We present, to our knowledge, the first reported case of germline neurofibromatosis Type 2 (NF2) associated with renal cell carcinoma unclassified with medullary phenotype (RCCU-MP) with somatic loss by immunohistochemistry of the SMARCB1 tumor suppressor gene located centromeric to NF2 on chromosome 22q. Our patient is a 15-year-old with germline neurofibromatosis Type 2 (NF2) confirmed by pathogenic mutation of c.-854-??46+??deletion. Her NF2 history is positive for a right optic nerve sheath meningioma, CNIII schwannoma requiring radiation therapy and post gross total resection of right frontotemporal anaplastic meningioma followed by radiation. At age 15 she developed new onset weight loss and abdominal pain due to RCCU-MP. Hemoglobin electrophoresis was negative for sickle hemoglobinopathy. Chemotherapy (cisplatin, gemcitabine and paclitaxel) was initiated followed by radical resection. Given the unique renal pathology of a high grade malignancy with loss of SMARCB1 expression via immunohistochemistry, and history of meningioma with MLH1 loss of expression and retained expression of PMS2, MSH2 and MSH6, further germline genetic testing was sent for SMARCB1 and mismatch repair syndromes. Germline testing was negative for mutation in SMARCB1. Therefore, this is the first reported case of RCCU-MP associated with germline NF2 mutation. This suggests the importance of closer surveillance in the adolescent and young adult population with NF2 with any suspicious findings of malignancy outside of the usual scope of practice with NF2.

INTRODUCTION We report the first known cases of pediatric glioblastoma (GBM) with prior clinical NF1 diagnoses, one with concurrent germline Lynch syndrome (LS) and NF1, and the other with somatic NF1 mutation and germline constitutional mismatch repair deficiency (CMMRD). METHODS Two pediatric GBM cases with prior NF1 clinical diagnoses based on neurocutaneous criteria were reviewed. Next generation sequencing and immunohistochemical staining were used for somatic and germline NF1 and MMR gene mutation detection, and for MMR protein expression, respectively. RESULTS Sixteen year old male with prior NF1 clinical diagnosis had resection of right frontal GBM revealing somatic mutations of POLE and PMS2, but not NF1. His father had confirmed LS with MSH2 mutation and no neurocutaneous stigmata. Patient’s germline testing revealed both pathogenic MSH2 plus NF1 mutations confirming LS and NF1. Treatment consisted of chemoradiation with temozolomide followed by adjuvant temozolomide with stable disease at 8 cycles. Nineteen year old male with former NF1 clinical diagnosis had 2 GBMs, first in left midbrain biopsied revealing somatic PMS2 and NF1 mutations underwent radiation then 7 cycles of temozolomide, then new left frontal GBM underwent resection followed by radiation and 5 cycles of pembrolizumab stable at 5th cycle. CONCLUSION Children with NF1 stigmata and GBM can have concurrent NF1 and LS, or CMMRD with NF1 somatic mutations. Our patients tolerated alkylating agents, despite risk for secondary malignancies as upfront therapy and at recurrence checkpoint inhibitors. Upfront therapy in GBM with mismatch repair syndrome with checkpoint inhibitors should be studied.

Introduction: Langerhans Cell Histiocytosis (LCH) is an inflammatory myeloid neoplastic disorder. Patients with recurrent or refractory LCH are at increased risk of mortality and long-term morbidity. The standard of care for high-risk LCH patients who are refractory to vinblastine/prednisone or who relapse is very high dose While mostly cytarabine/cladribine. While effective, this strategy also has very high treatment-related mortality. Clofarabine is a nucleoside analog with efficacy in other myeloid malignancies. Case reports have suggest that is has activity in LCH and other histiocytic disorders at moderate doses. The purpose of this study was to report the efficacy and toxicity profile of a restrospective cohort of patients with histiocytic disorders treated with clofarabine. Methods: Medical records were retrospectively reviewed for 26 pediatric patients with histiocytic disorders who were treated with clofarabine. Twenty-one of these patients had LCH and had failed at least one prior systemic therapy, while the remaining 5 patients had other histiocytic disorders (JXG, Rosai-Dorfman disease or mixed histiocytic disease). Patients were treated for a minimum of 6 months of with clofarabine (25 mg/m2/day x 5 days every 28 days), were reassessed for response at the end of therapy and monitored for relapse or progression post-treatment. Results: All patients in this series started treatment under the age of 18 years old (median=1.5 years; range: 0.3-16.3). Patients with LCH had received a median of 3 prior treatments (range:1-5). A majority of the patients (n = 17, 65%) were received all clofarabine infusions in an outpatient clinic. The most common adverse event was fever requiring hospital admission (n = 18; 69%), followed by Grade 3 neutropenia (n = 12; 46%), and intractable nausea/vomiting (n = 7; 27%). Additional adverse events included Grade 3 anemia, Grade 2 dehydration, Grade 3 cytopenias, and Grade 3 infection. Overall survival was 100%. LCH patients who completd 6-months of clofarabine had an 85% overall response (33% complete response, 52% partial response); 10% progressed on therapy and 5% had stable disease. Relapse occurred in 5 (28%) patients with LCH after completion of treatment (median time to relapse=22 months; range: 1-42). The odds of relapse was approximately 4-times greater in LCH patients with CNS involvement (n=16) compared to those without (n=4), and also in those with high risk disease (n=5) relative to standard risk (n=10). One of the patients who experienced disease recurrence received an additional 12 cycles of clofarabine and is currently doing well with no active disease. Conclusions: Clofarabine may be an effective and relatively safe salvage therapy for LCH and other histiocytic disorders. Future prospective trials for patients with refractory histiocytic disorders will directly compare efficacy and toxicity relative to other current salvage strategies with cytotoxic nucleoside analogs or targeted inhibitors. Disclosures No relevant conflicts of interest to declare.