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Patrice Chevallier, Myriam Labopin, Regis Peffault de La Tour, Bruno Lioure, Claude-Eric Bulabois, Anne Huynh, Didier Blaise, Pascal Turlure, Etienne Daguindau, Natacha Maillard, Ibrahim Yakoub-Agha, Gaelle Guillerm, Jeremy Delage, Nathalie Contentin, Jacques-Olivier Bay, Florence Beckerich, Jean-Henri Bourhis, Marie Detrait, Stéphane Vigouroux, Sylvie François, Faezeh Legrand, Thierry Guillaume, Mohamad Mohty
We have retrospectively compared survivals between acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients who received either a clofarabine/busulfan (CloB2A2) or a fludarabine/busulfan (FB2A2) RIC regimen for allogeneic stem cell transplantation. Between 2009 and 2014, 355 allotransplanted cases were identified from the SFGM-TC registry as having received either the FB2A2 (n = 316, 56% males, median age: 59.2 years, AML 78.5%, first complete remission [CR1] 72%, median follow-up: 20 months) or the CloB2A2 (n = 39, 62% males, median age: 60...
October 17, 2016: Cancer Medicine
Elias Jabbour, Stefan Faderl, Koji Sasaki, Tapan Kadia, Naval Daver, Naveen Pemmaraju, Keyur Patel, Joseph D Khoury, Carlos Bueso-Ramos, Zachary Bohannan, Farhad Ravandi, Gautam Borthakur, Srdan Verstovsek, Darla Miller, Rita Maduike, Chitra Hosing, Hagop M Kantarjian, Guillermo Garcia-Manero
BACKGROUND: The outcome of patients with higher risk myelodysplastic syndromes (MDS) after hypomethylating agent (HMA) failure is poor. This study evaluated the safety and activity of a combination of low-dose clofarabine and cytarabine for these patients. METHODS: Seventy patients with higher risk MDS who had no response, progressed, or relapsed after at least 4 cycles of HMA therapy were treated. RESULTS: The median age was 72 years. Thirty-nine percent of the patients had high-risk disease according to the International Prognostic Scoring System, and 50% of the patients had poor-risk cytogenetics...
October 14, 2016: Cancer
A K Burnett, N H Russell, R K Hills, J Kell, O J Nielsen, M Dennis, P Cahalin, C Pocock, S Ali, S Burns, S Freeman, D Milligan, R E Clark
The study was designed to compare clofarabine plus daunorubicin versus daunorubicin/ara-C in older patients with acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS). Eight hundred and six untreated patients in the UK NCRI AML16 trial with AML/high-risk MDS (median age, 67yrs; range 56-84) and normal serum creatinine were randomised to two courses of induction chemotherapy with either daunorubicin/ara-C (DA) or daunorubicin/clofarabine (DClo). Patients were also included in additional randomisations; +/- one dose of gemtuzumab ozogamicin in course 1; 2v3 courses and +/- azacitidine maintenance...
September 2, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Kristin V Ho, Dominic A Solimando, J Aubrey Waddell
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast...
November 2015: Hospital Pharmacy
Mohamad Mohty, Florent Malard, Didier Blaise, Noel Milpied, Gerard Socie, Anne Huynh, Oumedaly Reman, Ibrahim Yakoub Agha, Sabine Furst, Thierry Guillaume, Reza Tabrizi, Stephane Vigouroux, Pierre Peterlin, Jean El-Cheikh, Philippe Moreau, Myriam Labopin, Patrice Chevallier
In acute myeloid leukemia, the prognosis for patients with primary treatment failure remains very poor. In order to improve their outcome, we conducted a phase 2, prospective, multicenter trial to test the feasibility of a new sequential regimen combining a short course of intensive chemotherapy and a reduced intensity-conditioning regimen, before allogeneic stem-cell transplantation. Twenty-four patients (median age, 47 years) with acute myeloid leukemia in primary treatment failure have been included. Cytogenetics was poor in 15 patients (62%) and intermediate in 9 (38%)...
August 25, 2016: Haematologica
Andrea Ghelli Luserna Di Rorà, Ilaria Iacobucci, Enrica Imbrogno, Cristina Papayannidis, Enrico Derenzini, Anna Ferrari, Viviana Guadagnuolo, Valentina Robustelli, Sarah Parisi, Chiara Sartor, Maria Chiara Abbenante, Stefania Paolini, Giovanni Martinelli
During the last few years many Checkpoint kinase 1/2 (Chk1/Chk2) inhibitors have been developed for the treatment of different type of cancers. In this study we evaluated the efficacy of the Chk 1/2 inhibitor prexasertib mesylate monohydrate in B-/T- cell progenitor acute lymphoblastic leukemia (ALL) as single agent and in combination with other drugs. The prexasertib reduced the cell viability in a dose and time dependent manner in all the treated cell lines. The cytotoxic activity was confirmed by the increment of apoptotic cells (Annexin V/Propidium Iodide staining), by the increase of γH2A...
July 11, 2016: Oncotarget
J Magenau, P Westervelt, S Khaled, J McGuirk, P Hari, M Eapen, P S Becker, B Parkin, T Braun, B Logan, H Wang, M Jagasia, S D Rowley, D D H Kim, T Schechter, N Frey, B Scott, T Churay, S Lieland, S Forman, S Mineishi
Allogeneic hematopoietic cell transplantation (HCT) may produce long-term survival in AML after relapse or primary induction failure (PIF). However, outcomes of HCT performed for AML not in remission are historically poor given high relapse rates and transplant-related mortality. Preliminary studies suggest conditioning with clofarabine and myeloablative busulfan (CloBu4) may exert significant anti-leukemic effects without excessive toxicity in refractory hematologic malignancies. A prospective multicenter phase II trial was conducted to determine the efficacy of CloBu4 for patients proceeding directly to HCT with AML not in remission...
July 18, 2016: Bone Marrow Transplantation
Gheath Alatrash, Peter F Thall, Benigno C Valdez, Patricia S Fox, Jing Ning, Haven R Garber, Selma Janbey, Laura L Worth, Uday Popat, Chitra Hosing, Amin M Alousi, Partow Kebriaei, Elizabeth J Shpall, Roy B Jones, Marcos de Lima, Gabriela Rondon, Julianne Chen, Richard E Champlin, Borje S Andersson
Pretransplant conditioning regimens critically determine outcomes in the setting of allogeneic stem cell transplantation (allo-SCT). The use of nucleoside analogs such as fludarabine (Flu) in combination with i.v. busulfan (Bu) has been shown to be highly effective as a pretransplant conditioning regimen in acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and myelodysplastic syndrome (MDS). Because leukemia relapse remains the leading cause of death after allo-SCT, we studied whether clofarabine (Clo), a nucleoside analog with potent antileukemia activity, can be used to complement Flu...
October 2016: Biology of Blood and Marrow Transplantation
Colleen Delaney, Filippo Milano, Laura Cicconi, Megan Othus, Pamela S Becker, Vicky Sandhu, Ian Nicoud, Ann Dahlberg, Irwin D Bernstein, Frederick R Appelbaum, Elihu H Estey
BACKGROUND: The intensive chemotherapy regimens used to treat acute myeloid leukaemia routinely result in serious infections, largely due to prolonged neutropenia. We investigated the use of non-HLA-matched ex-vivo expanded cord blood progenitor cells to accelerate haemopoietic recovery and reduce infections after chemotherapy. METHODS: We enrolled patients with a diagnosis of acute myeloid leukaemia by WHO criteria and aged 18-70 years inclusive at our institution (Fred Hutchinson Cancer Research Center) into this phase 1 trial...
July 2016: Lancet Haematology
Jia-Jie Luan, Yu-Shan Zhang, Xiao-Yun Liu, Ya-Qin Wang, Jian Zuo, Jian-Guo Song, Wen Zhang, Wu-San Wang
To evaluate the time- and dose-dependent toxicity of clofarabine in mice and to further define the chronotherapy strategy of it in leukemia, we compared the mortality rates, LD50s, biochemical parameters, histological changes and organ indexes of mice treated with clofarabine at various doses and time points. Plasma clofarabine levels and pharmacokinetic parameters were monitored continuously for up to 8 hours after the single intravenous administration of 20 mg/kg at 12:00 noon and 12:00 midnight by high performance liquid chromatography (HPLC)-UV method...
May 2016: Kaohsiung Journal of Medical Sciences
Benigno C Valdez, Jonathan E Brammer, Yang Li, David Murray, Esmeralda C Teo, Yan Liu, Chitra Hosing, Yago Nieto, Richard E Champlin, Borje S Andersson
Novel approaches to pre-transplant conditioning are needed to improve treatment of advanced T-cell malignancies. We investigated the synergism of fludarabine (Flu), clofarabine (Clo), busulfan (Bu), and romidepsin (Rom) in T-cell lines and patient-derived cell samples. [Flu+Clo+Bu+Rom] had combination indexes of 0.4-0.5 at ∼50% cytotoxicity in PEER and SUPT1 cells, suggesting synergism. Drug exposure resulted in histone modifications, DNA-damage response (DDR), increased reactive oxygen species (ROS), decreased glutathione (GSH) and mitochondrial membrane (MM) potential, and apoptosis...
August 2016: Leukemia Research
Christan M Thomas, Cindy Ippoliti, Gail J Roboz, Eric Feldman, Dimitrios Savva, Sara James, Koen van Besien
No abstract text is available yet for this article.
May 31, 2016: Leukemia & Lymphoma
Audrey Grain, Anne Sirvent, Marion Strullu, Mechinaud Françoise, Mohamad Mohty, Thierry Guillaume, Patrice Chevallier, Fanny Rialland
No abstract text is available yet for this article.
May 17, 2016: Leukemia & Lymphoma
Barbara Spitzer, Miguel-Angel Perales, Nancy A Kernan, Susan E Prockop, Emily C Zabor, Nicholas Webb, Hugo Castro-Malaspina, Esperanza B Papadopoulos, James W Young, Andromachi Scaradavou, Rachel Kobos, Sergio A Giralt, Richard J O'Reilly, Farid Boulad
Relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains one of the leading causes of mortality in patients with leukemia. Treatment options in this population remain limited, with concern for both increased toxicity and further relapse. We treated 18 patients with acute leukemia for marrow ± extramedullary relapse after a previous alloHSCT with a myeloablative cytoreductive regimen including clofarabine, melphalan, and thiotepa followed by a second or third transplantation from the same or a different donor...
August 2016: Biology of Blood and Marrow Transplantation
Amir T Fathi, Daniel J DeAngelo, Kristen E Stevenson, Jonathan E Kolitz, Julie D Asch, Philip C Amrein, Eyal C Attar, David P Steensma, Martha Wadleigh, Julia Foster, Christine Connolly, Ilene Galinsky, Craig E Devoe, Richard M Stone, Donna S Neuberg, Karen K Ballen
BACKGROUND: Outcomes among older patients with acute lymphoblastic leukemia remain poor. This study sought to determine the efficacy of an intensified, multi-agent approach derived from a Dana-Farber consortium trial in younger adults for patients older than 50 years (trial identifier NCT00973752). METHODS: The primary endpoint was overall survival (OS) at 1 year. Patients received induction chemotherapy with vincristine, prednisone, doxorubicin, and pegylated asparaginase...
August 1, 2016: Cancer
Somsinee Wisitpitthaya, Yi Zhao, Marcus J C Long, Minxing Li, Elaine A Fletcher, William A Blessing, Robert S Weiss, Yimon Aye
The enzyme ribonucleotide reductase (RNR) is a major target of anticancer drugs. Until recently, suicide inactivation in which synthetic substrate analogs (nucleoside diphosphates) irreversibly inactivate the RNR-α2β2 heterodimeric complex was the only clinically proven inhibition pathway. For instance, this mechanism is deployed by the multifactorial anticancer agent gemcitabine diphosphate. Recently reversible targeting of RNR-α-alone coupled with ligand-induced RNR-α-persistent hexamerization has emerged to be of clinical significance...
July 15, 2016: ACS Chemical Biology
Katsuyoshi Koh, Chitose Ogawa, Yasuhiro Okamoto, Kazuko Kudo, Jiro Inagaki, Tsuyoshi Morimoto, Hideya Mizukami, Evelyne Ecstein-Fraisse, Atsushi Kikuta
A phase 1 study was conducted to evaluate the safety, pharmacokinetics (PK), efficacy and pharmacogenetic characteristics of clofarabine in seven Japanese pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients in Cohort 1 received clofarabine 30 mg/m(2)/day for 5 days, followed by 52 mg/m(2)/day for 5 days in subsequent cycles. Cohort 2 patients were consistently treated with 52 mg/m(2)/day for 5 days. No more than six cycles were performed. Every patient had at least one ≥Grade 3 adverse event (AE)...
August 2016: International Journal of Hematology
Božena Büttner, Reinhard Oertel, Johannes Schetelig, Jan Moritz Middeke, Martin Bornhäuser, Andreas Seeling, Holger Knoth
Combination of cytostatic agents is a basic principle in the treatment of cancer. For the treatment of acute myeloid leukemia (AML), purine analogs, like clofarabine and cytarabine act synergistically. Little is known, however, on their interaction in vivo. We developed a method for the simultaneous determination of clofarabine and cytarabine in human plasma. The substances were extracted from plasma samples by protein precipitation with acetonitrile. Cladribine was the internal standard (IS). The analytes were separated on Synergi HydroRP column (150mm×2...
June 5, 2016: Journal of Pharmaceutical and Biomedical Analysis
Woosuk Kim, Thuc M Le, Liu Wei, Soumya Poddar, Jimmy Bazzy, Xuemeng Wang, Nhu T Uong, Evan R Abt, Joseph R Capri, Wayne R Austin, Juno S Van Valkenburgh, Dalton Steele, Raymond M Gipson, Roger Slavik, Anthony E Cabebe, Thotsophon Taechariyakul, Shahriar S Yaghoubi, Jason T Lee, Saman Sadeghi, Arnon Lavie, Kym F Faull, Owen N Witte, Timothy R Donahue, Michael E Phelps, Harvey R Herschman, Ken Herrmann, Johannes Czernin, Caius G Radu
Deoxycytidine kinase (dCK), a rate-limiting enzyme in the cytosolic deoxyribonucleoside (dN) salvage pathway, is an important therapeutic and positron emission tomography (PET) imaging target in cancer. PET probes for dCK have been developed and are effective in mice but have suboptimal specificity and sensitivity in humans. To identify a more suitable probe for clinical dCK PET imaging, we compared the selectivity of two candidate compounds-[(18)F]Clofarabine; 2-chloro-2'-deoxy-2'-[(18)F]fluoro-9-β-d-arabinofuranosyl-adenine ([(18)F]CFA) and 2'-deoxy-2'-[(18)F]fluoro-9-β-d-arabinofuranosyl-guanine ([(18)F]F-AraG)-for dCK and deoxyguanosine kinase (dGK), a dCK-related mitochondrial enzyme...
April 12, 2016: Proceedings of the National Academy of Sciences of the United States of America
Michele B Daly, Megan E Roth, Laurent Bonnac, José O Maldonado, Jiashu Xie, Christine L Clouser, Steven E Patterson, Baek Kim, Louis M Mansky
BACKGROUND: HIV-1 replication kinetics inherently depends on the availability of cellular dNTPs for viral DNA synthesis. In activated CD4(+) T cells and other rapidly dividing cells, the concentrations of dNTPs are high and HIV-1 reverse transcription occurs in an efficient manner. In contrast, nondividing cells such as macrophages have lower dNTP pools, which restricts efficient reverse transcription. Clofarabine is an FDA approved ribonucleotide reductase inhibitor, which has shown potent antiretroviral activity in transformed cell lines...
2016: Retrovirology
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