237 results on '"Olin A"'
Search Results
2. Delivering intensive therapies to older adults with hematologic malignancies: strategies to personalize care
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Olin, Rebecca L.
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- 2019
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3. Bone marrow–specific loss of ABI1 induces myeloproliferative neoplasm with features resembling human myelofibrosis
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Chorzalska, Anna, Morgan, John, Ahsan, Nagib, Treaba, Diana O., Olszewski, Adam J., Petersen, Max, Kingston, Nathan, Cheng, Yan, Lombardo, Kara, Schorl, Christoph, Yu, Xiaoqing, Zini, Roberta, Pacilli, Annalisa, Tepper, Alexander, Coburn, Jillian, Hryniewicz-Jankowska, Anita, Zhao, Ting C., Oancea, Elena, Reagan, John L., Liang, Olin, Kotula, Leszek, Quesenberry, Peter J., Gruppuso, Philip A., Manfredini, Rossella, Vannucchi, Alessandro Maria, and Dubielecka, Patrycja M.
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- 2018
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4. North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: position on standards of care and areas of need
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Naveen Pemmaraju, Hagop Kantarjian, Kendra Sweet, Eunice Wang, Jayastu Senapati, Nathaniel R. Wilson, Marina Konopleva, Arthur E. Frankel, Vikas Gupta, Ruben Mesa, Matthew Ulrickson, Edward Gorak, Sumeet Bhatia, Tulin Budak-Alpdogan, James Mason, Maria Teresa Garcia-Romero, Norma Lopez-Santiago, Gabriela Cesarman-Maus, Pankit Vachhani, Sangmin Lee, Vijaya Raj Bhatt, William Blum, Roland B. Walter, Dale Bixby, Ivana Gojo, Madeleine Duvic, Raajit K. Rampal, Marcos de Lima, James Foran, Amir T. Fathi, Aric Cameron Hall, Meagan A. Jacoby, Jeffrey Lancet, Gabriel Mannis, Anthony S. Stein, Alice Mims, David Rizzieri, Rebecca Olin, Alexander Perl, Gary Schiller, Paul Shami, Richard M. Stone, Stephen Strickland, Matthew J. Wieduwilt, Naval Daver, Farhad Ravandi, Sumithira Vasu, Monica Guzman, Gail J. Roboz, Joseph Khoury, Muzaffar Qazilbash, Phyu P. Aung, Branko Cuglievan, Yazan Madanat, Mohamed A. Kharfan-Dabaja, Anna Pawlowska, Justin Taylor, Martin Tallman, Prajwal Dhakal, and Andrew A. Lane
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC’s inaugural meetings are presented herein.
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- 2023
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5. Increasing use of allogeneic hematopoietic cell transplantation in patients aged 70 years and older in the United States
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Muffly, Lori, Pasquini, Marcelo C., Martens, Michael, Brazauskas, Ruta, Zhu, Xiaochun, Adekola, Kehinde, Aljurf, Mahmoud, Ballen, Karen K., Bajel, Ashish, Baron, Frederic, Battiwalla, Minoo, Beitinjaneh, Amer, Cahn, Jean-Yves, Carabasi, Mathew, Chen, Yi-Bin, Chhabra, Saurabh, Ciurea, Stefan, Copelan, Edward, D'Souza, Anita, Edwards, John, Foran, James, Freytes, Cesar O., Fung, Henry C., Gale, Robert Peter, Giralt, Sergio, Hashmi, Shahrukh K., Hildebrandt, Gerhard C., Ho, Vincent, Jakubowski, Ann, Lazarus, Hillard, Luskin, Marlise R., Martino, Rodrigo, Maziarz, Richard, McCarthy, Philip, Nishihori, Taiga, Olin, Rebecca, Olsson, Richard F., Pawarode, Attaphol, Peres, Edward, Rezvani, Andrew R., Rizzieri, David, Savani, Bipin N., Schouten, Harry C., Sabloff, Mitchell, Seftel, Matthew, Seo, Sachiko, Sorror, Mohamed L., Szer, Jeff, Wirk, Baldeep M., Wood, William A., and Artz, Andrew
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- 2017
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6. A Risk-Adapted Study to Assess the Efficacy of Enasidenib and Subsequent Response-Driven Addition of Azacitidine for Newly Diagnosed IDH2-Mutant AML Patients: 3-Year Follow-up
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Eytan Stein, Sheng F Cai, Ying Huang, Andrew Dunbar, Maria R. Baer, Wendy Stock, Tibor Kovacsovics, William G. Blum, Gary J. Schiller, Rebecca L. Olin, James M. Foran, Mark R. Litzow, Tara L. Lin, Prapti A. Patel, Matthew C. Foster, Michael M. Boyiadzis, Robert H. Collins, Jordan Chervin, Abigail B. Shoben, Jo-Anne Vergilio, Nyla A. Heerema, Leonard Rosenberg, Timothy Chen, Ashley O. Yocum, Franchesca Druggan, Sonja Marcus, Mona Stefanos, Molly Martycz, Brian J. Druker, Alice S. Mims, Uma Borate, Amy Burd, John C. Byrd, and Ross L. Levine
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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7. A Phase 1b Dose Escalation and Expansion Study of SNDX-5613, Azacitidine (AZA) and Venetoclax (VEN) in Newly Diagnosed, Patients ≥ 60 Years with Untreated NPM1-Mutated/ FLT3-Wild Type AML or KMT2A-Rearranged Acute Myeloid Leukemia (AML)
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Joshua F. Zeidner, Matthew C. Foster, Mary Johnson, Ying Huang, Ronan T. Swords, Eytan Stein, James M. Foran, Maria R. Baer, Wendy Stock, Yazan F. Madanat, Tibor Kovacsovics, Rebecca L. Olin, William G. Blum, Gary J. Schiller, Tara L. Lin, Robert L. Redner, Zeina Al-Mansour, Emily K Curran, Nyla A. Heerema, Molly Martycz, Leonard Rosenberg, Sonja Marcus, Ashley O. Yocum, Timothy Chen, Mona Stefanos, Franchesca Druggan, Amy Burd, Ross L. Levine, Brian J. Druker, Uma Borate, John C. Byrd, and Alice S. Mims
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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8. Entospletinib (ENTO) in Combination with Cytarabine (Ara-C) and Daunorubicin (DNR) in Newly Diagnosed (ND) Adult Patients with NPM1-Mutated and FLT3-ITD Wild-Type Acute Myeloid Leukemia (AML) Is Associated with Good Response and Survival: A Phase 2 Sub-Study of the Beat AML Master Trial
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Uma Borate, Rui Li, Ying Huang, Ronan T. Swords, Elie Traer, Eytan Stein, James M. Foran, Maria R. Baer, Vu H. Duong, Wendy Stock, Olatoyosi Odenike, Prapti Patel, Robert H. Collins, Yazan F. Madanat, Tibor Kovacsovics, Michael W. Deininger, Catherine Smith, Rebecca L. Olin, Martha L. Arellano, William G. Blum, Gary J. Schiller, Tara L. Lin, Matthew C. Foster, Michael M. Boyiadzis, Robert L. Redner, Zeina Al-Mansour, Emily K Curran, Nyla A. Heerema, Theophilus J Gana, Molly Martycz, Leonard Rosenberg, Sonja Marcus, Ashley O. Yocum, Timothy Chen, Mona Stefanos, Franchesca Druggan, Amy Burd, Ross L. Levine, Brian J. Druker, John C. Byrd, and Alice S. Mims
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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9. Ameli-01: A Phase I Trial of UCART123v1.2, an Anti-CD123 Allogeneic CAR-T Cell Product, in Adult Patients with Relapsed or Refractory (R/R) CD123+ Acute Myeloid Leukemia (AML)
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David A. Sallman, Daniel J. DeAngelo, Naveen Pemmaraju, Shira Dinner, Saar Gill, Rebecca L. Olin, Eunice S. Wang, Marina Konopleva, Eileen Stark, Ana Korngold, Asifa Haider, Kate Backhouse, Carolyn Figliola, Daniel J. Lee, Mark G. Frattini, Carrie Brownstein, and Gail J. Roboz
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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10. North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: Position on Standards of Care and Areas of Need
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Pemmaraju, Naveen, primary, Kantarjian, Hagop M., additional, Sweet, Kendra L, additional, Wang, Eunice S., additional, Senapati, Jayastu, additional, Wilson, Nathaniel R, additional, Konopleva, Marina Y., additional, Frankel, Arthur E, additional, Gupta, Vikas, additional, Mesa, Ruben A., additional, Ulrickson, Matthew L., additional, Gorak, Edward, additional, Bhatia, Sumeet, additional, Budak-Alpdogan, Tulin, additional, Mason, James R, additional, Garcia-Romero, Maria Teresa, additional, Lopez-Santiago, Norma C, additional, Cesarman-Maus, Gabriela, additional, Vachhani, Pankit, additional, Lee, Sangmin, additional, Bhatt, Vijaya R., additional, Blum, William, additional, Walter, Roland B, additional, Bixby, Dale, additional, Gojo, Ivana, additional, Duvic, Madeleine, additional, Rampal, Raajit K., additional, de Lima, Marcos, additional, Foran, James M, additional, Fathi, Amir T., additional, Hall, Aric, additional, Jacoby, Meagan A, additional, Lancet, Jeffrey E., additional, Mannis, Gabriel N., additional, Stein, Anthony S., additional, Mims, Alice S., additional, Rizzieri, David, additional, Olin, Rebecca L., additional, Perl, Alexander E., additional, Schiller, Gary J., additional, Shami, Paul J, additional, Stone, Richard M., additional, Strickland, Stephen, additional, Wieduwilt, Matthew J, additional, Daver, Naval G., additional, Ravandi, Farhad, additional, Vasu, Sumithira, additional, Guzman, Monica L, additional, Roboz, Gail J., additional, Khoury, Joseph D., additional, Qazilbash, Muzaffar H, additional, Aung, Phyu, additional, Cuglievan, Branko, additional, Madanat, Yazan F, additional, Kharfan-Dabaja, Mohamed A, additional, Pawlowska, Anna B, additional, Taylor, Justin, additional, Tallman, Martin S., additional, Dhakal, Prajwal, additional, and Lane, Andrew A., additional
- Published
- 2022
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11. Entospletinib (ENTO) in Combination with Cytarabine (Ara-C) and Daunorubicin (DNR) in Newly Diagnosed (ND) Adult Patients with NPM1-Mutated and FLT3-ITD Wild-Type Acute Myeloid Leukemia (AML) Is Associated with Good Response and Survival: A Phase 2 Sub-Study of the Beat AML Master Trial
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Borate, Uma, primary, Li, Rui, additional, Huang, Ying, additional, Swords, Ronan T., additional, Traer, Elie, additional, Stein, Eytan, additional, Foran, James M., additional, Baer, Maria R., additional, Duong, Vu H., additional, Stock, Wendy, additional, Odenike, Olatoyosi, additional, Patel, Prapti, additional, Collins, Robert H., additional, Madanat, Yazan F., additional, Kovacsovics, Tibor, additional, Deininger, Michael W., additional, Smith, Catherine, additional, Olin, Rebecca L., additional, Arellano, Martha L., additional, Blum, William G., additional, Schiller, Gary J., additional, Lin, Tara L., additional, Foster, Matthew C., additional, Boyiadzis, Michael M., additional, Redner, Robert L., additional, Al-Mansour, Zeina, additional, Curran, Emily K, additional, Heerema, Nyla A., additional, Gana, Theophilus J, additional, Martycz, Molly, additional, Rosenberg, Leonard, additional, Marcus, Sonja, additional, Yocum, Ashley O., additional, Chen, Timothy, additional, Stefanos, Mona, additional, Druggan, Franchesca, additional, Burd, Amy, additional, Levine, Ross L., additional, Druker, Brian J., additional, Byrd, John C., additional, and Mims, Alice S., additional
- Published
- 2022
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12. A Phase 1b Dose Escalation and Expansion Study of SNDX-5613, Azacitidine (AZA) and Venetoclax (VEN) in Newly Diagnosed, Patients ≥ 60 Years with Untreated NPM1-Mutated/ FLT3-Wild Type AML or KMT2A-Rearranged Acute Myeloid Leukemia (AML)
- Author
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Zeidner, Joshua F., primary, Foster, Matthew C., additional, Johnson, Mary, additional, Huang, Ying, additional, Swords, Ronan T., additional, Stein, Eytan, additional, Foran, James M., additional, Baer, Maria R., additional, Stock, Wendy, additional, Madanat, Yazan F., additional, Kovacsovics, Tibor, additional, Olin, Rebecca L., additional, Blum, William G., additional, Schiller, Gary J., additional, Lin, Tara L., additional, Redner, Robert L., additional, Al-Mansour, Zeina, additional, Curran, Emily K, additional, Heerema, Nyla A., additional, Martycz, Molly, additional, Rosenberg, Leonard, additional, Marcus, Sonja, additional, Yocum, Ashley O., additional, Chen, Timothy, additional, Stefanos, Mona, additional, Druggan, Franchesca, additional, Burd, Amy, additional, Levine, Ross L., additional, Druker, Brian J., additional, Borate, Uma, additional, Byrd, John C., additional, and Mims, Alice S., additional
- Published
- 2022
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13. Hpscs in the BM Niches Are Possibly Regulated in a Sex-Specific Manner and Influenced Differently By Sex Hormones during Aging Hematopoiesis
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So, Eui Young, primary, Dubielecka, Patrycja M., additional, Liang, Olin, additional, Reginato, Anthony, additional, and Quesenberry, Peter J., additional
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- 2022
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14. Improved Gvhd and Relapse Free Survival Outcomes in Older Acute Leukemia Patients Receiving Young Haploidentical Donor Vs Older Matched Sibling Donor Reduced Intensity Conditioning Hematopoietic Cell Transplants
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Tam, Andrew H., primary, Logan, Aaron C., additional, Choi, Angela J., additional, Fong, Richard, additional, Damon, Lloyd E., additional, Olin, Rebecca L., additional, Dunavin, Neil, additional, Sayre, Peter H., additional, Gaensler, Karin L., additional, Smith, Catherine, additional, and Yan, Lily, additional
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- 2022
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15. A Risk-Adapted Study to Assess the Efficacy of Enasidenib and Subsequent Response-Driven Addition of Azacitidine for Newly Diagnosed IDH2-Mutant AML Patients: 3-Year Follow-up
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Stein, Eytan, primary, Cai, Sheng F, additional, Huang, Ying, additional, Dunbar, Andrew, additional, Baer, Maria R., additional, Stock, Wendy, additional, Kovacsovics, Tibor, additional, Blum, William G., additional, Schiller, Gary J., additional, Olin, Rebecca L., additional, Foran, James M., additional, Litzow, Mark R., additional, Lin, Tara L., additional, Patel, Prapti A., additional, Foster, Matthew C., additional, Boyiadzis, Michael M., additional, Collins, Robert H., additional, Chervin, Jordan, additional, Shoben, Abigail B., additional, Vergilio, Jo-Anne, additional, Heerema, Nyla A., additional, Rosenberg, Leonard, additional, Chen, Timothy, additional, Yocum, Ashley O., additional, Druggan, Franchesca, additional, Marcus, Sonja, additional, Stefanos, Mona, additional, Martycz, Molly, additional, Druker, Brian J., additional, Mims, Alice S., additional, Borate, Uma, additional, Burd, Amy, additional, Byrd, John C., additional, and Levine, Ross L., additional
- Published
- 2022
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16. Ameli-01: A Phase I Trial of UCART123v1.2, an Anti-CD123 Allogeneic CAR-T Cell Product, in Adult Patients with Relapsed or Refractory (R/R) CD123+ Acute Myeloid Leukemia (AML)
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Sallman, David A., primary, DeAngelo, Daniel J., additional, Pemmaraju, Naveen, additional, Dinner, Shira, additional, Gill, Saar, additional, Olin, Rebecca L., additional, Wang, Eunice S., additional, Konopleva, Marina, additional, Stark, Eileen, additional, Korngold, Ana, additional, Haider, Asifa, additional, Backhouse, Kate, additional, Figliola, Carolyn, additional, Lee, Daniel J., additional, Frattini, Mark G., additional, Brownstein, Carrie, additional, and Roboz, Gail J., additional
- Published
- 2022
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17. Venetoclax and idasanutlin in relapsed/refractory AML: a non-randomized, open-label phase 1b trial
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Daver, Naval G., primary, Dail, Monique, additional, Garcia, Jacqueline S., additional, Jonas, Brian A., additional, Yee, Karen W.L., additional, Kelly, Kevin R., additional, Vey, Norbert, additional, Assouline, Sarit, additional, Roboz, Gail J., additional, Paolini, Stefania, additional, Pollyea, Daniel A., additional, Tafuri, Agostino, additional, Brandwein, Joseph M., additional, Pigneux, Arnaud, additional, Powell, Bayard L., additional, Fenaux, Pierre, additional, Olin, Rebecca L., additional, Visani, Giuseppe, additional, Martinelli, Giovanni, additional, Onishi, Maika, additional, Wang, Jue, additional, Huang, Weize, additional, Green, Cherie, additional, Ott, Marion G., additional, Hong, Wan-Jen, additional, Konopleva, Marina Y., additional, and Andreeff, Michael, additional
- Published
- 2022
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18. North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: position on standards of care and areas of need
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Pemmaraju, Naveen, Kantarjian, Hagop, Sweet, Kendra, Wang, Eunice, Senapati, Jayastu, Wilson, Nathaniel R., Konopleva, Marina, Frankel, Arthur E., Gupta, Vikas, Mesa, Ruben, Ulrickson, Matthew, Gorak, Edward, Bhatia, Sumeet, Budak-Alpdogan, Tulin, Mason, James, Garcia-Romero, Maria Teresa, Lopez-Santiago, Norma, Cesarman-Maus, Gabriela, Vachhani, Pankit, Lee, Sangmin, Bhatt, Vijaya Raj, Blum, William, Walter, Roland B., Bixby, Dale, Gojo, Ivana, Duvic, Madeleine, Rampal, Raajit K., de Lima, Marcos, Foran, James, Fathi, Amir T., Hall, Aric Cameron, Jacoby, Meagan A., Lancet, Jeffrey, Mannis, Gabriel, Stein, Anthony S., Mims, Alice, Rizzieri, David, Olin, Rebecca, Perl, Alexander, Schiller, Gary, Shami, Paul, Stone, Richard M., Strickland, Stephen, Wieduwilt, Matthew J., Daver, Naval, Ravandi, Farhad, Vasu, Sumithira, Guzman, Monica, Roboz, Gail J., Khoury, Joseph, Qazilbash, Muzaffar, Aung, Phyu P., Cuglievan, Branko, Madanat, Yazan, Kharfan-Dabaja, Mohamed A., Pawlowska, Anna, Taylor, Justin, Tallman, Martin, Dhakal, Prajwal, and Lane, Andrew A.
- Published
- 2023
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19. Improved Gvhd and Relapse Free Survival Outcomes in Older Acute Leukemia Patients Receiving Young Haploidentical Donor Vs Older Matched Sibling Donor Reduced Intensity Conditioning Hematopoietic Cell Transplants
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Andrew H. Tam, Aaron C. Logan, Angela J. Choi, Richard Fong, Lloyd E. Damon, Rebecca L. Olin, Neil Dunavin, Peter H. Sayre, Karin L. Gaensler, Catherine Smith, and Lily Yan
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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20. Enasidenib (ENA) Monotherapy with Addition of Azacitidine in Non-Responders Is Effective in Older Patients with Newly Diagnosed IDH2 Mutated Acute Myeloid Leukemia (AML): A Completed Phase 2/1b Sub-Study of the Beat AML Master Trial
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Jordan Chervin, Ross L. Levine, Tara L. Lin, Ying Huang, William Blum, Sonja Marcus, Tibor Kovacsovics, Ashley O. Yocum, Franchesca Druggan, Gary J. Schiller, Brian J. Druker, Mona Stefanos, Uma Borate, Matthew C. Foster, Mark R. Litzow, John C. Byrd, Nyla A. Heerema, Robert H. Collins, Abigail B. Shoben, Wendy Stock, Leonard Rosenberg, Amy Burd, Michael Boyiadzis, James M. Foran, Rebecca L. Olin, Jo-Anne Vergilio, Prapti A. Patel, Maria R. Baer, Timothy L. Chen, Eytan M. Stein, and Alice S. Mims
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Azacitidine ,Beat (acoustics) ,Myeloid leukemia ,Cell Biology ,Hematology ,Newly diagnosed ,Enasidenib ,Biochemistry ,IDH2 ,Non responders ,Older patients ,Internal medicine ,medicine ,business ,medicine.drug - Abstract
Background: ENA is an oral, selective inhibitor of IDH2 approved for the treatment (Tx) of patients (pts) with relapsed/refractory IDH2 mutated (IDH2m) AML. Here we report the results of a Phase 2 expansion and Phase 1b of the Beat AML Master Trial Phase 2/1b sub-study to assess the efficacy of Tx of newly diagnosed (ND) IDH2m AML pts ≥ 60 years of age with ENA monotherapy (ENAm) and subsequent response-driven addition of AZA Tx. (ClinicalTrials.gov NCT03013998). Methods: The study initiated with a 3-outcome, 2-stage Phase 2 design, which enrolled patients on ENAm for up to 5 cycles. Pts without CR/CRi after 5 cycles of ENAm, or progression/intolerance prior to this time, were transferred to Phase 1b to receive ENA + AZA (Figure 1). Key eligibility included ND IDH2m AML pts with age ≥ 60 years and ECOG performance status 0-2. Pts received ENAm 100 mg/day in continuous 28-day cycles and ENA + AZA (75 mg/m2 days 1-7 every 28 days) for Phase 1b. Response was assessed using 2017 ELN AML criteria. The primary endpoint was CR/CRi rate. The 2-stage design required 24 pts and tested the null hypothesis (H0) that CR/CRi rate equaled 20% vs 50% and then expanded to test a revised H0 of 30% vs 50% in 60 pts (conditional alpha=0.025, power=77%). Expansion also allowed further assessment of safety of this treatment regimen. Results: At data cut off (06/18/2020), 60 pts enrolled, received ENAm, and were evaluable for the primary endpoint. Median age was 75 years and 52% were female (Table 1). Median time on ENAm was 4.7 months (mos). At data cut off, 12 pts were still on ENAm Tx. Most common reasons for discontinuing ENAm were Tx failure (defined as no response to treatment) (23 or 38%), disease progression (loss of response to treatment) (7 or 12%) and adverse events (AEs; 6 or 10%). Five pts (8%) went to transplant. CR/CRi was achieved in 28 pts (47%; adjusted 95% CI 28-59, unadjusted exact 95% CI 34-60) (Table 2). Responses were higher (p=0.04) among the 44 pts with IDH2 R140 (55%) as compared to the 16 with IDH2 R172 mutation (25%) further supporting distinct biology between these subsets. After a median follow up of 14.6 mos, the median overall survival (mOS) was 24.4 mos (95% CI 10.6-not reached). The median duration of response was not reached with 12 mos estimation of 57% (95% CI 34-75). Overall, 20 ENA-related serious adverse events (SAEs) occurred in 15 pts, the most common was differentiation syndrome (12 or 20%) and 1 had ENA-related SAE of tumor lysis syndrome (1.7%). One pt had ENA-related Grade 5 AE (renal failure/death). Most common AEs of any grade (in ≥20%) were nausea, anemia, and low potassium (Table 3). The 7-day/30-day/60-day deaths observed with ENAm were 2%/5%/11%, respectively. Phase 1b: Seventeen pts had inadequate response to ENAm and transferred to Phase 1b to receive ENA + AZA. Median time on Tx (including ENAm) was 6.2 mos and median time on Tx after pts started ENA + AZA was 2.1 mos (Table 2). Most common reasons for discontinuing ENA + AZA included Tx failure (5 or 29%), disease progression (2 or 12%), transplant, death and AEs (each 2 or 12%). CR/CRi was 41% (exact 95% CI 18-67). After a median follow up of 12.7 mos, the mOS from start of ENA + AZA combination Tx was 8.9 mos. Four ENA-related SAEs occurred in 3 pts on ENA + AZA Tx and the most common was differentiation syndrome (2 or 12.5%). One dose-limiting toxicity (Grade 3 nausea) related to both Txs was observed. Most common AEs (≥20%) of any grade were anemia, low albumin and vomiting (Table 3). One death occurred at day 13 of ENA + AZA. Conclusions: In newly diagnosed pts ≥60 years old with IDH2m AML, ENA had a low early death rate, high CR/CRi rate (47%, adjusted 95% CI 28-59), and yielded durable remissions. The most common unique toxicity with ENA was differentiation syndrome that occurred in 20% of patients. In pts who did not achieve CR/CRi with ENAm, a subset of patients achieved CR/CRi with addition of AZA. This combined approach of serial therapy with ENA monotherapy followed by AZA addition in pts with sub-optimal response resulted in a mOS exceeding 2 years for pts enrolled on study. Further focus on improving response among patients with IDH2 R172 mutations, identifying subsets of pts not responding to ENA monotherapy, and integrating new targeted agents into this treatment regimen are warranted. Figure 1 Disclosures Stein: Syndax: Consultancy, Research Funding; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Biotheryx: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy. Borate:Genentech: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Research Funding; AbbVie: Other: Investigator in AbbVie-funded clinical trials; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Baer:Takeda: Other: Institutional research funding; AbbVie: Other: Institutional research funding; Astellas: Other: Institutional research funding; Forma: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Incyte: Other: Institutional research funding. Kovacsovics:Agios: Honoraria; Astella: Honoraria; Pfizer: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Jazz: Honoraria. Schiller:Astellas Pharma: Honoraria, Research Funding; Celator: Research Funding; Constellation: Research Funding; Abbvie: Research Funding; Actinium: Research Funding; Ariad: Research Funding; Stemline: Speakers Bureau; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Deciphera: Research Funding; DeltaFly: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; FujiFilm: Research Funding; Gamida: Research Funding; Genentech-Roche: Research Funding; Geron: Research Funding; Jazz Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Gilead: Speakers Bureau. Olin:Astellas: Other: Site PI; Genentech: Other: Site PI; Pfizer: Other: Site PI; Daiichi Sankyo: Other: Site PI; Genentech: Consultancy; Amgen: Consultancy. Foran:Trillium: Research Funding; Xencor: Research Funding; H3Biosciences: Research Funding; Agios: Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Boehringer Ingelheim: Research Funding; Actinium: Research Funding; Aprea: Research Funding; Aptose: Research Funding; Kura Oncology: Research Funding; Takeda: Research Funding; Revolution Medicine: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Lin:Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Prescient Therapeutics: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Astellas Pharma: Research Funding; Aptevo: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Mateon Therapeutics: Research Funding; Ono Pharmaceutical: Research Funding; Jazz: Research Funding; Gilead Sciences: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Celgene: Research Funding. Patel:DAVA Pharmaceuticals: Honoraria; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy; France Foundation: Honoraria. Foster:Daiichi Sankyo: Consultancy; Bellicum Pharmaceuticals: Research Funding; Macrogenics: Consultancy, Research Funding. Druker:Leukemia & Lymphoma Society: Research Funding; Henry Stewart Talks: Patents & Royalties; Iterion Therapeutics (formerly Beta Cat Pharmaceuticals): Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Patient True Talks: Consultancy; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millipore (formerly Upstate Biotechnology): Patents & Royalties; MolecularMD (acquired by ICON): Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; McGraw Hill: Patents & Royalties; Merck & Co: Patents & Royalties; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dana-Farber Cancer Institute: Patents & Royalties; EnLiven: Consultancy, Research Funding; Aptose Therapeutics Inc. (formerly Lorus): Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; Blueprint Medicines: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Aileron Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Oregon Health & Science University: Patents & Royalties. Byrd:Acerta Pharma: Research Funding; Syndax: Research Funding; Vincera: Research Funding; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Trillium: Research Funding; Leukemia and Lymphoma Society: Other; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding. Levine:Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Amgen: Honoraria; Astellas: Consultancy; Morphosys: Consultancy; Novartis: Consultancy; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Lilly: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Gilead: Honoraria. Mims:Abbvie: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Novartis: Speakers Bureau. OffLabel Disclosure: Enasidenib is not approved for the treatment of newly diagnosed AML.
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- 2020
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21. Coagulation, an ancestral serine protease cascade, exerts a novel function in early immune defense
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Loof, Torsten G., Mörgelin, Matthias, Johansson, Linda, Oehmcke, Sonja, Olin, Anders I., Dickneite, Gerhard, Norrby-Teglund, Anna, Theopold, Ulrich, and Herwald, Heiko
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- 2011
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22. Hpscs in the BM Niches Are Possibly Regulated in a Sex-Specific Manner and Influenced Differently By Sex Hormones during Aging Hematopoiesis
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Eui Young So, Patrycja M. Dubielecka, Olin Liang, Anthony Reginato, and Peter J. Quesenberry
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
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23. Ivosidenib (IVO) in Combination with Azacitidine (AZA) in Newly Diagnosed (ND) Older Patients with IDH1 R132-Mutated Acute Myeloid Leukemia (AML) Induces High Response Rates: A Phase 2 Sub-Study of the Beat AML Master Trial
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Patel, Prapti, primary, Ruppert, Amy S., additional, Borate, Uma, additional, Stein, Eytan M., additional, Baer, Maria R., additional, Stock, Wendy, additional, Kovacsovics, Tibor, additional, Blum, William, additional, Arellano, Martha L., additional, Schiller, Gary J., additional, Olin, Rebecca L., additional, Foran, James M., additional, Litzow, Mark R., additional, Lin, Tara L., additional, Foster, Matthew C., additional, Redner, Robert L., additional, Al-Mansour, Zeina, additional, Cogle, Christopher R., additional, Boyiadzis, Michael M., additional, Swords, Ronan, additional, Collins, Robert H., additional, Vergilio, Jo-Anne, additional, Heerema, Nyla A., additional, Rosenberg, Leonard, additional, Yocum, Ashley Owen, additional, Marcus, Sonja, additional, Chen, Timothy, additional, Druggan, Franchesca, additional, Stefanos, Mona, additional, Gana, Theophilus J, additional, Shoben, Abigail B., additional, Druker, Brian J., additional, Burd, Amy, additional, Byrd, John C., additional, Levine, Ross L., additional, and Mims, Alice S., additional
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- 2021
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24. S1918: A Phase II/III Randomized Study of R-Minichop with or without Oral Azacitidine (CC-486) in Participants Age 75 Years or Older with Newly Diagnosed Diffuse Large B Cell Lymphoma, Grade IIIb Follicular Lymphoma, Transformed Lymphoma, and High-Grade B-Cell Lymphomas with MYC and BCL2 and/or BCL6 Rearrangements
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Brem, Elizabeth A, primary, Li, Hongli, additional, Beaven, Anne W., additional, Caimi, Paolo F., additional, Cerchietti, Leandro, additional, Alizadeh, Ash A., additional, Olin, Rebecca L., additional, Henry, Norah Lynn, additional, Dilon, Hildy, additional, Little, Richard F., additional, Laubach, Cara, additional, Leblanc, Michael L., additional, Friedberg, Jonathan W., additional, and Smith, Sonali M., additional
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- 2021
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25. Gilteritinib (GILT) Monotherapy with Addition of Decitabine (DEC) in Non-Responders in Older Newly Diagnosed (ND) FLT3 Mutated Acute Myeloid Leukemia (AML) Patients Having High and Low Variant Allele Frequency (VAF): A Phase 2/1b Sub-Study of the Beat AML Master Trial
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Traer, Elie, primary, Huang, Ying, additional, Mims, Alice S., additional, Stein, Eytan M., additional, Baer, Maria R., additional, Stock, Wendy, additional, Kovacsovics, Tibor, additional, Blum, William, additional, Arellano, Martha L., additional, Schiller, Gary J., additional, Olin, Rebecca L., additional, Foran, James M., additional, Litzow, Mark R., additional, Lin, Tara L., additional, Patel, Prapti, additional, Foster, Matthew C., additional, Redner, Robert L., additional, Al-Mansour, Zeina, additional, Cogle, Christopher R., additional, Boyiadzis, Michael M., additional, Swords, Ronan, additional, Collins, Robert H., additional, Vergilio, Jo-Anne, additional, Heerema, Nyla A., additional, Rosenberg, Leonard, additional, Yocum, Ashley O., additional, Marcus, Sonja, additional, Chen, Timothy, additional, Druggan, Franchesca, additional, Stefanos, Mona, additional, Gana, Theophilus J, additional, Shoben, Abigail B., additional, Druker, Brian J., additional, Burd, Amy, additional, Byrd, John C., additional, Levine, Ross L., additional, and Borate, Uma, additional
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- 2021
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26. Entospletinib (ENTO) and Decitabine (DEC) Combination Therapy in Older Newly Diagnosed (ND) Acute Myeloid Leukemia (AML) Patients with Mutant TP53 or Complex Karyotype Is Associated with Poor Response and Survival: A Phase 2 Sub-Study of the Beat AML Master Trial
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Duong, Vu H., primary, Ruppert, Amy S., additional, Mims, Alice S., additional, Borate, Uma, additional, Stein, Eytan M., additional, Baer, Maria R., additional, Stock, Wendy, additional, Kovacsovics, Tibor, additional, Blum, William G., additional, Arellano, Martha L., additional, Schiller, Gary J., additional, Olin, Rebecca L., additional, Foran, James M., additional, Litzow, Mark R., additional, Lin, Tara L., additional, Patel, Prapti A., additional, Foster, Matthew C., additional, Redner, Robert L., additional, Al-Mansour, Zeina, additional, Cogle, Christopher R., additional, Swords, Ronan T., additional, Collins, Robert H., additional, Vergilio, Jo-Anne, additional, Heerema, Nyla A., additional, Rosenberg, Leonard, additional, Yocum, Ashley O., additional, Marcus, Sonja, additional, Chen, Timothy, additional, Druggan, Franchesca, additional, Stefanos, Mona, additional, Gana, Theophilus J, additional, Shoben, Abigail B., additional, Druker, Brian J., additional, Burd, Amy, additional, Byrd, John C., additional, Levine, Ross L., additional, and Boyiadzis, Michael M., additional
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- 2021
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27. Treatment of invasive streptococcal infection with a peptide derived from human high-molecular weight kininogen
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Oehmcke, Sonja, Shannon, Oonagh, von Köckritz-Blickwede, Maren, Mörgelin, Matthias, Linder, Adam, Olin, Anders I., Björck, Lars, and Herwald, Heiko
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- 2009
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28. Beat AML S8 Group 2: Gilteritinib (GILT) in Combination with Decitabine (DEC) and Venetoclax (VEN) in Untreated FLT3 Mutated Acute Myeloid Leukemia (AML) Patients Age ≥60 with High and Low Variant Allele Frequency (VAF)
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Liu, Qiuying (Selina), Welkie, Rina Li, Huang, Ying, Swords, Ronan T., Lin, Tara L, Koenig, Kristin L, Madanat, Yazan F., Patel, Prapti A., Collins, Robert H., Blum, William, Arellano, Martha, Baer, Maria R., Stock, Wendy, Kovacsovics, Tibor J., Olin, Rebecca, Curran, Emily K, Stein, Eytan M., Schiller, Gary J., Zeidner, Joshua F., Redner, Robert L., Heerema, Nyla A., Martycz, Molly, Rosenberg, Leonard, Marcus, Sonja Gullen, Chen, Timothy, Stefanos, Mona, Levine, Ross L, Druker, Brian J., Yocum, Ashley Owen, Burd, Amy, Mims, Alice, Borate, Uma M., Byrd, John C., and Traer, Elie
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- 2023
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29. A CX3CR1 (fractalkine receptor) Small Molecular Antagonist (KAND567) Suppressed the Growth Promoting Effect of Monocytes on Chronic Lymphocytic Leukemia Cells
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Hojjat-Farsangi, Mohammad, Zhong, Wen, Mulder, Tom, Svensson, Ann, Lundin, Jeanette, Palma, Marzia, Schultz, Johan, Olin, Thomas, Wahlin, Bjorn, Osterborg, Anders, Kokhaei, Parviz, and Mellstedt, Hakan
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- 2023
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30. A Novel Online Decision Support Tool to Determine Practice Patterns and Concordance with Experts in the Treatment of Patients with Immune Thrombocytopenia
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Olin, Jacqueline L., Broome, Catherine M., Panch, Sandhya R, Rosenthal, Kristen, Quill, Timothy A., Shimano, Kristin A., and Al-Samkari, Hanny
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- 2023
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31. A Randomized Phase 2 Trial of 28-Day (Arm A) Versus 14-Day (Arm B) Schedule of Venetoclax + Azacitidine in Newly Diagnosed Acute Myeloid Leukemia Patients ≥ 60 Years
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Borate, Uma M., Huang, Ying, Johnson, Mary F., Zeidner, Joshua F., Swords, Ronan T., Koenig, Kristin L, Stein, Eytan M., Baer, Maria R., Stock, Wendy, Madanat, Yazan F., Olin, Rebecca, Blum, William, Schiller, Gary J., Lin, Tara L, Redner, Robert L., Curran, Emily K, Heerema, Nyla A., Martycz, Molly, Rosenberg, Leonard, Marcus, Sonja Gullen, Chen, Timothy, Stefanos, Mona, Levine, Ross L, Druker, Brian J., Yocum, Ashley Owen, Burd, Amy, Mims, Alice, and Byrd, John C.
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- 2023
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32. Influence of Pre-Treatment Features and Therapy Choice By Physicians on Overall Survival in Older Adults with Acute Myeloid Leukemia: A Report from the Beat AML Master Trial
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Borate, Uma M., Huang, Ying, Welkie, Rina Li, Swords, Ronan T., Traer, Elie, Stein, Eytan M., Lin, Tara L, Madanat, Yazan F., Patel, Prapti A., Collins, Robert H., Baer, Maria R., Duong, Vu H., Blum, William, Arellano, Martha, Stock, Wendy, Odenike, Olatoyosi, Redner, Robert L., Kovacsovics, Tibor J., Deininger, Michael W., Zeidner, Joshua F., Olin, Rebecca, Smith, Catherine C., Foran, James M., Schiller, Gary J., Curran, Emily K, Koenig, Kristin L, Heerema, Nyla A., Chen, Timothy, Martycz, Molly, Stefanos, Mona, Marcus, Sonja Gullen, Rosenberg, Leonard, Druker, Brian J., Levine, Ross L, Burd, Amy, Yocum, Ashley Owen, Mims, Alice, and Byrd, John C.
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- 2023
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33. Genomic Characterization of Newly Diagnosed Acute Myeloid Leukemia in Patients Age 60 Years and Older; A Report from the Beat AML Master Trial
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Hoff, Fieke W, Huang, Ying, Welkie, Rina Li, Swords, Ronan T., Traer, Elie, Stein, Eytan M., Lin, Tara L, Patel, Prapti A., Collins, Robert H., Baer, Maria R., Duong, Vu H., Blum, William, Arellano, Martha, Stock, Wendy, Odenike, Olatoyosi, Redner, Robert L., Kovacsovics, Tibor J., Deininger, Michael W., Zeidner, Joshua F., Olin, Rebecca, Smith, Catherine C., Foran, James M., Schiller, Gary J., Curran, Emily K, Koenig, Kristin L, Heerema, Nyla A., Chen, Timothy, Martycz, Molly, Stefanos, Mona, Marcus, Sonja Gullen, Rosenberg, Leonard, Druker, Brian J., Levine, Ross L, Burd, Amy, Yocum, Ashley Owen, Borate, Uma M., Mims, Alice, Byrd, John C., and Madanat, Yazan F.
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- 2023
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34. Enasidenib (ENA) Monotherapy with Addition of Azacitidine in Non-Responders Is Effective in Older Patients with Newly Diagnosed IDH2 Mutated Acute Myeloid Leukemia (AML): A Completed Phase 2/1b Sub-Study of the Beat AML Master Trial
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Stein, Eytan M., Huang, Ying, Borate, Uma, Baer, Maria R., Stock, Wendy, Kovacsovics, Tibor, Blum, William, Schiller, Gary J., Olin, Rebecca L., Foran, James M., Litzow, Mark, Lin, Tara, Patel, Prapti A., Foster, Matthew C, Boyiadzis, Michael, Collins, Robert H., Vergilio, Jo-Anne, Heerema, Nyla A, Rosenberg, Leonard, Yocum, Ashley Owen, Chen, Timothy, Druggan, Franchesca, Marcus, Sonja, Stefanos, Mona, Chervin, Jordan, Shoben, Abigail, Druker, Brian J., Burd, Amy, Byrd, John C., Levine, Ross L., and Mims, Alice S.
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- 2020
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35. Ivosidenib (IVO) in Combination with Azacitidine (AZA) in Newly Diagnosed (ND) Older Patients with IDH1 R132-Mutated Acute Myeloid Leukemia (AML) Induces High Response Rates: A Phase 2 Sub-Study of the Beat AML Master Trial
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Amy Burd, Matthew C. Foster, William Blum, James M. Foran, Sonja Marcus, Tibor Kovacsovics, Zeina Al-Mansour, Maria R. Baer, Robert H. Collins, Theophilus J Gana, Robert L. Redner, Franchesca Druggan, John C. Byrd, Amy S. Ruppert, Brian J. Druker, Leonard Rosenberg, Prapti A. Patel, Ronan Swords, Gary J. Schiller, Martha Arellano, Tara L. Lin, Wendy Stock, Abigail B. Shoben, Timothy L. Chen, Christopher R. Cogle, Mona Stefanos, Ashley O. Yocum, Alice S. Mims, Uma Borate, Eytan M. Stein, Ross L. Levine, Rebecca L. Olin, Nyla A. Heerema, Jo-Anne Vergilio, Mark R. Litzow, and Michael Boyiadzis
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Oncology ,medicine.medical_specialty ,IDH1 ,business.industry ,Immunology ,Azacitidine ,Myeloid leukemia ,Cell Biology ,Hematology ,Newly diagnosed ,Biochemistry ,Older patients ,Internal medicine ,Medicine ,business ,Beat (music) ,medicine.drug - Abstract
Background: IVO is an oral potent inhibitor of mutated IDH1 (IDH1m) enzyme, recently approved for the treatment (Tx) of ND adult patients (pts) with IDH1m AML ≥75 years old or with comorbidities precluding use of intensive induction chemotherapy, and adult pts with relapsed or refractory AML. In this Phase 2 sub-study of the Beat AML Master Trial, we evaluated the efficacy of IVO + AZA combination Tx in ND pts aged ≥60 years with IDH1m AML (ClinicalTrials.gov: NCT03013998) Methods: This open-label multicenter (16 sites / 9 enrolling) combination Tx study enrolled ND pts with R132 mIDH1 AML, utilizing the modified minimax Simon's 2-stage Phase 2 design. Pts received IVO + AZA for 6 cycles in the absence of disease progression (PD), unacceptable toxicity or stem cell transplant. Pts who achieved complete remission (CR)/complete remission with hematologic improvement (CRh)/complete remission with incomplete hematologic recovery (CRi) continued IVO + AZA for a total of 12 cycles, then IVO monotherapy until PD. Pts without CR/CRh/CRi after 6 cycles continued IVO + AZA if they demonstrated Tx benefit, as defined in Figure 1. Key eligibility included ND IDH1 R132 mutated AML pts aged ≥60 years and ECOG performance status 0 - 2 (Karnofsky ≥60). All pts received IVO 500 mg/day orally in continuous 28-day cycles + AZA 75 mg/m2 IV or SC on days 1-7 every 28 days. The primary endpoint was CR+CRh+CRi rate after 6 cycles of Tx. Response was assessed using modified 2017 ELN AML criteria. The modified minimax Simon's 2-stage design required 40 pts and tested the null hypothesis that the CR/CRh/CRi rate equaled 25% vs the alternative of 50% (one-sided alpha = 0.025, power 90%). Stage 1 required >5/16 responses for continued enrollment. Even though these criteria were met, the sponsor decided to discontinue the trial on 12/12/2019. Here we report the final primary endpoint results. Data were frozen 02/03/2021. Results: Between 07/2018 and 11/2019, 19 patients were enrolled with IDH1m AML; 18 started IVO + AZA Tx and are included in the analyses. At data freeze, 5 pts had died and 7 pts still on Tx were offered standard of care IVO. Median age of the pts was 75 years, 50% were ≥75 years, 61% were female and 89% were White (Table 1). The most common reasons for Tx discontinuation were trial discontinued by sponsor (7 or 39%), stem cell transplant (4 or 22%), and PD (3 or 17%). A total of 13 pts achieved CR/CRh/CRi (72%) by up to 6 cycles of Tx (Table 2 & Figure 2). Over the entire study period, 14 pts achieved CR/CRh/CRi (78%) with 8 CR (44%), 3 CRh (17%) and 3 CRi (17%). No deaths occurred within the first 60 days of Tx. After a median follow up of 19.8 months (mos), Page 2 median response duration was not reached, with 12-mos disease-free survival rate of 69%; also, median OS was not reached, with 12- and 18-mos OS rates of 100% and 73%, respectively. The median (range) time on Tx was 12 mos ( Conclusions: In ND pts with IDH1m AML and ≥60 years of age, IVO + AZA Tx was associated with a high CR/CRh/CRi rate, no early deaths (60 days) and a 1-year OS of 100%. IVO + AZA was acceptably tolerated and no unexpected toxicities occurred. Most common unique toxicities of IVO observed during the study were differentiation syndrome and QTc prolongation; these led to Tx discontinuation in only 1 pt. CR/CRh/CRi rate obtained with IVO +AZA is higher than that previously reported in studies with the individual agents or intensive chemotherapy approaches, suggesting a synergistic effect. Our overall response rate is similar to that reported recently for IVO + AZA in older ND IDH1 mutant AML pts, despite not including pts with morphologic leukemia-free state and partial remission. Based on these results, a global Phase 3 evaluation of IVO or placebo plus AZA is ongoing (NCT03173248). Figure 1 Figure 1. Disclosures Patel: BMS-Celgene, Agios: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding; Peerview: Honoraria. Ruppert: Telios Pharma: Consultancy. Borate: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Stein: Syros Pharmaceuticals, Inc.: Consultancy; Daiichi Sankyo: Consultancy; PinotBio: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Kovacsovics: AbbVie: Research Funding; Janssen Pharmaceuticals: Research Funding; Amgen Inc.: Research Funding; Novartis: Research Funding; Stemline: Honoraria; Jazz Pharmaceutials: Honoraria. Blum: Leukemia and Lymphoma Society: Research Funding; Nkarta: Research Funding; Celyad Oncology: Research Funding; Syndax: Honoraria; Xencor: Research Funding; Abbvie: Honoraria; Forma Therapeutics: Research Funding; AmerisourceBergen: Honoraria. Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Schiller: Sangamo: Research Funding; Takeda: Research Funding; Ono-UK: Consultancy, Research Funding; Gamida Cell Ltd.: Research Funding; Tolero: Research Funding; Samus: Research Funding; Karyopharm: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Bio: Research Funding; Mateon: Research Funding; Genentech-Roche: Research Funding; FujiFilm: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Actinium Pharmaceuticals, Inc: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Arog: Research Funding; Delta-Fly: Research Funding; Celator: Research Funding; Forma: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; PrECOG: Research Funding; Constellation Pharmaceuticals: Research Funding; Trovagene: Research Funding; Elevate: Research Funding; Deciphera: Research Funding; Actuate: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Daiichi-Sankyo: Research Funding; Onconova: Research Funding; Geron: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Abbvie: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Olin: Actinium: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Cellectis: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; Daiichi Sankyo: Research Funding; Astellas: Honoraria, Research Funding. Foran: pfizer: Honoraria; gamida: Honoraria; servier: Honoraria; kura: Research Funding; abbvie: Research Funding; takeda: Research Funding; trillium: Research Funding; revolution medicine: Honoraria; novartis: Honoraria; certara: Honoraria; sanofi aventis: Honoraria; bms: Honoraria; syros: Honoraria; taiho: Honoraria; OncLive: Honoraria; actinium: Research Funding; aptose: Research Funding; boehringer ingelheim: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Litzow: Pluristem: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Jazz: Other: Advisory Board; Amgen: Research Funding; Actinium: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Foster: Agios: Consultancy; Daiichi Sankyo: Consultancy; Macrogenics: Consultancy; Rafael Pharmaceuticals: Research Funding; Macrogenics: Research Funding; Bellicum Pharmaceuticals: Research Funding. Cogle: Celgene: Membership on an entity's Board of Directors or advisory committees; Aptevo therapeutics: Research Funding. Vergilio: Roche: Current equity holder in publicly-traded company; Foundation Medicine: Current Employment. Gana: Bausch: Current holder of individual stocks in a privately-held company; The Leukemia & Lymphoma Society: Consultancy. Druker: The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; EnLiven: Consultancy, Research Funding; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; GRAIL: Current equity holder in publicly-traded company; Nemucore Medical Innovations, Inc.: Consultancy; Merck & Co: Patents & Royalties; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Bristol-Myers Squibb: Research Funding; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Iterion Therapeutics: Membership on an entity's Board of Directors or advisory committees; Recludix Pharma, Inc.: Consultancy; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; Aileron: Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Vincerx Pharma: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Levine: QIAGEN: Membership on an entity's Board of Directors or advisory committees; Imago: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees; Zentalis: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Celgene: Research Funding; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Incyte: Consultancy; Janssen: Consultancy; Astellas: Consultancy; Morphosys: Consultancy; Gilead: Honoraria; Amgen: Honoraria; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Prelude: Membership on an entity's Board of Directors or advisory committees; Auron: Membership on an entity's Board of Directors or advisory committees. Mims: Leukemia and Lymphoma Society: Consultancy; Kura Oncology: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Aptevo: Research Funding; Xencor: Research Funding; Glycomemetics: Research Funding; Jazz Pharmaceuticals: Consultancy; Daiichi-Saynko: Consultancy. OffLabel Disclosure: IVO is an oral potent inhibitor of mutated IDH1 enzyme, recently approved for the treatment of ND adult patients with IDH1m AML âââ,¬Â°Ã,Â¥75 years old or with comorbidities precluding use of intensive induction chemotherapy, and adult pts with relapsed or refractory AML. The combination of AZA, a hypomethylating agent, and venetoclax, an oral BCL-2 inhibitor, is also FDA approved for newly diagnosed AML in adults 75 years or older, or who have comorbidities precluding intensive chemotherapy. This presentation will discuss the combination of IVO and AZA.
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- 2021
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36. Gilteritinib (GILT) Monotherapy with Addition of Decitabine (DEC) in Non-Responders in Older Newly Diagnosed (ND) FLT3 Mutated Acute Myeloid Leukemia (AML) Patients Having High and Low Variant Allele Frequency (VAF): A Phase 2/1b Sub-Study of the Beat AML Master Trial
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Alice S. Mims, Prapti A. Patel, Martha Arellano, Ronan Swords, Maria R. Baer, Nyla A. Heerema, William Blum, Matthew C. Foster, Tibor Kovacsovics, Amy Burd, Christopher R. Cogle, Mona Stefanos, Brian J. Druker, Timothy L. Chen, Gary J. Schiller, Uma Borate, Eytan M. Stein, Ross L. Levine, Franchesca Druggan, James M. Foran, Ashley O. Yocum, Robert L. Redner, Robert H. Collins, Jo-Anne Vergilio, Elie Traer, Ying Huang, Rebecca L. Olin, Tara L. Lin, Mark R. Litzow, Zeina Al-Mansour, Abigail B. Shoben, Sonja Marcus, Theophilus J Gana, John C. Byrd, Wendy Stock, Michael Boyiadzis, and Leonard Rosenberg
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Gilteritinib ,Decitabine ,Myeloid leukemia ,Cell Biology ,Hematology ,Variant allele ,Newly diagnosed ,Biochemistry ,Non responders ,Internal medicine ,medicine ,business ,Beat (music) ,medicine.drug - Abstract
Background: GILT is an oral potent selective FLT3 kinase inhibitor approved for marketing for the treatment (Tx) of patients (pts) with relapsed/refractory FLT3 mutated (FLT3m) AML but efficacy in older ND FLT3m AML pts is unknown. Furthermore, FLT3m can be present as a dominant or subclone and impact of FLT3 inhibitor therapy in this setting is uncertain. Here we report the results of a Phase 2/1b sub-study of the Beat AML Master Trial to assess the efficacy of GILT monotherapy (GILTm) in ND FLT3m AML pts aged ≥60 years with high and low VAF and the subsequent response-driven addition of DEC Tx. (ClinicalTrials.gov NCT03013998) Methods: The study was an open-label multicenter (15 sites), 3-outcome, 2-stage Phase 2 design that assigned pts to either Dominant FLT3/Group 1 (GP1) or Non-Dominant FLT3/Group 2 (GP2) as shown in Figure 1. Key eligibility criteria included ND FLT3m AML pts with high and low VAF and/or ITD ratio, aged ≥60 years, and ECOG performance status 0-2. In the Phase 2 study, all pts received GILTm 120 mg/day on days 1 - 28. Pts without CR/CRi after cycle 2 were transferred to the Phase 1b study to receive GILT + DEC (Figure 1). Phase 1b study utilized a standard 3+3 design to evaluate the safety/tolerability of concurrent GILT + DEC. Pts received GILT (dose level 1 [DL1] = 80 mg/day or dose level 2 [DL2] = 120 mg/day on days 1-28) + DEC 20 mg/m 2 IV on days 1-10 or 1-5 every 28 days. Primary endpoint was CR+CRi rate (Phase 2). Response was assessed using modified 2017 ELN AML criteria. The non-dominant GP2 was stopped for futility, GP1 was stopped early to modify trial to include venetoclax. Results: Phase 2 - Between 9/10/2018 to 2/11/2020, 19 / 20 enrolled pts (GP1: n = 9; GP2: n = 10) received GILTm and were included in analyses. Baseline pt characteristics are shown in Table 1. Median (range) time on GILTm was 3 cycles (1 - 18) in GP1 and 1 cycle (1 - 9) in GP2. Most common reasons for discontinuing Tx were Tx failure (TF; 44%) and relapse (33%) in GP1 and TF (70%) and disease progression (PD; 20%) in GP2. Overall CR+CRi was achieved in 4 pts (44%) in GP1 and 1 pt (10%) in GP2. Response duration are shown in Table 2. After median follow-up of 14.3 months (mos) and 19 mos in GP1 and GP2, respectively, 1-year OS was 56% and 76%. Most common Grade ≥3 adverse events (AEs) were febrile neutropenia and colitis (each 25%) in GP1; anemia and low platelet count in GP2 (each 30%). Overall, 7 pts had 15 serious AEs (SAEs) and all SAEs occurred in GP1 pts; most common SAE was colitis (25%) and 1 pt (13%) had a Tx-related Grade 3 SAE of tumor lysis syndrome. In GP2, 1 pt (10%) had Tx-related Grade 2 AE of differentiation syndrome. In GP1, 2 pts died within 60 days of Tx and none in GP2. Phase1b - After up to 2 cycles of GILTm, 12 pts with no CR/CRi (GP1: n = 4; GP2: n = 8) were transferred to receive GILT + DEC (Figure 1). At the time of this report, 1 pt with CRh remained on Tx. Median total time on Tx (including GILTm) was 4 cycles and median time on GILT + DEC Tx was 3 cycles (Table 2). Most common reasons for discontinuing Tx were PD (33%) and TF (25%); and 2 pts (17%) stopped Tx due to an AE. Pts were treated with DL1 GILT + DEC (n = 3), then DL2 GILT + DEC (n = 9); only 1 pt had dose-limiting toxicity (DLT) at DL2 (Grade 3 hyperbilirubinemia and pneumonitis requiring steroid therapy), hence, DL2 GILT + DEC was considered the MTD. CR+CRi rate was 25% in 3 pts, all at DL2 (Table 2). After a median follow-up of 17.8 mos, the 1-year OS from start of GILT + DEC Tx was 57%. Most common Grade ≥3 Tx-related AEs were anemia, febrile neutropenia and low WBC count (each 22%). Overall, 6 pts had 12 SAEs; 1 pt with SAE of Grade 4 sepsis died. Three GILT-related SAEs occurred in 1 pt - Grade 3 hyperbilirubinemia, and pneumonitis and Grade 1 transaminases increased. One pt died within 30 days and a second within 60 days of Tx. No difference was observed in GILT pharmacokinetics (PK) with or without DEC, however steady state Ctrough values were 1.4 to 2.3-fold greater than in relapsed/refractory AML pts (Admiral trial). Conclusions: In ND pts ≥60 years old with dominant FLT3 AML, GILTm induced a high 44% CR+CRi rate and long median OS (21.7 mos). Pts with non-dominant FLT3 had low 10% CR+CRi rate. GILTm was generally safe and was associated with differentiation syndrome in 1 pt. Concurrent GILT + DEC was acceptably tolerated, only 1 pt had a DLT, and the MTD was 120 mg/day GILT + DEC. A subset of pts with no CR/CRi during GILTm achieved remission with addition of DEC. Based on these results, a triple combination Tx study with venetoclax is currently enrolling. Figure 1 Figure 1. Disclosures Traer: Genentech: Membership on an entity's Board of Directors or advisory committees; Schrodinger: Research Funding; Incyte: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier/Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Membership on an entity's Board of Directors or advisory committees. Mims: Glycomemetics: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Aptevo: Research Funding; Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Genentech: Consultancy; Xencor: Research Funding; Kartos Pharmaceuticals: Research Funding; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Stein: Agios Pharmaceuticals, Inc: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; PinotBio: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Kovacsovics: AbbVie: Research Funding; Jazz Pharmaceutials: Honoraria; Janssen Pharmaceuticals: Research Funding; Amgen Inc.: Research Funding; Stemline: Honoraria; Novartis: Research Funding. Blum: Xencor: Research Funding; Abbvie: Honoraria; Nkarta: Research Funding; Celyad Oncology: Research Funding; AmerisourceBergen: Honoraria; Forma Therapeutics: Research Funding; Leukemia and Lymphoma Society: Research Funding; Syndax: Honoraria. Arellano: Syndax Pharmaceuticals, Inc: Consultancy; KITE Pharma, Inc: Consultancy. Schiller: Actinium Pharmaceuticals, Inc: Research Funding; Mateon: Research Funding; Tolero: Research Funding; Geron: Research Funding; Regimmune: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Celator: Research Funding; Sangamo: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; PrECOG: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Karyopharm: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell Ltd.: Research Funding; FujiFilm: Research Funding; Samus: Research Funding; Trovagene: Research Funding; Daiichi-Sankyo: Research Funding; Constellation Pharmaceuticals: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Abbvie: Research Funding; Actuate: Research Funding; Arog: Research Funding; Delta-Fly: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Ono-UK: Consultancy, Research Funding; Onconova: Research Funding; Deciphera: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Forma: Research Funding; Genentech-Roche: Research Funding; Bio: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Olin: Astellas: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Cellectis: Research Funding; Amgen: Honoraria; Abbvie: Honoraria; Actinium: Honoraria. Foran: taiho: Honoraria; syros: Honoraria; kura: Research Funding; boehringer ingelheim: Research Funding; sanofi aventis: Honoraria; trillium: Research Funding; aptose: Research Funding; abbvie: Research Funding; pfizer: Honoraria; gamida: Honoraria; actinium: Research Funding; takeda: Research Funding; certara: Honoraria; OncLive: Honoraria; bms: Honoraria; revolution medicine: Honoraria; servier: Honoraria; novartis: Honoraria; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Litzow: AbbVie: Research Funding; Jazz: Other: Advisory Board; Pluristem: Research Funding; Amgen: Research Funding; Omeros: Other: Advisory Board; Actinium: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Patel: BMS-Celgene, Agios: Membership on an entity's Board of Directors or advisory committees; Peerview: Honoraria; Aptevo Therapeutics: Research Funding. Foster: Bellicum Pharmaceuticals: Research Funding; Macrogenics: Research Funding; Rafael Pharmaceuticals: Research Funding; Macrogenics: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy. Cogle: Aptevo therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Vergilio: Foundation Medicine: Current Employment. Gana: The Leukemia & Lymphoma Society: Consultancy; Bausch: Current holder of individual stocks in a privately-held company. Druker: VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; GRAIL: Current equity holder in publicly-traded company; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; EnLiven: Consultancy, Research Funding; Iterion Therapeutics: Membership on an entity's Board of Directors or advisory committees; Recludix Pharma, Inc.: Consultancy; Pfizer: Research Funding; Merck & Co: Patents & Royalties; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Nemucore Medical Innovations, Inc.: Consultancy; Bristol-Myers Squibb: Research Funding; Blueprint Medicines: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aileron: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharma: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees. Levine: Auron: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Ajax: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Celgene: Research Funding; Roche: Honoraria, Research Funding; Zentalis: Membership on an entity's Board of Directors or advisory committees; Prelude: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Janssen: Consultancy; Gilead: Honoraria; Morphosys: Consultancy; Imago: Membership on an entity's Board of Directors or advisory committees; QIAGEN: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria. Borate: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy.
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- 2021
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37. S1918: A Phase II/III Randomized Study of R-Minichop with or without Oral Azacitidine (CC-486) in Participants Age 75 Years or Older with Newly Diagnosed Diffuse Large B Cell Lymphoma, Grade IIIb Follicular Lymphoma, Transformed Lymphoma, and High-Grade B-Cell Lymphomas with MYC and BCL2 and/or BCL6 Rearrangements
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Leandro Cerchietti, Michael LeBlanc, Anne W. Beaven, Richard F. Little, Sonali M. Smith, Rebecca L. Olin, Ash A. Alizadeh, Jonathan W. Friedberg, Cara Laubach, Hongli Li, Paolo F. Caimi, Hildy Dilon, Elizabeth Brem, and Norah Lynn Henry
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business.industry ,Immunology ,Follicular lymphoma ,Cell Biology ,Hematology ,Newly diagnosed ,medicine.disease ,BCL6 ,Biochemistry ,Oral Azacitidine ,law.invention ,Transformed Lymphoma ,medicine.anatomical_structure ,Randomized controlled trial ,law ,Cancer research ,Medicine ,business ,Diffuse large B-cell lymphoma ,B cell - Abstract
Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy; however, cure is highly dependent on the ability to deliver intensive, anthracycline-based chemoimmunotherapy. Advanced age is an important adverse feature in prognostic models, and nearly one third of cases occur in patients older than 75 years. There is no clear accepted standard of care for older patients with DLBCL due to under-representation of this group in randomized clinical trials. R-miniCHOP, a dose attenuated version of standard R-CHOP, is often chosen based on a prospective, single-arm phase II trial which showed a 2-year progression-free survival (PFS) of 47% (Peyrade, 2011), far lower than observed outcomes in patients younger than 80 yrs (Coiffier, 2002). Precise identification of older DLBCL patients who should be considered for curative versus palliative chemoimmunotherapy is difficult at an individual level; the challenge is to avoid both overtreatment with excessive toxicity and undertreatment with inferior outcomes. The FIL (Fondazione Italiana Linfomi; Italian Lymphoma Foundation) has developed an assessment tool accounting for age, comorbidities, and ability to perform activities of daily living (ADLs) and instrumental activities of living (IADLs). The FIL Tool classifies patients as "fit," "unfit," or "frail." When the FIL tool was prospectively applied to 1163 patients, 55% were fit, 28% were unfit, and 18% were frail. Three-year OS for the whole cohort was 65% and was strongly driven by fitness: 3-year OS was 75% for fit patients, 58% for unfit, and 43% for frail; similar outcomes were seen in a validation cohort (Merli F, 2021). However, treatment was not uniformly directed and was up to the treating physician. Epigenetic deregulation is a feature of DLBCL in older patients, and provides a rationale for targeting methylation. Pre-clinical models show that pre-treatment with hypomethylating agents improves the anti-tumor effect of R-CHOP (Clozel T, 2013). This work has led to early clinical studies of the hypomethylating agent azacitidine with R-CHOP in newly diagnosed DLBCL, with promising early efficacy and acceptable toxicity. The availability of oral azacitidine is an appealing additive approach and is agnostic to cell-of-origin. Based upon the need for improved outcomes in older patients and the promise of azacitidine in this setting, the National Clinical Trials Network (NCTN), led by SWOG, developed S1918, a randomized trial comparing R-miniCHOP to R-miniCHOP + oral azacitidine for older patients (> age 75) with newly diagnosed aggressive B-cell non-Hodgkin lymphomas. This study incorporates the FIL Tool for baseline frailty assessment and a serial comprehensive geriatric assessment (CGA) to evaluate effects of therapy on quality of life and functional status. This is the first randomized study in this population conducted in North America by the NCTN and will enroll a total of 384 eligible patients after a safety run-in phase. All patients will receive pre-phase therapy with vincristine 1mg x 1 and prednisone 60mg/m2 x 7 days (capped at 100mg/day); pre-phase therapy has been shown to improve performance status and decrease early treatment-related mortality (Owens CN, 2015). The primary objective of the phase II component is to determine if oral azacitidine + R-miniCHOP regimen should be tested further (Phase III) against R-miniCHOP alone based on estimates of 1-year progression-free survival (PFS). The primary objective of the phase III component is to compare the OS at 2 years between oral azacitidine + R-miniCHOP and R-miniCHOP alone. Key correlative tests will include circulating tumor DNA (ctDNA) assays at pre-specified timepoints to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has the potential to impact future trial design and to change the standard of care for patients 75 years and older with aggressive lymphoma in a number of ways given its randomized design, incorporation of geriatric assessments, and utilization of ctDNA correlatives. The prospective assessment of frailty, serial comprehensive geriatric assessments, and introduction of epigenetic modulation will hopefully improve outcomes for this population with significant need. Trial registration: ClinicalTrial.gov Identifier NCT04799275 Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820, and U10CA180821 Figure 1 Figure 1. Disclosures Brem: Morphosys/Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics/Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Consultancy; SeaGen: Speakers Bureau; KiTE Pharma: Membership on an entity's Board of Directors or advisory committees. Caimi: Seattle Genetics: Consultancy; Verastem: Consultancy; XaTek: Patents & Royalties: Royalties from patents (wife); Amgen Therapeutics.: Consultancy; Genentech: Research Funding; Kite Pharmaceuticals: Consultancy; ADC Theraputics: Consultancy, Research Funding; TG Therapeutics: Honoraria. Cerchietti: Bristol Myers Squibb: Research Funding; Celgene: Research Funding. Alizadeh: Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Roche: Consultancy, Honoraria; Janssen Oncology: Honoraria; Celgene: Consultancy, Research Funding; Gilead: Consultancy; Bristol Myers Squibb: Research Funding. Olin: Amgen: Honoraria; Cellectis: Research Funding; Pfizer: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding; Abbvie: Honoraria; Actinium: Honoraria; Astellas: Honoraria, Research Funding. Friedberg: Novartis: Other: DSMC ; Bayer: Other: DSMC ; Acerta: Other: DSMC . Smith: Celgene, Genetech, AbbVie: Consultancy; Alexion, AstraZeneca Rare Disease: Other: Study investigator.
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- 2021
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38. Entospletinib (ENTO) and Decitabine (DEC) Combination Therapy in Older Newly Diagnosed (ND) Acute Myeloid Leukemia (AML) Patients with Mutant TP53 or Complex Karyotype Is Associated with Poor Response and Survival: A Phase 2 Sub-Study of the Beat AML Master Trial
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Matthew C. Foster, Alice S. Mims, Uma Borate, Abigail B. Shoben, Ashley O. Yocum, Wendy Stock, Prapti A. Patel, Timothy L. Chen, Ronan Swords, Maria R. Baer, Tara L. Lin, Gary J. Schiller, Amy Burd, Martha Arellano, James M. Foran, Sonja Marcus, Brian J. Druker, William Blum, Michael Boyiadzis, Ross L. Levine, Theophilus J Gana, Zeina Al-Mansour, Vu H. Duong, Franchesca Druggan, John C. Byrd, Robert H. Collins, Leonard Rosenberg, Tibor Kovacsovics, Mona Stefanos, Robert L. Redner, Amy S. Ruppert, Mark R. Litzow, Rebecca L. Olin, Nyla A. Heerema, Christopher R. Cogle, Jo-Anne Vergilio, and Eytan M. Stein
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Oncology ,medicine.medical_specialty ,Entospletinib ,Combination therapy ,business.industry ,Immunology ,Mutant ,Myeloid leukemia ,Decitabine ,Cell Biology ,Hematology ,Newly diagnosed ,Biochemistry ,Internal medicine ,Complex Karyotype ,medicine ,business ,Beat (music) ,medicine.drug - Abstract
Background: In vitro studies and emerging clinical data suggest that inhibition of spleen tyrosine kinase may have an antileukemic effect in human AML. Pts with AML and TP53 mutations (TP53m) are commonly associated with older age (≥60 years) and complex karyotype (CK) and respond poorly to standard 7 + 3 induction (IND) chemotherapy with Methods: This multicenter (13 sites), open-label, Phase 2 combination Tx study utilized Simon's 2-stage Phase 2 design and enrolled AML pts with TP53m (identified molecularly) ± CK (Cohort A) or CK (≥3 metaphase abnormalities) without TP53m (Cohort B). Pts initially received 5 days of ENTO lead-in (which was later discontinued), followed by ENTO + DEC and those who achieved CR/CRh/CRi/MLFS with up to 3 cycles of IND proceeded to consolidation (CON) Tx for up to 11 cycles (Figure 1). Pts with CRi/MLFS after IND were allowed up to 6 cycles (IND + CON) to achieve CR/CRh or stayed on Tx if they got clinical benefit or went off Tx. CON was followed by maintenance (MTN) Tx for up to 2 years from start of study Tx. Pts were eligible if aged ≥60 years, ND, and had ECOG performance status 0 - 2. Pts received ENTO 400 mg orally twice daily for 5 days during ENTO lead-in, and then every 28 days during IND, CON, and MTN + DEC 20 mg/m 2 IV days 1-10 (IND) or days 1-5 (CON) every 28 days. Response was assessed using modified 2017 ELN AML criteria. The primary endpoint was composite complete remission (CCR) rate (CR + CRh) with up to 3 cycles of IND, and CRi/MLFS that achieved CR/CRh by up to 6 cycles (IND + CON). Beyond stage 1, pt accrual to Cohort A was allowed based on pts with CRi and to Cohort B was stopped early for futility. Results: Between Oct 2017 and Feb 2020, of the 63 pts enrolled (Cohort A = 48; Cohort B = 15), pts with confirmed eligibility who started study Tx were included in the analyses (Cohort A = 45; Cohort B = 13). During lead-in, 27 pts in Cohort A and 6 pts in Cohort B received ENTOm for 5 days. All pts received ENTO + DEC except 1 pt in Cohort A who withdrew consent (WOC). Median ages of the pts were 70 years (range 60 - 84) in Cohort A and 74 years (range 65 - 86) in Cohort B. Median time (range) on Tx was 2.2 mos and 4.8 mos in Cohort A and B, respectively. Most common reasons for Tx discontinuation were adverse event (AE; 27%), Tx failure (TF; 27%) and WOC (18%) in Cohort A; TF (31%), disease progression and relapse (each 15%) in Cohort B. In each cohort, 1 pt discontinued Tx due to death from leukemia and 1 pt in Cohort A in CRh due to development of an additional genetic abnormality. Four pts (9%) in Cohort A and 1 pt (8%) in Cohort B proceeded to transplant. The CCR (CR + CRh) rates with up to 6 cycles of Tx for Cohort A and B were 13.3% and 30.8%, respectively; overall CR + CRh rates were 17.8% and 38.5% (Table 1). In Cohort A, with a median follow-up of 11.5 months, 0% were 1-year disease-free and median OS (mOS) was 6.5 months. In Cohort B, with a median follow-up of 15.1 months, 25% were 1-year disease-free and mOS was 11.5 months. Deaths within 7-, 30-, and 60-days of Tx were 0, 3 and 11 in Cohort A and 0, 0 and 2 in Cohort B. Most common treatment-related Grade ≥3 AEs in Cohort A and B were febrile neutropenia (31% and 39%) and anemia (22% and 31%) (Table 2). Overall, 83 serious AEs (SAEs) were reported in 33 pts in Cohort A and 12 SAEs in 6 pts in Cohort B; most common SAEs in Cohort A were pneumonia (18%) and respiratory failure (11%), and in Cohort B sepsis, dehydration and acute kidney injury (each 15%). Most common treatment-related grade ≥3 laboratory abnormalities in Cohort A and B were neutrophils decreased (27% and 31%), WBC count decreased (20% and 23%), and lymphocyte count decreased (18% and 15%). Conclusions: ENTO + DEC demonstrated activity in ND AML pts aged ≥60 years with TP53m ± CK and CK without TP53 but induced low CR/CRh rates and short OS consistent with previously published poor CR rates and OS in these pts. Our results differ from the high remission rate and longer OS previously reported for DEC monotherapy in AML pts with TP53m. ENTO + DEC was safe and acceptably tolerated. Novel Tx strategies that can benefit AML pts with these most adverse risk factors are urgently needed. Figure 1 Figure 1. Disclosures Ruppert: Telios Pharma: Consultancy. Mims: Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Aptevo: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomemetics: Research Funding; Kartos Pharmaceuticals: Research Funding; Xencor: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Borate: Jazz Pharma: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Stein: Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Gilead Sciences, Inc.: Consultancy; Foghorn Therapeutics: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Daiichi Sankyo: Consultancy; Blueprint Medicines: Consultancy; PinotBio: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Kovacsovics: AbbVie: Research Funding; Janssen Pharmaceuticals: Research Funding; Amgen Inc.: Research Funding; Novartis: Research Funding; Stemline: Honoraria; Jazz Pharmaceutials: Honoraria. Blum: Amerisource Bergen; Abbvie, Syndax: Honoraria; Forma Therapeutics, Xencor; Celyad: Research Funding. Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Schiller: Actinium Pharmaceuticals, Inc: Research Funding; Gamida Cell Ltd.: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Karyopharm: Research Funding; Daiichi-Sankyo: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kaiser Permanente: Consultancy; Abbvie: Research Funding; AstraZeneca: Consultancy; Genentech-Roche: Research Funding; Delta-Fly: Research Funding; Cyclacel: Research Funding; Mateon: Research Funding; Actuate: Research Funding; Onconova: Research Funding; Geron: Research Funding; Sangamo: Research Funding; Arog: Research Funding; Ariad: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Trovagene: Research Funding; Ono-UK: Consultancy, Research Funding; Tolero: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Celator: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Astellas: Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Deciphera: Research Funding; FujiFilm: Research Funding; Samus: Research Funding; Regimmune: Research Funding; PrECOG: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Bio: Research Funding; Elevate: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biomed Valley Discoveries: Research Funding; Ono: Consultancy; Eli Lilly: Research Funding; Sellas: Research Funding; ASH foundation: Other: Chair-unpaid; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Olin: Astellas: Honoraria, Research Funding; Actinium: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding; Pfizer: Research Funding. Foran: certara: Honoraria; pfizer: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; servier: Honoraria; revolution medicine: Honoraria; trillium: Research Funding; takeda: Research Funding; abbvie: Research Funding; novartis: Honoraria; bms: Honoraria; OncLive: Honoraria; gamida: Honoraria; sanofi aventis: Honoraria; aptose: Research Funding; actinium: Research Funding; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Litzow: AbbVie: Research Funding; Omeros: Other: Advisory Board; Astellas: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Actinium: Research Funding; Amgen: Research Funding; Biosight: Other: Data monitoring committee. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Cogle: Aptevo therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Vergilio: Foundation Medicine: Current Employment; Roche: Current equity holder in publicly-traded company. Gana: Bausch: Current holder of individual stocks in a privately-held company; The Leukemia & Lymphoma Society: Consultancy. Druker: The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Aileron: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Recludix Pharma, Inc.: Consultancy; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharma: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; GRAIL: Current equity holder in publicly-traded company; Iterion Therapeutics: Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; EnLiven: Consultancy, Research Funding; Merck & Co: Patents & Royalties; Pfizer: Research Funding; Nemucore Medical Innovations, Inc.: Consultancy; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Levine: Isoplexis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Zentalis: Membership on an entity's Board of Directors or advisory committees; Imago: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Prelude: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Janssen: Consultancy; Celgene: Research Funding; Roche: Honoraria, Research Funding; Auron: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Astellas: Consultancy; Morphosys: Consultancy; QIAGEN: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Off-label use of entospletinib and decitabine.
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- 2021
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39. Excellent Outcomes Achieved with Medical Management of Chronic Phase CML Patients with Non-Hematologic TKI Intolerance
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Schoenbeck, Kelly L., primary, Tummala, Sirisha, additional, Olin, Rebecca L., additional, Goyal, Neha G., additional, Dhruva, Anand, additional, Damon, Lloyd E., additional, Logan, Aaron C., additional, Smith, Catherine C., additional, and Shah, Neil P., additional
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- 2020
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40. Excellent Outcomes Achieved with Medical Management of Chronic Phase CML Patients with Non-Hematologic TKI Intolerance
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Catherine C. Smith, Lloyd E. Damon, Aaron C Logan, Neha G. Goyal, Sirisha Tummala, Anand Dhruva, Rebecca L. Olin, Neil P. Shah, and Kelly L. Schoenbeck
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medicine.medical_specialty ,Hematology ,medicine.drug_class ,Nausea ,business.industry ,Immunology ,Retrospective cohort study ,Cell Biology ,Biochemistry ,Tyrosine-kinase inhibitor ,respiratory tract diseases ,Discontinuation ,Clinical trial ,Quality of life ,Median follow-up ,Internal medicine ,medicine ,medicine.symptom ,business - Abstract
Introduction:Tyrosine kinase inhibitor (TKI) intolerance is commonly encountered in patients with chronic myeloid leukemia in chronic phase (CML-CP). Clinical trials define non-hematologic TKI intolerance as grade 3-4 toxicities, but lower grade toxicities may also impair patients' quality of life and lead to changes in medical management. We sought to compare TKI-intolerant and -tolerant CML-CP patients and their clinical outcomes, including molecular responses, rates of progression, survival, and utilization of allogeneic stem cell transplant (alloSCT). Methods:We performed a single-center, retrospective cohort study of active CML-CP patients in our Hematology clinic between January 2017 and December 2019. We defined TKI intolerance as any grade non-hematologic toxicity that led to a change in TKI management, such as dose reduction or change of TKI. We also reviewed CML-CP patients who underwent alloSCT in the TKI era (2002-2019). AlloSCT patients were identified for chart review by ICD-10 codes and query of the institution's transplant database. Descriptive statistics, Chi-Square tests, and two-tailed t-tests were used to summarize the data. Results:We identified 216 CML-CP patients (Table 1), and 161 (74.5%) met criteria for non-hematologic TKI intolerance. The median age was 59 years-old in TKI-intolerant patients and 49 in tolerant patients (P=0.011). Most patients experienced TKI-intolerance from symptoms (93.2%, n=150); symptoms included fatigue (n=77, 59.2%), arthralgias (n=36, 27.7%), nausea (n=29, 22.3%), headache (n=16, 12.3%), and edema (n=15, 11.5%). The remaining patients were TKI-intolerant based on abnormal laboratory findings such as transaminitis or hyperglycemia (6.8%, n=11/161). Of the 161 TKI-intolerant patients at last follow-up, 130 (80.7%) remained on TKI, 19 (11.8%) were on prescribed discontinuation, 6 (3.72%) were non-adherent, 5 (3.1%) were off TKI for non-CML medical problems, and 1 (0.6%) was on omacetaxine. Dose reductions occurred in the majority who remained on TKIs (n=103/130, 79.2%) and prior to TKI discontinuation (n=13/19, 68.4%). Most TKI-intolerant patients (n=122/161, 75.8%) switched TKIs, with a median of 2 agents used (range 1-5). Of 55 TKI-tolerant patients, 46 (83.6%) were on TKI, 8 (14.5%) were on discontinuation, and 1 (1.8%) was non-adherent. Only 19.6% (n=9/46) patients were dose-reduced, and they rarely changed TKIs (median of 1 agent used). MR4.5 was achieved in 49% (n=79/161) of TKI-intolerant and 41.8% (n=23/55) of TKI-tolerant patients. Only 1 patient in each group progressed to accelerated phase. TKI-intolerant and -tolerant patients had similar times since diagnosis (with a median follow up of 81.7 months and 79.7 months, respectively). Five of 161 (3.1%) TKI-intolerant patients died, all from causes unrelated to CML and TKI therapy. None of the TKI-tolerant patients died during the abstraction period. Twenty CML-CP patients underwent alloSCT from year 2002-2019; 10 (50%) were transplanted for TKI intolerance without other transplant indications (Tables 2 and 3). Three of those 10 patients also had hematologic intolerance. Four (40%) TKI-intolerant patients resumed TKI post-transplant: 3 for disease relapse, 1 for sclerotic GVHD. Seven (70%) developed GVHD, with most cases being chronic (n=6), extensive (n=6), and severe/moderate (n=6). While 80% of patients achieved MR4.5 post-transplant (n=8/10), 30% (n=3/10) experienced transplant-related mortality (TRM) with a mean post-transplant survival of 38.5 months; the remaining 7 patients were alive at a median follow-up of 37.1 months. Conclusion: CML-CP patients with non-hematologic TKI-intolerance achieved similar clinical outcomes as TKI-tolerant patients despite dose reductions and/or switching TKIs. The use of alloSCT was rare in our practice, and CML-CP patients transplanted for TKI intolerance commonly resumed TKI post-alloSCT and frequently developed extensive GVHD. In light of the high survival rate achieved with medical management in CML-CP patients with non-hematologic TKI-intolerance, including no disease- or treatment-related deaths, this analysis does not support the use of alloSCT for patients with non-hematologic TKI-intolerance. Disclosures Schoenbeck: American Society of Hematology:Research Funding.Olin:Astellas:Other: Site PI;Genentech:Consultancy;Daiichi Sankyo:Other: Site PI;Amgen:Consultancy;Genentech:Other: Site PI;Pfizer:Other: Site PI.Logan:Amphivena:Research Funding;Autolus:Research Funding;Jazz:Research Funding;Kadmon:Research Funding;Kite:Research Funding;Pharmacyclics:Research Funding;Abbvie:Consultancy;Amgen:Consultancy;Novartis:Consultancy.Smith:Revolution Medicines:Other: Research Support, Research Funding;Abbvie:Other: Research Support, Research Funding;FujiFilm:Other: Research support, Research Funding;Daiichi Sanyko:Consultancy, Honoraria;Astellas Pharma:Honoraria, Other: Research Support, Research Funding;Sanofi:Honoraria.Shah:Bristol-Myers Squibb:Research Funding.
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- 2020
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41. Bone marrow-specific loss of
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Anna, Chorzalska, John, Morgan, Nagib, Ahsan, Diana O, Treaba, Adam J, Olszewski, Max, Petersen, Nathan, Kingston, Yan, Cheng, Kara, Lombardo, Christoph, Schorl, Xiaoqing, Yu, Roberta, Zini, Annalisa, Pacilli, Alexander, Tepper, Jillian, Coburn, Anita, Hryniewicz-Jankowska, Ting C, Zhao, Elena, Oancea, John L, Reagan, Olin, Liang, Leszek, Kotula, Peter J, Quesenberry, Philip A, Gruppuso, Rossella, Manfredini, Alessandro Maria, Vannucchi, and Patrycja M, Dubielecka
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STAT3 Transcription Factor ,NF-kappa B ,Down-Regulation ,Mice, Transgenic ,Mice, Inbred C57BL ,Cytoskeletal Proteins ,Mice ,src-Family Kinases ,Bone Marrow ,Primary Myelofibrosis ,Animals ,Humans ,Female ,Cell Self Renewal ,Cells, Cultured ,Gene Deletion ,Adaptor Proteins, Signal Transducing ,Signal Transduction - Abstract
Although the pathogenesis of primary myelofibrosis (PMF) and other myeloproliferative neoplasms (MPNs) is linked to constitutive activation of the JAK-STAT pathway, JAK inhibitors have neither curative nor MPN-stem cell-eradicating potential, indicating that other targetable mechanisms are contributing to the pathophysiology of MPNs. We previously demonstrated that Abelson interactor 1 (Abi-1), a negative regulator of Abelson kinase 1, functions as a tumor suppressor. Here we present data showing that bone marrow-specific deletion of
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- 2018
42. Precision Medicine Treatment in Older AML: Results of Beat AML Master Trial
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Burd, Amy, primary, Levine, Ross L., primary, Ruppert, Amy S., primary, Mims, Alice S., primary, Borate, Uma, primary, Stein, Eytan M., primary, Patel, Prapti A., primary, Baer, Maria R., primary, Stock, Wendy, primary, Deininger, Michael W., primary, Blum, William, primary, Schiller, Gary J., primary, Olin, Rebecca L., primary, Litzow, Mark, primary, Foran, James M., primary, Lin, Tara L., primary, Ball, Brian J, primary, Boyiadzis, Michael, primary, Traer, Elie, primary, Odenike, Olatoyosi, primary, Arellano, Martha L., primary, Walker, Alison R., primary, Duong, Vu H., primary, Collins, Robert H., primary, Heerema, Nyla A., primary, Vergilio, Jo-Anne, primary, Brennan, TIm, primary, Vietz, Christine, primary, Vittorio, Molly, primary, Rosenberg, Leonard, primary, Marcus, Sonja, primary, Yocum, Ashley Owen, primary, Stefanos, Mona, primary, Druker, Brian J., primary, and Byrd, John C., primary
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- 2019
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43. Characterizing Inclusion and Exclusion Criteria in Clinical Trials for CAR-T Cellular Therapy Among Adults with Hematologic Malignancies
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Jaggers, Jordon, primary, Klepin, Heidi D., additional, Wildes, Tanya M., additional, Olin, Rebecca L., additional, Artz, Andrew S., additional, Wall, Sarah A, additional, Jaglowski, Samantha, additional, William, Basem M., additional, Benson, Don M., additional, and Rosko, Ashley E., additional
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- 2019
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44. Updated Results from the Venetoclax (Ven) in Combination with Idasanutlin (Idasa) Arm of a Phase 1b Trial in Elderly Patients (Pts) with Relapsed or Refractory (R/R) AML Ineligible for Cytotoxic Chemotherapy
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Daver, Naval G., primary, Garcia, Jacqueline S, primary, Jonas, Brian A, primary, Kelly, Kevin R, primary, Assouline, Sarit, primary, Brandwein, Joseph M, primary, Fenaux, Pierre, primary, Olin, Rebecca L., primary, Martinelli, Giovanni, primary, Paolini, Stefania, primary, Pigneux, Arnaud, primary, Pollyea, Daniel A, primary, Powell, Bayard L, primary, Roboz, Gail J., primary, Tafuri, Agostino, primary, Vey, Norbert, primary, Visani, Giuseppe, primary, Yee, Karen W.L., primary, Dail, Monique, primary, Green, Cherie, primary, Kirschbrown, Whitney P, primary, Hong, Wan-Jen, primary, Ott, Marion G, primary, Onishi, Maika, primary, Wang, Jue, primary, Konopleva, Marina Y, primary, and Andreeff, Michael, primary
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- 2019
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45. Symptom Assessment in Patients with BCR-ABL-Negative Myeloproliferative Neoplasms at an Academic Medical Institution
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Schoenbeck, Kelly L., primary, Cerejo, Miguel Carlos, additional, Cornett, Patricia A., additional, Damon, Lloyd E., additional, Gaensler, Karin L., additional, Leavitt, Andrew D., additional, Logan, Aaron C., additional, Mannis, Gabriel N., additional, Olin, Rebecca L., additional, Salmasi, Giselle, additional, Sayre, Peter H., additional, Shah, Neil P., additional, Dhruva, Anand, additional, Atreya, Chloe E., additional, and Smith, Catherine C., additional
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- 2019
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46. Diffuse Large B Cell Lymphoma (DLBCL) Expresses ROR1 and a ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Tumor Cells
- Author
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Hojjat-Farsangi, Mohammad, primary, Ghaderi, Amineh, additional, Daneshmanesh, AmirHossein, additional, Lehto, Jemina, additional, Moshfegh, Ali, additional, Kokhaei, Parviz, additional, Vågberg, Jan, additional, Olsson, Elisabeth, additional, Löfberg, Charlotta, additional, Norström, Charlotta Carina, additional, Schultz, Johan, additional, Norin, Martin, additional, Olin, Thomas, additional, Drakos, Elias, additional, Rassidakis, George Z., additional, Österborg, Anders, additional, and Mellstedt, Håkan, additional
- Published
- 2019
- Full Text
- View/download PDF
47. A Phase 1 Dose Escalation Study of Milademetan in Combination with 5-Azacitidine (AZA) in Patients with Acute Myeloid Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)
- Author
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DiNardo, Courtney D., primary, Olin, Rebecca, additional, Ishizawa, Jo, additional, Sumi, Hiroyuki, additional, Xie, Jingdong, additional, Kato, Kazunobu, additional, Kumar, Prasanna, additional, and Andreeff, Michael, additional
- Published
- 2019
- Full Text
- View/download PDF
48. Cognitive Impairment Is Associated with Inferior Survival and Increased Non-Relapse Mortality in Older Allogeneic Hematopoietic Cell Transplant (alloHCT) Recipients: A Multicenter Retrospective Study
- Author
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Olin, Rebecca L., primary, Fretham, Caitrin, additional, Pasquini, Marcelo C., additional, Arora, Mukta, additional, Bhatt, Vijaya R., additional, Derman, Benjamin, additional, Giralt, Sergio A, additional, Huang, Li-Wen, additional, Koll, Thuy T., additional, Lee, Sang Mee, additional, Lin, Richard J, additional, Pang, Linda, additional, Popat, Uday, additional, Weisdorf, Daniel J., additional, and Artz, Andrew S., additional
- Published
- 2019
- Full Text
- View/download PDF
49. Direct Oral Anticoagulant Use and Outcomes in Patients with High and Intermediate Risk BCR-ABL-Negative Myeloproliferative Neoplasms
- Author
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Schoenbeck, Kelly L., primary, Salmasi, Giselle, additional, Cerejo, Miguel Carlos, additional, Cornett, Patricia A., additional, Damon, Lloyd E., additional, Logan, Aaron C., additional, Olin, Rebecca L., additional, Leavitt, Andrew D., additional, and Smith, Catherine C., additional
- Published
- 2019
- Full Text
- View/download PDF
50. ROR1 Small Molecule Inhibitor (KAN0441571C) Induced Significant Apoptosis of Mantle Cell Lymphoma (MCL) Cells
- Author
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Mellstedt, Håkan, primary, Ghaderi, Amineh, additional, Aschan, Johanna, additional, Mozaffari, Fariba, additional, Moshfegh, Ali, additional, Sander, Birgitta, additional, Schultz, Johan, additional, Norin, Martin, additional, Olin, Thomas, additional, Drakos, Elias, additional, Rassidakis, George Z., additional, Österborg, Anders, additional, and Hojjat-Farsangi, Mohammad, additional
- Published
- 2019
- Full Text
- View/download PDF
Catalog
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