Go, Ronald S.

AbstractHistological transformation in Waldenström macroglobulinemia (WM) is an uncommon complication, with limited data, particularly regarding the impact of MYD88 L265P mutation on transformation. We examined risk factors and outcomes associated with transformation in WM, highlighting the role of MYD88 L265P mutation. Patients with WM seen at Mayo Clinic, Rochester, USA and University Hospital of Reims, France, between 01/01/1996 and December 31, 2017 were included; 50 (4.3%) of 1147 patients transformed to a high‐grade lymphoma, with median time‐to‐transformation of 4.5 (range 0‐21) years in the transformed cohort. The MYD88 L265P mutation status was known in 435/1147 (38%) patients (406 with non‐transformed WM and 29 patients in transformed cohort). On multivariate analysis, MYD88 WT status alone was an independent predictor of transformation (odds ratio, 7[95%CI: 2.1‐23]; P = .003). Additionally, the MYD88 WT status was independently associated with shorter time‐to‐transformation (HR 7.9 [95%CI: 2.3‐27; P = .001]), with a 5‐year transformation rate of 16% for MYD88 WT vs 2.8% with MYD88 L265P mutated patients. Patients with transformation demonstrated a significant increase in risk of death compared to patients who did not transform (HR 5.075; 95%CI: 3.8‐6.8; P < .001). In conclusion, the MYD88 WT status is an independent predictor of transformation and associated with a shorter time‐to‐transformation. Additionally, transformation conferred an inferior overall survival in patients with WM.

Abstract Background: Over 10,000 new cases of myelodysplastic syndrome (MDS) are diagnosed in the US annually (MA X, Cancer 2007). Hypomethylating agents (azacitidine and decitabine), immunomodulating drugs (lenalidomide) and erythropoietin stimulating agents (epoetin α and darbepoetin) have been approved for more than a decade for the treatment of MDS. However, changes in overall outcome after the approval of these treatments are unknown. We used the National Cancer Data Base (NCDB), a nationwide oncology registry covering 70% of the US cancer population to answer these questions. Methods: We identified patients with MDS diagnosed from 2004-2013 using ICD-O-3 codes 9980-9983 and 9985-99912. Overall survival (OS) was estimated using the Kaplan-Meier method. We compared OS using the log-rank test according to demographic subgroups (sex, age [<40, 41-65, and ≥65 years], race [White, Black, Native American, Asian/Pacific Islander, and other], and ethnicity) across years of diagnosis (Period 1: 2004-2006, Period 2: 2007-2009, and Period 3: 2010-2013). Results: i) Characteristics: There were 54,953 MDS patients in our study. The median age at diagnosis was 76 years (78.7% older than 65) and 44% were females. White race (88.9%) was the most common, followed by black (7%). Four percent were Hispanics. A third (30.8%) of all patients were treated in academic centers. Three quarters (75.8%) had either Medicaid or Medicare insurance. ii) MDS Subtypes: 5q Syndrome was seen in 2008 cases (3.7%) while the most common subtype was MDS-Unclassifiable (U) (55.6%). Therapy related MDS (t-MDS) was seen in 1125 cases (2%), however coding for t-MDS was discontinued in 2009. Refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory cytopenia with multilineage dysplasia (RCMD), and refractory anemia with excess blasts were seen in 9%, 7.6%, 6%, and15.6%, respectively. iii) OS: Compared to their counterparts, patients who were male, older, had a diagnosis of RAEB, covered by Medicare insurance, and treated at non-academic centers had the worse OS (all P <0.001). Across Periods 1-3, we did not see improvement in OS among demographic subgroups except for those who were <40 years old (P=0.03). Conclusions: In the past decade, the overall outcome of MDS did not improve despite the advent of new therapies. More than half of the cases were classified as MDS-U reflecting the difficulty of subtyping MDS based on World Health Organization classification. We found disparity in outcomes by demographics and type of treatment facility. This is the largest study of MDS outcome to-date and should help in understanding the gaps and areas that need future research. Figure Figure. Disclosures Al-Kali: Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding.

Abstract Background: Anaplastic large cell lymphoma (ALCL) of the breast is a recently described clinicopathologic entity, almost always associated with breast implants, and does not overexpress the anaplastic lymphoma kinase (ALK) protein. Using the two largest US cancer databases, we describe its incidence, patterns of care, and clinical outcome. Methods: Incidence rate was calculated using 2000-2011 data from the Surveillance, Epidemiology, and End Results (SEER) Program and age-adjusted to the US 2000 standard population. For patient level data, we used the National Cancer Data Base (NCDB) Participant User File. We included all adult patients diagnosed from 1998-2011 with ALCL (ICD-O-3: 99714) who had breast as the primary site. Results: The incidence of breast ALCL was 0.001 per million. We identified 61 cases from NCDB. All of the patients were females and they were predominantly White (88.5%). The median age at diagnosis was 64 years (range, 18-90). The stage distribution was I (45.9%), II (21.3%), III (0%), IV (9.8%), and unknown (21.3%). The pattern of initial treatment was surgery alone (13.1%), chemotherapy alone (32.7%), chemotherapy and radiation (19.7%), surgery and chemotherapy (4.9%), surgery and radiation (4.9%), and tri-modality treatment (13.1%). In 7 patients (11.5%), no treatment was given. Two patients (1.6%) received stem cell transplant (1 autologous, 1 allogeneic) as part of initial treatment, one after chemotherapy and another one after surgery and chemotherapy. Overall survival data was available for patients diagnosed in 1998-2006 (29 patients). The median overall survival was 149.8 months (range, 2.6-157.9). Conclusions: ALCL of the breast is very rare. It presents mainly as early stage disease with very good prognosis. The patterns of care varied, although most patients received chemotherapy as part of the initial treatment. Table 1. Treatment type received Frequency Percent Cumulative Frequency Cumulative Percent Chemo only 20 32.79 20 32.79 Surgery only 8 13.11 28 45.90 Chemo, Radiation, No surgery 12 19.67 40 65.57 Chemo, Surgery, No radiation 3 4.92 43 70.49 Radiation, Surgery, No Chemo 3 4.92 46 75.41 All three combined 8 13.11 54 88.52 Nothing 7 11.48 61 100.00 Disclosures Parsons: Celgene: Speakers Bureau.

Abstract Background: Venous thromboembolism (VTE) contributes to significant morbidity, mortality, and socioeconomic burden. Though male sex is a known risk factor for recurrent VTE, there is a paucity of literature regarding sex-based sociodemographic differences as well as differences in VTE outcomes including hospital length of stay and mortality rates. Methods: We conducted a retrospective analysis from the National Inpatient Sample (NIS) database from 2012-2013. Inclusion criteria were age 18 years and older and primary discharge diagnosis of VTE Sociodemographic features and medical comorbidities were analyzed, as were hospital length of stay and in-hospital mortality rates. Results: 107,896 patients in the NIS, representing a national estimate of 539,480 patients hospitalized for VTE between 2012 and 2013, met inclusion criteria. 53% were female and 47% were male. Mean age was 63 years and on average women were older than men (65 years versus 62 years, p<0.001). There were significant differences between men and women with respect to race, primary insurance payor, and VTE location as well as medical comorbidities (Table 1). Median overall length of stay (LOS) was 4 days and in-hospital mortality rates were 2.1%. Female sex was associated with a small but significantly longer hospital LOS (RR 1.04, CI 1.03-1.05, p<0.001) which was also seen in subgroup analyses of lower extremity DVT (RR 1.05, CI 1.03-1.06, p<0.001) and pulmonary embolism (RR 1.03, CI 1.02-1.05, p<0.001) but not upper extremity (RR 1.04, CI 0.96-1.12, p=0.36). There were no significant sex-based differences in in-hospital mortality (2.2% in women versus 2.1% in men, p=0.15). In a multivariate model correcting for sociodemographic differences and medical comorbidities, there were no significant differences between women and men with respect to hospital LOS or in-hospital mortality (Table 2). Conclusion: We used data from the NIS to study a large number of patients hospitalized for VTE, and identified several sex-based disparities in sociodemographic factors and location of VTE. However, in a multivariable analysis correcting for these factors, sex was not associated with significant differences in hospital LOS or inpatient mortality rates. Disclosures Kapoor: Celgene: Research Funding; Takeda: Research Funding; Amgen: Research Funding.

Abstract BACKGROUND: Thrombocytopenia is a common hematologic condition associated with multiple etiologies ranging from benign to malignant to potentially life-threatening disorders. Given the heterogeneity of clinical presentations, available clinical information, and pertinent clinical history, there are inter-physician variations in the approach to the workup of thrombocytopenia in the hematology clinic. While a limited test repertoire may be adequate for many cases, more extensive testing may be warranted in others. We were interested in analyzing the various tests performed and testing approaches in the initial workup of thrombocytopenia. METHODS: We reviewed the records of 69 patients who were referred to our center between 2010 and 2015 for an initial workup of thrombocytopenia. We collected epidemiologic data, laboratory testing results, and pathologic findings. Pathologic results were classified as "normal" or "abnormal" and further subcategorized on the basis of review by two clinicians. Quantitative data were analyzed using JMP Pro 10.0.2 software. RESULTS: At the time of thrombocytopenia diagnosis, the median age was 59 years (range: 17-90) and majority were males (65%). The median platelet count was 91,000/µL (range: 3,000-146,000). Isolated thrombocytopenia was present in 51 cases (74%). Forty-four patients (64%) had a peripheral blood smear review and 4 (9%) contained abnormalities including hypogranular neutrophils, rouleaux formation, and target cells. Autoimmune workup included anti-platelet antibody (APA) in 34 (49%), anti-nuclear antibody (ANA) in 21 (30%), lupus anticoagulant (LA) in 4 (6%) and rheumatoid factor (RF) in 13 (19%) of cases. Autoimmune testing was positive for APA in 2 (5.9%), ANA in 4 (19%), LA in 0 (0%), and RF in 1 (8%) of patients who underwent testing, respectively. Common infectious workups included human immunodeficiency virus in 23 (33%), hepatitis A virus in 2 (3%), hepatitis B virus in 11 (16%), hepatitis C virus in 22 (32%), Epstein-Barr virus in 5 (EBV, 7%), cytomegalovirus in 7 (10%) and Helicobacter pylori in 5 (7%) of patients, and were negative in all cases except for one patient with evidence of active EBV infection. Sixteen patients (23%) underwent bone marrow biopsy, and 2 (12.5%) were diagnosed with hematologic malignancies including myelodysplastic syndrome and hairy cell leukemia. Based on results of these tests, 28 (41%) patients were diagnosed with primary immune thrombocytopenia, 19 (27%) with thrombocytopenia secondary to another medical condition, and 22 (32%) with thrombocytopenia of undefined etiology. CONCLUSION: Thrombocytopenia is a common laboratory finding, and workup involves significant inter-clinician variation, often involving multiple laboratory tests and in some cases invasive tests such as bone marrow biopsy. We found that autoimmune causes of thrombocytopenia were moderately common and infectious and malignant causes were rare. Our findings were based on a small cohort of patients but are likely to be representative of the clinical practice in a large tertiary care center. Large scale studies may be warranted to devise a protocol for a thorough yet cost-effective and stepwise initial workup of thrombocytopenia and to minimize unwarranted inter-clinician variation in such investigations. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Cytogenetic evaluation using fluorescence in situ hybridization (FISH) at the time of diagnosis is essential for initial risk stratification in multiple myeloma. The presence of specific cytogenetic abnormalities is known to confer a poor prognosis, less is known about the cumulative effect of multiple cytogenetic high-risk abnormalities. We aimed to evaluate the prognostic implications of the presence of multiple cytogenetic high-risk abnormalities at the time of diagnosis. Methods: We studied 226 patients who were diagnosed with multiple myeloma between July 2004 and July 2014 at Mayo Clinic Rochester, underwent FISH evaluation within six months of diagnosis, and presented with cytogenetic high-risk abnormalities. High-risk cytogenetics were defined as t(4;14), t(14;16), t(14;20), del(17p), or gain(1q). Bone marrow aspirates were evaluated for deletions, monosomies, trisomies, and tetrasomies using chromosome- or centromere-specific FISH probes. IGH rearrangements were evaluated using an IGH break-apart probe and evaluating up to five potential partners (FGFR3, CCND1, CCND3, MAF, and MAFB). Kaplan-Meier overall survival estimates were calculated and the log-rank test was used to compare overall survival in patients with single and multiple cytogenetic high-risk abnormalities. A multivariable-adjusted Cox regression model was used to assess the effect of multiple cytogenetic high-risk abnormalities on overall survival adjusting for age, sex, and Revised International Staging System (R-ISS) stage. P-values below 0.05 were considered statistically significant. Results: The median age at diagnosis was 65 years (32 - 90), 129 (57%) of the patients were male. The median overall survival was 3.5 years (3.1 - 4.9) for the entire cohort (n = 226), 4.0 years (3.3 - 5.1) for those with one cytogenetic high-risk abnormality (n = 182, 80%), and 2.6 years (1.7 - 3.1) for those with two cytogenetic high-risk abnormalities (n = 44, 20%). There were no patients with more than two cytogenetic high-risk abnormalities. Ninety-eight patients (45%) had a high-risk translocation, 77 (35%) had del(17p), 39 (18%) had a high-risk translocation plus del(17p), and 5 (2%) had gain(1q) plus either a high-risk translocation or del(17p). Figure 1 shows the Kaplan-Meier overall survival estimates stratified by the number of cytogenetic high-risk abnormalities (n = 226). The presence of two cytogenetic high-risk abnormalities (compared to one) was of prognostic significance after adjusting for age, sex, and R-ISS stage (HR 2.01, 95% CI 1.27 - 3.19, p = 0.003, n = 205). Conclusions: Approximately one in five patients with newly diagnosed high-risk multiple myeloma presented with two high-risk abnormalities at the time of diagnosis. These patients experienced inferior overall survival suggesting a cumulative effect of multiple cytogenetic high-risk abnormalities. The relatively low number of observed gain(1q) was likely related to the fact that not all patients were evaluated for that abnormality. Therefore the presented hazard ratio represents a conservative effect estimate and may underestimate the true effect. Figure 1 Figure 1. Disclosures Dispenzieri: GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; pfizer: Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Kumar:Janssen: Consultancy, Research Funding; BMS: Consultancy; AbbVie: Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Array BioPharma: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Kesios: Consultancy; Glycomimetics: Consultancy.

BACKGROUND: pPCL is a rare and aggressive form of multiple myeloma (MM) with poor survival outcomes compared to that experienced by MM patients. It has been traditionally defined by the presence of an absolute plasma cell count of > 2000/microL or >20% circulating plasma cells (cPCs) in the peripheral blood. However, several recent studies have validated the optimal cutoff for defining pPCL to be >5% cPCs on a peripheral blood smear due to equally poor outcomes in this less restrictive cohort. Hence, given the rarity of this disease entity, we evaluated the clinical outcomes and cytogenetic features of patients diagnosed with pPCL at our institution with the new proposed definition of pPCL by >5% cPCs on peripheral blood smear that were treated with novel agent induction therapies. METHODS: We evaluated all patients with pPCL diagnosed between 2000 - 2018 evaluated at Mayo Clinic in Rochester, Minnesota. Data regarding these patients were extracted from a prospectively maintained database and from the review of the electronic medical records. Patients were categorized as having high risk cytogenetics if any of the following abnormalities were present: del 17p, t(4;14), t(14;16) or t(14;20). Chi-square tests and Fisher exact tests were used to compare differences between the sub-groups of interest. Survival analysis was performed by the Kaplan-Meier method and differences assessed using the log rank test. RESULTS: This cohort consisted of 71 patients with pPCL with a median age of 62 years (range: 34-91) of which 33 (46%) were male. The median follow up was 46 months (95% CI: 41 - 90). The median bone marrow plasma cell content was 84% (Range: 10 - 100) and the median plasma cell percentage on the peripheral smear was 23% (range: 5 - 93). There were 48 (68%) patients with >20% cPCs in their peripheral blood smear. Only 23 (32%) patients had concurrent information on the number of cPCs by multiparametric flow cytometry at diagnosis and the median number of cPCs detected was 32,807 per 150,000 events analyzed (Range: 354 - 132,256). There were 15/54 (28%) patients who presented with a creatinine of 2 mg/dL or greater and 17/55 (31%) pts who presented with hypercalcemia (11 mg/dL or greater). Data for ISS classification was available in 45 patients and is as follows: Stage 1- 3 (7%) patients, Stage 2- 10 (22%) patients and Stage 3- 32 (71%) patients. Data on the presence of primary cytogenetic abnormalities were available in 60 (85%) patients of which 29 (49%) had high risk cytogenetics. The distribution of primary cytogenetic abnormalities among this cohort was as follows: t(11;14) - 27 (45%), t(4;14) - 5 (8%), t(14;16) - 8 (13%), t(14;20)- 3(5%) and del 17p- 15(25%). All patients received novel agent induction therapy with 40 (57%) of them having received at least one autologous stem cell transplant and 1 patient undergoing an allogeneic stem cell transplant. The median overall survival (OS) for all pPCL patients in this cohort was 23 months (95% CI: 19 - 38). The OS was similar in patient with 5-19% cPCs vs. >20% cPCs (24 vs. 23 months, P = 0.999). However, when the entire cohort was stratified by cytogenetic risk, the median OS was 51 months for standard risk vs. 19 months for high risk (P = 0.005) (FIGURE). There were only 17 (30%) patients in this cohort who were alive for 48 months or longer since diagnosis (i.e. twice the median OS of this cohort) and they were more likely to not have high risk cytogenetics at diagnosis (P = 0.05). CONCLUSION: In this analysis of one of the largest contemporary cohorts of pPCL patients, the outcomes of patients diagnosed with pPCL remain poor despite the use of novel agent induction therapy. However, some patients appear to do better than expected and this phenomenon may be influenced by the absence of high risk cytogenetics. Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Dingli:Karyopharm: Research Funding; Rigel: Consultancy; Millenium: Consultancy; Janssen: Consultancy; alexion: Consultancy. Lacy:Celgene: Research Funding. Kapoor:Glaxo Smith Kline: Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; Cellectar: Consultancy; Celgene: Honoraria; Janssen: Research Funding. Russell:Imanis: Equity Ownership. Leung:Omeros: Research Funding; Takeda: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Aduro: Membership on an entity's Board of Directors or advisory committees. Gertz:Celgene: Consultancy; Prothena Biosciences Inc: Consultancy; Appellis: Consultancy; Amgen: Consultancy; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; Janssen: Consultancy; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Annexon: Consultancy; Abbvie: Other: personal fees for Data Safety Monitoring board; Research to Practice: Consultancy; Teva: Speakers Bureau; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Spectrum: Consultancy, Research Funding; i3Health: Other: Development of educational programs and materials; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau.

Introduction: The landmark VE-BASKET trial demonstrated that Erdheim-Chester disease (ECD) patients with the BRAF-V600E mutation can be effectively treated with vemurafenib 1920 mg/day. However, all patients required dose reductions due to adverse effects. The efficacy of low dose BRAF-inhibitors is not well established in ECD. Further, as Langerhans cell histiocytosis (LCH) also harbors BRAF-V600E mutations in 50-60% of patients, BRAF-inhibitors may be effective in this disease as well. In this study, we evaluated the efficacy of low dose BRAF-inhibitors (vemurafenib and dabrafenib) in the treatment of ECD and LCH. Methods: We conducted a retrospective study of ECD and LCH patients who were seen at our institution from January 1998 to July 2018. All patients had a diagnosis of ECD and LCH determined by clinical criteria in conjunction with histopathologic findings. Based on the standard doses approved for malignant melanoma and ECD, patients were categorized into the low dose BRAF-inhibitor group if they were treated with vemurafenib < 960 mg/day or dabrafenib ≤ 150mg/day at any point in time. We used a simple response criteria that defined clinical progressive disease (PD) as worsening of symptoms attributed to ECD/LCH or radiologic PD as a progression or worsening of proven or suspected lesions due to ECD/LCH. The minimum duration for symptom improvement to be considered a response was set at 3 months. Results: A total of 89 ECD patients and 186 LCH patients were identified. Within the ECD cohort, 24 of 44 (55%) patients who were tested had the BRAF-V600E mutation. Eight patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis was 57 years (range 37-74) and 5 (63%) were male. The most common areas of involvement included bone (88%), cardiovascular system (63%), kidneys (63%), and brain parenchyma (50%). The median time of follow up was 66 months (range 23-165) and the median time on low-dose BRAF-inhibitor was 10 months (range 1-27) [Table 1]. Three patients had a starting dose of vemurafenib 1920 mg/day, 4 had 960 mg/day, and 1 had 480 mg/day. All patients required dose reductions and 50% of the patients ultimately discontinued vemurafenib due to side effects. Side effects included fatigue, pruritus, nausea, facial swelling, blisters, papillomas, and/or subcutaneous nodules. Four patients were able to remain on low-dose vemurafenib for a median follow up time of 24.5 months (range 12-28) with ongoing response and no signs of clinical or radiologic PD. Within the LCH cohort, 18 of 31 tested (58%) patients had the BRAF-V600E mutation. Four patients were included in the low dose BRAF-inhibitor group. The median age at diagnosis of this cohort was 43 years (range 34-69) and 2 (50%) were male. Areas of involvement included bone (100%), brain parenchyma (hypothalamus/optic stalk and pons; 50%), and skin (25%). The median time of follow up was 31 months (range 21-46) and the median time on low-dose BRAF-inhibitor was 4 months (range 3-24) [Table 2]. Two patients had a starting dose of vemurafenib 960mg/day. The patients with brain parenchymal involvement had a starting dose of dabrafenib 150mg/day or 100mg/day. All patients taking vemurafenib 960mg/day required dose reductions and one patient discontinued treatment due to skin blistering in her feet. In the patients taking dabrafenib, no side effects have yet been reported. 3 patients had an ongoing response and did not have clinical or radiologic PD. Patient #10 however, had clinical and radiologic PD after being on vemurafenib 720mg/day for 22 months. Conclusion: Our study suggests a potential role for lower doses of BRAF-inhibitors in ECD and LCH patients harboring BRAF-V600E mutations. Dabrafenib was found to be particularly efficacious and well-tolerated in LCH involving the brain parenchyma. However, patients who undergo dose reductions should be closely monitored due to the risk of disease progression. Careful balance of toxicities and efficacy is needed for optimizing patient outcomes with targeted therapies. Disclosures Bennani: Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Seattle Genetics: Other: Advisory board. OffLabel Disclosure: Vemurafenib and dabrafenib for Langerhans cell histiocytosis. Vemurafenib dosage for Erdheim-Chester disease is less than the approved dose of 960mg every 12 hours.

Introduction: Primary cold agglutinin disease (CAD) is a rare disorder and accounts for 15% of all autoimmune hemolytic anemia. It is associated with an underlying monoclonal protein, which is IgM kappa in the majority of patients. The IgM protein triggers complement mediated extravascular hemolysis. The underlying pathophysiology by which autoimmune hemolysis affects only a small subset of patients with IgM monoclonal protein is poorly understood. Changes in the IgM structure via post-translational modifications of light chains (LCs), such as glycosylation are enriched in patients with AL amyloidosis, another rare disorder where disease manifestations are driven by the protein structure. (Kumar S et al Leukemia 2017). We hypothesized that presence of post-translational glycosylation is a potential mechanism allowing the IgM protein to trigger complement mediated hemolysis in CAD. Methods: Serum samples of patients being evaluated for monoclonal protein disorders were analyzed by immuno-enrichment-based matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), termed MASS-FIX. Patients who had an underlying IgM monoclonal protein identified by MASS-FIX from 07/23/2018 to 5/14/2019 were included this study. Glycosylated LCs were identified by the shift in their molecular mass due to the added molecular mass of the carbohydrates. Glycosylation was compared in patients with IgM associated CAD vs. other IgM disorders. Results: 438 unique patients with an IgM monoclonal protein identified on MASS-FIX were included in the study. CAD was present in 3% (n=14) of patients. The primary underlying diagnosis in the remaining patients was monoclonal gammopathy of undetermined significance (MGUS): 47% (n=206), lymphoplasmacytic lymphoma (LPL)/Waldenstrom Macroglobulinemia (WM): 30% (n=132), non-LPL lymphoma: 6% (n=28), AL amyloidosis: 4% (n=19), CLL: 4% (n=18), cryoglobulinemia: 2% (n=10), multiple myeloma: 2% (n=9) and other: 0.5% (n=2) Glycosylation was present in 7% (31/438) of patients in this cohort. Glycosylation was significantly more prevalent in patients with CAD than other IgM gammopathies (64% vs. 5%, p &lt;0.001). CAD was present in 29% of patients with glycosylation and in only 1% of patients without glycosylation, p&lt;0.001. Disease characteristics of patients with CAD, including patients with and without glycosylated LCs are listed in Table 1. No statistically significant differences were observed in the features of CAD patients with and without glycosylation, though sample size was small. All patients (100%) had IgM kappa monoclonal protein. Median M-spike was 0.5 g/dL. The associated disorder was IgM MGUS in 50% of patients, LPL/WM in 29%, marginal zone lymphoma in 14% and a non-specific B-cell lymphoproliferative disorder in 7% of patients. Median hemoglobin was 11.2 g/dL. All patients had characteristic RBC agglutination on peripheral smear. Elevated LDH and undetectable haptoglobin were seen in 100% of patients. Cold agglutinin titer was positive (&gt;1:64) in 12 of 13 patients (85%) in whom it was tested. The remaining patient had a titer of 1:8. Polyspecific Coombs test/direct antiglobin test (DAT) was positive in 100% of patients (n=12 tested) and all patients who were tested with monospecific DAT had an antiC3 antibody (n=10). One patient also had monospecific anti IgG antibody. Transfusions were needed in 21% of patients. Other clinical manifestations included acrocyanosis in 43% (n=6) and Raynaud's phenomenon in 50% (n=7) of patients, respectively. Treatment for CAD included rituximab with or without steroids in 50% (n=7) of patients, rituximab-based chemotherapy in 29% (n=4) of patients, with observation alone in 21% (n=3) of patients. Conclusions: Modification of the IgM immunoglobulin structure by post-translational glycosylation of LCs was significantly more common in patients with CAD compared with other IgM monoclonal gammopathies (64% vs. 5%, p &lt;0.001). CAD was seen in only 1% of patients without glycosylation, while one-third of patients with glycosylation had CAD. This is a novel finding. As MASS FIX is now routinely done for detection of monoclonal proteins at our institution, the presence of LC glycosylation can provide diagnostic clues and can be a potential therapeutic target in the future. Future studies in larger, independent cohorts of patients are needed to confirm these findings. *SS & DLM contributed equally Disclosures Murray: The Binding Site: Patents & Royalties: US Patent Rights on Mass Spectroscopy Licensing agreement with The Binding Site, Research Funding. Dasari:The Binding Site: Patents & Royalties: US Patent Rights on Mass Spectroscopy Licensing agreement with The Binding Site, Research Funding. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding. Dispenzieri:Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Intellia: Consultancy; Akcea: Consultancy. Gertz:Spectrum: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; Prothena: Honoraria; Ionis: Honoraria; Alnylam: Honoraria.

Introduction: We have previously reported underrepresentation of female faculty at senior academic ranks in hematology/oncology (H/O). In this analysis we aimed to investigate the influence of sex in attaining leadership positions amongst academic hematologists/oncologists in United States. Methods: Faculty members were identified at 146 H/O fellowship programs listed on fellowship and residency electronic interactive database (FREIDA.) Data was collected on demographics, academic rank and research output using Doximity and Scopus databases. We compared the unadjusted characteristics of men and women by using two-sided t-tests and χ2 tests where appropriate. In primary analysis, logistic regression models were used to evaluate sex differences on probability of having full professorship (versus assistant and associate professorship) and of achieving leadership positions including division chief, Program Director (PD) and Associate Program Director (APD). Adjusted models included the following variables: clinical experience in years, number of publications, h-index, appointment at top 20 hospital, clinical trial investigator status and National Institutes of Health funding. Stratified analysis was performed adjusting for duration of clinical experience (≤15 vs >15 years) Results: Fewer women were full Professors (21.9% vs 78.1%), division chiefs (16.7% vs 83.3%), and PDs (30.5% vs 69.5) but the number was similar for Associate Program Directors (47.1% vs 52.9%). In a univariate unadjusted model, women were less likely to be full professors compared to men (OR 0.39; 95% confidence interval [CI], 0.31-0.48; P<.001). However, in the multivariable adjusted model no statistically significant sex difference in full professorship was found (OR 1.05; 95% CI 0.71, 1.57; P=.85; Table). The likelihood of full professorship was positively associated with clinical experience in years, number of first/last author publications, h-index, and being a primary investigator on at least one clinical trial.In a univariate unadjusted model, women were less likely to be division chiefs as compared to males (OR 0.35; 95% CI, 0.16, 0.80; P=.01). However, in the multivariable adjusted model, there was no statistically significant sex difference in achieving the position of division chief (OR 0.57; 95% CI 0.20, 1.58; P=.28; Table). No significant difference was found between females and males for being program directors or associate program directors in both univariate and multivariate analysis. Similarly, a stratified analysis adjusting for duration of clinical experience (≤15 vs >15 years) found no significant sex differences in attaining leadership position (Table) Conclusion: We found that women are underrepresented at higher academic ranks and in leadership positions in hematology/oncology, but that sex is not a significant negative predictor to women obtaining leadership positions after correcting for traditional predictors of academic success. However, "non-traditional" and therefore less measurable and analyzable factors such as networking, mentorship, sponsorship, gender bias, balancing work and home responsibilities and many others may contribute and should be further investigated. Disclosures No relevant conflicts of interest to declare.