Hematology Commons^™

Introduction: Moving Beyond Chemotherapy, F. Muggia, E. Teplinsky

Journal Articles

Epithelial ovarian cancer and related cancers arising in extrauterine Mullerian epithelium are generally chemosensitive—particularly to the platinum drugs, cisplatin and carboplatin, that form the backbone of first-line treatments upon diagnosis even at early stages. Doublets of platinums with paclitaxel have represented the standard-of-care since the late 1990s, with further notable advances taking place by intraperitoneal administration (in Gynecologic Oncology Group studies) after optimal surgical cytoreduction is achieved, and by divided doses of paclitaxel (in a Japanese GOG study). Adding another agent to improve on these results has otherwise proven to be quite challenging. Nevertheless, continued forays into introducing ‘targeted therapies’ …

Long-Term Follow-Up Of Mcl Patients Treated With Single-Agent Ibrutinib: Updated Safety And Efficacy Results, M. L. Wang, K. A. Blum, P. Martin, A. Goy, R. Auer, B. S. Kahl, W. Jurczak, R. H. Advani, J. C. Barrientos, S. Rule, +14 Additional Authors

Journal Articles

Ibrutinib, an oral inhibitor of Bruton tyrosine kinase, is approved for patients with mantle cell lymphoma (MCL) who have received one prior therapy. We report the updated safety and efficacy results from the multicenter, open-label phase 2 registration trial of Ibrutinib (median 26.7-month follow-up). Patients (N = 111) received oral ibrutinib 560 mg once daily, and those with stable disease or better could enter a long-term extension study. The primary end point was overall response rate (ORR). The median patient age was 68 years (range, 40-84), with a median of 3 prior therapies (range, 1-5). The median treatment duration was …

Acute Myeloid Leukemia Ontogeny Is Defined By Distinct Somatic Mutations, R. C. Lindsley, B. G. Mar, E. Mazzola, P. V. Grauman, S. Shareef, S. L. Allen, A. Pigneux, M. Wetzler, R. K. Stuart, B. L. Ebert, +9 Additional Authors

Journal Articles

Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Analysis of serial samples from individual patients revealed that these mutations occur early …

Successful Pregnancy Outcome In Paroxysmal Nocturnal Hemoglobinuria (Pnh) Following Escalated Eculizumab Dosing To Control Breakthrough Hemolysis, R. Sharma, A. Keyzner, J. Liu, T. Bradley, S. L. Allen

Journal Articles

Pregnancy in women with paroxysmal nocturnal hemoglobinuria (PNH) is associated with increased maternal and fetal morbidity and mortality. There is limited published experience regarding therapy of PNH during pregnancy. We describe a case of a 30 year old female with hypoplastic myelodysplastic syndrome and PNH. After two years of treatment with eculizumab, she became pregnant. She developed breakthrough hemolysis at 20 weeks gestation. Pharmacokinetic and pharmacodynamic studies demonstrated a subtherapeutic eculizumab level with absence of complement blockade. Escalation of her eculizumab dose successfully controlled hemolysis and restored therapeutic eculizumab level and activity. She delivered a healthy baby at 36 weeks.

Augmenting Nf-Kappab In Poor-Risk Cll: A General Paradigm For Other Cancers?, D. Tuveson, K. R. Rai

Journal Articles

No abstract provided.

Body Mass Index, Pam50 Subtype, And Outcomes In Node-Positive Breast Cancer: Calgb 9741 (Alliance), J. A. Ligibel, C. T. Cirrincione, M. Liu, M. Citron, J. N. Ingle, W. Gradishar, S. Martino, W. Sikov, R. Michaelson, W. T. Barry, +6 Additional Authors

Journal Articles

BACKGROUND: Obesity at diagnosis is associated with poor prognosis in women with breast cancer, but few reports have been adjusted for treatment factors. METHODS: CALGB 9741 was a randomized trial of dose density and sequence of chemotherapy for node-positive breast cancer. All patients received doxorubicin, cyclophosphamide, and paclitaxel, dosed by actual body weight. Height and weight at diagnosis were abstracted from patient records, and the PAM50 assay was performed from archived specimens using the NanoString platform. Relationships between body mass index (BMI), PAM50, and recurrence-free and overall survival (RFS and OS) were evaluated using proportional hazards regression, adjusting for number …

The Bruton Tyrosine Kinase Inhibitor Ibrutinib With Chemoimmunotherapy In Patients With Chronic Lymphocytic Leukemia, J. R. Brown, J. C. Barrientos, P. M. Barr, I. W. Flinn, J. A. Burger, A. Tran, F. Clow, D. F. James, K. Rai, S. O'Brien, +2 Additional Authors

Journal Articles

The safety and efficacy of ibrutinib, an oral inhibitor of Bruton tyrosine kinase, were evaluated with chemoimmunotherapy (CIT) in a multicenter phase 1b study. Patients with relapsed/refractory chronic lymphocytic leukemia received bendamustine and rituximab (BR) or fludarabine, cyclophosphamide, and rituximab (FCR) for up to 6 cycles with daily ibrutinib (420 mg) until progressive disease or unacceptable toxicity. Enrollment to FCR-ibrutinib closed early due to a lack of fludarabine-naive previously treated patients. No patients treated with BR-ibrutinib (n = 30) or FCR-ibrutinib (n = 3) experienced prolonged hematologic toxicity in cycle 1 (primary end point). Tolerability was as expected with either …

Tamibarotene In Patients With Acute Promyelocytic Leukaemia Relapsing After Treatment With All-Trans Retinoic Acid And Arsenic Trioxide, D. Sanford, F. Lo-Coco, M. A. Sanz, E. Di Bona, S. Coutre, J. K. Altman, M. Wetzler, S. L. Allen, F. Ravandi, H. Kantarjian, J. E. Cortes

Journal Articles

Treatment of acute promyelocytic leukaemia (APL) with arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) is highly effective first-line therapy, although approximately 5-10% of patients relapse. Tamibarotene is a synthetic retinoid with activity in APL patients who relapse after chemotherapy and ATRA, but has not been studied in relapse after treatment with ATO and ATRA. We report on a phase II study of tamibarotene in adult patients with relapsed or refractory APL after treatment with ATRA and ATO (n = 14). Participants were treated with tamibarotene (6 mg/m2 /d) during induction and for up to six cycles of consolidation. The …

Management Of Chronic Lymphocytic Leukemia In The Elderly, J. C. Barrientos

Journal Articles

No abstract provided.

Management Of Adverse Events Associated With Idelalisib Treatment: Expert Panel Opinion, S. E. Coutre, J. C. Barrientos, J. R. Brown, S. De Vos, R. R. Furman, M. J. Keating, D. Li, S. M. O'Brien, J. M. Pagel, A. D. Zelenetz, +3 Additional Authors

Journal Articles

Idelalisib is a first-in-class selective, oral, phosphatidylinositol 3-kinase delta (PI3Kdelta) inhibitor approved for the treatment of several types of blood cancer. Idelalisib has demonstrated significant efficacy and a tolerable safety profile in clinical trials. However, the US prescribing information contains a black box warning for fatal and/or severe diarrhea or colitis, hepatotoxicity, pneumonitis and intestinal perforation. An expert panel was convened to review the pathology of these treatment-emergent adverse events (TEAEs) to propose key management tools for patients receiving idelalisib therapy. This article provides an overview of idelalisib TEAEs reported in clinical trials, and a summary of the panel's recommendations …

Targeting Mutant Braf In Relapsed Or Refractory Hairy-Cell Leukemia, E. Tiacci, J. H. Park, L. De Carolis, S. S. Chung, A. Broccoli, S. Scott, F. Zaja, S. Devlin, K. R. Rai, M. S. Tallman, +31 Additional Authors

Journal Articles

Background BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues. Methods We conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily) - one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. STUDY: Primary end points were …

Phase Ii Double-Blind Placebo-Controlled Randomized Study Of Armodafinil For Brain Radiation-Induced Fatigue, B. R. Page, E. G. Shaw, L. Lu, D. Bryant, D. Grisell, G. J. Lesser, D. C. Monitto, M. J. Naughton, S. R. Savona, M. D. Chan, +3 Additional Authors

Journal Articles

BACKGROUND: Common acute-term side effects of brain radiotherapy (RT) include fatigue, drowsiness, decreased physical functioning, and decreased quality of life (QOL). We hypothesized that armodafinil (a wakefulness-promoting drug known to reduce fatigue and increase cognitive function in breast cancer patients receiving chemotherapy) would result in reduced fatigue and sleepiness for patients receiving brain RT. METHODS: A phase II, multi-institutional, placebo-controlled randomized trial assessed feasibility of armodafinil 150 mg/day in participants receiving brain RT, from whom we obtained estimates of variability for fatigue, sleepiness, QOL, cognitive function, and treatment effect. RESULTS: From September 20, 2010, to October 20, 2012, 54 participants …

Egfr And Her2: Is There A Role In Ovarian Cancer?, E. Teplinsky, F. Muggia

Journal Articles

Advanced ovarian cancer carries a grim prognosis and development of targeted therapies to improve outcomes has become an active area of research in this disease. The epidermal growth factor receptor (EGFR) and HER2/neu have shown to be overexpressed in ovarian cancer and there have been several clinical trials evaluating anti-EGFR and HER2 therapies in ovarian cancer. Unfortunately, the drugs have shown minimal efficacy and more recent work has now focused on identifying mechanisms of resistance and alternative ways of targeting these pathways. This review will discuss the currently published trials with anti-EGFR and HER2 agents in ovarian cancer and the …

In Support Of A Patient-Driven Initiative And Petition To Lower The High Price Of Cancer Drugs, A. Tefferi, K. Rai, A. I. Schafer, C. Schiffer, M. A. Sekeres, L. L. Siu, F. M. Stewart, M. Thompson, J. M. Vose, P. H. Wiernik, +109 Additional Authors

Journal Articles

No abstract provided.

Absolute Reticulocyte Count Acts As A Surrogate For Fetal Hemoglobin In Infants And Children With Sickle Cell Anemia., Emily Riehm Meier, Colleen Byrnes, Maxine Weissman, Y Terry Lee, Jeffery L Miller

Pediatrics Faculty Publications

Hemoglobin switching is largely complete in humans by six months of age. Among infants with sickle cell anemia (HbSS, SCA), reticulocytosis begins early in life as fetal hemoglobin (HbF) is replaced by sickle hemoglobin (HbS). The objective of this study was to determine if absolute reticulocyte count (ARC) is related to HbF levels in a cohort of pediatric SCA patients. A convenience sample of 106 children with SCA between the ages of 1 month and 20 years who were not receiving hydroxyurea or monthly blood transfusions were enrolled in this observational study. Hematologic data, including ARC and HbF levels, were …

Targeted Mutational Profiling Of Peripheral T-Cell Lymphoma Not Otherwise Specified Highlights New Mechanisms In A Heterogeneous Pathogenesis., J. H. Schatz, S. M. Horwitz, J. Teruya-Feldstein, Matthew A. Lunning, A. Viale, K. Huberman, N. D. Socci, N. Lailler, A. Heguy, I. Dolgalev, J. C. Migliacci, M. Pirun, M. L. Palomba, D. M. Weinstock, H-G Wendel

Journal Articles: Oncology and Hematology

No abstract provided.

Selective Lymphadenectomy In Endometrial Cancer: Retrospective Analysis Of Morbidity And Survival Data At A Tertiary Care Centre, Uzma Chishti, Aliya Aziz, Munazza Akhtar, Sana Sheikh

Department of Obstetrics & Gynaecology

Objective: To compare perioperative morbidity and survival data between patients with early-stage endometrial cancer who did or did not undergo selective lymphadenectomy.
Methods: Retrospective analysis of 180 patients with early-stage endometrial carcinoma treated between 1999 and 2008 was performed in Aga Khan University Hospital, Karachi, Pakistan.
Results: Data from 180 patients were analysed. The selective lymphadenectomy group contained 108 women (60%) and the no lymphadenectomy group contained 72 women (40%). The median number of lymph nodes removed was 9. The mean age and extent of disease, as assessed by staging, tumour size, myometrial invasion, and lymphovascular invasion were comparable between …

Dengue Hemorrhagic Fever Complicated By Intercostal Artery Hemorrhage., Syed Ahsan Ali, Sara Ahmed, Mehmood Riaz

Department of Medicine

Hemorrhagic manifestations are fairly common in Dengue hemorrhagic fever and are associated with increased mortality. During last few decades there have been increasing reports of Dengue infection with unusual manifestations. Here we present a case of dengue hemorrhagic fever complicated by spontaneous rupture of an intercostal artery leading to a large hematoma which was treated successfully with angio-embolization. To the authors' knowledge this is a first case of dengue hemorrhagic fever complicated by spontaneous intercostal artery hemorrhage.

Hiv Prevalence In Blood Donors And Recipients In Pakistan: A Meta-Analysis And Analysis Of Blood-Bank Data, Bushra Moiz, Barkat Ali, Muhammad Hasnain Chatha, Ahmed Raheem, Hasan Abbas Zaheer

Department of Pathology and Laboratory Medicine

Background:
The first instances of HIV-antibody detection in donated blood in Pakistan were reported in 1988. Since then, documentation of HIV in blood donors and of rates of transmission via transfusion has been limited. Previously assumed to have a low prevalence, HIV is an increasing health concern in Pakistan. Since there is no national, centralized blood-banking system, there are no reliable data on which to base estimated risks of transfusion-associated HIV infection. This study was therefore conducted to estimate the prevalence of HIV in blood donors and recipients in Pakistan between 1988 and 2012.
Methods:
Meta-analyses were undertaken of reported …

Calcium Supplementation Increases Blood Creatinine Concentration In A Randomized Controlled Trial, Elizabeth L. L. Barry, Leila A. A. Mott, Michal L. L. Melamed, Judith R. Rees, Anastasia Ivanova, Robert S. Sandler, Dennis J. Ahnen, Robert S. Bresalier, Robert W. Summers, Roberd M. Bostick, John A. Baron

Dartmouth Scholarship

Background: Calcium supplements are widely used among older adults for osteoporosis prevention and treatment. However, their effect on creatinine levels and kidney function has not been well studied.

Methods: We investigated the effect of calcium supplementation on blood creatinine concentration in a randomized controlled trial of colorectal adenoma chemoprevention conducted between 2004–2013 at 11 clinical centers in the United States. Healthy participants (N=1,675) aged 45–75 with a history of colorectal adenoma were assigned to daily supplementation with calcium (1200 mg, as carbonate), vitamin D3 (1000 IU), both, or placebo for three or five years. Changes in blood creatinine and total …

Leishmania Donovani Bodies In Bone Marrow, Natasha Ali, Shabneez Hussain

Department of Pathology and Laboratory Medicine

We report a case of a 5-year-old female, resident of Afghanistan, who presented with fever and massive splenomegaly. Bone marrow revealed Leishmania donovani bodies (LD bodies) in macrophages characterized by a kinetoplast and characteristic double dot appearance. She was diagnosed as visceral leishmaniasis which is transmitted by sandflies (Phlebotomus).

Production Of Recombinant Human Coagulation Factor Ix By Transgenic Pig, Weijie Xu

Department of Chemical and Biomolecular Engineering: Dissertations, Theses, and Student Research

Hemophilia B is the congenital bleeding disorder caused by deficiency in functional coagulation factor IX (FIX) and about 28,000 patients worldwide in 2012. And current treatment is restricted to protein-replacement therapy, which required FIX concentrates for patients’ life-time. Approximately 1 billion units FIX were consumed in 2012. However, still about 70-80% patients, mostly in developing countries, received inadequate or no treatment because of the unavailable and/or unaffordable FIX concentrates. Considering safety reasons, e.g. transmission of blood-borne diseases, the recombinant human FIX (rFIX) is recommended other than the plasma-derived FIX. However, only one rFIX is currently available on the market. The …

Late Stages Of Hematopoiesis And B Cell Lymphopoiesis Are Regulated By Α-Synuclein, A Key Player In Parkinson's Disease, Wenbin Xiao, Afshin Shameli, Clifford V. Harding, Howard J. Meyerson, Robert W. Maitta

Faculty Scholarship

α-Synuclein plays a crucial role in Parkinson's disease and dementias defined as synucleinopathies. α-Synuclein is expressed in hematopoietic and immune cells, but its functions in hematopoiesis and immune responses are unknown. We utilized α-synuclein(-/-) (KO) mice to investigate its role in hematopoiesis and B cell lymphopoiesis. We demonstrated hematologic abnormalities including mild anemia, smaller platelets, lymphopenia but relatively normal early hematopoiesis in KO mice compared to wild-type (WT) as measured in hematopoietic stem cells and progenitors of the different cell lineages. However, the absolute number of B220(+)IgM(+) B cells in bone marrow was reduced by 4-fold in KO mice (WT: …

Heterogeneous Red Blood Cell Adhesion And Deformability In Sickle Cell Disease, Yunus Alapan, Jane A. Little, Umut A. Gurkan

Faculty Scholarship

We present a microfluidic approach that allows simultaneous interrogation of RBC properties in physiological flow conditions at a single cell level. With this method, we studied healthy hemoglobin A (HbA) and homozygous sickle hemoglobin (HbS) containing RBCs using whole blood samples from twelve subjects. We report that HbS-containing RBCs are heterogeneous in terms of adhesion and deformability in flow.

Quality Of Life In Patients With Thalassemia Major In A Developing Country., Sarah H. Siddiqui, Ruba Ishtiaq, Faiza Sajid, Raihan Sajid

Department of Medicine

Objective: To determine the problems faced by thalassemic patients in their personal, psychological and social life.

Study Design: A cross-sectional multi-centre survey.

Place and Duration of Study: Karachi, Lahore and Quetta Centres of Fatimid Foundation, from October 2009 to October 2010.

Methodology: An indigenously developed Qualifty of Life (QoL) questionnaire modified from SF-36 questionnaire was administered to 101 transfusion dependent subjects suffering from thalassemia major. Variables were analyzed using SPSS version 15 for descriptive statistics.

Results: The mean age of the subjects was 10.5 years ranging from 6 - 21 years. Less than one third of the patients felt that …

Correlational Studies Of Organophosphate Levels And Endocrine Disruption, Immunomodulation, And Altered Glucose Homeostasis In A Human Population Study, Carrie Mckean

Dissertations

Organophosphate (OP) pesticides have become the most widely used insecticides since the removal of organochlorine pesticides (“Ch4 Organophosphate Insecticides.pdf,” n.d.) and are generally the most toxic of all pesticides to vertebrates (Soltaninejad & Abdollahi, 2009). As a result, ongoing research has been aimed at further understanding potential health effects from exposure.

The aim of this dissertation research project is to investigate and characterize correlations of OP body burden with human health effects. This research involves an investigation into three pertinent areas concerning OP exposure: thyroid disruption, altered hematology biomarkers, and alterations of glucose homeostasis. Data under investigation come exclusively from …

Response To Imatinib Mesylate In Patients With Early Chronic Phase Chronic Myeloid Leukemia And Derivative Chromosome 9 Deletion Or Clonal Evolution, Mohammad Usman Shaikh, Tariq Moatter, Naveen Naz Syed, Natasha Bahadur Ali, Salman Adil

Department of Pathology and Laboratory Medicine

Objectives: The significance of clonal evolution and derivative chromosome 9 in Philadelphia-positive CML is not fully characterized and studies have yielded conflicting results. After working on emergence of clonal evolution from our region, we continued to find out the response of Imatinib Mesylate on such cases of CML treated in our center.
Materials and methods: We conducted a cross sectional, prospective analysis on response of Imatinib Mesylate on patients with Philadelphia positive chronic myeloid leukemia with clonal evolution treated from period of September 2007 till 2010. Patients were grouped on basis of cytogenetic analysis performed by conventional cytogenetic and fluorescence …

Steady Increment Of Immature Platelet Fraction Is Suppressed By Irradiation In Single-Donor Platelet Components During Storage, Hong Hong, Wenbin Xiao, Robert W. Maitta

Faculty Scholarship

Circulating immature platelet fraction (IPF) reflects real-time thrombopoiesis and correlates with platelet recovery from thrombocytopenic presentations. To understand the dynamics of IPF in platelet transfusions, we quantified the %-IPF in single-donor platelet components (SDP) during prolonged storage. %-IPF significantly increased from baseline by day 5 post-donation. Absolute IPF counts (A-IPC) had similar significant increments. However, gamma-irradiation suppressed the increments of %-IPF and A-IPC by >50%. Ultrastructural analysis of SDP units at day 10 showed well preserved morphology of immature platelets. Our findings suggest that IPF might actively expand ex-vivo and may have a longer shelf life than their mature counterparts. …

Phase 2 Trial Of Cpx-351, A Fixed 5:1 Molar Ratio Of Cytarabine/Daunorubicin, Vs Cytarabine/Daunorubicin In Older Adults With Untreated Aml, J. E. Lancet, J. E. Cortes, D. E. Hogge, M. S. Tallman, T. J. Kovacsovics, L. E. Damon, R. Komrokji, S. R. Solomon, J. E. Kolitz, E. J. Feldman, +3 Additional Authors

Journal Articles

CPX-351 is a liposomal formulation of cytarabine: daunorubicin designed to deliver synergistic drug ratios to leukemia cells. In this phase 2 study, newly diagnosed older acute myeloid leukemia (AML) patients were randomized 2: 1 to first-line CPX-351 or 713 treatment. The goal was to determine efficacy and identify patient subgroups that may benefit from CPX-351 treatment. Response rate (complete remission 1 incomplete remission) was the primary end point, with event-free survival (EFS) and overall survival (OS) as secondary end points. The 126 patients entered were balanced for disease and patient-specific risk factors. Overall, CPX-351 produced higher response rates (66.7% vs …

Prognostic And Biologic Significance Of Dnmt3b Expression In Older Patients With Cytogenetically Normal Primary Acute Myeloid Leukemia, C. Niederwieser, J. Kohlschmidt, S. Volinia, S. P. Whitman, K. H. Metzeler, A. K. Eisfeld, K. Maharry, P. Yan, J. E. Kolitz, C. D. Bloomfield, +17 Additional Authors

Journal Articles

DNMT3B encodes a DNA methyltransferase implicated in aberrant epigenetic changes contributing to leukemogenesis. We tested whether DNMT3B expression, measured by NanoString nCounter assay, associates with outcome, gene and microRNA expression and DNA methylation profiles in 210 older (60 years) adults with primary, cytogenetically normal acute myeloid leukemia (CN-AML). Patients were dichotomized into high versus low expressers using median cut. Outcomes were assessed in the context of known CN-AML prognosticators. Gene and microRNA expression, and DNA methylation profiles were analyzed using microarrays and MethylCap-sequencing, respectively. High DNMT3B expressers had fewer complete remissions (CR; P=0.002) and shorter disease-free (DFS; P=0.02) and overall …