Marshall, Ariela L.

Abstract Background: Anemia is an extremely prevalent disease and contributes to a substantial percentage of worldwide years lived with disability. Clinicians generally agree that investigation of the gastrointestinal (GI) tract with colonoscopy and/or endoscopy is warranted in the presence of either overt clinical evidence of GI bleeding or in the presence of documented iron deficiency. However, little is known about the appropriateness of these procedures in the evaluation of patients without either overt GI bleeding or iron deficiency. Additionally, while a large number of colonoscopies and endoscopies are performed each year, the proportion of such procedures performed in the absence of suspect history or findings has not been characterized. Methods: We performed a retrospective review of all patients at Mayo Clinic Rochester who underwent endoscopy, colonoscopy, or both procedures between July 1, 2014 and June 30, 2015 for an indication of either "anemia" or "iron deficiency anemia." Sources of data included provider notes, laboratory values, procedure notes, and pathology reports. Information including patient demographic characteristics, medical comorbidities, laboratory values related to anemia, findings at the time of gastrointestinal procedure, and procedure-related complications was collected. Data was entered into an electronic database and data analysis was performed using Microsoft Excel. Results: 999 procedures were included, including 224 colonoscopies, 306 endoscopies, and 469 combined colonoscopy/endoscopies. Of the 999 total procedures, 78 (8%) had no documented pre-procedure hemoglobin value, 666 (67%) were performed after documented anemia (defined as hemoglobin ≤12 g/dL), and 255 (26%) were performed after a documented hemoglobin of >12 g/dL. Of the 675 procedures performed for "iron deficiency anemia," 462 (68%) patients had documented anemia and documented ferritin prior to the procedure, including only 237 (35%) with both hemoglobin ≤12 and ferritin ≤ 20. 388 (39%) had a documented pre-procedure patient and/or provider report of blood in the stool, and 111 (11%) had a documented pre-procedure positive hemoccult test. 365 (37%) of the 999 procedures identified a probable benign source of bleeding, 54 (5.4%) identified a probable malignant source, and 580 (58%) had no findings consistent with a bleeding source. Patients with documented anemia were more likely to have a probable bleeding source identified than those without documented anemia [46% versus 34%, p<.001]. Of the 83 patients with hemoglobin >12 and ferritin >20, only 1 procedure in 83 demonstrated a malignant finding, and this patient did have blood in the stool at the time of the procedure. There were 46 patients who underwent a procedure without any "warning signs" (either anemia and/or blood in the stool and/or positive hemoccult). Of these patients, 0 had a malignant finding. Conclusions: A large number of procedures performed for either "anemia" or "iron deficiency anemia" were done without pre-procedure documentation of anemia and/or iron deficiency. Documentation of anemia is associated with an increased chance of finding a source of bleeding during the procedure. There were no missed diagnoses of malignancy among patients undergoing procedures without anemia, blood in the stool, and/or positive hemoccult. Careful attention to documentation should be encouraged, and quality improvement initiatives requiring appropriate documentation prior to performing these procedures may be helpful. Disclosures No relevant conflicts of interest to declare.

Abstract BACKGROUND: Non-hereditary hemolytic anemia of unknown etiology after an exhaustive work-up is commonly known as direct antiglobulin test (DAT)-negative hemolytic anemia. Due to its rarity, limited data are available regarding this condition. We performed this retrospective study to determine the frequency, associated medical conditions, treatments used, and clinical outcome of patients with DAT- negative hemolytic anemia. METHODS: We included adult (age >18 years) patients with DAT-negative hemolytic anemia seen at Mayo Clinic from 1997-2015 who met all of the following criteria: a) hemoglobin (Hb)< 12 g/dL; b) presence of hemolysis (reticulocytosis, elevated lactate dehydrogenase, decreased haptoglobin, and/or elevated indirect bilirubin); c) DAT-negative; and d) unknown etiology of hemolytic anemia after extensive work-up appropriate for clinical context. Remission status after appropriate therapy for perceived hemolysis was defined as follows: a) complete remission (CR; Hb ≥12g/dL and normalization of at least one previously abnormal hemolytic marker); b) partial remission (PR; Hb: 10-11.9 g/dL with evidence of ongoing hemolysis); c) no remission (NR; neither CR nor PR). In order to calculate the relative frequency of DAT-negative hemolytic anemia, we also determined the number of DAT-positive hemolytic anemia cases during the same time period using the above criteria for hemolytic anemia. RESULTS: During the 19-year study period, 24 and 484 patients were diagnosed with DAT- negative and DAT-positive hemolytic anemia, respectively, a ratio of 1:20. Among those with DAT-negative hemolytic anemia, the majority were males (67%) and the median age at diagnosis was 70 years (range, 22-87). Six patients (25%) had pre-existing autoimmune conditions including immune thrombocytopenia (n=3), Crohn's disease (n=2), and Grave's disease (n=1). All patients had negative DAT by conventional method with one patient turning positive at 104 days after initial diagnosis. Enhanced DAT technique using 4°C low-ionic strength saline wash was performed in one case and was negative. In general, peripheral blood smear showed polychromasia, occasional spherocytes, and no schistocytes or bite cells. Additional work-ups performed based on clinical context and proportion of patients tested (all results negative or normal) were as follows: hemoglobin electrophoresis (54%), flow cytometry for paroxysmal nocturnal hemoglobinuria (92%), glucose 6-phosphate dehydrogenase level (67%), osmotic fragility test/eosin-5'-maleimide stain for hereditary spherocytosis (54%), other red blood cell enzymes (46%), computed tomographic scan of the body to look for occult malignancy (46%), and bone marrow biopsy (50%). The median hemoglobin at diagnosis was 8.5 g/dL (range, 4.5-11.8). Fourteen patients (58.3%) required blood transfusion during the course of their disease. Sixteen patients (67%) received prednisone as initial therapy with 19% CR and 38% PR response rates. Subsequent therapies included: rituximab (n=6; 40% PR), cyclophosphamide (n=2; 100% NR), mycophenolate mofetil (n=1; 100% NR), intravenous immunoglobulin (n=2; 100% NR), and splenectomy (n=6; 50% CR and 33.3% PR), respectively. The median follow-up for all cases was 32.9 months (range, 2-433). Six patients (25%) developed hematologic malignancies after a median follow-up of 8.7 months (range, 0.7-29.3), which included primary myelofibrosis (n=2), myelodysplastic syndrome (n=1), mantle cell lymphoma (n=1), non-Hodgkin lymphoma-not otherwise specified (n=1), and T-cell large granular lymphocyte leukemia (n=1). At last follow-up, 9 patients (38%) were in CR and 8 (33%) in PR. Relapses occurred in 67% and 0% of patients who received prednisone and splenectomy, respectively. CONCLUSION: At our institution, DAT-negative hemolytic anemia was approximately 20 times less common than DAT-positive hemolytic anemia. Most patients were treated with either immunosuppressive agents with or without splenectomy. Splenectomy was the most effective treatment. At least a quarter of the patients were eventually diagnosed with hematologic malignancies mostly within a year of DAT-negative hemolytic anemia diagnosis. Routine upfront evaluation for hematologic malignancies might be necessary for these patients. Disclosures No relevant conflicts of interest to declare.

Introduction Romiplostim is a fusion protein agonist of the thrombopoietin receptor, approved by the US FDA for the treatment of immune thrombocytopenia (ITP) after failure of glucocorticoid therapy. This agent has been examined in other settings, including its use in the management of the thrombocytopenic surgical patient (Marshall et al., Transfusion 2015) and its use for the treatment of refractory aplastic anemia (Gill et al., Br J Haematol 2016). Thrombocytopenia is a complication of chemotherapy in cancer patients that may lead to treatment delays, dose reductions, and discontinuation of therapy (Kuter DJ, Oncology 2015). This study is a retrospective, single-center review of cancer patients who either developed thrombocytopenia as a result of chemotherapy or who had an underlying pre-existing thrombocytopenic disorder (such as ITP or chronic liver disease) who were supported with romiplostim during all or part of their chemotherapy. Methods We performed a retrospective review of patients with solid tumor malignancies who received at least two sequential weekly doses of romiplostim concurrently with chemotherapy. We collected patient demographics, dates and doses of romiplostim administration with corresponding platelet (Plt) counts, and outcomes of therapy, including ability of the treating oncologist to administer chemotherapy before initiating and during use of romiplostim as measured by number of treatment cycles administered, number and duration of delays in therapy, and number and extent of clinically necessary dose reductions. Results Review of pharmaceutical dispensation records from at our institution from January 1, 2010 through April 1, 2016 revealed 19 patients concurrently treated with romiplostim and chemotherapy, with 15 meeting our inclusion criteria (Table 1). At initiation of romiplostim, 40% of patients had a Plt count ≥75 x 109/L and 26.7% of patients had a Plt count ≥100 x 109/L, with a median Plt count of 72 x 109/L (range, 21-145 x 109/L). Patients were treated with weekly injections of romiplostim, with platelet count measured at the time of drug administration; the most common starting dose was 3 mcg/kg. The average duration of romiplostim therapy required to achieve a platelet count ≥75 x 109/L was 13.6 days, and the average time to achieve a platelet count ≥100 x 109/L was 21.1 days. During treatment with romiplostim, 85.3% and 73.2% of all platelet counts measured were ≥75 x 109/L and ≥100 x 109/L, respectively (Figure 1). All patients were able to receive two or more cycles (range, 2-18) of chemotherapy while on romiplostim. Twelve patients (80%) had delays in receiving antineoplastic therapy attributed to thrombocytopenia prior to initiation of romiplostim, with an average per-patient cumulative delay time of 4.7 weeks; 5 patients (33.3%) concurrently treated with romiplostim and chemotherapy had such delays (p=0.010 by Pearson's chi-squared test), with an average per-patient cumulative delay time of 1 week. Eleven patients (73.3%) required at least 1 dose-reduction in chemotherapy attributed to thrombocytopenia prior to initiation of romiplostim; 4 patients (26.7%) required at least 1 such dose-reduction while receiving romiplostim (p=0.011 by Pearson's chi-squared test). Three patients required platelet transfusion and 10 patients required red blood cell (RBC) transfusion while receiving romiplostim, though 8 of the patients received RBC transfusions only for chemotherapy-associated anemia or fatigue. While receiving romiplostim, no patient suffered a thrombotic event, and 3 patients suffered from bleeding (1 patient developed grade 1 mucosal bleeding and 2 patients developed grade 3 gastrointestinal bleeding). Conclusion In patients with solid tumor malignancies with chemotherapy-associated thrombocytopenia or who have co-existing thrombocytopenic disorders (such as ITP or chronic liver disease), this study provides evidence that romiplostim is safe and increases the platelet count sufficiently in a majority of patients to allow subsequent chemotherapy to be given at full dose and on schedule. Table 1 Patient Characteristics. Table 1. Patient Characteristics. Fgure 1 Platelet Count Over Time. The dotted lines represent the platelet count trend of individual patients. The solid black line represents the platelet count trend of the study population (platelet counts averaged together over seven-day intervals). Fgure 1. Platelet Count Over Time. The dotted lines represent the platelet count trend of individual patients. The solid black line represents the platelet count trend of the study population (platelet counts averaged together over seven-day intervals). Disclosures Kuter: Protalex: Research Funding; ONO: Consultancy; Pfizer: Consultancy; 3SBios: Consultancy; Eisai: Consultancy; GlaxoSmithKline: Consultancy; Bristol-Myers Squibb: Research Funding; Genzyme: Consultancy; Shire: Consultancy; Amgen: Consultancy, Paid expert testimony; Shionogi: Consultancy; Rigel: Consultancy, Research Funding; Syntimmune: Consultancy; MedImmune: Consultancy; CRICO: Other: Paid expert testimony.

Abstract BACKGROUND: While hematologic cancers comprise only 10% of all malignancies, they are divided into >100 distinct World Health Organization subtypes. It is known that higher volume of care is generally associated with better clinical outcomes. However, such a volume-outcome relationship in the medical management of hematologic cancers has not been rigorously explored. The American Society of Clinical Oncology (ASCO) National Census of Oncology Practices shows that the majority of hematologist-oncologists in the United States (US) have a combined hematology-oncology practice (J Oncol Pract 2013). In this study, we estimated the annual number of new and established patients with major hematologic cancers seen on average by a hematologist-oncologist in the US. METHODS: We estimated the number of hematologist-oncologists working in the US using the ASCO workforce information system data from 2011. We utilized statistics from the Surveillance Epidemiology and End Results (SEER) Program to determine the incidence and 37-year limited prevalence of hematologic cancers in 2011. We used 'first malignant tumor per site' statistics as the tumor inclusion method. For potentially curable hematologic cancers (acute lymphocytic leukemia, acute myeloid leukemia, Burkitt lymphoma, diffuse large b-cell lymphoma, Hodgkin lymphoma, and marginal zone lymphoma), we used the estimated 1-5 year survival rates from SEER and excluded patients who survived >5 years, since relapses are rare afterwards. Because prevalence estimates of chronic myelomonocytic leukemia, myelodysplastic syndromes, and certain subtypes of non-Hodgkin lymphoma are unavailable, we were unable to calculate the number of annual established cases. For myeloproliferative neoplasms, we obtained the prevalence estimate from Mehta J, et al (Leuk Lymphoma 2014). We derived the distribution of major non-Hodgkin lymphoma subtypes from the National Cancer Data Base (NCDB) Participant User File. RESULTS: The ASCO workforce information reported a total of 13,084 hematologist-oncologists working in the US in 2011. The Table summarizes the average number of specific hematologic cancer cases seen per hematologist-oncologist in 2011. CONCLUSION: Hematologic cancers are relatively rare but complex. In the US, a hematologist-oncologist on average cares for only 1-2 new patients of any subtype of hematologic cancers annually. The number of established patients is correspondingly low. These numbers are expected to vary by practice setting and disease specialization. As the diagnosis and management of hematologic cancers becomes more sophisticated, future research should explore the potential of a volume to clinical outcome relationship for these providers. Table. Hematologic Cancer Average Annual Number of Cases per Hematologist-Oncologist in the US New Cases Established Cases All Cases Acute lymphocytic leukemia 0.4 1.4 1.8 Acute myeloid leukemia 1 1.5 2.5 Chronic lymphocytic leukemia 1.1 10.7 11.8 Chronic myeloid leukemia 0.4 2.7 3.1 Chronic myelomonocytic leukemia 0.1 - - Hodgkin lymphoma 0.7 2.7 3.4 Multiple myeloma 1.6 6.3 7.9 Myelodysplastic syndromes 1.2 - - Myeloproliferative neoplasms 0.6 22.2 22.8 Non-Hodgkin lymphoma 5.1 - - Anaplastic large cell 0.1 - - Burkitt 0.1 0.3 0.4 Diffuse large B-cell 2 6 8 Follicular 1.1 - - Hairy cell leukemia 0.1 - - Lymphoplasmacytic 0.1 - - Mantle-cell 0.3 - - Marginal zone 0.5 2.1 2.6 Peripheral T-cell, not otherwise specified 0.1 - - Disclosures No relevant conflicts of interest to declare.

PURPOSE: Subspecialty training programs rarely are available for advanced practice providers (APPs). New curricula are needed to prepare APPs with the skills and knowledge required to deliver high-quality care in hematology and blood and marrow transplantation (BMT). METHODS: A Web-based needs assessment survey was distributed to APPs currently working in hematology and BMT at three Mayo Clinic sites (Rochester, MN; Scottsdale, AZ; and Jacksonville, FL). The survey assessed participants’ perceptions of readiness to practice in hematology after completion of their APP education and identified APP learning needs. RESULTS: Of 68 APPs, 49 (72%; 34 nurse practitioners, 15 physician assistants) completed the survey. Twenty-eight APPs (57%) were new graduates, and 17 (35%) had no prior experience in hematology/BMT. All APPs held a master’s degree or higher (doctorate, 31%). Thirty-nine (80%) reported that less than 5% of their APP school curriculum was hematology focused. More than 90% felt unprepared to practice in hematology or BMT after their APP education and believed that hematology-specific training could improve their competency as providers and positively affect job satisfaction. APPs reported that they would like more formal training in the following areas of clinical focus: malignant and benign hematologic disorders, hematopathology, palliative care, transfusion medicine, infectious disease, and hematology-related pharmacology. They also preferred the following learning strategies: active learning from patient care, case-based teaching, and experience during hospital rounds. CONCLUSION: This needs-based assessment project confirmed the necessity to develop a hematology-specific fellowship for APPs and helped to optimize the curriculum.