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AMERICAN SOCIETY of HEMATOLOGY Mark Your Calendar ® for the Premier Hematology Meeting! 53rd ASH Annual Meeting and Exposition M E ETI N G DATE S: December 10-13, 2011 December 10-13, 2011 San Diego Convention Center U San Diego, CA E X P OS ITI ON DATE S: December 10-12, 2011 FR I DAY SATE LLITE SYM P OS IA: December 9, 2011 4Please note that this year’s meeting will take place the second weekend in December. Registration and Housing Early-Bird Registration and Housing ASH members only – online only July 19 – August 9 Advance Registration and Housing August 10 – November 9 Abstracts Abstract Submission Website Open Only electronic submissions will be permitted. June 14 – August 11 Exhibits Exhibit Hall Placement Open to All Companies Now – November 29 Questions? Contact the American Society of Hematology Phone: 202-776-0544 E-mail: [email protected] For detailed meeting information, please visit www.hematology.org. blood JOURNAL OF Blood, Journal of The American Society of Hematology (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly every Thursday, except for the last week in December, (51 times weekly), plus the ASH annual meeting abstracts in November, by the American Society of Hematology (ASH), 2021 L Street, NW, Suite 900, Washington, DC 20036. Printed in the United States of America. Periodicals postage paid at Washington, DC, and additional mailing offices. Postmaster: Send change-of-address information to Blood, Journal of the American Society of Hematology, Subscription Office, 2021 L Street, NW, Suite 900, Washington, DC 20036. Canadian regulations: Publications Mail Agreement No: 40038947. Return undeliverable Canadian addresses to: Circulation Dept. or DPGM, 4960-2 Walker Road, Windsor, ON N9A 6J3. 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Nonsubscribers may purchase 24-hour access to the full text of any article published in the preceding 12 months through the pay-per-view option on the Blood website. Subscription information, claims, and changes of address Customer service for subscribers: 1-866-328-8560 (US and Canada); 1-202-292-0280 (outside US and Canada); fax: 1-202-292-6010; e-mail: [email protected]. Correspondence regarding subscriptions and changes of address should be addressed to Blood Journal Subscription Office, 2021 L Street, NW, Suite 900, Washington, DC 20036. Checks should be made payable to “Blood Subscriptions.” ASH Members should send their change-of-address information to the ASH Membership Department, 2021 L Street, NW, Suite 900, Washington, DC 20036. All change-of-address notices should be sent at least 6 weeks before the first issue is to be mailed to the new address. Provide both old and new addresses. Claims: Claims must be submitted within 4 months of the publication date (6 months for international subscribers). The American Society of Hematology 2021 L Street, NW, Suite 900 Washington, DC 20036 Internet Blood Home Page: www.bloodjournal.org. ASH Home Page: www.hematology.org. Manuscript Submission: submit.bloodjournal.org. Copyright Copyright © 2011 by The American Society of Hematology. All rights reserved. No part of this publication may be reproduced (see exception below), stored in a retrieval system, translated, or transmitted in any form or by any means now or hereafter known, electronic or mechanical, without permission in writing from the Publisher, The American Society of Hematology. Address for correspondence: Blood Publishing Office, 2021 L Street, NW, Suite 900, Washington, DC 20036. Important notice: Authors retain certain nonexclusive copyrights. For further information on rights and permissions, see www.bloodjournal.org/misc/rights.shtml. 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Telephone: 201-767-4170; fax: 201-767-8065; e-mail: [email protected]. Disclaimer The ideas and opinions expressed in Blood do not necessarily reflect those of The American Society of Hematology or the Editors of Blood. Publication of an advertisement or other product mention in Blood should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with any questions about the features or limitations of the products mentioned. The American Society of Hematology does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other health care professional, relying on his or her independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Indexing & abstracting Blood is indexed and abstracted by Index Medicus, Excerpta Medica, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, SCISEARCH, Automatic Subject Citation Alert, ISI/ BIOMED, and BIOSIS. Hodgkin lymphoma— ≈10% refractory rates1 ≈ 30% relapse rates after complete response1 ≈50% of transplants fail2,3 Long-term health complications4 Reduced survival in some patients initially cured5 NoGoodCancer.com References 1. Quddus F, Armitage JO. Salvage therapy for Hodgkin’s lymphoma. Cancer J. 2009;15(2):161-163. 2. Sureda A, Constans M, Iriondo A, et al; The Grupo Español de Linfomas/Transplante Autólogo de Médula Osea (GEL/TAMO) Cooperative Group. Prognostic factors affecting long-term outcome after stem cell transplantation in Hodgkin’s lymphoma autografted after a first relapse. Ann Oncol. 2005;16(4):625-633. 3. Majhail NS, Weisdorf DJ, Defor TE, et al. Long-term results of autologous stem cell transplantation for primary refractory or relapsed Hodgkin’s lymphoma. Biol Blood Marrow Transplant. 2006;12(10):1065-1072. 4. Aleman BMP, van den Belt-Dusebout AW, Klokman WJ, Van’t Veer MB, Bartelink H, van Leeuwen FE. Long-term cause-specific mortality of patients treated for Hodgkin’s disease. J Clin Oncol. 2003;21(18):3431-3439. 5. Martinez C, Canals C, Alessandrino E, et al; Lymphoma Working Party of the EBMT. Relapse of Hodgkin’s lymphoma (HL) after autologous stem cell transplantation (ASCT): prognostic factors in 462 patients registered in the database of the EBMT. J Clin Oncol. 2010;28(15)(suppl):8060. Seattle Genetics and are US registered trademarks of Seattle Genetics, Inc. © 2011 Seattle Genetics, Inc., Bothell, WA 98021 All rights reserved BD Biosciences solutions for blood cell disorders Innovation is built in. The BD Biosciences track record of innovation in clinical flow cytometry spans more than 25 years. During that time, we’ve been delivering systems that are progressively more powerful, more dependable and easier to use. Today, the BD FACSCanto™ II system is one of the building blocks to support patient care for blood cell disorders. It delivers proven performance, reliability and ease of use in a benchtop analyzer. It can be configured with up to 3 lasers for support of up to 8 colors Class I (1) Laser Product. For Research Use Only. Not for use in diagnostic or therapeutic procedures. BD, BD Logo and all other trademarks are property of Becton, Dickinson and Company. © 2010 BD 23-12785-00 and is complemented by a full spectrum of BD conjugated antibody specificities including the BD Horizon™ V500 violet dyes that are optimized for use with the BD FACSCanto II. With innovation built in, you can depend on BD systems, software and reagents to make your job easier, your workflow more efficient and your results more reliable, today and tomorrow. Learn more about our solutions for blood cell disorders at bdbiosciences.com/go/canto. BD Biosciences 2350 Qume Drive San Jose, CA 95131 bdbiosciences.com Pursuing new options for patients through THE SCIENCE OF SELECTIVITY Clinical explorations of proteasome inhibition Onyx Pharmaceuticals is investigating new possibilities in the clinically validated strategy of proteasome inhibition. To learn more, please visit www.OnyxTrials.com. ©2011 Onyx Pharmaceuticals, Inc., South San Francisco, CA 1010-CARF-034-R2 July 2011 ilia emoph h in n ives tio e the l innova iv l ic e if l t p n o about elp pe er, scie xcited At Bay sion: H e is e m ’r e e l w ent. imp is why velopm h e d has a s ic h in W y tl hoose. hat curren they c d see w ments n t a a e h r c t ial es. resear potent nts’ liv ovative ie n t a in p r r o u o us f p in yo Look t develo s ie it un opport © 2010 Bayer HealthCare Pharmaceuticals Inc. All rights reserved. Bayer and the Bayer Cross are trademarks of Bayer. KN10000610 hilia hemop in n io lives vat ive the l ic inno e if l t p n o ie e er, sc Help p At Bay ission: m e l p im ial has a s potent . t e u s o o b o a h ding they c excited t, inclu n e e ’r e m p w develo is why cting Which long-a ently in r e r u id c v o s velop pr ent who de ins, to e s treatm t t o n r p ie t binant eat pa recom d to tr n a y p a her e what r FIX. rFVIII t and se FVIII o h o t c r s a r e o s ’ lives. inhibit tive re atients innova p r r o f u s o ou lop in y Look t s deve ie it n u opport © 2010 Bayer Schering Pharma AG. All rights reserved. Bayer and the Bayer Cross are trademarks of Bayer. G.PH.SM.Hem.2010-08-03.0180 How do you get double the exposure for the same price? Your classified advertisement in Blood gives you more exposure than you think. When you place a print advertisement, you will also receive a free 30-day* posting on the American Society of Hematology’s online Job Bank. This employment resource is located at www.hematology.org and is free for all job seekers. For more information on submitting a classified ad in Blood, contact Valerie Marvin at [email protected] or at 201-767-4170. CHRONIC LYMPHOCYTIC LEUKEMIA FOUNDATION The Chronic Lymphocytic Leukemia Foundation is soliciting applications for one or more $50,000 grants. The grants will act as seed money for innovative translational and/or clinical research for the treatment of CLL. Applications must not exceed five pages, excluding curriculum vitae and bibliography (NIH format). The application must include an Abstract; Specific Aims; Background and Significance; Preliminary Data; Experimental Design and Anticipated Results. The deadline for submission is October 1, 2011. Applications should be mailed to The CLL Foundation 1001 Fannin, Suite 1800, Houston, TX 77002 For additional information call 713.651.2964. *Your 30-day online posting will start when your print advertisement first appears in Blood. Free Blood PDA Downloads and How to Use Them What are PDA downloads? Blood PDA downloads are summaries of the latest Blood content sent directly to your Palm PDA or PocketPC PDA. The summaries consist of tables of contents, article abstracts, and full-text Inside Blood commentaries. Why use PDA downloads? Use Blood PDA downloads if it is more convenient to review the latest Blood content on your PDA than on your computer. Full text of articles can be read on Blood Online or in print. What are the requirements for PDA downloads? Blood PDA downloads work with the Palm operating system and the PocketPC 2002 operating system. They require a Macintosh or Windows computer with which you sync your PDA. You must register with HighWire Press (a free service), and you must download a small piece of software to your PDA via your desktop computer with which you sync your PDA. How do I set up my PDA? Once you have registered with HighWire Press, follow the instructions to download the HW View software. Then sync your PDA with your desktop computer to download your Blood content. How do I get future content? You must sync your PDA with your desktop computer each time you want the latest Blood content summaries. Then the summaries are on your PDA for your use away from your computer. Hematologists Everywhere ÊÌ iÊworld’s largest professional societyÊVViÀi`ÊÊ ÜÌ ÊÌ iÊcauses and treatment of blood disorders! Exclusive ASH member benefits include: UÊÊÊDiscounted registration for all ASH meetings]ÊVÕ`}ÊÌ iÊ>Õ>ÊiiÌ}]ÊÊ } } ÌÃÊvÊ-®]Ê>`Ê-Ì>ÌivÌ iÀÌÊ-Þ«ÃÕ UÊÊÊVViÃÃÊÌÊ>Õ>ÊiiÌ}Êearly-bird registrationÊ>`Êexclusive members-only hotelsÊÊ UÊÊÊÊ`Û>Vi`Ê>}ÃÊvÊÌ iÊ>Õ>ÊiiÌ}Ê«Ài>ÀÞÊ«À}À> UÊÊÊ «iÌ>ÀÞÊÃÕLÃVÀ«ÌÃÊÌÊÌ iÊ«ÀiiÀÊ i>Ì}ÞÊÕÀ>]ÊÊ Blood,Ê>`Ê>Ü>À`Ü}ÊiÜÃiÌÌiÀ] The Hematologist: ASH News and Reports UÊÊÊ1«`>ÌiÃÊÊÌ iÊ>ÌiÃÌÊdevelopments in the fieldÊÌ ÀÕ} ÊiiÜÃiÌÌiÀÃÊ UÊÊÊÃVÕÌÃÊÊi`ÕV>Ì>Ê«À`ÕVÌÃ]ÊÃÕV Ê>ÃÊÌ iÊASH Self-Assessment Program (ASH-SAP) UÊÊÊ`ÛV>VÞÊ>`ÊÀi«ÀiÃiÌ>ÌÊLivÀiÊÌ iÊ1°-°Ê }ÀiÃÃÊ>`ÊÌ iÀÊÊ }ÛiÀiÌÊ>}iViÃÊÌÊ«ÀÌiÊÌ iÊÌiÀiÃÌÃÊvÊ i>Ì}ÞÊÀiÃi>ÀV iÀÃÊÊ >`ÊVV>à UÊÊÊConsult a Colleague]Ê>ÊiÊÃiÀÛViÊvÀÊ-ÊiLiÀÃÊÌ >ÌÊ i«ÃÊv>VÌ>ÌiÊÊ Ì iÊiÝV >}iÊvÊvÀ>ÌÊLiÌÜiiÊ i>Ì}ÃÌÃÊ>`ÊÌ iÀÊ«iiÀà Don’t miss out; become an ASH member today! www.hematology.org/membership AMERICAN SOCIETY of HEMATOLOGY ® 53rd ASH Annual Meeting and Exposition December 10-13, 2011 U San Diego Convention Center U San Diego, CA 2011 Call for Annual Meeting Abstracts Don’t miss the chance to present your findings at ASH’s Annual Meeting! Presentation of cutting-edge scientific research is an essential part of the Society’s annual meeting, offering opportunities for investigators to share important data with their colleagues to help put research into action. All abstracts must be submitted electronically by Thursday, August 11, at 11:59 p.m. (Pacific Time). Visit the “Abstracts” section of the annual meeting page for complete details on the abstract submission and review process. Submit your abstract today! www.hematology.org/annualmeeting ' $ ( 5 ( % ) 2 /2 7 V Q U X W H 7&/5 3 Q H K : + 7 , : Important Safety Information Warnings and Precautions FOLOTYN may suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and anemia. Monitor blood counts and omit or modify dose for hematologic toxicities. Mucositis may occur. If ≥Grade 2 mucositis is observed, omit or modify dose. Patients should be instructed to take folic acid and receive vitamin B12 to potentially reduce treatment-related hematological toxicity and mucositis. H W D [ H U SUDODW Fatal dermatologic reactions may occur. Dermatologic reactions may be progressive and increase in severity with further treatment. Patients with dermatologic reactions should be monitored closely, and if severe, FOLOTYN should be withheld or discontinued. Tumor lysis syndrome may occur. Monitor patients and treat if needed. FOLOTYN can cause fetal harm. Women should avoid becoming pregnant while being treated with FOLOTYN and pregnant women should be informed of the potential harm to the fetus. Use caution and monitor patients when administering FOLOTYN to patients with moderate to severe renal function impairment. Elevated liver function test abnormalities may occur and require monitoring. If liver function test abnormalities are ≥Grade 3, omit or modify dose. 11080 CirclePoint Road, Suite 200 Westminster, CO 80020 www.allos.com ©2011 Allos Therapeutics, Inc. 5/11 Printed in USA FOL-1183-11 Please see accompanying brief s FOLOTYN is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. The indication for FOLOTYN is based on overall response rate. Clinical benefit such as improvement in progression-free survival or overall survival has not been demonstrated. Demonstrated response in relapsed or refractory PTCL1 < '7 <1 2H LQMHFWLRQ f Adverse Reactions The most common adverse reactions were mucositis (70%), thrombocytopenia (41%), nausea (40%), and fatigue (36%). The most common serious adverse events were pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. Use in Specific Patient Populations Nursing mothers should be advised to discontinue nursing or the drug, taking into consideration the importance of the drug to the mother. Drug Interactions Co-administration of drugs subject to renal clearance (e.g., probenecid, NSAIDs, and trimethoprim/ sulfamethoxazole) may result in delayed renal clearance. RYHUDOO UHVSRQVHUDWH &5&5X35 E\LQGHSHQGHQWFHQWUDOUHYLHZ&,² 2IWKHUHVSRQGHUV UHVSRQGHGZLWKLQ&\FOH ³0HGLDQWLPHWRÀUVWUHVSRQVH ZDVGD\VUDQJH ²GD\V PRQWK PHGLDQGXUDWLRQRIUHVSRQVHE\ FHQWUDOUHYLHZUDQJH ²GD\V ³&,²RISDWLHQWVKDGUHVSRQVHV ODVWLQJZHHNVUDQJH ²GD\V 'HPRQVWUDWHGUHVSRQVHLQ 3523(/³ WKHÀUVWODUJHSURVSHFWLYHVLQJOHDUP RSHQODEHOFOLQLFDOWULDOLQ37&/ Reference: 1. FOLOTYN Prescribing Information. Allos Therapeutics, Inc., 2011. Please see FOLOTYN Full Prescribing Information. *Per independent central review summary of Prescribing Information. www.FOLOTYN.com Brief summary of Full Prescribing Information for FOLOTYN® (pralatrexate injection)—Please consult Full Prescribing Information. N=111 Total INDICATIONS AND USAGE FOLOTYN is indicated for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). This indication is based on overall response rate. Clinical benefit such as improvement in progression-free survival or overall survival has not been demonstrated. WARNINGS AND PRECAUTIONS Bone Marrow Suppression FOLOTYN can suppress bone marrow function, manifested by thrombocytopenia, neutropenia, and anemia. Dose modifications are based on ANC and platelet count prior to each dose. Mucositis Treatment with FOLOTYN may cause mucositis. If ≥Grade 2 mucositis is observed, omit dose and follow guidelines in Table 1. Dermatologic Reactions FOLOTYN has been associated with severe dermatologic reactions, which may result in death. These dermatologic reactions have been reported in clinical studies (14/663 patients [2.1%]) and post marketing experience, and have included skin exfoliation, ulceration, and toxic epidermal necrolysis (TEN). These reactions may be progressive and increase in severity with further treatment, and may involve skin and subcutaneous sites of known lymphoma. Patients with dermatologic reactions should be monitored closely, and if severe, FOLOTYN should be withheld or discontinued. Tumor Lysis Syndrome Tumor lysis syndrome has been reported in patients with lymphoma receiving FOLOTYN. Patients receiving FOLOTYN should be monitored closely and treated for complications. Folic Acid and Vitamin B12 Supplementation Patients should be instructed to take folic acid and receive vitamin B12 to potentially reduce treatment-related hematological toxicity and mucositis. Pregnancy Category D FOLOTYN can cause fetal harm when administered to a pregnant woman. FOLOTYN was embryotoxic and fetotoxic in rats and rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Decreased Renal Function Although FOLOTYN has not been formally tested in patients with renal impairment, caution is advised when administering FOLOTYN to patients with moderate to severe impairment. Monitor patients for renal function and systemic toxicity due to increased drug exposure. Elevated Liver Enzymes Liver function test abnormalities have been observed after FOLOTYN administration. Persistent liver function test abnormalities may be indicators of liver toxicity and require dose modification. Monitor patients for liver function. ADVERSE REACTIONS The most common adverse reactions observed in patients with peripheral t-cell lymphoma (PTCL) treated with FOLOTYN were mucositis, thrombocytopenia, nausea, and fatigue. Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. The safety of FOLOTYN was evaluated in 111 PTCL patients in a single-arm clinical study in which patients received a starting dose of 30 mg/m2 once weekly for 6 weeks in 7-week cycles. The median duration of treatment was 70 days (range 1-540 days). Most Frequent Adverse Reactions Table 4 summarizes the most frequent adverse reactions, regardless of causality, using the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, version 3.0). Table 4 Adverse Reactions Occurring in PTCL Patients (Incidence ≥10% of patients) N=111 Total Preferred Term Grade 3 Grade 4 N % N % N % Any Adverse Event 111 100 48 43 34 31 Mucositisa 78 70 19 17 4 4 Thrombocytopeniab 45 41 15 14 21 19b Nausea 44 40 4 4 0 0 Fatigue 40 36 5 5 2 2 Anemia 38 34 17 15 2 2 Constipation 37 33 0 0 0 0 Pyrexia 36 32 1 1 1 1 Edema 33 30 1 1 0 0 Cough 31 28 1 1 0 0 Epistaxis 29 26 0 0 0 0 Vomiting 28 25 2 2 0 0 Neutropenia 27 24 14 13 8 7 Diarrhea 23 21 2 2 0 0 Dyspnea 21 19 8 7 0 0 Anorexia 17 15 3 3 0 0 a b c Grade 3 Grade 4 Preferred Term N % N % N Hypokalemia 17 15 4 4 1 % 1 Rash 17 15 0 0 0 0 Pruritus 16 14 2 2 0 0 Pharyngolaryngeal pain 15 14 1 1 0 0 Liver function test abnormalc 14 13 6 5 0 0 Abdominal pain 13 12 4 4 0 0 Pain in extremity 13 12 0 0 0 0 Back pain 12 11 3 3 0 0 Leukopenia 12 11 3 3 4 4 Night sweats 12 11 0 0 0 0 Asthenia 11 10 1 1 0 0 Tachycardia 11 10 0 0 0 0 Upper respiratory tract infection 11 10 1 1 0 0 Stomatitis or mucosal inflammation of the gastrointestinal and genitourinary tracts Five patients with platelets <10,000/µL Alanine aminotransferase, aspartate aminotransferase, and transaminases increased Serious Adverse Events Forty-four percent of patients (n=49) experienced a serious adverse event while on study or within 30 days after their last dose of FOLOTYN. The most common serious adverse events (>3%), regardless of causality, were pyrexia, mucositis, sepsis, febrile neutropenia, dehydration, dyspnea, and thrombocytopenia. One death from cardiopulmonary arrest in a patient with mucositis and febrile neutropenia was reported in this trial. Deaths from mucositis, febrile neutropenia, sepsis, and pancytopenia occurred in 1.2% of patients treated on all FOLOTYN trials at doses ranging from 30 to 325 mg/m2. Discontinuations Twenty-three percent of patients (n=25) discontinued treatment with FOLOTYN due to adverse reactions. The adverse reactions reported most frequently as the reason for discontinuation of treatment were mucositis (6%, n=7) and thrombocytopenia (5%, n=5). Dose Modifications The target dose of FOLOTYN was 30 mg/m2 once weekly for 6 weeks in 7-week cycles. The majority of patients (69%, n=77) remained at the target dose for the duration of treatment. Overall, 85% of scheduled doses were administered. Post Marketing Experience Toxic epidermal necrolysis has been identified during post approval use of FOLOTYN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure (see Warnings and Precautions). DRUG INTERACTIONS In vitro studies indicate that pralatrexate is not a substrate, inhibitor, or inducer of CYP450 isoenzymes and has low potential for drug-drug interactions at CYP450 isoenzymes. No formal clinical assessments of pharmacokinetic drug-drug interactions between FOLOTYN and other drugs have been conducted. The effect of co-administration of the uricosuric drug probenecid on pralatrexate pharmacokinetics was investigated in a Phase 1 clinical study. Co-administration of increasing doses of probenecid resulted in delayed clearance of pralatrexate and a commensurate increase in exposure. Due to the contribution of renal excretion (approximately 34%) to the overall clearance of pralatrexate, concomitant administration of drugs that are subject to substantial renal clearance (eg, NSAIDs, trimethoprim/sulfamethoxazole) may result in delayed clearance of pralatrexate. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D (see Warnings and Precautions). FOLOTYN can cause fetal harm when administered to a pregnant woman. Pralatrexate was embryotoxic and fetotoxic in rats at IV doses of 0.06 mg/kg/ day (0.36 mg/m2/day or about 1.2% of the clinical dose on a mg/m2 basis) given on gestation days 7 through 20. Treatment with pralatrexate caused a dose-dependent decrease in fetal viability manifested as an increase in late, early, and total resorptions. There was also a dose-dependent increase in post-implantation loss. In rabbits, IV doses of 0.03 mg/kg/day (0.36 mg/ m2/day) or greater given on gestation days 8 through 21 also caused abortion and fetal lethality. This toxicity manifested as early and total resorptions, post-implantation loss, and a decrease in the total number of live fetuses. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Nursing Mothers It is not known whether pralatrexate is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from this drug, a decision should be made whether to discontinue nursing or to discontinue FOLOTYN, taking into account the importance of FOLOTYN to the mother. Pediatric Use Pediatric patients were not included in clinical studies with FOLOTYN. The safety and effectiveness of FOLOTYN in pediatric patients have not been established. Geriatric Use In the PTCL efficacy study, 36% of patients (n=40) were 65 years of age and over. No overall differences in efficacy and safety were observed in patients based on age (<65 years compared with ≥65 years). No dosage adjustment is required in elderly patients with normal renal function. Hepatic Impairment Formal studies have not been performed with FOLOTYN in patients with hepatic impairment. Patients with the following laboratory values were excluded from the pralatrexate lymphoma clinical trials: total bilirubin >1.5 mg/dL; aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 × upper limit of normal (ULN); and AST or ALT >5 × ULN if documented hepatic involvement with lymphoma. Renal Impairment See Warnings and Precautions. OVERDOSAGE No specific information is available on the treatment of overdosage of FOLOTYN. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. Based on FOLOTYN’S mechanism of action the prompt administration of leucovorin should be considered. PATIENT COUNSELING INFORMATION See FDA-approved Patient Package Insert. Patients should be instructed to read the Patient Package Insert carefully. DOSAGE AND ADMINISTRATION FOLOTYN should be administered under the supervision of a qualified physician experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. Peripheral T-cell Lymphoma The recommended dose of FOLOTYN is 30 mg/m2 administered as an intravenous (IV) push over 3-5 minutes via the side port of a free-flowing 0.9% Sodium Chloride Injection, USP IV line once weekly for 6 weeks in 7-week cycles until progressive disease or unacceptable toxicity. Vitamin Supplementation Patients should take low-dose (1.0-1.25 mg) oral folic acid on a daily basis. Folic acid should be initiated during the 10-day period preceding the first dose of FOLOTYN, and dosing should continue during the full course of therapy and for 30 days after the last dose of FOLOTYN. Patients should also receive a vitamin B12 (1 mg) intramuscular injection no more than 10 weeks prior to the first dose of FOLOTYN and every 8-10 weeks thereafter. Subsequent vitamin B12 injections may be given the same day as treatment with FOLOTYN (see Warnings and Precautions). Monitoring and Dose Modifications Management of severe or intolerable adverse reactions may require dose omission, reduction, or interruption of FOLOTYN therapy. Monitoring Complete blood cell counts and severity of mucositis should be monitored weekly. Serum chemistry tests, including renal and hepatic function, should be performed prior to the start of the first and fourth dose of a given cycle. Dose Modification Recommendations Prior to administering any dose of FOLOTYN: • Mucositis should be ≤Grade 1. • Platelet count should be ≥100,000/µL for first dose and ≥50,000/µL for all subsequent doses. • Absolute neutrophil count (ANC) should be ≥1,000/µL. Doses may be omitted or reduced based on patient tolerance. Omitted doses will not be made up at the end of the cycle; once a dose reduction occurs for toxicity, do not re-escalate. For dose modifications and omissions, use the guidelines in Tables 1, 2, and 3. Table 1 FOLOTYN Dose Modifications for Mucositis a Mucositis Gradea on Day of Treatment Action Dose upon Recovery to ≤Grade 1 Grade 2 Omit dose Continue prior dose Grade 2 recurrence Omit dose 20 mg/m2 Grade 3 Omit dose 20 mg/m2 Grade 4 Stop therapy Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0) Table 2 FOLOTYN Dose Modifications for Hematologic Toxicities Blood Count on Day of Treatment Platelet <50,000/µL Duration of Toxicity 1 week Action Omit dose Dose upon Restart Continue prior dose 2 weeks Omit dose 20 mg/m2 3 weeks Stop therapy ANC 500-1,000/µL 1 week and no fever 1 week ANC 500-1,000/µL with fever 2 weeks or or recurrence ANC <500/µL 3 weeks or 2nd recurrence Omit dose Continue prior dose Omit dose, give G-CSF or GM-CSF support Omit dose, give G-CSF or GM-CSF support Continue prior dose with G-CSF or GM-CSF support 20 mg/m2 with G-CSF or GM-CSF support Stop therapy Table 3 FOLOTYN Dose Modifications for All Other Treatment-related Toxicities a Toxicity Gradea on Day of Treatment Action Dose upon Recovery to ≤Grade 2 Grade 3 Omit dose 20 mg/m2 Grade 4 Stop therapy Per National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI CTCAE, Version 3.0) Manufactured for: Allos Therapeutics, Inc. Westminster, CO 80020 1-888-ALLOS88 (1-888-255-6788) FOLOTYN, ALLOS, and the mobius triangle symbol are all registered trademarks of Allos Therapeutics, Inc. U.S. Patent: 6,028,071 and 7,622,470 Rev.3: January 2011 © 2011 Allos Therapeutics, Inc. All rights reserved. ® makes all the difference With CancerCare, the difference comes from: • Professional oncology social workers • Free counseling • Education and practical help • Up-to-date information • CancerCare for Kids® For needs that go beyond medical care, refer your patients and their loved ones to CancerCare. CancerCare’s free services help people cope with the emotional and practical concerns arising from a cancer diagnosis and are integral to the standard of care for all cancer patients, as recommended by the Institute of Medicine. Help and Hope 1-800-813-HOPE (4673) www.cancercare.org Author guide Blood, the Journal of the American Society of Hematology, published online and in print, provides an international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology. Acceptance of manuscripts is based on the originality and importance of the observations or investigations, the quality of the work and validity of the evidence, the clarity of presentation, and the relevance to our readership and field. Membership in the American Society of Hematology is not required for submission. All articles are expected to be concise, well organized and clearly written. Authors submit a manuscript with the understanding that the manuscript (or its essential substance) has not been published other than as an abstract in any language or format and is not currently submitted elsewhere for print or electronic publication. Blood receives over 5,000 online submissions per year and accepts about 25% of them after a thorough and impartial peer review. Accepted papers are published ahead of print as First Edition papers. The average time to first decision is 21.3 days. The average time from acceptance to publication is 7 weeks. Non-English-speaking authors are encouraged to visit the Authors Guide online at http:// bloodjournal.hematologylibrary.org/authors/authorguide.dtl to view links to professional editing services that may help improve the presentation of the paper. 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Primary research articles will be published under the following scientific categories: Clinical Trials and Observations; Gene Therapy; Hematopoiesis and Stem Cells; Immunobiology; Myeloid Neoplasia; Lymphoid Neoplasia; Phagocytes, Granulocytes and Myelopoiesis; Platelets and Thrombopoiesis; Red Cells, Iron and Erythropoiesis; Thrombosis and Hemostasis; Transfusion Medicine; Transplantation; and Vascular Biology. Authors are invited to contact the Editor-in-Chief (bloodeditor@ hematology.org) prior to submission if they are uncertain whether their work falls within the general scope. Immunobiology encompasses a wide spectrum of research, but Blood can accommodate only papers that have clear and important implications for hematology. Preference is given to papers focusing on human immunobiology and which have significant implications for understanding of normal or malignant hematologic processes. Papers on tumor immunology and tumor vaccine development may be appropriate if the target cells are hematologic malignancies, but Blood can no longer accommodate tumor immunology papers that focus solely on nonhematologic tumor models. Papers focusing on autoimmunity and utilizing nonhematologic models are not within the scope of Blood. Papers on the immune response to specific microbioBLOOD, 18 AUGUST 2011 䡠 VOLUME 118, NUMBER 7 logic pathogens are also generally outside the scope of Blood, except those focusing on the direct links of Epstein-Barr virus, hepatitis virus, or HTLV to hematologic malignancies. These and other papers felt to be outside the scope of Blood and more appropriate for an immunology, infectious diseases, or tumor immunology Journal will be returned to the author without full peer review. Regular Articles. Maximum length for a Regular Article is 5,000 words of text, not counting the abstract, tables, figure legends, and references; abstracts must not exceed 200 words and should be constructed as a single narrative paragraph with no subheadings or references. Submissions are limited to a total of 7 figures and digital images are required. There is no limit on the number of tables. References should be limited to 50. The sections of a Regular Article should be ordered Abstract, Introduction, Methods, Results, Discussion, Acknowledgments, Authorship Contributions and Disclosure of Conflicts of Interest, References, Tables, Figure Legends, and Figures. Supplemental files to be published online-only may include additional information regarding methodology, supplemental figures or tables, or primary data sets. Any involvement of medical writers/ researchers, particularly those employed or supported by the pharmaceutical industry, in the writing of an article must be clearly defined and disclosed in the Authorship and/or the Acknowledgments section as appropriate. This type of involvement must also be disclosed to the Editor-in-Chief in the cover letter. Definitive original research articles of exceptional scientific importance may be considered for designation as Plenary Papers. The decision to highlight an article as a Plenary Paper rests entirely with the Editors. Brief Reports. Short manuscripts definitively documenting either experimental results or informative clinical observations will be considered for publication in this category. Single-case reports or case series can almost never be accommodated, unless they elucidate novel and important disease biology or approaches to therapy. Brief Reports are not intended to allow publication of incomplete or preliminary findings. The review process is equally rigorous as for Regular Articles and the acceptance rate is lower. Brief Reports may not exceed 1,200 words of text not counting the abstract, figure legends, and references; abstracts must not exceed 150 words and should be a single paragraph with no subheadings. Only 2 figures/tables and 25 references may be included. The sections of a Brief Report should be ordered Abstract, Introduction, Methods sufficiently informative to allow reproduction of the data, followed by a combined Results and Discussion section, Acknowledgments, Authorship Contributions and Disclosure of Conflicts of Interest, References, Tables, Figure Legends, and Figures. e-Blood. e-Blood is a new manuscript category for publication of very well designed systems biology work (e.g., genomics, proteomics etc.) that is largely descriptive. Such work will be published as an online-only paper if utilization of the data by others will significantly advance the field. e-Blood articles will be fully citable, and will represent genuine Blood publication. They will undergo standard rigorous peer review if deemed potentially appropriate for publication by Blood Editors. Accepted e-Blood articles will be published in First Edition and then copyedited and composed identical to other Blood papers, but will not be included in a print edition of the Journal, although they will be listed in a printed Table of Contents when their final typeset version is available online. Papers may be submitted by authors directly for consideration as e-Blood articles, or may be recommended by Editors for publication as an e-Blood article after being considered for publication as a Regular Article, if deemed more appropriate for the e-Blood article type. 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Review Articles should focus on recent scientific or clinical advances in an area of broad interest to those in the field of hematology. Such articles must be concise and critical and should include appropriate references to the literature. All Review Articles, even those solicited by the Editors, are rigorously peer reviewed before a final publication decision is made. Review Articles should not exceed 5,000 words in length, must include an abstract of 200 words or fewer, and may not have more than 100 references. The use of tables and color figures to summarize critical points is encouraged; the Journal offers assistance with preparation or improvement of figures by professional illustrators, once the article is accepted. Any involvement of medical writers/researchers, particularly those employed or supported by the pharmaceutical industry, in the writing of a Review Article must be clearly defined and disclosed in the Authorship section. 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The length should not exceed 5,000 words; the abstract must not exceed 200 words; and references are limited to 100. Any involvement of medical writers/researchers, particularly those employed or supported by the pharmaceutical industry, in the writing of an article must be clearly defined and disclosed in the Authorship section. For How I Treat articles, this type of involvement must be discussed with the Editor-in-Chief before the submission of the article. Generally, involvement of medical writers/researchers supported by the pharmaceutical industry is not acceptable for How I Treat articles published in Blood. Perspectives. Perspectives are articles discussing significant topics and controversies relevant to hematology, generally from a more personal or opinion-based standpoint than a Review Article. Interested authors should correspond with the Editor-in-Chief prior to submission to discuss the suitability of the proposed subject matter. The length should not exceed 5,000 words; the abstract must not exceed 200 words; and references are limited to 100. Typically, xxii Perspectives should state the topic and background information concisely, discuss opposing viewpoints, and make recommendations for further investigations or actions. Inside Blood. The Editors invite experts in the field to write brief commentaries introducing and placing into context several selected primary research articles included in each issue of Blood. Plenary Papers. Definitive original research articles of exceptional scientific importance may be considered for designation as Plenary Papers. The decision to highlight an article as a Plenary Paper rests entirely with the Editors. Data Supplements. The Journal encourages the submission of Data Supplements linked to primary research articles, including videos and short movies, that enhance the understanding of the science discussed in the manuscript. Data Supplements must be submitted for peer review during the initial submission of the manuscript. The Editors will review the supplemental material along with the manuscript, but acceptance of the manuscript does not guarantee ultimate acceptance of the supplement. Blood Work. Blood welcomes submissions of photo micrographs and brief case descriptions to serve as a regular teaching feature and comprehensive reference accessible to physicians and hematology students around the world. These images and cases are published by the Journal monthly in the Blood Work section, in the first issue of each month. Each submission must contain a single, or at most two related, high-resolution figure(s) formatted as TIFFs (minimum 300 dpi) and a discussion of no more than 200 words describing the clinical case linked to the image(s). Generally each piece should have a single or very few authors and no references. If your submission is accepted, your figure(s) will also be submitted for consideration to the ASH Image Bank. All other policies governing submissions to the Journal also apply to Blood Work. There will be no submission fee and no color figure charges for publication if accepted. Letters to the Editor. Constructive comments on published articles or on current topics in hematology are welcome and will be published if appropriate and based on priority and interest to readership. Letters should include no more than 500 words of text, 5–10 references, and 1 figure or table. No abstract is required, but please include a brief title. Submission fees and page charges do not apply to Letters. Letters are screened by the Editor-in-Chief and, if deemed appropriate and relevant, may also be peer reviewed and/or accompanied by a Response from the authors of the initial article. Public Access. The American Society of Hematology supports free access to Blood on the broadest possible basis, although ASH and Blood cannot adopt or support a publishing model that is not economically sustainable over a long horizon. Blood maintains a 12-month access embargo to non-subscribers while offering an inexpensive pay-per-view option; however, online content older than 12 months is free to all. Also, significant sections of each new issue are immediately free-to-all online, including abstracts and tables of contents, Inside Blood commentaries, How I Treat articles, and 5 clinically relevant research articles or Review Articles per issue selected by the Editor-in-Chief. In addition, Blood ensures that patients looking for pertinent information can access any article without charge by contacting the Journal. Any author (including, but not limited to, those supported by the Howard Hughes Medical Institute or Wellcome Trust) wishing immediate public access for their accepted paper may pay an additional Public Access manuscript fee of $2,000. Upon receipt of payment, Blood will also deposit on behalf of the author the final edition of the published paper into PubMed Central. This fee does not apply to research funded by the National Institutes of Health. BLOOD, 18 AUGUST 2011 䡠 VOLUME 118, NUMBER 7 Check out ASH’s VIDEO LIBRARY for Useful Teaching Tools ASH offers a number of FREE videos that are perfect for students. ASH’s video library includes films on a variety of topics including: Cancer Cells vs. Healthy Cells Hereditary Spherocytosis How Lymphoma Develops How a Clot Becomes a Pulmonary Embolism The Components of Blood The Problem With Sickled Cells The Role of Proteins in Blood Clotting The Role of Red Blood Cells in Anemia Von Willebrand Factor and ADAMTS13 Additionally, this library includes short videos about patients dealing with various hematologic disorders, excerpted from the film “Blood Detectives.” 1772 BLOOD, 18 AUGUST 2011 䡠 VOLUME 118, NUMBER 7 SEKULOVIC et al Tert⫺/⫺ HSCs in the absence of an additional stimulation of HSC self-renewal divisions. The absence of telomere loss by serially transplanted Tert⫺/⫺ HSCs may be explained by the possible existence of telomerelength-independent barriers, alternative mechanisms for lengthening telomeres in dividing HSCs, and insufficient HSC turnover afterwhole bm transplantation. HSC replicative potential may be limited by more than just the length of their telomeres, as the expression of the catalytic component of telomerase was eventually able to prevent telomere shortening in HSCs subjected to more proliferation than that stimulated by 3 serial transplant cycles, but was not sufficient to sustain their transplant capacity.18 Thus, it cannot be excluded that HSC telomeres may stay long because of a telomerase-independent mechanism active in HSCs. Telomeric DNA may also be generated through recombination events, a mechanism known as alternative lengthening of telomeres (ALT)36 and shown to occur in embryonic stem cells and during early development.37 Recombination-based telomere elongation has also been identified in human tumors, immortalized human cell lines, telomerase-null mouse cell lines and late generation telomerasenull mice,38-40 and possibly occurs in other stem cells of Mus musculus (with, on average, very long telomeres) as well. Finally, it was recently shown that HSCs with the highest self-renewal capacity are maintained in a dormant state with their stem cell potential being subject to reversible activation on injury.41 Accordingly, it might be anticipated that the regeneration of hematopoiesis that is stimulated to occur in transplanted irradiated mice would involve a rapid induction and short-lived induction of HSC turnover, insufficient to affect their telomere length. Another explanation for the absence of detectable telomere shortening in WT HSCs in spite of their extensively stimulatation to self-renew is a potential up-regulation of endogenous telomerase levels by genes active in HSCs, in line with recent reports demonstrating telomere maintenance and elongation in induced pluripotent stem (iPS) cells.42 In the current study, we detected no significant difference in the telomere length in the progeny of GFP- and NA10hdtransduced WT BM cells cultured for up to 16-days after transduction (total of 20 days in culture) or transplanted immediately after transduction into primary recipients. Moreover, preliminary affymetrix expression analysis showed no difference in telomerase expression of nontransduced (fresh) and NUP98-HOXA10hdtransduced highly purified HSCs43 (data not shown). Thus our data argue that NA10hd does not trigger up-regulation of endogenous telomerase levels in HSCs. The fact that our findings are in disagreement with previous studies may also be explained in part by differences in the study designs and methodologies used for telomere length measurements. Allsopp et al used Q-FISH to measure telomere lengths in LSK cells and Southern blot analysis for whole BM cells; whereas, we inferred effects on HSCs from measurements applied to their granulocyte progeny and used flow-FISH for average telomere length measurements at the single cell level. Q-FISH requires cells to be stimulated in culture, arrested in metaphase and mounted onto slides44 to enable telomere lengths of individual chromosomes to be made on a limited number of cells. Accordingly, it is less quantitative than Flow-FISH. The more precise measurements possible with Flow-FISH indicate that self-renewal stress imposed by serial transplantation even in the presence of stimulation by NA10hd and in the absence of Tert does not result in significant telomere length erosion. Nevertheless, highly significant telomere length reduction (⬃ 10 kb) was apparent in the absence of Tert after the forced stimulation of prolonged self-renewal divisions in vitro and in vivo. Consistent with the previous data, we did not observe any difference in the frequency or competitive regenerative activity of WT and early (first) generation Tert⫺/⫺ HSCs. However, we noted levels of ␥-H2AX expression in the LSK population of later (second) generation Tert⫺/⫺ BM cells, as well as after extensive self-renewal induced by stimulating primitive NA10hd-transduced Tert⫺/⫺ hematopoietic cell proliferation. Interestingly, this occurred in cells that also showed an acquired deficiency in reconstituting ability post transplantation and self-renewal ability in vitro. Indeed, the appearance of this evidence of accumulating DNA damage in primitive Tert⫺/⫺ hematopoietic cells paralleled their reduced functional activity. Similar consequences of DNA damage accumulating in late generation aging Tert⫺/⫺ as well as WT HSCs has also been reported.25 Recent evidence showing that TERT protein can have a physiologic role independent of its canonical function in maintaining telomere homeostasis, suggests a broader involvement in the control of cellular transformation, proliferation, stem cell biology, survival and chromatin regulation.27-29,45-49 Furthermore, along with recent findings of others,27-29 we showed that telomerase may function as a regulator of the HSC self-renewal process, as our results revealed significant (⬃ 7-fold) decrease in capacity of Tert⫺/⫺ HSCs to expand in vitro in response to NA10hd stimulation, relative to their WT counterparts. However, it is important to note the lack of deleterious effects seen on the greatly expanded WT HSC populations generated in the presence of intracellular NA10hd in relatively short term (6-day) cultures. This included lack of effects on both telomere homeostasis and overall genomic integrity. Although the current findings cannot be safely extrapolated to human HSCs, as inbred mice possess significantly longer telomeres than humans,50 they do serve to underscore the importance of elucidating the mechanisms linking the 2 roles of telomerase, in telomere maintenance and in preserving HSC function, which are likely to be relevant to the rational development of strategies for the effective treatment of many patients with BM failure syndromes (ie, dyskeratosis congenita and/or aplastic anemia) or conversely with leukemia where this link may be uncoupled. Acknowledgments The authors acknowledge the expert technical assistance of Patty Rosten, Courteney Lai, members of the flow core of the Terry Fox Laboratory, Andy Johnson of the UBC shared FACS facility and staff of the animal facilities of the Biomedical Research Center and British Columbia Cancer Agency Research Center. The authors thank Lea Harrington for providing the Tert⫺/⫺ mouse strain. This work was supported by funds from a Canadian Institutes of Health Research (CIHR) Team Grant in Stem Cell Expansion; a CIHR Team Grant in Bone Marrow; CIHR operating grant MOP82382; National Institutes of Health grant HL065430; the Canadian Stem Cell Network; and the group grant from the Terry Fox Foundation. Work in the laboratory of P.M.L. is supported by grants from CIHR (MOP38075 and GMH79042). Authorship Contribution: S.S. and V.G. designed and performed the research and analyzed the data; I.V. performed and analyzed flow-FISH ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method] Brief Summary of Prescribing Information: Please see package insert for full prescribing information. INDICATIONS AND USAGE Clinical Trial Experience Control and Prevention of Bleeding Episodes Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in clinical practice. ADVATE is an antihemophilic factor (recombinant) indicated for control and prevention of bleeding episodes in adults and children with hemophilia A. Perioperative Management ADVATE is indicated in the perioperative management in adults and children with hemophilia A. ADVATE is not indicated for the treatment of von Willebrand’s disease. CONTRAINDICATIONS Known anaphylaxis to mouse or hamster protein or other constituents of the product. WARNINGS AND PRECAUTIONS General The clinical response to ADVATE may vary. If bleeding is not controlled with the recommended dose, the plasma level of factor VIII should be determined and a sufficient dose of ADVATE should be administered to achieve a satisfactory clinical response. If the patient’s plasma factor VIII level fails to increase as expected or if bleeding is not controlled after the expected dose, the presence of an inhibitor (neutralizing antibodies) should be suspected and appropriate testing performed. Anaphylaxis and Hypersensitivity Reactions Allergic-type hypersensitivity reactions, including anaphylaxis, are possible and have been reported with ADVATE. Symptoms have manifested as dizziness, paresthesias, rash, flushing, face swelling, urticaria, dyspnea, and pruritis. ADVATE contains trace amounts of mouse immunoglobulin G (MuIgG; maximum of 0.1 ng/IU ADVATE) and hamster (CHO) proteins (maximum of 1.5 ng/IU ADVATE). Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins. Discontinue ADVATE if hypersensitivity symptoms occur and administer appropriate emergency treatment. Neutralizing Antibodies Patients treated with AHF products should be carefully monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported following administration of ADVATE predominantly in previously untreated patients (PUPs) and previously minimally treated patients (MTPs). If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor VIII inhibitor concentration should be performed. Monitoring Laboratory Tests s -ONITOR PLASMA FACTOR 6))) ACTIVITY LEVELS BY THE ONESTAGE CLOTTING assay to confirm the adequate factor VIII levels have been achieved and maintained, when clinically indicated. s -ONITOR FOR DEVELOPMENT OF FACTOR 6))) INHIBITORS 0ERFORM THE Bethesda assay to determine if factor VIII inhibitor is present. If expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with the expected dose of ADVATE. Use Bethesda Units (BU) to titer inhibitors. – If the inhibitor is less than 10 BU per mL, the administration of additional antihemophilic factor concentrate may neutralize the inhibitor, and may permit an appropriate hemostatic response. – Adequate hemostasis may not be achieved if inhibitor titers are above 10 BU per mL. The inhibitor titer may rise following ADVATE infusion as a result of an anamnestic response to factor VIII. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents. ADVERSE REACTIONS The most serious adverse drug reactions (ADRs) seen with ADVATE are hypersensitivity reactions and the development of high-titer inhibitors necessitating alternative treatments to factor VIII. The most common ADRs observed in clinical trials (frequency > 2% of subjects) were: factor VIII inhibitor formation (observed predominantly in PUPs) and headache (6.1) Table 1. Adverse Events Reported by > 5% Treated of Study Subjectsa MedDRAb System Organ Class Number of Subjects There were 2,507 adverse events (AEs) reported in 215 subjects. None of the subjects withdrew from the studies due to adverse events. There were no deaths. Nineteen treated subjects reported no AEs during their participation. The most common AEs (product-related and unrelated, according to the investigator’s opinion) occurring in at least 5% of subjects who received at least 1 ADVATE study infusion are shown in Table 1. General disorders and administration site conditions The majority of the events in Table 1 appear to have been related to trauma, intercurrent mild respiratory or gastrointestinal disease or well-described complications of hemophilia. Ear pain 17 14 6.0 16 12 5.1 Diarrhoea 48 34 14.5 Nausea 25 19 8.1 Vomiting 53 38 16.2 Influenza like illness 17 13 5.6 Pain 21 18 7.7 Pyrexia 173 76 32.5 Ear infection 40 25 10.7 Influenza 22 18 7.7 Nasopharyngitis 121 62 26.5 Otitis media 12 12 5.1 Sinusitis 21 14 6.0 Upper respiratory tract infection 49 31 13.2 Accident 41 20 8.5 Fall 22 17 7.3 Joint sprain 16 14 6.0 Limb injury 141 44 18.8 Procedural pain 16 12 5.1 Arthralgia 79 40 17.1 5.6 Infections and infestations Fifty-six ADRs were reported in 27 subjects. Nearly all (53/56) were isolated events or occurred once in one subject with numerous subsequent infusions without reoccurrence. The most common ADRs with a frequency greater than or equal to 2% are shown in Table 2. Of all ADRs, none were reported in neonates, 16 were reported in infants, 7 were reported in children, 8 were reported in adolescents and 25 were reported in adults. Injury, poisoning and procedural complications IMMUNOGENICITY The development of factor VIII inhibitors with the use of ADVATE was evaluated in clinical studies with pediatric PTPs (<6 years of age with >50 factor VIII exposures) and PTPs (*10 years of age with >150 factor VIII exposures). Of 198 subjects who were treated for at least 10 exposure days or on study for a minimum of 120 days, 1 adult developed a low-titer inhibitor (2.0 [BU] in the Bethesda assay) after 26 exposure days. Musculoskeletal and connective tissue disorders In clinical studies that enrolled previously untreated subjects (defined as having had up to 3 exposures to a factor VIII product at the time of enrollment, 5 (20%) of 25 subjects who received ADVATE developed inhibitors to FVIII. Four patients developed high titer ( > 5 BU) and one patient developed low-titer inhibitors. Inhibitors were detected at a median of 11 exposure days (range 7 to 13 exposure days) to investigational product. Immunogenicity was also evaluated by measuring the development of antibodies to heterologous proteins. 182 treated subjects were assessed for anti-CHO cell protein antibodies. Of these patients, 3 showed an upward trend in antibody titer over time and 4 showed sustained but transient elevations of antibodies. 182 treated subjects were assessed for muIgGl protein antibodies. Of these 10 showed an upward trend in anti-mu IgG antibody titer over time and 2 showed sustained but transient elevations of antibodies. Four subjects who demonstrated antibody elevations reported isolated events of urticaria, pruritus, rash, and slightly elevated eosinophil counts. All of these subjects had numerous repeat exposures to the study product without recurrence of the events and a causal relationship between the antibody findings and these clinical events has not been established. Of the 181 subjects who were treated and assessed for the presence of anti-human von Willebrand factor (VWF) antibodies, none displayed laboratory evidence indicative of a positive serologic response. Respiratory, thoracic and mediastinal disorders 13 22 15 6.4 Headache 205 64 27.4 29.1 Cough 150 68 Nasal congestion 64 33 14.1 Pharyngolaryngeal pain 50 32 13.7 Rhinorrhoea 40 25 10.7 Rash 23 19 8.1 a Includes data from 234 treated subjects from 5 completed studies in PTPs, and 1 ongoing study in PUPs as of 27 March 2006. b MedDRA version 8.1 was used. c This percent is calculated relative to 234, the total number of treated subjects. Table 2. Summary of Most Common Adverse Drug Reactions (ADRs)a with a Frequency * 2% MedDRA System Organ Class MedDRA Preferred Term Number of Patients ADR Rate (% Patients)b Investigations Anti-factor VIII antibody positive 5c 2.14% Nervous System Disorders Headache 5 2.14% a ADR = Adverse Drug Reaction = adverse events considered by the investigator to be at least possibly related to administration of the product. b The ADVATE clinical program included 234 treated subjects from 5 completed studies in PTPs, and 1 ongoing study in PUPs as of 27 March 2006. c All 5 ADRs occurred in (PUPs) from an ongoing clinical study, and all were for the development of factor VIII inhibitors with a titer * 0.6 BU that were to be reported as a serious AE. The following adverse reactions have been identified during post approval use of ADVATE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Table 3. Post-Marketing Experience a U.S. License No. 140 15 Skin and subcutaneous tissue disorders Post Marketing Experience U.S. Patent Numbers: 4,757,006; 5,198,349; 5,250,421; 5,733,873; 5,919,766; 4,891,319; 5,955,448; 6,313,102; 5,891,873; 6,034,080; 6,649,386; 5,854,021; 5,470,954; 6,555,391; 6,936,441; 7,094,574; 6,100,061; 6,475,725; 6,586,573; 7,087,723 Joint swelling Pain in extremity Nervous system disorders Eight weeks later, the inhibitor was no longer detectable, and in vivoo recovery was normal at 1 and 3 hours after infusion of another marketed recombinant factor VIII concentrate. This single event results in a factor VIII inhibitor frequency in PTPs of 0.51% (95% CI of 0.03 and 2.91% for the risk of any factor VIII inhibitor development). No factor VIII inhibitors were detected in the 53 treated pediatric PTPs. Percentc of Subjects Constipation Gastrointestinal disorders Table 3 represents the post-marketing adverse reactions as MedDRA Preferred Terms. Baxter, Advate, Baxject and Recombinate are trademarks of Baxter International Inc. Baxter, Advate and Baxject are registered in the U.S. Patent and Trademark Office. Number of Events Ear and labyrinth disorders ADVATE has been evaluated in five completed studies in previously treated patients (PTPs) and one ongoing study in PUPs with severe to moderately severe hemophilia A (factor VIII ) 2% of normal). A total of 234 subjects have been treated with ADVATE as of March 2006. Total exposure to ADVATE was 84,539,784 IU (derived from 47 lots) in 44,926 infusions. The median duration of participation per subject was 370.5 (range: 1 to 1,256) days and the median exposure to ADVATE per subject was 128.0 (range: 1 to 598) days. Among patients treated with ADVATE, cases of serious allergic/ hypersensitivity reactions including anaphylaxis have been reported and factor VIII inhibitor formation (observed predominantly in PUPs). To enroll in the confidential, industry-wide Patient Notification System, call 1-888-UPDATE-U (1-888-873-2838). MedDRA Preferred Term Organ System [MedDRA Primary SOC] Preferred Term Immune system disorders Anaphylactic reactiona Hypersensitivitya Blood and lymphatic system disorders Factor VIII inhibition General disorders and administration site conditions Injection site reaction Chills Fatigue Malaise These reactions have been manifested by dizziness, paresthesias, rash, flushing, face swelling, urticaria, and/or pruritus. Baxter Healthcare Corporation Westlake Village, CA 91362 USA A Printed in USA Issued October 2009 LE-07-12904 In recombinant FVIII therapy... ...ADVATE is a complete package • Convenience — broad selection of dosage strengths (250 to • Pathogen safety — ADVATE is the only recombinant FVIII 3000 IU), short infusion time (up to 10 mL/min), BAXJECT II device, 3‡ and room temperature storage for up to 6 months therapy that is full-length and free of blood-based additives. Because no blood-derived components are added at any stage of the manufacturing process, the potential risk of pathogens that 1-3 may be carried in blood-based additives is eliminated • Commitment — patient support programs and healthcare professional (HCP) collaboration to stay at the forefront of hemophilia care There have been no confirmed reports of viral transmissions with recombinant FVIII therapies.1 † In clinical studies, ADVATE therapy demonstrated a low inhibitor rate with an overall incidence rate of 0.51% (95% confidence interval [CI], 0.03%-2.91%).5 ‡ Up to 30ºC/86ºF, not to exceed printed expiration date. After storage at room temperature, ADVATE must not be returned to the refrigerator. Two-year shelf life if refrigerated.3,6 • Efficacy — 93% of bleeds managed with 1 or 2 infusions in a 3,4* clinical study * Pivotal study of 108 PTPs with FVIII ⱕ2%.4 • Low rate of inhibitor development — in completed clinical studies, ⬍1% of previously treated patients (PTPs) developed an inhibitor 3-5† The development of inhibitors has been detected in patients receiving ADVATE. ADVATE [Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method] is indicated for control and prevention of bleeding episodes in adults and children with hemophilia A and for perioperative management in adults and children with hemophilia A. ADVATE is not indicated for the treatment of von Willebrand’s disease. Important Risk Information for ADVATE therapy ADVATE is contraindicated in patients with known anaphylaxis to mouse or hamster proteins or other constituents of the product. • If expected plasma factor VIII levels are not attained, or if bleeding is not controlled with an expected dose, test for the presence of inhibitors • The most serious adverse reactions seen with ADVATE are hypersensitivity reactions and the development of high-titer inhibitors necessitating alternative treatments to factor VIII • The most common adverse reactions observed in clinical trials (frequency ⱖ2% of subjects) were factor VIII inhibitor formation (observed predominantly in PUPs) and headache • Allergic-type hypersensitivity reactions, including anaphylaxis, are possible and have been reported with ADVATE. Symptoms have manifested as dizziness, paresthesia, rash, flushing, face swelling, urticaria, dyspnea, and pruritus. Discontinue use if hypersensitivity symptoms occur and administer appropriate emergency treatment • Patients treated with AHF products should be monitored for the development of factor VIII inhibitors. Inhibitors have been reported following administration of ADVATE predominantly in previously untreated patients (PUPs) and previously minimally treated patients (MTPs) Please see US brief summary of Prescribing Information on adjacent page. Licenses and licensing conditions may vary from country to country; therefore, please always consult your local full Prescribing Information. References: 1. The National Hemophilia Foundation. MASAC Recommendations Concerning the Treatment of Hemophilia and Other Bleeding Disorders. MASAC Document #190. June 2009. 2. McCormack PL, Plosker GL. Octocog alfa, plasma/albumin-free method. Drugs. 2005;65:2613-2620. 3. ADVATE Prescribing Information. Westlake Village, CA: Baxter Healthcare Corporation; October 2009. 4. Tarantino MD, Collins PW, Hay CRM, et al, and the rAHF-PFM Clinical Study Group. Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A. Haemophilia. 2004;10:428-437. 5. Shapiro A, Gruppo R, Pabinger I, et al. Integrated analysis of safety and efficacy of a plasma- and albumin-free recombinant factor VIII (rAHF-PFM) from six clinical studies in patients with hemophilia A. Expert Opin Biol Ther. 2009;9:273-283. 6. Data on file. Westlake Village, CA: Baxter Healthcare Corporation. Baxter, Advate, and Baxject are trademarks of Baxter International Inc. © Copyright (January 2010), Baxter Healthcare Corporation. All rights reserved. Printed in the U.S.A. HYL5133