Hu, Marie

7018 Background: Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm driven by MAPK-ERK mutations in majority of patients. Contemporary data on treatments and outcomes in adult LCH are lacking. Hence, we undertook this study to analyze a large cohort of adult LCH patients. Methods: This was a retrospective study of adult (≥18 years) LCH patients seen at our institution between 1998 and 2018. Results: We included 186 patients with adult LCH (median age 43; 19-88), and 54% were females. 70% of patients were diagnosed after 2007. Common presenting symptoms were cough/dyspnea (30%), rash (17%), pain/swelling in head (17%), and diabetes insipidus (10%). 70 (38%) patients had multisystem LCH, 62 (33%) had isolated pulmonary LCH, and 35 (19%) had unifocal LCH. Common sites of involvement included lung (59%), bone (37%), skin (21%), and nervous system (16%). 121 (65%) were smokers; 48% of these had lung disease, while 52% had multisystem disease. 18 of 31 tested (58%) patients had BRAF-V600E mutation. Most common first-line treatment was smoking cessation in 24 patients, and led to an overall response rate (ORR) of 83% in pulmonary lesions. Radiation therapy was used in 11 patients, and led to an ORR 82%. Surgical resection of lesion was done in 23 patients, with relapses in 24%. Systemic therapies were used in 78 (42%) patients (Table). Most common first-line systemic therapy was cladribine with ORR of 78%. Vemurafenib was used in 3 patients with BRAF-V600E, leading to an ORR of 67% . After a median follow-up of 23 months (0-261), 21 patients had died. Of these, 10 died of progressive LCH. Median OS was not reached, and mean OS was 196 months. Conclusions: This is the largest contemporary series of adult LCH. It shows that diverse clinical spectrum, ranging from benign course to a progressive multisystem disease. Although smoking cessation was an effective treatment for pulmonary LCH, a large subset required systemic chemotherapy. [Table: see text]

Introduction Langerhans cell histiocytosis (LCH) is an uncommon histiocytic disorder which is now categorized as a hematopoietic neoplasm. Most treatment and outcomes data in LCH are derived from pediatric studies, and there is a lack of FDA-approved treatment options for adult LCH. There is some evidence that cladribine may be toxic to monocytes and monocyte-derived dendritic cells. In this study, we report the efficacy of cladribine in adult LCH patients seen at our institution. Methods We retrospectively reviewed the charts of all LCH patients seen at our institution between 1998 and 2018. Where necessary, the radiological images and histopathological slides were reviewed by an expert radiologist and pathologist. Since prospective uniform response assessment was not performed, we utilized the clinical documentation and radiological reports to assess the overall response rate (ORR). All time to event analyses were performed from the time of cladribine initiation. Results We included a total of 37 adult LCH patients in the study. The median age at diagnosis for this cohort was 35 years (range, 21-76), and 51% were males. Although 31 (84%) patients had multi-system disease, all patients had more than one LCH lesion (multifocal). Most commonly involved organs were bone (65%), lung (60%), skin (38%), lymph nodes (30%), and pituitary/hypothalamus (27%). BRAF-mutational analysis was performed in 13 patients, with 7 (54%) demonstrating the presence of BRAF-V600E mutation. Cladribine was administered as first line therapy in 22 (59%) patients and subsequent line treatment in 15 (41%). Of the 15 patients who received cladribine in subsequent line, surgery (n=3), radiation (n=3), steroids (n=3), antibiotic with inhaled steroids (n=1), vinblastine (n=3), topical nitrogen mustard cream (n=1) and vemurafenib (n=1) were the treatments utilized before the initiation of cladribine. Two patients received the drug more than once during the course of their disease. The dosing of cladribine for all patients was based on one of the two intravenous regimens (0.14 mg/kg for days 1-5 every 28 days or 5 mg/m2 for days 1-5 every 28 days). The median follow-up for the entire cohort was 4.5 years (95% CI:2-7) and the treatment outcomes are shown in Table 1. Median number of cycles of cladribine administered was 1.5 (range, 1-9). Clinical/radiographic responses were noted in 29 (78%) patientsORR was 78%, with 24% complete responses and 54% partial responses (PR). Responses were seen in various disease sites: lung nodules/infiltrates (13/29, 45%), bone (12/29, 41%), lymph nodes (8/29, 28%), skin (3/29, 10%), pituitary/hypothalamus (4/29, 14%). Eight (22%) patients did not respond and had progressive disease (PD)- cystic/bullous lung disease (n=2), skin (n=2), abdominal/peritoneal lymph nodes (n=2), and hypothalamus (n=3).The treatment was well tolerated, with grade 3 or above adverse effects seen in three patients: two with lymphopenia requiring dose delays and one with congestive cardiac failure leading to drug discontinuation. After initial disease response, PD was seen in three patients. 89%, 78%, 64% of those who responded initially maintained their responses at years 1, 3, and 5, respectively (Table 1). The 5-year progression free survival (PFS) was 55% for the entire cohort. BRAF-status was evaluated on 13 of 37 patients in the entire cohort (35%): BRAFV600E positive [n=7 (53%)] and WT [n=6 (46%)]. Of the 7 patients who had BRAFV600E mutation, responses were seen in 71%, while 100% of those without BRAFV600E achieved a response (p=0.09). At the time of last follow-up, 9 patients (24%) were dead. Of those, cause of death were available on 5 patients; due to LCH (n=1), stroke (n=1), gastrointestinal hemorrhage (n=1), acute myeloid leukemia (n=2). Conclusion In our study, cladribine monotherapy yielded a high ORR, with the majority of patients achieving a PR. The responses were durable with a small risk of subsequent disease relapse. Responses were seen irrespective of the presence of BRAFV600E mutation. Cladribine was well tolerated overall, and may be considered a potential therapy for adult LCH patients. Disclosures Vassallo: Sun Pharmaceuticals: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Sun Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. OffLabel Disclosure: Cladribine for langerhans cell histiocytosis

Purpose: Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder that presents with a wide spectrum of clinical diseases, ranging from single-organ lesions to systemic disease. Although previously thought of as an immune disorder, LCH was reclassified as an inflammatory myeloid neoplasm in the 2016 Histocyte Society classification after discovery of BRAF V600E or MAP2K1 gain-of-function mutations and evidence of clonality in most LCH patients. In this revised classification, LCH was divided into single-system LCH, pulmonary LCH, or multisystem LCH. However, there is a lack of data on clinical features and outcomes in the subgroup of "unifocal" non-pulmonary LCH in adults. In this study, we sought to address the gaps in knowledge for unifocal adult LCH utilizing our institution's experience over 20 years. Methods: We retrospectively reviewed the medical records of 189 adult patients (defined as >18 years old at diagnosis) with histopathologically confirmed LCH who were seen at our tertiary referral center between 1997 and 2018. Of these, 44 met criteria for unifocal LCH at diagnosis after careful exclusion of other sites of disease involvement. Results: We included 44 adult patients with unifocal LCH at diagnosis, with median age 42 years (range 19 to 88) and 55% males. 84% were Caucasians and 50% were smokers. Most commonly involved disease sites included bone (43%), skin (25%), pituitary (14%), and gastrointestinal (11%), with common presenting symptoms of head pain/swelling (25%), skin rash (20%), abdominal pain/diarrhea (11%), and diabetes insipidus (9%). Resection/excision was the most common first line therapy in 24 patients (63%); none had local recurrence and 3 patients developed recurrence at a new site. Radiation was the second most common therapy in 6 patients, with an overall response rate of 83%; none had local recurrence and 1 patient had recurrence at a new site. Other less common first-line treatments included resection followed by radiation (2), topical immunosuppression (2), dexamethasone (1), cladribine (1), smoking cessation (1), and observation (1) (Table 1). Cladribine used as first-line therapy for pituitary LCH resulted in progressive disease, but cladribine used as second-line therapy in 2 cases (including one who had progressed to multisystem disease) resulted in partial remission with no further recurrence in both cases. Patients were followed for a median of 3.8 years (range 0.1 to 18.8), with 5 patients lost to follow-up. By time of last follow-up, 11 (28%) had developed recurrence: 1 had local recurrence, 5 developed disease at a new site within the same system (skin or bone), and 5 developed multisystem disease (Figure 1). Median time to recurrence was 2 years (range 0.2 to 6.6). 2 out of 5 patients tested for BRAF had a V600E mutation, both of whom had isolated unifocal bone disease and remained in complete remission following resection at time of last follow-up. Median overall survival (OS) from time of diagnosis was not reached and overall 5-year OS was 94%. 3 patients died, only 1 of progressive LCH. Conclusion: In our study, most patients with unifocal adult LCH achieved a complete remission with surgical resection or local radiation. None of the patients treated with resection or radiation developed local recurrence, but around 1 in 5 developed distant recurrence within 5 years. However, the overall prognosis was very good, and none of the patients in the cohort progressed to "high-risk" organ (liver, spleen, or bone marrow) involvement or pulmonary involvement. Further studies are warranted to assess the role of MAPK-ERK mutations in the prognosis of unifocal LCH. Disclosures Bennani: Seattle Genetics: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding. Vassallo:Sun Pharmaceuticals: Research Funding; Sun Pharmaceuticals: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding.