Myelodysplastic Syndrome

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MYELODYSPLASTIC SYNDROME ARSENIC TRIOXIDE Arsenic trioxide 0.3 mg/kg/day IV* Days 1 – 5, Week 1 only Followed by Arsenic trioxide 0.25 mg/kg/day IV* Twice weekly, Week 2 onwards *Administer over 1 – 2 hours. Continue arsenic trioxide until disease progression, major response or complete remission. Reference: Vey N, et al. J Clin Oncol 2006;24:2465 - 71. ARSENIC TRIOXIDE Arsenic trioxide 0.25 mg/kg/day IV* Days 1 – 5 – Week 1 and 2 *Administer over 1 – 2 hours. Repeat cycle every 28 days. Reference: Schilller GJ, et al. J Clin Oncol 2006;24:2456 - 64. AZACITIDINE Azacitidine 75 mg/m2/day SQ Days 1 – 7 Repeat cycle every 28 days to a maximum of 7 cycles if CR. Patients with PR/improvement continue therapy until CR or relapse. DOSE MODIFICATION: If a beneficial effect is not evident by the start of the 3rd cycle (Day 57), the dose may be increased by 33%. NOTE: Depending on the dose of azacitidine the volume of the SQ injection may be large, i.e., up to 4 mL. Check patient preferences for multiple injections. Reference: Silverman LR, et al. J Clin Oncol 2002;20:2429 – 40. DECITABINE Decitabine 15 mg/m2 Q8H IV* Days 1 – 3 *Administer over 3 hours. Repeat cycle every 6 weeks. Discontinue decitabine therapy if a partial response is not achieved after 6 cycles or if a complete remission is not attained after 8 cycles of therapy. Continue treatment for 2 cycles after achieving a complete remission. Reference: Kantarjian H, et al. Cancer 2006;106:1794 – 803. Last Updated on September 24, 2007 DECITABINE Decitabine 20 mg/m2/day IV* Days 1 – 5 *Administer over 1 hour. Repeat cycle every 4 weeks. DOSE MODIFICATION: Dose reductions were permitted for Grade 3-4 non-myelosuppressive toxicities or for prolonged myelosuppression defined as a hypocellular marrow (≤5% cellularity). References: Kantarjian H, et al. Blood 2007;109:52 – 7; Kantarjian HM, et al. Cancer 2007;109:265 – 73. IMATINIB (GLEEVEC®) Imatinib 400 mg/day PO Daily NOTE: Imatinib is indicated for the treatment of adult patients with MDS/MPD associated with platelet-derived growth factor receptor (PDGFR) gene rearrangements. Reference: Novartis Pharmaceuticals Package Insert, October 2006. LENALIDOMIDE (REVLIMID®) Lenalidomide 10 mg/day PO Daily DOSE MODIFICATIONS: Recommended for neutropenia and thrombocytopenia. Refer to the lenalidomide monograph in the Pharmacology Section. Reference: List A, et al. N Engl J Med 2006;355:1456 - 65. Last Updated on September 24, 2007 .

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214120Orig1s000
CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 214120Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA Multidisciplinary Review and Evaluation Application Number NDA 214120 Application Type Type 3 Priority or Standard Priority Submit Date 3/3/2020 Received Date 3/3/2020 PDUFA Goal Date 9/3/2020 Office/Division OOD/DHM1 Review Completion Date 9/1/2020 Applicant Celgene Corporation Established Name Azacitidine (Proposed) Trade Name Onureg Pharmacologic Class Nucleoside metabolic inhibitor Formulations Tablet (200 mg, 300 mg) (b) (4) Applicant Proposed Indication/Population Recommendation on Regulatory Regular approval Action Recommended Indication/ For continued treatment of adult patients with acute Population myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy. SNOMED CT for the Recommended 91861009 Indication/Population Recommended Dosing Regimen 300 mg orally daily on Days 1 through 14 of each 28-day cycle Reference ID: 4664570 NDA Multidisciplinary Review and Evaluation NDA 214120 Onureg (azacitidine tablets) TABLE OF CONTENTS TABLE OF CONTENTS ................................................................................................................................... 2 TABLE OF TABLES .......................................................................................................................................
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Intravesical Instillation of Azacitidine Suppresses Tumor Formation Through TNF-R1 and TRAIL-R2 Signaling in Genotoxic Carcinogen-Induced Bladder Cancer
cancers Article Intravesical Instillation of Azacitidine Suppresses Tumor Formation through TNF-R1 and TRAIL-R2 Signaling in Genotoxic Carcinogen-Induced Bladder Cancer Shao-Chuan Wang 1,2,3, Ya-Chuan Chang 2, Min-You Wu 2, Chia-Ying Yu 2, Sung-Lang Chen 1,2,3 and Wen-Wei Sung 1,2,3,* 1 Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan; [email protected] (S.-C.W.); [email protected] (S.-L.C.) 2 School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; [email protected] (Y.-C.C.); [email protected] (M.-Y.W.); [email protected] (C.-Y.Y.) 3 Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan * Correspondence: [email protected] or fl[email protected]; Tel.: +886-4-2473-9595 Simple Summary: Approximately 70% of all bladder cancer is diagnosed as non-muscle invasive bladder cancer and can be treated by transurethral resection of the bladder tumor, followed by intravesical instillation chemotherapy. Bacille Calmette-Guérin (BCG) is the first-line agent for intravesical instillation, but its accessibility has been limited for years due to a BCG shortage. Here, our aim was to evaluate the therapeutic role of intravesical instillation of azacitidine, a DNA methyltransferase inhibitor, in bladder cancer. Cell model experiments showed that azacitidine inhibited TNFR1 downstream pathways to downregulate HIF-1α, claspin, and survivin. Concomitant Citation: Wang, S.-C.; Chang, Y.-C.; upregulation of the TRAIL R2 pathway by azacitidine ultimately drove the tumor cells to apoptosis. Wu, M.-Y.; Yu, C.-Y.; Chen, S.-L.; Sung, Rats with genotoxic carcinogen-induced bladder cancer showed a significantly reduced in vivo tumor W.-W.
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LEUKEMIA CHEMOTHERAPY REGIMENS (Part 1 of 2) the Selection, Dosing, and Administration of Anti-Cancer Agents and the Management of Associated Toxicities Are Complex
LEUKEMIA CHEMOTHERAPY REGIMENS (Part 1 of 2) The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Drug dose modifications and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and because of individual patient variability, prior treatment, and comorbidities. Thus, the optimal delivery of anti-cancer agents requires a healthcare delivery team experienced in the use of such agents and the management of associated toxicities in patients with cancer. The chemotherapy regimens below may include both FDA-approved and unapproved uses/regimens and are provided as references only to the latest treatment strategies. Clinicians must choose and verify treatment options based on the individual patient. REGIMEN DOSING Acute Myeloid Leukemia (AML) Induction Therapy Cytarabine (Cytosar-U; ARA-C) + Days 1–3: An anthracycline (eg, daunorubicin at least 60mg/m2/day IV, an anthracycline idarubicin 10–12mg/m2/day IV, or mitoxantrone 10–12mg/m2/day IV), plus (daunorubicin [Cerubidine], Days 1–7: Cytarabine 100–200mg/m2/day continuous IV infusion. idarubicin [Idamycin], OR mitoxantrone [Novantrone])1, 2 Days 1–3: An anthracycline (eg, daunorubicin 45mg/m2/day IV, idarubicin 12mg/m2/day IV, or mitoxantrone 12mg/m2/day IV), plus Days 1–7: Cytarabine 100mg/m2/day continuous IV infusion. Intermediate-dose cytarabine3 Cycle 1 Days 1–7: Cytarabine 200mg/m2/day continuous IV infusion, plus Days 5–6: Idarubicin 12mg/m2/day IV. Cycle 2 Days 1–6: Cytarabine 1,000mg/m2 continuous IV infusion for 3 hrs twice daily, plus Days 3, 5 and 7: Amsacrine 120mg/m2/day.
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Vidaza, INN-Azacitidine
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Azacytidine Sensitizes Acute Myeloid Leukemia Cells to Arsenic Trioxide By
Chau et al. Journal of Hematology & Oncology (2015) 8:46 DOI 10.1186/s13045-015-0143-3 JOURNAL OF HEMATOLOGY & ONCOLOGY RESEARCH ARTICLE Open Access Azacytidine sensitizes acute myeloid leukemia cells to arsenic trioxide by up-regulating the arsenic transporter aquaglyceroporin 9 David Chau1†, Karen Ng1†, Thomas Sau-Yan Chan1, Yuen-Yee Cheng1,3, Bonnie Fong2, Sidney Tam2, Yok-Lam Kwong1 and Eric Tse1* Abstract Background: The therapeutic efficacy of arsenic trioxide (As2O3) in acute myeloid leukemia (AML) is modest, which is partly related to its limited intracellular uptake into the leukemic cells. As2O3 enters cells via the transmembrane protein aquaglyceroporin 9 (AQP9). Azacytidine, a demethylating agent that is approved for the treatment of AML, has been shown to have synergistic effect with As2O3. We tested the hypothesis that azacytidine might up-regulate AQP9 and enhances As2O3-mediated cytotoxicity in AML. Methods: Arsenic-induced cytotoxicity, the expression of AQP9, and the intracellular uptake of As2O3 were determined in AML cell lines and primary AML cells with or without azacytidine pre-treatment. The mechanism of AQP9 up-regulation was then investigated by examining the expression of transcription factors for AQP9 gene and the methylation status of their gene promoters. Results: As2O3-induced cytotoxicity in AML cell lines was significantly enhanced after azacytidine pre-treatment as a result of AQP9 up-regulation, leading to increased arsenic uptake and hence intracellular concentration. Blocking AQP9-mediated As2O3 uptake with mercury chloride abrogated the sensitization effect of azacytidine. AQP9 promoter does not contain CpG islands. Instead, azacytidine pre-treatment led to increased expression of HNF1A, a transcription activator of AQP9, through demethylation of HNF1A promoter.
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Vidaza U.S. Full Prescribing Information
-------------------------------CONTRAINDICATIONS------------------------------ HIGHLIGHTS OF PRESCRIBING INFORMATION Advanced Malignant Hepatic Tumors (4.1). These highlights do not include all the information needed to use Hypersensitivity to Azacitidine or Mannitol (4.2). VIDAZA safely and effectively. See full prescribing information for VIDAZA. -----------------------WARNINGS AND PRECAUTIONS------------------------ Anemia, Neutropenia and Thrombocytopenia: Monitor complete blood VIDAZA (azacitidine for injection), for subcutaneous or intravenous use counts (CBC) frequently (5.1). Initial U.S. Approval: 2004 Hepatotoxicity: Patients with severe preexisting hepatic impairment are at higher risk for toxicity (5.2). Renal Toxicity: Monitor patients with renal impairment for toxicity ----------------------------INDICATIONS AND USAGE--------------------------- since azacitidine and its metabolites are primarily excreted by the VIDAZA is a nucleoside metabolic inhibitor indicated for the treatment of kidneys (5.3). patients with the following FAB myelodysplastic syndrome (MDS) subtypes: Tumor Lysis Syndrome: VIDAZA may cause fatal or serious tumor Refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS) lysis syndrome, including in patients with MDS. Assess baseline risk (if accompanied by neutropenia or thrombocytopenia or requiring and monitor and treat as appropriate (5.4). transfusions), refractory anemia with excess blasts (RAEB), refractory anemia Embryo-Fetal Risk: VIDAZA can cause fetal harm. Advise females
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Current Treatment of Juvenile Myelomonocytic Leukemia
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A Phase II Study of Omacetaxine (OM) in Patients with Intermediate-1 and Higher Risk Myelodysplastic Syndrome (MDS) Post Hypomethylating Agent (HMA) Failure 2013-0870
Protocol Page A Phase II Study of Omacetaxine (OM) in Patients with Intermediate-1 and Higher Risk Myelodysplastic Syndrome (MDS) post Hypomethylating Agent (HMA) Failure 2013-0870 Core Protocol Information Short Title Omacetaxine in Patients with Intermediate-1 and Higher Risk MDS post HMA Failure Study Chair: Elias Jabbour Additional Contact: Jhinelle L. Graham Vicky H. Zoeller Leukemia Protocol Review Group Additional Memo Recipients: Recipients List OPR Recipients (for OPR use only) None Study Staff Recipients None Department: Leukemia Phone: 713-792-4764 Unit: 0428 Full Title: A Phase II Study of Omacetaxine (OM) in Patients with Intermediate-1 and Higher Risk Myelodysplastic Syndrome (MDS) post Hypomethylating Agent (HMA) Failure Protocol Type: Standard Protocol Protocol Phase: Phase II Version Status: Activated -- Closed to new patient entry as of 08/05/2018 Version: 08 Document Status: Saved as "Final" Submitted by: Vicky H. Zoeller--9/11/2017 12:24:33 PM OPR Action: Accepted by: Margaret Okoloise -- 9/14/2017 12:09:50 PM Which Committee will review this protocol? The Clinical Research Committee - (CRC) Protocol Body 2013-0870 March 6, 2017 1 A Phase II Study of Omacetaxine (OM) in Patients with Intermediate-1 and Higher Risk Myelodysplastic Syndrome (MDS) post Hypomethylating Agent (HMA) Failure 2013-0870 March 6, 2017 2 Table of Contents 1.0 Objectives .................................................................................................. 3 2.0 Background ..............................................................................................
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Sorafenib and Omacetaxine Mepesuccinate As a Safe and Effective Treatment for Acute Myeloid Leukemia Carrying Internal Tandem Du
Original Article Sorafenib and Omacetaxine Mepesuccinate as a Safe and Effective Treatment for Acute Myeloid Leukemia Carrying Internal Tandem Duplication of Fms-Like Tyrosine Kinase 3 Chunxiao Zhang, MSc1; Stephen S. Y. Lam, MBBS, PhD1; Garret M. K. Leung, MBBS1; Sze-Pui Tsui, MSc2; Ning Yang, PhD1; Nelson K. L. Ng, PhD1; Ho-Wan Ip, MBBS2; Chun-Hang Au, PhD3; Tsun-Leung Chan, PhD3; Edmond S. K. Ma, MBBS3; Sze-Fai Yip, MBBS4; Harold K. K. Lee, MBChB5; June S. M. Lau, MBChB6; Tsan-Hei Luk, MBChB6; Wa Li, MBChB7; Yok-Lam Kwong, MD 1; and Anskar Y. H. Leung, MD, PhD 1 BACKGROUND: Omacetaxine mepesuccinate (OME) has antileukemic effects against acute myeloid leukemia (AML) carrying an internal tandem duplication of Fms-like tyrosine kinase 3 (FLT3-ITD). A phase 2 clinical trial was conducted to evaluate a combina- tion treatment of sorafenib and omacetaxine mepesuccinate (SOME). METHODS: Relapsed or refractory (R/R) or newly diagnosed patients were treated with sorafenib (200-400 mg twice daily) and OME (2 mg daily) for 7 (first course) or 5 days (second course on- ward) every 21 days until disease progression or allogeneic hematopoietic stem cell transplantation (HSCT). The primary endpoint was composite complete remission, which was defined as complete remission (CR) plus complete remission with incomplete hematologic recovery (CRi). Secondary endpoints were leukemia-free survival (LFS) and overall survival (OS). RESULTS: Thirty-nine R/R patients and 5 newly diagnosed patients were recruited. Among the R/R patients, 28 achieved CR or CRi. Two patients showed partial remission, and 9 patients did not respond.
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Treating Acute Myeloid Leukemia (AML) If You've Been Diagnosed with Acute Myeloid Leukemia (AML), Your Cancer Care Team Will Discuss Your Treatment Options with You
cancer.org | 1.800.227.2345 Treating Acute Myeloid Leukemia (AML) If you've been diagnosed with acute myeloid leukemia (AML), your cancer care team will discuss your treatment options with you. Your options may be affected by the AML subtype, as well as certain other prognostic factors, as well as your age and overall state of health. How is acute myeloid leukemia treated? The main treatment for most types of AML is chemotherapy, sometimes along with a targeted therapy drug. This might be followed by a stem cell transplant. Other drugs (besides standard chemotherapy drugs) may be used to treat people with acute promyelocytic leukemia (APL). Surgery and radiation therapy are not major treatments for AML, but they may be used in special circumstances. ● Chemotherapy for Acute Myeloid Leukemia (AML) ● Targeted Therapy Drugs for Acute Myeloid Leukemia (AML) ● Non-Chemo Drugs for Acute Promyelocytic Leukemia (APL) ● Surgery for Acute Myeloid Leukemia (AML) ● Radiation Therapy for Acute Myeloid Leukemia (AML) ● Stem Cell Transplant for Acute Myeloid Leukemia (AML) Common treatment approaches The typical treatment approach for AML is different from the treatment approach for acute promyelocytic leukemia (APL). The response rates for treatment can vary based on the subtype of AML, as well as other factors. Treatment options might be different if the AML doesn't respond to the initial treatment or if it comes back later on. The treatment approach for children with AML can be slightly different from that used for adults. It's discussed separately in Treatment of Children With Acute Myeloid Leukemia 1 ____________________________________________________________________________________American Cancer Society cancer.org | 1.800.227.2345 (AML).
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Antiproliferative and Antitumor Effects of Azacitidine Against the Human Myelodysplastic Syndrome Cell Line SKM-1
ANTICANCER RESEARCH 32: 795-798 (2012) Antiproliferative and Antitumor Effects of Azacitidine Against the Human Myelodysplastic Syndrome Cell Line SKM-1 SACHIE KIMURA, KAZUYA KURAMOTO, JUNKO HOMAN, HARUNA NARUOKA, TAKESHI EGO, MASAKI NOGAWA, SEISHI SUGAHARA and HARUNA NAITO Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan Abstract. Background: The myelodysplastic syndromes of tumor suppressor genes such as CDKN2B, which codes for (MDS) are a group of stem cell disorders characterized by cyclin-dependent kinase 4 inhibitor B (also known as multiple dysplasia of one or more hematopoietic cell lineages and a tumor suppressor 2 or p15INK4B), may play an important role risk of progression to acute myeloid leukemia. The cytidine in neoplastic progression (1). analog azacitidine (Vidaza), a hypomethylating agent, In 2004, the cytidine analog azacitidine (5-azacytidine; improves survival in patients with MDS, but its mechanism of marketed as Vidaza by Nippon Shinyaku from 2011 in Japan) action is not well understood. Materials and Methods: The was the first drug to be approved by the USA Food and Drug effects of azacitidine on the MDS-derived cell line SKM-1 Administration for the treatment of MDS, and it increases were investigated by DNA methylation assay, cell proliferation median overall survival in higher-risk patients with MDS in assay, and a subcutaneous xenograft mouse model. Results: comparison to drugs used in conventional care regimens, Azacitidine and decitabine induced hypomethylation of the including the structurally related cytarabine (5). Azacitidine tumor suppressor gene cyclin-dependent kinase 4 inhibitor B acts by the dual mechanisms of DNA hypomethylation and (CDKN2B) in SKM-1 cells, whereas the deoxycytidine analog cytotoxicity.
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