DOCSLIB.ORG

Replacing Cyclophosphamide/Cytarabine

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Replacing Cyclophosphamide/Cytarabine ARTICLE Acute Lymphoblastic Leukemia Replacing cyclophosphamide/cytarabine/ Ferrata Storti Foundation mercaptopurine with cyclophosphamide/ etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG Haematologica 2019 Michael J. Burke,1* Wanda L. Salzer,2* Meenakshi Devidas,3 Yunfeng Dai,3 Lia Volume 104(5):986-992 Gore,4 Joanne M. Hilden,4 Eric Larsen,5 Karen R. Rabin,6 Patrick A. Zweidler- McKay,7 Michael J. Borowitz,8 Brent Wood,9 Nyla A. Heerema,10 Andrew J. Carroll,11 Naomi Winick,12 William L. Carroll,13 Elizabeth A. Raetz,13** Mignon L. Loh14** and Stephen P. Hunger15** 1Department of Pediatrics, Children’s Hospital of Wisconsin, Milwaukee, WI; 2U.S. Army Medical Research and Materiel Command, Fort Detrick, MD; 3Department of Biostatistics, Colleges of Medicine and Public Health & Health Professions, University of Florida, Gainesville, FL; 4Department of Pediatrics, Center for Cancer and Blood Disorders, Children’s Hospital Colorado and The University of Colorado School of Medicine, Aurora, CO; 5Department of Pediatrics, Maine Children’s Cancer Program, Scarborough, ME; 6Department of Pediatrics, Baylor College of Medicine, Houston, TX; 7ImmunoGen, Inc, Waltham, MA; 8Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD; 9Department of Laboratory Medicine, University of Washington, Seattle, WA; 10Department of Pathology, The Ohio State University School of Medicine, Columbus, OH; 11Department of Genetics, University of Alabama at Birmingham, AL; 12Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX; 13Department of Pediatrics, Perlmutter Cancer Center, New York University Langone Health, New York, NY; 14Department of Pediatrics, Benioff Children’s Hospital and the Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, CA and 15Department of Pediatrics, Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA Correspondence: *These authors contributed equally as first authors. MICHAEL J. BURKE **These authors contributed equally as senior authors. [email protected] ABSTRACT Received: August 20, 2018. ith modern chemotherapy, approximately 90% of patients Accepted: December 6, 2018. with pediatric acute lymphoblastic leukemia are now cured. Pre-published: December 13, 2018. WHowever, subsets of patients can be identified who remain at very high risk of relapse with expected 4-year disease-free survival rates <80%; such patients are appropriate candidates for intensive therapeutic doi:10.3324/haematol.2018.204545 strategies designed to improve survival. The AALL1131 trial was Check the online version for the most updated designed to determine, in a randomized fashion, whether substitution information on this article, online supplements, with cyclophosphamide/etoposide (experimental arm 1) would improve and information on authorship & disclosures: the 4-year disease-free survival of children, adolescents, and young www.haematologica.org/content/104/5/986 adults with very high-risk B-cell acute lymphoblastic leukemia compared to a modified Berlin-Frankfurt-Münster regimen (control arm). Patients 1- 30 years of age with newly diagnosed very high-risk B-cell acute lym- ©2019 Ferrata Storti Foundation phoblastic leukemia were randomized after induction in a 1:2 fashion to Material published in Haematologica is covered by copyright. the control arm or experimental arm 1 in which they were given All rights are reserved to the Ferrata Storti Foundation. Use of 2 2 published material is allowed under the following terms and cyclophosphamide (440 mg/m days 1-5)/ etoposide (100 mg/m days 1- conditions: 5) during part 2 of consolidation and delayed intensification. Prospective https://creativecommons.org/licenses/by-nc/4.0/legalcode. interim monitoring rules for efficacy and futility were included where Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- futility would be determined for a one-sided P-value ≥0.7664. The study poses is subject to the following conditions: was stopped for futility as the interim monitoring boundary was crossed https://creativecommons.org/licenses/by-nc/4.0/legalcode, [hazard ratio 0.606 (95% confidence interval: 0.297 - 1.237)] and the very sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing high-risk arm of AALL1131 was closed in February 2017. Using data cur- from the publisher. rent as of December 31, 2017, 4-year disease-free survival rates were 85.5±6.8% (control arm) versus 72.3±6.3% (experimental arm 1) (P-value = 0.76). There were no significant differences in grade 3/4 adverse events 986 haematologica | 2019; 104(5) Cyclophosphamide/etoposide in pediatric B-ALL between the two arms. Substitution of this therapy for very high-risk B-cell acute lymphoblastic leukemia patients on the Children’s Oncology Group AALL1131 trial (NCT02883049) randomized to cyclophosphamide/etoposide during part 2 of consolidation and delayed intensification did not improve disease-free survival. Introduction ther classified as VHR if they had any of the following criteria: ≥13 years of age; CNS3 leukemia at diagnosis; day 29 bone marrow 7,8 With modern chemotherapy regimens, approximately minimal residual disease ≥0.01% determined by flow cytometry; 90% of patients with pediatric B-cell acute lymphoblastic induction failure [>25% bone marrow blasts (M3) on induction leukemia (B-ALL) are now cured.1,2 However, subsets of day 29], severe hypodiploidy (DNA index <0.81 and/or <44 chro- patients remain at very high-risk (VHR) of relapse with an mosomes); intrachromosomal amplification of chromosome 21, or expected 4-year disease-free survival (DFS) rate <80%. lysine methyltransferase 2A (KMT2A, formerly mixed lineage Current post-induction intensification strategies, which leukemia, MLL) rearrangement. In addition, patients with National have focused on optimizing the use of drugs commonly Cancer Institute standard-risk B-ALL, enrolled on the COG study administered in ALL therapy, have delivered sub-optimal AALL0932 (NCT01190930) for standard-risk B-ALL (≥1 to <10 results for these VHR B-ALL patients. In the absence of a years of age with a white blood cell count <50x109/L), were classi- specific targeted intervention (such as Abl-tyrosine kinase fied as VHR following induction if they met any of the above VHR inhibitors in Philadelphia chromosome-positive ALL), criteria or if they had day 29 bone marrow minimal residual dis- intensive chemotherapy continues to be the mainstay of ease ≥0.01% in the absence of favorable cytogenetics (no trisomies treatment. We hypothesized that further optimization or of chromosomes 4 and 10 and no ETV6/RUNX1 fusion). Patients intensification of the dose and schedule of established with Down syndrome were not eligible for the VHR stratum given agents or combination regimens typically used to treat the concern of increased toxicity of the regimen. Toxicities were newly diagnosed ALL patients would probably not graded using the National Cancer Institute’s Common improve outcomes further for VHR B-ALL patients, and Terminology Criteria for Adverse Events version 4.0. The study therefore novel or targeted therapies should be investigat- was approved by the National Cancer Institute, the Pediatric ed. Given that there was not a molecularly targeted agent Central Institutional Review Board, and institutional review available for this population of patients at the time the boards at each participating COG institution. study was conceived, this trial was designed to test the use The AALL1131 study was originally designed to investigate the of different consolidation strategies, based on drugs not addition of clofarabine to cyclophosphamide/etoposide as experi- commonly used in frontline ALL trials, including fractionat- mental arm 2 versus cyclophosphamide/etoposide (experimental ed cyclophosphamide and etoposide. arm 1) versus the control arm in a 2:2:1 randomization for patients The Children’s Oncology Group (COG) AALL1131 trial with VHR B-ALL. The study design was later amended to a 2:1 thus aimed to determine, in a randomized fashion, whether randomization between experimental arm 1 and the control arm, replacing cyclophosphamide, cytarabine, and 6-mercaptop- retaining those patients initially randomized to experimental arm urine during consolidation or cyclophosphamide, cytara- 1 and the control arm, after the clofarabine arm (experimental arm bine, and 6-thioguanine during delayed intensification with 2) was closed because of unacceptable toxicity (September 2014).7 cyclophosphamide and etoposide (experimental arm 1) dur- Patients classified as VHR were subsequently randomized after ing the consolidation and reconsolidation phases of COG induction in a 1:2 fashion to cyclophosphamide (1 g/m2 day augmented Berlin-Frankfurt-Münster therapy (control arm)3 29)/cytarabine (75 mg/m2 days 29-33 and 36-40)/6-mercaptopurine would improve the 4-year DFS of children, adolescents, and (60 mg/m2 days 29-42 consolidation) or thioguanine (60 mg/m2 young adults with VHR B-ALL. The cyclophosphamide/ days 29-42 during part 2 of delayed intensification) (control arm) etoposide combination was well tolerated in prior relapse or cyclophosphamide (440 mg/m2, days 29-33)/etoposide (100 B-ALL studies4,5 and a similar
Load more

Recommended publications
  • Mitomycin C: Indications for Use and Safe Practice in Ophthalmology Published by American Society of Ophthalmic Registered Nurses
    Mitomycin C: Indications for Use and Safe Practice in Ophthalmology Published by American Society of Ophthalmic Registered Nurses Editor Susan Clouser, RN, MSN, CRNO American Society of Ophthalmic Registered Nurses 655 Beach Street, San Francisco, CA 94109 1 This publication includes independent authors’ guidelines for the safe use and handling of mitomycin C in ophthalmic practices. Readers should use these guidelines as a resource only. These guidelines should never take precedence over manufacturers’ recommended practices, facilities policies and procedures, or compliance with federal regulations. Information in this publication may assist facilities in developing policies and procedures specifc to their needs and practice environment. American Society of Ophthalmic Registered Nurses For questions regarding content or association issues contact ASORN at [email protected] or 1.415.561.8513. Copyright © 2011 by American Society of Ophthalmic Registered Nurses American Society of Ophthalmic Registered Nurses has the exclusive rights to reproduce this work, to prepare derivative works from this work, to publicly distribute this work, to publicly perform this work and to publicly display this work. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of American Society of Ophthalmic Registered Nurses. Printed in the United States of America 10 9 8 7 6 5 4 3 2 1 ACKNOWLEDGMENTS The development of this educational resource would not have been possible without the knowledge and expertise of the ophthalmologists and ophthalmic registered nurses who wrote the content and the subsequent reviewers who provided valuable input.
    [Show full text]
  • How to Manage Acute Promyelocytic Leukemia
    Leukemia (2012) 26, 1743 -- 1751 & 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12 www.nature.com/leu HOW TO MANAGEy How to manage acute promyelocytic leukemia J-Q Mi, J-M Li, Z-X Shen, S-J Chen and Z Chen Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML). The prognosis of APL is changing, from the worst among AML as it used to be, to currently the best. The application of all-trans-retinoic acid (ATRA) to the induction therapy of APL decreases the mortality of newly diagnosed patients, thereby significantly improving the response rate. Therefore, ATRA combined with anthracycline-based chemotherapy has been widely accepted and used as a classic treatment. It has been demonstrated that high doses of cytarabine have a good effect on the prevention of relapse for high-risk patients. However, as the indications of arsenic trioxide (ATO) for APL are being extended from the original relapse treatment to the first-line treatment of de novo APL, we find that the regimen of ATRA, combined with ATO, seems to be a new treatment option because of their targeting mechanisms, milder toxicities and improvements of long-term outcomes; this combination may become a potentially curable treatment modality for APL. We discuss the therapeutic strategies for APL, particularly the novel approaches to newly diagnosed patients and the handling of side effects of treatment and relapse treatment, so as to ensure each newly diagnosed patient of APL the most timely and best treatment. Leukemia (2012) 26, 1743--1751; doi:10.1038/leu.2012.57 Keywords: acute promyelocytic leukemia (APL); all-trans-retinoic acid (ATRA); arsenic trioxide (ATO) INTRODUCTION In this review, we introduce the therapeutic strategies of APL, Acute promyelocytic leukemia (APL) is a distinct subtype of acute including the treatment of newly diagnosed and relapsed myeloid leukemia (AML) characterized by its abnormal promye- patients, as well as the ways to deal with the side effects.
    [Show full text]
  • DRUG NAME: Thioguanine
    Thioguanine DRUG NAME: Thioguanine SYNONYM(S): 2-amino-6-mercaptopurine,1 6-TG, TG COMMON TRADE NAME(S): LANVIS® CLASSIFICATION: antimetabolite, cytotoxic2 Special pediatric considerations are noted when applicable, otherwise adult provisions apply. MECHANISM OF ACTION: Thioguanine is a purine antagonist.1 It is a pro-drug that is converted intracellullarly directly to thioguanine monophosphate3 (also called 6-thioguanylic acid)4 (TGMP) by the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT). TGMP is further converted to the di- and triphosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP).5 The cytotoxic effect of thioguanine is a result of the incorporation of these nucleotides into DNA. Thioguanine has some immunosuppressive activity.1 Thioguanine is specific for the S phase of the cell cycle.6 PHARMACOKINETICS: Oral Absorption • incomplete and variable (14-46%)7 • preferably taken on an empty stomach8; may be taken with food if needed • children9: <20% Distribution crosses the placenta10 cross blood brain barrier? negligible11 volume of distribution12 148 mL/kg plasma protein binding no information found Metabolism hepatic10 activation by4: • hypoxanthine-guanine phosphoribosyl transferase (HGPRT) elimination by4: • guanase to 6-thioxanthine • thiopurine methyltransferase (TPMT) to 2-amino-6-methyl thiopurine active metabolites3,4 thiopurine nucleotides inactive metabolites4 6-thioxanthine, 2-amino-6-methyl thiopurine Excretion renal excretion12; initially intact drug, then metabolites urine12
    [Show full text]
  • Severe Myelotoxicity Associated with Thiopurine S-Methyltransferase*3A
    Case Report DOI: 10.4274/tjh.2013.0082 Severe Myelotoxicity Associated with Thiopurine S-Methyltransferase*3A/*3C Polymorphisms in a Patient with Pediatric Leukemia and the Effect of Steroid Therapy Pediatrik Bir Lösemi Olgusunda Tiyopurin S-Metiltransferaz *3A/*3C Polimorfizmi ile İlişkili Ağır Miyelotoksisite-Steroid Tedavisinin Etkisi Burcu Fatma Belen1, Türkiz Gürsel1, Nalan Akyürek2, Meryem Albayrak3, Zühre Kaya1, Ülker Koçak1 1Gazi University Faculty of Medicine, Department of Pediatric Hematology, Ankara, Turkey 2Gazi University Faculty of Medicine, Department of Pathology, Ankara, Turkey 3Kırıkkale University Faculty of Medicine, Department of Pediatric Hematology, Ankara, Turkey Abstract: Myelosuppression is a serious complication during treatment of acute lymphoblastic leukemia and the duration of myelosuppression is affected by underlying bone marrow failure syndromes and drug pharmacogenetics caused by genetic polymorphisms. Mutations in the thiopurine S-methyltransferase (TPMT) gene causing excessive myelosuppression during 6-mercaptopurine (MP) therapy may cause excessive bone marrow toxicity. We report the case of a 15-year-old girl with T-ALL who developed severe pancytopenia during consolidation and maintenance therapy despite reduction of the dose of MP to 5% of the standard dose. Prednisolone therapy produced a remarkable but transient bone marrow recovery. Analysis of common TPMT polymorphisms revealed TPMT *3A/*3C. Key Words: Myelosuppression, Thiopurine S-methyl transferase, Acute leukemia Özet: Miyelosupresyon,
    [Show full text]
  • List of Drugs Not Repackaged by Safecor Health
    Drugs Not Repackaged by Safecor Health The following tables list specific medications that are not repackaged by Safecor Health due to regulatory restrictions or specific manufacturer requirements. The items not repackaged are alphabetically listed below, both by brand name (table 1) and generic name (table 2). Please note: Safecor Health cannot repackage any beta lactam antibiotics (such as penicillins, amoxicillin and cephalosporins) or potent chemotherapeutic agents. Also, due to FDA restrictions, we cannot repackage half- or quarter-tabs, compounded or diluted drugs, powders, and ointments or creams. Safecor Health can repackage most hazardous drugs on the NIOSH list. Contact us for a complete list of hazardous drugs repackaged by Safecor Health. Table 1. Do Not Repackage Drugs Sorted Alphabetically by Brand Name Brand Name(s) Generic Name(s) Reason Item Cannot Be Repackaged Adrucil Fluorouracil Potent chemotherapy agent Aspirin and Extended-Release Specific manufacturer recommendations for very Aggrenox Dipyridamole limited expiration dating Albenza Albendazole Cost per dose prohibitive Alkeran Melphalan Potent chemotherapy agent Augmentin Amoxicillin and Clavulanate Potassium Safecor Health does not repackage this drug class Manufacturer states, "dispense in original container," Belsomra Suvorexant on the drug label Manufacturer states, "dispense in original container," Biktarvy Bictegravir, Emtricitabine and Tenofovir Alafenamide on the drug label Bion Tears Dextran, Hypromellose Ophthalmic Drops Sterile and unpreserved CeeNU Lomustine
    [Show full text]
  • Immunomodulators
    Fact Sheet News from the IBD Help Center IMMUNOMODULATORS Medical treatment for Crohn’s disease and ulcerative colitis has two main goals: achieving remission (control or resolution of inflammation leading to symptom resolution with healing of the inflamed tissue) and then maintaining remission. To accomplish these goals, treatment is aimed at controlling the ongoing inflammation in the intestine—the cause of inflammatory bowel disease (IBD) symptoms. As the name implies, immunomodulators modify the activity of the immune system, in turn, decreasing the inflammatory response. Immunomodulators are most often used in organ transplantation to prevent rejection of the new organ as well as in autoimmune diseases such as rheumatoid arthritis. Since the late 1960s, they have also been used to treat people with IBD, where the normal regulation of the immune system is affected. Immunomodulators, by themselves or with another agent, may be appropriate in the following treatment situations: • Nonresponse or intolerance to aminosalicylates, antibiotics, or corticosteroids • Steroid-dependent disease or frequent need for steroids • Perianal (around the anus) disease that does not respond to antibiotics • Fistulas (abnormal channels between two loops of intestine, or between the intestine and another structure—such as the skin) • To bolster or optimize the effect of a biologic drug and prevent the development of resistance to biologic drugs • To prevent recurrence after surgery Because it can take up to three to six months to see an improvement in symptoms with immunomodulators, steroids may be started at the same time to produce a faster response. Lower doses of the steroid may be utilized in some cases, producing fewer side effects.
    [Show full text]
  • Acute Lymphoblastic Leukemia (ALL) (Part 1 Of
    LEUKEMIA TREATMENT REGIMENS: Acute Lymphoblastic Leukemia (ALL) (Part 1 of 12) Note: The National Comprehensive Cancer Network (NCCN) Guidelines® for Acute Lymphoblastic Leukemia (ALL) should be consulted for the management of patients with lymphoblastic lymphoma. Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies. The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. They are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any
    [Show full text]
  • Innovative Design of Early Phase Clinical Trials in Radiation Oncology
    Integration of chemotherapy and radiation therapy Adam P. Dicker, M.D., Ph.D. Chair, Department of Radiation Oncology Kimmel Cancer Center Jefferson Medical College of Thomas Jefferson University Philadelphia, PA No Disclosures 2 U.S. Cancer Statistics - 1998 1.2 Million New Cases Each Year 600,000 600,000 Localized Disseminated Tumors Tumors 570,000 Cured 70,000 Cured Via Surgery or Via Radiotherapy Chemotherapy Outline • Current Status • Rationale for combination of chemotherapy with Radiation • Mechanism of action and resistance • Disease sites and toxicity of combination therapies • New targets 4 The past decade • Radiotherapy has Improved & will Improve Further • Most Recent Advances Relate to Imaging & Planning • Future Advances will be in New Delivery Approaches • RT Dose and Fractionation Paradigms will Shift • RT Target Volume “Rules” will Also Shift • RT/Drug Interactions Could Dictate Dose & Fractionation Therapeutic Ratio Curves Reasons to use Chemoradiation • Sterilize micrometastases outside of the XRT portal • Tumor cell sensitization • Improved nutrition and reoxygenation to hypoxic tumor cell (decrease tumor burden) – Better blood supply to remaining tumor cells • Cells cycle into a more radiation sensitive phase • Inhibit cell division between radiation doses • Inhibit cellular repair of damage between therapies Rationale for combined chemotherapy and radiotherapy • Spatial cooperation • Toxicity independence • Action as a radiosensitizer (possible synergism) • Eliminate need for surgical procedure. – Not all patients
    [Show full text]
  • Mitomycin C in the Treatment of Chronic Myelogenous Leukemia
    Nagoya ]. med. Sci. 29: 317-344, 1967. MITOMYCIN C IN THE TREATMENT OF CHRONIC MYELOGENOUS LEUKEMIA AKIRA HosHINo 1st Department of Internal Medicine Nagoya University School oj Medicine (Director: Prof. Susumu Hibino) SUMMARY Studies made of the treatment with 66 courses of mitomycin C in 28 patients with chronic myelogenous leukemia are reported. The effect of mitomycin C was investigated according to the relation between drug and host factors, comparison with the effects of other agents, and drug resistance. Patients with less hematological and clinical symptoms responded better to mitomycin C therapy. The remission rate of cases treated intravenously with mitomycin C was 93.8% and of cases treated orally with mitomycin C was 72.0%. The remission rate of the total cases (intravenous and oral) treated with mitomycin C was 77.3%. The therapeutic effect of mitomycin C is considered to be equal or be somewhat superior to the effect of busulfan as a result of data on the occurrence of resistance, cross resistance, development of acute blastic crisis and life span. Busulfan was effective in patients resistant to mitomycin C, and mitomycin C did not clinically show cross resistance to alkylating agents. Two patients resist· ant to mitomycin C recovered the sensitivity to mitomycin C after treatment with busulfan or 6-mercaptopurine. Side effects were observed in 39.4% of 66 cases, but severe side effect causing suspension of mitomycin C was rare. I. INTRODUCTION Human leukemia serves as a useful investigative model in which the de­ finite effect of anti-cancer agents can be evaluated quantitatively by factors such as the improvement of hematological findings and clinical symptoms, the remission rate, and the prologation of life span.
    [Show full text]
  • WO 2010/111254 Al
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 30 September 2010 (30.09.2010) WO 2010/111254 Al (51) International Patent Classification: (US). YE, Weilan [US/US]; 119 Barkentine Street, Fos C07K 16/28 (2006.01) A61K 39/395 (2006.01) ter City, CA 94404 (US). C12N 15/13 (2006.01) A61P 35/00 (2006.01) (74) Agents: FANG, Carol, A. et al; Genentech, Inc., 1 DNA (21) International Application Number: Way, MS 49, South San Francisco, CA 94080 (US). PCT/US20 10/028291 (81) Designated States (unless otherwise indicated, for every (22) International Filing Date: kind of national protection available): AE, AG, AL, AM, 23 March 2010 (23.03.2010) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, English (25) Filing Language: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (26) Publication Language: English HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (30) Priority Data: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 61/163,241 25 March 2009 (25.03.2009) US NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, (71) Applicant (for all designated States except US): SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, GENENTECH, INC. [US/US]; 1 DNA Way, South San TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
    [Show full text]
  • Trisenox, INN-Arsenic Trioxide
    ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 1. NAME OF THE MEDICINAL PRODUCT TRISENOX 1 mg/ml concentrate for solution for infusion TRISENOX 2 mg/ml concentrate for solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION TRISENOX 1 mg/ml concentrate for solution for infusion Each ml of concentrate contains 1 mg of arsenic trioxide. Each ampoule of 10 ml contains 10 mg of arsenic trioxide. TRISENOX 2 mg/ml concentrate for solution for infusion Each ml of concentrate contains 2 mg of arsenic trioxide. Each vial of 6 ml contains 12 mg of arsenic trioxide. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Concentrate for solution for infusion (sterile concentrate). Clear, colourless, aqueous solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications TRISENOX is indicated for induction of remission, and consolidation in adult patients with: Newly diagnosed low-to-intermediate risk acute promyelocytic leukaemia (APL) (white blood cell count, ≤ 10 x 103/µl) in combination with all-trans-retinoic acid (ATRA) Relapsed/refractory acute promyelocytic leukaemia (APL) (previous treatment should have included a retinoid and chemotherapy) characterised by the presence of the t(15;17) translocation and/or the presence of the promyelocytic leukaemia/retinoic-acid-receptor-alpha (PML/RAR-alpha) gene. The response rate of other acute myelogenous leukaemia subtypes to arsenic trioxide has not been examined. 4.2 Posology and method of administration TRISENOX must be administered under the supervision of a physician who is experienced in the management of acute leukaemias, and the special monitoring procedures described in section 4.4 must be followed.
    [Show full text]
  • Mutagenicity of Cancer Chemotherapeutic Agents in the Sa/Mone//A/Mi Erosome Test
    [CANCER RESEARCH 37, 2209-2213, July 1977] Mutagenicity of Cancer Chemotherapeutic Agents in the Sa/mon e//a/Mi erosome Test William F. Benedict,1 Mary S. Baker, Lynne Haroun, Edmund Choi, and Bruce N. Ames2 Division ot Hematology-Oncology, Department of Medicine, Childrens Hospital, Los Angeles, California 90027 [W. F. B., M. S. B.¡,and Department oí Biochemistry, University of California, Berkeley, California 94720 ¡L.H., E. C., B. N. A.¡ SUMMARY This study examines several of these agents in the Salmo- ne//a/microsome mutagenesis test system (3-5, 24, 27). Seventeen cancer Chemotherapeutic agents were tested This in vitro test makes use of a set of histidine mutants of S. for their ability to mutate Salmonella typhimurium tester typhimurium for detecting mutagens and a mammalian liver strains in the Sa/moneWa/microsome mutagenicity test. microsomal preparation for converting carcinogens to their There was a high correlation between the mutagenicity and active, mutagenic forms. The test system has been validated carcinogenicity of a given agent. Carcinogens positive in in several recent studies (23-25, 32, 43). the test were Adriamycin, daunomycin, 1-propanol-3,3'-imi- nodimethanesulfonate, cyclophosphamide, isophospha- mide, hycanthone, chlornaphazin, nitrogen mustard, uracil MATERIALS AND METHODS mustard, melphalan, and thio-tepa. Two carcinogens, acti- nomycin D and bleomycin, were not detected as mutagens. Chemicals. The following drugs were obtained from The presumptive noncarcinogen, methotrexate, was nega Harry B. Wood, Drug Development Branch, Division of Can tive in the test. Tilorone and 6-mercaptopurine, tentatively cer Treatment, National Cancer Institute, Bethesda, Md.: classified as noncarcinogens, were mutagenic.
    [Show full text]