William A. Robinson

Background/Objectives: Mucosal melanoma is a rare, aggressive melanoma subtype with lower response rates to immune checkpoint inhibitors than cutaneous melanoma. We previously identified reduced expression of innate immune pathogen-sensing pathway genes in mucosal melanoma, including components of the retinoic acid-inducible gene-I (RIG-I) pathway, and found that decitabine can induce re-expression of these immune genes and tumor-associated antigens. This study evaluated epigenetic immune priming with oral decitabine/cedazuridine (DEC-C) combined with nivolumab in patients with unresectable or metastatic mucosal melanoma. Methods: NCT05089370 was an open-label, single-center, single-arm phase Ib/II trial. Patients received DEC-C (35 mg decitabine/100 mg cedazuridine) orally for five days followed by nivolumab 480 mg every four weeks. The primary endpoint was safety and determination of the recommended phase II dose (RP2D). Secondary endpoints included objective response rate (ORR) and survival outcomes. Exploratory endpoints assessed immune and epigenetic correlates. Results: Eight patients were enrolled. Treatment-related adverse events occurred in seven patients (88%), with dose-limiting toxicities observed in three (38%). The RP2D was not established due to premature trial closure. At data cut-off, two patients remained on treatment with ongoing partial responses. The ORR was 25% (95% CI, 3.2–65), median progression-free survival was 3.0 months (95% CI, 2.1–not reached), and median overall survival was 7.2 months (95% CI, 4.4–not reached). Treatment significantly decreased global DNA methylation and induced RIG-I pathway genes in circulating immune cells. Conclusions: DEC-C plus nivolumab was associated with frequent treatment-related toxicities consistent with the known safety profiles of decitabine and nivolumab and demonstrated on-target epigenetic and immune activity in circulating cells. Although two partial responses were observed, the small sample size and wide confidence interval preclude conclusions regarding efficacy. These findings support future biomarker-integrated studies evaluating epigenetic immune-priming combinations in mucosal melanoma, with prospective optimization of dose, schedule, and treatment setting.

Rare melanoma subtypes, including acral, mucosal, and uveal melanomas, exhibit limited responses to immune checkpoint inhibitors (ICI), yet the molecular mechanisms of immune resistance remain poorly defined. This study aimed to characterize transcriptional programs associated with immune evasion across melanoma subtypes and identify strategies to restore immune gene expression in rare melanomas. We performed transcriptomic profiling of xenografts derived from patients with melanoma and publicly available tumor datasets to compare intratumoral gene expression across cutaneous and rare melanoma subtypes. Cross-subtype analysis revealed convergent downregulation of innate immune pathogen sensing (IIPS) and type I interferon signaling pathways in rare melanomas compared with cutaneous tumors. Lower IIPS expression correlated with nonresponse to PD-1 blockade, which was associated with reduced CD8+ and memory CD4+ T-cell infiltration and enrichment of M2 macrophages inferred by CIBERSORT. Immunomodulatory compounds were screened in vitro to identify IIPS-inducing drugs, and decitabine was further evaluated in mucosal and uveal melanoma xenograft models. Decitabine treatment robustly induced IIPS and antigen presentation genes in rare melanoma cell lines and xenografts, with RNA sequencing confirming IIPS reexpression as the dominant transcriptional consequence. Silencing of IIPS genes represents a recurrent immune evasion mechanism in rare melanomas. Decitabine reverses this silencing, restoring innate and adaptive immune gene expression, and may serve as a therapeutic priming strategy to enhance ICI responsiveness in patients with rare melanoma subtypes.

Introduction: Hairy cell leukemia (HCL) is an uncommon hematopoietic stem cell disease known to have an underlying somatic BRAF ^V600E driver mutation. Currently, the most accepted treatment is five or seven consecutive days of outpatient infusion of cladribine (e.g., continuous infusion), despite frequent antibiotic use and hospitalization with this regimen. As a result, a few investigators have adopted weekly infusion of cladribine with similar or improved results and fewer side effects. Methods: We conducted a retrospective, single‐institution cohort study of 36 treatment‐naïve patients with HCL treated at the University of Colorado Hospital. Eighteen patients received intermittent weekly cladribine (intermittent cladribine [IC]) for 5–7 doses and 18 received standard daily cladribine (continuous cladribine [CC]) over 5–7 days. We report clinical cohort characteristics, response rates, progression‐free survival, overall survival, toxicity, hospitalization rates, and measurable residual disease monitoring in select patients using peripheral blood quantitative BRAF ^V600E PCR. Results: We report here our experience with 18 patients with newly diagnosed BRAF ‐mutated HCL treated with weekly cladribine at a single institution compared to 18 HCL patients who received continuous infusions. Baseline hematologic parameters and overall survival were comparable between groups ( p = 0.1135), but there was a higher rate of complete remission for patients treated with IC (94.4% vs. 61.1%) with significantly improved progression‐free survival ( p < 0.0001). We observed comparable rates of neutropenia, neutropenic fever, antibiotic use, and G‐CSF administration. There were fewer hospitalizations for patients treated with IC (4/18) compared to patients treated with CC (6/18). Rituximab exposure differed between groups, with 72% of patients in the IC cohort receiving rituximab compared with 27.2% in the CC cohort (although treatment status was documented for only 66.7% of patients in the CC cohort). Peripheral blood BRAF ^V600E allele burden significantly declined and correlated with clinical remission, but this was only performed in select patients who were treated in recent years. Conclusions: In this retrospective analysis, IC dosed weekly was associated with improved progression‐free survival and higher rates of complete remission compared to CC with comparable toxicity and fewer hospitalizations. These findings suggest a potential clinical benefit from this regimen. However, interpretation of these findings is limited by the non‐randomized design and differences in rituximab exposure between groups, which may have contributed to the observed outcomes and limited definitive conclusions. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission

Background/Objectives: Immunotherapy has significantly improved clinical outcomes for patients with late-stage melanoma, yet a substantial portion of patients fail to respond to these treatments. The variability in responses to immunotherapy, both among individual patients and across different melanoma subtypes, underscores the need to explore the influence of circulating factors such as oxylipins on therapeutic outcomes. This study investigated the relationship between serum oxylipin profiles and response to immune checkpoint inhibitor therapy in melanoma subtypes to identify potential metabolic biomarkers for treatment response. Methods: In a retrospective cohort study, serum samples from 43 stage III and stage IV melanoma patients treated at the University of Colorado Hospital from 2010 to 2023 were analyzed via ultra-high-pressure liquid chromatography-mass spectrometry. Melanoma patients were treated with anti-PD-1 monotherapy or combination immune checkpoint inhibitor therapy, and response was assessed using RECIST 1.1 criteria. Results: We determined that global oxylipin metabolite profiles are largely uniform pre- and post-treatment across melanoma subtypes, including cutaneous, acral, mucosal, and uveal melanoma. Prostaglandin J₂ was more abundant in rare melanoma subtypes, including acral, mucosal, and uveal melanoma, compared to cutaneous melanoma. Conclusions: Despite limited variation in serum oxylipin molecular species by subtype and response status, we observed significant differences in prostaglandin J₂, which could serve as a potential biomarker for immune checkpoint inhibitor therapy response in melanoma.

Trial inclusion/exclusion criteria

Supplementary figure 1. (A) Changes in other circulating cytokines. Colored box denotes the time when the patients were being treated with ATRA. (B) example gating strategy for CD8+ T cell activation.

Representativeness of study participants

Supplementary figure 2. Changes in other clinical hematologic measures. Colored box denotes the time when the patients were being treated with ATRA. * Denotes p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001.

All adverse events experienced by patients, including those unrelated to treatment

Characteristics of patients experiencing clinical benefit