Division Of Hematology Research Articles

VTE Incidence in RRMM Patients Treated with NOVEL Agents: A Monocentric Real Life Experience

INTRODUCTION: Venous thromboembolism (VTE) is very common in patients with malignancies. Compared to the general population, patients with multiple myeloma (MM) have a 9-fold increased risk of developing VTE. In patients treated with thalidomide or lenalidomide, current guidelines recommend systematic VTE prophylaxis with ASA in low risk patients while vitamin K antagonists (VKA) or low weight molecular heparin (LWMH) or unfractionated heparin (UFH) in high-risk patients, based on the type of anti-MM treatment that patients receive and patient-related individual risk factors (e. g. history of VTE). However, little is known on VTE prophylaxis in patients treated with next generation anti-myeloma drugs, such as pomalidomide, carfilzomib and monoclonal antibodies daratumumab and elotuzumab. Here, we describe the incidence of VTE in MM patients treated with third generation novel agents in real life. In addition, we stratify patients on drugs category-based regimens to evaluate strategy of VTE prophylaxis between different groups of patients. MATERIALS AND METHODS: A retrospective cohort of 137 patients affected by relapsed and/ or refractory multiple myeloma treated with novel agents was analyzed. Patients were followed at the Division of Hematology of Catania from April 2013 to June2019. Our series includes 75 patients exposed to Pomalidomide and Dexametasone (PomaD), 46 patients receiving Carfilzomib, Lenalidomide and desamethasone regimen (KRd), 14 patients exposed to Daratumumab(Dara), 27 patients to Daratumumab, Bortezomib and desamethasone (DaraVD), 4 patients to Daratumumab lenalidomide and desamethasone (DaraRd), and12 patients exposed to Elotuzumab and Lenalidomide (EloRd). Several patients were exposed to multiple lines of treatment with novel agents: the total number of analyzed treatments are 178. Patients were stratified to high or low risk for VTE: risk factors taken into account were obesity, history of VTE, central venous catheter, inhered thrombophilia, surgical procedures and comorbidities such as infections, immobilization, cardiac disease, chronic renal disease. Low risk patients had no or one risk factor; in case of two or more risk factors, the patients were classified as high risk. Low-dose aspirin (ASA 100 mg per os once daily) or equivalent was prescribed in low risk patients, low-molecular-weight heparin (LMWH) or equivalent was given to high risk patients. Only Dara treatment did not include standard prophylaxis in patients without risk factors. RESULTS: Real life observation revealed a low incidence of VTE (6 VTE-4,3%) in patients exposed to novel agents together with a standard prophylaxis in case of risk of thromboembolic complications. Forty patients were at high risk of VTE, while 97 patients were classified as low risk; VTE/PE occurred in 2 high risk patients who refused to make correct LMWH prophylaxis due to the discomfort of the subcutaneous administration, developing distal DVT respectively after cycle 1 and 2 of KRd. Two low risk patients treated with PomaD developed DVT of lower extremities during cycle 2 and 4; 2 low risk patients had pulmonary embolism during PomaD cycle 8. CONCLUSIONS: Low incidence of VTE in patients with RRMM receiving PomaD, KRd, EloRd, DaraVD, DaraRd, Dara or EloRd treatment is probably due to a correct risk assessment and subsequent prophylaxis in case of therapies including immunomodulators or in case of patients with high risk for thromboembolic complications. These data support the use of VTE risk stratification-based prophylactic strategies in myeloma patients treated with new drugs. Disclosures Conticello: Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Di Raimondo:Takeda: Consultancy; Amgen: Consultancy, Honoraria, Research Funding.

Clinical Utility of a Multi-Gene Next-Generation Sequencing Myeloid Panel in an Academic Hematology Practice

Background Next-generation sequencing (NGS) panels have created an unprecedented opportunity to interrogate a broad array of variants in a multiplex fashion. Few data have demonstrated how NGS testing impacts diagnosis and treatment decisions. In this retrospective analysis, we evaluated the clinical application of NGS myeloid panels (MP) in patients (pts) evaluated by physicians in the Stanford Division of Hematology. Methods The study was approved by the Stanford University IRB. The cohort consisted of 1,015 pts ≥18 years of age (median 66; range 18-96 years; 51% female). A total of 1,213 MPs obtained from peripheral blood (n=568) or bone marrow (n=645) from March 2017 to June 2018 were analyzed at Stanford (n=761) using the 54-gene TruSight® Myeloid Sequencing Panel (Illumina, San Diego, CA) or Oregon Health & Science University (n=452) using the GeneTrails® Hematologic Malignancies 76-Gene Panel. Electronic medical records were reviewed from t-3 to t+9 months from when MPs were obtained to assess physician reasoning for MP acquisition, documentation of results, and how results were clinically applied. We defined three categories of MP acquisition: 1) diagnostic clarification, 2) prognostication and/or management guidance, or 3) minimal residual disease (MRD) monitoring. We analyzed changes in clinical management, including addition of targeted or non-targeted therapeutics, clinical trial eligibility, or other practice recommendations. Results Of the 1,213 MPs, 882 (73%) demonstrated at least one pathogenic/ likely pathogenic variant (median 2; range 1-8). Median turn-around-time was 18 days (range 7-31) and average cost was $2,600. Of all MPs, 462 (38%) were obtained for diagnostic clarification, 732 (60%) for prognostication / management guidance in pts with known myeloid (n=701) or lymphoid (n=31) neoplasms, and 19 (2%) for MRD monitoring, although the assay was not designed for this indication. MPs were ordered to clarify a diagnosis for the following reasons: unexplained cytopenia(s) (n=199), molecular profiling for a suspected hematolymphoid neoplasm (n=156), unexplained -cytosis (n=86), and testing for other lab abnormalities (e.g. elevated serum tryptase, paraproteinemia) (n=18), or signs (e.g. splenomegaly, splenic vein thrombosis)(n=3). A pathogenic/likely pathogenic variant was found in 294 (64%) pts, confirming or establishing the presence of a myeloid (n=266) or lymphoid neoplasm (n=7) or resulting in a diagnosis of CHIP (n=9) or CCUS (n=12) in pts who did not meet 2016 World Health Organization diagnostic criteria for a hematolymphoid neoplasm (Fig. 1). Of the 732 MPs ordered for prognostication/ management guidance, 272 MPs (37%) were obtained in the initial workup of non-APL AML pts. The frequency of favorable (21%), intermediate (55%), and adverse risk (24%) genetics according to the European LeukemiaNet stratification in non-APL AML is shown in Figure 2a, which also denotes the frequency of favorable (9%) or adverse risk (70%) variants in MDS, and adverse risk variants in MF (52%), MDS/MPN (68%), and advanced systemic mastocytosis (44%). Among MPs obtained for prognostication/ management guidance, 163 (22%) led to a modification in clinical practice, divided between 132 (18%) which led the physician to change therapy (e.g. FDA-approved targeted therapy, clinical trial, or FDA-approved therapy, such as hypomethylating agents in MDS) and 31 (4%) resulted in a non-therapeutic change (e.g. expedited HSCT referral or more frequent follow-up)(Fig. 2b). 87 pts with a myeloid neoplasm had 184 repeat MPs for relapsed/refractory disease (n=52), transformation to higher-risk MDS or AML (n=45) or progressive cytopenias (n=87). Among these MPs, 38 (21%) identified a new pathogenic/likely pathogenic variant of which 29% (n=11) led to either a) initiation of targeted therapy with enasidenib in relapsed IDH2+ AML (n=3) or midostaurin for secondary FLT3+ AML from MDS (n=3), or b) consideration for a clinical trial with a splicing modulator for MDS characterized by a splicing variant (n=5). Conclusion In our academic hematology practice, two-thirds of MPs ordered for diagnostic clarification identified a pathogenic/likely pathogenetic variant that helped to confirm or establish a new diagnosis of a hematolymphoid neoplasm, CHIP, or CCUS. In addition, approximately 20% of MPs ordered for prognostication/ management guidance led to a change in clinical practice. Disclosures Gotlib: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Promedior: Research Funding; Pharmacyclics: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Allakos: Honoraria, Membership on an entity's Board of Directors or advisory committees; Deceiphera: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Clinical Features and Treatment for Neurolymphomatosis in the Rituximab Era: Single Institution Experience

Background: Neurolymphomatosis (NL) is a highly rare disorder defined as infiltration of peripheral nervous system by a lymphoproliferative neoplasm, both presented as the first manifestation of the malignancy (primary NL) or as a site of disease progression or relapse (secondary NL). Due to rarity of this disorder data on clinical features, best approach and outcome are limited. Furthermore diagnosis of this disease is often uncertain and based on radiological images only. Methods: We retrospectively reviewed clinical records of all histologically confirmed-NL, diagnosed and treated at the Division of Hematology of Mayo Clinic in Rochester, MN between January 2002 and December 2018. Clinical features and outcome were analyzed. Responses to therapy were assessed by post-treatment radiological changes and clinical symptoms improvement. Survival analysis such as progression free survival (PFS) and overall survival (OS) were estimated using Kaplan Meier curves with log-rank test. Comparison between subgroups was investigated using Fisher's exact test and Wilcoxon test for categorical and continuous variables, respectively. Results: Over a 16-year period 40 patients with biopsy-proven NL were included in study. Primary and secondary NL were 19 (48%) and 21 (52%) respectively, with a median age of 60.5 years (range 37-83) and male sex 24/40 (60%). The predominant histology was represented by B-cell lymphomas (39/40, 97%) with a vast majority large B-cell lymphoma (LBCL) 27/40 (67%) and only 1 case of T-cell lymphoma. The affected structures included brachial plexus (12/40, 35%), lumbosacral plexus (5/40, 12%), cauda equine and nerve roots (14/40, 35%), sciatic nerve (12/40, 30%), femoral nerve (4/40, 10%), cranial nerves (8/40, 20%), multiple nerves involved in 23/40 (57%). Four out of 40 cases had brain involvement and cerebrospinal fluid (CSF) was positive in 7/29 (24%). NL clinical manifestations included muscular weakness (33/4, 82%), sensory deficit (32/40, 80%), pain (28/40, 70%) and autonomic dysfunction (3/40, 7%). Magnetic resonance imaging (MRI) detected neural abnormalities in 35/36 cases (97%), CT imaging identified disease in 3/8 (37%) and FDG-PET scan was positive in 22/31 (71%); electromyography showed some grade of neuropathy in 28/29 (97%). Treatment included systemic chemotherapy in 38/40 (95%) cases, containing high dose methotrexate (HD-MTX) in 26/40 (65%) and rituximab in 20/40 (50%); 11/39 (28%) patients underwent consolidative autologous stem cell transplant (ASCT); 4/40 received consolidative radiotherapy (RT), 1/40 was treated with RT alone; intrathecal chemotherapy was infused in 1/40 cases; one patient with solely great auricular nerve NL involvement was cured with surgery only. Treatment efficacy evaluated by imaging and clinical improvement consisted with an overall response rate (ORR) of 73% (27/37) with a 24% (9/37) of complete remission (CR); No statistical difference in rate of response was observed by different systemic treatments. Of note, patients undergoing HDC-ASCT consolidation obtained 100% of ORR (n=10) versus 61.5% (n=16) achieved by others (P=0.03). With a median follow up of 45.1 months (range 0.5-186.7) a 36 months-OS of 77% (95% CI, 60-88) was observed for the whole cohort. A trend of longer survival rate for primary NL was observed, with a 36-month OS of 95% (95% CI, 72-99) vs. 55% (95% CI, 30-77) for secondary NL (p 0.134). A strong benefit in terms of outcome was observed for patients receiving rituximab-containing regimens with a 36 months-PFS of 72% (95% CI, 55-92) vs 28% (95% CI, 12-53) (P=0.001), and a 36 months-OS of 87% (CI 95%, 60-98) vs. 65% (95% CI , 41-84) (P=0.04) (figure 1); no survival difference was observed for patients treated with systemic therapy containing HD-MTX vs. others. ASCT consolidation was associated with a trend of improved survival with a 36 months-PFS of 69% (95% CI, 35-90) vs. 47% (95% CI, 29-66) for others (P=0.09). Conclusions: With the limit of a retrospective analysis, LBCL represent the predominant histologic subtype of NL; MRI and FGD-PET appeared to be the most accurate radiological tools to detect neural disease. Systemic treatments including rituximab should be preferred, HD-MTX seems to be not so effective while ASCT consolidation may be considered in selected patients. Due to the spare number of cases treated with RT its role cannot be clarified by our study. Disclosures Nowakowski: NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees.

Screening for post-traumatic stress disorders in 1017 cancer patients and correlation with anxiety, depression, and distress.

ObjectivePost‐traumatic stress disorder (PTSD) is a severe psychiatric disorder, which might develop after a traumatic event, like cancer diagnosis, and threatens the patient's psychological and/or physiological integrity. Anxiety, depression, and mental distress are known to be common in cancer patients; however, the frequency of PTSD was not investigated thoroughly in this patient group so far. Here, we aim to screen cancer patients for PTSD symptoms and determine a possible correlation with anxiety, depression, and distress.MethodsThe study was performed at the Divisions of Hematology and Oncology of the Medical University of Vienna from 2010 to 2018. Following written consent, patients were asked to fill out the validated self‐assessment questionnaire for PTSS‐10 and HADS. The study was approved by the institutional ethics committee of the Medical University of Vienna (EC Nr: 2255/2016).ResultsA total of 1017 adult cancer patients (513 male, 504 female) were included in a cross‐sectional single‐center study. Mean age was 57.6 years (SD 14.4 years); 31.7%, 14.6%, 13.2%, and 27.4% of patients outscored the predefined thresholds for self‐assessed cases of PTSD, anxiety, depression, and distress, respectively. Compared with men, women showed a higher prevalence of symptoms for PTSD (38.9% vs 24.5%; P < .001) and anxiety (20.4% vs 8.6%; P < .001). The scores of HADS‐A, HADS‐D, and the combined HADS score (distress) were significantly correlated with PTSS‐10 scores (P < .01). No differences in age were observed among the different score groups.ConclusionThe study shows a significant prevalence as well as a correlation of PTSD symptoms with anxiety, depression, and distress among cancer patients. Findings underscore the necessity of a serious screening for psychiatric disorders, especially in female patients. In order to enable multidisciplinary care for cancer patients and to reduce the burden for psychiatric disorders, interdisciplinary screening and treatment concepts, which take into account gender aspects, are urged.

Coexistence of Myeloid and Lymphoid Neoplasms: A Single-Center Experience.

The coexistence of a myeloid and a lymphoid neoplasm in the same patient is a rare finding. We retrospectively searched the records of the Hematology Division of the Second Department of Internal Medicine and Research Institute at Attikon University General Hospital of Athens from 2003 to 2018. Nine cases have been identified in a total of 244 BCR-/ABL1- negative MPN and 25 MDS/MPN patients and 1062 LPD patients referred to our institution between 2003 and 2018. Each case is distinct in the diversity of myeloid and lymphoid entities, the chronological occurrence of the two neoplasms, and the patient clinical course. All of them exhibit myeloproliferative (6 JAK2 V617F-positive cases) and lymphoproliferative features, with 1 monoclonal B-cell lymphocytosis (MBL), 3 B-chronic lymphocytic leukemias (B-CLL), 3 B-non-Hodgkin lymphomas (B-NHL), 1 multiple myeloma (MM), and 1 light and heavy deposition disease (LHCDD), while in three cases myelodysplasia is also present. The challenges in identifying and dealing with these rare situations in everyday clinical practice are depicted in this article.

2019 American Pancreatic Association Presidential Address

From the Division of Hematology and Oncology, Department of Medicine, UCSF Medical Center, San Francisco, CA. Address correspondence to: Margaret A. Tempero, MD, Department of Medicine (Hematology Oncology), UCSF Medical Center, Mission Bay Campus, Mission Hall 550 16th Street, Box 3211, San Francisco, CA 94143 (e-mail: [email protected]). The author declares no conflict of interest.

Comparative analysis of efficiency of bacteriological and molecular-biological methods for the assessment of microbial contamination of hospital environment objects

Aim. To conduct a comparative analysis of bacteriological and molecular biological research methods to assess the microbial contamination of objects of hospital environment as factors of microbial transmission. Materials and methods. A comprehensive laboratory investigation of nosocomial environment of surgical, intensive care, hematology divisions of a large multi- disciplinary clinic during 2017 was carried out, while 215 samples were selected. Results. Microbial contamination of hospital environment facilities accounted for 54,0% when carrying out bacteriological tests and 80,0% — in conducting molecular biological studies. Between the frequency of bacteriological isolation of microorganisms and the determination of DNA of pathogens in different departments of the hospital, a strong direct correlation was revealed (r=0.92). The coincidence of the results of the two methods of research in most cases was observed at high values of the number of DNA copies (800-10000). The molecular biological method of diagnosis revealed the Methicillin-resistant Staphylococcus 1.9 times more often and in 19,4±7,2% lactamase (MBL) genes in major gram-negative pathogens. Conclusion. The use of molecular biological methods allows to detect microorganisms on the objects of hospital environment much more often than during bacteriological examination.

Transformation to Academic Leadership: The Role of Mentorship and Executive Coaching.

The transition to academic leadership entails learning to utilize an enormous new collection of skills. Executive leadership coaching is a personalized training approach that is being increasingly used to accelerate the onboarding of effective leaders. Vanderbilt University Medical Center has invested in a robust coaching strategy that is offered broadly to institutional leaders. This case study details the early transformational learning of leadership skills by one new institutional leader in the first two years in an academic leadership role, telling the first-person account of the experience of being coached while independently leading a division of hematology and oncology at a highly ranked medical center. Over two years' time, assessed in 6-month intervals, the academician transitions into the role, and using scenarios from regular practice in this position, learns to incorporate core leadership principles into the daily activities of running a division. The transition to academic leadership involves a transformation; a conversion that can be accelerated, guided, and applied with a greater deal of sophistication through intentional coaching, and the application of principles of behavioral science and psychology. Much like the process of coaching a high performing athlete, an elite academician can be trained in skills that enhance their game and succeed in creating a winning team. The academic medical center (AMC) is an interesting social organization, made up of highly accomplished and well-educated people, brought together around a variety of missions and motivations: education, patient service, research, community building, financial margins, and citizenship to name a few. Moreover, the leadership of AMCs almost entirely comes from within this community, drawing people with talents in science, teaching, clinical research, and service into roles that industries reserve usually for MBAs, lawyers, and other professionals who undergo rigorous guided training. Fortunately, academics are well-equipped with skills in lifelong learning, focused curiosity, and tend to be ambitious to a fault. Thus, there is a steady pipeline of budding leaders in AMC's eager to tackle new challenges that will further their missions. Like major industries in the public and private sectors, the demands of leadership are significant. How to navigate the transitions from physician, teacher, or scientist to academic leader is not covered easily in any text. Vanderbilt University Medical Center has adopted a model of Leadership Coaching, akin to the Trusted Leadership Advisor model (Wasylyshyn, 2017). This case study details the experience of one new leader (first author), freshly plucked from the medical science proving ground. Accounts and description of the experiences and intentions of the leadership coach, Dick Kilburg, provide insight into the processes applied in facilitating this transition. Finally, observations of the transition from the vantage point of the primary supervisor (Department Chair, Nancy Brown) provide a further description of the coaching effect on the early development of an AMC leader. The experience of the client, Kimryn Rathmell (Kim), is told in first person narrative format-fitting for the intense and personal experience that accompanies the transition to a leadership role.

PB1963 CHARACTERISTICS OF NEWLY DIAGNOSED AUTOIMMUNE HEMOLYTIC ANEMIA: 5‐YEARS OF SINGLE‐CENTER EXPERIENCE

Background:Autoimmune hemolytic anemia (AIHA) is a rare autoimmune disease in which red blood cells (RBC) are targeted by autoantibodies confirmed with positive direct antiglobulin test (DAT), resulting in premature destruction of RBC. AIHA may be subdivided into warm antibody AIHA (wAIHA) and cold antibody AIHA (cAIHA), and also to primary and secondary depending on the presence of an underlying disorder. In addition to that, patients may have positive DAT but without features of hemolysis, and some of them will later develop AIHA.Aims:The aim of this study was to analyze characteristics of newly diagnosed DAT positive AIHA patients during the 5 years period in our tertiary center, as well to assess DAT positive patients without features of AIHA.Methods:This was a single‐center retrospective cohort study performed at the University Hospital Center (UHC) Zagreb, Zagreb, Croatia, Department of Internal Medicine, Division of Hematology. We included data for all consecutive adult patients with a newly diagnosis of DAT positive AIHA between 2014 and 2018, and also all DAT positive patients without features of hemolysis in that time period. This study was approved by the UHC Ethical Committee. Descriptive statistics was performed and included means ± SD or median (range) as appropriate for continuous variables and frequency (percentage) for categorical variables.Results:The data from 56 patients (50% women) with newly diagnosed DAT positive AIHA during the study period were analyzed. The median age at time of AIHA diagnosis was 67 years (range 22–90 years). Majority of AIHA was wAIHA (51 (91.1%) patients). AIHA was considered primary in only 14 (25%) patients and was associated with an underlying disorder in 42 (75%) patients. The various disorders were associated with secondary wAIHA, the most frequently B‐cell lymphoproliferative malignant diseases (33%), solid tumors (9.8%), myelodisplastic syndrome (9.8%) and autoimmune diseases (9.8%). Median hemoglobin level at the AIHA diagnosis was 71 g/L. 82.1% of patients received RBC transfusion. Seven (12.5%) patients did not require immunosuppressive treatment and other received mostly corticosteroids as the 1st line of therapy. Rituximab received 9 patients (17.6%) with wAIHA, mostly as the 2nd line of treatment. Eight patients (14.3%) with AIHA developed thrombosis (7 with wAIHA and 1 with cAIHA). During the 5‐years study period additional 120 patients with DAT positive results but without signs of hemolysis were detected.Summary/Conclusion:Data from our 5‐years single centre experience with AIHA are comparable with literature data. Majority of patients had secondary AIHA and wAIHA. Rituximab is used mostly as the second‐line treatment and corticosteroid‐sparing agent for wAIHA. Significant number of patients with DAT positive results but without features of hemolysis was detected, and they need to be closely monitored for possible development of AIHA.

PB2216 ARTERIAL AND VENOUS THROMBOSIS IN TREATED PATIENTS WITH MYELOPROLIFERATIVE NEOPLASMS

Background:Cardiovascular and thromboembolic events are the leading causes of morbidity and mortality for patients with myeloproliferative disorders (MPN).Aims:This retrospective study aimed to evaluate the incidence and the risk factors for the arterial and venous thrombosis in treated patients with MPN.Methods:The study included 329 adult MPN patients, 184 (56%) female, treated at University Hospital Center Zagreb, Department of Internal medicine, Division of Hematology and Zadar General Hospital, Hematology Unit. Patients were aged 24‐85 years (median 68), and were diagnosed as having essential thrombocythemia (ET) (n = 149, 45%), polycythaemia vera (PV)(n = 94, 29%), primary myelofibrosis (PMF)(n = 69, 21%) and unclassifiable MPN (n = 17, 5%). Diagnosis were made according to the 2008 WHO Classification. JAK‐2 mutation status was either established or revised in our center, but was unknown in 55 (17%) patients. Data about treatment and cardiovascular and thromboembolic incidents was retrieved from medical records.Results:Forty patients (12%) developed thrombosis after median of 36 (range 1‐240) months from the time of diagnosis. Fifteen (5%) patients developed venous thrombosis, twenty‐four (7%) arterial, while one (0,3%) patient both type of thrombosis. Regarding the disease type, thrombosis was described in 16 patients with ET (11%), 18 with PV (19%) and 6 with PMF (8%). The risk of thrombosis was the highest in patients with previous thrombotic events, but did not correlate with the type of therapy (cytoreductive and/or antiagreggation) nor the JAK‐2 status.Summary/Conclusion:The risk of both arterial and venous thrombosis was found to be increased in patients with MPN even after introducing appropriate treatment. The highest risk of post treatment thrombosis was found in patients with previously diagnosed thrombotic events.

FitFirms: A wellness option for oncology trainees.

10537 Background: Burnout in oncologists has been rising over the past decade. Burnout leads to poor patient outcomes and poor physician health. Younger oncologists are at higher risk for burnout. The Firm System was designed by Victor McKusick at the Johns Hopkins hospital in 1975 to integrate faculty and trainees into clinical and psychologically supportive cohorts. Here we describe an adapted Firm System called the FitFirms, which focused on social connectivity and altruistic service as means to combat burnout in oncology trainees. Methods: We divided the Hematology and Oncology Division of an academic Comprehensive Cancer Care center into four cohorts of faculty-fellow teams called FitFirms. Each FitFirm was named after a notable local or national female leader in the field of cancer medicine—The Henrietta Lacks Firm, The Jane Wright Firm, The Padmini Iyer Firm, and The Rita Mehta Firm. The faculty and fellows interacted on an at-minimum quarterly basis in casual social events and/or community service-oriented events for 15 months. The social events included group dinners, bowling, paint and game nights. The service events included participation in 5K walk/run fundraiser for our institution’s cancer center and support of a National Cancer Survivors Day event for US Veterans. A didactic discussion series was created to explore concepts of resiliency, work-life balance, and the role of art in medicine—mentored by faculty across the spectrum of oncologic disciplines (Surgical Oncology, Gynecologic Oncology, Palliative Care, and Health Communication). The Maslach Burnout Inventory survey was used to survey the oncology trainees before and after the interventions. Results: Nine pre-intervention surveys were collected with 78% of trainees describing themselves as on the burnout spectrum of feeling either ineffective, overextended, disengaged, or burned out (22% engaged). After 15 months, 10 post-intervention surveys were collected in which 60% of trainees described themselves on the burnout spectrum (40% engaged). Conclusions: The FitFirms are a novel system using social capital to reduce the problem of burnout in oncology trainees by engaging in social connectivity and altruistic service through faculty-mentored, historically-named divisional cohorts.

Clinical observation of desmopressin in the treatment of 15 patients with DDAVP

目的探讨去氨加压素（DDAVP）在血管性血友病（VWD）诊断和治疗中的应用价值。方法对2016年3月至2018年8月期间15例接受DDAVP治疗的VWD患者进行分析，观察治疗反应及患者用药前及用药后2 h凝血因子Ⅷ活性及血管性血友病因子（VWF）相关指标变化。结果15例VWD患者中，男7例，女8例，中位年龄23（6~46）岁。9例1型VWD患者中，7例达完全反应；1例2A型VWD患者达完全反应，5例3型VWD患者无反应。对5例患者进行VWF多聚体分析，结合其他VWF相关检测指标，DDAVP治疗效果与患者疾病分型相符合。结论DDAVP对1型VWD患者可达到较好疗效，对部分2型VWD及3型VWD患者反应不佳；VWD患者对DDAVP的治疗反应对治疗选择具有重要意义。

Acute Non Lymphoblastic Leukemia in the Department of Child Health School of Medicine, University of North Sumatera/ Dr. Pirngadi Hospital Medan (1983-1988): A Preliminary Study

A retrospective study on Acute Non Lymphoblastic Leukemia (ANLL) was conducted at the Sub Division of Pediatric Hematology, School of Medicine, University of North Sumatera/Dr. Pirngadi Hospital Medan, in a period of 5 years (1983-1988). There were 18 cases consisted of 14 (77.78%) males and 4 (22.22%) females with the age group of 0-2 years: 6 (30%), 2-8 years: 9 (50%), 8-15 years: 3 (30%). By the FAB classification, they were of FAB M-1: 1 (5.55%). FAB M-2: 1 (5.55%), FAB M-3: 1 (5.55%), FAB M-4: 2 (11.12%) and FAB M-6: 13 (72.23%). Only 7 (38.88%) were treated with cytostatics while the others received only supportive therapy. The result of cytostatic treatment was unsatisfactory: 4 (57.14%) died within the first 2 months of treatment, 3 (42.86%) discontinued their cytostatics treatment.

Efficacy and safety of second-line treatment in Thai patients with primary warm-type autoimmune hemolytic anemia

ABSTRACTObjectives:: To investigate the efficacy and safety of second-line treatment in Thai patients with primary warm-type autoimmune hemolytic anemia (AIHA) that failed corticosteroid treatment.Methods:: This descriptive retrospective study included patients aged >14 years who were diagnosed with and treated for primary warm-type AIHA at the Division of Hematology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, during January 2007 to December 2016. All 54 included patients failed first-line corticosteroid treatment after which second-line treatment was prescribed. Baseline clinical characteristics, laboratory results at diagnosis and at start of second-line treatment, type of second-line treatment, treatment outcome, and complications of treatment including death were collected.Results:: Included patients had a mean age at onset of 55.8 years (14.5–87.4) and 83.3% of patients were female. Most patients (63%) were refractory to steroids, and the rest of them relapsed while on steroids. The second-line medications were azathioprine (61.1%), cyclophosphamide (31.5%), chlorambucil (1.9%), danazol (3.7%), and rituximab (1.9%), with respective response rates of 78.8%, 58.8%, 1/1 patient, 2/2 patients, and 0/1 patient. Strong positive direct Coombs’ test (3+–4+) was the only predictive factor of treatment response (p = 0.008). Males had better relapse-free survival than females (not reached vs. 20.6 months) (p = 0.023). Approximately 40% of the patients who responded to second-line treatment relapsed at a median of 7.4 months.Conclusion:: Immunosuppressive drugs are the most common second-line treatment for primary warm-type AIHA in Thailand; however, relapse was common. Additional therapies are needed to reduce the relapse rate and prolong remission.

The chemical and laboratory investigation of hemolysis.

The abnormal breakdown of circulating red blood cells (RBCs), also known as hemolysis, is a significant clinical issue that can present as a primary disorder or arise secondary to another disease process. The evaluation for pathologic hemolysis (and the establishment of a hemolytic disorder) is heavily dependent on assays performed and overseen by the divisions of Hematology, Blood Bank/Transfusion Medicine, Clinical Chemistry, and Immunology in the clinical laboratory. Because of the wide variety of assays used across the spectrum of clinical pathology and potential pitfalls/limitations associated with this testing, the decision of which assay to choose and, perhaps more importantly, how to interpret results, can both be quite challenging. Thus, the aim of this manuscript is to provide a comprehensive review on the laboratory investigation of pathologic forms of hemolysis and hemolytic disorders. This chapter will: (1) introduce basic concepts on the pathophysiology of hemolysis and (2) examine assays available for hemolysis on a laboratory-by-laboratory basis, with a particular emphasis on the strengths, limitations, and clinical interpretations of each of these assays.

Mandibular and cheek swelling revealing the diagnosis of localized amyloidosis

Mandibular and cheek swelling revealing the diagnosis of localized amyloidosis

High Expression of NEK2 Mediated By p53 Contributes to Progression and Relapse of Multiple Myeloma

High expression of NEK2 mediated by p53 contributes to progression and relapse of multiple myelomaXiangling Feng1,2, Jiaojiao Guo1, Bowen Ouyang2, Yinghong Zhu1,Gang An3, Hao Zhen1, Jiliang Xia1, Yongjun Guan1, Xinying Zhao2, Lugui Qiu3, Jiaxi Zhou3, Fenghuang Zhan4,Wen Zhou11, Cancer Research Institute,Central South University, Changsha 410078, China. 2Xiang Ya School of Public Health, Central South University, Changsha, Hunan, China. USA. 3State Key Laboratory of Experimental Hematology, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin, China. 4Department of Internal Medicine, Division of Hematology, Oncology, and Blood & Marrow Transplantation, University of Iowa, Iowa City, USA. E-mail: wenzhou@csu.edu.cn.Background: Loss of p53 is an independent prognostic factor in patients with multiple myeloma (MM). Our previous studies found abnormal high expression of NEK2 was closely related to the poor prognosis and drug resistance of myeloma patients. However, it's unclear how NEK2 was up-regulated in MM. Through bioinformatics analysis, the binding site of p53 protein is found in NEK2 promoter, but the relationship and function of p53 and NEK2 in MM are poorly understood.Materials and Methods: In this study, p53-/- MM cell lines (ARP1 and KMS11) and p53 p53+/+ MM cell lines (MM1S and H929) were used for investigating the role of NEK2 in p53-/- MM cell. FISH was performed on interphase nuclei of MM primary cells to detect p53 and NEK2 copy numbers. Chromatin immunoprecipitation and fluorescence reporter system were applied for examining the binding site of p53 protein in the distal NEK2 promoter. CGH and RNA-seq were performed to validate copy number changes and variations in the expression of several transcripts.Results: The top 10% of MM patients with the highest NEK2 expression and lowest p53 had a significantly inferior OS (P<0.001) in TT2 and TT3 patients (GSE2658) and the expression of NEK2 increased significantly in myeloma cells during chemotherapy(GSE19554), while p53 decreased with the disease progression, suggesting a strong relationship with drug resistance. Single cell PCR showed increased NEK2 expression correlated with decreased p53 expression in single CD138+ plasma cell. FISH confirmed the loss of p53 in CD138+ plasma cells with amplification of NEK2 copies. Furthermore, NEK2 was also high expressed in p53 low expressed MM cells by Immunofluorescence (IF) (P<0.01). In addition, NEK2 was upregulated in p53-/- MM cell lines and HEK293 cells by deleted p53 gene with CRISPR technique both on mRNA and protein level (P<0.01), suggesting a negative correlation between the p53 and the expression level of NEK2. Meanwhile, when p53 deletion and NEK2 overexpression occur simultaneously, the phenomena of asymmetric mitosis and multipolar division are more obvious (P<0.001), suggested that the double hit of p53 deletion and NEK2 overexpression increases the chromosomal instability. Further in vivo study indicated the subcutaneous tumorigenesis in p53 deletion and NEK2 overexpression group was significantly greater than that of the single overexpression of NEK2 and deletion of p53 group (P<0.001), suggested that NEK2 overexpression and p53 deletion enhances the tumorigenic ability in vivo. While down-regulation of NEK2 by shRNA in p53 deletion cells, cell growth was inhibited in vitro and in vivo.To explore the relationship between p53 and NEK2, chromatin immunoprecipitation and fluorescence reporter system showed that p53 could bind to the promoter region of NEK2 and regulate its transcriptional expression. Further CGH analysis of the deletion of p53 expression in HEK293 cells can cause 1q21.4-44 amplification of the chromosome region of the NEK2 directly, which further confirmed by FISH. Finally, RNA-seq revealed several chromosome instability genes were abnormal expressed in NEK2 overexpression and p53 deletion double-hit group.Conclusion: In summary, p53 deletion and NEK2 overexpression induced cancer cell drug resistance, proliferation and chromosomal instability. p53 could bind to the promoter region of NEK2 and cause NEK2 amplification. Down-regulation of NEK2 by shRNA in p53 deletion cells inhibited cell growth in vitro and in vivo. Thus,The significance of this study will provide the pre-clinical application of the NEK2 inhibitor to overcome the drug resistance induced by p53 in MM. DisclosuresNo relevant conflicts of interest to declare.

Fibroblast Growth Factor-1 Inhibition Enhances FAS-Induced Apoptosis in Mantle Cell Lymphoma Cells By Accelerated BIRC2/3 Degradation

Fibroblast growth factor-1 Inhibition Enhances FAS-Induced Apoptosis in Mantle Cell Lymphoma Cells by Accelerated BIRC2/3 Degradation.Neeraj Jain1, Tamer Khashab1, Natalie Willingham2, Felipe Samaniego1 and Lalit Sehgal21 Department of Lymphoma/Myeloma, UT MD Anderson Cancer center, Houston, TX 770542 Division of Hematology, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USAIntroduction Mantle cell lymphoma (MCL) is an aggressive form of non-Hodgkin lymphoma that is characterized by the t(11:14)(q13:p32) translocation. MCL cells have altered cyclinD1 levels, impaired cell cycle regulation, DNA damage response, and likely defects in apoptosis signaling. Furthermore, up-regulated anti-apoptotic mediators such as the target of NF-κB BIRC2 and BIRC3 were correlated with decreased apoptosis signaling. Also many cancer cells and malignant tumors show a prevalent resistance to apoptosis induction by FAS. Thus, by understanding the underpinnings of apoptosis resistance, we will be in a better position to develop strategies that improve Fas-induced killing of lymphoma cells.Methods More detailed insight into MCL pathogenesis has been delayed until the recent development of a tissue culture system, using human mesenchymal stromal cells (hMSC), suitable for propagating primary MCL cells. Isolates of primary MCL cells were co-cultured with human mesenchymal stem cells (hMSCs) and the content of MCL-ICs was analyzed by flow-cytometry based on marker expression profile; CD34-CD3-CD45+CD19-. Cytokine array was used to identify the soluble factors enriched in the co-cultures and the expression of these factors was confirmed by RT-PCR analysis. The signaling pathways employed by the newly-identified factors were blocked in 3 MCL cell lines (JVM2, Mino, Z138) to confirm their essential role in survival of MCL cells and, more importantly, for MCL-ICs.Results Co-cultures of primary MCL isolates with hMSCs supported the growth of MCL cells for over 4 weeks with continued presence of MCL-ICs (CD34-CD3-CD45+CD19-) representing about 1% of MCL cells. We found that IL-6 produced by hMSCs triggered an FGF/FGFR autocrine loop in MCL-ICs. The extent of FGFR expression correlated tightly with expression of SOX11, a pathology related negative prognostic marker in MCL. MCL cell survival and growth was regulated via the FGFR-1 mediated BIRC2/3 axis. Blocking of this signaling pathway with FGFR-1 inhibitors consistently induced early degradation in BIRC2/3 levels and subsequently MCL cell death.Conclusion We established that propagation of primary MCL in co-cultures with hMSCs depends on activation of FGF/FGFR-1 autocrine loop that enhances BIRC2/3 protein expression and thus, supports survival of MCL cells. We identified the factors essential for survival of MCL and MCL-ICs that present new targets for improved MCL treatment strategies. This study reveals that inhibition of FGFR-1 signaling by specific inhibitor has a profound positive impact on extrinsic cell death signaling; it enhances FAS sensitivity by promoting processing of caspases through enhanced BIRC2/3 degradation. The capacity of FGFR-1 inhibition to target stability of BIRC2/3, underscores its potential for enhancing efficacy of conventional cancer therapies. DisclosuresSamaniego:ADC Therapeutics: Research Funding.

Retaining Parental Role Despite the Presence of Hematological Neoplastic Diseases: The Emanuela Project and the Role of the Hematologist

IntroductionThe diagnosis of a hematological neoplastic disease (HND) bears a great impact on the patient family, which suffers abrupt changes in living patterns because of prognosis, prolonged hospitalization and therapy related adverse events.Parents often believe that the best way to protect their children from suffering is to avoid communications about the disease, as “they wouldn't understand”.Many hospitals offer family support, usually managed by psychologists; we hypothesized that the hematologist can play a key role in this process, being the one who primarily takes care of the patient, possesses the scientific skills necessary to explain the disease and is viewed by the family members as the key player.Since 2010, patients admitted to the Hematology Division at San Gerardo Hospital in Monza - Italy, who have minors in their family can participate in the “Emanuela Project” (see below).MethodsThe aim of this pilot study is to evaluate the impact of this intervention on children health status as perceived by their parents either affected or unaffected by HND. Ten hospitalized patients with a HND disease diagnosed between November 2017 and May 2018, with at least one child aged 0-18 years were recruited after signing an informed consent.Intervention: children can visit their parents in a dedicated hospital room in the days after diagnosis and an informal talk with a hematologist and a psychologist is organized; the hematologist, using simple images and metaphors (e.g. “flowered garden” to represent the normal bone marrow), explains the illness and answers questions, while the psychologist helps children to express emotions about the situation. A questionnaire, administered 30-60 days after the intervention to all parents, explores their perceptions about changes in each child; itconsists of 18 multiple choice questions and 15 open questions.Data were analyzed with statistical software STATA. Open questions were fully read and interpreted by authors; T-LAB software was used to evaluate relevant recurring words .ResultsAll 10 patients that were offered the intervention consented to it; 9 out of 10 patients have returned their questionnaires by July 2018 Five of them were fathers (55.56%) and 4 mothers (44.44%), with a mean age 50.22+/- 9.19 (SD). Diagnoses were Acute Leukemia (5), Lymphoma (2) and Multiple Myeloma (2). Mean duration of hospital stay was 26.2 days (+/- 12.8 SD) .The study included 16 children, aged 4 to 18 (mean 10 +/- 5 SD). We analyzed 28 questionnaires. Data from multiple choice questions exploring changes in children behavior suggest that, according to both parents there was no substantial worsening in school performance, appetite, sleep patterns (see table 1). These findings suggest that talking to children about the disease didn't traumatize them, and gave some concrete and reassuring answers to unexpressed fears. An interesting finding is that 44% of children increased their need to be in contact with the ill parent, showing a strengthening of relationships inside the family. One relevant finding concerns the possibility to talk about HND inside the family: 93% of parents gave a score of 3 (=often) or 4(=always) to this question. 100% of parents stated that it was never necessary to keep clinic visits or hospital admissions hidden from their children; 80% never had to hide side effects of therapies. All healthy parents and 87.5% of sick ones found that communicating with their children was a correct strategy, and that this intervention by hematologist and psychologist was useful. According to 88% of them, such a difficult task is responsibility of parents and of a specific professional figure, the hematologist. The use of simple images and metaphors helped 85.7% of healthy parents and 62.5% of ill ones to understand the illness better. According to 75% of parents, the intervention also played a key role in improving their relationship with doctors. The T-Lab analysis of recurring words is presented in Tab 2.ConclusionsData indicate that for parent it is important to be supported by their hematologist in the difficult task of explaining their illness to their children. The Emanuela Project allows parents to retain a parental role despite their illness; communication contributes also to increase trust in the medical staff and compliance to physically and emotionally demanding treatments.These data will be compared to those obtained in nearby hospitals who do not offer such a service. DisclosuresGambacorti-Passerini:BMS: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding.

The Pros and Cons of Splenectomy in Transfusion Dependent Thalassemia Patient

▪IntroductionOne of the treatment modalities in transfusion dependent thalassemia (TDT) patient is splenectomy which aims to ameliorate red cell transfusion. However, not all thalassemia patients respond to splenectomy. Moreover, splenectomy may increase many unfavorable consequences. The study about the efficacy and complications after splenectomy is limited and the effect of splenectomy on iron overload is still unclear.This study aims to investigate the long-term efficacy of splenectomy, factor predicting a response to splenectomy, the consequences of splenectomy complications, CBC parameter changes and the effect on iron overload parameters after splenectomy.MethodsAll TDT patients (PRC transfusion ≥3 units/year), aged >15 years who had splenectomy were recruited from our hematology division data base. Clinical characteristics including age, sex, age at splenectomy, operation date, hemoglobin (Hb) typing were collected. PRC transfusion requirement (unit/year) and CBC were collected 1 year before splenectomy, 1 year and 5 year post splenectomy.In the complication cohort, TDT patients with intact spleen were recruited into control group. The sample size was calculated that at least 33 patients (66.6% from splenectomy group and 33.3% from non-splenectomy group) needed to be recruited to have 80% power to detect a difference in complication at an alpha level of 0.05.The diagnosis of pulmonary hypertension (PHT) was based on the echocardiogram performed by the cardiologist and using definition from the 2015 ESC guideline. The thrombosis events were collected from medical record. The iron overload was compared by serum ferritin, liver iron concentration (LIC) and cardiac iron concentration were assessed by MRI of liver and cardiac T2*.The associated factors of efficacy and complication for splenectomy were compared using Chi-squared test or Fisher exact test for categorical variables and T-test or Mann-Whitney test and repeated measure mixed model for continuous variables. Multivariate regression analysis was used to identify relationships between variables with the level of significance was defined as P value <0.05.ResultsFifty TDT patients were included from the data base. In term of splenectomy efficacy, 21 patients (42%) has been changed from TDT to non-transfusion dependent thalassemia (NTDT) patients after splenectomy and 25 patients (50%) had 50% reduction in PRC transfusion. The significant factors associated with changing from TDT to NTDT were genotype of thalassemia (P=0.001). HbH disease and beta thalassemia/HbE (β/E) patients were the group who had higher response (28.57% and 52.38%, respectively) compared to HbH with CS (9.52%) and homozygous beta-thalassemia (9.51%). Lower percentage of neutrophils (<50%) was associated with lower response (P=0.02). Older age at the time of splenectomy (>10 year old) was associated with higher response after splenectomy (P = 0.005).CBC before splenectomy, 1 and 5 years after splenectomy were compared. Mean Hb level was increased from 6.0 to 8.2 and 7.7 g/dL (P<0.001) and platelet was increased from 234,866 to 714,473 and 675,579 cells/cu.mm. (P<0.001).Sixty-four patients were included in the complication cohort, (44 patients in splenectomy group and 20 patients in non-splenectomy group). The baseline characteristics including age, sex, Hb, ferritin were similar between 2 groups. The splenectomy group had significant higher tricuspid valve regurgitation velocity (TRV) compared to non-splenectomy group (2.54 m/s vs. 2.31 m/s, P=0.029). The prevalence of PHT and thrombosis were higher in splenectomy group (27.3% vs. 15% and 9.1% vs. 0%, respectively). Serum ferritin, LIC and cardiac T2* were not different between the 2 groups. From multivariable analysis, the only significant factor for predicting PHT was the longer duration after splenectomy (p=0.045).ConclusionSplenectomy had benefit in some TDT patients. Factors that predict a higher response to splenectomy were thalassemia type (HbH and β/E), higher neutrophil percentage and older age at the time at splenectomy. Hb and platelet was significantly increased after splenectomy.In term of complication, splenectomy group had significant higher TRV and tended to have more prevalence of PHT and thrombosis. The longer time post splenectomy was the only significant factor for developing PHT. DisclosuresNo relevant conflicts of interest to declare.