12066 Background: Pruritus is a debilitating symptom in oncologic patients, sometimes leading to interruption of cancer therapy. Gabapentinoids such as gabapentin and pregabalin are effective for the treatment of uremic and neuropathic pruritus. We report on the safety and efficacy of gabapentinoids for oncologic pruritus defined as any pruritus originating from malignancy, oncologic therapies, or other cancer-associated toxicities, such as cutaneous graft-versus-host disease (GVHD). Methods: In this single-center retrospective cohort study conducted at the Memorial Sloan Kettering Cancer Center between 4/1/2019 and 8/1/2024, 224 patients who were prescribed gabapentinoids for oncologic pruritus were included. Patients taking gabapentinoids for indications other than pruritus were excluded. The primary efficacy endpoint was ≥ 1-grade improvement for pruritus severity on the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 scale. Results: The cohort was predominantly male (54%) and White (67%), with Black (14.3%) and Asian (12.5%) patients also represented; the mean age was 63.2 ± 15 years. Gabapentinoids were most prescribed for drug-induced causes (58.9%) and malignancy-related pruritus (14.3%). Of the drug-induced causes, immune checkpoint inhibitors (40.2%), monoclonal antibodies (12.9%; including mogamulizumab, brentuximab vedotin, and enfortumab vedotin), and tyrosine kinase inhibitors (11.4%) were the most common triggers. Pregabalin was more commonly prescribed compared to gabapentin (80.8% vs. 19.2%). Ninety percent of patients (n=202) experienced a ≥1-CTCAE grade improvement at a median total daily dosage of 50 mg (IQR, 25 mg) for pregabalin and 300 mg (IQR, 50 mg) for gabapentin. Median time for patient-reported improvement was 18.5 days and there was no significant difference in gabapentin response between pruritus etiologies. The most common adverse event was sedation (8.5%), with 3 patients discontinuing gabapentinoids due to fatigue. Conclusions: This study is the first to report that gabapentinoids are a safe and effective way to treat oncologic pruritus stemming from malignancy, cancer therapies, or cutaneous GVHD. Prospective trials would further establish gabapentinoids’ safety and efficacy profile in the oncologic population. Outcomes & adverse events of patients on gabapentinoids. Variable Category/Statistic N (%) CTCAE Grade Change Did Not Improve (0 Grade) 22 (9.8%) Improved 1 Grade 132 (58.9%) Improved ≥ 2 Grade 70 (31.3%) Antineoplastic Therapy Interrupted Due to Oncologic Pruritus Yes 26 (11.7%) No 157 (70.4%) Not Applicable 40 (17.9%) Adverse Events* Sedation 19 (8.5%) Leg Swelling 2 (0.9%) Other 9 (4.0%) *The remaining 194 (86.6%) patients did not report any adverse events related to the gabapentinoids.

Importance:Hypopigmented mycosis fungoides (HMF) is uncommon in adults, and data on clinicopathologic features and long-term outcomes remain sparse. Objective:To investigate the clinicopathologic features and outcomes of adults with HMF in a large multicenter cohort. Design, Setting, and Participants:This retrospective multicenter cohort study conducted from January 2011 to October 2023 at 6 US tertiary referral centers and included adults (18 years or older at diagnosis) with biopsy-confirmed HMF and hypopigmentation documented at diagnosis, with a median (range) follow-up of 39 (1-347) months. Data were analyzed from February to December 2025. Exposures:Clinical variant, immunophenotype predominance, and polymerase chain reaction-based T-cell receptor (TCR) gene rearrangement in peripheral blood and/or skin. Main Outcomes and Measures:Best overall response, defined as complete response, partial response, stable disease, or progressive disease, and progression to a higher stage. Results:The cohort included 224 adults with HMF (median [range] age, 44 [18-74] years), of whom 164 (73%) were women (60 men [27%]), 5 (2%) were Asian individuals, 1 (0.4%) was a Hispanic/Latino individual, 1 (0.4%) was a Middle Eastern individual, 19 (8%) were White individuals, and 186 (83%) were Black individuals; 219 (98%) presented with early-stage disease. Most had hypopigmented lesions only (159 [71%]), whereas 65 (29%) exhibited mixed-variant mycosis fungoides; outcomes were similar between groups. Among 141 patients with available immunophenotyping, 88 (63%) had CD8-positive predominance. Among 207 treated patients, most (179 [90%]) received skin-directed therapy alone. Among 198 evaluable patients, the best overall response was complete response for 52 (26%), partial response for 101 (51%), stable disease for 34 (17%), and progressive disease for 11 (6%). Over a median (range) follow-up of 39 (1-347) months, 14 of 224 patients (6%) experienced progression to a higher stage, including 5 of 219 patients (2%) with early-stage disease at baseline who experienced progression to advanced-stage disease. Peripheral blood TCR monoclonality was detected in 23 of 85 tested patients (27%) and was associated with poorer treatment response but not with disease progression. Conclusions and Relevance:The finding of this cohort study suggest that adult HMF demonstrated a generally indolent course, with favorable response to skin-directed therapy, irrespective of immunophenotype or mixed-variant presentation. Peripheral blood TCR monoclonality was associated with lower treatment response but not disease progression.

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma (CTCL), characterized by heterogeneous clinical behavior and variable prognosis. Accurate prognostication is essential for risk-adapted management. This review synthesizes emerging evidence on prognostic factors in MF and SS, with a focus on recent genomic advances. Traditional prognostic frameworks are outlined, highlighting the prognostic impact of demographics, stage, clinical features, and histologic findings. More advanced prognostics are then outlined, including genomic alterations and impact of the tumor microenvironment. We highlight realms in which integration of traditional and more biological prognostic frameworks can support more individualized treatment strategies.

Importance:Janus kinase 2 (JAK2) gene fusions characterize cytotoxic cutaneous T-cell lymphoma (CTCL) including primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (pcAETCL). The identification of these fusions is rarely reported in indolent CTCL. Objective:To characterize patients with CTCL to better understand the diagnostic, prognostic, and therapeutic significance of this molecular alteration in CTCL. Design, Setting, and Participants:A retrospective case series of patients with CTCL with JAK2 fusions identified between the years 2000 and 2025. Fusions were identified by a custom RNA sequencing panel and by a targeted hybrid-capture-based next-generation DNA sequencing-based panel. The study included a single referral cancer center in the US. Results:Overall, 43 patients (12 female [27.9%] and 31 male individuals [72.1%]; median [range] age, 45 [16-65] years) with CTCL who were found to have JAK2 gene fusions during evaluation and follow-up were included. Thirty-eight of the 43 identified patients (88.4%) with fusions of JAK2 and 10 different gene partners (most frequently ATXN2L, CAPRIN1, and PCM1) had mycosis fungoides (MF), CD30-positive lymphoproliferative disorders (LPD), or overlap presentations, whereas 4 pcAETCL and 1 peripheral T-cell lymphoma not otherwise specified were identified. Secondary genetic events included mutations of epigenetic and transcriptional regulators. Neither mutational burden, type, or fusion partner distinguished cases with early-stage or aggressive CTCL. Conclusions and Relevance:This case series found that JAK2 fusions were seen in aggressive cytotoxic CTCL as well as in T-cell lymphomas with more indolent behavior, possibly representing a precursor lesion to aggressive evolution with age and comorbidities. The prominence of these fusions supports a potentially larger role for JAK2 targeting in patients with early-stage MF, CD30-positive LPD, or overlap presentations.

ABSTRACT:Hemophagocytic lymphohistiocytosis (HLH) is an interferon gamma-driven hyperinflammatory syndrome with high morbidity and mortality. Identifying reliable prognostic biomarkers is challenging due to various predisposing conditions and triggers. C-X-C-motif ligand 9 (CXCL9) is a clinically validated biomarker and surrogate marker of interferon gamma-mediated inflammation. We aimed to identify the role of CXCL9 in predicting severe disease and death in adults with HLH using a multicenter retrospective cohort of consecutively hospitalized patients who underwent a clinical evaluation for HLH that included CXCL9 testing. Patients were classified as HLH if they met HLH-2004 and/or HScore criteria. Conditional inference decision trees and Cox regression models were used to identify which clinical variables associated with acute mortality in patients with HLH. Overall, 171 patients were reviewed, and 126 patients met HLH criteria. The median age was 55 years (interquartile range, 40-66), with 62% male and 51% White. CXCL9 was markedly elevated in patients with HLH. Unbiased decision tree modeling, incorporating all clinical laboratory values, identified only CXCL9 of >16 100 pg/mL as the optimal predictor of inpatient mortality. Cox regression models demonstrated that CXCL9 of >16 100 pg/mL was significantly associated with 90-day mortality when controlling for important covariates. This shorter time to death in the elevated CXCL9 subgroup remained significant even after subdividing patients into those with malignancy (n = 53) and nonmalignancy HLH (n = 73). Continuous increases in CXCL9 within the cohort strongly associated with greater mortality. CXCL9 is a novel clinical marker that identifies high-risk HLH independent of underlying disease and could be used to select patients for early and aggressive targeted immunomodulatory therapy.

Background Mogamulizumab is more effective in treating the blood component of mycosis fungoides (MF) and Sezary syndrome (SS), though some patients also experience significant skin improvement. The characteristics distinguishing those with a favorable skin response remain unclear. Objectives This study aimed to characterize MF/SS patients achieving skin response on mogamulizumab. Methods A retrospective chart review at a single cancer center included adult MF/SS patients who received at least one mogamulizumab cycle with follow-up. Skin response (≥ 50% clearance) and blood response (≥ 50% decrease in neoplastic cells/µL) were assessed alongside demographics, disease staging, and prior therapies. Results Among 56 patients (MF = 35; SS = 21), 43% achieved skin response, with a median time of 2.3 months (range 0.5-6.4). Blood response occurred in 90%, with a median time of 1.8 months (range 0.2-23). Skin-response was highest in patients with blood response (64%), blood disease (B2, 61%), and SS (57%) and was significantly associated with decreasing circulating Sezary cells (P < .001). Among patients without blood involvement (B0), 24% achieved skin response, primarily in erythrodermic cases (71% versus 11%, P = .01). Conclusions Mogamulizumab appears effective in inducing skin responses, particularly in advanced-stage and high blood-stage disease. Even in patients without blood compartment involvement, mogamulizumab therapy may still be beneficial, especially for patients with erythroderma. Skin responses are less common in early-stage MF. Patients with both advanced blood and skin disease may benefit from initiating mogamulizumab simultaneously with skin-directed therapy.

Introduction: Racial disparities in mycosis fungoides (MF) and Sezary syndrome (SS) are well-documented, with self-identified Black patients being diagnosed younger, with more advanced disease, and worse survival. (Su C et al. J Am Acad Dermatol. 2017; Wilson LD et al. Clin Lymphoma Myeloma Leuk. 2012). Our previous work showed that these disparities persist after adjusting for socioeconomic factors (Gandham AR et al. Clin Lymphoma Myeloma Leuk. 2024) suggesting genetic ancestry may contribute. We compared clinical characteristics and outcome of MF/SS patients stratified by self-reported race versus genetic ancestry. Methods: Patients with confirmed MF/SS were consented for genetic profiling via Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). Genetic ancestry was inferred using ADMIXTURE and single nucleotide polymorphisms (SNPs) captured by MSK-IMPACT (Arora K et al. Cancer discovery. 2022). Patients with ancestral fraction of >0.8 for any single population were assigned that population label; otherwise, they were considered admixed. Results: Genetic ancestry analysis of 161 MF/SS patients (104 self-reported White race, 30 Black, 7 Asian, 20 Other/Unknown) identified 74 as European (EUR), 21 Ashkenazi Jewish (ASJ), 23 African (AFR), 5 East/South Asian, 1 Native American and 37 as admixed. AFR patients were diagnosed 10 years younger than EUR/ASJ (p=0.01) and were less likely to present with stage IA disease compared to EUR/ASJ patients (0% vs 23.2%, p=0.01). Trends towards higher female dominance (52% vs. 35%, p=0.1), higher disease-related mortality (22% vs 12%, p=0.2) and worse progression-free survival (PFS, p=0.11) were observed in AFR patients. ASJ patients showed a trend toward improved PFS compared to EUR patients (p=0.08). Conclusions: Our novel ancestry-based stratification of MF/SS patients confirms disparities seen in self-reported race groups, supporting the need to further investigate specific genetic and non-genetic contributors to disparities in MF/SS patients.