Hook, Carl C.

Introduction: Romiplostim is a thrombopoietin receptor agonist approved by the US FDA for chronic immune thrombocytopenia (ITP) in patients who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The recommended dose is 1 mcg/kg/week subcutaneously, escalated weekly by increments of 1 mcg/kg to achieve and maintain a platelet count of 50 x 10 9 /L g ( Kuter et al 2021). It has been postulated that starting at the maximum recommended dose of 10 mcg/kg/week in patients with severe bleeding may swiftly increase platelets and minimize bleeding ( Roumier et al 2021). However, this approach may also increase the risk of major thrombotic events (TE). It is unclear if the more aggressive dosing strategy results in more rapid, robust responses and a tolerable safety profile compared to the FDA approved approach. Methods: This retrospective chart review included adult patients who initiated romiplostim while admitted for ITP at a Mayo Clinic Enterprise site from May 2018 to May 2022. Outcomes included rate of TE at 30 days and 90 days and time to first TE in patients receiving initial romiplostim doses of < 5 mcg/kg (low dose, LD) and > 5 mcg/kg (high dose, HD), median time to platelet response (defined as platelets > 30 x10 9/L and > 50 x10 9/L on 2 separate checks) in LD vs HD, and cost to the institution comparing LD to HD. Outcomes were summarized using descriptive statistics. Statistical analysis was done using BlueSky. Fischer's exact test and chi-squared were performed for categorical data, and Wilcoxon rank sum test were done for continuous variables. Results: Forty-five patients met eligibility criteria: 33 (73%) received initial romiplostim doses < 5 mcg/kg and 12 (27%) received doses > 5 mcg/kg. The majority of patients (43/45 (96%)) presented with platelets < 50 x 10 9/L. The median age was 65 years (68 in LD vs 57 HD). There were 24 (73%) males in the LD group vs five (42%) in the HD group. At baseline, 64% (n = 21) of LD patients and 75% (n = 9) of HD patients presented with bleeding. Major bleeding (defined by 2019 ASH ITP guidelines) was present in 21% (n= 7) vs 17% (n = 2) of patients, LD versus HD, respectively ( Neunert et al 2019). The overall incidence of TE in this study was 24% (n = 11): LD 5 (15%) and HD 6 (50%) (p = 0.044) at 90 days. Median days to TE was 21 days, 12 days in LD group (range 5-21) vs 24.5 days (range 14-58) in HD group (p = 0.067). TE included deep vein thrombosis (DVT, n = 6), DVT with pulmonary embolism (n = 1), portal vein thrombus (n = 1), multiple brain infarcts (n = 1), splenic vein thrombus (n = 1), and left atrial appendage thrombus (n = 1). The median platelet count at the time of TE was 304 x 10 9/L, 415 x 10 9/L (range 58-900) in the LD group vs 323 x 10 8/L (range 33-1427) in the HD group (p = 0.79). Thirty-two (71%) out of 45 patients had a response to romiplostim: 22 in the LD group (71%) vs 10 (83.3%) in the HD group (p = 0.698). Of the patients that responded, the median time to response was 6 days in the LD group vs 11.5 days in the HD group (p = 0.09) The median dose at time of initial response was 2 mcg/kg in the LD group and 6 mcg/kg in the HD group. Wholesale Acquisition Cost (WAC) was used to determine the cost per dose, rounded to the nearest vial size. The average WAC for the initial dose in LD patients was $1806.80 compared to $6061.79 in HD patients. Conclusion:There was a significantly increased incidence of thrombosis in patients admitted with ITP that received initial romiplostim doses > 5 mcg/kg, with no differences in the time to platelet response. Careful consideration of risks versus benefits should be given prior to initiating romiplostim at doses higher than recommended doses.

Background: Warm autoimmune hemolytic anemia (WAIHA) is mostly IgG mediated (IgG+C3-), which may at times fix complement (IgG+C3+). Whether the clinical outcome of complement-fixing (C3+) WAIHA is different from that of non-complement fixing (C3-) WAIHA remains unclear. The goal of this retrospective study was to describe and compare the clinical characteristics and treatment outcomes of patients with C3+ and C3- WAIHA. Methods: We included adult WAIHA patients seen at our institution from 2001-2023 who met all of the following criteria: A) age >18 years; B) direct antiglobulin test [DAT] IgG+ + C3+ with no cold agglutinin; and C) biochemical evidence of hemolysis. Response to treatment was based on the international consensus criteria: complete (CR; normal Hb or Hb ≥12 g/dL, with resolution of hemolysis); partial (PR; Hb >10 but <12 g/dL or Hgb >12 g/dL without resolution of hemolysis); or no response (neither CR nor PR). 223 WAIHA patients were found, and 132 patients were ultimately included. The most common reason for exclusion was a lack of complete DAT that included C3 testing. Results: There were 59 patients with C3- WAIHA and 73 patients with C3+ WAIHA, reflecting 44.7% and 55.3% of total patients respectively. Pertinent demographic, clinical, and treatment information are shown in Table 1. Slightly over half (52.3%) were males and the mean age (SD) was 63.9 years (18.1). Concomitant lymphoproliferative disease was present in 34.1% of the patients. The 3 most common treatments were steroids (97%), rituximab (66.7%), and splenectomy (18.2%). The median follow-up from diagnosis was 20.0 months (range, 1.0-251.8 months), and 14.4% of patients had died at the time of this analysis with no difference between the groups (P=0.82). There was no significant difference in the demographic composition, clinical findings, and treatment received in both groups. The number of treatments received were similar between C3- and C3+ WAIHA groups (Table 1). After first line of treatment, response was achieved in 86.4% and 94.4% of the C3- and C3+ groups (P=0.12), respectively. Additionally, 62.7% of the C3- group and 80.8% of the C3+ group were in PR or CR by their most recent CBC (P=0.02). 33.9% and 43.8% of the C3- and C3+ groups relapsed at least once (P=0.25). In those who relapsed, there was an average of 2.6 relapse events in the C3- WAIHA group compared to 1.8 relapse events in the C3+ WAIHA group (P=0.03). However, there was no difference in time to first relapse between the groups (P=0.51), shown in Figure 1. Conclusion: There have been retrospective descriptions of multiple AIHA subtypes and response rates to different therapies; however, this is one of the first studies to our knowledge to focus specifically on outcomes between complement subgroups. In our large group of patients with C3- and C3+ WAIHA, the clinical presentation, treatments utilized, and response to treatment were similar. Our data suggest that C3- and C3+ WAIHA can be approached and treated similarly.

101 Background: In the US, minority patients are underrepresented in cancer clinical trials. This is due to multiple factors, including socioeconomic barriers, limited medical insurance coverage and restrictive clinical trial eligibility, e.g., ANC cutoff. For the latter, conservative ANC cutoff disadvantages Black patients. Two-in-three Black individuals have a Duffy-null phenotype, that is associated with lower ANC with 5% prevalence of ANC <1,500 cells/µl. To improve Black patient accrual to cancer clinical trials, lowering the ANC cutoff was proposed as a potential solution over a decade ago. Its implementation is not known. This study evaluates the ANC cutoff values as part of the eligibility criteria for cancer clinical trials. Methods: We accessed the Clinicaltrials.gov website on 5/25/2023 and obtained the ANC cutoff of cancer clinical trials conducted in the US. We included adult therapeutic trials in the phases of recruiting, not yet recruiting, enrolling by invitation, and active-not yet recruiting. Trials with drug interventions were selected. Those focusing on surgical, behavioral, nutritional and radiotherapeutic interventions were excluded. All ANC cutoff values were converted to “cells/µl” for analysis. Results: A total of 911 trials were evaluated, and 470 met the eligibility criteria. Of the 470 trials, 366 (78%) involved solid malignancies, and 104 (22%) involved hematologic malignancies. Hematologic trials have significantly lower ANC cutoffs compared to solid tumor trials with median ANC cutoff of 1,000 (range, 250-2000) vs. 1,500 (range 250-3,000); p=<0.001. In all, 323 trials (68.7%) required patients to have ANC >1,500, and 116 trials (24.6%), primarily hematologic, required patients to have ANC >1,000. For myeloma and prostate cancer, two cancers with higher incidence among Blacks, 12.9% and 86.4% of the trials require ANC >1,500, respectively. All genitourinary, breast, head & neck, sarcoma, lung, skin, and neuroendocrine tumor trials excluded patients with ANC <1,000. Conclusions: Most hematologic malignancy trials have a more liberal ANC cutoff allowing patients with ANC <1,500 to participate. However, solid tumor trials remain more conservative, with 4 in 5 trials requiring an ANC cutoff of >1,500. A strict ANC cutoff remains a barrier to minority accrual.[Table: see text]

Abstract Background Tunneled central venous catheters have traditionally been used for administration of chemotherapy (chemo) for acute leukemia treatment. Peripherally inserted central catheters (PICC) are increasingly being used, but there is an increased risk of PICC-associated thrombosis (PAT). There is limited information on management of PAT in this subgroup of patients (pt). Methods In this retrospective cohort study we investigated the primary management of PICC related upper extremity venous thrombosis (TB) in pt with hematologic malignancy undergoing chemo at Mayo Clinic Rochester. Eligible pt were 18 years and older, had documentation of PICC placement at our institution, initiation of chemo within a week of PICC placement, and the TB was objectively documented by compression venous ultrasound (CVU). Superficial venous TB (SVT) was defined as TB of subcutaneous veins (basilic and cephalic) and deep venous TB (DVT) defined as TB of brachial, axillary, subclavian, or innominate superior vena cava and internal jugular veins. We retrospectively stratified initial management (IM) into 1) PICC removal alone (PR), 2) PR and therapeutic anticoagulation (AC), 3) AC alone, and 4) conservative management (CM) consisting of symptomatic care and observation. We also investigated factors influencing IM of PAT. Long term outcomes including incidence of pulmonary embolism (PE), post phlebitic syndrome and recurrence of TB were noted. Results Between 2006 and 2012, 190 pt with AML (n=160), MDS or MDS/MF (n=10), or ALL (n=20) met our study criteria. Overall, 40/190 (21.6%) developed PAT: AML n=38, ALL n=1, MDS/MF n=1. SVT occurred in 16/40 (40%) pt and DVT occurred in 24/40 (60%) pt. IM is shown in Table 1. One pt with SVT received AC for 6 weeks as well as PR. In this pt, IM included AC because of proximity of TB to deep veins. 7 pt had a follow up (f/u) CVU within 3 months demonstrating: TB progression (prog, n=1, IM with PR alone but with prog AC was started); TB stability (stab, n=2, both IM with PR alone) and TB resolution/improvement (R/I, n= 4, 2 IM with PR and 2 IM with CM) In the 5 pt with CM, 2 pt had f/u CVU demonstrating improvement, one pt had charted clinical improvement , and 2 pt had no charted clinical f/u. Of DVT pt on AC (n=14), 5 pt completed at least 2 months of AC. Reasons for early cessation (n=9) of AC included thrombocytopenia (tcp, n=4), hematoma (n=1), hematuria (n=1), subarachnoid hemorrhage (n=1), and unknown (n=1). One pt died 2 days after presence of DVT was noted. Two pt initially treated with PR alone developed a second TB with placement of a new PICC on contralateral arm and AC was subsequently initiated (duration: 3 months (n=1), and 8 days (n=1)). 14 pt with DVT had f/u CVU within 3 months which demonstrated prog (n=2), stab (n= 8), or R/I ( n=4) of TB (Table 2). The 2 pt with TB prog subsequently received longer term AC guided by platelet count. In 5 pt with PICC not initially removed, 3 pt had PR after completion of chemo. (1-4 days), one pt had PR at discharge (27 days from TB), and one pt had PICC in place on discharge. One pt with DVT experienced a PE within one year f/u. This pt had initially completed 3 days of AC which was stopped because of tcp. Conclusion In this cohort of patients with PAT, the most common IM consisted of PR, which appeared to result in a low recurrence rate among pt with SVT. In pt with DVT, the role of AC remains to be defined given the abbreviated course of AC in most pt. Though, the lack of CVU followup in all pt limits conclusions, there appeared to be a low rate of symptomatic prog. Initiation of AC was largely guided by platelet count and degree of occlusive symptoms. Thrombocytopenia was also the most commonly cited reason for discontinuing AC. Close clinical follow up aided by the use of CVU was integral to ensure that PAT did not lead to further adverse events. Disclosures: No relevant conflicts of interest to declare.

Abstract BACKGROUND: Complement-mediated thrombotic microangiopathies (TMAs) are a subset of TMAs in which the thrombocytopenia, microangiopathic hemolytic anemia, and end organ damage are caused by mutations in genes encoding the alternative complement pathway. Numerous complement genes have been implicated in complement-mediated TMAs including complement factor H (CFH), CD46 (MCP), complement factor I (CFI), complement component 3 (C3), complement factor B (CFB), factor H related 5 (CFHR5), and thrombomodulin (THBD) among others. Genetic analysis typically yields a mutation in 60% of patients whose TMA is presumed to be mediated by complement dysregulation. However, the description of novel disease-associated variants may increase this proportion. METHODS: A retrospective study of patients with TMAs diagnosed between 2000 and 2014 was performed. TMA diagnosis was made based on thrombocytopenia and evidence of microangiopathic hemolytic anemia. Analysis was performed with Alamut¨ software with additional in silico prediction tools (SIFT, MutationTaster, and Polyphen) for classification of gene variants. Variants of unknown significance (VUS) and likely pathogenic variants were further assessed using several mutation databases, including HGMD, ClinVar, and Factor H database RESULTS: Of patients diagnosed with a TMA, genetic analysis was performed in only a 10% of patients. Of the 29 patients with genetic studies performed, mutations were identified in 18 patients (62%). The majority of the mutations had been described previously in the literature, but four novel variants were identified: three missense and one splice-site. The table below summarizes these variants as well as laboratory findings on presentation. These were two variants of CFH, one variant of CFHR5, and one variant of CFI. In silico modeling of these variants revealed two polymorphisms likely to be pathogenic, one polymorphism likely benign given the lack of predicted splicing changes, and one VUS. Table 1. Protein Mutation Classification Age Sex Hemoglobin (g/dL) Platelets (thousands) Creatinine (mg/dL) CFH c.245-10_245-9dup Likely benign 61 F 11.6 51 6.7 CFH c.476G>A, p.Ser159Asn Likely pathogenic 43 F 9.1 101 9.1 CFHR5 c.1412G>A p.Gly471Glu Likely pathogenic 30 F 9.8 129 4.9 CFI c.1190T>A p.Val397Glu Unknown significance 51 M 9.4 125 6.1 DISCUSSION: With therapy available to target the alternative complement pathway, genetic analysis to identify genetic variants capable of causing complement mediated TMAs is an essential part of the evaluation. This genetic data must be interpreted and correlated with functional analysis and clinical phenotype. The reporting of novel variants in clinical databases, with inclusion of relevant clinical findings, is necessary to accurately classify and verify variants as pathologic mutations or benign polymorphisms. The full understanding of this diverse disease requires a more complete understanding of its genetics. While complement pathway-directed therapies are available, their rational use requires thorough interpretation of laboratory data, including genetic analysis. Disclosures Murray: Mayo Clinic: Patents & Royalties: Patent Application Filed.

Background: Large granular lymphocyte (LGL) leukemia is a lymphoproliferative disorder of mature cytotoxic T- or Natural Killer (NK)-cells. T-cell LGL (T-LGL) leukemia is characterized by accumulation of cytotoxic T-cells in blood and infiltration of the bone marrow, liver, or spleen. T-LGL leukemia may manifest as asymptomatic persistent lymphocytosis or present with a myriad of autoimmune diseases including autoimmune cytopenias. Population-based studies have not been reported in LGL leukemia. Here, we present clinical characteristics, natural history, and risk factors for poor survival in patients with T-LGL leukemia using the Surveillance, Epidemiology, and End Results Program (SEER) and the National Cancer Data Base (NCDB), the two largest national cancer registries in the US. Methods: We queried the SEER and NCDB databases using ICD-O histology code 9831 corresponding to LGL leukemia. The query was further refined to include patients with T-LGL leukemia only. Incidence rates (case/1,000,000) were calculated using 2000-2011 data from SEER and age-adjusted to the US 2000 standard population. Patient level data were obtained from the NCDB and used to describe patient characteristics such as demographics, year of diagnosis, treatment, and survival. Results: The incidence of LGL leukemia was 0.2 cases/1,000,000 individuals. The incidence did not change significantly over the period of time studied. The incidences according to racial groups were (mean, 95%CI): White 0.2 (0.18-0.24), Black 0.14 (0.07-0.24), American Indian/Alaska native 0.24 (0.03-0.8), and Asian/Pacific Islander 0.15 (0.07-0.25). The incidences among Blacks, American Indians/Alaska Natives, or Asian/Pacific Islanders were not significantly different compared to Whites. Patient-level data was available for 978 patients with T-LGL leukemia. The median age at diagnosis was 66.5 years (range, 19-90) with a male to female ratio of 1.05. Females were diagnosed at a younger age compared to males (65 vs. 68 years, p<0.05). Forty-five percent of the patients with T-LGL leukemia required some form of systemic treatment at the time of diagnosis. The vital status of 760 (77.7%) patients was known at the time of last follow up with a median follow up of 32 months (range, 0-152). At the time of last follow up, 75.5% were alive with the median overall survival (OS) of 108.4 months (Figure 1). Multivariate analysis that included age at diagnosis, sex, race, year of diagnosis, and Charlson-Deyo co-morbidity score, showed that older age (>60 years) and higher co-morbidity score (≥2) were independent predictors of poorer survival (Table 1). Conclusions: We present the first population-based study of patients with LGL leukemia, an extremely rare disease. The incidence has remained stable over the last decade and does not vary significantly among races. Most patients with T-LGL leukemia do not require treatment and the overall prognosis is relatively good. Table 1. Multivariable analysis showing predictors of mortality in patients with T-LGL leukemia Parameter Hazard Ratio Lower CI Upper CI P -Value Age <60 vs ≥ 60 years 2.73 1.90 4.04 <.0001 Male vs Female 0.82 0.61 1.09 0.19 White vs Other 0.99 0.97 1.00 0.23 Charlson-Deyo score <2 vs ≥2 2.03 1.29 3.06 0.003 Year of Diagnosis (2001-2006 vs. 2007-2012) 1.11 0.76 1.69 0.58 Figure 1. Overall survival in patients with T-LGL leukemia Figure 1. Overall survival in patients with T-LGL leukemia Disclosures No relevant conflicts of interest to declare.

Abstract INTRODUCTION: Erdheim-Chester Disease (ECD) is a rare hematologic disease manifesting as granulomatous or fibrotic infiltration of long bones and non-skeletal tissues by non-Langerhans foamy histiocytic (CD68+, CD1a-, S100-) cells. The clinical presentation can be diverse and any organ can be affected. It is estimated that less than 500 cases have been reported in the literature. METHODS: We retrospectively reviewed the medical records of patients evaluated at Mayo Clinic from January 2001 to May 2014. A tissue biopsy review by pathologists at Mayo Clinic was necessary for inclusion in the study. In all cases, the diagnosis of ECD was confirmed using clinical criteria in conjunction with histopathologic findings. Clinical data such as patient characteristics, disease presentation, management strategies, treatment responses, and survival time were collected. RESULTS: Forty-five patients with confirmed ECD were included in our study. The median age at diagnosis was 53 years (range, 32-78), while the median age of onset of symptoms prior to diagnosis was 24 months (range, 1-180). There was a male predilection with a male to female ratio of 2.4. The duration of follow-up ranged from 1-168 months (median, 20). At the time of last follow-up, 38 patients were alive and 5 were dead, while the vital statuses of 2 patients were unknown. The median and mean survival times from the time of diagnosis were 150 and 130 months respectively. The median survival time from the time of symptom onset was not reached and mean time was 154 months (Figures 1A and 1B). Bone pain was the most common presenting symptom (27%). Other common presentations included diabetes insipidus (24%), abdominal pain (22%), B symptoms (13%), visual changes (13%), renal failure/obstruction (11%), pleural effusion (9%), other neurologic symptoms (9%), ataxia (7%), pericardial effusion (7%), edema (7%), dyspnea (7%), and hypertension (7%). The organs/sites involved were bone (80%), central nervous system (59%), kidneys (56%), lungs (38%), retroperitoneum (33%), heart (22%), sinuses (22%), bone marrow (14%), adrenal glands (13%), liver (11%), spleen (11%), and skin (16%). Only 18 (40%) patients had the diagnosis established by the first biopsy. The rest required multiple biopsies before the diagnosis was confirmed (median, 2; range, 1-5). Testing for BRAF V600Ewas performed in 12 patients and 8 (67%) tested positive for the mutation. Eight patients have not required ECD-specific treatment so far. Of the 37 patients who required treatment, the median number of treatments received was 2 (range, 1-7). The systemic treatments received and their response rates are summarized in Table 1. Four patients received radiotherapy but none responded. At the time of the last follow up, 5 patients with BRAFV600E were receiving treatment with vemurafenib or dabrafenib. However, follow-up is insufficient for proper assessment of response. CONCLUSIONS: ECD is an extremely rare diagnosis as exemplified in our retrospective analysis. The diagnosis is often challenging due to protean and diverse clinical presentation as well as frequent inconclusive initial biopsies. There is usually a long-latency period of smoldering symptoms leading to definitive diagnosis. A high level of suspicion is essential in order to make the diagnosis and BRAFmutation analysis should be considered an integral part of work up even if biopsy is non-diagnostic. Traditional oncologic systemic therapies and even novel rheumatologic anti-inflammatory agents generally have limited objective activity. BRAF inhibitors offer a novel treatment option and results of prospective studies are eagerly awaited. Abstract 1405. Table 1: Summary of Response to Various Treatment Modalities in Patients with ECD Therapeutic Agent Number of Patients Treated Response (%) Complete Response Partial Response Stable Disease No response Corticosteroids 11 0 0 9 91 Methotrexate 9 0 0 11 89 Cyclophosphamide 4 0 0 25 75 2-CDA 12 8 17 25 50 Interferon-α 8 0 29 14 57 Vinorelbine 4 0 50 0 50 Tumor necrosis-α factor Inhibitors 7 0 0 14 86 Interleukin-1 Receptor Antagonists 6 17 17 0 67 Tamoxifen 2 0 50 0 50 Radiotherapy 4 0 0 0 100 Figure 1 Figure 1. Disclosures Off Label Use: We report among all treatments utilized at our institution for ECD including the use of steroids, immunosupressants, TNF blockers, interleukin-1 receptor antagonists, and BRAF inhibitors in patients with Erdheim Chester Disease. These treatments, though supported by other reports in the literature, have not been explicitly approved by the FDA for ECD..

e18514 Background: Standard induction therapy for acute myeloid leukemia (AML) includes “cytarabine and anthracycline”. Anthracyclines are known to cause acute, subacute and chronic cardiac complications ( Lefrak , EA et al, Cancer 1973:32(2):302-314; Singal, PK et al, NEJM 1998;339(13):900-905). It is recommended to do base line cardiac function assessment with echocardiogram prior to induction therapy containing anthracycline. This study was done to find the frequency of changes made in avoiding anthracycline usage following this evaluation. Methods: The Mayo clinic data base was interrogated to identify patients with newly diagnosed AML who underwent echocardiogram prior to anthracycline containing induction chemotherapy. Echocardiogram results, including left ventricular ejection fraction (LVEF), diastolic dysfunction, valvular disease, and any resultant treatment alterations were reviewed. Results: Three hundred twenty six patients were identified. The median (range) age was 61 (17-82) years and 62% were male. The median (range) LVEF was 65% (30-87), and 3 (0.9%) patients had LVEF < 50% (range 30-47%). Of these 3 patients, 1 had 4 vessel CABG a decade ago, his EF was 46% and treated with full dose idarubicin; 2 of them presented with blastic crisis, 1 had EF 46% and improved to 51% after 5 days and then given daunorubicin, the other one had an EF of 30% and treated with 50% dose reduced cytarabine alone. Sixty five (23%) patients had previous chemotherapy or radiation exposure, including 24 (7.4 %) with previous anthracycline, 14 (4.3%) had prior radiation to the chest wall. No patient with previous chemotherapy or radiation exposure had a reduced LVEF. Conclusions: Echocardiography prior to anthracycline therapy rarely detects abnormal LVEF. Screening echo may be helpful in those presented with leukemic blastic crisis or had previous exposure to chemo-radiation.