Peripheral T-Cell Lymphomas
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A Phase II Study on the Role of Gemcitabine Plus Romidepsin
Pellegrini et al. Journal of Hematology & Oncology (2016) 9:38 DOI 10.1186/s13045-016-0266-1 RESEARCH Open Access A phase II study on the role of gemcitabine plus romidepsin (GEMRO regimen) in the treatment of relapsed/refractory peripheral T-cell lymphoma patients Cinzia Pellegrini1, Anna Dodero2, Annalisa Chiappella3, Federico Monaco4, Debora Degl’Innocenti2, Flavia Salvi4, Umberto Vitolo3, Lisa Argnani1, Paolo Corradini2, Pier Luigi Zinzani1* and On behalf of the Italian Lymphoma Foundation (Fondazione Italiana Linfomi Onlus, FIL) Abstract Background: There is no consensus regarding optimal treatment for peripheral T-cell lymphomas (PTCL), especially in relapsed or refractory cases, which have very poor prognosis and a dismal outcome, with 5-year overall survival of 30 %. Methods: A multicenter prospective phase II trial was conducted to investigate the role of the combination of gemcitabine plus romidepsin (GEMRO regimen) in relapsed/refractory PTCL, looking for a potential synergistic effect of the two drugs. GEMRO regimen contemplates an induction with romidepsin plus gemcitabine for six 28-day cycles followed by maintenance with romidepsin for patients in at least partial remission. The primary endpoint was the overall response rate (ORR); secondary endpoints were survival, duration of response, and safety of the regimen. Results: The ORR was 30 % (6/20) with 15 % (3) complete response (CR) rate. Two-year overall survival was 50 % and progression-free survival 11.2 %. Grade ≥3 adverse events were represented by thrombocytopenia (60 %), neutropenia (50 %), and anemia (20 %). Two patients are still in CR with median response duration of 18 months. The majority of non-hematological toxicities were mild and transient. -
CTCL Treatment Algorithms How I Treat Advanced Stage CTCL
CTCL Treatment Algorithms How I treat advanced stage CTCL Francine Foss MD Professor of Medicine Hematology and Bone Marrow Transplantation Yale University School of Medicine New Haven, CT USA DISCLOSURES • SEATTLE GENETICS, SPECTRUM- consultant, speaker • MIRAGEN- consultant • MALLINRODT- consultant • KYOWA – investigator, consultant WHO-EORTC Classification of Cutaneous T-cell and NK Lymphomas- Incidence in US by SEER Registry Data Mycosis fungoides MF variants and subtypes (3836) Folliculotropic MF Pagetoid reticulosis Granulomatous slack skin Sézary syndrome (117) Adult T-cell leukemia/lymphoma Primary cutaneous CD30+ lymphoproliferative disorders (858) Primary cutaneous anaplastic large cell lymphoma Lymphomatoid papulosis Subcutaneous panniculitis-like T-cell lymphoma Extranodal NK/T-cell lymphoma, nasal type Primary cutaneous peripheral T-cell lymphoma, pleomorphic (1840) Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (provisional) Cutaneous γ/δ T-cell lymphoma Willemze R, et al. Blood. 2005;105:3768-3785. Skin manifestations and outcomes Patches, papules and T1 plaques covering < 10% of the skin T1 surface Patches, papules or T2 plaques covering ≥ T3 10% of the skin surface Tumors (≥ 1) T3 T2 Confluence of T4 erythematous lesions covering ≥ 80% BSA Skin stage 10 Yr relative survival T4 T1 100 % T2 67 % T3 39 % T4 41 % *Observed/expected survival x 100 for age-, sex-, and race- matched controls Zackheim HS, et al. J Am Acad Dermatol. 1999;40:418-425. Revisions to TNMB Classification, ISCL/EORTC Consensus Document -
Vorinostat—An Overview Aditya Kumar Bubna
E-IJD RESIDENTS' PAGE Vorinostat—An Overview Aditya Kumar Bubna Abstract From the Consultant Vorinostat is a new drug used in the management of cutaneous T cell lymphoma when the Dermatologist, Kedar Hospital, disease persists, gets worse or comes back during or after treatment with other medicines. It is Chennai, Tamil Nadu, India an efficacious and well tolerated drug and has been considered a novel drug in the treatment of this condition. Currently apart from cutaneous T cell lymphoma the role of Vorinostat for Address for correspondence: other types of cancers is being investigated both as mono-therapy and combination therapy. Dr. Aditya Kumar Bubna, Kedar Hospital, Mugalivakkam Key Words: Cutaneous T cell lymphoma, histone deacytelase inhibitor, Vorinostat Main Road, Porur, Chennai - 600 125, Tamil Nadu, India. E-mail: [email protected] What was known? • Vorinostat is a histone deacetylase inhibitor. • It is an FDA approved drug for the treatment of cutaneous T cell lymphoma. Introduction of Vorinostat is approximately 9. Vorinostat is slightly Vorinostat is a histone deacetylase (HDAC) inhibitor, soluble in water, alcohol, isopropanol and acetone and is structurally belonging to the hydroxymate group. Other completely soluble in dimethyl sulfoxide. drugs in this group include Givinostat, Abexinostat, Mechanism of action Panobinostat, Belinostat and Trichostatin A. These Vorinostat is a broad inhibitor of HDAC activity and inhibits are an emergency class of drugs with potential anti- class I and class II HDAC enzymes.[2,3] However, Vorinostat neoplastic activity. These drugs were developed with the does not inhibit HDACs belonging to class III. Based on realization that apart from genetic mutation, alteration crystallographic studies, it has been seen that Vorinostat of HDAC enzymes affected the phenotypic and genotypic binds to the zinc atom of the catalytic site of the HDAC expression in cells, which in turn lead to disturbed enzyme with the phenyl ring of Vorinostat projecting out of homeostasis and neoplastic growth. -
Istodax Refusal AR EPAR Final
15 November 2012 EMA/CHMP/27767/2013 Committee for Medicinal Products for Human Use (CHMP) Assessment report Istodax International non-proprietary name: romidepsin Procedure No. EMEA/H/C/002122 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telep one +44 (0)20 7418 8400 Facsimile +44 (0)20 7523 7455 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union Product information Name of the medicinal product: Istodax Applicant: Celgene Europe Ltd. 1 Longwalk Road Stockley Park UB11 1DB United Kingdom Active substance: romidepsin International Nonproprietary Name/Common Name: romidepsin Pharmaco-therapeutic group Other antineoplastic agents (ATC Code): (L01XX39) Treatment of adult patients with peripheral T-cell Therapeutic indication: lymphoma (PTCL) that has relapsed after or become refractory to at least one prior therapy Pharmaceutical forms: Powder and solvent for concentrate for solution for infusion Strength: 5 mg/ml Route of administration: Intravenous use Packaging: powder: vial (glass); solvent: vial (glass) Package sizes: 1 vial + 1 vial Istodax CHMP assessment report Page 2/92 Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 Information on Paediatric requirements ........................................................................ -
ISTODAX (Romidepsin) Must Be Fetus [See Use in Specific Populations (8.1)]
HIGHLIGHTS OF PRESCRIBING INFORMATION • Electrocardiographic (ECG) changes have been observed. Consider These highlights do not include all the information needed to use cardiovascular monitoring precautions in patients with congenital long ISTODAX safely and effectively. See full prescribing information for QT syndrome, a history of significant cardiovascular disease, and ISTODAX. patients taking medicinal products that lead to significant QT prolongation (5.3). ISTODAX® (romidepsin) for injection • Based on its mechanism of action, ISTODAX may cause fetal harm For intravenous infusion only when administered to a pregnant woman. Advise women of potential Initial US Approval: 2009 harm to the fetus (5.4, 8.1). • ISTODAX binds to estrogen receptors. Advise women of childbearing ---------------------------INDICATIONS AND USAGE---------------------------- potential that ISTODAX may reduce the effectiveness of estrogen- containing contraceptives (5.5). ISTODAX is a histone deacetylase (HDAC) inhibitor indicated for: • Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have -------------------------------ADVERSE REACTIONS------------------------------ received at least one prior systemic therapy (1). The most common adverse reactions in Study 1 were nausea, fatigue, infections, vomiting, and anorexia, and in Study 2 were nausea, fatigue, -----------------------DOSAGE AND ADMINISTRATION----------------------- anemia, thrombocytopenia, ECG T-wave changes, neutropenia, and • 14 mg/m2 administered intravenously (IV) over a 4-hour period on days lymphopenia (6). 1, 8 and 15 of a 28-day cycle. Repeat cycles every 28 days provided that the patient continues to benefit from and tolerates the drug (2.1). To report SUSPECTED ADVERSE REACTIONS, contact Gloucester • Treatment discontinuation or interruption with or without dose reduction Pharmaceuticals, Inc. at 1-866-223-7145 or the FDA at 1-800-FDA-1088 to 10 mg/m2 may be needed to manage adverse drug reactions (2.2). -
BC Cancer Benefit Drug List September 2021
Page 1 of 65 BC Cancer Benefit Drug List September 2021 DEFINITIONS Class I Reimbursed for active cancer or approved treatment or approved indication only. Reimbursed for approved indications only. Completion of the BC Cancer Compassionate Access Program Application (formerly Undesignated Indication Form) is necessary to Restricted Funding (R) provide the appropriate clinical information for each patient. NOTES 1. BC Cancer will reimburse, to the Communities Oncology Network hospital pharmacy, the actual acquisition cost of a Benefit Drug, up to the maximum price as determined by BC Cancer, based on the current brand and contract price. Please contact the OSCAR Hotline at 1-888-355-0355 if more information is required. 2. Not Otherwise Specified (NOS) code only applicable to Class I drugs where indicated. 3. Intrahepatic use of chemotherapy drugs is not reimbursable unless specified. 4. For queries regarding other indications not specified, please contact the BC Cancer Compassionate Access Program Office at 604.877.6000 x 6277 or [email protected] DOSAGE TUMOUR PROTOCOL DRUG APPROVED INDICATIONS CLASS NOTES FORM SITE CODES Therapy for Metastatic Castration-Sensitive Prostate Cancer using abiraterone tablet Genitourinary UGUMCSPABI* R Abiraterone and Prednisone Palliative Therapy for Metastatic Castration Resistant Prostate Cancer abiraterone tablet Genitourinary UGUPABI R Using Abiraterone and prednisone acitretin capsule Lymphoma reversal of early dysplastic and neoplastic stem changes LYNOS I first-line treatment of epidermal -
Romidepsin (Istodax) Reference Number: ERX.SPA
Clinical Policy: Romidepsin (Istodax) Reference Number: ERX.SPA. 267 Effective Date: 12.01.18 Last Review Date: 11.20 Line of Business: Commercial, Medicaid Revision Log See Important Reminder at the end of this policy for important regulatory and legal information. Description Romidepsin (Istodax®) is a histone deacetylase inhibitor. FDA Approved Indication(s) Istodax is indicated for the treatment of: • Cutaneous T-cell lymphoma (CTCL) in adult patients who have received at least one prior systemic therapy; • Peripheral T-cell lymphoma (PTCL) in adult patients who have received at least one prior therapy. o This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria. Health plan approved formularies should be reviewed for all coverage determinations. Requirements to use preferred alternative agents apply only when such requirements align with the health plan approved formulary. It is the policy of health plans affiliated with Envolve Pharmacy Solutions™ that Istodax and romidepsin injection solution are medically necessary when the following criteria are met: I. Initial Approval Criteria A. Cutaneous T-Cell Lymphoma (must meet all): 1. Diagnosis of CTCL (see Appendix D for examples of CTCL subtypes); 2. Prescribed by or in consultation with an oncologist or hematologist; 3. Age ≥ 18 years; 4. Request meets one of the following (a or b):* a. Dose does not exceed 14 mg/m2 for three days of a 28-day cycle; b. -
Maintenance Therapy in Lymphoma
Getting the Facts Helpline: (800) 500-9976 [email protected] Maintenance Therapy in Lymphoma Overview Maintenance therapy refers to the ongoing treatment of patients • What side effects might I experience? Are the side effects whose disease has responded well to frontline or firstline (initial) expected to increase as I continue on maintenance therapy? treatment. More and more cancer treatments have emerged that are • Does my insurance cover this treatment? effective at helping to place the cancer into remission (disappearance Is maintenance therapy better for me than active surveillance of signs and symptoms of lymphoma). Maintenance regimens are • followed by this same therapy if the lymphoma returns? used to keep the cancer in remission. Will the use of maintenance therapy have any impact on any Maintenance therapy typically consists of nonchemotherapy drugs • given at lower doses and longer intervals than those used during future therapies I may need? induction therapy (initial treatment). Depending on the type of Treatments Under Investigation lymphoma and the medications used, maintenance therapy may last for weeks, months, or even years. Brentuximab vedotin (Adcetris), Many agents are being studied in clinical trials as maintenance lenalidomide (Revlimid), and rituximab (Rituxan) are examples of therapy for different subtypes of lymphoma, either alone or as part of treatments used as maintenance therapy in various lymphomas. As a combination therapy regimen, including: new effective treatments with limited toxicity are developed, more • Bortezomib (Velcade) drugs are likely to be used as maintenance therapies. • Ibrutinib (Imbruvica) Although the medications used for maintenance treatments generally have fewer side effects than chemotherapy, patients may still • Ixazomib (Ninlaro) experience adverse events. -
Inhibiting HDAC6 and HDAC1 Upregulates Rhob with Divergent Downstream WAF1/CIP1 Targets, BIMEL Or P21 , Leading to Either Apoptosis Or Cytostasis Laura A
Inhibiting HDAC6 and HDAC1 upregulates RhoB with divergent downstream WAF1/CIP1 targets, BIMEL or p21 , leading to either apoptosis or cytostasis Laura A. Marlow1, Ilah Bok1, Robert C. Smallridge2,3, and John A. Copland1,3 1Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, and 2Division of Endocrinology, Internal Medicine Department, 3Endocrine Malignancy Working Group Mayo Clinic, 4500 San Pablo Road, Mayo Clinic, Jacksonville, Florida 32224 ABSTRACT RESULTS Background: Anaplastic thyroid carcinoma (ATC) is a highly aggressive Comparison of class I and I/II HDAC inhibitors Identification of HDAC1 and HDAC6 as repressors of RhoB undifferentiated carcinoma with a mortality rate near 100%. This high mortality rate is due to a multiplicity of genomic abnormalities resulting in A B C A C D Dose out curves Cell death HDAC screen the lack of effective therapeutic options. In order to find and apply effective class I/II hydroxamate targeted therapies, new molecular targets need to be discovered. Our lab ctrl Bel Vor Rom ctrl Bel Vor Rom Cleaved HDAC1 789 HDAC1 HDAC6 3840 HDAC6 HDAC1 789 HDAC1 HDAC6 3384 HDAC6 HDAC6 3840 HDAC6 nontarget HDAC6 3384 HDAC6 has previously identified that the upregulation of RhoB is therapeutically PARP nontarget 16T - beneficial in ATC and can serve as a molecular target. Methods: For studying BIMEL HDAC1 THJ IC50 ~ 400 nM, 250 nM HDAC6 RhoB and its epigenetic regulation, HDAC inhibitors and HDAC shRNAs are p21 used to examine the downstream effects of upregulated RhoB. RhoB RhoB Results:RhoB is repressed by HDAC1 and, for the first time, we identify p21 29T HDAC6 as another repressor of RhoB. -
Belinostat (Beleodaq®)
Belinostat (Beleodaq®) Belinostat (Beleodaq®) Pronounced: be-lin-oh-stat Classification: Histone Deacetylase Inhibitor About Belinostat (Beleodaq®) Belinostat is in a class of anti-cancer therapies called histone deacetylase (HDAC) inhibitors. Histone deacetylation is a biochemical process that is thought to play a role in promoting tumor growth. It does this by silencing some tumor suppressor genes, as well as other genes that are responsible for cell cycle progression, cell proliferation, programmed cell death (apoptosis), and differentiation (transformation of young cells into specialized cells). Therefore, blocking histone deacetylation may allow the body to block tumor growth and prevent progression. How to Take Belinostat Belinostat is given by intravenous (IV, into a vein) infusion. The dose and how often you receive this medication is based on your weight and will be decided by your provider. Your dose may be reduced if you are having severe side effects. Possible Side Effects of Belinostat There are a number of things you can do to manage the side effects of belinostat. Talk to your care team about these recommendations. They can help you decide what will work best for you. These are some of the most common or important side effects: Nausea and/or Vomiting Talk to your oncology care team so they can prescribe medications to help you manage nausea and vomiting. In addition, dietary changes may help. Avoid things that may worsen the symptoms, such as heavy or greasy/fatty, spicy or acidic foods (lemons, tomatoes, oranges). Try saltines, or ginger ale to lessen symptoms. Call your oncology care team if you are unable to keep fluids down for more than 12 hours or if you feel lightheaded or dizzy at any time. -
Histone Deacetylase Inhibitors
ANTICANCER RESEARCH 36 : 5019-5024 (2016) doi:10.21873/anticanres.11070 Review Histone Deacetylase Inhibitors: A Novel Therapeutic Weapon Αgainst Medullary Thyroid Cancer? CHRISTOS DAMASKOS 1,2* , SERENA VALSAMI 3* , ELEFTHERIOS SPARTALIS 2, EFSTATHIOS A. ANTONIOU 1, PERIKLIS TOMOS 4, STEFANOS KARAMAROUDIS 5, THEOFANO ZOUMPOU 5, VASILIOS PERGIALIOTIS 2, KONSTANTINOS STERGIOS 2,6 , CONSTANTINOS MICHAELIDES 7, KONSTANTINOS KONTZOGLOU 1, DESPINA PERREA 2, NIKOLAOS NIKITEAS 2 and DIMITRIOS DIMITROULIS 1 1Second Department of Propedeutic Surgery, “Laiko” General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 2Laboratory of Experimental Surgery and Surgical Research N.S. Christeas, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 3Blood Transfusion Department, Aretaieion Hospital, Medical School, National and Kapodistrian Athens University, Athens, Greece; 4Department of Thoracic Surgery, “Attikon” General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 5Medical School, National and Kapodistrian University of Athens, Athens, Greece; 6Colorectal Department, General Surgery, The Princess Alexandra Hospital NHS Trust, Harlow, U.K.; 71st Department of Pathology, School of Medicine, University of Athens, Athens, Greece Abstract. Background/ Aim : Medullary thyroid cancer (MTC) is and histone deacetylase (HDAC) seems to play a potential role highly malignant, metastatic and recurrent, remaining generally to gene transcription. On the -
Romidepsin Enhances the Efficacy of Cytarabine in Vivo, Revealing Histone Deacetylase Inhibition As a Promising Therapeutic Stra
LETTERS TO THE EDITOR treated with high-dose cytarabine developed severe Romidepsin enhances the efficacy of cytarabine myelosuppression in comparison to the other cohorts in vivo, revealing histone deacetylase inhibition as a (Figure 1B). In particular, there was a statistically signifi- promising therapeutic strategy for cant reduction in mean hemoglobin (98 vs. 42.5 g/L; KMT2A-rearranged infant acute lymphoblastic P<0.0001), white blood cell (2.43 vs. 0.13x109/L; leukemia P<0.0001) and platelet (757 vs. 294x109/L; P<0.0021) count between the mice treated with romidepsin and low- Acute lymphoblastic leukemia (ALL) in infants diag- dose cytarabine combination therapy compared to those nosed at less than 12 months of age is an aggressive malig- treated with high-dose cytarabine. nancy with a poor prognosis. Rearrangements of the Three xenograft models, PER-785, MLL-5 and MLL-14, KMT2A gene (KMT2A-r) are present in up to 80% of were used to determine the response to drug treatment by 1 cases, with 5-year event-free survival (EFS) less than 40%. EFS. MLL-5 and MLL-14 are well characterized patient- Dose intensive chemotherapy has been incorporated into derived xenografts which harbor t(10;11) and t(11;19) contemporary treatment regimens; however, this has translocations respectively.5 MLL-5 and MLL-14 were increased the burden of toxicity during therapy and late selected to test whether findings could be validated in 1,2 effects in survivors. There is a desperate need to identify independent models with distinct translocation partners. novel therapies to improve outcome.