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

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

Blood ◽

10.1182/blood.v120.21.2239.2239 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2239-2239

Author(s):

Valerie Arias ◽

Ehsan Shabbir ◽

Daniel Victorio ◽

Emily Sperling ◽

Naznin Haq ◽

...

Keyword(s):

Statistical Analysis ◽

Family History ◽

Iron Deficiency ◽

Board Of Directors ◽

Research Funding ◽

Pediatric Patients ◽

Deficiency Anemia ◽

Advisory Committees ◽

Formal Statistical Analysis ◽

History Of

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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Disease and Clinical Characteristics of Patients with Essential Thrombocythemia Enrolled in the MOST Study

Blood ◽

10.1182/blood-2018-99-112183 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4306-4306

Author(s):

Abdulraheem Yacoub ◽

Roger M. Lyons ◽

Srdan Verstovsek ◽

Ryan Shao ◽

David Tin Chu ◽

...

Keyword(s):

United States ◽

Observational Study ◽

Board Of Directors ◽

Essential Thrombocythemia ◽

Research Funding ◽

Clinical Characteristics ◽

The United States ◽

Advisory Committees ◽

History Of ◽

Equity Ownership

Abstract Introduction: Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm characterized by clonal platelet production and an increased risk for thrombotic and hemorrhagic events. Limited real-world data exist regarding the clinical characteristics and treatment patterns of ET in the United States; most prior data have been generated outside the United States. The Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST) is an ongoing observational study being conducted to describe contemporary demographics, burden of disease, clinical management, and patient-reported outcomes in patients with specific risk categories of myelofibrosis (MF) or ET in the United States. This analysis describes the clinical characteristics of patients with ET currently enrolled in MOST. Methods: MOST is a multicenter, noninterventional, prospective, observational study in patients with a clinical diagnosis of specific risk categories of MF or ET (NCT02953704). Eligible patients with ET included high-risk patients (≥ 60 years of age and/or a history of thromboembolic events [TEs]), or low-risk patients currently receiving ET-directed therapy. Key exclusion criteria included participation in blinded investigational drug studies, life expectancy ≤ 6 months, or diagnosis of other malignancy. Data regarding disease and clinical characteristics are collected at usual-care visits over a planned 36-month observation period. Patient demographics and clinical characteristics at enrollment were described with descriptive statistics. Results: At data cutoff (May 18, 2018), 793 eligible patients were enrolled from 85 sites since November 29, 2016. The median age at enrollment was 70 (range, 24-95) years, 66.5% were female, and 89.8% were Caucasian. The median time from ET diagnosis to enrollment was 4.2 (range, 0.0-42.1) years with a proportion of patients diagnosed within 1 year (19.5%), 1 to < 5 years (35.0%), 5 to < 10 years (21.7%), or ≥ 10 years (23.8%) of enrollment. Approximately 40% of patients were retired and 42.7% were working full- or part-time at enrollment. A total of 212 patients (26.7%) had a history of TE at the time of enrollment. The type of TE was available for 148 patients, the most common was arterial events (53.4%); 33.1% had venous, and 13.5% of patients had both arterial and venous events. Six hundred and eighty-eight patients (86.8%) were classified as high-risk. Assessments at the time of ET diagnosis, among evaluable patients, included bone marrow biopsy (51.4%; 393/765) and mutational testing (77.2%; 590/764). Three hundred and forty-nine patients had mutation test results reported at the time of diagnosis; of patients with JAK2 V617F test results reported at the time of diagnosis (n = 313), 78.6% were positive for JAK2 V617F (Table 1). Laboratory values and peripheral blood counts were reported for patients with available data (Table 2). The majority of patients (87.9%) had received at least 1 ET-directed therapy prior to enrollment, which in some cases was the same medication the patient was receiving at the time of enrollment. At the time of enrollment, 740 patients (93.3%) were receiving at least 1 current ET-directed therapy, including HU (71.6%; 530/740), anagrelide (13.1%; 97/740), ruxolitinib (4.7%; 35/740), interferon (3.0%; 22/740), and busulfan (0.3%; 2/740). Of 793 patients, the most frequently occurring relevant comorbid conditions were hypertension (52.7%), history of smoking (44.7%), and hyperlipidemia (24.1%). Among 761 patients with ET-related symptoms assessed at diagnosis, the most common symptoms documented by healthcare providers included constitutional (22.9%), vasomotor (16.0%), and spleen-associated symptoms (3.9%), and pruritus (2.6%). Conclusions: Prior real-world data in ET has predominately been generated outside of the United States or has been reported from single institutional experiences. The MOST study will provide a more complete picture of the patient characteristics and outcomes of patients receiving ET-directed therapy in the United States. Ultimately, these data will be important for determining ET treatment gaps and areas of unmet need. Disclosures Yacoub: Cara Therapeutics: Equity Ownership; Inycte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Ardelyx, INC.: Equity Ownership; Seattle Genetics: Honoraria, Speakers Bureau; Dynavax: Equity Ownership. Verstovsek:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Shao:ASH: Membership on an entity's Board of Directors or advisory committees; ASCO: Membership on an entity's Board of Directors or advisory committees. Agrawal:Incyte: Speakers Bureau. Sivaraman:Incyte: Employment. Colucci:Incyte: Employment, Equity Ownership. Yao:Incyte: Employment. Mascarenhas:Celgene: Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Janssen: Research Funding.

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Lintuzumab and Low-Dose Cytarabine Compared to Placebo and Low-Dose Cytarabine in Patients with Untreated Acute Myeloid Leukemia (AML) 60 Years and Older: Results of a Randomized, Double-Blinded Phase 2b Study,

Blood ◽

10.1182/blood.v118.21.3613.3613 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3613-3613 ◽

Cited By ~ 4

Author(s):

Jeffrey E. Lancet ◽

Mikkael A. Sekeres ◽

Brent L. Wood ◽

Laurie E. Grove ◽

Larissa Sandalic ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Low Dose ◽

P Value ◽

Advisory Committees ◽

History Of ◽

Equity Ownership ◽

Double Blinded ◽

Low Dose Cytarabine

Abstract Abstract 3613 Background: Older adults with AML who decline intensive induction chemotherapy lack effective therapeutic options, as evidenced by a median overall survival (OS) of ∼5 months with low-dose cytarabine treatment (Burnett 2007). Leukemic blast cells express CD33 in most patients with AML. While antitumor activity has been previously demonstrated by CD33-directed agents, none of these are currently available. Lintuzumab (SGN-33) is a humanized antibody directed to CD33 that was studied in patients with myeloid malignancies and demonstrated tolerability with modest monotherapy activity. To determine if the addition of lintuzumab to low-dose cytarabine could prolong survival in older patients with untreated AML, a randomized, placebo-controlled, double-blinded phase 2b study was conducted (ClinicalTrials.gov #NCT00528333). Methods: The study was conducted at 72 international sites between November 2007 and August 2010. Patients were >60 years of age with centrally confirmed, previously untreated AML; the minimum blast percentage required was 20% with ≥50% CD33 expression. Maximum allowed WBC at baseline was 30,000/μL. All patients declined treatment with intensive induction chemotherapy. Cytarabine 20 mg was administered SC twice daily on Days 1–10 of each 28-day cycle (12 cycles maximum). Patients were randomized to additionally receive either lintuzumab 600 mg or placebo IV: in Cycle 1 on Days 1, 8, 15, and 22, and on Days 1 and 15 of subsequent cycles. Patients were stratified according to age, ECOG performance status (PS), and history of antecedent hematologic disorder (AHD). Cytogenetic risk was determined at baseline according to Fröling 2006. The primary endpoint of the study was OS, determined using an unstratified log rank test. Secondary endpoints included peripheral blood count recovery, transfusion requirements, infection rates, and quality of life. As patients choosing less-intensive therapy often incorporate quality of life into their treatment decision, follow-up bone marrow biopsies were not required in the study. Results: 211 patients were randomized in the study (107 lintuzumab arm, 104 placebo arm). The study arms appeared balanced; overall, the median patient age was 70 years (range 60–90), 53% were female, and baseline ECOG PS was 0/1 (55%) or 2 (45%). Baseline blast percentages were ≥30% in 74% of patients and 23% had a history of AHD. A median of 95% CD33 expression was documented at baseline in either bone marrow or peripheral blood. Median number of treatment cycles was 4 in the lintuzumab arm and 3 in the placebo arm. At the time of the analysis, 24 patients were alive and the maximum follow-up was 32 months. The estimated median OS for the lintuzumab + low-dose cytarabine arm was 4.7 months compared with 5.1 months for the placebo + low-dose cytarabine arm with a hazard ratio (lintuzumab to placebo) of 0.96, indicating that lintuzumab was not associated with a treatment effect (P value 0.76, 95% CI [0.72, 1.28]). Rates of infections or fevers of unknown origin requiring hospitalization or IV antibiotics did not differ between the study arms. Overall, 28% of patients were observed to have no peripheral blasts, ANC >1.0 x109/L, platelets >100 × 109/L, and no transfusions for at least 1 week. The median OS among all patients was 5.0 months, which was significantly impacted by cytogenetic risk (8.7 months for standard-risk compared with 4.5 months for high-risk; P value 0.0024). The incidence of adverse events (AEs) was comparable between the treatment groups, with the exception of infusion-related reactions which occurred more frequently in the lintuzumab arm. The most common ≥ Grade 3 non-hematologic AEs in the study were pneumonia (12%) and sepsis (8%). Conclusions: In this randomized, placebo-controlled, double-blinded phase 2b trial, the combination of lintuzumab and low-dose cytarabine did not improve OS compared with placebo and low-dose cytarabine. While lintuzumab was not effective, CD33 remains a compelling target for AML because it is widely expressed by malignant cells and appears to be absent from pluripotent hematopoietic stem cells. This was the largest study to date of patients treated with low-dose cytarabine; the median OS across both treatment arms was 5 months. A similar outcome was observed in the subgroup of patients with high-risk cytogenetics, confirming that low-dose cytarabine remains a valid comparator in trials of older patients with AML. Disclosures: Lancet: Seattle Genetics, Inc.: Research Funding. Off Label Use: Lintuzumab is an investigational monoclonal antibody directed against CD33. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Celgene Corp.: Honoraria; Seattle Genetics, Inc.: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Wood:Seattle Genetics, Inc.: Research Funding. Grove:Seattle Genetics, Inc.: Equity Ownership; Seattle Genetics, Inc.: Employment. Sandalic:Seattle Genetics, Inc.: Equity Ownership; Seattle Genetics, Inc.: Employment. Sievers:Seattle Genetics: Employment, Equity Ownership. Jurcic:Seattle Genetics, Inc.: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Research Funding.

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Baseline Laboratory Parameters Potentially Associated with Thrombophilia in Patients with Chronic ITP.

Blood ◽

10.1182/blood.v120.21.2191.2191 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2191-2191

Author(s):

Raymond S.M. Wong ◽

Kalpana Bakshi ◽

Andres Brainsky

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Protein S ◽

Coagulation Cascade ◽

Published Data ◽

Employment Equity ◽

Advisory Committees ◽

Increased Risk ◽

History Of ◽

Equity Ownership

Abstract Abstract 2191 Background: The concept that chronic immune thrombocytopenia (cITP) may be pro-thrombotic has progressively gained acceptance as reports show an increased risk of thromboembolism (TEE) among cITP patients. A report from the Danish National Patient Registry showed an incidence of venous TEE of 5.32/1000 patient years (PYs) among cITP patients and 2.04/1000 PYs in a reference cohort (Severinsen 2010). Similar results were found in a US claims database study (Bennett 2008). ITP experts have gradually acknowledged this higher risk, but the reason for it is not understood. Many hematologic markers have been shown to be indicators of thrombophilia or activation of the clotting cascade (Jenkins 2012; De Stefano 2002; Tsai 2002); to our knowledge they have not been systematically and prospectively studied in cITP patients. Aim: Describe the frequency of potential laboratory predictors of thrombophilia in cITP. Methods: Adults with cITP were enrolled in an ongoing study to evaluate effects of eltrombopag on the bone marrow. A “thrombophilia panel” of suspected/known indicators of a thrombophilic state or activation of the coagulation cascade was collected at baseline. Patients could not have been treated with thrombopoietin receptor (TPO-R) agonists 6 months prior to enrollment. Patients with history of TEE and ≥2 risk factors for thrombosis were not eligible for enrollment. Results: Baseline thrombophilia panels were available for all 167 patients. Median age was 41 years; 108 (65%) patients were female. Approximately half of the patients were Caucasians (48.5%), while 31.1% and 19.2% had Central South and East Asian heritage. Median time since ITP diagnosis was 3.9 years (range, 0.2–45.7). Thirteen (8%) patients reported prior exposure to TPO-R agonists. Most patients (95%) had no family history of TEE and no patient had a history of TEE. Most patients (81%; Table 1) had abnormal levels of at least one well-known or suspected predictor of thrombosis or marker of activation of the coagulation cascade, and 93 (56%) had >1 abnormality. The most frequent abnormalities were elevated Factor VIII (48%), elevated d-dimer (32%), lupus anticoagulant (26%), and deficient protein S (22%; Table 2). Discussion: To our knowledge this is the only published prospective study of a thrombophilia profile in a cohort of cITP patients. Recently published data suggest that patients with cITP have a higher risk of TEE but no adequate explanation for this has been furnished. The fact that a high proportion of patients in this study had markers of thrombophilia or activation of clotting provides a working hypothesis that may at least partially elucidate this trait. Summary/conclusions: The multiple baseline abnormalities in possible predictors of thrombophilia may support the theory that ITP is pro-thrombotic, but they need to be assessed in and compared to the general population to allow proper understanding of their implications. The potential correlation of these abnormalities with TEE in this cohort will be reported upon study conclusion. Disclosures: Wong: GlaxoSmithKline: Research Funding; Pfizer: Research Funding; Biogen-Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding; Johnson & Johnson: Research Funding; MSD: Research Funding; Roche: Research Funding; Bristol-Myers Squibb: Research Funding. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties.

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Clonal Hematopoiesis in Older Women with Extremely Skewed, Non-Random X-Inactivation Is Associated with Previous Cardiovascular and Cerebrovascular Events

Blood ◽

10.1182/blood-2018-99-120323 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2574-2574

Author(s):

Emily Marre ◽

Julia Erin Wiedmeier ◽

Zhenzhen Zhang ◽

Hyunjung Lee ◽

Dana Parker ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

X Inactivation ◽

High Cholesterol ◽

Advisory Committees ◽

Clonal Hematopoiesis ◽

History Of ◽

Equity Ownership ◽

Humara Assay

Abstract Age-related clonal hematopoiesis (CH) is a common condition that is associated with an increased risk of hematologic malignancies (HM) and cardiovascular disease (CVD). The majority of candidate driver mutations occur in epigenetic regulatory genes such as ASXL1, DNMT3A, and TET2 genes. However, a significant proportion of older people harbor clonal hematopoiesis without candidate driver mutations. In older women, clonal hematopoiesis can also be detected by the human androgen receptor A gene (HUMARA) assay regardless of the presence or absence of candidate driver mutation(s). The HUMARA assay evaluates non-random X-inactivation (NRX-I) as a marker for clonal hematopoiesis. The purpose of this study is to evaluate the association between NRX-I and cardiovascular risk factors and other health correlates. We screened for NRX-I in 904 women ages 65 and older participating in an ongoing, prospective cohort study in Oregon (Women Engaged in Advancing Health Research [WEAR] study). This approach was used to enhance the investigation of changes in CH that occur over time that may prove to be impactful for health outcomes. We examined the HUMARA results and any association with previous health history using a cross-sectional study design. Analysis of variance and logistic regression analyses were used to examine the relationship between HUMARA assay results and baseline CVD risk, controlling for age and race. HUMARA assay results were quantified and 3 groups were established: random X-inactivation, NRX-I, and extremely skewed NRX-I. No significant differences were detected between groups with respect to age, race, education, reproductive health indices or body mass index. With respect to cardiovascular risk factors, women with extreme NRX-I were more likely to be lifetime non-smokers compared to women without NRX-I and those with NRX-I with less skewing (P: 0.049), though no difference was seen in the proportion of current smokers (P: 0.213) and the total pack years smoked by those with a smoking history (P: 0.846).The proportion of subjects reporting statin or other cholesterol lowering medication did significantly differ between groups, with 24.3% women without NRX-I reporting statin use, versus 30.4% in women with NRX-I, and 36.7% in women with NRX-I extreme skewing (P: 0.005). Post-hoc pairwise tests showed significant differences between women with no NRX-I and women with NRX-I extreme skewing (P: 0.004). Cardiovascular event history differed significantly between the three groups of interest. 5.6% of women without NRX-I reported a history of transient ischemic attack (TIA), cerebral vascular accident (CVA), or myocardial infarction (MI) versus 7.0% in the NRX-I group and 11.0% in the NRX-I with extreme skewing group (P: 0.05). Post-hoc pairwise tests showed significant differences between women with no NRX-I and women with NRX-I extreme skewing (P: 0.043). The adjusted odds of TIA, CVA, or MI more than doubled (OR: 2.15, 95%CI: 1.14-3.42) among women with extremely skewed HUMARA results compared to women with NRX-I, controlling for age, high cholesterol, smoking history, hypertension, and type II diabetes. Cholesterol was also found to be independently associated with TIA, CVA, and MI. Women with hypercholesterolemia were 1.84 times as likely to report a history of TIA, CVA, or MI compared to women without hypercholesterolemia (95% CI: 1.06, 3.20). In summary, prediction of major adverse cardiac events is based on the presence of traditional risk factors including high blood pressure, high cholesterol, uncontrolled diabetes, smoking, and family history. Yet there is significant residual risk; many will still die from CVD without these risk factors. NRX-I, in addition to enriching for mutations known to confer CVD and HM risk; may be a marker for additional and unique health risks. An association between NRX-I, high cholesterol, and history of TIA, CVA, and MI, supports the current biological hypothesis that clonal hematopoiesis, perhaps irrespective of the cause or underlying driver mutation, is a driver for CVD. Disclosures Druker: Celgene: Consultancy; Fred Hutchinson Cancer Research Center: Research Funding; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Beta Cat: Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oregon Health & Science University: Patents & Royalties; McGraw Hill: Patents & Royalties; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Research Funding; Monojul: Consultancy; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; Henry Stewart Talks: Patents & Royalties; Millipore: Patents & Royalties; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding. Dao:Incyte: Consultancy.

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Use of Blood Transfusions In Paroxysmal Nocturnal Hemoglobinuria Patients with and without Aplastic Anemia Enrolled In the Global PNH Registry

Blood ◽

10.1182/blood.v116.21.2241.2241 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2241-2241

Author(s):

Hubert Schrezenmeier ◽

Robert A Brodsky ◽

Petra Muus ◽

Monica Bessler ◽

Jeffrey Szer ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Employment Equity ◽

Advisory Committees ◽

Clone Size ◽

History Of ◽

Equity Ownership ◽

To Receive

Abstract Abstract 2241 Background: 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, pulmonary hypertension, pain, anemia, and severe fatigue. PNH clones occur in a number of patients with concomitant aplastic anemia (AA) and other bone marrow disorders (BMD). Some patients with PNH and/or BMD may require red blood cell (RBC) transfusions to treat anemia due to hemolysis or bone marrow hypoplasia. Aims: To characterize the use of RBC transfusions among PNH patients with and without underlying AA. Methods: Enrollment data from 117 clinical sites participating in the observational PNH Registry in 16 countries on 5 continents was analyzed. Patients are included in the Registry regardless of the proportion of cells with deficiency of glycosylphosphatidyl-inositol anchored proteins (GPI-AP), bone marrow pathology, symptoms, or treatments. Sites collect clinical history at enrollment and additional data every 6 months. Demographic data, use of transfusions and other treatments, lab results, and symptoms are summarized for PNH patients with and without AA. Results: As of June 30, 2010 there were 655 enrolled patients in the Registry (53% female, median age 43). At enrollment, 28% of patients had history of AA and 45% had no history of BMD. Patients with underlying AA had lower median GPI-AP deficient granulocytes than those without BMD (median = 53% vs. 86%, respectively, p<.01) and patients in both groups had similar evidence of hemolytic activity when stratified by clone size (median LDH fold above normal upper limit was 0.90 vs. 0.94, p=.39 for patients with and without AA and clone size <10%; median = 3.41 vs. 4.84, p=.08 for AA vs. no BMD and clone size ≥50%). Not all PNH patients required transfusions: 56% of all patients required transfusions in the year prior to enrollment. Although patients with and without AA were equally likely to be treated with blood transfusions in the year prior to study enrollment overall, some differences emerged when stratified by clone size. For patients with clone size <50%, AA patients were almost twice as likely to receive transfusion in the previous year as patients without BMD (39% vs. 20%, p=.08). However, regardless of underlying AA, the proportion of patients receiving transfusions, in the prior year increased as clone size increased (29%, 31%, and 69% for clone sizes <10%, 10–49%, and ≥50%, respectively, p<.01). When patients were stratified by percent reticulocytes at enrollment (below vs. above the median value of 4.16%), 45% vs. 75% received transfusion in the prior year (p<.01). Among patients receiving a transfusion in the year prior to enrollment, the mean number of RBC units transfused was 9.6 for patients with underlying AA and 7.9 for patients with no BMD (p=.10). However, approximately twice as many patients with AA received 20+ RBC units in that year compared to patients without BMD (20% vs. 11%, p=.09). Number of transfused units in that year was similar by clone size (mean 9.5 vs. 8.6 for clone size <50% vs. ≥50%, p=.57). Concomitant treatment with anticoagulants or immunosuppressants was similar among patients who had received a transfusion in the past year compared to patients with no transfusions (39% vs. 33%, p=.13 and 26% vs. 22%, p=.25 respectively). Patients with AA had more bruising and bleeding while patients without BMD had more hemoglobinuria, dysphagia, and abdominal pain. Transfused patients with AA had more fatigue than non-transfused patients with AA (68% vs. 48%, p=.02). Conclusions: A substantial proportion (56%) of patients with PNH, but not all, required at least one transfusion in the year prior to enrolling in the registry, independent of underlying AA. The proportion of patients who had at least one transfusion increased with clone size. Among patients who had at least one transfusion, there was a trend for patients with underlying AA to receive more RBC units than patients without BMD. PNH patients with AA have fewer GPI-AP deficient granulocytes but demonstrate elevated hemolysis similar to patients without history of BMD when patients with similar clone sizes were compared. This Global PNH Registry, which remains open to accrual ([email protected]), should help to redefine prospectively the long-term natural history of PNH, its treatments, and the outcomes of treatment. Disclosures: Schrezenmeier: Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Brodsky: Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Muus: Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Bessler: Alexion Pharmaceutical Inc: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Taligen: Consultancy. Szer: Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Maciejewski: Celgene: Research Funding; Eisai: Research Funding; Alexion: Consultancy. Socié: Alexion: Honoraria, 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. Kanakura: Alexion: Membership on an entity's Board of Directors or advisory committees. Hoechsmann: Alexion: Speakers Bureau. Rosse: Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khursigara: Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Karnell: Alexion Pharma International: Employment, Equity Ownership. Bedrosian: Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Hillmen: Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Examining the Clinical Features and Underlying Cardiovascular Risk Among Patients with Polycythemia Vera in the REVEAL Study

Blood ◽

10.1182/blood.v128.22.1934.1934 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1934-1934 ◽

Cited By ~ 1

Author(s):

Brady L. Stein ◽

Ahmad Naim ◽

Michael R. Grunwald ◽

Alison R. Moliterno ◽

Stephen T. Oh ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Clinical Characteristics ◽

The United States ◽

Employment Equity ◽

Advisory Committees ◽

Reveal Study ◽

History Of ◽

Equity Ownership

Abstract Background:Patients with polycythemia vera (PV) often present with a broad range of clinical characteristics that may contribute to increased risks of cardiovascular (CV) morbidity and mortality, including thrombotic events (TE). Limited contemporary real-world data have been reported about the clinical burden of PV and treatment patterns in the United States. The ongoing REVEAL study collects data on disease burden, clinical management, patient-reported outcomes, and healthcare resource utilization for patients with PV in the United States. This analysis reports clinical characteristics, including underlying CV risk factors, for patients enrolled in the REVEAL study as of April 28, 2016. Methods: REVEAL is a multicenter, nonrandomized, prospective, observational study enrolling patients ≥18 years of age with a PV diagnosis who are actively managed in an academic or community setting. For this analysis, data regarding PV disease and diagnosis, clinical characteristics, and treatment patterns were collected at enrollment during usual-care visits and were based on physician assessment, electronic medical records, and local laboratory values. Ten-year CV risk factors selected for this analysis were adapted from the Framingham Heart Study for CV diseases. Results: At data cutoff, 2307 patients were available for this analysis. Mean (SD) age was 66.3 (12.2) years, 54.4% were male, 89.9% were white, 62.7% had at least some college education, and 51.1% were retired. Approximately 6% of patients had a family history of PV, primarily in parents (35.1%) and siblings (33.8%). A history of second malignancies was reported for 344 patients (14.9%). The majority of patients (84.6%) were diagnosed with PV based on an abnormal blood test alone or in combination with a bone marrow test. Among patients who were diagnosed with a mutational test (n=1078), 95.2% were diagnosed via an abnormal JAK2V617F test result. Abnormal hemoglobin (57.3%), hematocrit (55.4%), or both (47.5%) were among the most common blood values assessed for PV diagnosis. At diagnosis, 58.5% of patients were classified with high-risk PV (age ≥60 years or history of a TE); this percentage increased to 77.3% at REVEAL enrollment. The average (SD) disease duration from diagnosis to enrollment was 5.8 (6.1) years. At enrollment, 91.5% of patients were under active management for PV (phlebotomy ± aspirin, 34.0%; hydroxyurea ± aspirin, 27.0%; and phlebotomy + hydroxyurea ± aspirin, 23.2%). Underlying CV risk factors that were either diagnosed or treated in 86.0% of enrolled patients included hypertension (66.5%), history of smoking (46.2%), current smoking at enrollment (10.9%), obesity (34.2%), hyperlipidemia (27.4%), and diabetes (14.8%). At enrollment, 431 (18.7%) patients reported having ≥1 TE, including 181 patients who had a TE between PV diagnosis and enrollment. Venous and arterial TEs were reported in 11.1% and 8.6% of patients, respectively. Most commonly reported venous TEs were deep vein thrombosis (5.9%) and pulmonary embolism (2.5%); most common arterial TEs were cerebrovascular arterial thrombosis including transient ischemic attack (5.1%) and acute myocardial infarction (1.7%). Increased rates of TEs were observed among patients with hyperlipidemia (23.6%) and hypertension (21.0%; Table 1), compared with patients who did not have any risk factors (10.5%). Conclusion: A large proportion of patients in the REVEAL study had 1 or more underlying CV risks, including age, hypertension, smoking, obesity, hyperlipidemia, and diabetes, which may contribute to the risk of thrombosis. Longitudinal data from REVEAL will provide a better understanding of how these factors affect CV outcomes over time. Disclosures Stein: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Naim:Incyte Corporation: Employment, Equity Ownership. Grunwald:Janssen: Research Funding; Forma Therapeutics: Research Funding; Medtronic: Equity Ownership; Alexion: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Oh:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; CTI: Research Funding. Paranagama:Incyte Corporation: Employment, Equity Ownership. Cordaro:Incyte Corporation: Employment, Equity Ownership. Sun:Incyte Corporation: Employment, Equity Ownership. Parasuraman:Incyte Corporation: Employment, Equity Ownership. Boccia:Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau; Gilead: Speakers Bureau; Genentech: Consultancy, Honoraria, Speakers Bureau; Eisai: Consultancy, Honoraria, Speakers Bureau. Mesa:Ariad: Consultancy; CTI: Research Funding; Gilead: Research Funding; Galena: Consultancy; Novartis: Consultancy; Promedior: Research Funding; Celgene: Research Funding; Incyte Corporation: Research Funding.

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Extended Mutational Profiling By MSK-IMPACTTM Identifies Mutations Predicting Thromboembolic Risk in Patients with Solid Tumor Malignancy

Blood ◽

10.1182/blood-2019-124242 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 633-633

Author(s):

Andrew Dunbar ◽

Kelly Bolton ◽

Sean M. Devlin ◽

Francisco Sanchez-Vega ◽

Jianjiong Gao ◽

...

Keyword(s):

Board Of Directors ◽

Solid Tumor ◽

Research Funding ◽

Tumor Type ◽

Molecular Signatures ◽

Advisory Committees ◽

Large Patient ◽

History Of ◽

Equity Ownership ◽

Tumor Types

Background: Cancer-associated thrombosis (CAT) is a leading cause of death in cancer patients after cancer itself. Risk factors for CAT include tumor type/stage, body mass index (BMI), blood cell counts and chemotherapy exposure. These factors form the basis of prediction algorithms for CAT risk, including most notably the Khorana Risk Score. However, significant limitations exist with these currently-available risk prediction models. Emerging data suggest that a tumor's molecular profile can impact venous thromboembolism (VTE) risk. Mutations of ALK, EGFR, IDH1, ROS1, and KRAS for example have been shown to modulate the risk of CAT; however, these studies were limited by the number of mutations and specific tumor types analyzed. We hypothesized that extended molecular testing in a large patient cohort would allow for improved detection of molecular signatures associated with CAT. We analyzed deep-coverage targeted sequencing data (up to 341 genes) of tumor samples from 11,776 cancer patients to identify gene mutations associated with VTE. Methods: Adult patients with any solid tumor diagnosis who had their tumors sequenced using MSK-IMPACT from 1/2014 to 12/2016 were retrospectively assessed for CAT events using redundant algorithmic methods and individual chart reviews. The endpoint was defined as the first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis (DVT). An episode of upper extremity DVT was considered a competing event. The observation period was limited to 365 days after IMPACT blood control sampling. Cause-specific Cox proportional hazards regression was used to test for an association between gene and CAT risk, adjusting for clinical covariates including age, cancer type, cytotoxic chemotherapy (time-dependent), anticoagulant use, stage (metastatic/non-metastatic) and prior history of VTE. Separate multivariate models evaluated the association for the 60 most frequently-mutated genes identified, along with ALK, MET, ROS1 which were included based on existing literature suggesting an effect on VTE risk. Final p-values were adjusted for false discovery using the Benjamini-Hochberg procedure, and the threshold for statistical significance was set at 0.10. Patients with multiple cancer diagnoses were excluded. Results: Out of 11,776 individuals we observed 727 CAT events (6.2% of cohort). The most commonly represented tumor types were lung (18%), breast (15%) and colorectal cancer (10%); see Figure for a breakdown of CAT incidence by tumor type. Most (72%) of patients were metastatic at time of IMPACT testing and 4% were on anticoagulation therapy. Statistically significant predictors of CAT included cytotoxic chemotherapy (HR 1.61 [1.37-1.9]; p<0.001), history of VTE preceding cancer diagnosis (HR 2.48 [1.62-3.79]; p<0.001), and presence of metastatic disease (HR 2.48 [1.94-3.16]; p<0.001). Molecular profiling of tumors revealed STK11 (HR 1.93 [1.42-2.64]; adjusted p=0.002), KRAS (HR 1.42 [1.17-1.72]; adjusted p=0.012), KEAP1 (HR 1.78 [1.18-2.69]; adjusted p=0.095), and MET (HR 1.8 [1.17-2.78]; adjusted p=0.095) somatic mutations were associated with a significant increase in the risk of CAT, independent of tumor type. However, it should be noted that a majority of these genes were specific to lung cancer highlighting the prevalence of this tumor type within the IMPACT cohort. Additionally, the presence of IDH1 mutations in primary brain tumors correlated with a decreased risk of CAT in comparison to wild-type IDH1 (HR 0.34 [0.16-0.69]; adjusted p=0.068), consistent with previous studies. See Table for an extended report of regression coefficients. Conclusions: This work is the first large-scale analysis to elucidate cancer-specific genomic determinants of CAT. Using a large patient cohort, we found that somatic tumor mutations in STK11, KRAS, IDH1, KEAP1, and MET modulate the risk of venous thromboembolism in solid tumor patients. Further analysis is needed to validate these findings and identify additional molecular signatures unique to individual tumor types. We hope these findings will ultimately translate into improved risk stratification for patients at risk of CAT. Disclosures Mones: Janssen: Research Funding. Iyengar:Puma Biotechnology: Consultancy; Novartis: Consultancy. Hyman:AstraZeneca: Consultancy, Research Funding; Fount: Consultancy, Equity Ownership; Pfizer: Consultancy; Chugai Pharma: Consultancy; Loxo Oncology: Research Funding; Boehringer Ingelheim: Consultancy; Bayer Pharmaceuticals: Consultancy, Research Funding; Genentech / Roche: Consultancy; PUMA Biotechnology: Research Funding; CytomX Therapeutics: Consultancy. Park:Merck: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding; Astellas: Research Funding; Ipsen: Consultancy. Khorana:Bayer: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy. Soff:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Mantha:Medical Case Management Group: Consultancy; MJH Live Events: Other: Give CME talk; Heidell, Pittoni, Murphy & Bach, LLP: Consultancy; Daboia Consulting LLC: Equity Ownership; Janssen: 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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Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽

10.1182/blood-2019-127523 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1961-1961

Author(s):

John F. DiPersio ◽

Jonathan Hoggatt ◽

Steven Devine ◽

Lukasz Biernat ◽

Haley Howell ◽

...

Keyword(s):

Single Dose ◽

Adverse Events ◽

Board Of Directors ◽

Preliminary Data ◽

Research Funding ◽

Fold Change ◽

Employment Equity ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

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