exhibited upregulation of signaling of TNF from the CD8 Naïve compartment (p=0.048, Wilcoxon), IFNG from the CD8 EM (p=0.073, Wilcoxon) and TEMRA (p=0.048, Wilcoxon) populations along with IFNG (p=0.073, Wilcoxon) from NK cells. CD14+ and CD14+16+ Monocytes on the other hand showed enrichment of LGALS9 (p=0.03 (CD14+), p=0.048 (CD14+CD16), Wilcoxon) in the PR group at EOC2 relative to responders. Finally, longitudinal tracking of T cell clonality showed preferential progressive expansion of TEMRA cells after the therapy. We mapped hyperexpanded (more than 16 copies) clonotypes, presumed to be tumor-reactive, to various CD8+ T cell subsets. These hyperexpanded clonotypes are mapped to the TEMRA, TEX and TEM CD8+ T cells. Analysis of TCR repertoires clonality and diversity also demonstrated a reduced richness and increased clonality of CD8+ TCRs in responders. Summary/Conclusion These preliminary analyses of D-IPd quadruplet therapy of RRMM indicate that paired single cell RNA and TCR sequencing of BM T cells suggests a selective expansion of clonotypic CD8+ T cells. When considering patient response, the only PD patient profiled in this study maintained an exhaustive signature (LAG3, PDCD1) in multiple T cell compartments at BL. The differential expression of the receptor ligand pairs after treatment between different clinical response groups suggests an altered TME response that may inform future therapeutic stratification. These results support further explorations of rational combinations of targeted and immune therapies for greater efficacy in this disease.

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults, with a dismal 5-year survival rate of ~6.5%. Vasogenic cerebral edema is a severe complication that occurs in the majority of GBM patients, leading to a significant increase in intracranial pressure, neurological deficits, and increased mortality rates. GBM-associated edema is almost exclusively managed by the corticosteroid dexamethasone, the use of which is associated with immunosuppression and interference with radiation therapy. While there is considerable research on edema formation, little is known about how edema resolution occurs in GBM, particularly in response to dexamethasone or other anti-edema therapies. This gap in understanding highlights the need for new approaches to treat edema effectively. The water channel aquaporin-4 (AQP4), a key player in the brain’s water homeostasis, is upregulated in GBM compared to the normal brain. To investigate the role of AQP4 in GBM-associated edema, we used the RCAS/tv-a system to generate de novo GBM with different driver mutations in Aqp4 knockout (KO) and wild-type (WT) mice. Our results indicated that Aqp4 KO tumor-bearing mice had shortened survival and increased edema content. Additionally, Aqp4 loss decreased astrocyte coverage specifically in the tumor core but not the tumor periphery. Our single cell RNA-seq data suggested that Aqp4 loss led to an astrocytic shift towards a less reactive, progenitor-like state, while also decreasing the myeloid and CD8+ T cell population in the tumor microenvironment. Interestingly, tumor-bearing mice treated with anti-VEGFA antibody, which has anti-edema properties, showed increased expression of Aqp4 and reduced vessel leakage. This suggests that AQP4 plays a critical role in mediating the effects of anti-VEGFA therapy. Overall, this study highlights the important role of AQP4 in the resolution of edema, while also revealing its additional effects on astrocyte activation and the immune microenvironment in GBM.

Abstract Background: The goal of this study is to evaluate the immunomodulatory effects of daratumumab-(anti-CD38)-based therapy on fHRMM patients enrolled in the MMRF sponsored MyDRUG umbrella clinical trial (NCT03732703) over the duration of therapy and to correlate immune changes with patient response. Methods: fHRMM who had received 1-3 prior therapies (exposed to at least one proteasome inhibitor and an IMiD) were given a combination of daratumumab (D), ixazomib (I), pomalidomide (P) and dexamethasone (d) (D-IPd) quadruplet therapy. Bone marrow (BM) aspirates were then collected from patients prior to therapy (BL), after 2 cycles (EOC2), after 4 cycles (EOC4) of the quadruplet therapy and at the end of treatment or disease progression (EOT). Immune and tumor fractions were enriched by CD138 selection. Here, CD138- bone marrow mononuclear cells were isolated and transcriptionally profiled by scRNAseq and scTCRseq. Results: Single-cell RNA and TCR profiles were generated from ∼90,000 cells across 41 samples from 16 subjects. scRNAseq identified CD3+ T cells, NK cells, classical and non-classical monocytes and B cells. CD8+ T cells were further resolved into their subsets including precursor (TPEX) and terminally exhausted T cells (TEX) within the bone marrow microenvironment. Within the CD8+ T cell compartment, an expansion of the effector memory (TEM) cell population was observed following 2-cycles of therapy (EOC2). However, this TEM expansion was not sustained at timepoint EOC4. Towards the end of therapy, enrichment of precursors to exhausted and terminal dysfunctional effector memory cells (TEMRA) was observed. Subjects with partial (PR), very good partial (VGPR) and complete (CR) best overall responses showed an initial increase in TEM cells followed by a slow expansion of TEX and TEMRA cells over time. Longitudinal tracking of T cell clonality showed preferential progressive expansion of TEMRA cells after the therapy. We mapped hyperexpanded (more than 16 copies) clonotypes, presumed to be tumor-reactive, to various CD8+ T cell subsets. These hyperexpanded clonotypes mapped to the TEMRA, TEX and TEM CD8+ T cells. Analysis of TCR repertoires clonality and diversity also demonstrated a reduced richness and increased clonality of CD8+ TCRs in responders. Conclusions: Paired single cell RNA and TCR sequencing of BM T cells from RRMM patients receiving D-IPd quadruplet therapy revealed a selective expansion of clonotypic CD8+ T cells with a clonal replacement of BM exhausted clonotypes by dysfunctional circulating CD8+ T cells in responders over time. Citation Format: Chaitanya R. Acharya, Darwin D'souza, Reyka Jayasinghe, Mark Hamilton, Zhihong Zhihong, Seunghee Kim-Schulze, Hearn J. Cho, Shaji Kumar, George Mulligan. The immunomodulatory effects of daratumumab-based therapy on functional high-risk relapse/refractory multiple myeloma (fHRMM) patients enrolled in the MyDRUG trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5258.

Background Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. Methods Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2–5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. Results M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. Conclusions Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.

AbstractObjectivesT-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell leukemia usually characterized by inv(14)(q11.2q32)/t(14;14)(q11.2;q32). In this study, we aimed to investigate the clinicopathologic features and molecular profile of T-PLL associated with t(X;14)(q28;q11.2).MethodsThe study group included 10 women and 5 men with a median age of 64 years. All 15 patients had a diagnosis of T-PLL with t(X;14)(q28;q11.2).ResultsAll 15 patients had lymphocytosis at initial diagnosis. Morphologically, the leukemic cells had features of prolymphocytes in 11 patients, small cell variant in 3, and cerebriform variant in 1. All 15 patients had hypercellular bone marrow with an interstitial infiltrate in 12 (80%) cases. By flow cytometry, the leukemic cells were surface CD3+/CD5+/CD7+/CD26+/CD52+/TCR α/β+ in 15 (100%) cases, CD2+ in 14 (93%) cases, CD4+/CD8+ in 8 (53%) cases, CD4+/CD8– in 6 (40%) cases, and CD4–/CD8 + in 1 (7%) case. At the cytogenetic level, complex karyotypes with t(X;14)(q28;q11.2) were seen in all 15 patients assessed. Mutational analysis showed mutations of JAK3 in 5 of 6 and STAT5B p.N642H in 2 of 6 patients. Patients received variable treatments, including 12 with alemtuzumab. After a median follow-up of 17.2 months, 8 of 15 (53%) patients died.ConclusionsT-PLL with t(X;14)(q28;q11.2) frequently shows a complex karyotype and mutations involving JAK/STAT pathway, and it is an aggressive disease with a poor outcome.