A Survey of the Etiology of Immune Thrombocytopenia (ITP).

Abstract Abstract 2239 Introduction: Socioeconomic, environmental, lifestyle and genetic factors play a role in the etiology of ITP but are poorly understood. A self-reported questionnaire was designed to study these relationships and how these factors prior to the diagnosis of ITP relate to treatment response and disease progression in order to gain insight into the etiology of ITP. Methods: To design the questionnaire that would address topics of interest: 1) 60 ITP patient interviews were performed and 2) the questionnaire was reviewed by project coordinators, nurse practitioners, Platelet Disorder Support Association (PDSA) members, and hematologists. The input was incorporated into a further-revised questionnaire, which was then administered to both “pediatric” (patients <18 years of age at the time of diagnosis) and adult ITP patients from the Platelet Disorders Center at Weill Cornell - New York Presbyterian Hospital. Formal statistical analysis to relate responses to one question to responses of another to define sub-groups of patients is ongoing. Results: 109 patients were enrolled. Ages ranged from 2–78 years of age; median age was 55 years, with 21 females and 33 “pediatric” patients. The most frequent environmental exposures in adults were automotive exhaust (n=14) and Teflon (n=12). In pediatrics, preservatives and insecticides (n=8) and Teflon (n=7) were most common. The most prevalent hazardous substances in both groups were cleaning supplies (n=16 adults, n=9 “pediatric”) and chlorinated water (n=13 adult, n=9 “pediatric”). 13 adults also had exposure to gasoline or diesel fumes. Refer to figure 1. 51(47%) patients reported at least one infection prior to diagnosis with ITP. The most common were Strep throat (n=12); influenza (n=9), and respiratory tract infections (n=8). Twenty-four (22%) patients reported at least one autoimmune disease, including celiac (n=2) and discoid lupus (n=2).Twenty-one patients reported a family history of Type II diabetes, 12 Type I diabetes, 13 osteoarthritis and 10 rheumatoid arthritis. Eight (7%) patients reported at least one inflammatory disease including: Crohn's disease (n=3), Inflammatory bowel disease (n=7), Systemic lupus erythematous and Vitiligo(each n=1). Thirty-seven (34%) patients reported surgeries prior to diagnosis of ITP, especially: appendectomy (n=8) and tonsil removal (n=8). Twenty-three patients traveled close to date of diagnosis, 58 patients reported more stress than usual (i.e. death of a relative, loss of employment); 13 patients reported a drastic change in diet (i.e. decreasing calories (n=7) or becoming vegetarian (n=5)). Vitamin supplementation for vitamin C and D (each n=17), E (n=12) and B (n=11) were common. In addition, 11 vitamin deficiencies were reported, vitamin D (n=5), vitamin B12 (n=3) and other (n=3). The most frequent allergic reactions included: 31 (28%) patients with hay fever, 9 patients with allergies to milk, 7 patients with poison ivy or skin irritation, 6 patients with eczema, and 4 with allergic rhinitis. Other medical conditions reported were: hypothyroidism (n=10), hyperthyroidism (n=9), high blood pressure (N=16), high cholesterol (N=14), and anemia (N=13) [9 additional patients included 4 with iron deficiency anemia and 5 with a family history of iron deficiency anemia]. Seven patients reported a lack of prenatal care in their mothers' pregnancy and 7 were premature. Medications reported include: acetaminophen (n=53), antibiotics (n=36), antihistamines (n=22), and hormone therapy (n=17). Vaccinations received close to date of diagnosis include: flu vaccine (n=10) and T-dap (n=9). Prednisone was reported most frequently as both the best therapy to minimize symptoms (n=18) and the worst (n=16). Conclusion: Our pilot study intended to capture critical information and to further development of the questionnaire. We can see if there are groups of patients in whom onset and other characteristics relate to outcomes including response to treatment. Following formal statistical analysis of the material acquired (in progress and anticipated by early September), the next step will be for a final updated version of the questionnaire to be posted on the PDSA web site in order to accrue responses from a much larger number of patients. The questionnaire will also be given to a non-ITP patient population to serve as controls. Disclosures: Bussel: Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy. Off Label Use: The use of romiplostim in pediatric patients was examined in this study.

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Iron Deficiency Anemia in Infants and Toddlers – Role of Milk and Constipation

Blood ◽

10.1182/blood.v120.21.5171.5171 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5171-5171

Author(s):

Madhavi Lakkaraja ◽

Lesley Small ◽

Maura Frank ◽

Aliza Solomon ◽

Nicole Kucine ◽

...

Keyword(s):

Iron Deficiency ◽

Board Of Directors ◽

Research Funding ◽

Deficiency Anemia ◽

Infants And Toddlers ◽

Iron Intake ◽

Advisory Committees ◽

Phone Calls ◽

History Of ◽

Equity Ownership

Abstract Abstract 5171 Introduction: One of the most common nutritional deficiencies in the world is iron-deficiency anemia and young children are at high risk of developing it. In spite of fortification of foods in the United States, there is a high prevalence of anemia in infants and toddlers increasing their risk of neuro-developmental effects. Constipation is defined as delay or difficulty in defecation ≥ 2 weeks. Around one year of age, various changes are commonly implemented in a child's diet including introduction of whole milk and solids. Children may then present with sub-clinical colitis, constipation and anemia secondary to blood loss in stool or develop anemia due to increased consumption of milk. The American Academy of Pediatrics (AAP) recommends screening for anemia at 1 year and 2 year visits. The only clue to intolerance to milk may be symptomatic constipation and treating the anemia and switching the type of milk often helps to resolve this problem. This study explores the relation between iron deficiency, constipation and milk. Methods: This is an ongoing prospective study, which has been extended from Cornell to different centers. Data presented here is only from the Cornell principal site. Children between 6 months and 30 months visiting the resident's pediatric clinic and having routine blood work drawn as a part of their visit were included in the study. The National Health Sciences (NHS) Constipation questionnaire was administered to the parents of these children; ≥ 2 was considered Constipation. In addition, a detailed diet history of the child, and history of medicines and illness was taken and questions were asked about family history of anemia, constipation and allergies. If the mother was breast feeding, questions were asked about her dairy intake. Comparisons were made between children with and without constipation/iron deficiency. If the child had Hemoglobin (Hgb) <11, the child was started on Iron as per clinic policy, and phone calls were made to check for compliance with Iron. In addition letters including a printed calendar and a note on Iron rich foods were mailed out to the parents. Results: Two hundred five children, 92 females and 113 males between 8 and 30 months mean age 16. 7 months, are enrolled in the study. Seventy-two children (35 %) were constipated (score ≥2). Forty-two children (20. 5%) had Hgb <11. Children who had Hgb < 11 were not more constipated (45%) than those who had Hgb ≥11 (35%). In the Hgb <11 group, there was no significant difference in Hgb between children with and without constipation (p = 0. 19), however there was a difference in Hgb between infants with a Constipation score 0 and score 1 (p = 0. 03). Of the 42 children who had Hgb <11, 3 were later found to have sickle trait or alpha thalassemia trait, which were identified when iron intake did not improve the Hgb level. Compliance with Iron: Of the 39 children who were on Iron, 9 parents could not be reached via phone. Only 6 parents gave no Iron at all but another 12 did not give Iron properly resulting in 18/30 or 60% of infants/toddlers not receiving an adequate trial of replacement Iron. Among the side effects of Iron, one parent felt Iron caused rash on back and wanted multivitamin with Iron after finishing a month's course, one child had discoloration of teeth, so the parent gave it with juice. Two parents with infants with apparent true milk protein allergy colitis said constipation improved with diet change and iron. Conclusions: The prevalence of mild anemia is high in infants and toddlers. There was no clear association of constipation and anemia. Compliance is one of the key factors for Iron replacement therapy and in view of how erratic compliance was, it is imperative to give proper instructions to the parent while prescribing Iron. Material to better indicate which foods were rich in iron and follow-up phone calls were included in the management to optimize iron intake of anemic children. We will include more patients, more closely monitor the change in the diet of the child, and monitor responses to Iron therapy in children with low Hgb. In addition, different practices at other involved centers e. g. Brooklyn hospital Center may allow comparison of the time of screening (9 months v/s 1 year) and testing with Hemoglobin/Hematocrit versus a full Complete Blood Count with indices. Disclosures: Bussel: Amgen: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai, Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shinogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Portola: Consultancy.

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Risk Factors for the Development of High-Titer Inhibitors in 260 Children with Severe Hemophilia a Born Between 1990 and 2009: The Remain Study

Blood ◽

10.1182/blood.v128.22.3774.3774 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3774-3774

Author(s):

Maria Elisa Mancuso ◽

Kathelijn Fischer ◽

Elena Santagostino ◽

Johannes Oldenburg ◽

Helen Platokouki ◽

...

Keyword(s):

Family History ◽

Board Of Directors ◽

Research Funding ◽

Hemophilia A ◽

High Titer ◽

High Dose ◽

Severe Hemophilia ◽

Advisory Committees ◽

History Of

Abstract The development of anti-FVIII antibodies (i.e., inhibitors) is the major side effect of severe hemophilia A treatment. Inhibitors mainly develop in children during the first 50 exposure days and are classified in low-and high-titer (i.e., peak titer < or > 5 UB/ml). High-titer inhibitors have the major clinical impact. At diagnosis however, the real nature of the antibody is not clear in all patients, since some low-titer inhibitors may progress to high-titer. The determinants of the evolution from low- to high-titer inhibitors are still unclear and the aim of the present study was to investigate potential risk factors associated with the progression from low- to high-titer inhibitors. This study is a follow-up study of the PedNet Registry and includes 260 children with severe hemophilia A and clinically relevant inhibitors, born between 1990 and 2009 and consecutively recruited from 31 hemophilia centers in 16 countries. Clinical and laboratory data were collected from the date of first positive inhibitor test and covered a minimum of 3-years follow-up. Factors potentially associated with progression from low- to high-titer inhibitor development were analyzed using univariate and multivariate logistic regression. F8 mutation type was known in 247 patients (95%), including 202 (82%) null mutations (i.e., large deletions, nonsense mutations and inversions). Positive family history of inhibitors was present in 37 of 99 (37%) with positive family history of hemophilia. At diagnosis 49% (n=127) had low-titer inhibitors, however, upon FVIII re-exposure, 50% of low-titer inhibitors progressed to high-titer and only 25% of patients (n=69) had persistent low-titer inhibitors. Within the first 3 years of follow-up, immune tolerance induction (ITI) was equally implemented in around 80% of low-and high-titer patients but it was started later in children with high-titers (median time to ITI start 4.5 vs 0.3 months; p<0.001) in whom daily regimens and high-dose FVIII were more frequently adopted (89, 67% vs 41, 50% and 98, 74% vs 35, 43%; p=0.01 and <0.001, respectively). Overall high-titer inhibitor development was associated with null F8 mutations (OR 2.8, 95%CI 1.4-5.5) and family history of inhibitors (OR 3.9, 95%CI 1.2-12.6). The progression from low- to high-titer inhibitors during follow up, was associated with the use of high-dose ITI regimens (i.e., >100 IU/kg/day) with an OR of 3.9 (95%CI 1.5-10.0), independent from the effects of F8 mutation type (adjusted OR 3.6, 95%CI 1.4-9.8) and family history of inhibitors (adjusted OR 6.7, 95%CI 1.1-42.6). No difference was found by comparing the use of daily versus non-daily ITI. In conclusion, in a cohort of 260 children with severe hemophilia A and inhibitors, 49% presented with low-titers at diagnosis and 46% of them progressed to high-titers during follow-up. Progression to high-titer inhibitors was associated with the use of high-dose ITI. These results suggest that intensive ITI should be avoided as initial strategy in low-titer inhibitor patients. Disclosures Mancuso: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi/Biogen Idec: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Speakers Bureau; Bayer Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Consultancy. Fischer:Wyeth/Pfizer: Research Funding; Biogen: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Biotest Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau. Santagostino:Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Sobi: Consultancy; Biogen Idec: Consultancy; Roche: Consultancy; Grifols: Consultancy; Pfizer: Consultancy; Baxalta: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy. Escuriola:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding. Liesner:BPL: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Cangene: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biogen: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria. Nolan:Sobi: Research Funding; Biogen: Research Funding.

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Clinical Characteristics and Prognosis of Thirty-Three Patients with Myeloid Neoplasms and DDX41 Mutation: Mayo Clinic Experience

Blood ◽

10.1182/blood-2021-144400 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3691-3691

Author(s):

Ahmad Nanaa ◽

Aref Al-Kali ◽

David S. Viswanatha ◽

James M. Foran ◽

Talha Badar ◽

...

Keyword(s):

Family History ◽

Board Of Directors ◽

Solid Tumors ◽

Mayo Clinic ◽

Research Funding ◽

Clinical Characteristics ◽

Advisory Committees ◽

Dead Box ◽

History Of ◽

Normal Cytogenetics

Abstract Background: The DEAD-box helicase 41 (DDX41), an RNA helicase, have been described as a component of the RNA spliceosome (Cheah et al. International Journal of Hematology 2017). Although DDX41 mutations predispose to late-onset higher grade myeloid neoplasms (MN), these patients may have a trend toward favorable prognosis and outcomes. In this work, we describe the clinical characteristics and survival outcomes of isolated and co-mutated DDX41 patients (pts). Methods: We retrospectively analyzed 4,524 consecutive pts who underwent next-generation sequencing (NGS) (OncoHeme 42 genes panel, Mayo Clinic) testing and included 32 pts harboring pathogenic DDX41 mutation and one pt with proven DDX41 germline variant of unknown significance (VUS). Chart review of DDX41-mutated (m) cases between 2009 and 2021 was conducted after IRB approval. We compared overall survival (OS) of unmatched 27 t(8;21)AML and 40 inv(16) AML pts with 10 m DDX41-AML pts. JMP® Pro 14.1.0 Software was used for statistical analysis. Results: DDX41 mutations characteristics: Our cohort included 19 (58%) myelodysplastic syndromes (MDS), 10 (30%) acute myelogenous leukemia (AML), 2 (6%) myeloproliferative neoplasms (MPN), one clonal cytopenia of undetermined significance (CCUS) (3%) and one (3%) germline carrier. Germline testing was carried out in 10 pts, 9 of whom (90%) were confirmed to be germline). The start-loss variant (p.M1I) was the most common mutation type (N=10, 31%). Other types were frameshift (N=9, 28%), missense mutation (N=8, 25%), nonsense (N=3, 9%), and splice site mutation (N=2, 2%). Twenty-one (65.6%) DDX41 mutations clustered in the N-terminus (NT), 7 (22%) in the helicase-C domain (HCD), and 4 (12.5%) in the DEAD-box domain. Compared to NT mutations, patients with HCD mutation had no family history of solid tumors and were more likely to have an accompanying additional DDX41-VUS (0% vs 70%; p=.001) and (N=6, 86% vs. N=2,10%; p=.0001); respectively. I solated vs. co-mutated DDX41: Twenty (60%) pts were isolated-DDX41 and 13 (40%) were co-mutated. The median DDX41-VAF was 48% vs. 45% (p= .2) in the isolated compared to the co-mutated cases, respectively. The median number of co-mutations in the 13 co-mutated cases was 1 (range,1-3) with DNMT3A (38%), ASXL1 (30%), JAK2 (N=3, 23%), and EZH2 (N=2, 15%) were the most common co-mutations detected. Isolated DDX41 had more males (85% vs. 54%, p=.05), the p.M1I variant (47% vs. 8%, p=.02), normal cytogenetics (100% vs. 91%, p= .02), and less family history of solid tumors (77% vs. 33%, p= .02) compared to their co-mutated counterparts. However, there was no difference in OS (p=.99). Comparison of clinical characteristics and hematological features of isolated and co-mutated DDX41 pts are reported in (Table 1). Treatment and survival outcomes in DDX41-MDS/AML : Twenty-three (80%) patients were treated, MDS pts received hypomethylating agents (HMA) (N=10, 71%), HMA plus Venetoclax (HMA+VEN) (N=1, 7%), erythropoiesis-stimulating agents (N=2, 14%) and lenalidomide (N=1 ,7%). AML pts were treated with induction chemotherapy (N=6, 67%) and HMA+VEN (N=3, 33%). Overall response rate of MDS/AML patients was 77% and 100% of AML pts achieved complete remission (CR) when treated with induction chemotherapy or HMA+VEN regimen. There was no significant difference in OS between responders vs. non-responders 2-yr-OS (90% vs. 50%; p=.38) and treated vs. untreated 2-yr-OS (83% vs. 100%; p=.52). Comparing m DDX41-AML vs. core binding factor-AML: After a median follow-up of 33.3 months, all m DDX41-AML patients were alive. There was a significantly better OS in mDDX41-AML patients compared to pts with t(8;21) AML with 2-yr-OS (100% vs. 51%; p=.024) and a trend of better survival when compared to inv(16) AML 2-yr-OS (100% vs. 84%; p=.2). Conclusion We describe the characteristics and outcomes of m DDX41 patients. We demonstrated that isolated and co-mutated m DDX41 patients have different features. Isolated DDX41 patients had male predominance, more p.M1I variant, normal cytogenetics and less family history of solid tumors. In this study we found that m DDX41 AML has high response to treatment and has comparable (if not possibly better) OS compared to other "favorable risk" AML. This study, although limited by the small number of patients, supports the universal testing for DDX41 mutation in adults with MN diagnosis. Figure 1 Figure 1. Disclosures Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Foran: abbvie: Research Funding; OncLive: Honoraria; boehringer ingelheim: Research Funding; trillium: Research Funding; pfizer: Honoraria; takeda: Research Funding; revolution medicine: Honoraria; bms: Honoraria; gamida: Honoraria; actinium: Research Funding; aptose: Research Funding; novartis: Honoraria; servier: Honoraria; taiho: Honoraria; syros: Honoraria; sanofi aventis: Honoraria; certara: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Salama: Mayo Clinic: Current Employment, Other: Mayo Clinic had the contractual work for the central pathology review for this study and I was one of the reviewing pathologists; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Litzow: Astellas: Research Funding; Biosight: Other: Data monitoring committee; Amgen: Research Funding; AbbVie: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board. Patnaik: Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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Association between the Risk of Low/High-Count Monoclonal B-Cell Lymphocytosis (MBL) and the Chronic Lymphocytic Leukemia (CLL) Polygenic Risk Score (PRS)

Blood ◽

10.1182/blood-2018-99-116414 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5538-5538

Author(s):

Geffen Kleinstern ◽

Sara J. Achenbach ◽

Dennis P. Robinson ◽

Aaron D. Norman ◽

Kari G. Chaffee ◽

...

Keyword(s):

Family History ◽

Board Of Directors ◽

Research Funding ◽

Polygenic Risk Score ◽

Advisory Committees ◽

High Count ◽

Polygenic Risk ◽

Increased Risk ◽

History Of ◽

Age And Sex

Abstract Background MBL is a precursor state to CLL, with a prevalence of ~5-8% in the general population and 15-18% in CLL families. To date, 41 single nucleotide polymorphisms (SNPs) have been found to be associated with CLL. We previously showed that a PRS of the weighted average of the number of risk alleles of these SNPs is associated with CLL risk using cases and controls from the International Lymphoma Epidemiology (InterLymph) Consortium. We validated this score in an independent sample of CLL cases and controls from the Genetic Epidemiology of CLL (GEC) Consortium, a cohort of families with ≥2 members with CLL. In the CLL families we also reported an association between the PRS and MBL risk, where 93% of MBLs were low-count MBL. Here we evaluate the PRS in an independent sample ascertained from the Mayo Clinic Biobank. Methods The Mayo Clinic Biobank is a large-scale bio-repository of adult patients assembled to provide a wide array of health-related research studies. Biobank participants (N=2530) were screened for MBL using a highly-sensitive, 8-color (CD38, CD45, Kappa, Lambda, CD19, CD23, CD5 and CD20) flow-cytometry assay on stored cryopreserved peripheral blood mononucleotide cells. Low-count and high-count MBL were defined as those individuals who had <85% and ≥85 clonal B-cells out of total B-cells, respectively. Individuals without MBL ("controls") were frequency matched to MBLs based on age and sex, after excluding non-Caucasian and non-interpretable flow results. Participants were genotyped using the Illumina OmniExpress array. Standard genotyping quality-control metrics were applied. We computed the PRS as previously published and categorized it by quintiles based on values previously used with InterLymph controls. The middle quintile served as the reference category. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age at consent, sex, and socioeconomic status. In addition, we compared the median PRS by low-count MBL and high count MBL using the Mann-Whitney U test. Results We identified 276 MBLs overall and 2109 controls; 97% (N=267) of MBLs had low-count MBL and only 3% (N=9) had high-count MBL. We then selected 844 controls frequency matched to the MBL cases on age and sex. Family history of leukemia/lymphoma was 11.3% among MBLs overall and 8.8% among controls. The median PRS was 7.88 and 7.46 (Figure) among MBLs overall and controls, respectively. The continuous PRS had a 1.75-fold increased risk for MBL overall (CI:1.5-2.1, P=2.65x10-12). Compared to the middle quintile, the highest quintile had 2.2-fold increased risk for MBL overall (CI:1.5-3.3, P=1.46x10-4) and the lowest quintile had 0.6-fold decreased risk (CI:0.4-0.96, P=0.03). The median PRS for low-count and high count MBL were 7.86 and 8.04, respectively. The continuous PRS had a 1.75-fold increased risk for low-count MBL (CI:1.5-2.1, P=4.81x10-12) and a 1.89-fold increased risk for high-count MBL (CI:0.8-4.2, P=0.13), however, the effect is not statistically significant between high-count and low-count MBL (P=0.89). Conclusion In this independent sample, we validated our previous findings that the CLL PRS is associated with MBL risk. Although the sample size of high-count MBL was limited (N=9), there is evidence of a weak trend towards a higher PRS compared to low-count MBL and controls Larger sample size of high-count MBL is warranted in order to stratify MBL risk by low-count and high-count MBL. These results may help identify individuals at higher risk of MBL including low-count and high-count MBL, beyond the risk associated with age and family history of CLL. Figure: Polygenic risk score distribution by control and MBL status Figure. Figure. Disclosures Parikh: Janssen: Research Funding; Pharmacyclics: Honoraria, Research Funding; Gilead: Honoraria; Abbvie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; MorphoSys: Research Funding. Cerhan:Nanostring: Research Funding; Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board. Kay:Janssen: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morpho-sys: Membership on an entity's Board of Directors or advisory committees. Shanafelt:Genentech: Research Funding; Pharmacyclics: Research Funding; GlaxoSmithKline: Research Funding; Jansen: Research Funding.

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DDX41 Variant of Unknown Significance (VUS) Have Distinct Clinical and Diagnostic Features but Are Associated with Similar Prognosis and Co-Mutation Patterns As Pathogenic DDX41: Analysis of the Mayo Clinic (MC) Myeloid Next-Generation Sequencing (NGS) Cohort

Blood ◽

10.1182/blood-2021-145115 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3693-3693

Author(s):

Talha Badar ◽

Ahmad Nanaa ◽

Rong He ◽

Aref Al-Kali ◽

David S. Viswanatha ◽

...

Keyword(s):

Family History ◽

Board Of Directors ◽

Research Funding ◽

Hematological Malignancies ◽

Advisory Board ◽

Advisory Committees ◽

Diagnostic Features ◽

Variant Of Unknown Significance ◽

Unknown Significance ◽

History Of

Abstract Background: DDX41 gene is located on chromosome 5q35 and is believed to be a tumor suppressor gene involved in splicing of mRNA. Mutated DDX41 have been identified as germline mutation (m) in families with cases of myeloid neoplasm and have shown to cause acquisition of other somatic mutations resulting in MDS/AML. At the same time, somatic pathogenic DDX41 mutations are known to occur. Variant of unknown significance (VUS) is an intermediate tier between benign and pathogenic (path) mutations (hence uncertain) and can be re-classified based on their clinical impact. In this report we analyzed the clinical impact and relevance of DDX41VUS in patients (pts) being evaluated for myeloid disorders. Methods: We reviewed 4,524 consecutive pts who underwent NGS (MC OncoHeme 42 genes panel) testing between 2018 and 2021 performed on cases of suspected or known myeloid disorders. We identified 58 (1%) consecutive pts with DDX41VUS, among them one pt had proven concurrent DDX41 germline VUS and 7 pts with DDX41VUS had concurrent DDX41path mutation. We analyze clinical characteristics of pts with DDX41VUS and compared it with cohort of 32 DDX41path mutated pts. Results: Baseline characteristics are summarized in Table 1, and Figure 1 illustrates DDX41VUS per case with variant allele frequency (VAF) and observed concurrent mutations. The median VAF for DDX41 VUS was 48 % (range, 14-91%). Co-mutations were found in 14 (28%) pts with VUS, and the reminder (n=44, 72 %) had isolated DDX41VUS. Among them AML (16 [32%]), MDS (14 [28%]), cytopenia (14 [28%]) MPN (3 [6%]), CNL (1 [2%]) and aplastic anemia (1 [2%]) were the commonly occurring myeloid disorder (Table 1, Figure 1). Eleven of 14 pts with isolated cytopenia had isolated DDX41VUS. Conversely, among 15 evaluable pts with isolated DDX41VUS, 13 (87%) pts had normal cytogenetics and 40% of pts had family history of solid or hematological malignancies. We observed a significant difference in hematologic diagnoses: DDX41VUS patients were significantly less often diagnosed with MDS or CCUS, and more often associated with cytopenias NOS. Recurrent, non-random DDX41VUS sequences were observed; most frequent occurring amino acid change among the 58 pts were Gly173Arg (n=6), Met155lle (n=5), Pro258Leu (n=3) Arg479Gln (n=3), Val303Met (n=2), Lys331del (n=2), Arg479His (n=2) and Tyr33His (n=2) (Figure 1). 5 of 6 pts with Gly173Arg had isolated DDX41VUS, and among them 4 were diagnosed with MDS suggesting this could be a clonal event, and possible driver mutation, notable in Figure 1. The median overall survival (OS) of pts with high risk MDS/AML harboring DDX41VUS was not reached (60% alive at 2 years). Between pts with DDX41path and DDX41VUS, proportion of pts with co-mutations (p >0.99), cytogenetic abnormalities (p >0.99), family history of malignancies (p 0.52), time to treatment (p >0.99), MDS progression to AML (p 0.36) and OS (among high risk MDS/AML pts) (p 0.55) was not significantly different, suggesting that phenotypic features of DDX41VUS are similar to DDX41path , and that both carry a similar, more indolent prognosis (Table 1). Conclusion: Our reports demonstrated that DDX41VUS occurs in 1% of patients with myeloid disorders and shares distinct diagnostic features but comparable prognostic features vs. DDX41path, including family history of hematological malignancies. It is possible that many of the cases with 'cytopenias' and DDX41VUS would meet criteria for CCUS if the variant was isolated classified as pathogenic, confirming the importance of extending our understanding of DDX41 variants. Further analysis to characterize the biological impact of DDX41VUS is underway. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Novartis: Research Funding; Astex: Other: Research support to institution. Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Litzow: Astellas: Research Funding; Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Pluristem: Research Funding; Amgen: Research Funding; Biosight: Other: Data monitoring committee; Actinium: Research Funding; AbbVie: Research Funding. Foran: boehringer ingelheim: Research Funding; abbvie: Research Funding; takeda: Research Funding; trillium: Research Funding; revolution medicine: Honoraria; bms: Honoraria; servier: Honoraria; novartis: Honoraria; pfizer: Honoraria; aptose: Research Funding; taiho: Honoraria; certara: Honoraria; sanofi aventis: Honoraria; syros: Honoraria; actinium: Research Funding; gamida: Honoraria; OncLive: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

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Identifying Factors That Predict for Unplanned Readmissions for Acute Myeloid Leukemia Patients Receiving Consolidation Cytarabine Based Therapies

Blood ◽

10.1182/blood-2019-128807 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3433-3433

Author(s):

Caitlin Siebenaller ◽

Madeline Waldron ◽

Kelly Gaffney ◽

Brian P. Hobbs ◽

Ran Zhao ◽

...

Keyword(s):

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Smoking Status ◽

Consolidation Therapy ◽

Peripheral Vascular ◽

Consolidation Chemotherapy ◽

Advisory Committees ◽

History Of ◽

Acute Myeloid

Background: Younger patients (pts) with acute myeloid leukemia (AML) who enter a remission after intensive induction chemotherapy routinely receive at least one cycle of consolidation therapy with high dose cytarabine (HiDAC). This is commonly administered over a five-day inpatient stay, after which pts are discharged home as their blood counts nadir. It is thus a natural consequence of therapy that readmission for febrile neutropenia (FN) occurs, which can impact measures of quality and value in this population. Precise descriptions of incidence, type, and severity of infection, if identified, are lacking, and thus it is unknown to what standard cancer centers should be held for anticipated readmission. We measured these rates, and attempted to identify predictive factors for readmission. Methods: Adult AML pts ≥ 18 years of age who received at least one cycle of HiDAC consolidation (1000-3000 mg/m2 for six doses) in 2009-2019 were included. Our primary aim was to identify predictive factors for readmission after the first cycle of consolidation chemotherapy. The following pt characteristics and co-morbid conditions were analyzed: age, gender, body mass index (BMI), smoking status, AML cytogenetic risk status, history of diabetes, peripheral vascular disease, cardiovascular disease, chronic pulmonary disease, hepatic impairment, and other cancers. Secondary aims included: estimating rates of all-cause readmissions among all HiDAC cycles, defining the rate of FN readmissions, estimating rates of intensive care unit (ICU) admissions, clinical (e.g., probable pneumonia per imaging) and microbiologically-documented infections, prophylactic (ppx) medications used, and mortality. Statistical analyses interrogated potential risk factors for evidence of association with hospital readmission after the first cycle of consolidation chemotherapy. Results: We identified 182 AML pts who fit inclusion criteria. The median age was 50 years (range 19-73); 55% were female and 45% were male. Statistical analyses revealed no association with readmission after cycle 1 for cytogenetic risk (p=0.85), history of heart failure (p= 0.67), chronic pulmonary disease (p=1), connective tissue disease (p=0.53), cerebrovascular accident (p=0.63), diabetes (p=0.63), gender (p=0.07), history of lymphoma (p=0.53), other solid tumors (p=0.53), liver disease (p=1), myocardial infarction (p=0.71), peripheral vascular disease (p=1), or smoking status (p= 0.52). For 480 HiDAC cycles analyzed (88% at 3000 mg/m2), the overall readmission rate was 50% (242/480), of which 85% (205/242) were for FN. Those readmissions which were not FN were for cardiac complications (chest pain, EKG changes), non-neutropenic fevers or infections, neurotoxicity, bleeding or clotting events, or other symptoms associated with chemotherapy (nausea/vomiting, pain, etc.). Median time to FN hospital admission was 18 days (range 6-27) from the start of HiDAC. Of the 205 FN readmissions, 57% had documented infections. Of these infections, 41% were bacteremia, 23% fungal, 16% sepsis, 12% other bacterial, and 8% viral. Of 480 HiDAC cycles, ppx medications prescribed included: 92% fluoroquinolone (442/480), 81% anti-viral (389/480), 30 % anti-fungal (142/480), and 3% colony stimulating factor (14/480). Only 7% (14/205) of FN readmissions resulted in an ICU admission, and 1% (3/205) resulted in death. Conclusions: Approximately half of patients treated with consolidation therapy following intensive induction therapy can be expected to be readmitted to the hospital. The majority of FN readmissions were associated with clinical or microbiologically documented infections and are not avoidable, however ICU admission and death associated with these complications are rare. Readmission of AML pts following HiDAC is expected, and therefore, should be excluded from measures of value and quality. Disclosures Waldron: Amgen: Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Advani:Macrogenics: Research Funding; Abbvie: Research Funding; Kite Pharmaceuticals: Consultancy; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Research Funding. Nazha:Incyte: Speakers Bureau; Abbvie: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria. Gerds:Imago Biosciences: Research Funding; Roche: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sierra Oncology: Research Funding. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees.

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BCX9930, a Potent, Selective, Oral Factor D Inhibitor, Demonstrates Proof-of-Concept As Monotherapy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Blood ◽

10.1182/blood-2020-138838 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-15

Author(s):

Austin Kulasekararaj ◽

Jacques Le Roux Malherbe ◽

Andrew McDonald ◽

Melanie Cornpropst ◽

Phil Collis ◽

...

Keyword(s):

South Africa ◽

Board Of Directors ◽

Research Funding ◽

Total Bilirubin ◽

Proof Of Concept ◽

Advisory Committees ◽

Clone Size ◽

The Past ◽

History Of ◽

Pre Treatment

INTRODUCTION: PNH, a rare, chronic, life-threatening disease, is characterized by hemolytic anemia due to uncontrolled activity of the complement alternative pathway (AP), bone marrow failure, and thrombosis. Inhibition of C5 by intravenously administered eculizumab and ravulizumab reduces intravascular hemolysis, but PNH red blood cells (RBCs) become opsonized and susceptible to extravascular hemolysis (Risitano et al, Blood 2009). Only approximately half of PNH patients become transfusion independent with eculizumab treatment (Hillmen et al, NEJM 2006). BCX9930 is a potent, selective, orally administered inhibitor of complement factor D. Inhibition of factor D may prevent both intravascular and extravascular hemolysis in PNH. In healthy subjects, BCX9930 showed linear pharmacokinetics and dose-related AP suppression, and was safe and generally well-tolerated over a wide dose range. Here we describe safety and laboratory data establishing proof-of-concept for BCX9930 monotherapy in PNH patients in Study BCX9930-101 (NCT04330534). METHODS: Ongoing Study BCX9930-101 includes an open-label, dose-ranging evaluation of BCX9930 in PNH subjects who may either be naïve to C5 inhibitors (and receive BCX9930 as monotherapy) or have an incomplete treatment response to eculizumab or ravulizumab (with BCX9930 added to existing treatment). Up to 4 sequential cohorts each use a forced titration design for the first 28 days (Figure 1). Subjects enrolled in South Africa can participate in an individualized 48-week extension if they derive benefit at Day 28. Clinical benefit from BCX9930 is evaluated using laboratory monitoring and symptom assessment. Safety and tolerability are evaluated via clinical and laboratory monitoring, causality of adverse events is assessed by investigators, and the study is overseen by an independent Data Monitoring Committee. Data from Cohort 1 through 28 days is reported; data from the extension and subsequent cohorts will be subsequently summarized as available. RESULTS: To date, four C5 inhibitor naïve PNH subjects in South Africa have enrolled in Cohort 1. These subjects had PNH for a median of 4.5 years; 2 subjects had a history of transfusions in the past year; 1 subject each had a history of aplastic anemia or major thrombosis. Pre-treatment lactate dehydrogenase (LDH), total bilirubin, hemoglobin (Hb), reticulocyte count, and RBC PNH Type III clone size ranged from 3.7-11.1 × ULN, 0.61-3.3 mg/dL, 6.1-11.6 g/dL, 0.13-0.29 × 106/µL, and 41.4%-88.6% respectively. Treatment over 28 days with 50 mg twice daily (BID; Days 1-14) and 100 mg BID (Days 15-28) of BCX9930 produced dose-dependent, clinically meaningful improvements across hemolysis biomarkers (Figure 2). Decreases were observed in LDH (4/4), reticulocytes (4/4), and total bilirubin (2/2 subjects with elevated pre-treatment values). Increases were observed in Hb (3/4) and PNH RBC clone size (4/4). One subject showed an initial response to BCX9930 50 mg BID, followed by worsening indicators of hemolysis temporally associated with an upper respiratory tract infection (URTI; onset on Day 7). With an increase in dose to 100 mg BID and resolution of the URTI, LDH and reticulocytes fell and Hb rose. All four subjects reported one or more PNH-associated symptoms, including hemoglobinuria, jaundice, fatigue, erectile dysfunction, headache and abdominal pain, prior to enrollment. With the exception of one subject with persistent hemoglobinuria, all symptoms resolved by Day 28 on BCX9930. Three subjects experienced moderate headache that resolved in < 3 days after initiating BCX9930. One subject developed a rash during treatment with amoxicillin for an URTI; the rash resolved while continuing BCX9930 dosing. One subject on concomitant chronic corticosteroids and azathioprine had an unrelated fatal serious adverse event of disseminated varicella during the study extension. Based on review of safety data, Cohort 2 opened at doses of 200 mg BID and 400 mg BID and, in the 3 subjects who continued into the extension, the dose was titrated to ≥ 200 mg BID. CONCLUSIONS: Oral BCX9930 elicited rapid changes in laboratory parameters indicative of reduced hemolysis and clinical benefit and was safe and generally well-tolerated over a 28-day dosing interval. These interim results establish proof of concept for monotherapy with BCX9930 in the treatment of C5-inhibitor naïve PNH patients and support evaluation of higher doses. Disclosures Kulasekararaj: Alexion:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Ra Pharma:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;BioCryst Pharmaceuticals, Inc.:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Apellis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartis:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau;Celgene:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Speakers Bureau.Malherbe:Key Oncologics:Honoraria, Other: Conference sponsor;Novartis:Other: Conference sponsor;Astellas:Honoraria, Other: Conference sponsor;Takeda:Consultancy;Acino:Honoraria;Shire:Other: Conference sponsor;BioCryst Pharmaceuticals, Inc.:Consultancy;Janssen:Consultancy, Honoraria, Other: Conference sponsor;Roche:Honoraria, Other: Conference sponsor.McDonald:venetoclax advisory board in South Africa (in CLL context):Consultancy;Alberts Cellular Therapy:Current Employment.Cornpropst:BioCryst Pharmaceuticals, Inc.:Current Employment.Collis:BioCryst Pharmaceuticals, Inc.:Current Employment.Davidson:BioCryst Pharmaceuticals, Inc.:Current Employment.Chen:BioCryst Pharmaceuticals, Inc.:Current Employment.Tower:BioCryst Pharmaceuticals, Inc.:Current Employment.Gesty-Palmer:BioCryst Pharmaceuticals, Inc.:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Sheridan:BioCryst Pharmaceuticals, Inc.:Current Employment.Risitano:Alexion:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Alnylam:Research Funding;Novartis:Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Pfizer:Speakers Bureau;Achillion:Membership on an entity's Board of Directors or advisory committees;Apellis:Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Biocryst:Membership on an entity's Board of Directors or advisory committees;RA pharma:Research Funding;Amyndas:Consultancy;Samsung:Membership on an entity's Board of Directors or advisory committees;Roche:Membership on an entity's Board of Directors or advisory committees;Jazz:Speakers Bureau.

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A Global Registry of Patients with Paroxysmal Nocturnal Hemoglobinuria.

Blood ◽

10.1182/blood.v114.22.3007.3007 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3007-3007

Author(s):

Robert Brodsky ◽

Hubert Schrezenmeier ◽

Petra Muus ◽

Monica Bessler ◽

Jeffrey Szer ◽

...

Keyword(s):

Bone Marrow ◽

Natural History ◽

Board Of Directors ◽

Research Funding ◽

Health Care Services ◽

Clinical Symptoms ◽

Marrow Transplant ◽

Advisory Committees ◽

Care Services ◽

History Of

Abstract Abstract 3007 Poster Board II-983 Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disease characterized by complement-mediated hemolysis which can lead to life-threatening complications including thrombosis, kidney disease, and pulmonary hypertension. The natural history of PNH is highly variable and has previously been captured by retrospective assessment. However, the clinical presentation and prognosis of the disease has changed with the increased awareness of PNH, the increased use of more sensitive diagnostic tests, and the availability of new treatment. Specifically, the development of targeted but potentially life-long therapies, such as terminal complement blockade, necessitates the collection of long-term outcomes data in this patient population. We have established a global PNH Registry in order to redefine the natural history of PNH capturing a wide range of patients from all over the world. The goal of the present analysis is to describe the data collected for the patients in the Registry and demonstrate its use as an ongoing repository of information on symptoms, course, complications and treatment in patients with a PNH clone. The first patient was enrolled in January 2005, with data contributed from 62 clinical sites in 12 countries on 4 continents as of July 2009. Patients are included in the Registry regardless of amount of clone, bone marrow pathology, symptoms, or treatments. Sites collect data at enrollment and every 6 months including demographics, diagnostics and flow cytometry, other lab tests including LDH, medical conditions such as bone marrow pathology and major adverse vascular events (MAVE), clinical symptoms, medications and transfusions, qualitative assessments, bone marrow transplant, and mortality. Patients complete a questionnaire every 6 months including health-related quality-of-life, symptoms, and use of health care services. As of July 2009 there were 368 enrolled patients in the Registry (51% female, 49% male). Mean age at enrollment was 43.6 ±16.7, while mean age at first PNH symptoms was 35.9±16.7. At enrollment, median GPI-deficient granulocyte percentage (GPI-DG) was 80.4%, while 10% of patients had a GPI-DG <10. Of those patients with a GPI-DG <10, 81% had bone marrow pathology (62% with aplastic anemia, 16% with myelodysplastic syndrome, 3% other pathology) compared to 38% of patients with GPI-DG 350. MAVE was increased in patients with GPI-DG 350 compared to <10 (22% vs. 8%), as were LDH levels (median 1042 vs. 239 U/L). Patients with GPI-DG <10 reported high levels of significant clinical symptoms (fatigue 59%; dyspnea 52%; abdominal pain 41%) and symptom reporting was generally increased in patients with higher GPI-DG levels. Treatment in the year prior to Registry enrollment primarily consisted of transfusions (42%), anticoagulation therapy (30%), eculizumab (29%), and immunosuppression (23%), although these varied by GPI-DG level. Clinicians assessed 14% of patients with a Karnofsky score of 70 or lower (i.e., not capable of work or normal activity). Patients' assessment of their overall health, social functioning, and fatigue worsened and use of health care services increased with higher GPI-DG. At this time, median follow up is 12.8 months, although 25% of patients have been followed for at least 30 months. Two patients received a bone marrow transplant and 8 are deceased. In conclusion, preliminary data show that greater GPI-DG is associated with less underlying bone marrow pathology, more hemolysis, more thromboses, and more patient-reported symptoms. New clinical sites and geographic regions are encouraged to participate in the Registry ([email protected]). This global PNH Registry should help to redefine prospectively the long-term natural history of PNH, its treatments, and the outcomes of treatment. Disclosures: Brodsky: Alexion: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Muus:Alexion: Membership on an entity's Board of Directors or advisory committees. Bessler:Alexion: Membership on an entity's Board of Directors or advisory committees. Szer:Alexion: Membership on an entity's Board of Directors or advisory committees. Rotoli:Author Deceased: Author Deceased. Maciejewski:Celgene: Speakers Bureau; Gemzyne: Research Funding; Taligen: Membership on an entity's Board of Directors or advisory committees. Socie:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Urbano-Ispizua:Alexion: Membership on an entity's Board of Directors or advisory committees. Rosse:Alexion: Membership on an entity's Board of Directors or advisory committees. Karnell:Alexion: Employment. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Hillmen:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Osteoarticular Pain after Discontinuation of Tyrosine Kinase Inhibitors (TKI): A French Cohort

Blood ◽

10.1182/blood.v126.23.137.137 ◽

2015 ◽

Vol 126 (23) ◽

pp. 137-137 ◽

Cited By ~ 9

Author(s):

Marc G Berger ◽

Bruno Pereira ◽

Charlotte Oris ◽

Sandrine Saugues ◽

Pascale Cony-Makhoul ◽

...

Keyword(s):

Clinical Trials ◽

Tyrosine Kinase ◽

Medical History ◽

Board Of Directors ◽

Tyrosine Kinase Inhibitors ◽

Research Funding ◽

Kinase Inhibitors ◽

Duration Of Treatment ◽

Advisory Committees ◽

History Of

Abstract Context: The Tyrosine Kinase Inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML) increasing dramatically the survival of CML patients and leading to a residual disease with a sustained and deep molecular response. In this subset of very good responder patients, the attempts of stopping treatment in different clinical trials were successfully achieved without relapse. The Swedish team in the EURO-SKI protocol already reported cases of musculoskeletal pain occurring after cessation of TKI (Richter et al., JCO, 2014). Since several clinical trials regarding TKI discontinuation have been also run in France, we decided to retrospectively collect data using the pharmacovigilance system of the different Trials collected prospectively. Method: 428 patients from STIM2 (n=204) and EURO-SKI (n=224) trials were systematically analyzed from the case report from each trial. For the EURO-SKI only French patients were included. Statistical analysis was performed using Stata 13 software (StataCorp LP, College Station, TX, US). Comparisons between the independent groups were realized using the Chi-squared or Fisher's exact tests for categorical variables, and using Student t-test or Mann-Whitney test for quantitative. Multivariate analyses were performed to take into account adjustment on covariates fixed according to univariate results and clinically relevance. Results: Among the 428 patients the main characteristics were as follow i,e; 208 (48.6%) men and 220 (51.4%) women, with a median age of 77.5 years (24-93). Sokal scores (n=449) were low in 187 (41.6%) patients, intermediate in 188 (41.9%) patients and high in 74 (16.5%) patients. A withdrawal TKI syndrome (WS) was reported for 102 (23.8%) patients (100 after imatinib and 2 after nilotinib). 2). The WS consists in bone and articular pains and arthritis and affects the upper limbs, shoulders and cervical rachis, with a grade 1 or 2 in most patients and grade 3 in 22% of patients . The prevalence of WS depends on the trials, 34.8% in EURO-SKI group and 13.8% in STIM2 group (p<0.001). The WS was treated by non-steroidal anti-inflammatory drugs, corticosteroids or by local infiltration. The median duration of WS was 7 months (range: 3-30 months, 24 exploitable cases). We did not observe any difference between WS group and the group without painful syndrome in terms of sex ratio (p=0.92), age (p=0.33), sokal score (p=0.15), BCR-ABL transcript (p=0.42) or duration of CML (p=0.24). However the median duration of TKI therapy appeared longer in this subgroup (median: 88.8 months vs 79.8 months (p=0.02). There was no biological inflammatory syndrome and the results of medical imaging were inconclusive. However, a medical history of osteoarticular pains or disease appeared as predisposing to withdrawal syndrome (22.9% in WS group vs 9.8% in control group; p=0.002). Finally the two factors, duration of treatment and medical history were confirmed using multivariate analysis (RR=1.73 and 1.76 respectively). Among 19 exploitable cases suffering CML relapse and requiring further TKI treatment, pain disappeared in 7 patients (37%) within a median period of 3.5 weeks. Conclusion: About 23% of patients who stopped TKIs experienced a TKI WS and all TKI seems to be concerned. The predisposing factors were a medical history of osteoarticular pain or disease, and the duration of treatment. So patients and physicians should be aware and recommendations should be proposed for patients who have treated longtime with a history of arthritis. Disclosures Legros: Novartis: Research Funding, Speakers Bureau; ARIAD: Speakers Bureau; BMS: Speakers Bureau. Nicolini:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rousselot:Novartis: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Rea:Novartis: Honoraria; BMS: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Mahon:Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy.

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Appropriateness of Thrombophilia Testing in Tertiary Care Centers in Edmonton

Blood ◽

10.1182/blood.v126.23.4470.4470 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4470-4470

Author(s):

Alabdurubalnabi Zainab ◽

Salma Shivji ◽

Cynthia Wu

Keyword(s):

Family History ◽

Board Of Directors ◽

Protein C ◽

Protein S ◽

Test Results ◽

Advisory Committees ◽

Increased Risk ◽

History Of ◽

Thrombophilia Testing

Abstract INTRODUCTION Thrombophilia is associated with an increased risk of venous thromboembolism (VTE). Despite this link, determining the presence or absence of such conditions has no role in VTE management including determining the choice or duration of anticoagulant therapy. Testing can be potentially harmful when results are misinterpreted or impact patient anxiety and insurance eligibility. METHODS We performed a retrospective chart review of adult patients presenting to the emergency department (ED) or were admitted to the University of Alberta Hospital (UAH), Royal Alexandra Hospital (RAH) and Grey Nuns Hospital (GNH) and underwent any number of thrombophilia tests (including factor V Leiden [FVL], prothrombin gene mutation [PT20210], protein C [PC], protein S [PS], antithrombin [AT] and antiphospholipid antibody testing). To assess for appropriateness of testing, categories of data were collected including presence of other strong risk factors obviating the need to look for other causes, indicators for higher yield (age of patient, presence of family history of VTE, idiopathic nature of VTE), presence of factors that confound testing (such as therapeutic anticoagulation) and relevant follow up (appropriate repeat testing when necessary). We also collected basic patient demographics, VTE details and ordering physician/service details to evaluate under what circumstances testing may be ordered more frequently. RESULTS 134 charts of patients tested for thrombophilia were reviewed between 2007-2013 at UAH and RAH Hospitals. A total of 965 thrombophilia tests were done (see analysis table). 13.4% of the testing was ordered by hematologists, 23.1% by neurologists, 52.2% by other internists. Overall, all patients had tests performed inappropriately, lacked appropriate follow up or had uninterpretable results and none had documented counseling prior to thrombophilia testing. CONCLUSIONS Thrombophilia testing is frequently ordered inappropriately and not adequately followed up. Strategies to educate physicians on indications and limitations of testing are warranted. These strategies can help decrease over/under/misinterpretation of thrombophilia testing as well as result in significant savings to the health care system if testing can be reduced. Table 1. Demographics Sample Size Males Females Total 74 (55.22%) 60 (44.78%) 134 (100%) Age at time of testing (Yrs) Range 19-88 Average 48.7 Patients' Test Results Test Times Performed Abnormal Results APCR 134 (100%) 32 (23.8%) FVL genetic test 58 (43%) 21 (39%) PT20210 105 (77%) 4 (3.8%) Protein C 100 (74.1%) 8 (8%) Protein S 99 (73.3%) 16 (16.2%) AT levels 99 (73.3%) 19 (19.2%) Anticardiolipin Ab 117 (86.7%) 4 (3.4%) Lupus Anticoagulant 109 (81.3%) 10 (10.2%) Provoking Factors Patients with One or More Provoking Factors Major 10 7.4% Moderate 74 56% Minor 29 21.8% No Provoking Factors 49 36.8% Family History of VTE 12 8.9% Protein C and Protein S Testing Done During Acute VTE 64 64% Patient was on Warfarin 25 25% Number of Abnormal Test Results 24 16% Number of Repeated Abnormal Tests 0 0% AT Testing Total Tests Performed 99 73.3% Done During Acute VTE 62 63% Patient was on Therap. Heparin or LMWH 62 62.6% Number of Abnormal Test Results 19 19.2% Abnormal Tests Repeated? 7 37% Repeat Tests Showing Normal Results 3 57% APA Testing Tests were Repeated After 12 Weeks for Confirmation 11% Disclosures Wu: Leo Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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