Hematology Clinic Research Articles

Assessment of disease knowledge gaps among beta thalassemia major patients and their caregivers

BackgroundThalassemia constitutes a major health issue in Egypt. It is associated with significant mortality and morbidity that arise mainly from iron overload secondary to blood transfusions.MethodsWe conducted this cross-sectional study at Cairo University children hospitals aiming at assessing the patients’ and their caregivers’ knowledge about thalassemia, and to identify factors affecting their knowledge in the period from December 2020 to August 2021.ResultsThe study included 45 thalassemia patients aged 10–14 years and 45 caregivers of patients who were less than 10 years of age. A knowledge questionnaire was generated from an educational script prepared by the investigators and translated into Arabic language. Thirty-one patients and 44 caregivers responded to the questionnaire individually, while 15 patient/parent pairs worked on the questionnaire together at their request. Age of patients ranged from 2 to 14 years, majority were males. Disease duration ranged from 0 to 13 years and the majority were following in the pediatric hematology clinic on a monthly basis. Candidates showed strong knowledge in areas related to symptoms and signs. On the other hand, they showed critical knowledge gaps in the areas of blood transfusions complications and iron chelation. Patients and caregivers scored similarly in various questionnaire topics with no significant difference. Gender, consanguinity, similar conditions in the family and frequent follow-up did not affect the score of the study participants, though longer duration of illness was positively correlated with the overall scores.ConclusionsThalassemia patients and their caregivers have significant knowledge gaps in areas of chelation therapy and transfusion complications.

Tissue Factor Positive Extracellular Vesicles and Risk of Thromboembolism in Diffuse Large B-Cell Lymphoma: A Prospective Exploratory Study

Cancer is associated with an increased risk of venous thromboembolism (VTE). Cancer patients experience hypercoagulability, which increases the risk of VTE. Thrombus formation in VTE is initiated by tissue factor (TF), located in the blood vessels, and exposed in vascular injury. TF is also found on the surface of tumor cells. Extracellular vesicles (EVs) are small membrane vesicles formed from activated or apoptotic cells. In cancer, TF+ and TF- EVs can be observed in the blood, where the TF+ EV number is higher in cancer patients than in healthy controls. The association of EVs with VTE in patients with lymphoma has not been established. The present study was designed to explore the role of TF+ EVs in the development and prediction of VTE in a homogenous lymphoma patient population, i.e., diffuse large B-cell lymphoma (DLBCL). The concentration of total EVs and EVs-expressing tissue factor (CD142) was determined with a protocol developed by Karolinska Institute, Sweden. In brief, samples were stained with Annexin V-FITC and CD142-APC (Thermo Fisher Scientific, Waltham, MA, USA). Megamix-Plus SSC (BioCytex, Marseille, France) was used to gate the EVs' size; samples were analyzed on the BD FACSCanto™. EVs were defined as vesicles ≤1.0 µm in size and positive for Annexin V. Flow cytometry data were evaluated with FlowJo software (version 10.8.1, BD, Ashland, OR, USA). Peripheral blood samples obtained pre-treatment from 62 newly diagnosed or relapsed patients with DLBCL have been collected at Clinic for Hematology at the University Clinical Center of Serbia. The clinical and routine laboratory data have been collected from hospital records. Patients who had completed a minimum of one chemotherapy cycle were followed for all VTE events from the time of diagnosis to 3 months after the last cycle of therapy. VTE was diagnosed objectively based on radiographic studies (duplex venous ultrasound, contrast-enhanced thoracic computed tomography scan, magnetic resonance imaging - for central nervous system thrombosis), clinical examination, and laboratory evaluation. All probable cases of VTE were reviewed by a final diagnosis committee composed of two specialists (internist and radiologist). The median patients' age was 59 years (range, 20-87 years); 51.6% were males. Most patients were newly diagnosed, 38.7% had advanced stage (III and IV) disease, and 47.8% had ECOG performance status >1. Total concentration of EVs and TF+ EVs were higher in DLBCL patients compared to healthy volunteers (448 [167-868] x109 EVs/L (median [IQR]) vs 159 [151-159], p=0.009 and 140 [50-272] vs 13 [12-23], p<0.001). The concentration of EVs and TF+ EVs was not different between patients who developed VTE during follow-up (n=11) and those who did not (n=51) (530 [167-1318] (median [IQR]) vs (447 [163-822], p>0.05 and (214 [33-385]) vs 140 [50-255], p>0.05). After a median follow-up of 32 months, neither EVs nor TF+ EVs were associated with overall survival in DLBCL patients in Cox regression analysis. In conclusion, while the concentration of TF+ EVs is increased in patients with DLBCL, it is not significantly associated with VTE incidence. The role of TF+ EVs activity in VTE in DLBCL patients remains to be established in future studies. Vladimir Otasevic and Charlotte Gran equally contributed as first authors Darko Antic and Jovan Antovic equally contributed as senior authors

Incidence of Typical Neutrophil Count with Fy(a-b-) Status Among Hematology Referrals for Neutropenia at an Urban Safety-Net Hospital

Typical neutrophil count with Fy(a-b-) status, known variously as Duffy null phenotype or Benign Ethnic Neutropenia, causes asymptomatic neutropenia without clinical sequelae.[i][ii] Fy(a-b-) phenotype is correlated to homozygosity of a single nucleotide polymorphism in the promoter region of atypical chemokine receptor 1 (ACKR1; formerly known as DARC), a decoy chemokine receptor, and may protect against malaria infection.[iii][iv] This genotype is enriched in malaria-endemic regions.[v] 25% to 50% of people of African ancestry in the United States are thought to have Fy(a-b-) status and are often erroneously identified as having pathologically low neutrophil counts. We performed a retrospective chart review of new neutropenia referrals to Hematology Clinic at Boston Medical Center (BMC) to evaluate diagnostic patterns for typical neutrophil count with Fy(a-b-) status. Overall, 103 new referrals for evaluation of neutropenia were made to BMC Hematology Clinic from 1/2020 to 2/2022, of which 78 were included for further analysis. Demographic and laboratory data are summarized in the accompanying Table. Typical neutrophil count with Fy(a-b-) status was identified as the primary etiology for neutropenia in 64.1% (50 of 78 referrals), of which 41 (82%) identified as African American or Black or were born in an African or Caribbean country. Of patients suspected of having Duffy null phenotype, 66% (33 of 50 patients) underwent confirmatory blood bank testing, and 97% (32 of 33) of these patients were found to have Fy(a-b-) status. Average cost of laboratory visit was calculated for each new referral using the Outpatient Price Transparency Tool from BMC Billing Department, which is based on chargemaster prices for the hospital. Patients with typical neutrophil count with Fy(a-b-) status on average had lower, but not negligible, cost of workup ($363.82 vs $689.46; p<.005 by unpaired student's T test assuming unequal variance) and were statistically less likely to have a follow up appointment (p=0.039 by unpaired student's T test assuming unequal variance) compared to those without. Though this phenotype reflects normal variation of white cell count in non-White populations, it is a "...label that illustrates how common phenotypes seen in non-White individuals continue to be considered nonstandard in the medical community." Workup of referrals that have typical neutrophil count with Fy(a-b-) status is not currently recommended, unless they have a change in their baseline white cell count or new, atypical features concerning for a secondary etiology.[vi] In our study, asymptomatic referrals were the majority and represent an unnecessary cost burden on an overtaxed healthcare system. Fy(a,b) antigen testing provides a low-cost alternative to hematology referral for confirmation of Fy(a-b-) status for patients or providers who require reassurance. Expanded use of serological Fy(a,b) antigen testing by primary care providers for patients with ancestry from malaria-endemic regions and chronic, asymptomatic neutropenia could reduce cost of care and referrals to Hematology clinic. [i] Ortiz MV, Meier ER, Hsieh MM. Identification and Clinical Characterization of Children With Benign Ethnic Neutropenia. J Pediatr Hematol Oncol. 2016 Apr;38(3):e140-3. doi: 10.1097/MPH.0000000000000528. PMID: 26925714; PMCID: PMC5102334. [ii] Merz LE, Achebe M. When non-Whiteness becomes a condition. Blood. 2021 Jan 7;137(1):13-15. doi: 10.1182/blood.2020008600. PMID: 33181819. [iii] Reich D et al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS Genet. 2009 Jan;5(1):e1000360. doi: 10.1371/journal.pgen.1000360. Epub 2009 Jan 30. PMID: 19180233; PMCID: PMC2628742. [iv] Miller LH, Mason SJ, Clyde DF, McGinniss MH. The resistance factor to Plasmodium vivax in blacks. The Duffy-blood-group genotype, FyFy. N Engl J Med. 1976 Aug 5;295(6):302-4. doi: 10.1056/NEJM197608052950602. PMID: 778616. [v] Haddy TB, Rana SR, Castro O. Benign ethnic neutropenia: what is a normal absolute neutrophil count? J Lab Clin Med. 1999 Jan;133(1):15-22. doi: 10.1053/lc.1999.v133.a94931. PMID: 10385477. [vi] Gibson C, Berliner N. How we evaluate and treat neutropenia in adults. Blood (2014) 124 (8): 1251-1258. https://doi.org/10.1182/blood-2014-02-482612 Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Evaluation of the Efficacy of Flow-Cytometry in the Work-up of Leukopenia: An Institutional Retrospective Analysis

Flow-cytometry is an advantageous test which was first used in the 1950s and has now expanded to include the various fields of Immunology, Hematology, Oncology, Blood-banking and Genetic disorders. However, it is a relatively expensive and time-consuming test. We noticed that in our institution, many of the referrals for leukopenia were being evaluated by the flow-cytometry test. Hence, we aimed to review the utility and efficacy of this test with a focus on highlighting the areas where it can be avoided. We designed a retrospective study to examine data from all leukopenia/neutropenia referrals made to our center in the timespan of 1993-2018. The study included all patients aged >18 years; excluded any patients who were not directly seen in the hematology clinic by the time of data collection. The study protocol was approved by our Institutional review board (IRB). We received de-identified data, reviewed those charts, categorized them based on their reason for referral; presence of underlying cardiovascular disease, liver disease, rheumatological disease, hepatomegaly, splenomegaly. We then looked at what percentage of these patients received flow-cytometry analysis and how many of them turned out to be positive for hematologic malignancies.We further conducted statistical analysis using SAS to examine these trends. After filtering out patients based on exclusion criteria we ended up with 152 patients in our study. The reason for referral was varied and included bi-cytopenias (6.5%), concern for malignancy(1.31%), aplastic anemia (2.63%), pancytopenia (3.2%) with the majority being for neutropenia (44.7%). We found co-existing cardiovascular disease in 4.6% of patients which included congenital heart disease (28.5%), atrial fibrillation (42%), coronary artery disease (28.5%), congestive heart failure (14.2%) and supraventricular tachycardia (14.2%). Co-existing liver disease was seen in 15% of the patients and was categorized as Hepatitis C infection (47.3%), cirrhosis of the liver (36.8%) and metastatic neoplasm to the liver (5.26%). Rheumatological disease was seen in 13% of patients with the causes being rheumatoid arthritis (47%), Systemic lupus erythematosus (30%), Myasthenia gravis (5.8%), Felty's syndrome (5.8%), and Sarcoidosis (5.8%).Hepatomegaly was seen in 3% of patients and splenomegaly was seen in 7.8% of patients. Flow-cytometry analysis was done in 36% of patients and not done in 64% of patients. It was positive in only 3.9% of patients which resulted in diagnosis of Acute myeloid leukemia (0.65%), Large granular leukemia(0.65%), Myelodysplastic syndrome(0.65%) and Natural-Killer cell lymphoproliferative disorder (0.65%). Further work up revealed elevated IgG, monoclonal gammopathy, aplastic anemia in 1.97% of patients. The overall predominant causes of leukopenia were benign ethnic neutropenia (17%), medication related (12.5%), autoimmune (5.2%), malignancy (3.9%), viral (4.6%), toxic (2.6%) causes. The medications which caused neutropenia were antibiotic and antifungal (1.31%), anti-seizure (3.2%), immunosuppressant and immunomodulatory (3.2%), psychiatric (2.6%).During evaluation of leukopenia, a thorough history can rule out toxic and medication-related causes. The review of old medical records and laboratory results can lead to the diagnosis of chronic benign and congenital leukopenia which can avert unwarranted testing. Abstinence from alcohol may lead to reversal of the neutropenia if alcohol is the toxin responsible. Viral testing for HIV and hepatitis should be performed. Evaluation for autoimmune causes is much needed. Since the overall positivity of flow-cytometry was very low in our analysis (3.9%), we propose that such thorough preliminary evaluation can avoid the need for many of these tests. The data showed that leukopenia referrals come with a wide range of underlying causes including congenital disorders (benign ethnic, familial, congenital neutropenia) and acquired disorders (infection, toxins, medications, nutritional, rheumatological, autoimmune, idiopathic, hematologic malignancies). Peripheral blood flow-cytometry although sensitive for detecting some hematologic malignancies, is unnecessary in the majority of cases. Hence, we highlight here the varied benign causes of neutropenia and quantify them as seen in a tertiary referral center to enable decisions on the judicious use of this test. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Study to Evaluate the Utility and Appropriateness of Diagnostic Workup for Leukocytosis in the Hematology Clinic

Background: Leukocytosis is a common abnormality in the complete blood count (CBC) that is often first noted by general practitioners. In addition to many benign causes of leukocytosis, malignant causes such as CML, myeloproliferative neoplasms (MPNs), and MDS/MPN overlap syndromes, must be evaluated for select patients by a hematology specialist. While some recommendations for evaluation and diagnostic workup for leukocytosis exist, the real-world appropriateness and utility of further serologic tests or diagnostic procedures, including bone marrow biopsy, remain largely unknown. The aim of this study is to determine hematological parameters in patients referred for evaluation of leukocytosis that are associated with MDS/MPN diagnoses and are therefore useful to the hematologist in selecting appropriate patients for further diagnostic testing. Methods: A retrospective chart review was conducted of 803 adult patients referred to the hematology clinic at a single institution between 2016-2021. 487 patients were included based on the inclusion criteria that they were referred for evaluation of leukocytosis and did not have a prior established hematologic diagnosis. Demographic and laboratory data were collected including CBCs, anemia workup, leukocytosis workup, JAK2 V617F mutation and BCR-ABL mutation results, and bone marrow biopsy results. Clinician notes were reviewed from the medical record to verify appropriate patient selection and data points. Statistical analyses were performed using Chi-Square/Fisher exact tests to evaluate for hematological parameters that are associated with the identification of MDS/MPNs as well as other hematologic malignancies, and a multivariable logistic regression model was used to analyze the association between hematological parameters and diagnosis of MDS/MPN. Results: 487 patients were included in analysis: 70% female, 44.6% white, 30% black or African American, and 25.5% Hispanic or Latino. After evaluation by a hematologist, 14.6% of patients were diagnosed with a hematologic malignancy, and 8% were diagnosed with MDS/MPN. Higher WBC, particularly greater than 15 x 109/L, was associated with diagnosis of MDS/MPN, any hematologic malignancy, and testing positive for BCR/ABL or JAK2 V617F (p <0.0001). Patients with an absolute neutrophil count (ANC) > ULN (7.8), absolute eosinophil count (AEC) > ULN (0.6), absolute basophil count (ABC) > ULN (0.3), platelet count >600, ferritin >50, and vitamin B12 > ULN (920) were more likely to be diagnosed with MDS or MPN (p <0.0001, <0.0001, <0.0001, <0.0001, 0.02, and 0.0006 respectively). These laboratory findings were also significantly associated with diagnosis of any hematologic malignancy, and many were associated with testing positive for BCR/ABL or JAK2 V617F mutations (ANC, AEC, ABC, and platelet count). Multivariable analysis results shows that ABC >= 0.3 (OR=27.7, 95% CI=3 - 255.3), platelet count >= 600 (OR=16.9, 95% CI=1.9 - 146.4), and vitamin B12 > 920 (OR=5.8, 95% CI=1.2 - 28.4) significantly increase the risk of being diagnosed with MDS/MPN. Conclusions: This retrospective study identified hematological parameters in patients referred for evaluation of leukocytosis including elevated ANC, AEC, ABC, and platelet count that were significantly associated with testing positive for BCR/ABL mutation or JAK2 V617F mutation. These parameters, in addition to vitamin B12 and ferritin, were associated with positive identification of hematologic neoplasms and specifically MDS/MPNs. These parameters may guide hematologists in selecting appropriate patients for further serologic or procedural testing, such as JAK2 V617F and BCR/ABL mutation testing and bone marrow biopsy, in order to avoid unnecessary testing and decrease the financial cost of evaluation.

Categorization of Patient Reviews in a Hematology Clinic

Introduction: Patient reviews of physicians and hospitals are frequently collected after patient visits. This information is used in a multitude of ways, including ranking provider services, national hospital rankings, informing other patients of expectations, hospital improvements, etc. Often, the ranking of a physician is reflective of the entire patient experience rather than the provider as an individual. We opted to look at recent rankings from our outpatient hematology department to help determine where patients were identifying specific issues. Methods: Using 174 patient comments as collected by NRC Health ® on an outpatient hematology unit focused on both malignant and benign hematology in a hybrid academic/community practice in Orlando Florida, we divided patient comments into different sections. These included comments directed toward:Individual providerClinic or front office staffTime based concerns (time to get roomed to see physician, time for check out, time for results of tests, etc.)Financial concernsScheduling concernsConcerns related to emergency rooms or inpatient saysOther (medication refills, intake paperwork, parking issues) Every patient comment for reviews that were less than "five stars" were reviewed and categorized into the above categories. If telehealth was used, we separately looked at comments related to these visits. Results: Of 174 returned comments, there were 46 (26%) returned comments were less than "five stars". The concerns were directed toward:Individual provider: 4 timesHospital staff: 11 timesTime based concerns: 14 timesFinancial concerns: 2 timesScheduling concerns: 5 timesConcerns related to emergency rooms or inpatient says: 4 timesOther: 6 times When a visit was telehealth based, 14/15 patients left a positive review. The one negative review was a patient having a difficult time with the specific virtual platform used for the visit. Conclusion: Of 174 patient surveys being returned, 46 left a comment identifying a grievance or a point for improvement. Rarely (8%) was the individual provider the point of concern. Much more often, time based concerns or staff related concerns were highlighted as areas for improvement. When telehealth was used, these problems were never mentioned, perhaps highlighting a benefit for these platforms.

Association of Noninvasive Peripheral Blood Hemoglobin Assessments with Venous Blood Draws Among Sickle Cell Patients

Introduction: Sickle cell disease (SCD) is the most common genetic blood disorder, affecting an estimated 100,000 people in the US and over 20 million worldwide. SCD costs one and a half billion dollars of economic loss annually in the US, resulting in sustained burden to the families and the healthcare systems (Value in Health 2021;24:1095). Many patients living with SCD require frequent blood draws and may have to have a central line for routine blood draws. A blood hemoglobin (Hgb) level is the central information about the pathophysiology of SCD including anemia. Low blood Hgb levels have shown as a potential indicator of painful vaso-occlusion crises (Blood 2021;137:2010). Blood Hgb levels are checked for evaluation of new symptoms, medication monitoring, and routine follow up. Real-time and noninvasive monitoring of blood Hgb levels would be clinically beneficial, but less feasible through frequent invasive blood draws. Developing a reliable, self-educated, and completely non-invasive mobile health (mHealth) tool for real time blood Hgb assessments can directly benefit many patients living with SCD, minimizing the number of iatrogenic blood loss from frequent blood draws and improving the quality of care. Methods: Our team has recently developed an mHealth algorithm that can reliably estimate a blood Hgb level from a photo of a peripheral tissue site at individual's inner eyelid (palpebral conjunctiva) (Figure 1a). We conducted a pilot study to determine the exact relationship between peripherally detected blood Hgb levels (accessed from the inner eyelid) and blood Hgb tests (venous blood draws) performed at a clinical laboratory. Fifteen patients with SCD aged from 14 to 73 years were recruited at Hematology Clinic at University Hospital of the Indiana University School of Medicine. Acquisitions of the inner eyelid photos in RAW format were conducted by Samsung Galaxy S21 immediately before or after a blood draw. Blood Hgb levels from the inner eyelid's photo were computed using the previously developed statistical learning algorithm (Optica 2020;7:563); the first step was to recovery a spectrum from an RGB image (spectral learning) and the second step was to compute blood Hgb content using a spectral analysis (Figure 1a). Results: The linear correlation between the peripheral mHealth blood Hgb levels and the venous blood Hgb levels in the blood (i.e., the gold standard) shows a value of 0.82 with a p-value of 0.0002 (Figure 1b). A Bland-Altman analysis was also conducted as a non-parametric statistical method. The limits of agreement (LOA) were defined by a 95% prediction interval of the standard deviation of the differences between the mHealth and conventional blood Hgb levels. 95% Bland-Altman LOA was +/-2.3 g/dL (Figure 1b) and within LOA, the data points were uniformly scattered, indicating no significant bias. This level of performance is comparable to point-of-care blood sampling (finger prick) testing and noninvasive medical devices (Respiratory Care 2019;64:1343). Conclusion: This preliminary study supports the feasibility of peripheral and noninvasive mHealth blood Hgb assessments among patients with SCD. Importantly, peripheral mHealth blood Hgb levels are significantly associated with conventional venous blood Hgb tests among SCD patients. Thus, the mHealth technology can lay the groundwork for empowering individual patients by offering an easily accessible tool for quickly estimating blood Hgb levels by a smartphone. This mHealth technology has potential advantages including mobility, simplicity, and affordability for rapid and real-time blood Hgb quantification among patients living with SCD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Natural History of Patients with Clonal Hematopoiesis Seen in Hematology Clinics

Background: The International Consensus Classification (ICC) recently recognized clonal hematopoiesis of indeterminate potential (CHIP) as a clinically defined pre-malignant state. A subgroup of patients with clonal hematopoiesis (CH), herein termed progressors, ultimately develop to a frank clinical diagnosis, while others, herein termed non-progressors, may have CH indefinitely with variable risk of progression. Although eight years have passed since the large-scale descriptions of CHIP as an age-related phenomenon, the risk factors for progression and management guidelines are still not well-defined. Moreover, while many quaternary care centers have developed CHIP databases, little is known about the epidemiology of CHIP from tertiary care centers that draw patients from the community setting. Methods: Patients with CH were identified via concurrent morphologic, cytogenetic, and molecular diagnostics of bone marrow aspirates reviewed by UMass Hematopathology between 2013 and 2022. CH was defined here as per the 2022 ICC: presence of a somatic mutation with variant allele frequency (VAF) ≥ 2% on molecular diagnostics or non-myelodysplastic syndrome (MDS)-defining clonal cytogenetic aberration in a patient without morphologic evidence of myeloid neoplasm. Patients with germline mutations were excluded. Independent review of all bone marrow aspirates was performed by at least two pathologists. This study included a pre-selected group of patients who had an indication for bone marrow evaluation; reasons for performing bone marrow evaluation included presentation with pancytopenia (41.7%), anemia (14.6%), leukocytosis (12.5%), thrombocytopenia (6.3%), leukopenia (4.2%), bicytopenia (4.2%), staging workup for a lymphoma (4.2%), erythrocytosis (4.2%), thrombocytosis (4.2%), abnormal radiographic marrow signal (2.1%), eosinophilia (2.1%). A total of 48 patients with CH were identified. Results: A total of 102 aberrations were found among 48 patients with CH. The mean, median, mode, and range for CH aberrations were 2.15, 1.5, 1, and 5, respectively. The mean age at detection of CH for non-progressors was 69.2 ± 1.8 years vs. 63.1 ± 3.5 years for progressors (p = 0.072). The most prevalent somatic variants in CH were: TET2 (29.1%), DNMT3A (14.5%), and gross structural abnormalities (7.7%) (Panel A, outer circle). Progressors had a distinct profile (Panel A, inner circle). Zero of 48 patients with CH carried TP53, IDH1, or EZH2 aberrations. The most prevalent genomic disruptions were missense mutations (45.6%), nonsense mutations (15.6%), and frameshift deletions (13.3%). We assessed the clinical trajectory of patients with CH (Panel B). Nine (18.8%) of 48 patients progressed to neoplasm (confirmed by bone marrow evaluation). Median overall survival (OS) at the time of analysis was 6.85 years, with longest follow up of 9.58 years. For non-progressors, median OS was not reached. For progressors, median OS was 6.85 years (from time of identification of CH). Median time from identification of CH to frank neoplasm was 1.05 years. For progressors, median time from diagnosis of frank neoplasm to death was 1.76 years. Of the 14 patients harboring DNMT3A, TET2, or ASXL1 (DTA) mutations alone, without mutations in other biological clusters, none (0%) progressed (Panel B,blue bars). Conclusion: In contrast to the original reports of CH, which studied unselected patients from multiple consortia, the patients in our study were pre-selected for suspicion of an underlying hematologic condition, reflecting real-world data. CH spans multiple functional clusters that are recurrently mutated in MDS and/or acute myeloid leukemia (AML), with the notable exception of TP53, IDH1, and EZH2. This may be due to more rapid progression to malignancy for those mutations, with only a transient, if any, CH state. All patients who progressed with DTA mutations did so only in the presence of additional mutations - at least a second mutation was required for DTA cases to progress. There was a trend toward significance for younger mean age at CH detection for progressors vs. non-progressors. Lead-time bias may skew OS results for patients found to have CH at an early point; and CH detected at a younger age may be more likely progress, leading to shorter OS. Systematic studies are needed to more comprehensively profile CH and develop formalized risk-adapted management strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Characterization of Inborn Errors of Immunity in Recurrent Autoimmune Cytopenias in Children: A Report from Central California Cohort

Abstract Autoimmune cytopenias are characterized by autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and/or autoimmune neutropenia. Evans syndrome (ES) is a condition characterized by simultaneous or sequential development of AIHA and ITP and/or immune neutropenia. Inborn errors of immunity driven multilineage cytopenias including ES requires further characterization to identify therapeutic targets. We evaluated our cohort of children with immune cytopenias to characterize mutations in inborn disorders of immunity and response to targeted therapy. To this end, we retrospectively reviewed the medical records of children between the ages of 0-21 years who presented to our hematology clinic with recurrent immune cytopenia between the years of 2018-2021. Rheumatological diseases, lymphoproliferative disorders, bone marrow failure syndromes, infections, drugs, toxins and metabolic disorders were excluded in the study. Children presenting with isolated idiopathic thrombocytopenic purpura or neutropenia were also excluded from the study. We utilized lymphocyte immunophenotyping and next generation sequencing involving 474 known genes (Invitae: Test code-08100) causing primary immunodeficiency in our pediatric patients with recurrent AIHA or multilineage immune cytopenias. Of the 59 patients with AIHA and multilineage immune cytopenias, 18 (30.5%) had recurrence of cytopenias after initial diagnosis. The age ranged from 1-20 years and 33% (n=6) were of the female gender (Table 1). AIHA (n=5, 28 %) and ES (n=5, 28%) were the most common presentation in patients with recurrent cytopenias. Autoimmune pancytopenia (n=4, 22.2%) was another common presentation. One child progressed to autoimmune pancytopenia after being diagnosed with AIHA. Pathogenic mutations in inborn errors of immunity were identified in 38.8% of the children. No mutations or variants were identified in 5 children (28%). Majority of patients received immunomodulatory treatments (Table 2) which resulted in remission (n=12, 66.6%). Immune cytopenias associated with Di-George syndrome were responsive to sirolimus with both children attaining remission. There was a death in the cohort related to the underlying condition. In conclusion, inborn errors of immunity were identified in recurrent immune cytopenias. Targeted therapies helped to achieve durable remission in children with specific mutations. Larger studies are warranted to understand the long-term therapeutic response in these children. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Hydroxyurea Therapy in Reducing Pain Crises, Hospital Admissions, and Length of Stay Among Sickle Cell Patients in the Eastern Region of Saudi Arabia.

Background In Saudi Arabia, sickle cell disease (SCD) is a major public health issue, especially in the eastern region. Sickle cell patients have major health-related issues, resulting in a poor quality of life and increased morbidity. Abnormal hemoglobin production in SCD causes various complications, such as vaso-occlusive crises, hemolytic episodes, and acute chest syndrome. These disease manifestations increase the need for hospital admission and long-term care. Most therapies for SCD are supportive and include episodic red blood cell transfusions, narcotics, antibiotics, and intravenous fluids. Hydroxyurea is a disease-modifying therapy. This study aimed to assess the effectiveness of hydroxyurea therapy on reducing pain crises, hospital admissions, and length of stay for SCD patients and discern reasons that would prevent SCD patients from using hydroxyurea as a treatment option. Methodology We conducted a descriptive cross-sectional study on SCD patients from the eastern Saudi Arabian province. The study included 202 SCD patients from hematology clinics and medical wards. We used a validated questionnaire tested for reliability after a pilot study of 15 randomly selected patients. We surveyed participants on demographic data, use of hydroxyurea, compliance with the regimen, hospitalization rates, durations, and complications. The study used IBM SPSS Statistics for Windows, Version 22.0. (IBM Corp., Armonk, NY) to analyze the data. All statistical analysis was done using two-tailed tests. P-values < 0.05 were considered statistically significant. Results The study included 202 participants who agreed to participate and completed the study questionnaire. The respondents comprised 150 SCD patients (74.3%) and 52 caregivers of SCD patients (25.7%). Patient ages ranged from one year to older than 36 years (mean age: 26.8 ± 12.3 years). The most common reason for not using hydroxyurea was that it was never offered to patients as a treatment option (40.9% of respondents), followed by respondents who had never heard of it (34.4%), think that they do not need it (24.7%), and fears of long-term consequences (23.7%). More hydroxyurea users (35.1%) suffered no acute painful crises during the last year than nonusers (32%), and more nonusers suffered more than four crises (20%) than hydroxyurea users (9.1%; p=.046). As for hospitalization due to SCD-related complications, 66.2% of hydroxyurea users were never hospitalized, while 51.2% of nonusers were never hospitalized. While 19.5% of hydroxyurea users were hospitalized one to two times, 28.8% of nonusers were hospitalized one to two times (p=.049). Conclusions The study revealed that hydroxyurea is effective in reducing painful vaso-occlusive crises and the number of hospital admissions. The prevalence of hydroxyurea use among SCD patients in the eastern province of Saudi Arabia remains low. Therefore, education campaigns and programs to increase awareness among health care providers regarding the benefits of hydroxyurea use are warranted in our region to help improve patient outcomes.

Alterations in the Humoral Immunophenotype of Children with Sickle Cell Disease on Hydroxyurea

Background: Sickle Cell Disease (SCD) is a red blood cell disorder associated with hemolysis and inflammation affecting homeostasis of the blood system. Both innate and T-cell driven adaptive immune systems are involved in SCD-linked inflammation. The involvement of B-cell compartment in etiology of SCD is much less studied. While complex interactions of ischemia-reperfusion, inflammation, and hemolysis affecting the bone marrow and immune system have been studied in adults with SCD, much less is known how their interplay affects SCD etiology in children. Objective: To determine the range of immune changes we assessed the frequency of 12 immune populations via flow cytometry, evaluated B cell related cytokines, and performed bulk RNA sequencing of the peripheral blood (PB) of pediatric patients with SCD as compared to pediatric race-matched controls as well adult patients with SCD as compared to adult race-matched controls. Method: Adult control PB was obtained from Rhode Island Blood Center. Pediatric control and pediatric and adult SCD PB were obtained from Rhode Island Hospital Hematology and Primary Care clinics. All informed consents/assents were obtained. PB samples were stained using markers identifying 12 immune populations including CD8, CD4, T Regulatory, B cells, Plasmablasts, Monocytes, Dendritic, Granulocytes, Neutrophils, Basophils, Eosinophils, and Stem Cells. Flow cytometry was performed on BDTM LSRII and analyzed using FlowJo. RNA was isolated from pediatric SCD or control PB and RNA-seq was performed by Novogene. Plasma from all patients (SCD and controls) was processed for cytokine analysis using Biolegend's LEGENDplex Human B Cell Panel. Demographics, clinical, and laboratory data were obtained from chart review. Results: Thirteen pediatric patients (ages 1-16, mean 8.7 years) and 12 adult patients (ages 8-15, mean 32.2 years) with SCD on Hydroxyurea were enrolled. HbSS genotype was found in 92.3% pediatrics and 66.7% adults. Mean Hydroxyurea dose was 23.4 mg/kg or 20.0 mg/kg for pediatric or adult SCD, respectively. Five pediatric controls (ages 9-14, mean 11.4 years) and 10 adult controls (ages 18-53, mean 31.0 years) were enrolled. Laboratory data indicated elevated hemolysis in pediatric and adult SCD with mean Absolute Reticulocyte Count (ARC) 203 ± 94.2 for pediatric SCD and 214 ± 169 for adult SCD. Flow cytometry data revealed 1.9-fold increase (p= 0.012) of CD3+CD4+ cells in Pediatric SCD versus pediatric controls, this change was not seen in adult SCD versus adult controls (Table 1). Pediatric SCD patients had 3.5-fold increase (p=0.005) in CD19+ B cells without further increase in differentiated B cells, this change was not seen in adult SCD versus adult controls (Table 1). Subsequent analysis of B cell related cytokines revealed significant increase in IL2 (p =0.013), IL4 (p=0.026), TNFβ (p= 0.039), and IL13 (p=0.034) in pediatric SCD versus pediatric controls; there was no significance for these cytokines in adult SCD versus adult controls. BAFF was elevated in both pediatric and adult SCD versus age-matched controls (p=0.041 and p=0.005, respectively). Finally, bulk RNA sequencing of pediatric SCD or control PB indicated significant changes in transcripts linked to humoral immunity. Over Representation Analysis (ORA) of cell type revealed upregulation of transcripts linked to pro-B cells (29 genes), plasma cells (37 genes) and CD34 Positive Pre-B cells (10 genes), (Figure 1). These results suggested significant alteration of the B cell maturation in pediatric SCD samples. Conclusions: Our data indicate significant changes in CD4+ and CD19+ cells in pediatric SCD patients versus controls. Increased CD4+ cell frequencies in children with SCD were previously reported (PMID 29926339). Our new finding of altered humoral immunity and differentiation of B cells noted by flow cytometry were consistent with elevated B-cell related cytokine levels in pediatric SCD versus pediatric controls. Elevated levels of pro-B cells, plasma cells, and CD34+ pre-B cell transcripts detected by RNA-seq in pediatric SCD patients versus controls further confirmed humoral alterations in pediatric SCD samples. Our findings point to previously unreported effect of SCD on the humoral immune system in children with SCD treated with Hydroxyurea, warranting further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Short Telomere Syndromes and Inherited Predisposition to Bone Marrow Diseases: The MDACC Experience

Introduction: Telomeres are noncoding nucleotide repeats at chromosomal ends, which provide genomic stability and are maintained and regulated by specific protein complexes. Their length physiologically decreases with age, although it is known that germline mutations in telomeric regulators can accelerate this process, which is related to a wide variety of clinical situations. Herein we report on the experience of patients diagnosed with Short Telomere Syndromes (STS) evaluated in the Hereditary Hematologic Malignancy Clinic (HHMC) of the MD Anderson Cancer Center. Methods: We retrospectively analyzed clinical characteristics and outcomes of patients with a diagnosis of STS referred or diagnosed in the HHMC. Germline mutation origin was confirmed by genetic analysis of cultured skin fibroblasts or blood/saliva in patients without hematologic disease. Telomere length was assessed by Flow-FISH techniques in a clinically validated external laboratory (John Hopkins Medical Laboratories, Baltimore, MD). Individuals with confirmed STS were recommended to follow a specialized cancer surveillance program to achieve early-diagnosis or prevention of potential complications related to STS. A baseline bone marrow evaluation was recommended to evaluate underlying morphology and assess for somatic comutations. Results: A total of 24 patients with STS were identified (13 males, 54%), with a median age of presentation to the clinic of 53 years old (5-78). Although the reasons of referral for STS testing for each individual patient were diverse, they can be summarized in these categories: unexplained cytopenia (n=9), myeloid malignancy with relevant PMH or FH (n=8), affected sibling (n=5), skin lesions (n=1) and multiple cancer diagnosis (n=1). Pathogenic or likely pathogenic germline variants were confirmed in the TERT gene (n=13, 54%), TERC gene (n=7, 29%), RTEL1 (n=2, 8%), while 2 patients had no telomere-related detectable mutations (Figure 1). Telomere flow-FISH confirmed age-predicted telomere length <1st percentile for age in 67(%). All patients underwent a bone marrow biopsy, being described as hypocellullar in 17 patients (71%). With the bone marrow evaluation, eleven patients were diagnosed with myelodysplastic syndrome (MDS, 46%), two patients with acute leukemia (myeloid and mixed phenotype, 8%), two patients with clonal cytopenia of unknown significance (CCUS, 8%), one aplastic anemia (4%) and eight patients (33%) did not have hematologic malignancy. During the follow-up, three patients underwent an allogeneic stem cell transplantation due to their hematologic disease. Solid neoplasms are frequent in patients with STS, and 11 patients (46%) had a PMH of at least one solid tumor with a median age of 54 (33-78 yrs). Squamous cell carcinoma was the most frequent histology (6/11 patients). Sixteen patients (67%) had a positive FH of cancer in one or more first or second-degree sibling. Pulmonary fibrosis (PF) was diagnosed in 4 patients (17%), two with TERT mutations and two with TERC mutations. Moreover, 7 patients (4 diagnosed with PF,30%) had a positive FH of PF in first degree siblings. Liver diseases were also frequent: 3 patients had non-alcoholic hepatic cirrhosis, one patient had chronic hepatitis with periportal fibrosis and one with idiopathic portal hypertension. One patient had received a liver transplantation and one required a lung transplantation prior to presentation to the HHMC. Finally, twelve patients (50%) were reported to have premature grey hair and eight patients were reported to have nail dysplasia and/or skin abnormalities related to STS (such as unexplained reticular rash). A summary of the described patients is depicted in Figure 2. Conclusion: STS are genetic diseases that can go unnoticed until adulthood. Patients with myeloid malignancies (especially MDS) with hypocellular bone marrow and suspicious findings (i.e. FH or PMH of PF, premature grey hair, long standing cytopenias) should be considered for underlying STS. An early diagnosis is essential to start cancer surveillance programs and provide timely genetic counseling to the patient and relatives. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Classical Hematology Referrals at an NCI-Designated Cancer Center: Lessons Learned

Background: Multiple factors have contributed to the decline of classical hematology (CH) as a specialty. CH-workforce shortage coupled with overwhelming demands for CH consultations have created a crisis. This CH crisis may be especially acute at academic centers where CH is practiced in the milieu of cancer-care. This has broad effects on the quality of CH care, on the referral systems, and on the careers and professional satisfaction of hematologists at these centers focused on CH and on those focused on hematological malignancies. The objective of this study was to conduct an analysis of CH outpatient-referrals in order to develop strategic plans for dealing with the CH crisis. Methods: A single referral office at the Cancer Center (CC) handles all adult (age >18 years) hematology referrals (electronic and all other). All hematological malignancies are triaged immediately for ideal scheduling by specific Cancer-Center algorithms and are not part of this study. From October 1, 2021 to June 30, 2022, all other referrals to hematology were prospectively triaged daily by one of the authors (A.B.K) to define the category of CH problem from the reason for referral given by the referring provider. Referrals were not refused unless confirmed at triage that no CH problem was evident, and those turned away are included as part of this analysis. Video-based appointments were offered for all Thrombosis referrals and for confirmed iron deficiency anemia. Electronic consultation (opinion rendered without patient seen) at our CC is available exclusively for select CH problems and restricted to patients with Medicare who give written consent and are not part of this analysis. Results: A total of 1505 CH referrals were received in the 9-month period. Of these, 951 (63%) were female, and 551 male (37%) with median age 53 (range 18-92 yrs.). 67 referrals (4.5%) were turned down. Of these, 25 were solid tumors, 21 were not hematology problems, 12 had normalized their abnormal hematology laboratory data (that were the basis of the referral), 8 with MGUS were triaged to the plasma cell-disorder clinic, and one 15-yr-old was referred to pediatric hematology. During the study-period, there were 2074 medical oncology referrals and 647 referrals for malignant hematology. CH referrals therefore comprise 36% of all hematology-oncology referrals and 70% of all hematology referrals at the Cancer Center. Thrombotic disorders were the most common of the accepted CH referrals at 311 (22%); of these 199 (64%) were for VTE. Other categories included 185 (13%) referrals for anemia, and 181 (12.7%) for iron deficiency. Video-visits were used for 294 of all CH referrals (20%), and the rest were in-person. Conclusions: CH referrals are a little more than one third of all hematology and medical oncology referrals at the CC. Telemedicine (video) visits and elimination of barriers to electronic consultations for select CH problems can help cope with the demands for CH consultation. There are significant opportunities for partnership with and education for primary care services to care for straightforward CH referrals (iron deficiency and provoked venous thromboembolism) that will substantially reduce costs and enhance quality of care. Significant increase in faculty focused on CH is needed to cope with current demand, especially if CH services and special programs (Thrombosis Clinic, Hemoglobinopathy Clinic, and Rare Hematological Disorder Clinic) are to be advertised. This shift will also allow focused career-development for hematologists at the CC. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Quality Improvement Initiative to Improve Implementation of Guideline-Concordant Hereditary Myeloid Malignancy Syndrome Evaluation

Background: Myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are traditionally thought of as sporadic disorders. Recently, there has been increasing awareness of hereditary myeloid malignancy syndromes (HMMS) and their impact on MDS/AML treatment decisions, other organ and cancer surveillance, and at-risk family member management. Detection of patients with an HMMS is challenging due to variable expressivity, lack of physical signs, incomplete family history information, and limited provider awareness. In 2021, the National Comprehensive Cancer Network (NCCN) guidelines added recommendations for genetic evaluation of patients with MDS/AML meeting certain clinical or molecular criteria to facilitate identification of patients with an HMMS. The impact of utilizing these criteria on the proportions of patients with MDS/AML needing germline genetic evaluation and their efficacy in detecting the subset with an HMMS have not been studied. We established a quality improvement (QI) committee to implement and test the utility and efficacy of NCCN MDS/AML referral criteria. Methods: A QI committee, including a cancer geneticist, a molecular pathologist, hematology faculty and fellows, clinical pharmacists, research coordinators, and a genetic counselor, was formed to implement NCCN recommendations and evaluate patients with MDS/AML for referral to the UW Hereditary Hematology Clinic. At each monthly meeting, clinical and family history and molecular data are reviewed for patients with MDS/AML who had a next-generation sequencing panel performed in the prior month. Patients meeting criteria for referral are identified, and an HMMS evaluation referral recommendation note is written in the electronic medical record and routed to the patient's primary hematologist. To assess the impact of implementing these guidelines on need for HMMS evaluations in routine MDS/AML care, we compared the proportion of patients meeting criteria and referral rates before (1/2019-8/2021) and after (9/2021-4/2022) our intervention. Results: From 9/1/21 through 4/31/22, 42 patients (20 AML, 22 MDS) were reviewed by the committee. 34 patients had a new diagnosis, whereas eight had an established diagnosis but had molecular data obtained for the first time after 9/1/2021. Overall, 23 patients (55%) met criteria for referral. Six patients met clinical criteria, seven patients met molecular criteria, and 10 patients met both clinical and molecular criteria. Eight patients were ultimately referred for HMMS evaluation, corresponding to a referral rate of 35%. Two patients were found to have a pathogenic variant in DDX41, two patients had at least one variant of unknown significance (VUS), one patient had negative testing, and three patients have pending results. For the 15 patients who were not referred, three were deceased at the time of committee meeting, two were pursuing hospice, one patient declined, and one patient was lost to follow-up; the remaining eight patients were not referred for unknown reasons. In the pre-intervention cohort, 71 of 114 patients met criteria for referral (63%), and 8 were ultimately referred for HMMS evaluation, corresponding to a referral rate of 11%. One patient had a pathogenic variant in ANKRD26, two patients had at least one VUS, four patients had negative testing, and one patient declined genetic evaluation. Conclusion: Implementation of current NCCN germline genetic testing criteria for MDS/AML resulted in ~60% of unselected MDS/AML patients meeting referral criteria for HMMS evaluation. Formalized referral recommendations in the form of a QI committee referral note in the medical record increased provider referrals from 11% to 35% in those meeting criteria. Clinical acuity and patient mortality were the largest barriers to referral for HMMS evaluation in this patient population. Among the small proportion actually referred, 5% of patients in the intervention cohort and 1% of patients in the pre-intervention cohort were found to have an HMMS. This experience demonstrates that implementing current NCCN guidelines via a QI committee will significantly increase the proportion of patients recommended to have HMMS evaluation and increases detection of patients with HMMS. Whether these criteria can be refined to maximize detection while minimizing burden on patient care and the healthcare system warrants further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Iron Deficiency Is Commonly Observed in Female Multiple Sclerosis (MS) Patients with Relapsed/Refractory or Primary Progressive Disease Referred for Biological Therapies

Introduction Iron deficiency with or without anemia is common, symptomatic, and often underdiagnosed in women. Aging related iron deposition in the brain has been associated with multiple chronic neurological conditions, including multiple sclerosis (MS). MS is an autoimmune and inflammatory neurologic disease with a variable presentation and disease severity resulting from demyelination in the central nervous system. In MS, iron deficiency has been associated with more severe depressive symptoms and poorer quality of life. Overlapping symptoms shared by iron deficient and MS patients include fatigue, cognitive dysfunction and restless leg. Recognizing and treating iron deficiency is important in MS patients and may play a role in improving quality of life. Methods We conducted a retrospective study from January 2017 to December 2021 of MS patients referred to OHSU hematology clinic for therapy with monoclonal antibodies including ocrelizumab, rituximab, or natalizumab. Patient demographic, clinical, treatment and laboratory characteristics were reviewed. Iron deficiency was defined by presence of Ferritin < 50 ng/ml. Patients identified as iron deficient were reviewed for further gastro-intestinal and gynecologic work-up. Results A total of 307 patients with MS were identified. The median age was 49.3 (range 18-84), 104 were males (average age 50.7 at time of study) and 203 were female (average age 48.5 years at time of study). The majority of patients received ocrelizumab, with a minority receiving rituximab due to insurance coverage and rare patients receiving natalizumab. Ferritin levels were available in 114 patients. Of 20 male patients whose ferritin was checked, 4 were iron deficient. Of 94 female patients whose ferritin was checked, 56 (60%) were found to have past or current iron deficiency. In 15 of these 56 patients, GI findings were noted including: rectal cancer, adenomas, esophagitis, gastritis, large hiatal hernias, inflammatory bowel disease, H. pylori and bariatric surgery. The average age of women with GI findings was 48.7 years with an average ferritin of 19.2 ng/ml. In 12 patients, obstetric and gynecologic conditions were diagnosed. The average age of women with OB/GYN sources was 31.2 years with an average ferritin of 21 ng/ml (range). Three patients had combined GI and GYN causes, 4 were pending GI evaluations and 22 were not worked up for cause. Twenty-two women received treatment with intravenous iron products (iron dextran, iron sucrose, ferumoxytol, ferric carboxymaltose). In the 22 women treated with intravenous iron, 4 developed progressive MS symptoms leading to change in therapy. Conclusion Results show a high frequency of iron deficiency in women with multiple sclerosis. GI and GYN sources were the main causes for iron deficiency. Intravenous iron was used in a subset of patients with iron deficiency. Worsening MS related symptoms were observed in 4 patients treated with intravenous iron. All women with multiple sclerosis should be evaluated for iron deficiency and investigated for cause if iron deficiency is found. Future studies on the effects of adequately diagnosing and treating iron deficiency in patients with multiple sclerosis are warranted.

Do Children with Immune Thrombocytopenia Have Cerebral Microbleeds?

Background Children with immune thrombocytopenia (ITP) have a low platelet count due to autoimmune destruction and reduced platelet production. ITP increases bleeding risk, with potentially devastating consequences. However, most children have mild disease that resolves spontaneously (Cooper 2014). For this reason, international guidelines recommend observation unless there is overt bleeding (Neunert et al. 2019; Provan et al. 2019). This has resulted in fewer patients exposed to treatment, but there are few data evaluating the safety and impact of this approach. Patients with ITP often have petechiae associated with thrombocytopenia. We hypothesised that a similar process may be occurring in the brain parenchyma. Using susceptibility weighted magnetic resonance imaging (SW-MRI-a technique that is particularly sensitive to haemosiderin deposition), we have previously identified occult cerebral microbleeds (CMBs) in 43% of thrombocytopenic adults with ITP (Cooper et al. 2020). Studies in other disorders have associated CMBs with impaired cognitive function (Morrison et al. 2017). This method has not previously been used to evaluate thrombocytopenic children. Methods 38 children aged 8-17 years old with a diagnosis of ITP and a platelet count under 30 x109/L at any time during their disease course, underwent SW-MRI. Recruitment was from the paediatric immune haematology clinic at Imperial College Healthcare NHS Trust specialist ITP centre. SW-MRI were assessed by two neuroradiologists blinded to clinical details. Number, size and location of CMBs were correlated with clinical metadata including paediatric bleeding questionnaire (PBQ) score, validated cognitive testing (Cogstate), health-related quality of life (HRQoL) scores and fatigue scores. We compared imaging data to 20 age-matched healthy controls (siblings from another SW-MRI Imperial College study using the same imaging protocol). Results The study cohort was 55% male with median age of 12.4 years (range 8-18 years). 66% had chronic ITP (lasting over 12 months) and 76% had active disease (platelet count below 100 x109/L or were on treatment) at the time of MRI. Median disease duration was 33 months (range 1-129 months). Of the cohort, 73% had received treatment including: tranexamic acid, steroids, thrombopoietin-receptor agonists-TPO-RA, intravenous immunoglobulins (IVIg), rituximab and others, with a median treatment episodes of 3 and 68% are currently on TPO-RA treatment. Of 38 patients, 5 (13%) had a detectable CMB (median 3 CMBs, range 1-10); no CMBs were detected in controls. All patients with CMBs had chronic ITP. The patient with the highest CMB burden had 10 CMBs in total (Figure 1). He had multi-refractory disease, 3002 days with a platelet count under 10 x 109/L, a paediatric bleeding score of 14 and minimal responses to IVIg, prednisone, dexamethasone, rituximab, eltrombopag, romiplostim, sirolimus and mycophenolate mofetil. There was a statistically significant correlation with higher PBQ score and the presence of CMBs (p=0.047 using the Mann-Whitney U test); no participants with a bleeding score under 4 had a CMB (PBQ median score 5, range 1-19); conversely many patients with a higher bleeding score did not have a CMB either (Figure 2). There was no correlation with disease duration and CMBs. Cognitive impairment, fatigue and reduced HRQoL were not associated with CMBs. Discussion Although there is heterogeneity in this cohort, the high proportion of chronic ITP and treated patients reflects referrals to an ITP specialist centre. The proportion of children with a CMB is lower than in adults, however disease duration is shorter in this cohort. As none of the children with acute ITP or a bleeding score less than 4 had CMBs, this may support the practice of observing asymptomatic patients whilst awaiting spontaneous remission, although confirmation from a larger cohort is needed. SW-MRI may also be valuable in stratifying patients with intermediate bleeding scores for therapy. In this study, CMBs were not associated with poor HRQoL, fatigue or cognitive impairment. A national study with differing centres is required to better understand the significance of this novel finding of CMBs in childhood ITP. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical and Epidemiological Features and Therapeutic Options of Avascular Necrosis in Sickle Cell Patients: A Cross-Sectional Study

Background: Vascular necrosis (AVN) is a well-described debilitating complication in sickle cell disease (SCD) patients, and the management is usually challenging. Data about the clinical presentation, risk factors, radiological features, and management options are lacking. This study aims to evaluate the clinical and epidemiological features and therapeutic options of avascular necrosis in sickle cell patients in Qatar. Patients and methods: A cross-sectional study was conducted on a group of 49 sickle cell disease patients who are suffering from avascular necrosis and attending a hematology clinic at the National Center for Cancer care & research hospital (NCCCR), Hamad Medical Corporation (HMC), Qatar between Jan-2011 to Jan2021. Clinical presentation, age at first AVN diagnosis, hemoglobin S level, affected joints, hydroxyurea treatment and compliance, and stage at diagnosis were recorded. Management options included conservative physiotherapy, hyperbaric oxygen, core decompression, and hip replacement. Results: Forty-nine adult patients with sickle cell disease complicated by avascular necrosis were reviewed. The median age of the study population is 32 years (range: 18-64) and the median age of AVN diagnosis is 26 years (range: 11-44). 25 patients (51 %) were males. 41 patients (83.6%) had hemoglobin SS, 3 (6.1%) with hemoglobin S/D (double Heterozygosity), 3 (6.1%) hemoglobin C/S, 1 (2.1%) with hemoglobin S/E, and 1 (2.1%) with sickle/thalassemia. 37 (75.5%) patients suffered from multiple joints AVN while 12(24.5%) had single joint involvement. 31 (63.3%) patients had bilateral hip AVN and 18 (36.7%) had shoulder involvement. The majority of the patients (79%) were symptomatic where joint pain and a limited range of motion were the most common symptoms. 30 patients (61%) of the recruited population were on Hydroxyurea; six of them (20%) were non-compliant. Based on FICAT and Alert classification of AVN, 8 (16.3%) patients had stage I, 13(26.5%) had stage II, 9 (18.4%) had stage III and 13 (26.5%)patients were at stage IV; 6(12.3%) patients were at stage V. 57 % of patients had stage III and above at diagnosis. 20 (40.8%) were managed with a conservative approach with physiotherapy only, 11 (22.4%) received hyperbaric oxygen with good response, 6(12.2%) underwent hip core decompression and 12(24.5%) underwent a hip replacement. Conclusion: The majority of AVN patients had an advanced stage and multiple joint involvements at diagnosis. We suggest a low threshold of joint imaging for early detection and prevention of further complications. Hyperbaric oxygen, if implemented early, might be a possible option to avoid or delay surgical intervention. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

An Analysis of e-Iron: Updates from a Year of Experience with a Novel IV Iron Telemedicine Platform

Introduction: Intravenous iron (IVI) is increasingly being recognized as a safe and effective strategy in addressing the needs of patients with iron deficiency anemia (IDA) who fail to respond to oral iron, or are unable to tolerate it. However, convoluted referral processes frequently act as a barrier between referring providers and the infusion facility, resulting in significant underutilization of IVI. Capitalizing on a robust e-consult platform operational at our institution, e-IRON was built as a function in the EPIC EMR, to facilitate 'electronic’ referral for consideration for IVI, and in this way simplify and expedite the process of IVI referral. Using a template-based design, the e-IRON order 'gathers’ key information (indication, experience with oral iron, current lab-work), which, together with a 'chart-review', are evaluated by a specialist hematologist within 3 days. If IVI is deemed appropriate, this is scheduled directly. If a face-to-face hematology appointment is required, this is similarly scheduled. Where IVI is not deemed appropriate, guidance as to alternate management is provided. We previously demonstrated in a small cohort that e-IRON expedites hematologist assessment of patients’ candidacy for IVI, and significantly shortens the time from referral to infusion scheduling. Similarly, we demonstrated that only a small fraction of patients required in-person appointments. We now share our experience with a larger cohort, adding outcomes data, with an analysis of patient parameters observed in the year subsequent to e-IRON referral. Results: Over 1 year, 477 unique consults were placed. The overall rate of IVI approval was 65%, with similar results for each indication. The most common reason for denial (10.3%) was failure to document a failed trial of oral iron. In 8.4% IVI was denied because required information, typically current labwork, was not provided. Detailed chart review was performed on a sub-cohort of 119 (25%) patients, focusing on post e-IRON outcomes in an evaluation period of 1 year after the initial consult. In 76 patients (64%) IVI was approved, and of these 67 (88%) received at least their first dose, occurring a median of 12 days after the e-IRON consult was placed. In patients approved for IVI, and who received infusion, an average increase of 2.48 g/dL ((95% CI 2.48 - 3.20) was observed. Regardless of indication and intervention, patients had an average increase in Hb of 2.03 g/dL (95%CI 1.69-2.38) from their pre-consult value to their first post-consult value. All scheduled regimens comprised 1 or 2 infusions, using either iron dextran, or ferric carboxymaltose. The average dose was 1200 mgs, ranging from 750 to 2000 mgs. No adverse reactions to IVI were reported in this cohort. Of 15 patients in whom a trial of oral iron was recommended, 8 responded satisfactorily, 2 'failed’ their trial and subsequently received IVI, and in 5 follow-up was incomplete. Eight patients required blood transfusion during the evaluation period, most commonly in the context of peri-partum hemorrhage. In 19 patients, repeat e-IRON consults were placed during the evaluation period, and in 13 of these IVI was approved and administered, typically after information missing from the initial consult was provided. Follow up regarding patients’ anemia by the referring provider within 4 months of e-IRON occurred in 37 of 43 (86%) patients in whom IVI was not approved, and 63 of 76 (82%) in whom it was. Conclusions: Since the hematologist's involvement with the vast majority of e-IRON patients is limited to a brief chart review, concern had been expressed that this 'hands-off’ approach might result in suboptimal subsequent management and follow up. However this was not borne out in this outcome analysis, wherein we saw high rates of infusion completion in scheduled patients, and compliance with e-IRON recommendations on the part of referring providers. Our continued experience with e-iron verifies the feasibility and efficiency of a telemedicine approach in expediting the management of patients requiring IVI. In the vast majority of cases e-IRON enables unprecedentedly rapid determination of management and facilitation of IVI when appropriate, dispensing with the costly and time consuming traditional requirement of a face-to-face visit to the hematology clinic. The resultant benefits to patients, their primary care providers, and to over-burdened specialty providers are self-evident. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Breaking Down Barriers and Addressing Mental Wellness in Pediatric Sickle Cell Patients

Sickle cell disease is an inherited hemoglobinopathy that is characterized with multi-organ involvement and frequent pain crises. Over the last two decades, a growing body of clinical evidence has pointed out that these somatic complaints can give rise to neuropsychiatric disorders, among which anxiety and depression are the most common, that worsen the health-related quality of life of these patients. Mood disorders can in turn increase fatigue and pain through a psychosomatic component. Although mental health is deemed to play an important role in their health outcomes, at this time, we don't have standardized approach to screening sickle cell patients for depression at most sickle cell centers across the country and at Texas Children's Hospital(TCH). The objective of this Quality Improvement (QI) study is to increase the annual depression screening rate from 0 to 50% in English/Spanish speaking patients who are 12 years and older with an established diagnosis of Sickle Cell Disease (SCD) who present for follow-up care to the Texas Children's Hospital - West Campus (TCH-WC). Our QI project consisted of three distinct PDSA cycles. Prior to the start of the first PDSA cycle, we did not have a streamlined approach for depression screening. The physician team would verbally screen for depression and Social Work was consulted as needed. During our first PDSA cycle, a clinical psychologist was integrated into our monthly Hematology-Pulmonary Joint Clinic and all patients with SCD who presented to Joint Clinic were assessed for depression by the psychologist as part of the psychological evaluation. During the second PDSA cycle, all patients with SCD over the age of 12 who presented to Joint Clinic (with psychologist present) were given the Patient Health Questionnaire-9 modified for Adolescents (PHQ-A) by the Medical Assistant prior to the start of the medical appointment. After the physician team completed their visit, the psychologist addressed concerns raised on the PHQ-A, completed the psychological evaluation and provided appropriate intervention. During the third and final PDSA cycle, the PHQ-A was given to all patients with SCD above the age of 12 who presented to hematology clinic (including those outside of Joint Clinic during which the psychologist was not present). During this cycle, the MA gave the patient the PHQ-A at the start of the visit. The MA then followed an outlined and detailed algorithm. If patient scored 0-6 on the PHQ-A, no intervention was performed. If patient scored 7-9 on the PHQ-A, psychological resources were provided via handout. If patient scored > 10 on the PHQ-A, Social Work referral was placed and patient was preferably seen same day. If patient screened positive for suicide, an urgent Social Work referral was made and patient was seen same day prior to leaving clinic for further evaluation. During our first PDSA cycle, 19 patients above the age of 12 presented to Joint Clinic. Seventeen patients were seen by the psychologist. Twenty-four percent (4/17) of patients were given the PHQ-A; 50% of patients screened positive. Twenty-four percent (4/17) of patients were referred for outpatient follow-up with psychology. During our second PDSA cycle, 14 patients above the age of 12 presented to Joint Clinic. Ninety-three percent (13/14) of patients were given the PHQ-A; 7% (1/14) of patients screened positive for depression. Twenty-one percent (3/14) of patients were referred for outpatient follow-up with psychology. During our third PDSA cycle, 54 patients above the age of 12 presented to Hematology Clinic. Eighty percent (43/54) of eligible patients were given the PHQ-A. Fourteen percent of patients endorsed mild symptoms of depression; 23% of patients endorsed moderate to severe symptoms of depression; 23% of patients endorsed suicidal ideation. Eighty percent of patients with moderate to severe depression received same day Social Work Assessment. One hundred percent of patients with suicidal ideation received same day Social Work assessment. During the first three PDSA's cycle of our project, we achieved our goal of screening greater than 50% of eligible patients with SCD and providing same day intervention. In the future, we will need to examine if there are any downstream effects that negatively impact the clinic flow while administering the questionnaire. We also hope to expand screening for all patients with SCD over the age of 12 across Texas Children's Hospital campuses.

Clinical Outcomes of Patients Referred for Asymptomatic Neutropenia at a Single Academic Center: A Focus on Racial Disparities

Introduction Asymptomatic neutropenia is a common referral to Hematology. Differentiating between a normal variant and an underlying hematologic disorder is further complicated by discrepancies in blood cell count reference ranges that differ among institutions. In the following study, we aim to describe the demographic characteristics and laboratory and clinical outcomes of patients referred for asymptomatic neutropenia to an academic classical hematology practice. Methods In this retrospective cohort study, we included all adult patients referred for evaluation of asymptomatic neutropenia to the Classical Hematology Clinic at Oregon Health & Science University from 2018 through 2021. Asymptomatic neutropenia was defined as an absolute neutrophil count (ANC) below the internal reference range of 1.8 x 109/L, without a history of abnormal infection. Patients who had other cytopenias were included in the study as long as the primary referral reason was asymptomatic neutropenia. Patient demographics, pertinent medical history, baseline laboratory values, diagnostic testing and results, and subsequent clinical diagnoses were obtained through individual chart review. A clinically significant outcome was defined as a newly diagnosed hematologic disorder, including both pre-malignant and malignant conditions. Standard descriptive statistics were used to summarize baseline and outcome characteristics. Results We identified 102 patients who were referred over the 3-year period and who met the study inclusion criteria. The median age was 56 years (range: 19 - 96), 10% of patients identified as Asian, 18% as Black, and 68% as White (Table 1), which was disproportionate to local population demographics in Portland Oregon (9% Asian, 6% Black, and 75% White). The average ANC at referral was 1.0 x 109/L. 55% of patients had an ANC between 1.8 x 109/L - 1.0 x 109/L, 34% had an ANC between 1.0 x 109/L - 0.5 x 109/L and 11% had an ANC less than 0.5 x 109/L. The average number of tests performed at referral, including repeat complete blood cell count with differential, was 6. Bone marrow biopsies were obtained in 15 patients who had an average ANC 0.6 x 109/L (standard deviation 0.46). The most common clinical outcome was idiopathic persistent neutropenia in 50% of patients, with resolution of neutropenia in occurring in 28% of patients. Among patients with an ANC > 1.0 x 109/L, only 1 patient was found to have a clinically relevant underlying disorder (HIV infection). In total, twenty-three percent of patients were found to have a clinically significant outcome with mean ANC of 0.65 x 109/L: Myelodysplastic syndrome (n=6), Immune thrombocytopenic purpura (n=4), Large granular lymphocytic leukemia (LGL) (n=3), Chronic lymphocytic leukemia (n=2), monoclonal gammopathy of undetermined significance (MGUS) (n=2), Hairy cell leukemia (n=1), B cell lymphoma (n=1), Multiple myeloma (n=1), and Acute Myeloid Leukemia (n=1). Only two of these patients with clinically significant findings (MGUS and LGL leukemia) were Black. Among Black patients who underwent testing for Duffy antigens, nearly 100% of patients were positive for the Duffy null phenotype [Fy(a-b-)], though one patient was [Fy(a-b+)]. In Non-Black patients tested, only 25% were positive for this phenotype. Conclusion Among patients referred to our institution for asymptomatic neutropenia, none of the patients with ANC > 1.0 x 109/L had an underlying hematologic disorder detectable by standard peripheral blood neutropenia workup. Black individuals were disproportionately represented, more likely to harbor the Duffy null phenotype, and less likely to have a clinically significant outcome. Our findings elucidate the need for standardized reference ranges that include demographic variants and are more representative of the community they serve, as current thresholds may inadvertently flag benign as abnormal, leading to significant emotional and financial implications, as well as inequitable treatment decision-making. Abbreviations: ANC, absolute neutrophil count; CBC, complete blood cell count; MDS, Myelodysplastic syndrome; ITP, Immune thrombocytopenic purpura; LGL, Large granular lymphocytic leukemia; CLL, Chronic lymphocytic leukemia; MGUS, monoclonal gammopathy of undetermined significance; AML, Acute myeloid leukemia Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal