Gaucher disease (GD) is a progressive macrophage lipidosis capable of causing disabling and life-threatening complications. Anecdotal experiences suggest that GD may go undiagnosed for many years, leading to severe complications that are preventable or reversible by enzyme replacement therapy (ERT) with imiglucerase. We conducted surveys of patients and Hematology-Oncology specialists to assess the frequency of diagnostic delays. Additionally, we report a series of patients who suffered diagnostic delays and as a result developed disabilities including potentially life-threatening manifestations of GD. Of 136 patients surveyed, the average time from first appearance of GD symptoms to final diagnosis was 48.7 ± 123.6 months. More than two-thirds were evaluated and managed by a Hematologist-Oncologist (Hem-Onc). A global survey of 406 Hem-Oncs found that only 20% considered GD in the differential diagnosis for all of its classic symptoms (cytopenia, hepatosplenomegaly, bone pain); the diagnosis considered most likely included leukemia, lymphoma, and multiple myeloma. To illustrate actual consequences of diagnostic delays, we describe 14 patients with GD who suffered from symptoms for up to 10 years before correct diagnosis. Diagnostic delays led to complications that are preventable or reversible with ERT (i.e., avascular necrosis, severe bleeding, chronic bone pain, life-threatening sepsis, pathologic fractures, growth failure, liver pathology). Patients homozygous for N370S mutation in this series were vulnerable to diagnostic delays. In conclusion, prolonged diagnostic delays occur in GD and may result in severe disease manifestations. Our findings suggest that physician education will increase the likelihood of prompt detection of GD and improve its management with ERT with imiglucerase when indicated. Am. J. Hematol. 82:697-701, 2007. V

e16798 Background: There are no accepted guidelines for testing individuals at elevated risk for developing pancreatic duct adenocarcinoma (PC). We initiated a prospective screening and surveillance program for individuals at elevated risk for PC. Methods: Eligibility for the Pancreatic Cancer Early Detection Protocol (PCEDP) was based on germ line status and/or family history of PC, provided that the imparted risk was either five times that of the general population or 7.5% lifetime risk for developing PC. Testing was continued alternating between Endoscopic Ultrasound (EUS) and Magnetic Resonance Imaging (MRI) of the abdomen. Objectives were was to analyze the number, type, and location of pancreatic conditions found and their associations with genetic or family history; and to evaluate the outcomes and/or complications that may have resulted from our testing. Results: From April 2014 through October 2019 we received 238 queries, out of which 75 individuals (31%) enrolled in the PCEDP. Eligibility was based upon individual’s germ line only (45%), family history only (32%), and both (23%). Germ line mutations were observed in 34 (BRCA2), 9 (BRCA1), 4 (ATM), 3 (PALB2), and 3 (CDKN2A) individuals. Median age at consent was 57, 60% were female,and88%, 4%, 3%, and 1% self-identified as Caucasian, African American, Hispanic, and Asian, respectively. 133 EUS procedures and 83 MRIs have been performed. No serious adverse events occurred. Standard Insurance approved and paid for the vast majority of tests. Four individuals withdrew (5%) and three (4%) were lost to follow up. Ten individuals (13%) were found to have abnormal findings in the pancreas and therefore met an endpoint of the study, including seven anechoic cysts and three suspected intraductal papillary mucinous neoplasms (IPMN). All individuals with endpoints were recommended to continue surveillance with EUS. Eight of the ten endpoints were found on baseline EUS, one one from baseline MRI, and one was found on the 3rd EUS. One of the individuals with a 2.5cm IPMN seen on baseline EUS underwent a subsequent distal pancreatectomy, with pathology revealing high grade dysplasia. Conclusions: Screening and surveillance for PC using EUS alternating with MRI was feasible and well tolerated in our population of individuals with an elevated risk. Baseline EUS was successful in detecting 10/75 = 13% of enrollees with some abnormal pancreatic finding, including one requiring intervention with a high grade pre-malignant IPMN.

Gaucher disease (GD) is a progressive lysosomal storage disease that can lead to life-threatening complications. Anecdotal experiences of patients and physicians suggest that symptoms and signs of the disease may go undiagnosed for many years, resulting in severe yet preventable complications. We conducted surveys of patients and Hematology/Oncology specialists to assess the frequency of diagnostic delays. Furthermore, we reviewed a series of patients in whom prolonged misdiagnosis resulted in serious complications of GD. Of 136 patients surveyed, the average time from first appearance of GD symptoms to final diagnosis was 3–4 years. Up to 86% of patients reported having visited a Hematologist/Oncologist (Hem/Onc) concerning their condition and two thirds reported current management of their symptoms by a Hem/Onc. The frequency of intial symptoms at presentation to Hem/Oncs is depicted in Table 1. In a global survey of 406 Hem/Oncs, only 20% of respondents considered GD in the differential diagnosis when presented with all six classic symptoms: anemia, thrombocytopenia, hepatomegaly, splenomegaly, bone pain, bone crisis. In contrast, the diagnoses considered more frequently for this constellation of symptoms were leukemia (65%), lymphoma (36%), and multiple myeloma (22%). When asked to list additional signs and symptoms of GD other than the six classic symptoms, 47% could not list any additional manifestations; the common signs and symptoms of easy bruising and bleeding, fatigue, and pathological fractures were identified by 9%, 5%, and 4% of respondents, respectively. Fifty-three percent of surveyed Hem/Oncs considered their specialty the best equipped to manage Gaucher patients and their self-assessed knowledge of GD on a scale of 1 (not at all knowledgeable) to 10 (extremely knowledgeable) was 4.1±2.4, with responses showing normal distribution around the mean. In a review of 14 patients with GD in whom up to 10 years elapsed from the appearance of symptoms to final diagnosis of GD, reversible or preventable complications occured including avascular necrosis, bleeding, chronic bone pain, life-threatening sepsis, pathologic fractures, growth failure and liver pathology. In this series, patients with GBA genotype N370S/N370S, which is typically associated with a mild GD phenotype, were most vulnerable to diagnostic delays. In conclusion, prolonged diagnostic delays occur frequently in GD that may result in severe complications. Physician education is needed to increase early detection of patients with GD and improve its management, and Hem/Oncs have a unique opportunity for timely diagnosis and optimal management of this treatable disorder. Table 1. Symptoms of Patients Presenting to Hematologists/Oncologists Signs and Symptoms Percentage of Patients (n = 92) *Including thrombocytopenia, anemia, epistaxis, chronic infection, leg pain, enlarged liver and/or spleen Easy bruising or bleeding 51.1% Enlarged abdomen 46.7% Fatigue 31.5% Pain in bone and joints/bone fractures 26.1% Delayed growth 17.4% Other* 29.3%

Background: Subcutaneous Panniculitis-like T-cell lymphoma (SPTCL) is a rare, often aggressive T-cell lymphoma. Recently it has been appreciated that there are two clinical courses, whereby some patients have rapidly progressive disease and others have a chronic course. The likelihood of an aggressive course may be dependent on the T-cell receptor phenotype expressed by the tumor, with γ/δ expression portending a worse outcome than α/β expression. In the WHO-EORTC classification γ/δ expressing cases of SPTCL are provisionally renamed as Primary Cutaneous γ/δ T-cell lymphoma. Although most reported cases have been treated with combination chemotherapy, there are no prospective trials for the treatment of SPTCL. With chemotherapy, only a minority of patients have durable remissions; the majority have either primarily refractory disease or relapses. Bexarotene is an oral retinoid used for the treatment of mycosis fungoides and other T cell lymphomas. Patients and methods: We treated eight SPTCL patients with bexarotene. There were four women and four men, with a median age of 56 years (range 23–80). All patients presented with disseminated subcutaneous nodules, Stage IV, but without extracutaneous involvement. Three patients presented with pancytopenia, without bone marrow involvement, suggestive of hemophagocytic syndrome. Four patients had an elevated LDH and four had ECOG PS > 2. Five patients received bexarotene as primary treatment. Three patients had progression of disease after previous combination chemotherapy. Doses of bexarotene ranged from 100mg/m2 – 450 mg/m2. All patients received at least one month of therapy. Results: Overall 5/8 (63%) patients responded. Two patients progressed at one and three months. One of these patients could only tolerate 100mg/m2. One patient had stable disease for four months. Two patients had partial responses (PR) lasting 10 and 18 months. One of the PR patients was given chemotherapy to induce a remission prior to a planned allogeneic stem cell transplant. They progressed on CHOP and ICE and then responded again to bexarotene. Three patients achieved a complete response (CR). Two remain in CR at 14 and 26 months on bexarotene. The other patient had a CR lasting 33 months. Bexarotene was then discontinued due to hypertriglyceridemia, and the patient developed new lesions within three months. As expected with bexarotene, toxicities of treatment were limited to hypertriglycerides and hypothyroidism. IPI was not predictive of response to therapy. Both patients with documented γ/δ T-cell receptors achieved a PR. Conclusion: Bexarotene showed a high response rate in SPTCL, which characteristically responds poorly to chemotherapy. These responses included patients with both γ/δ and α/β T-cell receptors. Given bexarotene’s favorable toxicity profile and demonstrated activity, it represents an excellent treatment option for patients with this rare T-cell lymphoma. Further study is required to determine whether bexarotene is best used as a single agent, or as part of combination or sequential therapies.

BACKGROUND: Metastasis is the primary cause of death in breast cancer, yet no current therapies specifically inhibit metastasis. TMEM (Tumor Microenvironment of Metastasis) are the portal for tumor cell intravasation into the circulation and subsequent metastasis (Harney et al Cancer Discov 2015 [PMCID:4560669). The potent Tie2 kinase inhibitor rebastinib inhibits intravasation at TMEM sites, reduces circulating tumor cell (CTC) burden, prevents distant metastases, and improves survival in breast cancer animal models when added to either P or E (Karagiannis et al STM 2017 [PMCID:5592784]; Harney et al MCT 2017 [PMCID:28838996]). We hypothesized that the addition of rebastinib to antitubulin therapy (P or E) in patients with HER2- MBC would be safe, and by inhibiting TMEM function, would also reduce CTC burden by blocking hematogenous dissemination. METHODS: The primary objective was to determine the safety and recommended phase 2 dose (RP2D) of rebastinib (2 dose levels: 50 mg or 100 mg PO BID) in combination with P (80 mg/m2 x 12 weeks) or E (1.4 mg/m2 on day 1 & 8 q 21 days) using a standard 3+3 design (1 cycle = 21 days). Secondary objectives included evaluating the effect of the P/E + rebastinib combination on CTCs (TelomeScan). Dose limiting toxicity (DLT) was defined as grade 3-4 febrile neutropenia, thrombocytopenia, and non-hematologic toxicity during the first 6 weeks of therapy. Eligibility included HER2- MBC, ECOG PS 0-1, progression after a CDK4/6 inhibitor if ER+. Patients with ≤ 2 prior non-taxane chemotherapy regimens received P+ rebastinib, whereas those with ≥ 2 chemo regimens (including a taxane) received E+ rebastinib. RESULTS: Of 10 treated patients, 6 received rebastinib + P and 4 received rebastinib + E (2 non-evaluable due to rapid disease progression [n=1] and non-compliance [n=1]). Among 10 patients who received 48 treatment cycles, only 1 patient (treated with eribulin) had grade 3 events (anemia and neuropathy after week 6) potentially related to treatment. When combined with P, the RP2D of rebastinib was 100 mg PO BID, with DLT occurring in 0/6 patients. When combined with E, 0/2 evaluable patients had a DLT at 50 mg BID of rebastinib (accrual ongoing). Best response included partial response/stable disease in 4(2PR/2SD) of 5 treated with P+ rebastinib (1 too early), and 2(1PR/1SD) of 4 treated with E+ rebastinib. CTCs decreased during therapy (baseline vs. day 43, median decrease 99.7 %) and 4/8 patients converted from CTC+ to CTC-. CONCLUSIONS: When combined with P x 12 weeks, the RP2D of rebastinib is 100 mg PO BID. The P/E + rebastinib combinations are associated with antitumor activity and exhibit pharmacodynamic evidence suggesting TMEM function blockade. We plan to further evaluate the P+ rebastinib combination as neoadjuvant therapy in the I-SPY program, and continue further evaluation of P/E + rebastinib combinations in MBC. Citation Format: Jesus D. Anampa, Xiaonan Xue, Sun-young Oh, Noah Kornblum, Sara Sadan, Maja Oktay, John Condeelis, Joseph A. Sparano. Phase Ib study of rebastinib plus antitubulin therapy with paclitaxel (P) or eribulin (E) in patients with HER2 negative metastatic breast cancer (MBC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT021.

10533 Background: The BAP1 gene ( B RCA1-Associated Protein) encodes a protein ubiquitin carboxyl-terminal hydrolase (BAP1), which removes ubiquitin moieties and regulates various cellular functions including DNA repair. This association has driven interest in defining if BAP1 variants confer susceptibility to PARP inhibitors (PARPi). Germline and somatic BAP1 alterations are both rare, mostly unique, often classified as VUS’s, and associated with a broad range of overlapping tumor types. Based on the identification of a BAP1 R146K VUS variant in tumor, also previously identified as germline, an analysis of BAP1 codon 146 alterations was initiated to explore potential genetic and therapeutic implications. Methods: 394,756 tumor specimens were tested using hybrid capture-based genomic profiling (Foundation Medicine) for all variant types and Tumor Mutational Burden (TMB). BAP1 codon 146 cases were analyzed for clinicogenomic features and germline results when available. Results: BAP1 codon 146 variants were identified in 23 unique patients across the following tumor types: cholangiocarcinoma (CCA) (4), mesothelioma (4), NSCLC (3), RCC (2), ocular melanoma (2), and carcinoma of unknown primary (CUP) (3); many of which overlap with known and suspected germline associated BAP1 syndromic tumor types. BAP1 R146 mutations were classified as VUS in 16 patients and 7 were likely or known pathogenic. In 20 of the 23 cases where zygosity could be determined 16 (80%) were homozygous and 4 (20%) were heterozygous. In 2 of the 3 NSCLC cases, the BAP1 variant appeared likely somatic and/or associated with a high TMB. A previously reported germline BAP1 variant in a RCC patient, R146K, occurred 5 times in our tumor database. One case which was homozygous in tumor and confirmed in germline occurred in a patient who had both breast and CCA. She also had a sibling with RCC who shared the germline BAP1 R146K variant along with multiple 1st and 2nd degree relatives with RCC, mesothelioma, melanoma, liver cancer, colon cancer, and a cancer of unknown primary. Conclusions: Codon 146 of BAP1 localizes to the UCH (ubiquitin carboxyl hydrolase) domain, which includes the BARD1 interaction region. Loss of BAP1 activity as a consequence of germline or somatic mutation likely impacts ubiquitination status and activity of downstream proteins, such as those involved in DNA repair. For patients with suspected BAP1 inactivating alterations, often seen in non-homologous recombination deficiency related tumor types, PARPi therapy may be relevant. As demonstrated here, variants identified through tumor testing may also aid in re-classification of germline VUS’s. These results support the further investigation and validation of BAP1 alterations for germline risk stratification and therapeutic strategies with either PARPi and/or other therapies specific to tumors with impaired chromatin remodeling.

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