Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation

Total Page:16

File Type:pdf, Size:1020Kb

Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation cancers Review Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation Jessica Stokes 1, Megan S. Molina 1,2 , Emely A. Hoffman 1, Richard J. Simpson 1,2,3,4 and Emmanuel Katsanis 1,2,4,5,6,* 1 Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA; [email protected] (J.S.); [email protected] (M.S.M.); [email protected] (E.A.H.); [email protected] (R.J.S.) 2 Department of Immunobiology, University of Arizona, Tucson, AZ 85721, USA 3 Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85721, USA 4 The University of Arizona Cancer Center, Tucson, AZ 85721, USA 5 Department of Medicine, University of Arizona, Tucson, AZ 85721, USA 6 Department of Pathology, University of Arizona, Tucson, AZ 85721, USA * Correspondence: [email protected]; Tel.: +1-520-626-7053 Simple Summary: Bendamustine is a chemotherapeutic agent used to treat a variety of cancers. It has recently been used in the context of allogeneic hematopoietic cell transplantation (HCT), a treatment mostly used to treat blood cancers. Given before or after transplantation of donor blood or bone marrow cells, bendamustine has been shown to reduce the side effects of the transplant, including graft-versus-host disease, where the donated cells attack the recipient’s tissues, while also promoting the anti-cancer effects of the transplant. These are exciting findings and show that bendamustine may be used to influence the immune system, called immunomodulation, in a beneficial manner. We report our research and review the available literature outlining these immunomodulatory effects of bendamustine, in hopes that it will promote further investigations utilizing this agent in allogeneic Citation: Stokes, J.; Molina, M.S.; transplants, ultimately improving patient outcomes. Hoffman, E.A.; Simpson, R.J.; Katsanis, E. Immunomodulatory Abstract: Bendamustine (BEN) is a unique alkylating agent with efficacy against a broad range Effects of Bendamustine in of hematological malignancies, although investigations have only recently started to delve into Hematopoietic Cell Transplantation. Cancers 2021, 13, 1702. https:// its immunomodulatory effects. These immunomodulatory properties of BEN in the context of doi.org/10.3390/cancers13071702 hematopoietic cell transplantation (HCT) are reviewed here. Pre- and post-transplant use of BEN in multiple murine models have consistently resulted in reduced GvHD and enhanced GvL, with Academic Editor: Aline Bozec significant changes to key immunological cell populations, including T-cells, myeloid derived sup- pressor cells (MDSCs), and dendritic cells (DCs). Further, in vitro studies find that BEN enhances Received: 2 March 2021 the suppressive function of MDSCs, skews DCs toward cDC1s, enhances Flt3 expression on DCs, Accepted: 1 April 2021 increases B-cell production of IL-10, inhibits STAT3 activation, and suppresses proliferation of T- Published: 3 April 2021 and B-cells. Overall, BEN has a broad range of immunomodulatory effects that, as they are further elucidated, may be exploited to improve clinical outcomes. As such, clinical trials are currently Publisher’s Note: MDPI stays neutral underway investigating new potential applications of BEN in the setting of allogeneic HCT. with regard to jurisdictional claims in published maps and institutional affil- Keywords: bendamustine; hematopoietic cell transplantation iations. 1. Introduction Copyright: © 2021 by the authors. Bendamustine (BEN) was developed in East Germany in 1963, where investigators Licensee MDPI, Basel, Switzerland. quickly discovered its utility in treating a number of leukemias and lymphomas [1]. BEN This article is an open access article distributed under the terms and was synthesized from nitrogen mustard and, therefore, contains a 2-chloroethylamine conditions of the Creative Commons alkylating group and is classified as an alkylating agent. As such, BEN is able to crosslink Attribution (CC BY) license (https:// DNA, forming repairable intra-strand lesions, as well as non-repairable inter-strand lesions. creativecommons.org/licenses/by/ The accumulation of cross-linked DNA lesions caused by BEN administration ultimately 4.0/). leads to cell death, with the most robust accumulation occurring in highly proliferative Cancers 2021, 13, 1702. https://doi.org/10.3390/cancers13071702 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 1702 2 of 17 cells, such as hematopoietic cells and cancerous cells. This feature of BEN is common to many chemotherapeutic compounds, including cyclophosphamide and melphalan, both of which are also alkylating agents. However, bendamustine (4-(5-[bis(2-chloroethyl)amino]- 1-methyl-2-benzimidazolyl) butyric acid hydrochloride) has a unique molecular structure, consisting of a benzimidazole ring connected to a nitrogen mustard moiety, and is a purine analog in addition to a cytotoxic alkylating agent [2,3]. The benzimidazole ring is meant to confer anti-metabolite properties and is a unique feature that is not found on any other cytotoxic compound. Although few studies have investigated BEN as an anti-metabolite, it is thought that the benzimidazole ring may be able to bind to enzymes and confer biological effects in this manner [4]. While it is not clearly understood how, BEN has been reported to induce a higher frequency of and more stable double-strand breaks in DNA compared to other alkylating agents, including melphalan, cyclophosphamide, and carmustine [5,6]. Further, when comparing the effects of BEN on solid tumor cell lines (HeLa cells) and lymphoma cell lines (U2932), BEN was found to induce cell cycle arrest at lower concentrations in hemato- logical malignancies, consistent with its clinical applications in the treatment of leukemias, lymphomas, and myelomas [7]. Among the few mechanistic studies performed on BEN, it has been shown that BEN regulates apoptotic and DNA repair pathways, inhibits mitotic checkpoints, and induces p53-dependent stress pathways [2]. BEN has similarly been shown to induce cell cycle disruption, causing G2 arrest via Cdc25 and p53 [6]. More recent studies have corroborated these findings, demonstrating that BEN induces S or G2 cell cycle arrest in a dose-dependent manner [7]. BEN is given intravenously and has a very high (95%) protein binding capacity, primarily binding to albumin, while the remaining unbound portion (5%) is biologically active. BEN undergoes significant first-pass metabolism in the liver, primarily via a cytochrome p450 enzyme complex [4], and is metabolized into two major metabolites: dihydroxy-bendamustine (HP2) and bendamustine ethyl ester (BM1EE) [8]. Nearly half of BEN is eliminated in urine in an unmetabolized form via renal excretion. BEN has a biphasic half-life, with T1/2 alpha = ~10 min and T1/2 beta = ~30 min in humans, although this pharmacokinetic property varies based on dose and species. Due to its high degree of metabolism in the liver, in addition to its renal excretion, BEN may be contraindicated in patients with renal dysfunction and severe liver damage [4,9,10]. The adverse effects of BEN are very similar to those of typical alkylating agents in the nitrogen mustard family and include nausea, vomiting, diarrhea, loss of appetite, weight loss, mucositis, immunosuppression, anemia, and thrombocytopenia [11]. Until 1990, BEN was only available in East Germany where it was marketed as Ribo- mustin [1]. In 2008, the United States Food and Drug Administration (FDA) approved BEN for the treatment of chronic lymphocytic leukemia (CLL) under the tradename Treanda [1]. BEN was approved for the treatment of rituximab-resistant non-Hodgkin’s lymphoma soon after [1,12]. In 2015, BEN HCl was approved in the United States under the tradename Bendeka [2]. Clinical trials are underway in the United States to assess a range of cancers that may be successfully treated with this agent [2]. Currently, BEN is indicated for CLL, multiple myeloma, breast cancer, small-cell lung cancer, and non-Hodgkin’s lymphoma [2]. Although we have limited knowledge of the precise mechanisms of action of BEN, its utility in the clinical setting has quickly expanded. It has been used as an effective lymphodeplet- ing agent prior to infusion of chimeric antigen receptor (CAR) T-cells [13]. BEN has also been employed as a component of conditioning regimens for autologous hematopoietic cell transplantation (HCT) to treat multiple myeloma, Hodgkin’s lymphoma, mantle cell lymphoma, and other non-Hodgkin’s lymphomas [10,14–17]. More recently, BEN has been implemented in the context of clinical allogeneic HCT and has been studied in murine HCT models, both highlighting its immunomodulatory effects and suggesting favorable immunomodulation resulting in graft-versus-host disease (GvHD) and tumor control. Cancers 2021, 13, 1702 3 of 17 2. BEN as Pre-Transplant Conditioning in Murine Models Bone marrow transplantation as a clinical treatment evolved from radiation studies in mice and guinea pigs in the 1950s, which demonstrated that bone marrow cell infusion can rescue animals from lethal radiation [18]. In 1956, Ford et al. confirmed that donor bone marrow cells engraft in the recipient [19]. In the same year, Barnes et al. reported that donor bone marrow cells can exert anti-leukemic effects [20]. Subsequently, in 1957, the first report of a human bone marrow transplant was published by Thomas et al. [21]. Since its inception, bone marrow transplantation or hematopoietic cell transplantation (HCT) has become a widely implemented approach
Recommended publications
  • Fludarabine Phosphate Powder for Solution for Injection Or Infusion
    For the use only of a Registered Medical Practitioner or a Hospital or a Laboratory This package insert is continually updated. Please read carefully before using a new pack. Fludarabine Phosphate Powder for Solution for Injection or Infusion FLUDARA® NAME OF THE MEDICINAL PRODUCT Fludara 50 mg powder for solution for injection/infusion COMPOSITION Active ingredient: Each vial contains 50 mg fludarabine phosphate I.P. 1 ml of reconstituted solution for injection/infusion contains 25 mg fludarabine phosphate. Excipients: Mannitol, Sodium hydroxide (to adjust the pH to 7.7). INDICATIONS Fludara is indicated for the treatment of patients with B -cell chronic lymphocytic leukemia (CLL) who have not responded to at least one standard alkylating-agent containing regimen. DOSAGE AND METHOD OF ADMINISTRATION Method of administration Fludara must be administered only intravenously. No cases have been reported in which paravenously administered Fludara led to severe local adverse reactions. However, unintentional paravenous administration must be avoided. Dosage regimen Adults Fludara solution for injection/infusion should be administered under the supervision of a qualified physician experienced in the use of antineoplastic therapy. The recommended dose is 25 mg fludarabine phosphate/m² body surface given daily for 5 consecutive days every 28 days by the intravenous route. Each vial is to be made up in 2 ml water for injection. Each ml of the resulting solution for injection/infusion will contain 25 mg fludarabine phosphate (see section ‘Instructions for use/handling’). The required dose (calculated on the basis of the patient's body surface) is drawn up into a syringe. For intravenous bolus injection, this dose is further diluted into 10 ml of 0.9 % sodium chloride.
    [Show full text]
  • Fludarabine Phosphate (NSC 312878) Infusions for the Treatment of Acute Leukemia: Phase I and Neuropathological Study1
    [CANCER RESEARCH 46, 5953-5958, November 1986] Fludarabine Phosphate (NSC 312878) Infusions for the Treatment of Acute Leukemia: Phase I and Neuropathological Study1 David R. Spriggs,2 Edward Stopa, Robert J. Mayer, William Schoene, and Donald W. Kufe3 Dana Farber Cancer Institute [D. R. S., R. J. M.. D. W. K.J and Department ofPathology, Brigham and Women 's Hospital [E. S., W. SJ, Boston, Massachusetts 0211S ABSTRACT a relationship between dose and lethargy. The schedule of drug administration in these studies was not a 5-day infusion. A Fludarabine phosphate (NSC 312878), an adenosine deaminase resist ant analogue of 9-/9-D-arabinofuranosyladenine, has entered clinical trials. single bolus was used in one study while the other used a single bolus followed by a 48-h infusion. Eleven patients with acute leukemia in relapse received 14 courses of fludarabine phosphate as a 5-day continuous infusion administered at Based on the myelosuppressive effects of fludarabine phos doses of 40 to 100 mg/m2/day. Toxicity was characterized by uniform phate in Phase I testing, we instituted a Phase I and II trial to myelosuppression, as well as occasional nausea, vomiting, and hepato- identify the toxicity and efficacy of fludarabine phosphate in toxicity. Three episodes of metabolic acidosis and lactic acidemia were the treatment of acute leukemia. The drug was administered as noted. In addition, three patients suffered neurotoxicity. Two of these a 5-day continuous infusion at a starting dose equivalent to the three patients had a severe neurotoxicity syndrome characterized by maximum tolerated dose reached in patients with solid tumors.
    [Show full text]
  • Hodgkin Lymphoma Treatment Regimens
    HODGKIN LYMPHOMA TREATMENT REGIMENS (Part 1 of 5) Clinical Trials: The National Comprehensive Cancer Network 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 health care 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 provided only to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® 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 way. Classical Hodgkin Lymphoma1 Note: All recommendations are Category 2A unless otherwise indicated. Primary Treatment Stage IA, IIA Favorable (No Bulky Disease, <3 Sites of Disease, ESR <50, and No E-lesions) REGIMEN DOSING Doxorubicin + Bleomycin + Days 1 and 15: Doxorubicin 25mg/m2 IV push + bleomycin 10units/m2 IV push + Vinblastine + Dacarbazine vinblastine 6mg/m2 IV over 5–10 minutes + dacarbazine 375mg/m2 IV over (ABVD) (Category 1)2-5 60 minutes.
    [Show full text]
  • Fludarabine-Based Versus Chop-Like Regimens with Or Without Rituximab in Patients with Previously Untreated Indolent Lymphoma
    OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Fludarabine-based versus CHOP-like regimens with or without rituximab in patients with previously untreated indolent lymphoma: a retrospective analysis of safety and efficacy Xiao-xiao Xu1 Abstract: Fludarabine-based regimens and CHOP (doxorubicin, cyclophosphamide, vincristine, Bei Yan2 prednisone)-like regimens with or without rituximab are the most common treatment modalities Zhen-xing Wang3 for indolent lymphoma. However, there is no clear evidence to date about which chemotherapy Yong Yu1 regimen should be the proper initial treatment of indolent lymphoma. More recently, the use of Xiao-xiong Wu2 fludarabine has raised concerns due to its high number of toxicities, especially hematological Yi-zhuo Zhang1 toxicity and infectious complications. The present study aimed to retrospectively evaluate both the efficacy and the potential toxicities of the two main regimens (fludarabine-based and CHOP-like 1 Department of Hematology, Tianjin regimens) in patients with previously untreated indolent lymphoma. Among a total of 107 patients Medical University Cancer Institute and Hospital, Tianjin Key Laboratory assessed, 54 patients received fludarabine-based regimens (FLU arm) and 53 received CHOP or of Cancer Prevention and Therapy, CHOPE (doxorubicin, cyclophosphamide, vincristine, prednisone, or plus etoposide) regimens Tianjin, 2Department of Hematology, (CHOP arm). The results demonstrated that fludarabine-based regimens could induce significantly First Affiliated Hospital of Chinese People’s Liberation Army General improved progression-free survival (PFS) compared with CHOP-like regimens. However, the Hospital, Beijing, 3Department of FLU arm showed overall survival, complete response, and overall response rates similar to those Stomach Oncology, Tianjin Medical University Cancer Institute and of the CHOP arm.
    [Show full text]
  • Bendamustine and Cytosine Arabinoside: a Highly Synergistic Combination Visco C*, Carli G and Rodeghiero F Further DNA Synthesis [24]
    Open Access Austin Journal of Cancer and Clinical Research Editorial Bendamustine and Cytosine Arabinoside: A Highly Synergistic Combination Visco C*, Carli G and Rodeghiero F further DNA synthesis [24]. The synergistic effect of bendamustine Department of Cell Therapy and Hematology, San Bortolo and cytarabine could be related to the individual mechanism of Hospital, Italy action of the two drugs, whose serial administration would avoid *Corresponding author: Carlo Visco, Department of the saturation of the common pathways. Cells escaping the cell cycle Cell Therapy and Hematology, San Bortolo Hospital, Via arrest induced by bendamustine and trying to repair their damage Rodolfi 37, 36100 Vicenza, Italy, Tel: +39 0444 753626; would be prone to incorporate the metabolite ara-CTP into DNA, Fax: +39 0444 920708; Email: [email protected] as reported by Staib [19] in acute myeloid leukemia cells. Indeed, the Received: January 07, 2015; Accepted: March 16, sequential treatment with bendamustine followed by cytarabine was 2015; Published: April 03, 2015 proven to be more effective than simultaneous addition of the two drugs (Figure 2) [21-23]. The S phase of the cell cycle is a crucial step Editorial of replication in mantle cell lymphoma (MCL) cells, where cyclin D1 Bendamustine is a bifunctional compound that has shown clinical overexpression deregulates the cell cycle at the G1/S phase transition, activity against various human cancers including non-Hodgkin’s and and is likely the engine continuously pushing cells towards S-phase Hodgkin’s lymphoma [1,2], chronic lymphocytic leukemia (CLL) [3], (Figure 3). Indeed, both drugs are known to be particularly active in multiple myeloma [4,5], breast cancer [6], and small-cell lung cancer patients with MCL.
    [Show full text]
  • ©Ferrata Storti Foundation
    Lymphoproliferative Disorders original paper haematologica 2001; 86:1165-1171 Response to fludarabine in B-cell http://www.haematologica.it/2001_11/1165.htm chronic lymphocytic leukemia patients previously treated with chlorambucil as up-front therapy and a CHOP-like regimen as second line therapy VINCENZO LISO,* STEFANO MOLICA,# SILVANA CAPALBO,* ENRICO POGLIANI,@ COSIMA BATTISTA,* GIORGIO BROCCIA,^ MARCO MONTILLO,§ ANTONIO CUNEO,° PIETRO LEONI,** GIORGINA SPECCHIA,* GIANLUIGI CASTOLDI° *Institute of Hematology, University of Bari; °Section of Hematology, Department of Biomedical Sciences, University of Ferrara; #Division of Hematology and Clinical Oncology, “A. Pugliese” Hospital, Catanzaro; @Division of Hematology “San Gerardo dei Tintori” New Hospital, Monza; ^Division of Hema- tology, “A. Businco” Hospital, Cagliari; §Department of Hema- Correspondence: Vincenzo Liso, MD, Hematology, University of Bari, Policlinico, piazza G. Cesare 11, 70124 Bari, Italy. tology, Niguarda “Ca’ Granda” Hospital, Milan; Institute of Phone: international +39.080.5478711. Fax: international +39.080. Hematology, University of Ancona, Italy 5428978. E-mail: [email protected] Background and Objectives. Fludarabine (FAMP) is the response rate was 40.3% with FAMP (p = the most active single agent in relapsed and refrac- 0.037) and only 17.5% with CHOP (p = 1.0). Among tory patients with B-cell chronic lymphocytic 35 patients resistant to a CHOP-like regimen, the leukemia (B-CLL). However, it is not clear whether response rate was 29.8% (p = 0.066) after
    [Show full text]
  • A Bendamustine Resistance Gene Signature in Diffuse Large B-Cell Lymphoma and Multiple Myeloma
    Issa et al. Cancer Drug Resist 2021;4:208-22 Cancer DOI: 10.20517/cdr.2020.76 Drug Resistance Original Article Open Access A bendamustine resistance gene signature in diffuse large B-cell lymphoma and multiple myeloma Issa Ismail Issa1,2, Rasmus Froberg Brøndum1,2, Hanne Due1,2, Linnéa Schmidt1,2, Martin Bøgsted1,2, Karen Dybkær1,2 1Department of Haematology, Aalborg University Hospital, Aalborg 9000, Denmark. 2Department of Clinical Medicine, Aalborg University, Aalborg 9000, Denmark. Correspondence to: Prof. Karen Dybkær, Department of Haematology, Aalborg University Hospital, Sdr. Skovvej 15, Aalborg 9000, Denmark. E-mail: [email protected] How to cite this article: Issa II, Brøndum RF, Due H, Schmidt L, Bøgsted M, Dybkær K. A bendamustine resistance gene signature in diffuse large B-cell lymphoma and multiple myeloma. Cancer Drug Resist 2021;4:208-22. http://dx.doi.org/10.20517/cdr.2020.76 Received: 4 Sep 2020 First Decision: 12 Oct 2020 Revised: 30 Oct 2020 Accepted: 5 Nov 2020 Available online: 19 Mar 2021 Academic Editor: Godefridus J. Peters Copy Editor: Cai-Hong Wang Production Editor: Jing Yu Abstract Aim: Bendamustine is primarily used for treatment of indolent lymphomas but has shown efficacy in some patients with diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Molecular-based patient stratification for identification of resistant patients, who will benefit from alternative treatments, is important. The aim of this study was to develop a resistance gene signature (REGS) from bendamustine dose-response assays in cultures of DLBCL and MM cell lines, enabling prediction of bendamustine response in DLBCL and MM patients.
    [Show full text]
  • Immune Recovery After Fludarabine–Cyclophosphamide
    Leukemia (2010) 24, 1310–1316 & 2010 Macmillan Publishers Limited All rights reserved 0887-6924/10 www.nature.com/leu ORIGINAL ARTICLE Immune recovery after fludarabine–cyclophosphamide–rituximab treatment in B-chronic lymphocytic leukemia: implication for maintenance immunotherapy L Ysebaert1,2,3,6, E Gross1,2,6,EKu¨hlein4, A Blanc1,2, J Corre5, JJ Fournie´1,2, G Laurent1,2,3 and A Quillet-Mary1,2 1Inserm U563, Toulouse F-31300, France; 2Universite´ Toulouse III Paul-Sabatier, Centre de Physiopathologie de Toulouse Purpan, Toulouse F-31300, France; 3CHU Toulouse, Hopital Purpan, Service d’He´matologie, Toulouse F-31300, France; 4CHU Toulouse, Hopital Rangueil, Laboratoire d’Immunologie, Toulouse F-31300, France and 5CHU Toulouse, Hopital Purpan, Laboratoire d’He´matologie, Toulouse F-31300, France Thirty B-cell chronic lymphocytic leukemia patients were during the post-treatment period.1 It has also been proposed that treated with fludarabine–cyclophosphamide–rituximab (FCR) immunosuppression could also contribute to the emergence of and immune cell counts (natural killer (NK) cells, CD4, CD8, Tcd second malignancies, including leukemia and Richter’s syn- and monocytes) were monitored from the end of treatment drome, which has been observed in the setting of both B-CLL (EOT) up to 36 months (M36). Moreover, nonleukemic peri- 3–5 pheral blood lymphocyte cytotoxicity (PBL/CTC) as well as and Waldenstro¨m’s disease. rituximab (RTX)-dependent PBL/CTC was also measured at the Whether FCR therapy could affect some specific immune cell initiation of therapy, EOT and M12. These parameters were population and natural effector cell function is unknown. This correlated with post-FCR monitoring of the minimal residual question is still of interest based on two considerations.
    [Show full text]
  • Prodrugs: a Challenge for the Drug Development
    PharmacologicalReports Copyright©2013 2013,65,1–14 byInstituteofPharmacology ISSN1734-1140 PolishAcademyofSciences Drugsneedtobedesignedwithdeliveryinmind TakeruHiguchi [70] Review Prodrugs:A challengeforthedrugdevelopment JolantaB.Zawilska1,2,JakubWojcieszak2,AgnieszkaB.Olejniczak1 1 InstituteofMedicalBiology,PolishAcademyofSciences,Lodowa106,PL93-232£ódŸ,Poland 2 DepartmentofPharmacodynamics,MedicalUniversityofLodz,Muszyñskiego1,PL90-151£ódŸ,Poland Correspondence: JolantaB.Zawilska,e-mail:[email protected] Abstract: It is estimated that about 10% of the drugs approved worldwide can be classified as prodrugs. Prodrugs, which have no or poor bio- logical activity, are chemically modified versions of a pharmacologically active agent, which must undergo transformation in vivo to release the active drug. They are designed in order to improve the physicochemical, biopharmaceutical and/or pharmacokinetic properties of pharmacologically potent compounds. This article describes the basic functional groups that are amenable to prodrug design, and highlights the major applications of the prodrug strategy, including the ability to improve oral absorption and aqueous solubility, increase lipophilicity, enhance active transport, as well as achieve site-selective delivery. Special emphasis is given to the role of the prodrug concept in the design of new anticancer therapies, including antibody-directed enzyme prodrug therapy (ADEPT) andgene-directedenzymeprodrugtherapy(GDEPT). Keywords: prodrugs,drugs’ metabolism,blood-brainbarrier,ADEPT,GDEPT
    [Show full text]
  • Bendamustine: Treanda®; Bendeka®; Belrapzo™
    Bendamustine: Treanda®; Bendeka®; Belrapzo™ RTD (Intravenous) Document Number: IH-0130 Last Review Date: 03/01/2021 Date of Origin: 01/01/12 Dates Reviewed: 12/2011, 02/2013, 09/2013, 12/2013, 03/2014, 06/2014, 09/2014, 12/2014, 03/2015, 05/2015, 11/2015, 02/2016, 05/2016, 08/2016, 11/2016, 02/2017, 05/2017, 08/2017, 11/2017, 02/2018, 05/2018, 09/2018, 12/2018, 03/2019, 06/2019, 09/2019, 12/2019, 03/2020, 06/2020, 09/2020, 03/2021 I. Length of Authorization 1-3,5,8,13 • Non-Hodgkin’s Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL), Waldenström’s Macroglobulinemia (WM)/Lymphoplasmacytic Lymphoma (LPL), Classic Hodgkin Lymphoma (cHL): o Coverage will be provided for six months and may NOT be renewed. • Multiple Myeloma: o Coverage will be provided for eight months and may NOT be renewed. II. Dosing Limits A. Quantity Limit (max daily dose) [NDC Unit]: Treanda 100 mg lyophilized powder for injection: 6 vials every 21 days Treanda 25 mg lyophilized powder for injection: 3 vials every 21 days Bendeka 100 mg/4 mL multi-dose vial: 6 vials every 21 days Belrapzo 100 mg/4 mL RTD multi-dose vial: 6 vials every 21 days B. Max Units (per dose and over time) [HCPCS Unit]: NHL: • 600 billable units every 21 days WM/LPL: • 450 billable units every 28 days cccHL:cHL: • 600 billable units every 28 days CLL/SLL & MMMultipleMultiple MMMyelomaMyelomayeloma:::: • 500 billable units every 28 days Proprietary & Confidential © 2021 Magellan Health, Inc. III. Initial Approval Criteria 1 Coverage is provided in the following
    [Show full text]
  • 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.
    [Show full text]
  • Real Life Use of Bendamustine in Elderly Patients with Lymphoid Neoplasia
    Journal of Personalized Medicine Article Real Life Use of Bendamustine in Elderly Patients with Lymphoid Neoplasia Irene Dogliotti 1, Simone Ragaini 2 , Francesco Vassallo 3, Elia Boccellato 2, Gabriele De Luca 2, Francesca Perutelli 2 , Carola Boccomini 3, Michele Clerico 2, Barbara Botto 3, Daniele Grimaldi 2, Lorella Orsucci 3, Simone Ferrero 2 , Candida Vitale 2 , Dario Ferrero 2, Marta Coscia 2,† and Federica Cavallo 2,*,† 1 Stem Cell Transplant Unit, A.O.U., Città della Salute e della Scienza di Torino, 10126 Turin, Italy; [email protected] 2 Division of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Torino, A.O.U., Città della Salute e della Scienza di Torino, 10126 Turin, Italy; [email protected] (S.R.); [email protected] (E.B.); [email protected] (G.D.L.); [email protected] (F.P.); [email protected] (M.C.); [email protected] (D.G.); [email protected] (S.F.); [email protected] (C.V.); [email protected] (D.F.); [email protected] (M.C.) 3 Division of Hematology, A.O.U., Città della Salute e della Scienza di Torino, 10126 Turin, Italy; [email protected] (F.V.); [email protected] (C.B.); [email protected] (B.B.); [email protected] (L.O.) * Correspondence: [email protected]; Tel.: +39-01-1633-4556; Fax: +39-01-1633-6507 † These authors equally contributed to the manuscript. Abstract: Background. Bendamustine is a cytotoxic alkylating drug with a broad range of indications as a single agent or in combination therapy in lymphoid neoplasia patients.
    [Show full text]