Scheckel, Caleb

Background: Langerhans cell histiocytosis (LCH) is the most common histiocytic disorder that is now recognized as a neoplasm by the World Health Organization. It is generally classified based on the site and extent of disease involvement (single system or multisystem). Pulmonary LCH (pLCH), an uncommon interstitial lung disease associated with smoking, often presents as isolated pulmonary disease. It is unclear whether patients with clinically isolated pLCH have extra-pulmonary lesions at diagnosis or during the course of their disease. The role of [18F] fluorodeoxyglucose positron emission tomography-computed tomography (FDG-PET-CT) in the staging of pLCH remains unclear. Our study aims to better characterize the utility of radiographic staging studies at time of diagnosis and prevalence of extrapulmonary disease at follow up in pLCH. Methods: We conducted a retrospective study of patients presenting with clinical findings consistent with isolated pLCH seen at the Mayo Clinic from January 2000 to January 2020. All patients had a diagnosis of pLCH determined by chest imaging studies [computed tomography (CT) or high-resolution CT (HRCT)] or by histopathologic findings from surgical or transbronchial lung biopsy. Histopathologic findings for the diagnosis of pLCH required the presence of Langerhans cells (S100+/CD1a+/Langerin+). Patients were excluded if they had clinically apparent extra-pulmonary organ involvement at the time of diagnosis. BRAF V600E mutation was determined by immunohistochemistry (IHC) or cell-free DNA (cfDNA). Staging was defined as FDG-PET-CT or whole body CT imaging obtained within 3 months of diagnosis of pLCH. Extra-pulmonary LCH involvement was determined by imaging characteristics or by histopathologic findings. Descriptive statistics and overall survival (OS) were analyzed with JMP software, version 14 (SAS Institute Inc., Cary, NC). Results: A total of 112 patients with clinically isolated pLCH were identified. The median age at diagnosis was 45 years (range 21-73), and 48 (43%) were male. The majority (n=110, 99%) were former or current smokers with a median pack year of 25 (range 1-57). Three (3%) patients were noted to have occupational industrial exposure. Nine patients had a history of another cancer prior to their diagnosis and staging of pLCH [lung (n=4), breast (n=2), neuroendocrine (n=2), thyroid (n=1)]. Presenting symptoms included dyspnea on exertion 49 (44%), cough 18 (16%), chest pain 14 (13%), and 29 (28%) were incidentally discovered on imaging studies. On HRCT, the following characteristics were observed: 42 (38%) cystic, 32 (29%) cystic and nodular, 37 (33%) nodular, 1 (<1%) ground glass opacities. Seventy (63%) patients had lung biopsy confirmation, of which 11 (16%) patients underwent BRAF V600Emutation testing (7 by IHC, 4 by cfDNA). Six (55%) of these 11 patients were positive for BRAF V600E mutation. 34 (30%) patients underwent radiographic staging studies within 3 months of diagnosis of pLCH (25 FDG-PET-CT and 9 whole-body CT), and none of these imaging studies showed evidence of extra-pulmonary disease. Of the patients who had at least one year of follow-up (n=52), one (2%) developed extra-pulmonary disease. This patient did not undergo initial staging studies, developed headaches and was found to have a large calvarial lytic lesion within 2 months of pLCH diagnosis (BRAF V600E+). Among those who did not undergo staging at diagnosis (n=78), long term (>5 years) follow up data were available for 23 (29%), and none developed extra-pulmonary disease as determined by clinical notes or imaging studies. No patient had evidence of new extra-pulmonary involvement or second malignancy at the time of last known follow-up. After a median follow-up duration of 2.4 years (95% CI: 1.5-3.6, range: 0.1-17) ten (9%) patients died, of which 5 died of pLCH related complications. The median OS for entire cohort was 15 years (95% CI 9.1-not reached, Figure 1). Conclusion: Our study shows that adult patients with clinically isolated pLCH rarely present with extra-pulmonary manifestations at diagnosis or at follow up. These findings suggest a limited role of routine radiographic staging studies in pLCH unless clinically indicated. Studies on longer follow up of this cohort would provide further insights into the natural history of pLCH and are underway. Disclosures Bennani: Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board; Kite/Gilead: Research Funding; Affimed: Research Funding. Shah:Dren Bio: Consultancy.

Introduction: The 2013 ASH Choosing Wisely campaign recommends against thrombophilia testing in patients with major transient risk factors for venous thromboembolism (VTE). Our Special Coagulation Laboratory (SCL) offers an algorithmic approach to thrombophilia testing which includes assays for lupus anticoagulant, dysfibrinogenemia, anticoagulant proteins (protein C, protein S, antithrombin), activated protein C resistance with reflex to factor v Leiden (if indicated), and prothrombin G20210A mutation. Samples are received through Mayo Clinic Laboratories (MCL), national and international reference laboratory (often with limited or no clinical information) and from internal Mayo Clinic practice. We hypothesized that thrombophilia testing would decline in cases where it was recommended against following the publication of testing guidelines. Methods: We audited the external thrombophilia testing samples between2013-2019 and internal samples between 2014-2019 (periods during which they were available). For the internal samples, complete test volumes were only available 2014-2019. Because external clients may either adopt internal testing or contract with a different reference laboratory, many clients may not have been retained over the entire observed period. To better understand the ordering practices of consistent clients, external clients which did not have thrombophilia testing sent to MCL each year of the observed period were excluded. We separated internal ordering practices by hematology and oncology or thrombophilia clinic staff and trainees contrasted with those of other specialties. Results: MCL received 18,529 external thrombophilia testing samples from 322 external healthcare systems during the observed period. From 37 clients, 5,878 (38.2%) samples met inclusion criteria. Annual volume of samples ranged from 890 in 2013 to 861 in 2019 (861-1046). Special coagulation lab processed 11,639 internal thrombophilia tests during the observed periods. There was a consistent small annual increase in testing with 1,398 performed in 2014 and 2,430 in 2019. Of 11651 tests ordered, only 18.6% (2167) were ordered by people most likely to be familiar with ASH choosing wisely campaign. Annual thrombophilia testing ordered by hematology and oncology or thrombophilia clinic staff increased from 307 in 2014 to 387 in 2019 (307-432). However, the ordering practices of these providers as a proportion of overall practices declined from 22.0% (307/1398) in 2014 to 15.9 % (387/2430) in 2019. Table Discussion: Our preliminary data showed no significant trend in thrombophilia ordering practices among included external clients since publication of the ASH Choosing Wisely guidelines on thrombophilia testing. Internally we found a consistent small rise in numbers of thrombophilia tests ordered since 2014 but this may reflect changes in patient volume. We observed that the majority of internal thrombophilia testing was ordered by non-hematology/oncology or thrombophilia providers who are perhaps less likely to be familiar with ASH Choosing Wisely guidelines. The proportion of testing ordered by hematology & oncology or thrombophilia providers declined during the observed period. Our findings are limited by lacking information on the indication and appropriateness for testing as well as possibility of change in patient population. However the overall trend in test volumes and specialty of ordering providers deserves attention and highlight the value in educating other medical societies on ASH Choosing Wisely recommendations for thrombophilia testing. Future work will focus on appropriateness for thrombophilia testing including the indication and time (remote from anticoagulation and acute thrombotic episode), location of testing (inpatient vs. outpatient), as well as investigating if testing has changed patient management, which may help in creating new Choosing Wisely recommendations for thrombophilia testing. Figure 1. Disclosures Pruthi: HEMA Biologics: Honoraria; Bayer Healthcare: Honoraria; Merck: Honoraria; Instrumentation Laboratory: Honoraria; Genentech Inc.: Honoraria; CSL Behring: Honoraria.

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.

126 Background: Pharmacogenomics (PGx) is a developing field in individualized medicine concerned with understanding genetic polymorphisms that may explain inter-individual variation in drug efficacy and toxicity. Understanding these polymorphisms is a key tool in guiding clinician’s selection and dosing of specific medications to optimally manage patient symptoms. Common pharmacogenes that impact analgesic prescribing include: CYP2D6, OPRM1, and COMT; for mood disorders: CYP2C19. This cross-sectional study explored the activity of pharmacogenes of clinical significance in palliative medicine with either Level 1 or 2 evidence. Methods: We performed PGx testing on 50 new referrals to the palliative medicine clinic with an active malignancy. Each patient underwent PGx testing with clinical pharmacist review and interpretation prior to their initial office appointment. Results: In our cohort 54% were men and the mean age was 64.7 (24-87). The average number of medications, medication allergies, and creatinine clearance were 10.5 (1-22), 1.3 (0-13), and 78.4 (31-120), respectively. Among the pharmacogenes impacting opiate and antiemetic prescribing, 14% (7/50) of patients were poor metabolizers of CYP2D6 and 8% (4/50) were rapid or ultra-rapid metabolizers. Another 60% (30/50) showed intermediate metabolism which would impact initial dosing. Poor metabolism of COMT or OPRM1 was seen in 8% (4/50) with another 36% (18/50) demonstrating rapid metabolism. Activity for the pharmacogene CYP2C19, which impacts many psychotropics, revealed 32% (16/50) rapid or ultra-rapid metabolizers and no poor metabolizers. Overall, 66% (33/50) of patients had pharmacogene activity suggestive of significant clinical impact necessitating either drug avoidance due to toxicity risks or substantial dose adjustment to be efficacious. Conclusions: Polymorphisms impacting pharmacotherapy were common in our cohort. Patients with difficult-to-control symptoms or multiple medication toxicities can utilize PGx testing as a guide to symptom relief. As PGx technology becomes readily accessible and economical, opportunities for patients to have precision genomic information guide healthcare decisions is expected to increase.

Introduction: The compulsive craving and consumption of non-food substances, known as pica, is a well-documented symptom associated with iron deficiency anemia (IDA). Olfactory cravings associated with IDA are a recently described phenomenon known as desiderosmia. In our practice we observed a subset of patients with IDA who report specific tactile cravings associated with mastication. Methods: This study included patients from the Mayo Clinic (Rochester, MN) and Ankara Training and Research Hospital (Ankara, Turkey) Hematology practices who self-reported tactile mastication cravings during initial evaluation for IDA between 1/1/18 and 6/30/19. Information including sociodemographics, substance craved, values of hemoglobin (Hgb), mean corpuscular volume (MCV), and ferritin before and after iron replacement therapy, and symptom resolution after treatment were recorded. Results: We observed 12 patients with IDA who self-reported chew cravings during initial evaluation. All patients were female and the median age was 41.5 years (33-59). Of these 12 patients, median baseline Hgb, MCV, and ferritin were 9.4 g/dL (6.6-12.9), 73.7 fL (59.1-95.1), and 6 µg/L (2-21), respectively. Tactile cravings included chewing gum (3), mastic gum (2), ginseng (1), dry oats (1), crackers (1), pickles (1), chips (1), sawdust (1), and knitting rope (1). Many patients reported the frequency and satisfaction of these cravings resulted in jaw pain as well as the persistence of cravings despite this discomfort. Only 16.7% (2/12) reported concurrent ice pica. In total, 9 patients proceeded with observed treatment of their IDA with clinical follow-up and laboratory confirmation of iron repletion. Oral (ferrous glyconate or ferrous fumarate) and intravenous (ferric carboxymaltose, iron sucrose, or low molecular weight iron dextran) iron replacement were used in 33.3% (3/9) and 66.7% (6/9) patients, respectively. Post-treatment median laboratory values include: Hgb 12.7 g/dL (10.8-14.7), MCV 80.1 fL (76.1-91.7), and ferritin 98 µg/L (24-398). Overall, 88.9% (8/9) reported resolution of chew cravings after iron repletion. The lone patient with persistent symptoms had a baseline ferritin of 10 µg/L, improved to 398 µg/L after replacement, and settled back at 42 µg/L three months later. Discussion: Our patient experience provides suggestive evidence that oral tactile craving symptoms, distinct from ice pica, exists in a subset of patients suffering from IDA. For this, we propose the term "desideromastica" derived from the Latin words "desiderare" for desire and "mastica" for chew. "Desidero" can also be indicative of a reduction in iron, which relates to iron deficiency. Our hope in naming this relatively unexplored symptom associated with IDA will encourage additional clinicians to share their experience and guide future investigation. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: Primary refractory and early relapsed acute myeloid leukemia (RR-AML) continue to pose a therapeutic challenge. Salvage therapy treatment regimens for refractory and relapsed disease are not standardized but include the commonly-used mitoxantrone, etoposide, and cytarabine (MEC) and cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M). Previous studies have suggested a potential benefit of CLAG-M, and therefore we performed an analysis of consecutive patients selected to receive either CLAG-M or MEC as salvage therapy for RR-AML. Methods: The study included 150 consecutive patients with RR-AML who received either CLAG-M or MEC between 09/01/2009 and 12/31/2017. Patients were identified through a pharmacy database based on use of mitoxantrone. Baseline disease and patient-related characteristics and clinical outcomes including allogeneic transplantation (ASCT) were obtained by systematic review of EMR. Overall survival (OS) and progression free survival (PFS) were estimated according to the Kaplan Meier method and log-rank test was used to compare outcomes between patients who received either of the two regimens. Results: There were 150 consecutive treated patients with RR-AML included in this analysis, 34 patients received CLAG-M and 116 patients received MEC. The median age was 57 years (18-76), and, and 52% were male. Forty-seven (31%) were treated for early relapsed disease (<6 months after successful induction), 17% (>6 months after induction), and the remainder had primary refractory disease (mean number of induction regimens was 1.8, range 1-6). AML risk was defined by cytogenetic criteria. There were a predominance of intermediate-risk subtypes at 47% (71/150) and followed by high-risk at 37% (55/150). Overall CR/CRi rates for CLAG-M and MEC were 74% (23/31) and 58% (63/108) in patients eligible for analysis (p=0.18). The median follow-up from relapse was 23.5 months (1-76). The median OS was 9.5 months for CLAG-M and 10.0 months for MEC (HR=0.88, 95%CI=0.54-1.41, p=0.59). In total, 76 patients (51%) were able to proceed to ASCT following salvage therapy with either CLAG-M or MEC. Among transplant recipients 56% (19/34) and 49% (57/116) were treated with CLAG-M and MEC, respectively. Median OS after ASCT was 13.0 months for CLAG-M and 31.0 months for MEC (HR=1.76, 95%CI=0.87-3.56, p=0.12). The median OS for refractory AML was 13.0 and 66.0 months for CLAG-M and MEC recipients, respectively (HR=0.92, 95%CI=0.46-1.84, p=0.24). Median OS for those with early relapse was 12.0 months for CLAG-M and 10.0 months for MEC (HR=0.69, 95%CI=0.22-2.11, p=0.51). Lastly, among those who had late relapse, median OS was 9.0 and 48.0 months for CLAG-M and MEC, respectively (HR=17.6, 95%CI=1.57-198, p<0.001). A univariate analysis was performed to investigate the impact of factors associated with OS, including treatment, age, gender, whether they proceeded to ASCT, cytogenetic risk type, and donor source. ASCT was associated with significant improvement in both PFS (HR=0.24, 95%CI=0.16- 0.37, p<0.001) and OS (HR=0.26, 95%CI=0.17-0.40, p<0.001) in this cohort. Age greater than 65 was associated with worse PFS (HR=1.02, 95%CI=1.00-1.03, p=0.04) but not OS (HR=1.01, 95%CI=1.00-1.03, p=0.06) after controlling for other variables including the impact of ASCT. Discussion: Despite a lower 30-day induction mortality we did not identify significant differences in outcomes among patients selected to receive CLAG-M vs. MEC. There was a statistically significant improvement in survival in patients who had late relapses and were treated with MEC, and a trend towards improvement in OS of those treated with MEC who proceeded to ASCT. As expected, ASCT was associated with significant improvement in OS in this cohort, and our results strongly support the use of ASCT as consolidation of remission after relapse for AML. Our data suggests that MEC may be a superior regimen, in particular including those with late relapse. Figure. Figure. Disclosures Foran: Agios: Research Funding; Xencor, Inc.: Research Funding. Al-Kali:Novartis: Research Funding. Palmer:Novartis: Research Funding.