Vassallo, Robert

Abstract Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm. To date, there is a lack of U.S. Food and Drug Administration–approved treatments in adult LCH to establish optimal first-line therapy. We conducted a retrospective, single-center case series evaluating the use of BRAF inhibitors in adult patients with BRAFV600E- LCH proven by biopsy. Our case series is the first to report the use of BRAF inhibitors as first-line therapy in adults with LCH. We also report the efficacy with single-agent dabrafenib in adult LCH. All but one of our patients had favorable response to targeted therapy.

Abstract Background Langerhans cell histiocytosis (LCH) is a heterogeneous disease whose myriad manifestations result from accumulation of Langerhans cells in a variety of organs most commonly including skin, bone, central nervous system, liver, lymph nodes, and bone marrow. The disease can affect people of any age. Treatment is primarily driven by disease extent and organ involvement and can range from focused radiation or surgery to multi-agent chemotherapy. There is a relatively high recurrence rate following complete remissions with conventional chemotherapy. In the first-time-in-human (FTIH) study of the oral pan-AKT inhibitor afuresertib (GSK2110183), in patients with hematologic malignancies, a patient with refractory multi-system LCH experienced a prolonged period (> 3 years) of clinical benefit on 125mg oral once daily afuresertib. This observation led to the evaluation of the use of afuresertib in patients with LCH. Methods This single-arm, open-label trial was designed to evaluate the efficacy and safety of afuresertib, administered at 125 mg once daily, in adults and adolescents with relapsed/refractory LCH and adults with treatment-naïve LCH. Secondary objectives included pharmacokinetics. Diagnosis of LCH was confirmed by pathology review of archival tissue. The Histiocyte Society criteria were used for response evaluation at three and six months with safety and pharmacokinetic assessments performed at pre-specified intervals. BRAF status from archival tissue was evaluated by Sanger sequencing. Results 17 patients (16 adults, 10 females) were enrolled; median age was 38 years (15-75). 3/17 patients had isolated pulmonary disease, 1/17 had single-system multifocal-bone disease, 1/17 had single-system skin disease, and 12/17 had multi-system disease. Seven patients were treatment-naïve; 10 had relapsed/refractory disease, including the one adolescent. The most frequent (>20% of patients) adverse events (AEs), regardless of causality, were nausea (59%), fatigue (59%), upper respiratory infection (47%), diarrhea (47%), dyspepsia (35%), bone pain (39%), asthenia (24%), memory impairment (24%), decreased appetite (24%) and vomiting (24%). Most AEs were Grade 1 or 2 in severity; no Grade 4 AEs were reported and no Grade 3 AEs occurring in more than 1 subject were reported. 6/17 (35%) had afuresertib dose modifications (interruption or reduction). Afuresertib plasma concentrations in the adult patients were similar to values seen in adult patients with other hematologic malignancies in the FTIH study. Following a single dose, the concentration-time profile in the adolescent patient was similar to adults in the FTIH study (Tmax = 3h: Cmax 229 ng/ml: AUC24 = 3893 ng*h/mL). 15 patients had archival tissues collected for BRAF testing; 13 had DNA suitable for analysis. 2/13 was BRAF V600E mutant and 11/13 were BRAF wild type. Upon evaluation of the all-treated patient population, 5/17 (29%) patients were reported as better at the three and/or six month disease assessment. Among the 5 responders, three were treatment-naïve and two had relapsed/refractory disease. The median duration on study for all patients was 214 (44-426) days. For the 5 patients who responded, the median duration on study was 372 (255-426) days. Conclusion The pharmacokinetic and safety profile of afuresertib in patients with LCH was consistent with that observed in patients with other hematologic malignancies evaluated in the FTIH study. Afuresertib was active in patients with both treatment-naïve and relapsed/refractory disease. Additional evaluation, including molecular profiling, may be warranted alone or in combination with BRAF inhibitors or established therapies for LCH to determine the optimal population of patients with LCH who might benefit from afuresertib Disclosures: Vassallo: GlaxoSmithKline: Research Funding. Oliff:GlaxoSmithKline: Employment. Morris:GlaxoSMithKline: Employment. Reedy:GlaxoSmithKline: Employment. Portnoy:GlaxoSmithKline: Stock, prior employee Other. Smith:GlaxoSmithKline: Employment, Equity Ownership. Noble:GlaxoSmithKline: Employment, stock Other. Murnane:GlaxoSmithKline: Employment, stock Other. Szabo:GlaxoSmithKline: Employment. Heaney:Novartis: Research Funding; Sanofi-Aventis: Consultancy, Research Funding; Onconova: Research Funding; Incyte: Consultancy, Research Funding.

Abstract Introduction Histiocytic neoplasms are rare hematological malignancies that have protean clinical manifestations and can pose significant management challenges. Recently, vemurafenib was approved by the US-FDA for treatment of BRAF-V600-mutant Erdheim-Chester disease (ECD). However, there is a lack of FDA-approved therapies for other histiocytic neoplasms such as Langerhans cell histiocytosis (LCH) and Rosai-Dorfman disease (RDD). Over the last 5 years, immune checkpoint inhibitors such as programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have shown significant improvement in outcomes among patients with several hematological and solid organ malignancies. In order to identify appropriate treatment candidates for these therapies, predictive biomarkers have been developed in various cancers. Evidence from solid tumors has suggested a favorable response to checkpoint inhibitor therapy with higher tumor mutational burden (TMB), defined as the number of mutations within a tumor genome. Next generation sequencing (NGS) of various tumors has shown an association between TMB of < 5 mutations/megabase (mut/Mb) to be associated with an absence of benefit from checkpoint inhibitors. In addition, high levels of PD-1/PD-L1 expression and microsatellite instability (MSI) are also correlated with response to therapy. The latter may be a result of somatic or germline alterations in DNA mismatch repair genes. In this study, we report the results for these biomarkers using NGS in patients with histiocytic neoplasms. Methods We utilized TempusTM NGS platform to analyze the tissue specimen of patients with histiocytic neoplasm. The Tempus xO Assay (Tempus Labs; Chicago, IL) combines a 1,711 gene targeted somatic and germline DNA sequencing panel with RNA-sequencing to detect both germline and somatic single nucleotide polymorphisms, indels, copy number variants, and gene rearrangements causing chimeric mRNA transcript expression in a wide array of solid tumor types. The assay utilizes formalin-fixed paraffin-embedded tumor samples and matched blood samples. TMB was calculated and reported as somatic mutations in tumor tissue per million base-pairs or mut/Mb. RNA sequencing was utilized to assess for PD-L1 and PD-1 gene expressions as compared to matched tumor and normal reference sets. Both PD-L1 and PD-1 gene expressions were reported as percentiles. DNA mismatch repair status was predicted by analysis of alterations in five common mismatch repair genes in somatic and germline DNA (MSH2, MSH6, MLH1, PMS2, and EPCAM). If there were no alterations identified in these genes, the mismatch repair status was predicted as microsatellite stable (MSS). Results A total of 13 patients with histiocytic neoplasms were included in the study. The distribution of individual histiocytic neoplasms was as follows: RDD (n=9), ECD (n=3), and LCH (n=1). The median TMB for RDD and ECD patients was 0.17 mut/Mb. For the one patient with LCH, the TMB level was 0.51 mut/Mb. Individual TMB levels are shown in figure 1. PD-L1 and PD-1 expression levels are depicted in table 1. Compared to normal reference sets, the PD-L1 expression was elevated in one patient each with RDD and ECD, and PD-1 expression was elevated in two patients each with RDD and ECD. For both ECD patients with higher PD-1 expression, NGS also showed presence of BRAF-V600E in the tumor tissue. The LCH patient had a low level of PD-L1 and PD-1 expression. For patients where evaluation of DNA mismatch repair was feasible on the tissue specimen (n=4), none showed related somatic or germline alterations. Conclusions In our series, the histiocytic neoplasms RDD, ECD, and LCH demonstrated low levels of TMB. None of the RDD and ECD patients were found to have alterations in DNA mismatch repair genes. Other markers of immunotherapy such as PD-L1/PD-1 expression appeared to be higher in ECD patients with BRAF-V600E, but in only a small subset of RDD patients. The low TMB seen in our study suggests that these histiocytic neoplasms may be less likely to respond to immune checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 agents as compared to the tumors with high TMB. Disclosures No relevant conflicts of interest to declare.

Exhausted-like CD8 + resident memory T cells in the lung limit immune activation–driven fibrosis.

Rheumatoid arthritis (RA) is a common chronic autoimmune disorder that characteristically causes joint inflammation and damage. In addition, many patients develop extraarticular manifestations which may cause significant comorbidity and premature mortality.Some respiratory tract involvement of the upper and lower airways and parenchymal disease features are unique to RA, including cricoarytenoid arthritis and RA pulmonary nodulosis, and others, especially the interstitial parenchymal involvement, occur in many other idiopathic and autoimmune diseases. The pathophysiology of lung disease is not well understood. Rheumatoid lung disease may even predate the onset of joint disease, and could be triggered by chronic airway and alveolar epithelial injury. Chronic systemic inflammation and risk factors such as cigarette smoking, infection, host genetics, and immune dysregulation are contributors. Treatment of the respiratory disease is directed at reducing the systemic inflammation of RA. Less well understood is the management of the interstitial lung disease of RA, for which antifibrotic and immune suppressive agents may be helpful. The management of RA-related lung disease is perhaps the major remaining hurdle in reduction of the disease burden related to extraarticular manifestations of this disease.

ObjectiveRheumatoid arthritis (RA) is postulated to originate at mucosal surfaces, particularly the airway mucosa. To investigate this hypothesis, we determined the association between RA and asthma, passive smoke exposure, and age at start of smoking.MethodsFor this case–control study, we identified 1,023 cases of RA (175 incident) within a single‐center biobank population, using a rules‐based algorithm that combined self‐report with 2 diagnostic codes. Exposures were self‐reported on biobank questionnaires. Logistic regression models were used to calculate the association of exposures with RA, adjusting for potential confounders. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated.ResultsAfter adjustment for allergies, urban environment, and passive smoke exposure, asthma was found to be associated with RA in the full cohort (OR 1.28 [95% CI 1.04–1.58; P = 0.02]) but not the incident RA cohort (OR 1.17 [95% CI 0.66–2.06; P = 0.60]). History of allergic disease was associated with RA in both the full cohort (OR 1.30 [95% CI 1.12–1.51; P < 0.001]) and the incident RA cohort (OR 1.61 [95% CI 1.11–2.33; P = 0.01]), especially food allergy, which was significantly associated with RA in the full cohort (OR 1.38 [95% CI 1.08–1.75; P = 0.01]) and showed a trend toward significance in the incident RA cohort (OR 1.83 [95% CI 0.97–3.45; P = 0.06]). Passive smoke exposure at home or work was not associated with RA. Finally, age at start of smoking was not associated with increased odds of developing RA in either the full cohort (OR 1.03 [95% CI 1.00–1.06; P = 0.03]) or the incident RA cohort (OR 1.00 [95% CI 0.92–1.08; P = 0.98]).ConclusionAsthma and allergies may be associated with increased risk of RA. Passive smoke exposure and early age at start of smoking do not appear to influence risk of RA.

Interleukin (IL)-17 is a T helper 17 cytokine implicated in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). Although IL-17A has a well-established role in murine pulmonary fibrosis models, its role in the tissue remodeling and fibrosis occurring in idiopathic pulmonary fibrosis (IPF) and RA-associated interstitial lung disease (RA-ILD) is not very well defined. To address this question, we utilized complimentary studies to determine responsiveness of human normal and pathogenic lung fibroblasts to IL-17A and used lung biopsies acquired from patients with IPF and RA-ILD to determine IL-17A receptor (IL-17RA) expression. Both normal and pathogenic IPF lung fibroblasts express functional IL-17RA and respond to IL-17A stimulation with cell proliferation, generation of extracellular matrix (ECM) proteins, and induction of myofibroblast transdifferentiation. Small interfering RNA (siRNA) silencing of IL-17RA attenuated this fibroblast response to IL-17A on ECM production. These fibroblast responses to IL-17A are dependent on NF-κB-mediated signaling. In addition, inhibiting Janus activated kinase (JAK) 2 by either siRNA or a selective pharmacological inhibitor, AZD1480—but not a JAK1/JAK3 selective inhibitor, tofacitinib—also significantly reduced this IL-17A-induced fibrogenic response. Lung biopsies of RA-ILD patients demonstrate significantly higher IL-17RA expression in areas of fibroblast accumulation and fibrosis, compared with either IPF or normal lung tissue. These observations support a direct role for IL-17A in lung fibrosis that may be particularly relevant in the context of RA-ILD.