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3. Safety, pharmacokinetics, and pharmacodynamics of panobinostat in children, adolescents, and young adults with relapsed acute myeloid leukemia

Author

Karol, Seth E, Cooper, Todd M, Mead, Paul E, Crews, Kristine R, Panetta, John C, Alexander, Thomas B, Taub, Jeffrey W, Lacayo, Norman J, Heym, Kenneth M, Kuo, Dennis J, Schiff, Deborah E, Bhojwani, Deepa, Ge, Yubin, Klco, Jeffery M, Ribeiro, Raul C, Inaba, Hiroto, Pui, Ching‐Hon, and Rubnitz, Jeffrey E

Subjects
Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Oncology and Carcinogenesis, Hematology, Genetics, Cancer, Pediatric Cancer, Clinical Research, Clinical Trials and Supportive Activities, Rare Diseases, Pediatric, Pediatric Research Initiative, Childhood Leukemia, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adolescent, Adult, Child, Female, Humans, Leukemia, Myeloid, Acute, Male, Neoplasm Recurrence, Local, Panobinostat, Young Adult, acute myeloid leukemia, childhood, relapse, Public Health and Health Services, Oncology & Carcinogenesis, Oncology and carcinogenesis, Public health
Abstract

BackgroundNovel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia (AML).MethodsTo determine whether the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, a phase 1 trial was performed in which 17 pediatric patients with relapsed or refractory AML received panobinostat (10, 15, or 20 mg/m2 ) before and in combination with fludarabine and cytarabine.ResultsAll dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the 9 patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, 7 demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, 8 of the 17 patients (47%), including 5 of the 6 patients treated at dose level 3, achieved complete remission. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status.ConclusionsPanobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation. This suggests that it should be further studied in AML.

Published
2020

4. Genomic subtyping and therapeutic targeting of acute erythroleukemia

Author

Iacobucci, Ilaria, Wen, Ji, Meggendorfer, Manja, Choi, John K, Shi, Lei, Pounds, Stanley B, Carmichael, Catherine L, Masih, Katherine E, Morris, Sarah M, Lindsley, R Coleman, Janke, Laura J, Alexander, Thomas B, Song, Guangchun, Qu, Chunxu, Li, Yongjin, Payne-Turner, Debbie, Tomizawa, Daisuke, Kiyokawa, Nobutaka, Valentine, Marcus, Valentine, Virginia, Basso, Giuseppe, Locatelli, Franco, Enemark, Eric J, Kham, Shirley KY, Yeoh, Allen EJ, Ma, Xiaotu, Zhou, Xin, Sioson, Edgar, Rusch, Michael, Ries, Rhonda E, Stieglitz, Elliot, Hunger, Stephen P, Wei, Andrew H, To, L Bik, Lewis, Ian D, D’Andrea, Richard J, Kile, Benjamin T, Brown, Anna L, Scott, Hamish S, Hahn, Christopher N, Marlton, Paula, Pei, Deqing, Cheng, Cheng, Loh, Mignon L, Ebert, Benjamin L, Meshinchi, Soheil, Haferlach, Torsten, and Mullighan, Charles G

Subjects
Agricultural, Veterinary and Food Sciences, Biological Sciences, Bioinformatics and Computational Biology, Genetics, Agricultural Biotechnology, Human Genome, Pediatric, Clinical Research, Rare Diseases, Pediatric Cancer, Orphan Drug, Hematology, Childhood Leukemia, Precision Medicine, Cancer, Biotechnology, Cancer Genomics, 2.1 Biological and endogenous factors, 4.1 Discovery and preclinical testing of markers and technologies, Adolescent, Adult, Child, Child, Preschool, Female, Genomics, Homeodomain Proteins, Humans, Infant, Infant, Newborn, Leukemia, Erythroblastic, Acute, Male, Mutation, Myeloid-Lymphoid Leukemia Protein, Nuclear Proteins, Nucleophosmin, Prognosis, Tumor Suppressor Protein p53, Young Adult, fms-Like Tyrosine Kinase 3, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Acute erythroid leukemia (AEL) is a high-risk leukemia of poorly understood genetic basis, with controversy regarding diagnosis in the spectrum of myelodysplasia and myeloid leukemia. We compared genomic features of 159 childhood and adult AEL cases with non-AEL myeloid disorders and defined five age-related subgroups with distinct transcriptional profiles: adult, TP53 mutated; NPM1 mutated; KMT2A mutated/rearranged; adult, DDX41 mutated; and pediatric, NUP98 rearranged. Genomic features influenced outcome, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Targetable signaling mutations were present in 45% of cases and included recurrent mutations of ALK and NTRK1, the latter of which drives erythroid leukemogenesis sensitive to TRK inhibition. This genomic landscape of AEL provides the framework for accurate diagnosis and risk stratification of this disease, and the rationale for testing targeted therapies in this high-risk leukemia.

Published
2019

8. International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia

Author

Hrusak, Ondrej, de Haas, Valerie, Stancikova, Jitka, Vakrmanova, Barbora, Janotova, Iveta, Mejstrikova, Ester, Capek, Vaclav, Trka, Jan, Zaliova, Marketa, Luks, Ales, Bleckmann, Kirsten, Möricke, Anja, Irving, Julie, Konatkowska, Benigna, Alexander, Thomas B., Inaba, Hiroto, Schmiegelow, Kjeld, Stokley, Simone, Zemanova, Zuzana, Moorman, Anthony V., Rossi, Jorge Gabriel, Felice, Maria Sara, Dalla-Pozza, Luciano, Morales, Jessa, Dworzak, Michael, Buldini, Barbara, Basso, Giuseppe, Campbell, Myriam, Cabrera, Maria Elena, Marinov, Neda, Elitzur, Sarah, Izraeli, Shai, Luria, Drorit, Feuerstein, Tamar, Kolenova, Alexandra, Svec, Peter, Kreminska, Olena, Rabin, Karen R., Polychronopoulou, Sophia, da Costa, Elaine, Marquart, Hanne Vibeke, Kattamis, Antonis, Ratei, Richard, Reinhardt, Dirk, Choi, John K., Schrappe, Martin, and Stary, Jan

Published
2018
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9. The genetic basis and cell of origin of mixed phenotype acute leukaemia

Author

Alexander, Thomas B., Gu, Zhaohui, Iacobucci, Ilaria, Dickerson, Kirsten, Choi, John K., Xu, Beisi, and Payne-Turner, Debbie

Subjects
Acute leukemia -- Genetic aspects -- Care and treatment -- Research, Gene expression -- Research, Gene mutation -- Research, Genomics, T cells, Antigens, Tumors, Promiscuity, Clinical trials, Genetic research, Medical schools, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Mixed phenotype acute leukaemia (MPAL) is a high-risk subtype of leukaemia with myeloid and lymphoid features, limited genetic characterization, and a lack of consensus regarding appropriate therapy. Here we show that the two principal subtypes of MPAL, T/myeloid (T/M) and B/myeloid (B/M), are genetically distinct. Rearrangement of ZNF384 is common in B/M MPAL, and biallelic WT1 alterations are common in T/M MPAL, which shares genomic features with early T-cell precursor acute lymphoblastic leukaemia. We show that the intratumoral immunophenotypic heterogeneity characteristic of MPAL is independent of somatic genetic variation, that founding lesions arise in primitive haematopoietic progenitors, and that individual phenotypic subpopulations can reconstitute the immunophenotypic diversity in vivo. These findings indicate that the cell of origin and founding lesions, rather than an accumulation of distinct genomic alterations, prime tumour cells for lineage promiscuity. Moreover, these findings position MPAL in the spectrum of immature leukaemias and provide a genetically informed framework for future clinical trials of potential treatments for MPAL.A large-scale genomics study shows that the cell of origin and founding mutations determine disease subtype and lead to the expression of multiple haematopoietic lineage-defining antigens in mixed phenotype acute leukaemia., Author(s): Thomas B. Alexander [sup.1] [sup.2] , Zhaohui Gu [sup.3] , Ilaria Iacobucci [sup.3] , Kirsten Dickerson [sup.3] , John K. Choi [sup.3] , Beisi Xu [sup.4] , Debbie Payne-Turner [...]

Published
2018
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17. Preliminary Safety and Efficacy of Venetoclax and Selinexor in Combination with Chemotherapy in Pediatric and Young Adult Patients with Relapsed or Refractory Acute Myeloid Leukemia: Selclax

Author

Zarnegar-Lumley, Sara, Karol, Seth E., Pounds, Stanley, Klco, Jeffery M., Sulis, Maria Luisa, Kuo, Dennis John, Heym, Kenneth Matthew, Ludwig, Kathleen, McLean Stevens, Alexandra, Alexander, Thomas B., Faulk, Kelly Elizabeth, Sabnis, Himalee S., Tasian, Sarah K., Taub, Jeffrey, Place, Andrew E., and Rubnitz, Jeffrey E.

Published
2023
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19. Venetoclax and Navitoclax in Pediatric Patients with Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Author

Rubnitz, Jeffrey E., primary, Alexander, Thomas B., additional, Laetsch, Theodore W., additional, Khaw, Seong Lin, additional, Pullarkat, Vinod A., additional, Opferman, Joseph T., additional, Roberts, Kathryn G, additional, Rosenwinkel, Lindsey, additional, Tong, Bo, additional, Pesko, John C., additional, Badawi, Mohamed, additional, Vishwamitra, Deeksha, additional, Kim, Su Young, additional, Mullighan, Charles G, additional, and Lacayo, Norman J., additional

Published
2020
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20. Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma

Author

Grande, Bruno M., primary, Gerhard, Daniela S., additional, Jiang, Aixiang, additional, Griner, Nicholas B., additional, Abramson, Jeremy S., additional, Alexander, Thomas B., additional, Allen, Hilary, additional, Ayers, Leona W., additional, Bethony, Jeffrey M., additional, Bhatia, Kishor, additional, Bowen, Jay, additional, Casper, Corey, additional, Choi, John Kim, additional, Culibrk, Luka, additional, Davidsen, Tanja M., additional, Dyer, Maureen A., additional, Gastier-Foster, Julie M., additional, Gesuwan, Patee, additional, Greiner, Timothy C., additional, Gross, Thomas G., additional, Hanf, Benjamin, additional, Harris, Nancy Lee, additional, He, Yiwen, additional, Irvin, John D., additional, Jaffe, Elaine S., additional, Jones, Steven J. M., additional, Kerchan, Patrick, additional, Knoetze, Nicole, additional, Leal, Fabio E., additional, Lichtenberg, Tara M., additional, Ma, Yussanne, additional, Martin, Jean Paul, additional, Martin, Marie-Reine, additional, Mbulaiteye, Sam M., additional, Mullighan, Charles G., additional, Mungall, Andrew J., additional, Namirembe, Constance, additional, Novik, Karen, additional, Noy, Ariela, additional, Ogwang, Martin D., additional, Omoding, Abraham, additional, Orem, Jackson, additional, Reynolds, Steven J., additional, Rushton, Christopher K., additional, Sandlund, John T., additional, Schmitz, Roland, additional, Taylor, Cynthia, additional, Wilson, Wyndham H., additional, Wright, George W., additional, Zhao, Eric Y., additional, Marra, Marco A., additional, Morin, Ryan D., additional, and Staudt, Louis M., additional

Published
2019
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21. Verification, characterization, and debugging of the HP PA 7200 processor

Author

Alexander, Thomas B., Dickey, Kent A., Goldberg, David N., La Fetra, Ross V., McGee, James R., Noordeen, Nazeem, and Prakash, Akshya

Subjects
Microprocessor, Microprocessor upgrade, Hewlett-Packard Co. -- Product information, HP PA-RISC PA-7200 (Microprocessor) -- Design and construction -- Product information, Central processing units -- Product information, Microprocessors -- Product information
Abstract

To guarantee a high-quality product the HP PA 7200 CPU chip was subjected to functional and electrical verification. Th's article describes the testing methods, the debugging tools and approaches, and […]

Published
1996

22. Corporate business servers: an alternative to mainframes for business computing

Author

Alexander, Thomas B., Robertson, Kenneth G., Lindsay, Dean T., Rogers, Donald L., Obermeyer, John R., Keller, John R., Oka, Keith Y., and Jones, II, Marlin M.

Subjects
System design, Performance improvement, Multiprocessing, Hewlett-Packard Co. -- Product information, HP 9000 Corporate Business Server T500 (HP PA-RISC-based system) -- Design and construction -- Product information, Multiprocessing -- Product information, System design -- Product information, Systems analysis -- Product information
Abstract

The overall design objective for the HP 9000 Model T500 corporate business server (Fig. 1) was to set new standards for commercial systems performance and affordability. Combining expandable hardware, PA-RISC […]

Published
1994

23. Efficacy of ALL Therapy for WHO2016-Defined Mixed Phenotype Acute Leukemia: A Report from the Children's Oncology Group

Author

Orgel, Etan, primary, Alexander, Thomas B., additional, Wood, Brent, additional, Kahwash, Samir, additional, Devidas, Meenakshi, additional, Dai, Yunfeng, additional, Alonzo, Todd A, additional, Mullighan, Charles G., additional, Inaba, Hiroto, additional, Hunger, Stephen P., additional, Gamis, Alan S, additional, Carroll, Andrew J., additional, Heerema, Nyla A., additional, Berman, Jason, additional, Woods, William G, additional, Loh, Mignon L., additional, Zweidler-McKay, Patrick A., additional, and Horan, John T, additional

Published
2017
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28. Acute Leukemia of Ambiguous Lineage: A Comprehensive Survival Analysis Enables Designing New Treatment Strategies

Author

Hrusak, Ondrej De Haas, Valerie Luks, Ales Janotova, Iveta and Mejstrikova, Ester Bleckmann, Kirsten Moricke, Anja and Irving, Julie Konatkowska, Benigna Alexander, Thomas B. and Inaba, Hiroto Schmiegelow, Kjeld Stokley, Simone Rossi, Jorge Gabriel Felice, Maria Sara Dalla-Pozza, Luciano and Morales, Jessa Dworzak, Michael Buldini, Barbara Basso, Giuseppe Campbell, Myriam Cabrera, Maria Elena Marinov, Neda and Elitzur, Sarah Izraeli, Shai Luria, Drorit Feuerstein, Tamar Kolenova, Alexandra Svec, Peter Kreminska, Elena and Rabin, Karen R. Polychronopoulou, Sophia da Costa, Elaine and Marquart, Hanne Vibeke Kattamis, Antonis Ratei, Richard and Reinhardt, Dirk Moorman, Anthony V. Schrappe, Martin Stary, Jan

Published
2016

29. The Genomic Landscape of Childhood and Adult Acute Erythroid Leukemia

Author

Iacobucci, Ilaria, primary, Wen, Ji, additional, Meggendorfer, Manja, additional, Carmichael, Catherine, additional, Choi, John K, additional, Masih, Katherine, additional, Li, Yongjin, additional, Payne, Debbie, additional, Tomizawa, Daisuke, additional, Kiyokawa, Nobutaka, additional, Janke, Laura J., additional, Alexander, Thomas B., additional, Pounds, Stanley, additional, Shi, Lei, additional, Valentine, Marcus, additional, Basso, Giuseppe, additional, Locatelli, Franco, additional, Kham Kow Yin, Shirley, additional, Yeoh Eng Juh, Allen, additional, Rhonda, Ries E, additional, Stieglitz, Elliot, additional, Wei, Andrew, additional, Lewis, Ian D, additional, D'Andrea, Richard, additional, Kile, Benjamin T., additional, Zhang, Jinghui, additional, Loh, Mignon L., additional, Meshinchi, Soheil, additional, Haferlach, Torsten, additional, and Mullighan, Charles, additional

Published
2016
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30. Genomic Landscape of Pediatric Mixed Phenotype Acute Leukemia

Author

Alexander, Thomas B., primary, Gu, Zhaohui, additional, Choi, John K, additional, Loh, Mignon L., additional, Horan, John, additional, Buldini, Barbara, additional, Basso, Giuseppe, additional, Elitzur, Sarah, additional, Zwaan, C. Michel, additional, de Haas, Valerie, additional, Yeoh, Allen Eng Juh, additional, Reinhardt, Dirk, additional, Tomizawa, Daisuke, additional, Lammens, Tim, additional, De Moerloose, Barbara, additional, Zhou, Li, additional, Hori, Hiroki, additional, Moorman, Anthony V., additional, Moore, Andrew S., additional, Hrusak, Ondrej, additional, Meshinchi, Soheil, additional, Orgel, Etan, additional, Devidas, Meenakshi, additional, Hunger, Stephen P., additional, Guidry Auvil, Jamie M, additional, Smith, Malcolm A., additional, Davidsen, Tanja M., additional, Hermida, Leandro C., additional, Gesuwan, Patee, additional, Marra, Marco A., additional, Ma, Yussanne, additional, Mungall, Andrew J., additional, Moore, Richard, additional, Gerhard, Daniela S., additional, Cao, Xueyuan, additional, Shi, Lei, additional, Pounds, Stanley, additional, Inaba, Hiroto, additional, and Mullighan, Charles, additional

Published
2016
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31. Acute Leukemia of Ambiguous Lineage: A Comprehensive Survival Analysis Enables Designing New Treatment Strategies

Author

Hrusak, Ondrej, primary, De Haas, Valerie, additional, Luks, Ales, additional, Janotova, Iveta, additional, Mejstrikova, Ester, additional, Bleckmann, Kirsten, additional, Moricke, Anja, additional, Irving, Julie, additional, Konatkowska, Benigna, additional, Alexander, Thomas B., additional, Inaba, Hiroto, additional, Schmiegelow, Kjeld, additional, Stokley, Simone, additional, Rossi, Jorge Gabriel, additional, Felice, Maria Sara, additional, Dalla-Pozza, Luciano, additional, Morales, Jessa, additional, Dworzak, Michael, additional, Buldini, Barbara, additional, Basso, Giuseppe, additional, Campbell, Myriam, additional, Cabrera, Maria Elena, additional, Marinov, Neda, additional, Elitzur, Sarah, additional, Izraeli, Shai, additional, Luria, Drorit, additional, Feuerstein, Tamar, additional, Kolenova, Alexandra, additional, Svec, Peter, additional, Kreminska, Elena, additional, Rabin, Karen R., additional, Polychronopoulou, Sophia, additional, da Costa, Elaine, additional, Marquart, Hanne Vibeke, additional, Kattamis, Antonis, additional, Ratei, Richard, additional, Reinhardt, Dirk, additional, Moorman, Anthony V, additional, Schrappe, Martin, additional, and Stary, Jan, additional

Published
2016
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32. Burkitt Lymphoma Genome Sequencing Project (BLGSP): Introduction

Author

Gerhard, Daniela S, primary, Grande, Bruno, additional, Griner, Nicholas, additional, Casper, Corey, additional, Gerdts, Sarah E., additional, Omoding, Abraham, additional, Orem, Jackson, additional, Mbulaiteye, Sam M, additional, Ogwang, Martin D., additional, Reynolds, Steven J., additional, Bhatia, Kishor, additional, Ayers, Leona, additional, Choi, John K, additional, Mullighan, Charles G., additional, Sandlund, John T., additional, Alexander, Thomas B., additional, Abramson, Jeremy S., additional, Gross, Thomas G., additional, Noy, Ariela, additional, Bethony, Jeffrey, additional, Leal, Fabio, additional, Greiner, Timothy C, additional, Jaffe, Elaine S., additional, Harris, Nancy Lee, additional, Gastier-Foster, Julie M., additional, Bowen, Jay, additional, Hanf, Benjamin, additional, Schmitz, Roland, additional, Martin, Jean-Paul, additional, Martin, Marie-Reine, additional, Irvin, John D., additional, Miller, Ellen, additional, Gesuwan, Patee, additional, Hermida, Leandro C., additional, Davidsen, Tanja M., additional, Mungall, Andrew J., additional, Ma, Yussanne, additional, Marra, Marco A., additional, Morin, Ryan D., additional, and Staudt, Louis M., additional

Published
2016
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