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e19538 Background: Chronic neutrophilic leukemia (CNL) is a rare and aggressive myeloproliferative neoplasm with poor survival. No standard of care exists. Case reports describe allogeneic stem cell transplantation (ASCT) as the only curative therapy. Using the National Cancer Database (NCDB), we studied prognostic factors and survival outcomes of CNL. Methods: Patients diagnosed in 2004-2015 were included. 9963/3 was the ICD-O-3 code. Overall survival (OS) was analyzed using the Kaplan-Meier method. Hazard ratios (HR) with confidence intervals (CI) were calculated using Cox proportional hazards model. Variables significant in univariate analysis were included in a multivariate analysis. Data on incidence was obtained from the Surveillance, Epidemiology, and End Results Program (SEER) 21 Registries (2004-2015). The analysis was done with SEER*Stat software. Incidence was age-adjusted to the U.S. 2000 standard population. Results: A total of 121 CNL patients were in NCDB. The median age at diagnosis was 70 years (range 21-90); 74 (61%) were males and 107 (88%) were ≥ 50 years. The median follow up time was 5.8 years (interquartile range [IQR] 2.9-7.4). 32 (26%) had a Charlson Deyo score (CDS) > 1. 80 (70%) had government insurance, while 34 (30%) had private insurance. Median OS was 2.2 years (IQR 0.8-6.7). OS was 70% at 1 year, 29% at 5 years, and 11% at 10 years. The year of diagnosis was not associated with improved OS (HR: 0.95 (95% CI: 0.88-1.02), p =0.14). 71 (59%) patients received chemotherapy. The median time to chemotherapy from the day of diagnosis was 15 days (IQR 7-35). The OS of those who received chemotherapy was 71% at 1 year and 27% at 5 years versus 69% and 32% at 1- and 5- years for those who did not ( p= 0.38). 2 patients received ASCT (age 52 and 61 years) as initial therapy and both were alive at 5 years. Factors predicting inferior OS on univariate analysis were age ≥ 50 years at diagnosis ( p= 0.005), male ( p< 0.001), CDS > 1 ( p= 0.038), and government insurance ( p= 0.004). The table shows the multivariate (MV) analysis. The overall incidence of CNL was 0.1 cases/1,000,000 individuals and did not change significantly from 2004-2015. The incidences by male, female, White, Black, and American Indian/Alaska Native were also 0.1 cases/1,000,000 individuals. Conclusions: OS and incidence of CNL have not changed over the years. Age ≥ 50 years, male gender, and use of government insurance predicted inferior OS. [Table: see text]

Abstract The most common genetic abnormality in multiple myeloma is the deletion of chromosome 13, seen in almost half of newly diagnosed patients. Unlike chronic lymphocytic leukemia, where a recurrent minimally deleted region including MIR15A/MIR16-1 has been mapped, the deletions in multiple myeloma predominantly involve the entire chromosome and no specific driver gene has been identified. Additional candidate loci include RB1 and DIS3, but while biallelic deletion of RB1 is associated with disease progression, DIS3 is a common essential gene and complete inactivation is not observed. The Vk*MYC transgenic mouse model of multiple myeloma spontaneously acquires del(14), syntenic to human chromosome 13, and Rb1 complete inactivation, but not Dis3 mutations. Taking advantage of this model, we explored the role in multiple myeloma initiation and progression of two candidate loci on chromosome 13: RB1 and MIR15A/MIR16-1. Monoallelic deletion of Mir15a/Mir16-1, but not Rb1, was sufficient to accelerate the development of monoclonal gammopathy in wild-type mice and the progression of multiple myeloma in Vk*MYC mice, resulting in increased expression of Mir15a/Mir16-1 target genes and plasma cell proliferation, which was similarly observed in patients with multiple myeloma. Significance: In the absence of a defined, minimally deleted region the significance of del(13) in multiple myeloma has remained controversial. Here we show that haploinsufficiency of Mir15a/Mir16-1, but not Rb1, upregulates the cell cycle–regulatory network, inducing monoclonal gammopathy in mice and promoting multiple myeloma progression in both mice and men. See related commentary by Walker, p. 16. This article is highlighted in the In This Issue feature, p. 5

PURPOSE Trastuzumab deruxtecan (T-DXd, formerly DS-8201a) is a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload. A dose escalation and expansion phase I study evaluated the safety and activity of T-DXd in patients with advanced HER2-expressing/mutated solid tumors. Here, results for T-DXd at the recommended doses for expansion (RDE) in patients with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization−) breast cancer (ClinicalTrials.gov identifier: NCT02564900 ) are reported. PATIENTS AND METHODS Eligible patients had advanced/metastatic HER2-low–expressing breast cancer refractory to standard therapies. The RDE of 5.4 or 6.4 mg/kg T-DXd were administered intravenously once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. Antitumor activity and safety were assessed. RESULTS Between August 2016 and August 2018, 54 patients were enrolled and received ≥ 1 dose of T-DXd at the RDE. Patients were extensively pretreated (median, 7.5 prior therapies). The confirmed objective response rate by independent central review was 20/54 (37.0%; 95% CI, 24.3% to 51.3%) with median duration of response of 10.4 months (95% CI, 8.8 month to not evaluable). Most patients (53/54; 98.1%) experienced ≥ 1 treatment-emergent adverse event (TEAE; grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase; decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered fatal events associated with T-DXd–induced interstitial lung disease (ILD)/pneumonitis as determined by an independent adjudication committee. CONCLUSION The novel HER2-targeted ADC, T-DXd, demonstrated promising preliminary antitumor activity in patients with HER2-low breast cancer. Most toxicities were GI or hematologic in nature. ILD is an important identified risk and should be monitored closely and proactively managed.

Introduction Despite continuous improvement of clinical outcome in multiple myeloma (MM), disease relapse remains a major challenge, leading to progressively shorter remissions and fewer treatment options. Strategies attempting to counteract this challenge include recent efforts resulting in an increase in the availability of novel promising anti-MM agents and targeting specific genetic profiles of the disease. In this context, we aim to develop predictive models of sensitivity and resistance to novel compounds by connecting an ex vivo high-throughput drug screen with genetic, transcriptomics, FISH, and clinical features. Methods Twenty compounds (afatinib, afuresertib, belinostat, buparlisib, cobimetinib, CPI-0610, crenolanib, dinaciclib, dovitinib, JQ1, LGH447, osimertinib, OTX015, panobinostat, romidepsin, selinexor, sunitinib, trametinib, venetoclax, and vorinostat) were selected based on overall promising anti-MM activity from an ex vivo high throughput drug screen with a panel of 79 single agents incubated for 24 hours. The area under the curve (AUC) was used to rank order the ex vivo responses for each compound and the lowest and highest quartile samples were identified for further analysis. Clinical data and FISH data, including t(11;14), t(4;14), t(14;16), del(17p), +1q, monosomy 13, and MYC rearrangement, were collected. Targeted DNA sequencing was performed using a 2.3 Mb custom capture panel covering 139 MM-relevant genes. mRNA-sequencing was performed and differential gene expression analysis in the highest and lowest quartile identified subsets of markers positively and negatively associated with the AUC response for a given compound. An additional unbiased selection of markers using lasso techniques was performed, resulting in predictive generalized linear models (GLM) for each agent. Responses from the remaining intermediate samples were estimated with the predictive models, with overall predictive ability assessed by correlating predicted AUCs with their actual counterparts. Results Our integrative analysis was performed on 50 primary patient samples (36% untreated and 64% relapsed MM). Venetoclax, dinaciclib, romidepsin, panobinostat, osimertinib, belinostat and selinexor were the most active compounds in the cohort. Interestingly, LGH447, dovitinib, selinexor, JQ1, OTX-015, cobimetinib, and trametinib showed increased activity in relapsed MM when compared to untreated samples (Wilcoxon Test; p&lt;0.05). We generated GLMs using an average of 92 markers (range 64-107) per compound, combining mRNA-sequencing expression with FISH and mutation data. The analysis proposed in the present study was validated through the unbiased selection of BCL2 among the subset of markers included in the GLM predicting sensitivity to venetoclax, a first-in-class orally bioavailable selective BCL2 inhibitor. Expression level of critical NF-kB and cell cycle genes, such as BIRC3, CKS1B, PAX5, NFKB2, and CCND2, were included in 60% of our predictive models. Mutations of DNA repair genes (ATM,TP53) were included in the GLMs of three epigenetic therapies, one histone deacetylase inhibitor and two BET inhibitors, associated to ex vivo resistance to the drugs. The presence of monosomy 13 was also a marker for ex vivo resistance for five epigenetic therapies, four HDAC inhibitors and one BET inhibitor. The three BET inhibitors, JQ1, CPI-0610, and OTX015, were among the compounds most accurately predicted by our integrative approach, with Spearman correlation values between 0.773-0.858. Overall, our models accurately predicted the ex vivo response for 16 (80%) of the compounds (r&gt;0.7). Five (25%) of these compounds displayed a remarkably accurate prediction model in both training (highest and lowest quartiles) and validation (intermediate quartiles) samples (r&gt;0.8). Conclusions The GLM data integration approach enabled the establishment of effective predictive models, identifying FISH, transcriptomics, and mutations of putative driver genes important in anti-MM agent responsiveness. In addition, the resulting dataset is promising for future research focusing on the discovery of novel mechanisms of action and establishing markers of sensitivity and resistance to novel compounds. We are currently increasing our dataset and seek to create an omnibus approach that predicts responses to multiple anti-MM agents simultaneously. Disclosures Bergsagel: Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy. Stewart:Amgen: Consultancy, Research Funding; Bristol Myers-Squibb: Consultancy; Celgene: Consultancy, Research Funding; Ionis: Consultancy; Janssen: Consultancy, Research Funding; Oncopeptides: Consultancy; Ono: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy.

Warfighter performance may be compromised through the impact of load carriage on dynamic postural stability. Men and women may experience this impact to differing extents due to postural stability differences. Therefore, the authors investigated the effect of load magnitude on dynamic postural stability in men and women during a landing and stabilization task. Dynamic postural stability of 32 subjects (16 women) was assessed during the unilateral landing of submaximal jumps under 3 load conditions: +0%, +20%, and +30% body weight. Dynamic postural stability was measured using the dynamic postural stability index, which is calculated from ground reaction force data sampled at 1200 Hz. Two-way mixed-measures analysis of variance compared dynamic postural stability index scores between sexes and loads. Dynamic postural stability index scores were significantly affected by load (P = .001) but not by sex or by the sex by load interaction (P > .05). Dynamic postural stability index scores increased between the 0% (0.359 ± 0.041), 20% (0.396 ± 0.034), and 30% (0.420 ± 0.028) body weight conditions. Increased load negatively affects dynamic postural stability with similar performance decrements displayed by men and women. Men and women warfighters may experience similar performance decrements under load carriage conditions of similar relative magnitudes.

AbstractDysfunction of glutamate neurotransmission in the nucleus accumbens (NAc) has been implicated in the pathophysiology of alcohol use disorders (AUD). Neurogranin (Ng) is exclusively expressed in the brain and mediates N‐methyl‐d‐aspartate receptor (NMDAR) hypo‐function by regulating the intracellular calcium‐calmodulin (Ca2+‐CaM) pathway. Ng null mice (Ng–/– mice) demonstrate increased alcohol drinking compared to wild‐type mice, while also showing less tolerance to the effect of alcohol. To identify the molecular mechanism related to alcohol seeking, both in vivo microdialysis and label‐free quantification proteomics comparing Ng genotype and effects of alcohol treatment on the NAc are utilized. There is significant difference in glutamate and gamma‐aminobutyric acid (GABA) neurotransmission between genotypes; however, alcohol administration normalizes both glutamate and GABA levels in the NAc. Using label‐free proteomics, 427 protein expression changes are identified against alcohol treatment in the NAc among 4347 total proteins detected. Bioinformatics analyses reveal significant molecular differences in Ng null mice in response to acute alcohol treatment. Ingenuity pathway analysis found that the AKT network is altered significantly between genotypes, which may increase the sensitivity of alcohol in Ng null mice. The pharmacoproteomics results presented here illustrate a possible molecular basis of the alcohol sensitivity through Ng signaling in the NAc.

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.