262 results on '"Jean Khoury"'
Search Results
2. Protocol Number: HJKC3-0003. Treatment Free Remission After Combination Therapy With Asciminib (ABL001) Plus Tyrosine Kinase Inhibitors (TKI) in Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients Who Relapsed After a Prior Attempt at TKI Discontinuation
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H. Jean Khoury Cure CML Consortium and Ehab L Atallah, Professor
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- 2024
3. Asciminib as Initial Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase (ALERTCML)
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H. Jean Khoury Cure CML Consortium
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- 2024
4. Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia
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Jorge Cortes, Moshe Talpaz, Hedy P. Smith, David S. Snyder, Jean Khoury, Kapil N. Bhalla, Javier Pinilla-Ibarz, Richard Larson, David Mitchell, Scott C. Wise, Thomas J. Rutkoski, Bryan D. Smith, Daniel L. Flynn, Hagop M. Kantarjian, Oliver Rosen, and Richard A. Van Etten
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5′-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib (clinicaltrials.gov Identifier:00827138).
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- 2017
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5. Tratamento cirúrgico de tumores malignos envolvendo ombro e membro superior: estudo de 10 casos
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Leonardo José Vieira, João Paulo Vieira, Alexandre Ferreira Oliveira, Rosyane Rena de Freitas, Felipe Torres Rabêlo, Rafael Rabello Lista Mira, and Jean Khoury José
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Neoplasias ,Cirurgia ,Membro Superior ,Ombro ,Desarticulação ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Para alguns pacientes com neoplasias em região de ombro e/ou membro superior, a desarticulação interescapulotorácica (Cirurgia de Berger) ou a desarticulação escápulo-umeral, embora radicais, são o tratamento cirúrgico de escolha. No entanto, em casos selecionados, a escapulectomia ou a cirurgia de Tikhoff-Linberg (ressecção interescapulotorácica supra-umeral) pode ser uma alternativa. Neste trabalho, avaliamos 10 pacientes submetidos às diversas cirurgias em região de ombro e membro superior, de 2000 a 2003, nos hospitais ASCOMCER, Oncológico e Dr. João Felício, de Juiz de Fora (MG), procedendo à discussão sobre a modalidade cirúrgica aplicada a cada caso, a relação entre tipo histológico, localização do tumor e/ou comprometimento de feixe vásculo-nervoso com a indicação de uma ou outra cirurgia, a recorrência local ou sistêmica relacionada à técnica cirúrgica, a utilização de terapias neoadjuvantes e adjuvantes à cirurgia, o tempo de acompanhamento clínico sem indício de recidiva e óbitos.
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- 2004
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6. Ganglioneuroma de suprarrenal
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Rafael Rabello Lista Mira, Tereza Cristina Bernardo Fernandes, Ivan Cesar Said Resende, José Gabriel Timóteo Tostes, and Jean Khoury José
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Surgery ,RD1-811 - Full Text
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7. Providing Personalized Prognostic Information for Adult Leukemia Survivors
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Lee, Stephanie J., Storer, Barry, Wang, Hailin, Lazarus, Hillard M., Waller, Edmund K., Isola, Luis M., Klumpp, Thomas R., Umejiego, John Bosco C., Savani, Bipin N., Loren, Alison W., Cairo, Mitchell S., Camitta, Bruce M., Cutler, Corey S., George, Biju, Jean Khoury, H., Marks, David I., Rizzieri, David A., Copelan, Edward A., Gupta, Vikas, Liesveld, Jane L., Litzow, Mark R., Miller, Alan M., Schouten, Harry C., Gale, Robert Peter, Cahn, Jean-Yves, and Weisdorf, Daniel J.
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- 2013
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8. A phase 1 trial of itacitinib, a selective JAK1 inhibitor, in patients with acute graft-versus-host disease
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Madan Jagasia, Karl Staser, Michael Pratta, Gary J. Schiller, Jaebok Choi, Yi-Bin Chen, Peter Langmuir, Gabrielle Meyers, Miguel-Angel Perales, Haris Ali, Leah Gehrs, Ying Yan, H. Jean Khoury, Nithya Srinivas, John F. DiPersio, Mark A. Schroeder, and Michael C. Arbushites
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Adult ,medicine.medical_specialty ,Adolescent ,Anemia ,medicine.medical_treatment ,Clinical Trials and Supportive Activities ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Gastroenterology ,law.invention ,Rare Diseases ,Randomized controlled trial ,Adrenal Cortex Hormones ,Stem Cell Research - Nonembryonic - Human ,Clinical Research ,law ,hemic and lymphatic diseases ,Internal medicine ,Clinical endpoint ,Humans ,Medicine ,Adverse effect ,Protein Kinase Inhibitors ,6.2 Cellular and gene therapies ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Evaluation of treatments and therapeutic interventions ,Janus Kinase 1 ,Hematology ,Stem Cell Research ,medicine.disease ,Clinical trial ,Orphan Drug ,surgical procedures, operative ,Tolerability ,6.1 Pharmaceuticals ,Steroids ,business - Abstract
Acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic cell transplantation (HCT) is a primary cause of nonrelapse mortality and a major barrier to successful transplant outcomes. Itacitinib is a Janus kinase (JAK)1–selective inhibitor that has demonstrated efficacy in preclinical models of aGVHD. We report results from the first registered study of a JAK inhibitor in patients with aGVHD. This was an open-label phase 1 study enrolling patients aged ≥18 years with first HCT from any source who developed grade IIB to IVD aGVHD. Patients with steroid-naive or steroid-refractory aGVHD were randomized 1:1 to itacitinib 200 mg or 300 mg once daily plus corticosteroids. The primary endpoint was safety and tolerability; day 28 overall response rate (ORR) was the main secondary endpoint. Twenty-nine patients (200 mg, n = 14; 300 mg, n = 15) received ≥1 dose of itacitinib and were included in safety and efficacy assessments. One dose-limiting toxicity was reported (grade 3 thrombocytopenia attributed to GVHD progression in a patient receiving 300 mg itacitinib with preexisting thrombocytopenia). The most common nonhematologic treatment-emergent adverse event was diarrhea (48.3%, n = 14); anemia occurred in 11 patients (38%). ORR on day 28 for all patients in the 200-mg and 300-mg groups was 78.6% and 66.7%, respectively. Day 28 ORR was 75.0% for patients with treatment-naive aGVHD and 70.6% in those with steroid-refractory aGVHD. All patients receiving itacitinib decreased corticosteroid use over time. In summary, itacitinib was well tolerated and demonstrated encouraging efficacy in patients with steroid-naive or steroid-refractory aGVHD, warranting continued clinical investigations. This trial was registered at www.clinicaltrials.gov as #NCT02614612.
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- 2020
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9. The genomic landscape across 474 surgically accessible epileptogenic human brain lesions
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Javier A López-Rivera, Costin Leu, Marie Macnee, Jean Khoury, Lucas Hoffmann, Roland Coras, Katja Kobow, Nisha Bhattarai, Eduardo Pérez-Palma, Hajo Hamer, Sebastian Brandner, Karl Rössler, Christian G Bien, Thilo Kalbhenn, Tom Pieper, Till Hartlieb, Elizabeth Butler, Giulio Genovese, Kerstin Becker, Janine Altmüller, Lisa-Marie Niestroj, Lisa Ferguson, Robyn M Busch, Peter Nürnberg, Imad Najm, Ingmar Blümcke, and Dennis Lal
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Neurology (clinical) ,Technology Platforms - Abstract
Understanding the exact molecular mechanisms involved in the aetiology of epileptogenic pathologies with or without tumour activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants in low-grade epilepsy-associated tumours (7.92 ± 5.65 single-nucleotide variants) than in brain tissue from malformations of cortical development (6.11 ± 4 single-nucleotide variants) or hippocampal sclerosis (5.1 ± 3.04 single-nucleotide variants). Tumour tissues also had the largest number of likely pathogenic variant carrying cells. low-grade epilepsy-associated tumours had the highest proportion of samples with one or more somatic copy-number variants (24.7%), followed by malformations of cortical development (5.4%) and hippocampal sclerosis (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among low-grade epilepsy-associated tumours. For germline variant-associated malformations of cortical development genes such as TSC2, DEPDC5 and PTEN, germline single-nucleotide variants were frequently identified within large loss of heterozygosity regions, supporting the recently proposed ‘second hit’ disease mechanism in these genes. We detect somatic variants in 12 established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the aetiology of low-grade epilepsy-associated tumours (e.g. BRAF) and malformations of cortical development (e.g. SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with low-grade epilepsy-associated tumours and NRAS Q61 mutated protein with a complex malformation of cortical development characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21–q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical-genetic analyses showed that the numbers of somatic single-nucleotide variant across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with low-grade epilepsy-associated tumours. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening and guides future directions for clinical implementation of epilepsy surgery genetics.
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- 2022
10. Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib
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Cortes, Jorge E., Jean Khoury, H., Kantarjian, Hagop, Brümmendorf, Tim H., Mauro, Michael J., Matczak, Ewa, Pavlov, Dmitri, Aguiar, Jean M., Fly, Kolette D., Dimitrov, Svetoslav, Leip, Eric, Shapiro, Mark, Lipton, Jeff H., Durand, Jean-Bernard, and Gambacorti-Passerini, Carlo
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- 2016
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11. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
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Joshua E. Motelow, Gundula Povysil, Ryan S. Dhindsa, Kate E. Stanley, Andrew S. Al- len, Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Ka- therine Tashman, Felecia Cerrato, Caroline Cusick, Tarjinder Singh, Henrike Heyne, Andrea E. Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Namrata Gupta, Benjamin M. Neale, Gianpiero L. Cavalleri, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Hakon Hakonarson, Erin L. Heinzen, Ingo Helbig, Patrick Kwan, Anthony G. Marson, Slave ? Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Randy Stewart, Sarah Weckhuysen, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Roland Krause, Patrick May, Kevin McKenna, Brigid M. Regan, Caitlin A. Bennett, Costin Leu, Stephanie L. Leech, Terence J. O'Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Quratulain Zulfiqar Ali, Tara R. Sadoway, Heinz Krestel, Andre ? Schaller, Savvas S. Papacostas, Ioanna Kou- siappa, George A. Tanteles, Yiolanda Christou, Katalin Sterbova ?, Marke ? ta Vlckova ?, Lucie Sedlackova, Petra Lassuthova ?, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Bernd A. Neubauer, Friedrich Zimprich, Martha Feucht, Eva M. Reinthaler, Wolfram S. Kunz, Ga ?bor Zsurka, Rainer Surges, Tobias Baumgart- ner, Randi von Wrede, Manuela Pendziwiat, Hiltrud Muhle, An- nika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Mu ?ller-Schlu ?ter, Gerhard Kluger, Martin Ha ?usler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Stephan Lauxmann, Christian Boßelmann, Josua Kegele, Christian Hengs- bach, Sarah Rau, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, IngoBorggra ?fe, ChristophJ.Schankin, SusanneSchubert-Bast, Herbert Schreiber, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Markus Wolff, Dieter Dennig, Rene Madeleyn, Reetta Ka ?lvia ?inen, Anni Saarela, Oskari Timonen, Tarja Linnankivi, Anna-Elina Lehesjoki, Sylvain Rheims, Gaetan Lesca, Philippe Ryvlin, Louis Maillard, Luc Valton, Philippe Derambure, Fabrice Bartolomei, Edouard Hirsch, Ve ?ronique Michel, Francine Chas- soux, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Mark D. Baker, Beata Fonferko-Shadrach, Charlotte Law- thom, Joseph Anderson, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Norman Delanty, Colin P. Doherty, Arif Shukralla, Hany El-Naggar, Peter Widdess-Walsh, Nina Barisic, Laura 12 The American Journal of Human Genetics 108, 1-18, June 3, 2021 Please cite this article in press as: Epi25 Collaborative, Sub-genic intolerance, ClinVar, the epilepsies: A whole-exome sequencing study of 29, 165 individuals, The American Journal of Human Genetics (2021), https://doi.org/10.1016/j.ajhg.2021.04.009 Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Francesca Ragona, Federico Zara, Michele Iacomino, An- tonella Riva, Francesca Madia, Maria Stella Vari, Vincenzo Salpie- tro, Marcello Scala, Maria Margherita Mancardi, Lino Nobili, Elisa- betta Amadori, Thea Giacomini, Francesca Bisulli, Tommaso Pippucci, Laura Licchetta, Raffaella Minardi, Paolo Tinuper, Lor- enzo Muccioli, Barbara Mostacci, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carmen Barba, Shinichi Hirose, At- sushi Ishii, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Ahmad Beydoun, Wassim Nasreddine, Nathalie Khoueiry Zgheib, Birute Tumiene, Algirdas Utkus, Lynette G. Sadleir, Chontelle King, S. Hande Caglayan, Mutluay Arslan, Zuhal Yap?c?, P?nar To- paloglu, Bulent Kara, Uluc Yis, Dilsad Turkdogan, Asl? Gun- dogdu-Eken, Nerses Bebek, Meng-Han Tsai, Chen-Jui Ho, Chih- Hsiang Lin, Kuang-Lin Lin, I-Jun Chou, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Jeffrey L. Noebels, Alicia Goldman, Robyn M. Busch, Lara Jehi, Imad M. Najm, Lisa Ferguson, Jean Khoury, Tracy A. Glauser, Peggy O. Clark, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jac- queline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, David A. Greenberg, Colin A. Ellis, Ethan Goldberg, Katherine L. Helbig, Mahgenn Cosico, Priya Vaidis- waran, Eryn Fitch, Samuel F. Berkovic, Holger Lerche, Daniel H. Lowenstein, David B. Goldstein., Motelow J.E., Povysil G., Dhindsa R.S., Stanley K.E., Allen A.S., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Cusick C., Singh T., Heyne H., Byrnes A.E., Churchhouse C., Watts N., Solomonson M., Lal D., Gupta N., Neale B.M., Cavalleri G.L., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Sisodiya S.M., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bennett C.A., Leu C., Leech S.L., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Ali Q.Z., Sadoway T.R., Krestel H., Schaller A., Papacostas S.S., Kousiappa I., Tanteles G.A., Christou Y., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Neubauer B.A., Zimprich F., Feucht M., Reinthaler E.M., Kunz W.S., Zsurka G., Surges R., Baumgartner T., von Wrede R., Pendziwiat M., Muhle H., Rademacher A., van Baalen A., von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Lauxmann S., Bosselmann C., Kegele J., Hengsbach C., Rau S., Steinhoff B.J., Schulze-Bonhage A., Borggrafe I., Schankin C.J., Schubert-Bast S., Schreiber H., Mayer T., Korinthenberg R., Brockmann K., Wolff M., Dennig D., Madeleyn R., Kalviainen R., Saarela A., Timonen O., Linnankivi T., Lehesjoki A.-E., Rheims S., Lesca G., Ryvlin P., Maillard L., Valton L., Derambure P., Bartolomei F., Hirsch E., Michel V., Chassoux F., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Baker M.D., Fonferko-Shadrach B., Lawthom C., Anderson J., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Delanty N., Doherty C.P., Shukralla A., El-Naggar H., Widdess-Walsh P., Barisic N., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Ragona F., Zara F., Iacomino M., Riva A., Madia F., Vari M.S., Salpietro V., Scala M., Mancardi M.M., Nobili L., Amadori E., Giacomini T., Bisulli F., Pippucci T., Licchetta L., Minardi R., Tinuper P., Muccioli L., Mostacci B., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Barba C., Hirose S., Ishii A., Suzuki T., Inoue Y., Yamakawa K., Beydoun A., Nasreddine W., Khoueiry Zgheib N., Tumiene B., Utkus A., Sadleir L.G., King C., Caglayan S.H., Arslan M., Yapici Z., Topaloglu P., Kara B., Yis U., Turkdogan D., Gundogdu-Eken A., Bebek N., Tsai M.-H., Ho C.-J., Lin C.-H., Lin K.-L., Chou I.-J., Poduri A., Shiedley B.R., Shain C., Noebels J.L., Goldman A., Busch R.M., Jehi L., Najm I.M., Ferguson L., Khoury J., Glauser T.A., Clark P.O., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Greenberg D.A., Ellis C.A., Goldberg E., Helbig K.L., Cosico M., Vaidiswaran P., Fitch E., Berkovic S.F., Lerche H., Lowenstein D.H., Goldstein D.B., Epi25 Collaborative, Institut de Neurosciences des Systèmes (INS), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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0301 basic medicine ,focal epilepsy ,Whole Exome Sequencing ,Cohort Studies ,Epilepsy ,0302 clinical medicine ,Genetic Marker ,Missense mutation ,Exome ,whole-exome sequencing ,generalized epilepsy ,ComputingMilieux_MISCELLANEOUS ,Genetics (clinical) ,Exome sequencing ,seizures ,Genetics ,ClinVar ,Phenotype ,epileptic encephalopathy ,Epi25 ,intolerance ,Case-Control Studie ,Human ,Genetic Markers ,seizure ,Disease Association ,Biology ,Article ,03 medical and health sciences ,Exome Sequencing ,medicine ,Humans ,Genetic Predisposition to Disease ,Genetic Testing ,Generalized epilepsy ,Gene ,Louvain ,[SCCO.NEUR]Cognitive science/Neuroscience ,Correction ,Genetic Variation ,medicine.disease ,epilepsy ,Human genetics ,030104 developmental biology ,Case-Control Studies ,Human medicine ,Cohort Studie ,Genetic generalized epilepsy ,030217 neurology & neurosurgery - Abstract
Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
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- 2021
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12. Outcomes of Chronic Phase Chronic Myeloid Leukemia after Treatment with Multiple Tyrosine Kinase Inhibitors
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Angela Hatcher, Elliott F. Winton, Fuad El-Rassi, Jessica Neely, Vamsi Kota, Meena Joseph, Jee Hyun Kong, Jean Khoury, Martha Arellano, Leonard T. Heffner, Brittany Hill, Manila Gaddh, and Audrey S Kim
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Oncology ,medicine.medical_specialty ,Myeloid ,medicine.drug_class ,lcsh:Medicine ,Blastic Phase ,Article ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,0302 clinical medicine ,tyrosine kinase inhibitor ,chronic myeloid leukemia ,hemic and lymphatic diseases ,Internal medicine ,medicine ,chronic phase ,treatment-free remission ,business.industry ,lcsh:R ,Myeloid leukemia ,General Medicine ,Chronic phase chronic myeloid leukemia ,Discontinuation ,respiratory tract diseases ,medicine.anatomical_structure ,survival rates ,030220 oncology & carcinogenesis ,business ,Tyrosine kinase ,After treatment ,030215 immunology - Abstract
We sought to evaluate the outcomes of chronic phase (CP) chronic myeloid leukemia (CML) in an era where five tyrosine kinase inhibitors (TKIs) are commercially available for the treatment of CML. Records of patients diagnosed with CP CML, treated with TKIs and referred to our center were reviewed. Between January 2005 and April 2016, 206 patients were followed for a median of 48.8 (1.4&ndash, 190.1) months. A total of 76 (37%) patients received one TKI, 73 (35%) received two TKIs and 57 (28%) were exposed to >, 3 TKIs (3 TKIs, n = 33, 4 TKIs, n = 17, 5 TKIs, n = 7). Nineteen (9.2%) patients progressed to advanced phases of CML (accelerated phase, n = 6, myeloid blastic phase, n = 4, lymphoid blastic phase, n = 9). One third (n = 69) achieved complete molecular response (CMR) at first-line treatment. An additional 55 patients achieved CMR after second-line treatment. Twenty-five patients (12.1%) attempted TKI discontinuation and 14 (6.8%) stopped TKIs for a median of 6.3 months (range 1&ndash, 53.4). The 10-year progression-free survival and overall survival (OS) rates were 81% and 87%, respectively. OS after 10-years, based on TKI exposure, was 100% (1 TKI), 82% (2 TKIs), 87% (3 TKIs), 75% (4 TKIs) and 55% (5 TKIs). The best OS was observed in patients tolerating and responding to first line TKI, but multiple TKIs led patients to gain treatment-free remission.
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- 2020
13. Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a multicenter, open-label phase 2 trial
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Michael D. Howell, Miguel-Angel Perales, Madan Jagasia, Fitzroy Dawkins, Salman Fazal, Laura Connelly-Smith, Nirav N. Shah, Haris Ali, Yi-Bin Chen, Michael C. Arbushites, H. Jean Khoury, Mark A. Schroeder, and Chuan Tian
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Adult ,Male ,medicine.medical_specialty ,Ruxolitinib ,Adolescent ,Anemia ,medicine.drug_class ,Immunology ,Peripheral edema ,Drug Resistance ,Phases of clinical research ,Graft vs Host Disease ,Neutropenia ,Biochemistry ,Gastroenterology ,Young Adult ,Adrenal Cortex Hormones ,Internal medicine ,Nitriles ,Medicine ,Humans ,Adverse effect ,Aged ,business.industry ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Transplantation ,Pyrimidines ,Treatment Outcome ,Hematologic Neoplasms ,Corticosteroid ,Pyrazoles ,Female ,medicine.symptom ,business ,medicine.drug - Abstract
Patients who develop steroid-refractory acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation have poor prognosis, highlighting an unmet therapeutic need. In this open-label phase 2 study (ClinicalTrials.gov identifier: NCT02953678), patients aged at least 12 years with grades II to IV steroid-refractory aGVHD were eligible to receive ruxolitinib orally, starting at 5 mg twice daily plus corticosteroids, until treatment failure, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) at day 28; the key secondary end point was duration of response (DOR) at 6 months. As of 2 July 2018, 71 patients received at least 1 dose of ruxolitinib. Forty-eight of those patients (67.6%) had grade III/IV aGVHD at enrollment. At day 28, 39 patients (54.9%; 95% confidence interval, 42.7%-66.8%) had an overall response, including 19 (26.8%) with complete responses. Best ORR at any time was 73.2% (complete response, 56.3%). Responses were observed across skin (61.1%), upper (45.5%) and lower (46.0%) gastrointestinal tract, and liver (26.7%). Median DOR was 345 days. Overall survival estimate at 6 months was 51.0%. At day 28, 24 (55.8%) of 43 patients receiving ruxolitinib and corticosteroids had a 50% or greater corticosteroid dose reduction from baseline. The most common treatment-emergent adverse events were anemia (64.8%), thrombocytopenia (62.0%), hypokalemia (49.3%), neutropenia (47.9%), and peripheral edema (45.1%). Ruxolitinib produced durable responses and encouraging survival compared with historical data in patients with steroid-refractory aGVHD who otherwise have dismal outcomes. The safety profile was consistent with expectations for ruxolitinib and this patient population.
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- 2020
14. Safety and survival outcomes for bloodless transplantation in patients with myeloma
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Amelia Langston, Hanna Jean Khoury, Kelly Valla, Nisha Joseph, Chikaodili O. Obidike, Leonard T. Heffner, Edmund K. Waller, Dhwani Almaula, Ajay K. Nooka, Sagar Lonial, Christopher R. Flowers, Michael Graiser, Jonathan L. Kaufman, and Lawrence H. Boise
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Cancer Research ,medicine.medical_specialty ,Neutrophil Engraftment ,Platelet Engraftment ,business.industry ,medicine.disease ,University hospital ,Surgery ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,Oncology ,030220 oncology & carcinogenesis ,Medicine ,In patient ,030212 general & internal medicine ,business ,Hospital stay ,Multiple myeloma - Abstract
High-dose therapy (HDT) and autologous stem cell transplantation (ASCT) are established components in the treatment of multiple myeloma; however, undergoing transplantation usually requires hematopoietic support, which poses a challenge among patients who are unwilling to receive blood products. Most transplant centers decline HDT/ASCT to these patients because of safety concerns. Here, the authors' institutional data on safety, engraftment parameters, and survival outcomes after bloodless ASCT (BL-ASCT) are examined among patients with myeloma. This retrospective case-control study included patients who underwent BL-ASCT and Transfusion-supported ASCT (TS-ASCT) at Emory University Hospital between August 2006 and August 2016. In total, 24 patients who underwent BL-ASCT and 70 who underwent TS-ASCT were included. The median time for neutrophil engraftment, platelet engraftment and the median length of hospital stay all were equivalent for both groups. There were no transplant-related cardiovascular complications or mortality in either the BL-ASCT group or the TS-ASCT group. The median progression-free survival was 36 months and 44 months in the BL-ASCT and TS-ASCT groups, respectively (P = .277), and the median OS was not reached in either group at a median follow-up of 59 months after ASCT (P = .627). There was no transplant-related mortality at the 100-day or 1-year mark in either group. BL-ASCT is safe and feasible; transplant-related mortality, cardiovascular and hematologic complications are similar to those associated with TS-ASCT. Furthermore, BL-ASCT can yield similar engraftment and survival parameters comparable to those observed with TS-ASCT.
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- 2018
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15. Long-term efficacy and safety of dasatinib in patients with chronic myeloid leukemia in accelerated phase who are resistant to or intolerant of imatinib
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Eduardo Bullorsky, Hanna Jean Khoury, Jane F. Apperley, John F. DiPersio, Diane Healey, Lewis C. Strauss, Oliver G. Ottmann, Dong-Wook Kim, Hagop M. Kantarjian, Giuseppe Saglio, Jorge E. Cortes, Christopher Arthur, and Aude Charbonnier
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Myeloid ,medicine.drug_class ,Dasatinib ,Antineoplastic Agents ,Leukemia, Myeloid, Accelerated Phase ,Drug resistance ,lcsh:RC254-282 ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,Correspondence ,Medicine ,Humans ,neoplasms ,Protein Kinase Inhibitors ,Neoplasm Staging ,Randomized Controlled Trials as Topic ,Science & Technology ,business.industry ,Myeloid leukemia ,Imatinib ,Hematology ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Treatment Outcome ,Nilotinib ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Retreatment ,Imatinib Mesylate ,FOLLOW-UP ,business ,Life Sciences & Biomedicine ,medicine.drug - Abstract
Treatment with a frontline BCR-ABL1 tyrosine kinase inhibitor (TKI; e.g., imatinib, dasatinib, and nilotinib) allows patients with chronic myeloid leukemia (CML) in chronic phase (CP) to achieve a near normal life expectancy1, whereas treatment for CML in accelerated phase (AP) is more problematic. While reports describe outcomes for patients with CML-AP at initial diagnosis2,3, outcomes have been historically worse once CP disease has progressed to AP. Approximately 50% of patients with CML-AP who receive imatinib as initial treatment develop imatinib resistance4 and experience disease progression5. Second-generation TKIs are indicated for patients with CML-CP or advanced CML resistant to/intolerant of prior therapy (including imatinib)6. After initial approval of dasatinib twice a day (BID) for the treatment of patients with CML resistant to/intolerant of imatinib in all stages, this phase 3 CA180-035 study (NCT00123487) was developed to investigate once (QD) or twice (BID) a day dasatinib treatment in patients with CML-AP, CML in blast phase, or Ph+ acute lymphoblastic leukemia resistant to/intolerant of imatinib.
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- 2018
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16. Novel de novo TREX1 mutation in a patient with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations mimicking demyelinating disease
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Jean Khoury, Sunil K. Srivastava, Richard A. Prayson, Gabrielle Macaron, M. Kathryn Liszewski, Daniel Ontaneda, Rula A. Hajj-Ali, Robert A. Bermel, Joanna C. Jen, Hafsa Mamsa, and Justis P. Ehlers
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Pathology ,medicine.medical_specialty ,Mutation ,business.industry ,medicine.medical_treatment ,TREX1 Gene ,Multiple sclerosis ,General Medicine ,Immunotherapy ,medicine.disease ,medicine.disease_cause ,Leukoencephalopathy ,03 medical and health sciences ,0302 clinical medicine ,Neurology ,Retinal vasculopathy ,medicine ,Demyelinating disease ,030212 general & internal medicine ,Neurology (clinical) ,business ,Pathological ,030217 neurology & neurosurgery - Abstract
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is a rare fatal autosomal dominant vasculopathy associated with mutations in the TREX1 gene. Only one de novo case has been reported in the literature. We report the long-term clinical, radiological, and pathological presentation of a patient with a de novo and novel mutation in this gene. Description of the clinical, genetic, imaging and pathologic characteristics is important to better characterize RVCL-S and prevent unnecessary interventions. RVCL-S should be considered in patients with tumefactive brain lesions unresponsive to immunotherapy.
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- 2021
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17. HMG-CoA synthase 1 is a synthetic lethal partner of BRAFV600E in human cancers
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Jun Fan, Fangping Chen, Omar Abdel-Wahab, Fadlo R. Khuri, Siyuan Xia, Taha Merghoub, Hanna Jean Khoury, Brian Pollack, Zhiyu Qian, Shuangping Liu, Sagar Lonial, Lawrence H. Boise, Ruiting Lin, Yaozhu Pan, Jack L. Arbiser, Liang Zhao, Hee-Bum Kang, Michael R. Rossi, Jing Chen, Ragini R. Kudchadkar, David H. Lawson, and Guoqing Qian
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0301 basic medicine ,Gene knockdown ,Mutation ,Cell growth ,Cell Biology ,Biology ,Protein degradation ,medicine.disease_cause ,Biochemistry ,Molecular biology ,03 medical and health sciences ,Enzyme activator ,030104 developmental biology ,0302 clinical medicine ,RNA interference ,030220 oncology & carcinogenesis ,Cancer cell ,Ketogenesis ,Cancer research ,medicine ,Molecular Biology - Abstract
Contributions of metabolic changes to cancer development and maintenance have received increasing attention in recent years. Although many human cancers share similar metabolic alterations, it remains unclear whether oncogene-specific metabolic alterations are required for tumor development. Using an RNAi-based screen targeting the majority of the known metabolic proteins, we recently found that oncogenic BRAFV600E up-regulates HMG-CoA lyase (HMGCL), which converts HMG-CoA to acetyl-CoA and a ketone body, acetoacetate, that selectively enhances BRAFV600E-dependent MEK1 activation in human cancer. Here, we identified HMG-CoA synthase 1 (HMGCS1), the upstream ketogenic enzyme of HMGCL, as an additional "synthetic lethal" partner of BRAFV600E Although HMGCS1 expression did not correlate with BRAFV600E mutation in human melanoma cells, HMGCS1 was selectively important for proliferation of BRAFV600E-positive melanoma and colon cancer cells but not control cells harboring active N/KRAS mutants, and stable knockdown of HMGCS1 only attenuated colony formation and tumor growth potential of BRAFV600E melanoma cells. Moreover, cytosolic HMGCS1 that co-localized with HMGCL and BRAFV600E was more important than the mitochondrial HMGCS2 isoform in BRAFV600E-expressing cancer cells in terms of acetoacetate production. Interestingly, HMGCL knockdown did not affect HMGCS1 expression levels, whereas HMGCS1 knockdown caused a compensating increase in HMGCL protein level because of attenuated protein degradation. However, this increase did not reverse the reduced ketogenesis in HMGCS1 knockdown cells. Mechanistically, HMGCS1 inhibition decreased intracellular acetoacetate levels, leading to reduced BRAFV600E-MEK1 binding and consequent MEK1 activation. We conclude that the ketogenic HMGCS1-HMGCL-acetoacetate axis may represent a promising therapeutic target for managing BRAFV600E-positive human cancers.
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- 2017
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18. Comparing outcomes of matched related donor and matched unrelated donor hematopoietic cell transplants in adults with B‐Cell acute lymphoblastic leukemia
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Marcos de Lima, Ruta Brazauskas, H. Jean Khoury, Wael Saber, Daniel J. Weisdorf, Brenda M. Sandmaier, Eric Segal, Hai-Lin Wang, and Michael Martens
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Graft Rejection ,Male ,Cancer Research ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Severity of Illness Index ,Gastroenterology ,Cohort Studies ,0302 clinical medicine ,HLA Antigens ,Cause of Death ,Young adult ,Histocompatibility Testing ,Graft Survival ,Hazard ratio ,Age Factors ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Leukemia ,Treatment Outcome ,Oncology ,030220 oncology & carcinogenesis ,Female ,Unrelated Donors ,Adult ,medicine.medical_specialty ,Allogeneic transplantation ,Adolescent ,Lower risk ,Risk Assessment ,Article ,Young Adult ,03 medical and health sciences ,Sex Factors ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Survival analysis ,Aged ,Proportional Hazards Models ,Retrospective Studies ,business.industry ,medicine.disease ,Survival Analysis ,Surgery ,Transplantation ,business ,030215 immunology - Abstract
BACKGROUND Allogeneic hematopoietic cell transplantation (HCT) using human leukocyte antigen (HLA)–matched related donors (RDs) and allogeneic HCT using HLA-matched unrelated donors (URDs) produce similar outcomes for patients with acute myelogenous leukemia, whereas the donor source has been reported to be a predictor of outcomes in myelodysplastic syndrome. METHODS Post-HCT outcomes for 1458 acute lymphoblastic leukemia patients from 2000 to 2011 were analyzed, and RD and URD transplants were compared. RESULTS The median age was 37 years (range, 18-69 years). In the multivariate analysis, HLA 8/8 allele–matched URD recipients had similar transplant-related mortality (TRM) and all-cause mortality in comparison with RD recipients (hazard ratios [HRs], 1.16 [95% confidence interval (CI), 0.91-1.48] and 1.01 [95% CI, 0.85-1.19], respectively); 7/8 URD recipients had a greater risk of TRM and all-cause mortality in comparison with RD recipients (HRs, 1.92 [95% CI, 1.47-2.52] and 1.29 [95% CI, 1.05-1.58], respectively). The risk of TRM and all-cause mortality was also greater for 7/8 URD recipients versus 8/8 URD recipients. Compared with RD recipients, both 8/8 and 7/8 URD recipients had a lower risk of relapse (HRs, 0.77 [95% CI, 0.62-0.97] and 0.75 [95% CI, 0.56-1.00], respectively). Both 8/8 and 7/8 URD recipients had a greater risk of acute graft-versus-host disease (GVHD; HRs, 2.18 [95% CI, 1.76-2.70] and 2.65 [95% CI, 2.06-3.42], respectively) and chronic GVHD (HRs, 1.28 [95% CI, 1.06-1.55] and 1.46 [95% CI, 1.14-1.88], respectively) in comparison with RD recipients. CONCLUSIONS In the absence of RD transplantation, 8/8 URD transplantation is a viable alternative with similar survival outcomes, whereas 7/8 URD transplantation is associated with poorer overall survival. Cancer 2017;123:3346-55. © 2017 American Cancer Society.
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- 2017
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19. Immune responses and long-term disease recurrence status after telomerase-based dendritic cell immunotherapy in patients with acute myeloid leukemia
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Casey C. Case, Kevin Nishimoto, Edward D. Wirth, Debasish Sen, Jane S. Lebkowski, William Blum, Laurence Elias, Hanna Jean Khoury, Patrick S. Stiff, Anita Reddy, John F. DiPersio, and Robert H. Collins
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0301 basic medicine ,Oncology ,Cancer Research ,Telomerase ,medicine.medical_specialty ,medicine.medical_treatment ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Telomerase reverse transcriptase ,neoplasms ,business.industry ,Immunogenicity ,Cancer ,Myeloid leukemia ,Leukapheresis ,Immunotherapy ,medicine.disease ,Thrombocytopenic purpura ,030104 developmental biology ,030220 oncology & carcinogenesis ,embryonic structures ,Immunology ,business - Abstract
BACKGROUND Telomerase activity in leukemic blasts frequently is increased among patients with high-risk acute myeloid leukemia (AML). In the current study, the authors evaluated the feasibility, safety, immunogenicity, and therapeutic potential of human telomerase reverse transcriptase (hTERT)-expressing autologous dendritic cells (hTERT-DCs) in adult patients with AML. METHODS hTERT-DCs were produced from patient-specific leukapheresis, electroporated with an mRNA-encoding hTERT and a lysosomal-targeting sequence, and cryopreserved. A total of 22 patients with a median age of 58 years (range, 30-75 years) with intermediate-risk or high-risk AML in first or second complete remission (CR) were enrolled. hTERT-DCs were generated for 24 patients (73%). A median of 17 intradermal vaccinations (range, 6-32 intradermal vaccinations) containing 1×107 cells were administered as 6 weekly injections followed by 6 biweekly injections. A total of 21 patients (16 in first CR, 3 in second CR, and 2 with early disease recurrence) received hTERT-DCs. RESULTS hTERT-DCs were well tolerated with no severe toxicities reported, with the exception of 1 patient who developed idiopathic thrombocytopenic purpura. Of the 19 patients receiving hTERT-DCs in CR, 11 patients (58%) developed hTERT-specific T-cell responses that primarily were targeted toward hTERT peptides with predicted low human leukocyte antigen (HLA)-binding affinities. With a median follow-up of 52 months, 58% of patients in CR (11 of 19 patients) were free of disease recurrence at the time of their last follow-up visit; 57% of the patients who were aged ≥60 years (4 of 7 patients) also were found to be free of disease recurrence at a median follow-up of 54 months. CONCLUSIONS The generation of hTERT-DCs is feasible and vaccination with hTERT-DCs appears to be safe and may be associated with favorable recurrence-free survival. Cancer 2017;123:3061–72. © 2017 American Cancer Society.
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- 2017
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20. Does the frequency of molecular monitoring after tyrosine kinase inhibitor discontinuation affect outcomes of patients with chronic myeloid leukemia?
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Martha Arellano, Vamsi Kota, Audrey S Kim, Hanna Jean Khoury, Amelia Langston, Brittany Hill, Leonard T. Heffner, Jee Hyun Kong, Fuad El-Rassi, Anand Jillella, Elliott F. Winton, Zhengjia Chen, and Imre Bodó
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Cancer Research ,medicine.medical_specialty ,business.industry ,medicine.drug_class ,Cancer ,Myeloid leukemia ,Imatinib ,medicine.disease ,Tyrosine-kinase inhibitor ,Confidence interval ,Discontinuation ,Dasatinib ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,business ,Bosutinib ,030215 immunology ,medicine.drug - Abstract
BACKGROUND To the authors' knowledge, the optimal frequency of monitoring after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic myeloid leukemia (CML) has not been established. Data regarding the discontinuation of second-generation TKIs used in first-line treatment or after the failure of first-line treatment with TKIs are limited. Herein, the authors report real-world experience with “reduced frequency” molecular monitoring in patients with CML in all phases who discontinued treatment with imatinib, dasatinib, or bosutinib. METHODS The records of patients who discontinued TKIs were reviewed. Patients who discontinued TKIs were monitored prospectively on an intended schedule of monthly blood quantitative reverse transcriptase-polymerase chain reaction for BCR-ABL1 for 3 months, quarterly for 12 months, and every 6 months thereafter until loss of major molecular response (MMR). After loss of MMR, the TKI that previously was discontinued was reinitiated. RESULTS Between January 2010 and September 2015, a total of 24 patients in chronic (21 patients), accelerated (2 patients), and lymphoid blast (1 patient) phase discontinued imatinib (16 patients), dasatinib (5 patients), or bosutinib (3 patients) used in the front-line treatment or beyond. Blood quantitative reverse transcriptase-polymerase chain reaction for BCR-ABL1 was performed 1.3 ± 0.7 times within the first 3 months (24 patients) and 2.7 ± 1.4 times in the following 12 months (18 patients). With a median follow-up of 36.5 months (range, 3.2-67.4 months), the probabilities of treatment-free remission at 1 year and 2 years were 65.7% (95% confidence interval, 55.8%-75.6%) and 59.7% (95% confidence interval, 49.1%-70.3%), respectively. Loss of MMR was observed in 9 patients at a median of 2.8 months (range, 1.8-14.2 months) after discontinuation of TKIs. CONCLUSIONS With the limitations of a small sample size, the results of the current study demonstrate that less frequent monitoring of BCR-ABL1 does not appear to affect outcomes, and that discontinuation of TKIs used as first-line treatment or beyond after resistance or intolerance to first-line treatment appears feasible. Cancer 2017;123:2482–88. © 2017 American Cancer Society.
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- 2017
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21. Prevention of Dietary-Fat-Fueled Ketogenesis Attenuates BRAF V600E Tumor Growth
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Lawrence H. Boise, Guoqing Qian, Brian Pollack, Lingtao Jin, Siyuan Xia, Taha Merghoub, Ragini R. Kudchadkar, Shuangping Liu, Jack L. Arbiser, Hanna Jean Khoury, Fadlo R. Khuri, Liang Zhao, Hee-Bum Kang, Jun Fan, Young Rock Chung, Omar Abdel-Wahab, Qun-Ying Lei, David H. Lawson, Jin-Tang Dong, Lu Zhou, Jing Chen, Baotong Zhang, Benjamin H. Lee, Zhiyu Qian, Evmorfia Konstantakou, Ruiting Lin, Yaozhu Pan, and Sagar Lonial
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Proto-Oncogene Proteins B-raf ,0301 basic medicine ,medicine.medical_specialty ,Physiology ,medicine.medical_treatment ,Mice, Nude ,Ketone Bodies ,Biology ,Article ,Acetoacetates ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Ketogenesis ,medicine ,Animals ,Humans ,Melanoma ,neoplasms ,Molecular Biology ,Cell Proliferation ,Hypolipidemic Agents ,Cancer prevention ,3-Hydroxybutyric Acid ,Cancer ,Cell Biology ,medicine.disease ,Dietary Fats ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Endocrinology ,Pyrones ,Tumor progression ,030220 oncology & carcinogenesis ,Mutation ,Cancer research ,Ketone bodies ,Female ,Injections, Intraperitoneal ,V600E ,Ketogenic diet - Abstract
Summary Lifestyle factors, including diet, play an important role in the survival of cancer patients. However, the molecular mechanisms underlying pathogenic links between diet and particular oncogenic mutations in human cancers remain unclear. We recently reported that the ketone body acetoacetate selectively enhances BRAF V600E mutant-dependent MEK1 activation in human cancers. Here we show that a high-fat ketogenic diet increased serum levels of acetoacetate, leading to enhanced tumor growth potential of BRAF V600E-expressing human melanoma cells in xenograft mice. Treatment with hypolipidemic agents to lower circulating acetoacetate levels or an inhibitory homolog of acetoacetate, dehydroacetic acid, to antagonize acetoacetate-BRAF V600E binding attenuated BRAF V600E tumor growth. These findings reveal a signaling basis underlying a pathogenic role of dietary fat in BRAF V600E-expressing melanoma, providing insights into the design of conceptualized "precision diets" that may prevent or delay tumor progression based on an individual's specific oncogenic mutation profile.
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- 2017
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22. Cytogenetic risk determines outcomes after allogeneic transplantation in older patients with acute myeloid leukemia in their second complete remission: A Center for <scp>I</scp> nternational <scp>B</scp> lood and <scp>M</scp> arrow <scp>T</scp> ransplant <scp>R</scp> esearch cohort analysis
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Martin S. Tallman, Taiga Nishihori, Vikas Gupta, Mohamed A. Kharfan-Dabaja, Ulrike Bacher, Zachariah DeFilipp, Marcos de Lima, Yi Bin Chen, Hai-Lin Wang, Mahmoud Aljurf, H. Jean Khoury, David A. Rizzieri, Richard F. Olsson, Robert Peter Gale, Partow Kebriaei, Brenda M. Sandmaier, Hillard M. Lazarus, Amer Beitinjaneh, Armin Rashidi, Fotios V. Michelis, Mei-Jie Zhang, Daniel J. Weisdorf, Betul Oran, Wael Saber, and theMedicalCollegeofWisconsin
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Cancer Research ,medicine.medical_specialty ,Univariate analysis ,business.industry ,medicine.medical_treatment ,Hazard ratio ,Retrospective cohort study ,Hematopoietic stem cell transplantation ,3. Good health ,Surgery ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,Cumulative incidence ,Risk factor ,business ,Survival rate ,030215 immunology - Abstract
BACKGROUND Allogeneic hematopoietic cell transplantation (HCT) offers curative potential to a number of older patients with acute myeloid leukemia (AML) in their first complete remission. However, there are limited data in the literature concerning post-HCT outcomes for older patients in their second complete remission (CR2). METHODS The purpose of the current study was to retrospectively investigate within the Center for International Blood and Marrow Transplant Research database parameters influencing posttransplant outcomes for patients 60 years of age or older undergoing HCT for AML in CR2. RESULTS In total, 196 patients from 78 centers were identified; the median age was 64 years (range, 60-78 years). Seventy-one percent had a Karnofsky performance status ≥ 90 at the time of HCT. Reduced-intensity conditioning regimens were used in 159 patients (81%). A univariate analysis demonstrated a 3-year overall survival (OS) rate of 42% (95% confidence interval [CI], 35%-49%), a leukemia-free survival rate of 37% (95% CI, 30%-44%), a cumulative incidence of nonrelapse mortality of 25% (95% CI, 19%-32%), and a cumulative incidence of relapse (CIR) of 38% (95% CI, 31%-45%). A multivariate analysis demonstrated that cytogenetic risk was the only independent risk factor for OS (P = .023) with a hazard ratio (HR) of 1.14 (95% CI, 0.59-2.19) for intermediate-risk cytogenetics and an HR of 2.32 (95% CI, 1.05-5.14) for unfavorable-risk cytogenetics. For CIR, cytogenetic risk was also the only independent prognostic factor (P = .01) with an HR of 1.10 (95% CI, 0.47-2.56) for intermediate-risk cytogenetics and an HR of 2.98 (95% CI, 1.11-8.00) for unfavorable-risk cytogenetics. CONCLUSIONS Allogeneic HCT is a curative treatment option for older patients with AML in CR2, particularly for those with favorable or intermediate cytogenetic risk. Cancer 2017;123:2035–2042. © 2017 American Cancer Society.
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- 2017
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23. ERRATUM: Managing acute promyelocytic leukemia in patients belonging to the Jehovah’s Witness congregation
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Martha Arellano, Manila Gaddh, Hanna Jean Khoury, Amelia Langston, Leonard T. Heffner, Anand Jillella, Vamsi Kota, and Abhishek Mangaonkar
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Acute promyelocytic leukemia ,medicine.medical_specialty ,Pediatrics ,Hematology ,business.industry ,lcsh:RC633-647.5 ,Jehovah s witness ,lcsh:Diseases of the blood and blood-forming organs ,medicine.disease ,Internal medicine ,Medicine ,In patient ,business ,Editor - Abstract
Not available.
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- 2019
24. Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia
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David L. Mitchell, Daniel L. Flynn, Richard A. Larson, Kapil N. Bhalla, Moshe Talpaz, David S. Snyder, Bryan D. Smith, Scott C. Wise, Oliver Rosen, Richard A. Van Etten, Thomas J. Rutkoski, Hedy Smith, Hagop M. Kantarjian, Javier Pinilla-Ibarz, Jorge E. Cortes, and Jean Khoury
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Adult ,Male ,0301 basic medicine ,Myeloid ,Maximum Tolerated Dose ,Immunology ,Chronic Myeloid Leukemia ,Fusion Proteins, bcr-abl ,Drug resistance ,Cardiorespiratory Medicine and Haematology ,Pharmacology ,Young Adult ,03 medical and health sciences ,Myelogenous ,0302 clinical medicine ,Refractory ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,medicine ,Humans ,Protein Kinase Inhibitors ,Aged ,Aged, 80 and over ,business.industry ,Myeloid leukemia ,Articles ,Hematology ,Middle Aged ,medicine.disease ,3. Good health ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,Peripheral neuropathy ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Pharmacodynamics ,Mutation ,Quinolines ,Female ,Drug Monitoring ,business - Abstract
A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5′-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib (clinicaltrials.gov Identifier:00827138).
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- 2016
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25. Long‐term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib
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Carlo Gambacorti-Passerini, Kay Noonan, Hanna Jean Khoury, Dong-Wook Kim, Jeffrey H. Lipton, Hagop M. Kantarjian, Jorge E. Cortes, Philippe Schafhausen, Eric Leip, Tim H. Brümmendorf, Ewa Matczak, Cortes, J, Khoury, H, Kantarjian, H, Lipton, J, Kim, D, Schafhausen, P, Matczak, E, Leip, E, Noonan, K, Brümmendorf, T, and GAMBACORTI PASSERINI, C
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Adult ,0301 basic medicine ,medicine.medical_specialty ,Adolescent ,Nausea ,Dasatinib ,Antineoplastic Agents ,Pharmacology ,Gastroenterology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Nitriles ,Humans ,Medicine ,Cumulative incidence ,Longitudinal Studies ,Adverse effect ,Research Articles ,Aged ,Aged, 80 and over ,Salvage Therapy ,Aniline Compounds ,business.industry ,Remission Induction ,Myeloid leukemia ,Imatinib ,Hematology ,Middle Aged ,Survival Analysis ,Pyrimidines ,Treatment Outcome ,030104 developmental biology ,Nilotinib ,030220 oncology & carcinogenesis ,Leukemia, Myeloid, Chronic-Phase ,Disease Progression ,Imatinib Mesylate ,Quinolines ,medicine.symptom ,business ,Bosutinib ,Research Article ,medicine.drug - Abstract
American journal of hematology 91(12), 1206-1214 (2016). doi:10.1002/ajh.24536, Published by Wiley-Liss, New York, NY
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- 2016
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26. Does FLT3 mutation impact survival after hematopoietic stem cell transplantation for acute myeloid leukemia? A Center for International Blood and Marrow Transplant Research (CIBMTR) analysis
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Abhinav Deol, Corey Cutler, Ayman Saad, Steven M. Devine, Martin Bornhäuser, Yi-Bin Chen, Donald Bunjes, Jean-Yves Cahn, Madan Jagasia, Daniel J. Weisdorf, Ran Reshef, Kwang Woo Ahn, Siddhartha Ganguly, Richard F. Olsson, John Koreth, H. Schouten, Geoffrey L. Uy, Baldeep Wirk, Peter H. Wiernik, Robert J. Soiffer, Minoo Battiwalla, Mahmoud Aljurf, Edmond K Waller, Mitchell Sabloff, Marcos de Lima, Ann E. Woolfrey, Taiga Nishihori, Hanna Jean Khoury, Brenda M. Sandmaier, Mehdi Hamadani, Bruce M. Camitta, Robert Peter Gale, Thomas C. Shea, Salyka Sengsayadeth, Rammurti T. Kamble, Wael Saber, Jacob M. Rowe, David I. Marks, Jane L. Liesveld, Yoshihiro Inamoto, Hai-Lin Wang, Joseph H. Antin, Mark R. Litzow, and Hillard M. Lazarus
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Oncology ,Cancer Research ,medicine.medical_specialty ,Hematology ,business.industry ,medicine.medical_treatment ,Cancer ,Myeloid leukemia ,Hematopoietic stem cell transplantation ,medicine.disease ,Minimal residual disease ,Surgery ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,030220 oncology & carcinogenesis ,Internal medicine ,Relative risk ,Fms-Like Tyrosine Kinase 3 ,medicine ,business ,Survival rate ,030215 immunology - Abstract
BACKGROUND Patients with FMS like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML) have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (HCT). METHODS Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were used to evaluate 511 adult patients with de novo AML who underwent HCT during 2008 through 2011 to determine whether FLT3 mutations had an impact on HCT outcomes. RESULTS In total, 158 patients (31%) had FLT3 mutations. Univariate and multivariate analyses revealed an increased risk of relapse at 3 years in the FLT3 mutated group compared with the wild-type (WT) group (38% [95% confidence interval (CI), 30%-45%] vs 28% [95% CI, 24%-33%]; P = .04; relative risk, 1.60 [95% CI, 1.15-2.22]; P = .0048). However, FLT3 mutation status was not significantly associated with nonrelapse mortality, leukemia-free survival, or overall survival. Although more patients in the FLT3 mutated group died from relapsed primary disease compared with those in the WT group (60% vs 46%), the 3-year overall survival rate was comparable for the 2 groups (mutated group: 49%; 95% CI, 40%-57%; WT group: 55%, 95% CI, 50%-60%; P = .20). CONCLUSIONS The current data indicate that FLT3 mutation status did not adversely impact overall survival after HCT, and about 50% of patients with this mutation who underwent HCT were long-term survivors. Cancer 2016;122:3005-3014. © 2016 American Cancer Society.
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- 2016
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27. Targeting 6-phosphogluconate dehydrogenase in the oxidative PPP sensitizes leukemia cells to antimalarial agent dihydroartemisinin
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Sagar Lonial, Shaoxiong Wu, Hanna Jean Khoury, Jing Chen, Changliang Shan, Fadlo R. Khuri, Titus J. Boggon, Martha Arellano, Shannon Elf, Siyuan Xia, Manila Gaddh, Jun Fan, Ruiting Lin, Benjamin H. Lee, and Yaozhu Pan
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0301 basic medicine ,Cancer Research ,Emodin ,Cell Survival ,leukemia cell proliferation ,medicine.medical_treatment ,Mice, Nude ,Dihydroartemisinin ,Pharmacology ,Biology ,Article ,Pentose Phosphate Pathway ,Antimalarials ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Genetics ,medicine ,Animals ,Humans ,Viability assay ,Antimalarial Agent ,Phosphogluconate dehydrogenase ,Molecular Biology ,hemolytic anemia ,Leukemia ,Phosphogluconate Dehydrogenase ,Drug Synergism ,medicine.disease ,Cancer metabolism ,Xenograft Model Antitumor Assays ,Artemisinins ,3. Good health ,030104 developmental biology ,Cell culture ,030220 oncology & carcinogenesis ,Cancer cell ,anti-malarial agent ,Female ,6-phosphogluconate dehydrogenase ,K562 Cells ,K562 cells - Abstract
The oxidative pentose phosphate pathway (PPP) is crucial for cancer cell metabolism and tumor growth. We recently reported that targeting a key oxidative PPP enzyme, 6-phosphogluconate dehydrogenase (6PGD), using our novel small molecule 6PGD inhibitors Physcion and its derivative S3, shows anti-cancer effects. Notably, humans with genetic deficiency of either 6PGD or another oxidative PPP enzyme, glucose-6-phosphate dehydrogenase (G6PD), exhibit non-immune hemolytic anemia upon exposure to aspirin and various anti-malarial drugs. Inspired by these clinical observations, we examined the anti-cancer potential of combined treatment with 6PGD inhibitors and anti-malarial drugs. We found that stable knockdown of 6PGD sensitizes leukemia cells to anti-malarial agent dihydroartemisinin (DHA). Combined treatment with DHA and Physcion activates AMP-activated protein kinase, leading to synergistic inhibition of human leukemia cell viability. Moreover, our combined therapy synergistically attenuates tumor growth in xenograft nude mice injected with human K562 leukemia cells and cell viability of primary leukemia cells from human patients, but shows minimal toxicity to normal hematopoietic cells in mice as well as red blood cells and mononucleocytes from healthy human donors. Our findings reveal the potential for combined therapy using optimized doses of Physcion and DHA as a novel anti-leukemia treatment without inducing hemolysis.
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- 2016
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28. Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib
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H. Jean Khoury, Jean M. Aguiar, Carlo Gambacorti-Passerini, Svetoslav Dimitrov, Ewa Matczak, Jeffrey H. Lipton, Dmitri Pavlov, Mark Shapiro, Hagop M. Kantarjian, Jean-Bernard Durand, Kolette D. Fly, Jorge E. Cortes, Tim H. Brümmendorf, Michael J. Mauro, and Eric Leip
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medicine.medical_specialty ,Ejection fraction ,Performance status ,business.industry ,Phases of clinical research ,Imatinib ,Hematology ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Imatinib mesylate ,030220 oncology & carcinogenesis ,Internal medicine ,Concomitant ,medicine ,business ,Intensive care medicine ,Adverse effect ,Bosutinib ,030215 immunology ,medicine.drug - Abstract
Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long-term bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth-line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first-line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow-up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib-treated patients were 7%/10% overall with similar incidences observed with first-line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in >2% of bosutinib patients. Exposure-adjusted vascular/cardiac TEAE rates (patients with events/patient-year) were low for second-line or later bosutinib (0.037/0.050) and not significantly different between first-line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status >0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first-line and relapsed/refractory settings following long-term treatment in patients with Ph+ leukemia. Am. J. Hematol. 91:606-616, 2016. © 2016 Wiley Periodicals, Inc.
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- 2016
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29. Myeloablative vs reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chronic myeloid leukemia
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Ronald Sobecks, Wael Saber, Richard F. Olsson, Jack W. Hsu, Matt Kalaycio, Melhem Solh, Zachariah DeFilipp, Sandeep Jain, Nirav N. Shah, Ann E. Woolfrey, Attaphol Pawarode, Andrew Daly, Jacob M. Rowe, Betty K. Hamilton, Amer Assal, Zhen-Huan Hu, Hillard M. Lazarus, Siddhartha Ganguly, Yoshihiro Inamoto, Harry C. Schouten, Olle Ringdén, Celalettin Ustun, Sunita Nathan, Kwang Woo Ahn, Edward A. Copelan, Mark R. Litzow, Ayman Saad, Jean A. Yared, Abraham S. Kanate, Robert K. Stuart, Uday R. Popat, Saurabh Chhabra, Jan Cerny, Bipin N. Savani, H. Jean Khoury, Shahinaz M. Gadalla, Robert Peter Gale, Sachiko Seo, Edwin P. Alyea, and Gerhard C. Hildebrandt
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Oncology ,Adult ,Male ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Recurrence ,Internal medicine ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Humans ,Transplantation, Homologous ,Cumulative incidence ,Prospective Studies ,Survival rate ,neoplasms ,Alemtuzumab ,Proportional Hazards Models ,Transplantation ,Hematology ,business.industry ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Middle Aged ,medicine.disease ,respiratory tract diseases ,Survival Rate ,Leukemia ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Multivariate Analysis ,Female ,business ,030215 immunology - Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment of chronic myeloid leukemia (CML). Optimal conditioning intensity for allo-HCT for CML in the era of tyrosine kinase inhibitors (TKIs) is unknown. Using the Center for International Blood and Marrow Transplant Research database, we sought to determine whether reduced-intensity/nonmyeloablative conditioning (RIC) allo-HCT and myeloablative conditioning (MAC) result in similar outcomes in CML patients. We evaluated 1395 CML allo-HCT recipients between the ages of 18 and 60 years. The disease status at transplant was divided into the following categories: chronic phase 1, chronic phase 2 or greater, and accelerated phase. Patients in blast phase at transplant and alternative donor transplants were excluded. The primary outcome was overall survival (OS) after allo-HCT. MAC (n = 1204) and RIC allo-HCT recipients (n = 191) from 2007 to 2014 were included. Patient, disease, and transplantation characteristics were similar, with a few exceptions. Multivariable analysis showed no significant difference in OS between MAC and RIC groups. In addition, leukemia-free survival and nonrelapse mortality did not differ significantly between the 2 groups. Compared with MAC, the RIC group had a higher risk of early relapse after allo-HCT (hazard ratio [HR], 1.85; P = .001). The cumulative incidence of chronic graft-versus-host disease (cGVHD) was lower with RIC than with MAC (HR, 0.77; P = .02). RIC provides similar survival and lower cGVHD compared with MAC and therefore may be a reasonable alternative to MAC for CML patients in the TKI era.
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- 2018
30. Upper gastrointestinal acute graft-versus-host disease adds minimal prognostic value in isolation or with other graft-versus-host disease symptoms as currently diagnosed and treated
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Hideki Nakasone, Sarah Nikiforow, Taiga Nishihori, David I. Marks, Amin M. Alousi, Donna Przepiorka, Joseph H. Antin, Joseph Pidala, Ned Waller, Baldeep Wirk, Daniel J. Weisdorf, Hanna Jean Khoury, Margaret L. MacMillan, Richard F. Olsson, Corey Cutler, Gorgun Akpek, Daniel R. Couriel, Michael T. Hemmer, Tao Wang, Ran Reshef, Sophie Paczesny, Sung Won Choi, Ken Meehan, Yoshihiro Inamoto, Hélène Schoemans, Stephen R. Spellman, Vijay Reddy, Mary M. Horowitz, and Mukta Arora
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Male ,Gastrointestinal Diseases ,Graft vs Host Disease ,Disease ,Gastroenterology ,RETROSPECTIVE ANALYSIS ,0302 clinical medicine ,ENDOSCOPIC EVALUATION ,Medicine ,MYCOPHENOLATE-MOFETIL ,Acute leukemia ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematopoietic stem cell ,Hematology ,Middle Aged ,Allografts ,3. Good health ,Survival Rate ,medicine.anatomical_structure ,surgical procedures, operative ,030220 oncology & carcinogenesis ,Female ,Life Sciences & Biomedicine ,CLINICAL-TRIALS ,PREDICT SURVIVAL ,Adult ,medicine.medical_specialty ,Adolescent ,BONE-MARROW ,ACUTE GVHD ,Article ,Disease-Free Survival ,03 medical and health sciences ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,Acute graft versus host disease ,Humans ,Upper gastrointestinal ,Aged ,IBMTR SEVERITY INDEX ,Immunosuppression Therapy ,Science & Technology ,business.industry ,STEM-CELL TRANSPLANTATION ,medicine.disease ,RANDOMIZED-TRIAL ,Clinical trial ,Graft-versus-host disease ,Myelodysplastic Syndromes ,business ,Stem Cell Transplantation ,030215 immunology - Abstract
Upper gastrointestinal acute graft-versus-host disease is reported in approximately 30% of hematopoietic stem cell transplant recipients developing acute graft-versus-host disease. Currently classified as Grade II in consensus criteria, upper gastrointestinal acute graft-versus-host disease is often treated with systemic immunosuppression. We reviewed the Center for International Blood and Marrow Transplant Research database to assess the prognostic implications of upper gastrointestinal acute graft-versus-host disease in isolation or with other acute graft-versus-host disease manifestations. 8567 adult recipients of myeloablative allogeneic hematopoietic stem cell transplant receiving T-cell replete grafts for acute leukemia, chronic myeloid leukemia or myelodysplastic syndrome between 2000 and 2012 were analyzed. 51% of transplants were from unrelated donors. Reported upper gastrointestinal acute graft-versus-host disease incidence was 12.1%; 2.7% of recipients had isolated upper gastrointestinal acute graft-versus-host disease, of whom 95% received systemic steroids. Patients with isolated upper gastrointestinal involvement had similar survival, disease-free survival, transplant-related mortality, and relapse as patients with Grades 0, I, or II acute graft-versus-host disease. Unrelated donor recipients with isolated upper gastrointestinal acute graft-versus-host disease had less subsequent chronic graft-versus-host disease than those with Grades I or II disease (P=0.016 and P=0.0004, respectively). Upper gastrointestinal involvement added no significant prognostic information when present in addition to other manifestations of Grades I or II acute graft-versus-host disease. If upper gastrointestinal symptoms were reclassified as Grade 0 or I, 425 of 2083 patients (20.4%) with Grade II disease would be downgraded, potentially impacting the interpretation of clinical trial outcomes. Defining upper gastrointestinal acute graft-versus-host disease as a Grade II entity, as it is currently diagnosed and treated, is not strongly supported by this analysis. The general approach to diagnosis, treatment and grading of upper gastrointestinal symptoms and their impact on subsequent acute graft-versus-host disease therapy warrants reevaluation. ispartof: HAEMATOLOGICA vol:103 issue:10 pages:1708-1719 ispartof: location:Italy status: published
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- 2018
31. Intravenous Busulfan Compared with Total Body Irradiation Pretransplant Conditioning for Adults with Acute Lymphoblastic Leukemia
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Ayman Saad, Minoo Battiwalla, Richard E. Champlin, Gorgun Akpek, Stephen J. Forman, Mark P. Hertzberg, Partow Kebriaei, Mahmoud Aljurf, Marc Bierings, Rammurti T. Kamble, Michael A. Pulsipher, Jan Cerny, Sid Ganguly, Kirk R. Schultz, Muna Qayed, Aleksandr Lazaryan, William J. Hogan, Mei-Jie Zhang, Attaphol Pawarode, Andrew S. Artz, Taiga Nishihori, Hillard M. Lazarus, Bipin N. Savani, Marcos de Lima, Harry C. Schouten, Ashish Bajel, Miguel Angel Diaz, Betty K. Hamilton, Geoffrey L. Uy, Karen K. Ballen, Robert Peter Gale, Cesar O. Freytes, Ibrahim Aldoss, Hai-Lin Wang, Celalettin Ustun, Jean-Yves Cahn, Matthew J. Wieduwilt, Ian Nivison-Smith, Sachiko Seo, Nandita Khera, Lynn Savoie, Brenda M. Sandmaier, Claudio Anasetti, Jonathan E. Brammer, Daniel J. Weisdorf, Ann A. Jakubowski, Richard F. Olsson, David I. Marks, Matthew D. Seftel, Michael R. Grunwald, Nelli Bejanyan, Navneet Majhail, Y. Inamoto, Vinod Pullarkat, Stefan O. Ciurea, Mark R. Litzow, Christopher Bredeson, Zachariah DeFilipp, Edward A. Copelan, Jaap-Jan Boelens, H. Jean Khoury, Joseph C. Alvarnas, Ann E. Woolfrey, Jean Yared, Ravi Vij, Maxim Norkin, Mitchell Sabloff, Mary M. Horowitz, William A. Wood, B. Mona Wirk, Gerhard C. Hildebrandt, Agnes S. M. Yong, Amer Beitinjaneh, Ulrike Bacher, David A. Rizzieri, and Christopher G. Kanakry
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Adult ,Male ,Melphalan ,medicine.medical_specialty ,Transplantation Conditioning ,Adolescent ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Acute lymphoblastic leukemia ,Gastroenterology ,Disease-Free Survival ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Total body irradiation ,medicine ,Humans ,Clofarabine ,Survival rate ,Busulfan ,Transplantation ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Allografts ,Allogeneic transplant ,Fludarabine ,Survival Rate ,030220 oncology & carcinogenesis ,Administration, Intravenous ,Female ,business ,Whole-Body Irradiation ,Follow-Up Studies ,030215 immunology ,medicine.drug - Abstract
Total body irradiation (TBI) has been included in standard conditioning for acute lymphoblastic leukemia (ALL) before hematopoietic cell transplantation (HCT). Non-TBI regimens have incorporated busulfan (Bu) to decrease toxicity. This retrospective study analyzed TBI and Bu on outcomes of ALL patients 18–60 years old, in first or second complete remission (CR), undergoing HLA-compatible sibling, related, or unrelated donor HCT, who reported to the Center for International Blood and Marrow Transplant Research from 2005 to 2014. TBI plus etoposide (25%) or cyclophosphamide (75%) was used in 819 patients, and intravenous Bu plus fludarabine (41%), clofarabine (30%), cyclophosphamide (15%), or melphalan (13%) was used in 299 patients. Bu-containing regimens were analyzed together, since no significant differences for patient outcomes were noted between them. Bu patients were older, with better performance status; took longer to achieve first CR and receive HCT; were treated more recently; and were more likely to receive peripheral blood grafts, antithymocyte globulin, or tyrosine kinase inhibitors. With median follow-up of 3.6 years for Bu and 5.3 years for TBI, adjusted 3-year outcomes showed treatment-related mortality Bu 19% versus TBI 25% (P = .04); relapse Bu 37% versus TBI 28% (P = .007); disease-free survival (DFS) Bu 45% versus TBI 48% (P = .35); and overall survival (OS) Bu 57% versus TBI 53% (P = .35). In multivariate analysis, Bu patients had higher risk of relapse (relative risk, 1.46; 95% confidence interval, 1.15 to 1.85; P = .002) compared with TBI patients. Despite the higher relapse, Bu-containing conditioning led to similar OS and DFS following HCT for ALL.
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- 2018
32. Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial
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Michael W. Deininger, Carlo Gambacorti-Passerini, Stephanie Lustgarten, Hagop M. Kantarjian, Martin Müller, Jorge E. Cortes, Delphine Rea, Michele Baccarani, Timothy P. Hughes, Dong-Wook Kim, Ronald Paquette, Daniel J. DeAngelo, Victor M. Rivera, Philipp le Coutre, Neil P. Shah, Charles Chuah, Elisabetta Abruzzese, Javier Pinilla-Ibarz, Franck E. Nicolini, Frank G. Haluska, François Guilhot, Jane F. Apperley, H. Jean Khoury, Moshe Talpaz, Andreas Hochhaus, Cortes, J, Kim, D, Pinilla-Ibarz, J, le Coutre, P, Paquette, R, Chuah, C, Nicolini, F, Apperley, J, Khoury, H, Talpaz, M, Deangelo, D, Abruzzese, E, Rea, D, Baccarani, M, Müller, M, Gambacorti-Passerini, C, Lustgarten, S, Rivera, V, Haluska, F, Guilhot, F, Deininger, M, Hochhaus, A, Hughes, T, Shah, N, and Kantarjian, H
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Male ,Time Factors ,Clinical Trials and Observations ,NILOTINIB ,Biochemistry ,RECOMMENDATIONS ,chemistry.chemical_compound ,0302 clinical medicine ,MED/15 - MALATTIE DEL SANGUE ,hemic and lymphatic diseases ,1114 Paediatrics And Reproductive Medicine ,Cumulative incidence ,Philadelphia Chromosome ,IMATINIB-RESISTANT ,BCR-ABL ,Philadelphia chromosome positive ,Aged, 80 and over ,education.field_of_study ,DASATINIB ,Ponatinib ,CHRONIC MYELOGENOUS LEUKEMIA ,Imidazoles ,Hematology ,Middle Aged ,Prognosis ,Dasatinib ,Pyridazines ,Survival Rate ,030220 oncology & carcinogenesis ,Female ,Safety ,TYROSINE KINASE INHIBITOR ,Life Sciences & Biomedicine ,medicine.drug ,Adult ,medicine.medical_specialty ,Population ,Immunology ,Antineoplastic Agents ,acute lymphoblastic leukemia ,Philadelphia chromosome ,1102 Cardiovascular Medicine And Haematology ,CML PATIENTS ,03 medical and health sciences ,Young Adult ,chronic myeloid leukemia ,Internal medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,BCR-ABL INHIBITOR ,medicine ,Humans ,Adverse effect ,education ,CHRONIC MYELOID-LEUKEMIA ,Survival rate ,Aged ,Salvage Therapy ,Science & Technology ,business.industry ,1103 Clinical Sciences ,Cell Biology ,medicine.disease ,chemistry ,Nilotinib ,Drug Resistance, Neoplasm ,ADVERSE EVENTS ,business ,030215 immunology ,Follow-Up Studies - Abstract
Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n = 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ≥90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients. This trial was registered at www.clinicaltrials.gov as #NCT01207440.
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- 2018
33. Abstract 162: Microhemorrhages in MRI Predict Infectious Intracranial Aneurysm in Infective Endocarditis
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Jean Khoury, Cory Rice, Dolora Wisco, Lucy Zhang, Sung Min Cho, Andrew B. Buletko, Prateek Thatikunta, Ken Uchino, and Robert J. Marquardt
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Advanced and Specialized Nursing ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Magnetic resonance imaging ,medicine.disease ,Infectious intracranial aneurysm ,Infective endocarditis ,Susceptibility weighted imaging ,Angiography ,medicine ,Endocarditis ,Neurology (clinical) ,Radiology ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background: MRI features such as cerebral microbleeds and sulcal susceptibility weighted imaging (SWI) or gradient-echo T2* (GRE-T2*) lesions have been reported to be associated with the presence of infectious intracranial aneurysm (IIA) in infective endocarditis (IE). We aimed to describe the MRI imaging features that predict the presence of IIA. Methods: The derivation cohort comprised 116 IE patients with neurological evaluation at a single tertiary referral center from January 2015 to July 2016. The MRI predictors associated with IIA was evaluated, and we developed the MRI imaging predictors and assessed sensitivity and specificity. External validation was performed in a cohort of 129 IE patients who underwent digital subtraction angiogram (DSA) at the same center from 2010-2014. We assessed the validity using a receiver operating characteristic curve (ROC). Results: Of 116 IE patients in the derivation cohort, 10 (9%) had IIAs. Of 129 in the validation cohort, 19 (15%) IIAs were identified. The MRI imaging predictors for IIA consist of 1) contrast enhancement with SWI lesions, 2) cerebral microbleeds > 5mm plus sulcal SWI lesions, and 3) any MRI hemorrhages. The sensitivity for the presence of IIA in each group of the derivation cohort was: 90%, 80%, and 100%, respectively. The sensitivity in the validation cohort was: 47%, 68%, and 94% respectively. The specificity in the derivation cohort was: 87%, 85%, and 18%. In the validation cohort, the specificity was similar (87%, 75%, and 27%). Conclusions: The suggested MRI imaging predictors can be used as a sensitive and specific tool to support clinical decision-making, especially when invasive DSA is considered for assessment for presence of IIA. The absence of MRI hemorrhages may not necessitate the need for DSA.
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34. Abstract WP331: Intracranial Hemorrhage in Infective Endocarditis: Underlying Arterial and Parenchymal Disease
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Ken Uchino, Cory Rice, Lucy Zhang, Jean Khoury, Dolora Wisco, and Sung Min Cho
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Advanced and Specialized Nursing ,Pathology ,medicine.medical_specialty ,business.industry ,Infective endocarditis ,Parenchyma ,medicine ,cardiovascular diseases ,Neurology (clinical) ,Disease ,Cardiology and Cardiovascular Medicine ,medicine.disease ,business - Abstract
Introduction: Intracranial hemorrhage (ICH) is a known complication of infective endocarditis (IE). We aimed to explore radiologic findings that may explain the cause of ICH and the prognosis of these patients. Methods: We reviewed records of infective endocarditis cases with intraparenchymal hemorrhage (IPH) and subarachnoid hemorrhage (SAH) who underwent magnetic resonance imaging (MRI) and cerebral angiography at a single tertiary center from 2010 to 2014. All patients fulfilled modified Duke’s criteria for infective endocarditis. Results: We identified 36 patients our inclusion criteria. Eleven (30%) had IPH only, 10 (28%) had SAH, and 15 (42%) had both. The most common presenting symptoms were focal neurological deficit (39%, n=14), encephalopathy (25%, n=9), followed by headache (19%, n=7). The hemorrhage was silent in (19%, n=7) cases. Twelve patients (33%) had mycotic aneurysms but only 4 had evidence of rupture (11%). Ten (28%) had distal arterial irregularities on angiography suggestive of vasculitis. Thirteen (36%) had evidence of microabscesses on MRI, and 22 (61%) had cerebral ischemia on MRI, of which 6 had a hemorrhagic transformation. In 24 out of 25 SAH cases cortical sulcal hemorrhage was seen and only one SAH was in the basal cistern. In 14 (56%) of these cortical SAHs had adjacent restricted diffusion lesion on the MRI. Among 21 patients undergoing valvular repair, only 2 (1%) were complicated with new intracranial hemorrhage that had no relation to the presence of microhemorrhages on MRI (p=0.42). Conclusion: Intracranial hemorrhage in infective endocarditis is rarely related to mycotic aneurysms. Parenchymal involvement of infection or vascular inflammation may be the underlying causes for IPH and SAH in these patients.
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35. Abstract WP325: Peri-operative Neurological Complications of Valve Surgery for Infective Endocarditis Patients With Stroke
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Jean Khoury, Lucy Zhang, Dolora Wisco, Sung Min Cho, Cory Rice, and Ken Uchino
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Advanced and Specialized Nursing ,medicine.medical_specialty ,Valve surgery ,business.industry ,Perioperative ,medicine.disease ,Surgery ,Valvular disease ,Infective endocarditis ,medicine ,cardiovascular diseases ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,business ,Stroke - Abstract
Introduction: Surgical valve repair is often delayed for infective endocarditis (IE) patients with stroke. We compared neurological outcome of early and delayed valve surgery and identified pre-surgical imaging characteristics that were associated with perioperative neurological complications. Methods: We reviewed 228 patients with acute IE diagnosed by modified Duke’s Criteria who underwent cerebral angiogram (CA) between January 2010 - December 2016 at a single center. Patients without pre-surgical CT and MRI were excluded. Date of IE diagnosis was defined as date of antibiotic initiation. Early surgery was defined as valve replacement ≤14 days from date of IE diagnosis, delayed as >14 days. Peri-operative neurological complication is any new clinical or radiologic diagnosis of ischemic or hemorrhagic stroke, and seizure. Results: 148 of 228 patients underwent valve surgery. 69 patients (46.6%) had early surgery at median 9 days after IE diagnosis, and 79 patients (53.4%) had delayed surgery at median 28 days. On pre-surgical imaging, acute to subacute ischemic stroke was seen in 81% of the early group (n=56) and 78% of the delayed group (n=62, p=0.69). However, 22.8% of patients (n=18) in the delayed group had evidence of subarachnoid hemorrhage (SAH) compared to 10.1 % of patients in the early group (n=7, p=0.04). Despite this finding, delayed group did not have higher rate of perioperative neurological complication than that of the early group (24.1% vs 13%, p=0.95). Overall, 15 surgical patients (10.1%) had perioperative neurological complications: 4 with acute ischemic stroke, 9 with ICH, 1 with both an infarct and ICH, and 3 with seizures. 33.3% of patients who had a perioperative neurological complication had evidence of SAH on pre-surgical imaging (n=6) compared to 14.6% of patients who did not have any neurological complications (n=19, p=0.012). In the group of patients with complications, SAH found prior to surgery were all cortical in the sulci, and 3 cases of SAH were associated with presence of infectious intracranial aneurysm found on pre-surgical CA. Conclusion: In IE patients with stroke, presence of sulcal SAH on pre-surgical imaging is associated with developing perioperative neurological complications irrespective of surgical timing.
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- 2018
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36. Abstract 163: Natural History of Infectious Intracranial Aneurysms Undergoing Antibiotic Treatment
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Dolora Wisco, Cory Rice, Sung Min Cho, Jean Khoury, Ken Uchino, M. Shazam Hussain, Lucy Zhang, and Prateek Thatikunta
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Advanced and Specialized Nursing ,medicine.medical_specialty ,medicine.drug_class ,business.industry ,Antibiotics ,Clinical course ,Mycotic aneurysm ,medicine.disease ,Infectious intracranial aneurysm ,Surgery ,Natural history ,Infective endocarditis ,medicine ,Endocarditis ,cardiovascular diseases ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,business ,Complication - Abstract
Introduction: Infectious intracranial aneurysm (IIA, or mycotic aneurysm) is a cerebrovascular complication of infective endocarditis. We aimed to describe the clinical course of IIAs during antibiotic treatment. Methods: We reviewed medical records of persons with infective endocarditis who underwent cerebral angiography at a single tertiary referral center from 2011-2016. Aneurysms were followed with subsequent angiography for bad outcome (growth, rupture or new IIA formation) or good outcome (regression or resolution) until endovascular therapy, aneurysm resolution, or end of observation. Results: Of 618 patients included, 40 (6.5%) had 43 IIAs. Eighteen (42%) aneurysms underwent initial endovascular treatment. Twenty-five unruptured aneurysms were treated with antibiotics alone for a median 36 days (interquartile range (IQR) 9-57). Nine (36%) aneurysms had bad outcome (2 new IIA formation, 7 enlargement) at median 8 days, IQR 1-25. Angiography revealed good outcome in 7 (28%) patients (6 resolution, 1 regression) at median 36 days, IQR 16-49. Two patients had no IIA change after median 27 days, and both underwent endovascular treatment. Seven aneurysms had no angiographic reevaluations but no rupture during clinical follow-up for median 4 days, IQR 3-12. There were no aneurysmal ruptures during observation. Conclusion: IIAs represent a dynamic disease. Only a quarter of IIAs resolve with antibiotics alone.
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- 2018
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37. Practical Management of Toxicities Associated With Bosutinib in Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia
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Carlo Gambacorti-Passerini, Tim H. Brümmendorf, Hanna Jean Khoury, and Gambacorti Passerini, C
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Oncology ,medicine.medical_specialty ,Reviews ,Salvage therapy ,Antineoplastic Agents ,03 medical and health sciences ,Myelogenous ,0302 clinical medicine ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,hemic and lymphatic diseases ,Internal medicine ,Nitriles ,medicine ,Humans ,In patient ,Salvage Therapy ,Tyrosine kinase inhibitors ,Aniline Compounds ,Philadelphia Chromosome Positive ,business.industry ,Chronic myeloid leukemia ,Myeloid leukemia ,Hematology ,medicine.disease ,BCR-ABL1 ,respiratory tract diseases ,Leukemia ,030220 oncology & carcinogenesis ,Quinolines ,Bosutinib ,Safety ,business ,030215 immunology ,Proto-oncogene tyrosine-protein kinase Src ,medicine.drug - Abstract
Bosutinib (SKI-606) is an oral, dual Src/Abl tyrosine kinase inhibitor (TKI) approved for treatment of patients with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) that is resistant or intolerant to prior TKI therapy or for whom other TKIs are not appropriate choices. The objective of this review is to provide a longitudinal summary of toxicities that may arise during treatment with second-line or later bosutinib in patients with Ph+ chronic phase CML and to provide strategies for managing these toxicities. As bosutinib is not currently indicated for newly diagnosed CML, toxicities associated with first-line treatment are not reviewed. Recognition and optimal management of these toxicities can facilitate patient compliance and affect treatment outcomes.
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- 2018
38. Pretransplant Consolidation Is Not Beneficial for Adults with ALL Undergoing Myeloablative Allogeneic Transplantation
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Richard F. Olsson, Nelli Bejanyan, Edward A. Copelan, Wael Saber, Partow Kebriaei, William J. Hogan, Daniel J. Weisdorf, Matthew D. Seftel, Jacob M. Rowe, Hai-Lin Wang, Brenda M. Sandmaier, Marcos de Lima, Christopher G. Kanakry, Veronika Bachanova, Shahrukh K. Hashmi, Robert Peter Gale, Aleksandr Lazaryan, Betty K. Hamilton, Hillard M. Lazarus, Rodrigo Martino, Celalettin Ustun, David I. Marks, Mei-Jie Zhang, Mohamed A. Kharfan-Dabaja, Martin S. Tallman, Gary J. Schiller, and H. Jean Khoury
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Time Factors ,medicine.medical_treatment ,Graft vs Host Disease ,Myeloablative.conditioning ,0302 clinical medicine ,Myeloablative conditioning ,Stem Cell Research - Nonembryonic - Human ,Recurrence ,Cumulative incidence ,Cancer ,Hematology ,Hematopoietic Stem Cell Transplantation ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Treatment Outcome ,6.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Homologous ,Adult ,medicine.medical_specialty ,Allogeneic transplantation ,Clinical Trials and Supportive Activities ,Clinical Sciences ,Immunology ,Consolidation chemotherapy ,Article ,03 medical and health sciences ,Young Adult ,Rare Diseases ,Clinical Research ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Aged ,Transplantation ,Chemotherapy ,business.industry ,Evaluation of treatments and therapeutic interventions ,Consolidation Chemotherapy ,Myeloablative Agonists ,Stem Cell Research ,Survival Analysis ,Confidence interval ,Allogeneic transplant ,Good Health and Well Being ,Relative risk ,business ,ALL ,030215 immunology - Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) is curative for patients with acute lymphoblastic leukemia (ALL) who achieve complete remission (CR1) with chemotherapy. However, the benefit of consolidation chemotherapy remains uncertain in patients undergoing alloHCT. We compared clinical outcomes of 524 adult patients with ALL in CR1 who received >2 (n = 109), 1 (n = 93), or 0 cycles (n = 322) of consolidation before myeloablative alloHCT from 2008 to 2012. As expected, time to alloHCT was longer with increasing cycles of consolidation. Patients receiving 1, or 0 cycles of consolidation had an adjusted 3-year cumulative incidence of relapse of 20%, 27%, and 22%; 1-year transplant-related mortality (TRM) of 16%, 18%, and 23%; adjusted 3-year leukemia-free survival (LFS) of 54%, 48%, and 47%; and 3-year overall survival (OS) of 63%, 59%, and 54% (all P values >.40). Multivariable analysis confirmed that consolidation was not prognostic for LFS (relative risk, 1.20, 95% confidence interval,.86 to 1.67; P=.28 for no consolidation; RR, 1.18, 95% confidence interval,.79 to 1.76; P=.41 for 1 cycle versus.>:2 cycles = reference). Similarly, consolidation was not associated with OS, relapse, TRM, or graft-versus-host disease. We conclude that consolidation chemotherapy does not appear to provide added benefit in adult ALL patients with available donors who undergo myeloablative alloHCT in CR1. (C) 2017 American Society for Blood and Marrow Transplantation.
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- 2018
39. Epileptic encephalopathy and brain iron accumulation due to WDR45 mutation
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Ahsan N.V. Moosa, Jean Khoury, and Prakash Kotagal
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business.industry ,Epileptic encephalopathy ,General Medicine ,Biology ,Bioinformatics ,medicine.disease ,Epilepsy ,WDR45 ,Text mining ,Neurology ,Mutation (genetic algorithm) ,medicine ,Neurology (clinical) ,business - Published
- 2019
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40. Incidence and management of myelosuppression in patients with chronic- and accelerated-phase chronic myeloid leukemia treated with omacetaxine mepesuccinate
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Sandra E. Kurtin, Elizabeth Li, Jeffrey H. Lipton, Hagop M. Kantarjian, Meir Wetzler, Mihaela Munteanu, Jorge E. Cortes, Michele Baccarani, H. Jean Khoury, Luke P. Akard, and Franck E. Nicolini
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Adult ,Male ,Oncology ,Harringtonines ,Cancer Research ,medicine.medical_specialty ,Pancytopenia ,Leukemia, Myeloid, Accelerated Phase ,Neutropenia ,Article ,Leukocyte Count ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Omacetaxine mepesuccinate ,medicine ,Humans ,Blood Transfusion ,Aged ,Aged, 80 and over ,business.industry ,Incidence ,Disease Management ,Myeloid leukemia ,Cancer ,Hematology ,Middle Aged ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Clinical trial ,Treatment Outcome ,chemistry ,030220 oncology & carcinogenesis ,Homoharringtonine ,Leukemia, Myeloid, Chronic-Phase ,Toxicity ,Immunology ,Female ,business ,030215 immunology - Abstract
Omacetaxine mepesuccinate (Synribo®) is an inhibitor of protein synthesis indicated for the treatment of patients with chronic- or accelerated-phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors. Myelosuppression is the most common and clinically significant toxicity experienced by patients treated with omacetaxine. Here, we further examine the patterns of hematologic toxicity observed in clinical trials and describe the approach to management as well as resolution of events. Omacetaxine-related myelosuppression typically occurs more frequently during induction cycles. In general, the myelosuppression observed with omacetaxine treatment is manageable and reversible, and long-term administration is feasible. Careful monitoring, dose delays and reduction in administration days, and appropriate supportive care are critical for successful management of hematologic toxicity. Concerns regarding myelosuppression, observed with many cancer treatments, should not prevent eligible patients from receiving omacetaxine, particularly CML patients with unsatisfactory responses to multiple lines of prior treatment.
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- 2015
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41. CMV reactivation drives posttransplant T-cell reconstitution and results in defects in the underlying TCRβ repertoire
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Harlan Robins, Amelia Langston, Audrey Grizzle, Jennifer Robertson, Jason A. Conger, Muna Qayed, John T. Horan, Bruce R. Blazar, Aneesh K. Mehta, Aneesah Garrett, J. Cheeseman, Knut Finstermeier, Edmund K. Waller, Divya Koura, Cindy Desmarais, Leslie S. Kean, Rithun Mukherjee, Hanna Jean Khoury, Benjamin Watkins, Linda Stempora, Allan D. Kirk, and Yvonne Suessmuth
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Adult ,Male ,Adolescent ,Receptors, Antigen, T-Cell, alpha-beta ,T cell ,Immunology ,Plenary Paper ,Cytomegalovirus ,CD8-Positive T-Lymphocytes ,Biology ,Biochemistry ,Deep sequencing ,Young Adult ,medicine ,Transplantation, Homologous ,Humans ,Child ,Aged ,Repertoire ,Hematopoietic Stem Cell Transplantation ,High-Throughput Nucleotide Sequencing ,virus diseases ,Hematopoietic stem cell ,CD28 ,Cell Biology ,Hematology ,Middle Aged ,Flow Cytometry ,Virology ,Granzyme B ,Transplantation ,medicine.anatomical_structure ,Cytomegalovirus Infections ,Female ,Virus Activation ,CD8 - Abstract
Although cytomegalovirus (CMV) reactivation has long been implicated in posttransplant immune dysfunction, the molecular mechanisms that drive this phenomenon remain undetermined. To address this, we combined multiparameter flow cytometric analysis and T-cell subpopulation sorting with high-throughput sequencing of the T-cell repertoire, to produce a thorough evaluation of the impact of CMV reactivation on T-cell reconstitution after unrelated-donor hematopoietic stem cell transplant. We observed that CMV reactivation drove a >50-fold specific expansion of Granzyme B(high)/CD28(low)/CD57(high)/CD8(+) effector memory T cells (Tem) and resulted in a linked contraction of all naive T cells, including CD31(+)/CD4(+) putative thymic emigrants. T-cell receptor β (TCRβ) deep sequencing revealed a striking contraction of CD8(+) Tem diversity due to CMV-specific clonal expansions in reactivating patients. In addition to querying the topography of the expanding CMV-specific T-cell clones, deep sequencing allowed us, for the first time, to exhaustively evaluate the underlying TCR repertoire. Our results reveal new evidence for significant defects in the underlying CD8 Tem TCR repertoire in patients who reactivate CMV, providing the first molecular evidence that, in addition to driving expansion of virus-specific cells, CMV reactivation has a detrimental impact on the integrity and heterogeneity of the rest of the T-cell repertoire. This trial was registered at www.clinicaltrials.gov as #NCT01012492.
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- 2015
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42. Long‐term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors
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Tim H. Brümmendorf, Kathleen Turnbull, Eric Leip, Ewa Matczak, Hanna Jean Khoury, Nathalie Bardy-Bouxin, Mark Shapiro, Carlo Gambacorti-Passerini, Hagop M. Kantarjian, Jorge E. Cortes, Dong-Wook Kim, Anna G. Turkina, GAMBACORTI PASSERINI, C, Kantarjian, H, Kim, D, Khoury, H, Turkina, A, Brümmendorf, T, Matczak, E, Bardy Bouxin, N, Shapiro, M, Turnbull, K, Leip, E, and Cortes, J
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Male ,Quinoline ,Gastroenterology ,Piperazines ,Blast Crisi ,Antineoplastic Agent ,0302 clinical medicine ,Aged, 80 and over ,Aniline Compounds ,Hematology ,Myeloid leukemia ,Aniline Compound ,Middle Aged ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,3. Good health ,Leukemia ,Treatment Outcome ,030220 oncology & carcinogenesis ,Benzamides ,Toxicity ,Imatinib Mesylate ,Quinolines ,Female ,Survival Analysi ,Nitrile ,Bosutinib ,Human ,Research Article ,medicine.drug ,Adult ,Diarrhea ,medicine.medical_specialty ,Adolescent ,Fever ,Protein Kinase Inhibitor ,Antineoplastic Agents ,Follow-Up Studie ,03 medical and health sciences ,Benzamide ,Internal medicine ,Nitriles ,medicine ,Humans ,Piperazine ,Protein Kinase Inhibitors ,Survival analysis ,Aged ,business.industry ,Imatinib ,Pneumonia ,Original Articles ,medicine.disease ,Survival Analysis ,Surgery ,Pyrimidines ,Imatinib mesylate ,Pyrimidine ,Drug Resistance, Neoplasm ,Blast Crisis ,business ,Follow-Up Studies ,030215 immunology - Abstract
Long‐term efficacy and safety of bosutinib (≥4 years follow‐up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated‐phase [AP, n = 79] chronic myeloid leukemia [CML], blast‐phase [BP, n = 64] CML, acute lymphoblastic leukemia [ALL, n = 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1–88.6), 2.8 (0.03–55.9), 0.97 (0.3–89.2) months. Among AP and BP patients, 57% and 28% newly attained or maintained baseline overall hematologic response (OHR); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 years (most by 12 months). In responders at 1 versus 4 years, Kaplan‐Meier (KM) probabilities of maintaining OHR were 78% versus 49% (AP) and 28% versus 19% (BP); KM probabilities of maintaining MCyR were 65% versus 49% (AP) and 21% versus 21% (BP). Most common AEs (AP, BP) were gastrointestinal (96%; 83%), primarily diarrhea (85%; 64%), which was typically low grade (maximum grade 1/2: 81%; 59%) and transient; no patient discontinued due to diarrhea. Serious AEs occurred in 44 (56%) AP and 37 (58%) BP patients, most commonly pneumonia (n = 9) for AP and pyrexia (n = 6) for BP; 11 and 13 died within 30 days of last dose (2 considered bosutinib‐related [AP] per investigator). Responses were durable in ∼50% AP responders at 4 years (∼25% BP patients responded at year 1, suggesting possible bridge‐to‐transplant role in BP patients); toxicity was manageable.Am. J. Hematol. 90:755–768, 2015. © 2015 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc.
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- 2015
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43. Phase 1 dose escalation trial of ilorasertib, a dual Aurora/VEGF receptor kinase inhibitor, in patients with hematologic malignancies
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Lisa Roberts-Rapp, Peter Ansell, Guillermo Garcia-Manero, Martha Arellano, Wijith Munasinghe, Hao Xiong, Brian Oliver, Emily A. Knight, Qin Qin, Raoul Tibes, Justin L. Ricker, Hagop M. Kantarjian, Mark D. McKee, Daniel H. Albert, Hanna Jean Khoury, and Tapan M. Kadia
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Male ,Maximum Tolerated Dose ,Azacitidine ,Aurora inhibitor ,Aminopyridines ,Antineoplastic Agents ,Pharmacology ,Article ,chemistry.chemical_compound ,Aurora kinase ,Growth factor receptor ,Aurora Kinases ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,Pharmacology (medical) ,Protein Kinase Inhibitors ,Aged ,Acute leukemia ,business.industry ,Phenylurea Compounds ,Vascular endothelial growth factor ,Receptors, Vascular Endothelial Growth Factor ,Oncology ,chemistry ,Hematologic Neoplasms ,Female ,business ,Tyrosine kinase ,medicine.drug ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Background Ilorasertib (ABT-348) is a novel inhibitor of Aurora kinase, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors, and the Src families of tyrosine kinases. Ilorasertib alone or in combination with azacitidine demonstrated activity in preclinical models in various hematological malignancies, indicating that pan-Aurora kinase and multiple kinase inhibition may have preferential antileukemic activity. This phase 1 trial determined the safety, pharmacokinetics, and preliminary antitumor activity of ilorasertib alone or combined with azacitidine in advanced hematologic malignancies. Patients and methods Fifty-two patients (median age, 67 years; 35 % with >4 prior regimens) with acute myelogenous leukaemia (AML; n = 38), myelodysplastic syndrome (n = 12), or chronic myelomonocytic leukaemia (n = 2) received 3 or 6 doses of ilorasertib per 28-day cycle and were assigned to arm A (once-weekly oral), B (twice-weekly oral), C (once-weekly oral plus azacitidine), or D (once-weekly intravenous) treatment. Results Maximum tolerated doses were not determined; the recommended phase 2 oral monotherapy doses were 540 mg once weekly and 480 mg twice weekly. The most common grade 3/4 adverse events were hypertension (28.8 %), hypokalemia (15.4 %), anemia (13.5 %), and hypophosphatemia (11.5 %). Oral ilorasertib pharmacokinetics appeared dose proportional, with a 15-hour half-life and no interaction with azacitidine. Ilorasertib inhibited biomarkers for Aurora kinase and VEGF receptors, and demonstrated clinical responses in 3 AML patients. Conclusions Ilorasertib exhibited acceptable safety and pharmacokinetics at or below the recommended phase 2 dose, displayed evidence of dual Aurora kinase and VEGF receptor kinase inhibition, and activity in AML.
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- 2015
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44. Final analysis of the efficacy and safety of omacetaxine mepesuccinate in patients with chronic- or accelerated-phase chronic myeloid leukemia: Results with 24 months of follow-up
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Charles Chuah, Jeffrey H. Lipton, Elizabeth Li, Agnès Guerci-Bresler, Mauricette Michallet, Franck E. Nicolini, Andrzej Hellmann, Luke P. Akard, Delphine Rea, Mihaela Munteanu, Michele Baccarani, Krzysztof Warzocha, Meir Wetzler, Hagop M. Kantarjian, H. Jean Khoury, Jorge E. Cortes, Purvish M. Parikh, Raghunadharao Digumarti, and Laurence Legros
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Cancer Research ,medicine.medical_specialty ,Pediatrics ,Protein synthesis inhibitor ,business.industry ,Myeloid leukemia ,Cancer ,medicine.disease ,Gastroenterology ,Hematologic Response ,Confidence interval ,Discontinuation ,chemistry.chemical_compound ,Oncology ,chemistry ,Internal medicine ,Omacetaxine mepesuccinate ,Toxicity ,medicine ,business - Abstract
BACKGROUND Omacetaxine, a protein synthesis inhibitor, is indicated in the United States for the treatment of patients with chronic-phase (CP) or accelerated-phase (AP) chronic myeloid leukemia (CML) with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors. METHODS The final analysis, with 24 months of follow-up, included additional efficacy and safety analyses to assess the benefit of long-term omacetaxine administration (1.25 mg/m2 twice daily for 14 days every 28 days followed by 7 days every 28 days) in CP-CML and AP-CML patients receiving >3 cycles. RESULTS Eighteen percent of CP-CML patients achieved a major cytogenetic response (MCyR) with a median duration of 12.5 months (95% confidence interval [CI], 3.5 months to not reached [NR]); responses were maintained for ≥12 months in 3 of 14 responders, and the median overall survival (OS) was 40.3 months (95% CI, 23.8 months to NR). Among patients with AP-CML, 14% achieved or maintained a major hematologic response for a median of 4.7 months (95% CI, 3.6 months to NR); MCyR was not achieved, and the median OS was 14.3 months (95% CI, 6.7-18.7 months). In patients with CP-CML and patients with AP-CML who received >3 cycles of treatment (n = 50 and n = 14, respectively), the median OS was 49.3 months (95% CI, 23.8 months to NR) and 24.6 months (95% CI, 12-37.2 months), respectively. Grade 3 or higher hematologic toxicities were the major side effects (79% and 73% for CP-CML and AP-CML, respectively), with discontinuation due to toxicity in 10% of CP patients and in 5% of AP patients. CONCLUSIONS These results suggest that the long-term administration of omacetaxine is feasible with dose adjustments to manage toxicities and that omacetaxine provides a durable benefit for some patients. Cancer 2015;121:1637–1644. © 2015 American Cancer Society.
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- 2015
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45. Open pipelines for integrated tumor genome profiles reveal differences between pancreatic cancer tumors and cell lines
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Bassel F. El-Rayes, Jeremy Goecks, Shishir K. Maithel, H. Jean Khoury, Michael R. Rossi, and James Taylor
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Cancer Research ,Receptor, ErbB-2 ,pancreatic cancer ,Biology ,Genome ,Cell Line ,Proto-Oncogene Proteins p21(ras) ,Transcriptome ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Pancreatic cancer ,medicine ,Humans ,Exome ,Radiology, Nuclear Medicine and imaging ,Cancer Biology ,Genetics ,Analysis pipelines ,Genome, Human ,Sequence Analysis, RNA ,genomic tumor profiles ,Gene Expression Profiling ,High-Throughput Nucleotide Sequencing ,Cancer ,bioinformatics ,medicine.disease ,3. Good health ,Pancreatic Neoplasms ,Gene expression profiling ,Oncology ,Mutation ,Genomic Profile ,ras Proteins ,Human genome ,galaxy ,Genes, Neoplasm - Abstract
We describe open, reproducible pipelines that create an integrated genomic profile of a cancer and use the profile to find mutations associated with disease and potentially useful drugs. These pipelines analyze high-throughput cancer exome and transcriptome sequence data together with public databases to find relevant mutations and drugs. The three pipelines that we have developed are: (1) an exome analysis pipeline, which uses whole or targeted tumor exome sequence data to produce a list of putative variants (no matched normal data are needed); (2) a transcriptome analysis pipeline that processes whole tumor transcriptome sequence (RNA-seq) data to compute gene expression and find potential gene fusions; and (3) an integrated variant analysis pipeline that uses the tumor variants from the exome pipeline and tumor gene expression from the transcriptome pipeline to identify deleterious and druggable mutations in all genes and in highly expressed genes. These pipelines are integrated into the popular Web platform Galaxy at http://usegalaxy.org/cancer to make them accessible and reproducible, thereby providing an approach for doing standardized, distributed analyses in clinical studies. We have used our pipeline to identify similarities and differences between pancreatic adenocarcinoma cancer cell lines and primary tumors.
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- 2015
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46. Long-term evaluation of cardiac and vascular toxicity in patients with Philadelphia chromosome-positive leukemias treated with bosutinib
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Jorge E, Cortes, H, Jean Khoury, Hagop, Kantarjian, Tim H, Brümmendorf, Michael J, Mauro, Ewa, Matczak, Dmitri, Pavlov, Jean M, Aguiar, Kolette D, Fly, Svetoslav, Dimitrov, Eric, Leip, Mark, Shapiro, Jeff H, Lipton, Jean-Bernard, Durand, Carlo, Gambacorti-Passerini, Cortes, J, Jean Khoury, H, Kantarjian, H, Brümmendorf, T, Mauro, M, Matczak, E, Pavlov, D, Aguiar, J, Fly, K, Dimitrov, S, Leip, E, Shapiro, M, Lipton, J, Durand, J, and GAMBACORTI PASSERINI, C
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Adult ,Aged, 80 and over ,Male ,Aniline Compounds ,Adolescent ,Hypercholesterolemia ,Age Factors ,Hyperlipidemias ,Middle Aged ,Cardiotoxicity ,Article ,Young Adult ,Risk Factors ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Nitriles ,Imatinib Mesylate ,Quinolines ,Humans ,Female ,Vascular Diseases ,Protein Kinase Inhibitors ,Hematology, TKI , Ph+ leukemia ,Aged ,Retrospective Studies - Abstract
Vascular and cardiac safety during tyrosine kinase inhibitor (TKI) therapy is an emerging issue. We evaluated vascular/cardiac toxicities associated with long-term bosutinib treatment for Philadelphia chromosome-positive (Ph+) leukemia based on treatment-emergent adverse events (TEAEs) and changes in QTc intervals and ejection fraction in two studies: a phase 1/2 study of second-/third-/fourth-line bosutinib for Ph+ leukemia resistant/intolerant to prior TKIs (N = 570) and a phase 3 study of first-line bosutinib (n = 248) versus imatinib (n = 251) in chronic phase chronic myeloid leukemia. Follow-up time was ≥48 months (both studies). Incidences of vascular/cardiac TEAEs in bosutinib-treated patients were 7%/10% overall with similar incidences observed with first-line bosutinib (5%/8%) and imatinib (4%/6%). Few patients had grade ≥3 vascular/cardiac events (4%/4%) and no individual TEAE occurred in2% of bosutinib patients. Exposure-adjusted vascular/cardiac TEAE rates (patients with events/patient-year) were low for second-line or later bosutinib (0.037/0.050) and not significantly different between first-line bosutinib (0.015/0.024) and imatinib (0.011/0.017; P ≥ 0.267). Vascular/cardiac events were managed mainly with concomitant medications (39%/44%), bosutinib treatment interruptions (18%/21%), or dose reductions (4%/8%); discontinuations due to these events were rare (0.7%/1.0%). Based on logistic regression modelling, performance status0 and history of vascular or cardiac disorders were prognostic of vascular/cardiac events in relapsed/refractory patients; hyperlipidemia/hypercholesterolemia and older age were prognostic of cardiac events. In newly diagnosed patients, older age was prognostic of vascular/cardiac events; history of diabetes was prognostic of vascular events. Incidences of vascular and cardiac events were low with bosutinib in the first-line and relapsed/refractory settings following long-term treatment in patients with Ph+ leukemia. Am. J. Hematol. 91:606-616, 2016. © 2016 Wiley Periodicals, Inc.
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- 2016
47. Peritransplantation Red Blood Cell Transfusion Is Associated with Increased Risk of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation
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Cassandra D. Josephson, Edmund K. Waller, John D. Roback, Michael Graiser, Amelia Langston, Cynthia R. Giver, H. Jean Khoury, Zaid Al-Kadhimi, Sakura Hosoba, Akira Andoh, James C. Zimring, Ana G. Antun, Jean L. Koff, Neeta Shenvi, Sheliagh Barclay, and Kirk A. Easley
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Adult ,Male ,Risk ,medicine.medical_specialty ,Blood transfusion ,medicine.medical_treatment ,Graft vs Host Disease ,Hematopoietic stem cell transplantation ,Platelet Transfusion ,030204 cardiovascular system & hematology ,Gastroenterology ,Perioperative Care ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Platelet ,Aged ,Retrospective Studies ,Transplantation ,business.industry ,Incidence (epidemiology) ,Hazard ratio ,Hematopoietic Stem Cell Transplantation ,Retrospective cohort study ,Hematology ,Middle Aged ,medicine.disease ,HLA Mismatch ,Survival Analysis ,surgical procedures, operative ,Graft-versus-host disease ,Female ,business ,Erythrocyte Transfusion ,030215 immunology - Abstract
More than 90% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receive red blood cell (RBC) or platelet transfusions in the peritransplantation period. We tested the hypothesis that transfusions are associated with the development of severe (grade III-IV) acute graft-versus-host disease (aGVHD) or mortality after allo-HSCT in a retrospective study of 322 consecutive patients receiving an allogeneic bone marrow or granulocyte colony-stimulating factor-mobilized blood stem cell graft for a hematologic malignancy. Counting transfused RBC and platelet units between day −7 pretransplantation and day +27 post-transplantation, but excluding transfusions administered after a diagnosis of aGVHD, yielded medians of 5 RBC units and 2 platelet units transfused. Sixty-three patients (20%) developed a maximal grade III-IV aGVHD with onset up to day +150 post-transplantation (median aGVHD onset of 28 days). HLA mismatch (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.2 to 4.7; P = .01), and transfusion of more than the median number of RBC units (HR, 2.1; 95% CI, 1.1 to 3.7; P = .02) were independently associated with greater risk of grade III-IV aGVHD in a multivariable analysis model. Disease risk strata (HR, 1.7; 95% CI, 1.2 to 2.4 for high risk versus low risk; P = .005) and transfusion of more than the median number of RBC units (HR, 1.4; 95% CI, 1.0 to 2.0; P = .054) were independently associated with inferior overall survival. These data support our hypothesis that peritransplantation RBC transfusions are associated with the risk of developing severe aGVHD and worse overall survival following allo-HSCT, and suggest that strategies to reduce routine RBC transfusion may favorably reduce the incidence and severity of GVHD.
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- 2017
48. Retraction Statement. Paper 'Low-Dose Vitamin D Prevents Muscular Atrophy and Reduces Falls and Hip Fractures in Women after Stroke: A Randomized Controlled Trial' by Sato et al. Cerebrovasc Dis 2005;20:187-192
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Paul Cantagrel, Kazunori Toyoda, Prateek Thatikunta, Osamu Onodera, Kazuyuki Nagatsuka, Sohei Yoshimura, Muhammad Ibrahimi, Jochen A. Sembill, Satoru Ohtomo, Kate Morrell, Ken Uchino, Teiji Tominaga, Stephan Bohlhalter, Masatoshi Koga, Nice Ren, Yuki Sakamoto, Kamal Gupta, Hidefuku Gi, Takuya Kanamaru, Diogo C. Soriano, Marilyn M. Rymer, Robert J. Marquardt, Ana Carolina Coan, Matthias Lamy, Tim Vanbellingen, Thomas Nyffeler, Dolora Wisco, Chikako Nito, Pierre Agius, Kateri J. Spinelli, Shintaro Nagaoka, Antje Giede-Jeppe, Jillian Naylor, Julius Hartwich, Oh Young Bang, Herbert H.G. Castro, Philip Hoelter, Neil Rane, Alexis N Simpkins, Noortje A.M. Maaijwee, Utako Birgit Barnikol, Miriam Koome, Leonid Churilov, Ji Hyun Kim, Airlane Pereira Alencar, Reza Masoomi, Ryosuke Otsuji, Eunhee Kim, Yoshiaki Ikai, Julian Hardman, Kazushi Maeda, Tobias Struffert, Junya Aoki, Tobias Nef, Matthew Wicklund, Christian Dohmen, Lisa R Yanase, Junji Uno, Julia Prigent, Thomas Liebig, Seong-Beom Koh, Fabricio O Lima, João A. G. Ricardo, Waleed Brinjikji, Bruce C.V. Campbell, René M. Müri, Hiroaki Arai, Christoph Kabbasch, Richard Leigh, Jean Khoury, Mathieu Puyade, Christian Dias, Anastasios Mpotsaris, Rashmi Thapa, Vivek N. Iyer, Hannes Lücking, Arata Abe, Isabela M. Benseñor, Hagen B. Huttner, Stefan Schwab, Seunghwa You, Dominik Madžar, Yoshiteru Shimoda, Cory Rice, Pierre Ingrand, Christopher P. Wood, Sung-Min Cho, Raymond Reichwein, Li L. Min, Katsuharu Kameda, Tobias Pflugshaupt, Aline Berthomet, Tomotaka Tanaka, Hiroaki Nozaki, Mashhood Wani, Satoshi Suda, Vanessa D. Beuscher, Yoshitaka Yamaguchi, Alev Kalkan, Jean-Philippe Neau, Beatrice Ottiger, Kazumi Kimura, Lucy Zhang, Deena M. Nasr, Jonathan Ciron, Kentaro Suzuki, Alessandra C. Goulart, Druckerei Stückle, Andrew B. Buletko, Buddhadeb Dawn, Paulo A. Lotufo, Zubair Shah, Dario Cazzoli, Jin-Man Jung, Megan Hyers, Ziyuan Chen, Seiji Okubo, Noriko Matsumoto, Henning Stetefeld, Stefan T. Gerner, Yuki Go, Angelica Lee, Jan Borggrefe, Wagner M Avelar, Lindsay Lucas, Kyungmi Oh, Takashi Shimoyama, Ken Okada, Woo-Keun Seo, Joji B. Kuramatsu, John Chen, Jean-Claude Chomel, Kanako Muraga, Gina Norato, Volker Maus, Mohammad El-Ghanem, Karissa Schwartz, Jenniffer Mako, Tamela Stuchiner, Gereon R. Fink, Masahiro Mishina, Maximilian I. Sprügel, and Paola Palazzo
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0301 basic medicine ,medicine.medical_specialty ,030109 nutrition & dietetics ,business.industry ,Statement (logic) ,Low dose ,medicine.disease ,law.invention ,03 medical and health sciences ,Atrophy ,Neurology ,Randomized controlled trial ,law ,Vitamin D and neurology ,Physical therapy ,Medicine ,Neurology (clinical) ,Cardiology and Cardiovascular Medicine ,business ,Stroke - Published
- 2017
49. Safety and efficacy of second-line bosutinib for chronic phase chronic myeloid leukemia over a five-year period: final results of a phase I/II study
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Philippe Schafhausen, Kay Noonan, H. Jean Khoury, Tim H. Brümmendorf, Jeffrey H. Lipton, Rocco J. Crescenzo, Carlo Gambacorti-Passerini, Liza DeAnnuntis, Mark Shapiro, Nathalie Bardy-Bouxin, Eric Leip, Hagop M. Kantarjian, Jorge E. Cortes, Dong-Wook Kim, Gambacorti-Passerini, C, Cortes, J, Lipton, J, Kantarjian, H, Kim, D, Schafhausen, P, Crescenzo, R, Bardy-Bouxin, N, Shapiro, M, Noonan, K, Leip, E, Deannuntis, L, Brümmendorf, T, and Khoury, H
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Adult ,medicine.medical_specialty ,Myeloid ,Adolescent ,Chronic Myeloid Leukemia ,Chronic Myelogenous Leukemia, Bosutinib, Second-line therapy, tyrosine kinase inhibitor ,Antineoplastic Agents ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,MED/15 - MALATTIE DEL SANGUE ,Median follow-up ,Internal medicine ,Nitriles ,medicine ,Humans ,Cumulative incidence ,Survival analysis ,Aged ,Aniline Compounds ,business.industry ,Myeloid leukemia ,Imatinib ,Hematology ,Middle Aged ,medicine.disease ,Survival Analysis ,Peptide Fragments ,Leukemia ,medicine.anatomical_structure ,Treatment Outcome ,030220 oncology & carcinogenesis ,Leukemia, Myeloid, Chronic-Phase ,Imatinib Mesylate ,Quinolines ,business ,Bosutinib ,030215 immunology ,medicine.drug ,Follow-Up Studies - Abstract
Bosutinib is a Src/Abl tyrosine kinase inhibitor indicated for adults with newly-diagnosed Philadelphia positive chronic myeloid leukemia or with resistant/intolerant disease. We report the final results of a phase I/II study of second-line bosutinib in chronic phase chronic myeloid leukemia patients after imatinib failure (n=284). Median follow up and treatment durations were 54.8 (range 0.6-96.3) and 25.6 (0.2-96.3) months, respectively. At years 2 and 5, 54% and 40% of patients, respectively, remained on bosutinib. Cumulative major cytogenetic response and complete cytogenetic response rates (newly-attained or maintained from baseline) were 58% and 46%, respectively, by year 2 and 60% and 50% by year 5. Kaplan-Meier probability of maintaining major and complete cytogenetic response was 76% and 78%, respectively, at year 2 and 71% and 69% at year 5. Cumulative incidence of on-treatment disease progression/death was similar at years 5 (19%) and 2 (15%); Kaplan-Meier overall survival was 91% at year 2 and 84% at year 5. Of 169 patients who had discontinued bosutinib by year 5, 38 did so after year 2, most commonly for disease progression (n=11). Most adverse events initially occurred within two years. Overall, gastrointestinal events were the most common (diarrhea 86%, nausea 46%, vomiting 37%); the most common grade 3/4 toxicity was thrombocytopenia (25%). None of the 4 on-treatment deaths in years 3-5 were related to bosutinib. Bosutinib demonstrated durable efficacy and manageable toxicity through year 5 confirming its importance in the treatment of chronic phase chronic myeloid leukemia patients resistant/intolerant to prior imatinib. This trial was registered at clinicaltrials.gov identifier: 00261846.
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- 2017
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50. Effects of Bosutinib Treatment on Renal Function in Patients With Philadelphia Chromosome-Positive Leukemias
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Ewa Matczak, Moshe Talpaz, Elly Barry, H. Jean Khoury, Eric Leip, Jeffrey H. Lipton, Amit Lahoti, Carlo Gambacorti-Passerini, Dong-Wook Kim, Hagop M. Kantarjian, Jorge E. Cortes, Tim H. Brümmendorf, Cortes, J, Gambacorti Passerini, C, Dong Wook, K, Kantarjian, H, Lipton, J, Lahoti, A, Talpaz, M, Matczak, E, Barry, E, Leip, E, Brümmendorf, T, and Khoury, H
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Male ,Cancer Research ,Tyrosine kinase inhibitor ,Kidney Function Tests ,Gastroenterology ,chemistry.chemical_compound ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Philadelphia Chromosome ,Aged, 80 and over ,Clinical Trials as Topic ,Aniline Compounds ,Leukemia ,Hematology ,Philadelphia Chromosome Positive ,Chronic myeloid leukemia ,Middle Aged ,Oncology ,Creatinine ,030220 oncology & carcinogenesis ,Quinolines ,Female ,Kidney Diseases ,Bosutinib ,Glomerular Filtration Rate ,medicine.drug ,Adult ,Adverse event ,medicine.medical_specialty ,Adolescent ,Renal function ,Antineoplastic Agents ,Young Adult ,03 medical and health sciences ,Internal medicine ,Nitriles ,medicine ,Humans ,In patient ,Adverse effect ,Protein Kinase Inhibitors ,Aged ,Neoplasm Staging ,Retrospective Studies ,business.industry ,Imatinib ,Patient Outcome Assessment ,chemistry ,Immunology ,Renal toxicity ,business ,030215 immunology - Abstract
Clinical lymphoma, myeloma & leukemia 17(10), 684-695.e6 (2017). doi:10.1016/j.clml.2017.06.001, Published by Elsevier, Amsterdam [u.a.]
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- 2017
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