85 results on '"Todd M. Cooper"'
Search Results
2. Figure S1 from Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium
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Kimberly Stegmaier, Mignon L. Loh, Marian H. Harris, Jeffrey W. Tyner, Lewis B. Silverman, Katherine A. Janeway, Lia Gore, Neal I. Lindeman, Annette S. Kim, Stephen P. Hunger, Alexandre Puissant, Andrew E. Place, Elliot Stieglitz, Katherine Tarlock, Amy Saur Conway, Amanda L. Robichaud, Angela Su, Neekesh V. Dharia, Matthew P. Jacobson, Diego Garrido Ruiz, Wilian A. Cortopassi, Anjali Cremer, Cristina F. Contreras, Haley L. Faust, Tasleema Patel, Cristina E. Tognon, Alma Imamovic, Shan Lin, Yuting Li, Giacomo Gotti, Nicole Ocasio-Martinez, Catherine M. Clinton, Asmani A. Adhav, Lisa Gennarini, Jeffrey A. Magee, Matthew J. Barth, Jing Chen, Justine M. Kahn, Peter D. Cole, Neerav N. Shukla, Jennifer L. McNeer, Nathan Gossai, Patrick A. Brown, Michael J. Burke, Kelly W. Maloney, Melinda Pauly, Todd M. Cooper, Beth Apsel Winger, Traci M. Blonquist, Kristen Stevenson, Maria Luisa Sulis, Sarah K. Tasian, and Yana Pikman
- Abstract
VAF concordance
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- 2023
3. Figure S3 from Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium
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Kimberly Stegmaier, Mignon L. Loh, Marian H. Harris, Jeffrey W. Tyner, Lewis B. Silverman, Katherine A. Janeway, Lia Gore, Neal I. Lindeman, Annette S. Kim, Stephen P. Hunger, Alexandre Puissant, Andrew E. Place, Elliot Stieglitz, Katherine Tarlock, Amy Saur Conway, Amanda L. Robichaud, Angela Su, Neekesh V. Dharia, Matthew P. Jacobson, Diego Garrido Ruiz, Wilian A. Cortopassi, Anjali Cremer, Cristina F. Contreras, Haley L. Faust, Tasleema Patel, Cristina E. Tognon, Alma Imamovic, Shan Lin, Yuting Li, Giacomo Gotti, Nicole Ocasio-Martinez, Catherine M. Clinton, Asmani A. Adhav, Lisa Gennarini, Jeffrey A. Magee, Matthew J. Barth, Jing Chen, Justine M. Kahn, Peter D. Cole, Neerav N. Shukla, Jennifer L. McNeer, Nathan Gossai, Patrick A. Brown, Michael J. Burke, Kelly W. Maloney, Melinda Pauly, Todd M. Cooper, Beth Apsel Winger, Traci M. Blonquist, Kristen Stevenson, Maria Luisa Sulis, Sarah K. Tasian, and Yana Pikman
- Abstract
Analysis of Beat AML data.
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- 2023
4. Supplementary Methods from Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium
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Kimberly Stegmaier, Mignon L. Loh, Marian H. Harris, Jeffrey W. Tyner, Lewis B. Silverman, Katherine A. Janeway, Lia Gore, Neal I. Lindeman, Annette S. Kim, Stephen P. Hunger, Alexandre Puissant, Andrew E. Place, Elliot Stieglitz, Katherine Tarlock, Amy Saur Conway, Amanda L. Robichaud, Angela Su, Neekesh V. Dharia, Matthew P. Jacobson, Diego Garrido Ruiz, Wilian A. Cortopassi, Anjali Cremer, Cristina F. Contreras, Haley L. Faust, Tasleema Patel, Cristina E. Tognon, Alma Imamovic, Shan Lin, Yuting Li, Giacomo Gotti, Nicole Ocasio-Martinez, Catherine M. Clinton, Asmani A. Adhav, Lisa Gennarini, Jeffrey A. Magee, Matthew J. Barth, Jing Chen, Justine M. Kahn, Peter D. Cole, Neerav N. Shukla, Jennifer L. McNeer, Nathan Gossai, Patrick A. Brown, Michael J. Burke, Kelly W. Maloney, Melinda Pauly, Todd M. Cooper, Beth Apsel Winger, Traci M. Blonquist, Kristen Stevenson, Maria Luisa Sulis, Sarah K. Tasian, and Yana Pikman
- Abstract
Supplementary Data file including supplementary methods and clinical case vignettes.
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- 2023
5. Table S3 from Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium
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Kimberly Stegmaier, Mignon L. Loh, Marian H. Harris, Jeffrey W. Tyner, Lewis B. Silverman, Katherine A. Janeway, Lia Gore, Neal I. Lindeman, Annette S. Kim, Stephen P. Hunger, Alexandre Puissant, Andrew E. Place, Elliot Stieglitz, Katherine Tarlock, Amy Saur Conway, Amanda L. Robichaud, Angela Su, Neekesh V. Dharia, Matthew P. Jacobson, Diego Garrido Ruiz, Wilian A. Cortopassi, Anjali Cremer, Cristina F. Contreras, Haley L. Faust, Tasleema Patel, Cristina E. Tognon, Alma Imamovic, Shan Lin, Yuting Li, Giacomo Gotti, Nicole Ocasio-Martinez, Catherine M. Clinton, Asmani A. Adhav, Lisa Gennarini, Jeffrey A. Magee, Matthew J. Barth, Jing Chen, Justine M. Kahn, Peter D. Cole, Neerav N. Shukla, Jennifer L. McNeer, Nathan Gossai, Patrick A. Brown, Michael J. Burke, Kelly W. Maloney, Melinda Pauly, Todd M. Cooper, Beth Apsel Winger, Traci M. Blonquist, Kristen Stevenson, Maria Luisa Sulis, Sarah K. Tasian, and Yana Pikman
- Abstract
Reasons for not using recommended targeted therapy.
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- 2023
6. Figure S4 from Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium
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Kimberly Stegmaier, Mignon L. Loh, Marian H. Harris, Jeffrey W. Tyner, Lewis B. Silverman, Katherine A. Janeway, Lia Gore, Neal I. Lindeman, Annette S. Kim, Stephen P. Hunger, Alexandre Puissant, Andrew E. Place, Elliot Stieglitz, Katherine Tarlock, Amy Saur Conway, Amanda L. Robichaud, Angela Su, Neekesh V. Dharia, Matthew P. Jacobson, Diego Garrido Ruiz, Wilian A. Cortopassi, Anjali Cremer, Cristina F. Contreras, Haley L. Faust, Tasleema Patel, Cristina E. Tognon, Alma Imamovic, Shan Lin, Yuting Li, Giacomo Gotti, Nicole Ocasio-Martinez, Catherine M. Clinton, Asmani A. Adhav, Lisa Gennarini, Jeffrey A. Magee, Matthew J. Barth, Jing Chen, Justine M. Kahn, Peter D. Cole, Neerav N. Shukla, Jennifer L. McNeer, Nathan Gossai, Patrick A. Brown, Michael J. Burke, Kelly W. Maloney, Melinda Pauly, Todd M. Cooper, Beth Apsel Winger, Traci M. Blonquist, Kristen Stevenson, Maria Luisa Sulis, Sarah K. Tasian, and Yana Pikman
- Abstract
combination of MEK inhibitor with venetoclax is synergistic.
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- 2023
7. Table S1 from Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium
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Kimberly Stegmaier, Mignon L. Loh, Marian H. Harris, Jeffrey W. Tyner, Lewis B. Silverman, Katherine A. Janeway, Lia Gore, Neal I. Lindeman, Annette S. Kim, Stephen P. Hunger, Alexandre Puissant, Andrew E. Place, Elliot Stieglitz, Katherine Tarlock, Amy Saur Conway, Amanda L. Robichaud, Angela Su, Neekesh V. Dharia, Matthew P. Jacobson, Diego Garrido Ruiz, Wilian A. Cortopassi, Anjali Cremer, Cristina F. Contreras, Haley L. Faust, Tasleema Patel, Cristina E. Tognon, Alma Imamovic, Shan Lin, Yuting Li, Giacomo Gotti, Nicole Ocasio-Martinez, Catherine M. Clinton, Asmani A. Adhav, Lisa Gennarini, Jeffrey A. Magee, Matthew J. Barth, Jing Chen, Justine M. Kahn, Peter D. Cole, Neerav N. Shukla, Jennifer L. McNeer, Nathan Gossai, Patrick A. Brown, Michael J. Burke, Kelly W. Maloney, Melinda Pauly, Todd M. Cooper, Beth Apsel Winger, Traci M. Blonquist, Kristen Stevenson, Maria Luisa Sulis, Sarah K. Tasian, and Yana Pikman
- Abstract
MTT recommendation tiering system.
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- 2023
8. Table S4 from Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium
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Kimberly Stegmaier, Mignon L. Loh, Marian H. Harris, Jeffrey W. Tyner, Lewis B. Silverman, Katherine A. Janeway, Lia Gore, Neal I. Lindeman, Annette S. Kim, Stephen P. Hunger, Alexandre Puissant, Andrew E. Place, Elliot Stieglitz, Katherine Tarlock, Amy Saur Conway, Amanda L. Robichaud, Angela Su, Neekesh V. Dharia, Matthew P. Jacobson, Diego Garrido Ruiz, Wilian A. Cortopassi, Anjali Cremer, Cristina F. Contreras, Haley L. Faust, Tasleema Patel, Cristina E. Tognon, Alma Imamovic, Shan Lin, Yuting Li, Giacomo Gotti, Nicole Ocasio-Martinez, Catherine M. Clinton, Asmani A. Adhav, Lisa Gennarini, Jeffrey A. Magee, Matthew J. Barth, Jing Chen, Justine M. Kahn, Peter D. Cole, Neerav N. Shukla, Jennifer L. McNeer, Nathan Gossai, Patrick A. Brown, Michael J. Burke, Kelly W. Maloney, Melinda Pauly, Todd M. Cooper, Beth Apsel Winger, Traci M. Blonquist, Kristen Stevenson, Maria Luisa Sulis, Sarah K. Tasian, and Yana Pikman
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Compound sensitivity data for primary patient samples.
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- 2023
9. Table S2 from Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium
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Kimberly Stegmaier, Mignon L. Loh, Marian H. Harris, Jeffrey W. Tyner, Lewis B. Silverman, Katherine A. Janeway, Lia Gore, Neal I. Lindeman, Annette S. Kim, Stephen P. Hunger, Alexandre Puissant, Andrew E. Place, Elliot Stieglitz, Katherine Tarlock, Amy Saur Conway, Amanda L. Robichaud, Angela Su, Neekesh V. Dharia, Matthew P. Jacobson, Diego Garrido Ruiz, Wilian A. Cortopassi, Anjali Cremer, Cristina F. Contreras, Haley L. Faust, Tasleema Patel, Cristina E. Tognon, Alma Imamovic, Shan Lin, Yuting Li, Giacomo Gotti, Nicole Ocasio-Martinez, Catherine M. Clinton, Asmani A. Adhav, Lisa Gennarini, Jeffrey A. Magee, Matthew J. Barth, Jing Chen, Justine M. Kahn, Peter D. Cole, Neerav N. Shukla, Jennifer L. McNeer, Nathan Gossai, Patrick A. Brown, Michael J. Burke, Kelly W. Maloney, Melinda Pauly, Todd M. Cooper, Beth Apsel Winger, Traci M. Blonquist, Kristen Stevenson, Maria Luisa Sulis, Sarah K. Tasian, and Yana Pikman
- Abstract
Inhibitor Recommendation Usage Summary.
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- 2023
10. Figure S2 from Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium
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Kimberly Stegmaier, Mignon L. Loh, Marian H. Harris, Jeffrey W. Tyner, Lewis B. Silverman, Katherine A. Janeway, Lia Gore, Neal I. Lindeman, Annette S. Kim, Stephen P. Hunger, Alexandre Puissant, Andrew E. Place, Elliot Stieglitz, Katherine Tarlock, Amy Saur Conway, Amanda L. Robichaud, Angela Su, Neekesh V. Dharia, Matthew P. Jacobson, Diego Garrido Ruiz, Wilian A. Cortopassi, Anjali Cremer, Cristina F. Contreras, Haley L. Faust, Tasleema Patel, Cristina E. Tognon, Alma Imamovic, Shan Lin, Yuting Li, Giacomo Gotti, Nicole Ocasio-Martinez, Catherine M. Clinton, Asmani A. Adhav, Lisa Gennarini, Jeffrey A. Magee, Matthew J. Barth, Jing Chen, Justine M. Kahn, Peter D. Cole, Neerav N. Shukla, Jennifer L. McNeer, Nathan Gossai, Patrick A. Brown, Michael J. Burke, Kelly W. Maloney, Melinda Pauly, Todd M. Cooper, Beth Apsel Winger, Traci M. Blonquist, Kristen Stevenson, Maria Luisa Sulis, Sarah K. Tasian, and Yana Pikman
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Correlation between Ras pathway mutation VAF and in vitro sensitivity to MEK inhibitors.
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- 2023
11. Supplementary Data from Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium
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Kimberly Stegmaier, Mignon L. Loh, Marian H. Harris, Jeffrey W. Tyner, Lewis B. Silverman, Katherine A. Janeway, Lia Gore, Neal I. Lindeman, Annette S. Kim, Stephen P. Hunger, Alexandre Puissant, Andrew E. Place, Elliot Stieglitz, Katherine Tarlock, Amy Saur Conway, Amanda L. Robichaud, Angela Su, Neekesh V. Dharia, Matthew P. Jacobson, Diego Garrido Ruiz, Wilian A. Cortopassi, Anjali Cremer, Cristina F. Contreras, Haley L. Faust, Tasleema Patel, Cristina E. Tognon, Alma Imamovic, Shan Lin, Yuting Li, Giacomo Gotti, Nicole Ocasio-Martinez, Catherine M. Clinton, Asmani A. Adhav, Lisa Gennarini, Jeffrey A. Magee, Matthew J. Barth, Jing Chen, Justine M. Kahn, Peter D. Cole, Neerav N. Shukla, Jennifer L. McNeer, Nathan Gossai, Patrick A. Brown, Michael J. Burke, Kelly W. Maloney, Melinda Pauly, Todd M. Cooper, Beth Apsel Winger, Traci M. Blonquist, Kristen Stevenson, Maria Luisa Sulis, Sarah K. Tasian, and Yana Pikman
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Patient sequencing data, by patient number and diagnosis.
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- 2023
12. Supplemental Table and Figure Legends from A Phase I Study of Quizartinib Combined with Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study
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Patrick A. Brown, Colleen Annesley, Daniel Magoon, Guy Gammon, Javier Oesterheld, Lewis B. Silverman, Steven G. DuBois, Jessica A. Pollard, Keith August, Lia Gore, Bill H. Chang, Paul Gaynon, Richard Sposto, Jemily Malvar, Elena Eckroth, Jeannette Cassar, and Todd M. Cooper
- Abstract
Supplemental Figure 1 and Figure 2 Legends Supplemental Tables 1-5 Legends
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- 2023
13. Supplemental Figures and Tables from A Phase I Study of Quizartinib Combined with Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study
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Patrick A. Brown, Colleen Annesley, Daniel Magoon, Guy Gammon, Javier Oesterheld, Lewis B. Silverman, Steven G. DuBois, Jessica A. Pollard, Keith August, Lia Gore, Bill H. Chang, Paul Gaynon, Richard Sposto, Jemily Malvar, Elena Eckroth, Jeannette Cassar, and Todd M. Cooper
- Abstract
Supplemental Figure 1 and Figure 2 Supplemental Tables 1-5
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- 2023
14. Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia
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Eline J.M. Bertrums, Jenny L. Smith, Lauren Harmon, Rhonda E. Ries, Yi-Cheng J. Wang, Todd A. Alonzo, Andrew J. Menssen, Karen M. Chisholm, Amanda R. Leonti, Katherine Tarlock, Fabiana Ostronoff, Era L. Pogosova-Agadjanyan, Gertjan J.L. Kaspers, Henrik Hasle, Michael Dworzak, Christiane Walter, Nora Muhlegger, Cristina Morerio, Laura Pardo, Betsy Hirsch, Susana Raimondi, Todd M. Cooper, Richard Aplenc, Alan S. Gamis, Edward A. Kolb, Jason E. Farrar, Derek Stirewalt, Xiaotu Ma, Tim I. Shaw, Scott N. Furlan, Lisa Eidenschink Brodersen, Michael R. Loken, Marry M. Van den Heuvel-Eibrink, C. Michel Zwaan, Timothy J. Triche, Bianca F. Goemans, and Soheil Meshinchi
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Hematology - Abstract
NUP98 fusions c omprise a family o f rare r ecurrent a lterations i n A ML, associated w ith adverse outcomes. To define the underlying biology and clinical implications of this family of fusions, we performed comprehensive transcriptome, epigenome, and immunophenotypic profiling of 2,235 children and young adults with AML and identified 160 NUP98 rearrangements (7.2%), including 108 NUP98-NSD1 (4.8%), 32 NUP98-KDM5A (1.4%) and 20 NUP98-X cases (0.9%) with 13 different fusion partners. Fusion partners defined disease characteristics and biology; patients with NUP98-NSD1 or NUP98-KDM5A had distinct immunophenotypic, transcriptomic, and epigenomic profiles. Unlike the two most prevalent NUP98 fusions, NUP98-X variants are typically not cryptic. Furthermore, NUP98-X cases are associated with WT1 mutations, and have epigenomic profiles that resemble either NUP98- NSD1 or NUP98-KDM5A. Cooperating FLT3-ITD and WT1 mutations define NUP98-NSD1, and chromosome 13 aberrations are highly enriched in NUP98-KDM5A. Importantly, we demonstrate that NUP98 fusions portend dismal overall survival, with the noteworthy exception of patients bearing abnormal chr13.
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- 2023
15. Integrated stem cell signature and cytomolecular risk determination in pediatric acute myeloid leukemia
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Benjamin J. Huang, Jenny L. Smith, Jason E. Farrar, Yi-Cheng Wang, Masayuki Umeda, Rhonda E. Ries, Amanda R. Leonti, Erin Crowgey, Scott N. Furlan, Katherine Tarlock, Marcos Armendariz, Yanling Liu, Timothy I. Shaw, Lisa Wei, Robert B. Gerbing, Todd M. Cooper, Alan S. Gamis, Richard Aplenc, E. Anders Kolb, Jeffrey Rubnitz, Jing Ma, Jeffery M. Klco, Xiaotu Ma, Todd A. Alonzo, Timothy Triche, and Soheil Meshinchi
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Myeloid ,Pediatric Research Initiative ,Childhood Leukemia ,Pediatric Cancer ,General Physics and Astronomy ,Acute ,General Biochemistry, Genetics and Molecular Biology ,Rare Diseases ,Recurrence ,Clinical Research ,Genetics ,Humans ,Child ,Cancer ,Pediatric ,screening and diagnosis ,Leukemia ,Multidisciplinary ,Gene Expression Profiling ,Human Genome ,Hematology ,General Chemistry ,Stem Cell Research ,4.1 Discovery and preclinical testing of markers and technologies ,Leukemia, Myeloid, Acute ,Detection ,Neoplastic Stem Cells ,RNA ,Biomarkers - Abstract
Relapsed or refractory pediatric acute myeloid leukemia (AML) is associated with poor outcomes and relapse risk prediction approaches have not changed significantly in decades. To build a robust transcriptional risk prediction model for pediatric AML, we perform RNA-sequencing on 1503 primary diagnostic samples. While a 17 gene leukemia stem cell signature (LSC17) is predictive in our aggregated pediatric study population, LSC17 is no longer predictive within established cytogenetic and molecular (cytomolecular) risk groups. Therefore, we identify distinct LSC signatures on the basis of AML cytomolecular subtypes (LSC47) that were more predictive than LSC17. Based on these findings, we build a robust relapse prediction model within a training cohort and then validate it within independent cohorts. Here, we show that LSC47 increases the predictive power of conventional risk stratification and that applying biomarkers in a manner that is informed by cytomolecular profiling outperforms a uniform biomarker approach.
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- 2022
16. Aberrantly low STAT3 and STAT5 responses are associated with poor outcome and an inflammatory gene expression signature in pediatric acute myeloid leukemia
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Alan S. Gamis, Todd A. Alonzo, Robert B. Gerbing, Alexandra M. Stevens, Rhonda E. Ries, Todd M. Cooper, T.-K. Man, Yi-Cheng Wang, Xin Long, Padmini Narayanan, Soheil Meshinchi, and Michele S. Redell
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Male ,0301 basic medicine ,Cancer Research ,STAT3 ,0302 clinical medicine ,Recurrence ,Granulocyte Colony-Stimulating Factor ,STAT5 Transcription Factor ,Tumor Microenvironment ,Child ,Pediatric AML ,STAT5 ,Interleukin-13 ,biology ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,General Medicine ,Progression-Free Survival ,Up-Regulation ,Leukemia, Myeloid, Acute ,Haematopoiesis ,Mitochondrial respiratory chain ,Oncology ,Child, Preschool ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,Stem cell ,Research Article ,STAT3 Transcription Factor ,Transcriptional Activation ,Microenvironment ,Stromal cell ,Adolescent ,MAP Kinase Signaling System ,Antineoplastic Agents ,Inflammation ,Young Adult ,03 medical and health sciences ,Cell Line, Tumor ,medicine ,Humans ,Proportional Hazards Models ,Cryopreservation ,Sequence Analysis, RNA ,business.industry ,Gene Expression Profiling ,Tumor Suppressor Proteins ,Granulocyte-Macrophage Colony-Stimulating Factor ,Infant ,030104 developmental biology ,Bone marrow stroma ,Drug Resistance, Neoplasm ,Culture Media, Conditioned ,Multivariate Analysis ,biology.protein ,Cancer research ,Transcriptome ,business - Abstract
The relapse rate for children with acute myeloid leukemia is nearly 40% despite aggressive chemotherapy and often stem cell transplant. We sought to understand how environment-induced signaling responses are associated with clinical response to treatment. We previously reported that patients whose AML cells showed low G-CSF-induced STAT3 activation had inferior event-free survival compared to patients with stronger STAT3 responses. Here, we expanded the paradigm to evaluate multiple signaling parameters induced by a more physiological stimulus. We measured STAT3, STAT5 and ERK1/2 responses to G-CSF and to stromal cell-conditioned medium for 113 patients enrolled on COG trials AAML03P1 and AAML0531. Low inducible STAT3 activity was independently associated with inferior event-free survival in multivariate analyses. For inducible STAT5 activity, those with the lowest and highest responses had inferior event-free survival, compared to patients with intermediate STAT5 responses. Using existing RNA-sequencing data, we compared gene expression profiles for patients with low inducible STAT3/5 activation with those for patients with higher inducible STAT3/5 signaling. Genes encoding hematopoietic factors and mitochondrial respiratory chain subunits were overexpressed in the low STAT3/5 response groups, implicating inflammatory and metabolic pathways as potential mechanisms of chemotherapy resistance. We validated the prognostic relevance of individual genes from the low STAT3/5 response signature in a large independent cohort of pediatric AML patients. These findings provide novel insights into interactions between AML cells and the microenvironment that are associated with treatment failure and could be targeted for therapeutic interventions. Supplementary Information The online version contains supplementary material available at 10.1007/s12094-021-02621-w.
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- 2021
17. Distinct Latent Trajectory Phenotypes of Left Ventricular Function Associated with Differential Survival Among Children Treated for Acute Myeloid Leukemia: A Report from the Children's Oncology Group
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Kelly D. Getz, Robert B. Gerbing, Todd A. Alonzo, Yimei Li, Kasey J Leger, Jessica A. Pollard, Dava Szalda, Lillian Sung, Todd M. Cooper, Edward A. Kolb, Alan S. Gamis, Bonnie Ky, and Richard Aplenc
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
18. Expanding the High-Risk Definition for Children with Newly Diagnosed Acute Myeloid Leukemia
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Adam J. Lamble, Rhonda E. Ries, Todd A. Alonzo, Yi-Cheng Wang, Jason E Farrar, Benjamin J. Huang, Matthew A. Kutny, Jessica A. Pollard, Richard Aplenc, Alan S. Gamis, Edward A. Kolb, Todd M. Cooper, and Soheil Meshinchi
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
19. CXCR4 (CD184) Expression in Pediatric AML Is Associated with Bone Marrow Retention, Specific Disease Characteristics, and Worse Outcomes: A Report of 1004 Patients from the Children's Oncology Group AAML1031 Protocol
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Andrew J. Menssen, Chad A. Hudson, Todd A. Alonzo, Robert B. Gerbing, Laura Pardo, Fan-Chi Hsu, Loren L. Lott, Fangyan Dai, Keely Ghiradelli, Yi-Cheng Wang, E. Anders Kolb, Todd M. Cooper, Jessica A. Pollard, Michael R. Loken, Richard Aplenc, Lisa Eidenschink Brodersen, and Soheil Meshinchi
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
20. Safety and Activity of Flotetuzumab in Pediatric and Young Adult Patients with Relapsed/Refractory Acute Myeloid Leukemia: Results from the COG PEPN1812 Phase 1 Trial
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Adam J. Lamble, Xiaowei Liu, Charles Minard, Olga Militano, Melanie Brooke Bernhardt, Todd M. Cooper, Edward A. Kolb, Erin H. Breese, Elizabeth Fox, Sarah K Tasian, and Brenda J. Weigel
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
21. Pathogenic TP53 mutations Are Associated with a Poor Prognosis in De Novo AML
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Adam J. Lamble, Rhonda E. Ries, Alice Dang, Todd A. Alonzo, Karen Chisholm, Pandurang Kolekar, Yanling Liu, Quang Tran, Todd M. Cooper, Richard Aplenc, Alan S. Gamis, Edward A. Kolb, Xiaotu Ma, and Soheil Meshinchi
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
22. Single-Cell Multiomics for Residual Disease Detection in Acute Myelogenous Leukemia after Allogeneic Hematopoietic Cell Transplantation
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Melinda Ann Biernacki, Olivia Waltner, Sami B Kanaan, Rula Green Gladden, Shruti Bhise, Todd M. Cooper, Monica Thakar, Soheil Meshinchi, Marie Bleakley, Xueyan Chen, and Scott N Furlan
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
23. Phase I Study of Tagraxofusp with or without Chemotherapy in Pediatric Patients with Relapsed or Refractory CD123-Expressing Hematologic Malignancies: A Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium Trial
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Adam J. Lamble, Yueh-Yun Chi, Bill H. Chang, Anupam Verma, Kelly E Faulk, Alexandra McLean Stevens, Lauren Pommert, Sarah Tucker, Benjamin Brookhart, Nirali N. Shah, Christopher L. Brooks, Tariq I. Mughal, Alan S. Wayne, Soheil Meshinchi, and Todd M. Cooper
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
24. Blood Count Recovery Following Induction Therapy for Acute Myeloid Leukemia in Children Does Not Predict Survival
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Lauren Pommert, Todd M. Cooper, Robert B. Gerbing, Lisa Brodersen, Michael Loken, Alan Gamis, Richard Aplenc, Todd A. Alonzo, and Edward Anders Kolb
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Cancer Research ,Oncology ,hemic and lymphatic diseases ,IWG criteria ,pediatric acute myeloid leukemia ,childhood acute myeloid leukemia ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,clinical trial response assessment ,RC254-282 - Abstract
International Working Group (IWG) and European LeukemiaNet (ELN) response definitions are utilized to evaluate the efficacy of new agents for childhood acute myeloid leukemia (AML) for regulatory purposes. However, these criteria are not consistent with definitions used in pediatric AML trials or with standard pediatric practice to proceed with subsequent therapy cycles prior to IWG/ELN-defined count recovery. We retrospectively analyzed data from the two most recent Phase 3 pediatric AML clinical trials conducted by the Children’s Oncology Group (COG) to assess the incidence, timing, and prognostic significance of count recovery following induction chemotherapy. Of the patients with fewer than 5% bone marrow blasts at the end of first induction, 21.5% of patients proceeded to a second induction cycle prior to achieving ANC ≥ 500 cells/μL and platelets ≥ 50,000 cells/μL, both well below the IWG/ELN thresholds of ANC > 1000 cells/μL and platelets > 100,000 cells/μL. In these two sequential childhood AML Phase 3 trials, neither ANC nor platelet recovery predicted survival. Intensification of treatment through the initiation of subsequent therapy cycles prior to attainment of IWG/ELN-defined CR is common practice in clinical trials for children with AML, suggesting that updated response definitions are needed for pediatric AML.
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- 2022
25. Paediatric Strategy Forum for medicinal product development for acute myeloid leukaemia in children and adolescents
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Elly Barry, Gilles Vassal, Thomas Winkler, Gregory H. Reaman, Kerri Nottage, Anne Borgman, Florence Binlich, Dirk Reinhardt, Jan-Henning Klusmann, Delphine Heenen, C. Michel Zwaan, Silvia Mappa, Bouchra Benettaib, Koen Norga, Su Young Kim, Gertjan J.L. Kaspers, Malcolm A. Smith, Peter C. Adamson, Renaud Capdeville, Lynley V. Marshall, Linda Fogelstrand, David Delgado, Mark W. Kieran, Sarah K. Tasian, E. Anders Kolb, Julie Guillot, Paula Goodman Fraenkel, Hesham Mohamed, G. Lesa, Henrik Hasle, Andrew D.J. Pearson, Franca Ligas, J. Morris, Stephen J. Simko, Todd M. Cooper, Dominik Karres, Erica Brivio, Andrew S. Moore, Douglas V. Faller, and Nicole Scobie
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,Childhood leukemia ,Drug development ,Disease ,Article ,Acute myeloid leukaemia ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Agency (sociology) ,medicine ,Intensive care medicine ,Paediatric oncology ,business.industry ,Paediatric Strategy Forum ,medicine.disease ,Minimal residual disease ,3. Good health ,Clinical trial ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,New product development ,Cancer therapeutics ,business - Abstract
Purpose: The current standard-of-care for front-line therapy for acute myeloid leukaemia (AML) results in short-term and long-term toxicity, but still approximately 40% of children relapse. Therefore, there is a major need to accelerate the evaluation of innovative medicines, yet drug development continues to be adult-focused. Furthermore, the large number of competing agents in rare patient populations requires coordinated prioritisation, within the global regulatory framework and cooperative group initiatives. Methods: The fourth multi-stakeholder Paediatric Strategy Forum focused on AML in children and adolescents. Results: CD123 is a high priority target and the paediatric development should be accelerated as a proof-of-concept. Efforts must be coordinated, however, as there are a limited number of studies that can be delivered. Studies of FLT3 inhibitors in agreed paediatric investigation plans present challenges to be completed because they require enrolment of a larger number of patients than actually exist. A consensus was developed by industry and academia of optimised clinical trials. For AML with rare mutations that are more frequent in adolescents than in children, adult trials should enrol adolescents and when scientifically justified, efficacy data could be extrapolated. Methodologies and definitions of minimal residual disease need to be standardised internationally and validated as a new response criterion. Industry supported, academic sponsored platform trials could identify products to be further developed. The Leukaemia and Lymphoma Society PedAL/EUpAL initiative has the potential to be a major advance in the field. Conclusion: These initiatives continue to accelerate drug development for children with AML and ultimately improve clinical outcomes.
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- 2020
26. Phase I/II Study of CPX-351 Followed by Fludarabine, Cytarabine, and Granulocyte-Colony Stimulating Factor for Children With Relapsed Acute Myeloid Leukemia: A Report From the Children’s Oncology Group
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Todd A. Alonzo, Bassem I. Razzouk, Richard Aplenc, Michael J. Absalon, Robert B. Gerbing, Jessica A. Pollard, E. Anders Kolb, Todd M. Cooper, Kasey J. Leger, and Betsy A. Hirsch
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Adult ,Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Adolescent ,Daunorubicin ,Young Adult ,Recurrence ,Internal medicine ,Granulocyte Colony-Stimulating Factor ,Humans ,Medicine ,Child ,business.industry ,Cytarabine ,Infant ,Myeloid leukemia ,ORIGINAL REPORTS ,medicine.disease ,Granulocyte colony-stimulating factor ,Fludarabine ,Clinical trial ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,Child, Preschool ,Female ,business ,Vidarabine ,medicine.drug - Abstract
PURPOSE Effective regimens are needed for children with relapsed acute myeloid leukemia (AML). AAML1421 is a phase I/II study of CPX-351, a liposomal preparation of daunorubicin and cytarabine. AAML1421 sought to determine the recommended phase II dose (RP2D) of CPX-351 and the response rate after up to 2 cycles of therapy. PATIENTS AND METHODS Children > 1 and ≤ 21 years of age with relapsed/refractory AML were eligible for dose finding; those in first relapse were eligible for the efficacy phase. Dose-limiting toxicity (DLT) assessment occurred during cycle 1. Two cycles of therapy were offered (cycle 1: CPX-351; cycle 2: FLAG [fludarabine 30 mg/m2/dose on days 1-5; cytarabine 2,000 mg/m2/dose on days 1-5; and granulocyte-colony stimulating factor 5 µg/kg/dose, days 1-5 and day 15 through absolute neutrophil count > 500/µL]). Response was assessed after each cycle. RESULTS Thirty-eight patients enrolled: 6 in the dose-finding phase and 32 in the efficacy phase. During dose finding, 1/6 patients experienced a DLT (grade 3 decrease in ejection fraction). The RP2D was 135 units/m2 on days 1, 3, and 5. Toxicities of grade ≥ 3 during cycle 1 included fever/neutropenia (45%), infection (47%), and rash (40%). There was no toxic mortality. Best responses included 20 complete response (CR; 54%), 5 CR with partial recovery of platelet count (CRp; 14%), and 5 CR with incomplete blood count recovery (14%). Twenty-one of 25 with CR/CRp had no detectable residual disease (RD; 84%) by flow cytometry. Hematopoietic stem cell transplantation (HSCT) was used as consolidation in 29/30 responders (96.7%); 20/25 (80%) had no RD before HSCT. CONCLUSION The RP2D of CPX-351 is 135 units/m2/dose on days 1, 3, and 5. Toxicity was manageable, and protocol therapy was effective. Response rates are superior to prior published North American cooperative group clinical trials for children with AML in first relapse.
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- 2020
27. CBFB-MYH11 fusion transcripts distinguish acute myeloid leukemias with distinct molecular landscapes and outcomes
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Alan S. Gamis, Todd M. Cooper, Scott N. Furlan, Katherine Tarlock, Yanling Liu, Timothy I. Shaw, Todd A. Alonzo, Pandurang Kolekar, Yi-Cheng Wang, E. Anders Kolb, Rhonda E. Ries, Jason E. Farrar, Benjamin J. Huang, Kassra Taghizadeh, Erin L. Crowgey, Jenny L. Smith, Lisa Wei, Xiaotu Ma, Robert B. Gerbing, Amanda R. Leonti, Richard Aplenc, Timothy J. Triche, Kohei Hagiwara, and Soheil Meshinchi
- Subjects
Oncology ,Myeloid ,medicine.medical_specialty ,Oncogene Proteins, Fusion ,Pediatric Cancer ,Childhood Leukemia ,Acute ,Core Binding Factor beta Subunit ,Exon ,Risk groups ,Rare Diseases ,Internal medicine ,Intensive therapy ,Genetics ,Medicine ,Humans ,Acute myeloid leukemias ,Fusion ,Cancer ,Cbfb myh11 ,Oncogene Proteins ,Pediatric ,Leukemia ,Myosin Heavy Chains ,business.industry ,Breakpoint ,Hematology ,Transcriptome Sequencing ,Leukemia, Myeloid, Acute ,Cohort ,business ,Biotechnology - Abstract
Patients with inv(16)/CBFB-MYH11 AML are considered favorable risk, however, nearly one-third relapse despite intensive therapy. Despite efforts to define risk groups within this favorable risk cohort, CBFB-MYH11 AML patients continue to be treated as a uniform cohort. Through transcriptome sequencing of 186 patients with inv(16) AML, we demonstrate that fusion junction breakpoints (exon 5-exon 33 versus other) are highly associated with outcome. The presence of exon 17 KIT mutations provides additional prognostic significance. Additionally, we provide insights into the transcriptional landscapes that differentiate these distinct CBFB-MYH11 AML subtypes. Children's Oncology Group trials include CCG-2961 (registered at www.clinicaltrials.gov as NCT00002798), AAML03P1 (NCT00070174), AAML0531 (NCT00372593), and AAML1031 (NCT01371981).
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- 2021
28. Temsirolimus combined with cyclophosphamide and etoposide for pediatric patients with relapsed/refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium trial (TACL 2014-001)
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Sarah K. Tasian, Lewis B. Silverman, James A. Whitlock, Richard Sposto, Joseph P. Loftus, Eric S. Schafer, Kirk R. Schultz, Raymond J. Hutchinson, Paul S. Gaynon, Etan Orgel, Caroline M. Bateman, Todd M. Cooper, Theodore W. Laetsch, Maria Luisa Sulis, Yueh-Yun Chi, Jemily Malvar, Alan S. Wayne, and Susan R. Rheingold
- Subjects
Sirolimus ,Adolescent ,TOR Serine-Threonine Kinases ,Alanine Transaminase ,Hematology ,MTOR Inhibitors ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Phosphoproteins ,Phosphatidylinositol 3-Kinases ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Child ,Cyclophosphamide ,Etoposide ,Phosphoinositide-3 Kinase Inhibitors - Abstract
Phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling is commonly dysregulated in acute lymphoblastic leukemia (ALL). The TACL2014-001 phase I trial of the mTOR inhibitor temsirolimus in combination with cyclophosphamide and etoposide was performed in children and adolescents with relapsed/refractory ALL. Temsirolimus was administered intravenously (IV) on days 1 and 8 with cyclophosphamide 440 mg/m2 and etoposide 100 mg/m2 IV daily on days 1-5. The starting dose of temsirolimus was 7.5 mg/m2 (DL1) with escalation to 10 mg/m2 (DL2), 15 mg/m2 (DL3), and 25 mg/m2 (DL4). PI3K/mTOR pathway inhibition was measured by phosphoflow cytometry analysis of peripheral blood specimens from treated patients. Sixteen heavily-pretreated patients were enrolled with 15 evaluable for toxicity. One dose-limiting toxicity of grade 4 pleural and pericardial effusions occurred in a patient treated at DL3. Additional dose-limiting toxicities were not seen in the DL3 expansion or DL4 cohort. Grade 3/4 non-hematologic toxicities occurring in three or more patients included febrile neutropenia, elevated alanine aminotransferase, hypokalemia, mucositis, and tumor lysis syndrome and occurred across all doses. Response and complete were observed at all dose levels with a 47% overall response rate and 27% complete response rate. Pharmacodynamic correlative studies demonstrated dose-dependent inhibition of PI3K/mTOR pathway phosphoproteins in all studied patients. Temsirolimus at doses up to 25 mg/m2 with cyclophosphamide and etoposide had an acceptable safety profile in children with relapsed/refractory ALL. Pharmacodynamic mTOR target inhibition was achieved and appeared to correlate with temsirolimus dose. Future testing of next-generation PI3K/mTOR pathway inhibitors with chemotherapy may be warranted to increase response rates in children with relapsed/refractory ALL.
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- 2021
29. Matched Targeted Therapy for Pediatric Patients with Relapsed, Refractory, or High-Risk Leukemias: A Report from the LEAP Consortium
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Cristina E. Tognon, Alma Imamovic, Peter D. Cole, Anjali Cremer, Todd M. Cooper, Alexandre Puissant, Catherine Clinton, Asmani A. Adhav, Patrick A. Brown, Kristen E. Stevenson, Mignon L. Loh, Justine M. Kahn, Nathan Gossai, Elliot Stieglitz, Wilian A. Cortopassi, Andrew E. Place, Stephen P. Hunger, Michael J. Burke, Lewis B. Silverman, Annette S. Kim, Nicole Ocasio-Martinez, Diego Garrido Ruiz, Jeffrey W. Tyner, Matthew J. Barth, Lisa M. Gennarini, Yana Pikman, Neal I. Lindeman, Maria Luisa Sulis, Lia Gore, Beth Apsel Winger, Neekesh V. Dharia, Traci M. Blonquist, Yuting Li, Kimberly Stegmaier, Marian H. Harris, Jeffrey A. Magee, Katherine Tarlock, Neerav Shukla, Melinda Pauly, Kelly W. Maloney, Matthew P. Jacobson, Angela Su, Tasleema Patel, Giacomo Gotti, Cristina F. Contreras, Shan Lin, Haley L. Faust, Amanda L. Robichaud, Jing Chen, Sarah K. Tasian, Katherine A. Janeway, Amy Saur Conway, and Jennifer L. McNeer
- Subjects
0301 basic medicine ,Oncology ,Male ,medicine.medical_treatment ,Targeted therapy ,Cohort Studies ,0302 clinical medicine ,2.1 Biological and endogenous factors ,Prospective Studies ,Molecular Targeted Therapy ,Aetiology ,Child ,Cancer ,Pediatric ,Leukemia ,Tumor ,Hematology ,Local ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Disease Progression ,Female ,Development of treatments and therapeutic interventions ,Biotechnology ,medicine.medical_specialty ,Pediatric Cancer ,Childhood Leukemia ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,MEDLINE ,03 medical and health sciences ,Rare Diseases ,Refractory ,Clinical Research ,Internal medicine ,Biomarkers, Tumor ,medicine ,Genetics ,Humans ,business.industry ,Human Genome ,medicine.disease ,Precision medicine ,United States ,Clinical trial ,030104 developmental biology ,Neoplasm Recurrence ,Orphan Drug ,Good Health and Well Being ,Relapsed refractory ,Feasibility Studies ,Neoplasm Recurrence, Local ,business ,Biomarkers - Abstract
Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. Significance: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations. See related commentary by Bornhauser and Bourquin, p. 1322. This article is highlighted in the In This Issue feature, p. 1307
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- 2021
30. Safety, pharmacokinetics, and pharmacodynamics of panobinostat in children, adolescents, and young adults with relapsed acute myeloid leukemia
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Seth E. Karol, Kenneth Heym, Jeffery M. Klco, Jeffrey E. Rubnitz, Hiroto Inaba, Norman J. Lacayo, Raul C. Ribeiro, Deborah Schiff, Thomas B. Alexander, Paul E. Mead, John C. Panetta, Ching-Hon Pui, Yubin Ge, Todd M. Cooper, Deepa Bhojwani, Jeffrey W. Taub, Kristine R. Crews, and Dennis John Kuo
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,medicine.medical_treatment ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Pharmacokinetics ,Internal medicine ,Panobinostat ,medicine ,Humans ,030212 general & internal medicine ,Child ,Chemotherapy ,business.industry ,Histone deacetylase inhibitor ,Myeloid leukemia ,Minimal residual disease ,Fludarabine ,Leukemia, Myeloid, Acute ,chemistry ,030220 oncology & carcinogenesis ,Cytarabine ,Female ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
BACKGROUND: Novel therapies are urgently needed for pediatric patients with relapsed acute myeloid leukemia. METHODS: To determine if the histone deacetylase inhibitor panobinostat could be safely given in combination with intensive chemotherapy, we performed a phase I trial in which 17 pediatric patients with relapsed or refractory acute myeloid leukemia received panobinostat (10 mg/m(2), 15 mg/m(2), or 20 mg/m(2)) prior to and in combination with fludarabine and cytarabine. RESULTS: All dose levels were tolerated, with no dose-limiting toxicities observed at any dose level. Pharmacokinetic studies demonstrated that exposure to panobinostat was proportional to the dose given, with no associations between pharmacokinetic parameters and age, weight, or body surface area. Among the nine patients who had sufficient (>2%) circulating blasts on which histone acetylation studies could be performed, seven demonstrated at least 1.5-fold increases in acetylation. Although no patients had a decrease in circulating blasts after single-agent panobinostat, eight of the 17 patients (47%) achieved complete remission, including five of six patients treated at dose level 3. Among the 8 complete responders, 6 (75%) attained negative minimal residual disease status. CONCLUSIONS: Panobinostat can be safely administered with chemotherapy and results in increased blast histone acetylation, suggesting that it should be further studied in acute myeloid leukemia. This trial is registered with ClinicalTrials.gov (NCT02676323).
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- 2020
31. A strategy to reduce cumulative anthracycline exposure in low-risk pediatric acute myeloid leukemia while maintaining favorable outcomes
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Katherine A. Minson, Todd M. Cooper, Kristen E Allen, Caitlin Monroe, Frank G. Keller, Jonathan Metts, Himalee S. Sabnis, Sharon M. Castellino, and William G. Woods
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Oncology ,Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Anthracycline ,Adolescent ,medicine.medical_treatment ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Humans ,Doxorubicin ,Anthracyclines ,Dosing ,Child ,Retrospective Studies ,Cardiotoxicity ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,Cytarabine ,Infant ,Hematology ,Prognosis ,Chemotherapy regimen ,Survival Rate ,Regimen ,Leukemia, Myeloid, Acute ,030220 oncology & carcinogenesis ,Child, Preschool ,Female ,Neoplasm Recurrence, Local ,business ,030215 immunology ,medicine.drug ,Follow-Up Studies - Abstract
Background Advances in risk stratification have improved the 3-year disease-free survival (DFS) and overall survival (OS) of low-risk pediatric acute myeloid leukemia (LR-AML) to approximately 70 % and 85 % respectively. LR-AML is defined by favorable cytogenetic/molecular features and/or optimal early response to therapy. However, cumulative anthracycline exposure in contemporary Children’s Oncology Group (COG) regimens approach a doxorubicin equivalent exposure of 540 mg/m2; with rates of non-infection related left ventricular systolic dysfunction (LVSD) approaching 15 %. This is a major cause of toxicity in these patients and precludes the further use of anthracyclines in the relapsed setting; therefore, strategies that reduce cardiotoxicity while maintaining excellent outcomes are needed. Patients and methods Twenty-seven pediatric patients with LR-AML were treated with an anthracycline-reduced approach (Aflac-AML regimen) between 2011 and 2016. Patients received four courses of therapy including three high-dose cytarabine containing courses and a cumulative doxorubicin equivalent exposure of 390 mg/m2, a 28 % reduction in anthracycline dosing compared to current COG regimens. Results The 3-year DFS and OS was 70.0 % and 85.5 % respectively, from end of Induction I (first chemotherapy cycle) with a median follow-up of 3.2 years. These survival outcomes are comparable to current LR-AML regimens. Only two patients developed non-infection related LVSD during therapy and more importantly, none developed LVSD after completion of therapy. Conclusion These findings suggest that LR-AML outcomes can be maintained using a reduced anthracycline chemotherapy regimen, resulting in lower cardiac toxicity. This new chemotherapy backbone is now being tested prospectively (NCT04326439) to further validate its use in pediatric LR-AML.
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- 2020
32. Decitabine and Vorinostat with Chemotherapy in Relapsed Pediatric Acute Lymphoblastic Leukemia: A TACL Pilot Study
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Rebecca Gardner, Javier Oesterheld, Steven G. DuBois, Paul S. Gaynon, Kenneth Heym, Van Huynh, Sima Jeha, Maria Luisa Sulis, Cara A Rabik, Richard Sposto, Erin M. Guest, Michelle L. Hermiston, Alan S. Wayne, Akira Yuno, Julia Glade-Bender, David S. Ziegler, Shannon Kelley, Patrick A. Brown, Jessica A. Pollard, Bill H. Chang, Sunmin Lee, Rumen Kostadinov, Lia Gore, Anupam Verma, Theodore W. Laetsch, Joel A. Kaplan, Jane B. Trepel, Michael J. Burke, Midhat S. Farooqi, Byunggil Yoo, Robyn M. Dennis, Todd M. Cooper, Deepa Bhojwani, and Min-Jung Lee
- Subjects
0301 basic medicine ,Male ,Cancer Research ,medicine.medical_treatment ,Pilot Projects ,Gastroenterology ,Dexamethasone ,Polyethylene Glycols ,Bortezomib ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Child ,Cancer ,Pediatric ,Vorinostat ,Leukopenia ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Prognosis ,Survival Rate ,Oncology ,Local ,Vincristine ,Child, Preschool ,030220 oncology & carcinogenesis ,6.1 Pharmaceuticals ,Female ,medicine.symptom ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Pediatric Cancer ,Childhood Leukemia ,Clinical Trials and Supportive Activities ,Oncology and Carcinogenesis ,Decitabine ,Neutropenia ,Article ,03 medical and health sciences ,Young Adult ,Rare Diseases ,Clinical Research ,Internal medicine ,medicine ,Genetics ,Humans ,Asparaginase ,Oncology & Carcinogenesis ,Preschool ,Salvage Therapy ,Chemotherapy ,Mitoxantrone ,business.industry ,Infant ,Evaluation of treatments and therapeutic interventions ,medicine.disease ,030104 developmental biology ,Neoplasm Recurrence ,Good Health and Well Being ,Doxorubicin ,Pharmacodynamics ,Neoplasm Recurrence, Local ,business ,Febrile neutropenia ,Follow-Up Studies - Abstract
Purpose: Treatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution. Patients and Methods: We report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1–21) were treated in this trial. Results: The most common grade 3–4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia (n = 1); seizure, somnolence, and delirium (n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia (n = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects. Conclusions: Despite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690.
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- 2020
33. Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients With Acute Myeloid Leukemia: A Report From the Children's Oncology Group
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Robert B. Gerbing, Kasey J. Leger, Jessica A. Pollard, E. Anders Kolb, Alan S. Gamis, Richard Aplenc, Lillian Sung, Todd M. Cooper, Todd A. Alonzo, Kelly D. Getz, and Bonnie Ky
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Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,Myeloid ,Cardiotonic Agents ,Treatment outcome ,Systolic function ,030204 cardiovascular system & hematology ,Ventricular Function, Left ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,In patient ,Dexrazoxane ,Child ,Cardioprotection ,business.industry ,Infant, Newborn ,Myeloid leukemia ,Infant ,ORIGINAL REPORTS ,medicine.disease ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Treatment Outcome ,030220 oncology & carcinogenesis ,Child, Preschool ,Female ,business ,medicine.drug - Abstract
PURPOSE To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk or noncardiac toxicities of the chemotherapy regimens. PATIENTS AND METHODS This was a multicenter study of all pediatric patients with AML without high allelic ratio FLT3/ITD treated in the Children’s Oncology Group trial AAML1031 between 2011 and 2016. Median follow-up was 3.5 years. Dexrazoxane was administered at the discretion of treating physicians and documented at each course. Ejection fraction (EF) and shortening fraction (SF) were recorded after each course and at regular intervals in follow-up. Per protocol, anthracyclines were to be withheld if there was evidence of left ventricular systolic dysfunction (LVSD) defined as SF < 28% or EF < 55%. Occurrence of LVSD, trends in EF and SF, 5-year event-free survival (EFS) and overall survival (OS), and treatment-related mortality (TRM) were compared by dexrazoxane exposure. RESULTS A total of 1,014 patients were included in the analyses; 96 were exposed to dexrazoxane at every anthracycline course, and 918 were never exposed. Distributions of sex, age, race, presenting WBC count, risk group, treatment arm, and compliance with cardiac monitoring were similar for dexrazoxane-exposed and -unexposed patients. Dexrazoxane-exposed patients had significantly smaller EF and SF declines than unexposed patients across courses and a lower risk for LVSD (26.5% v 42.2%; hazard ratio, 0.55; 95% CI, 0.36 to 0.86; P = .009). Dexrazoxane-exposed patients had similar 5-year EFS (49.0% v 45.1%; P = .534) and OS (65.0% v 61.9%; P = .613) to those unexposed; however, there was a suggestion of lower TRM with dexrazoxane (5.7% v 12.7%; P = .068). CONCLUSION Dexrazoxane preserved cardiac function without compromising EFS and OS or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during frontline treatment of pediatric AML.
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- 2020
34. A phase 1 study of azacitidine combined with chemotherapy in childhood leukemia: a report from the TACL consortium
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Todd M. Cooper, Xiaojing Yang, Yoav Messinger, Alan S. Wayne, Andrew E. Place, Richard Sposto, Jemily Malvar, Bodour Salhia, Weili Sun, Luciano Dalla-Pozza, Lia Gore, Henrique Bittencourt, Gangning Liang, Chris Fraser, Paul S. Gaynon, Timothy J. Triche, and Peter A. Jones
- Subjects
0301 basic medicine ,Oncology ,medicine.medical_specialty ,Myeloid ,Childhood leukemia ,medicine.medical_treatment ,Immunology ,Azacitidine ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Letter to Blood ,computer.programming_language ,Chemotherapy ,Extramural ,business.industry ,Cell Biology ,Hematology ,medicine.disease ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,TACL ,Multicenter study ,030220 oncology & carcinogenesis ,business ,computer ,medicine.drug - Abstract
TO THE EDITOR: Despite improvements in treating childhood leukemia, relapses remain the primary cause of death.[1][1][⇓][2][⇓][3]-[4][4] On relapse, leukemic cells are more resistant to chemotherapy. Thus, there is an urgent need to incorporate new strategies to treat childhood leukemia.
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- 2018
35. Combining Atovaquone with Intensive Conventional Chemotherapy for Pediatric Acute Myeloid Leukemia (AML) Is Feasible and Well Tolerated
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Eunji Jo, Alicia E. Mangubat-Medina, Allison Weisnicht, Cara A Rabik, Susan G. Hilsenbeck, Todd M. Cooper, Hana Paek, Michelle C Alozie, Alexandra M. Stevens, Zachary T. Ball, Michele S. Redell, Minhua Li, Hailey H Oviedo, Alan K Gonzalez, Claire E. Bocchini, Haopei Wang, Maci Terrell, Raushan Rashid, Noah J Keogh, and Eric S. Schafer
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Pediatric acute myeloid leukemia ,Cell Biology ,Hematology ,Biochemistry ,Internal medicine ,medicine ,Conventional chemotherapy ,business ,Atovaquone ,medicine.drug - Abstract
Background Relapse free survival of pediatric AML remains only 60%. Current standard myelosuppressive therapy has been maximized, so novel therapies with minimal toxicities are needed to improve outcomes. Previously, we found atovaquone (AQ), an FDA-approved drug that treats pneumocystis jiroveci pneumonia (PJP), reduces AML burden - by suppressing oxidative phosphorylation (OXPHOS) - in xenograft mice. Clinically achievable concentrations of AQ for anti-PJP are 40-80µM, but the anti-leukemia effects are observed as low as 10µM (Stevens et al, Bld Adv, 2019). This makes AQ an ideal drug to incorporate into AML treatment. AQ is a daily administered oral medication, and plasma levels depend on patient compliance, absorption, and entero-hepatic recirculation, which can be compromised due to the patient population and adverse events (AE) of chemotherapy. Here we investigated the feasibility of incorporating AQ into standard pediatric AML treatment. Methods Patients with de novo AML were enrolled at two children's hospitals in the USA. Daily administration of AQ at established PJP prophylaxis dosing was combined with standard chemotherapy for AML, based on the Medical Research Council (MRC) backbone of cytarabine 100mg/m2 q12h x 10 days, and daunorubicin 50mg/m2/dose on days 1, 3, and 5. As it was unclear if our AQ dosing would provide adequate PJP prophylaxis, it was left to provider discretion to give additional PJP protection. AQ compliance, AEs (per NCI CTCAE v5), parent/caregiver ease of administration score (scale: 1-5, 1=very difficult, 5=very easy to administer) and peripheral blood/bone marrow pharmacokinetics (PK) were collected during Induction 1. Real time AQ plasma concentration results were not provided. To address feasibility of achieving adequate levels, all gastrointestinal (GI) AEs ≥ grade 2 were collected, in addition to grade 4 or greater AEs. Patients who took at least 85% of planned doses and missed less than 2 consecutive doses of AQ were eligible for analyses. Correlative biology studies assessed AQ induced apoptosis at 30uM, effects on OXPHOS and relevant signaling activities. Patient derived xenografts (PDX) were established and treated with AQ. This trial is registered with ClinicalTrials.gov (NCT03568994). Results A total of 26 pediatric AML patients enrolled (ages 8 months - 19.7 years, mean 10.7 years); 24 patients were evaluable for this study. Two patients had Grade ≥ 3 GI toxicities that prohibited enteral administration so they were excluded from AQ PK and ease of administration analyses. We found that 14/24 (58%) patients achieved plasma levels above the target anti-leukemia concentration (10µM) by day 11. At the end of induction, 19/24 (75%) patients achieved plasma levels above 10µM, but only 7/24 (29%) patients achieved adequate levels for PJP prophylaxis (40µM). Only 1 patient achieved levels above 40µM throughout the trial [FIG A]. Mean ease of administration score was 3.8. For the youngest patients (x ≤ 2.6years), the average score was 3.4 which was not significantly different from older patients (ANOVA, p > 0.05) [FIG B]. Ease of administration scores showed no association with plasma levels (Pearson's correlation, p > 0.05). Finally, correlative biology studies in patient samples demonstrated robust AQ-induced apoptosis, OXPHOS suppression, and prolonged survival in a PDX model receiving AQ [FIG C]. Conclusion Our data demonstrate the feasibility of combining AQ with traditional chemotherapy for pediatric AML. Patients of all ages were able to tolerate AQ and no AEs were attributable to AQ administration. The target anti-leukemic concentration of AQ in the plasma (> 10uM) was frequently achieved, but concentrations of > 40uM at standard dosing were rare. Low plasma levels of AQ did not correlate with the presence of GI related AEs or weight loss, so plasma levels should be monitored to ensure sufficient PJP prophylaxis. Our correlative biology results support suppression of OXPHOS as the primary mechanism of action by which AQ exerts its anti-leukemia effect, and AQ may be an active anti-leukemia agent for pediatric AML patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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- 2021
36. Single-Cell Transcriptomics for Residual Disease Detection in Acute Myelogenous Leukemia Post Allogeneic Hematopoietic Cell Transplantation
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Todd M. Cooper, Sami B. Kanaan, Soheil Meshinchi, Shruti Bhise, and Scott N. Furlan
- Subjects
Hematopoietic cell ,Disease detection ,business.industry ,Single cell transcriptomics ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Transplantation ,Myelogenous ,Leukemia ,Cancer research ,Medicine ,business - Abstract
Detection of residual disease is a critical component of modern, risk-adapted therapy for Acute Myeloid Leukemia (AML). However, the genetic and phenotypic diversity of AML has made the development of a universal assay for disease assessment particularly challenging. While purely mutation-based tests promise high sensitivity, they are not broadly applicable given molecular heterogeneity and complex clonal evolution. Single-cell approaches, such as multiparameter flow cytometry (MFC), are more broadly applicable and increasingly accepted as the standard in clinical care. However, the limited number of leukemia-specific cell-surface markers and high numbers of shared markers between malignant myeloid blasts and healthy progenitors make MFC data extremely challenging to interpret. Motivated to develop a broadly applicable assay that can provide a more confident assessment of residual disease, we developed a platform using droplet-partitioned single-cell RNA sequencing accompanied by a computational pipeline specifically tailored to quantify residual disease after allogeneic HCT (alloHCT). With bone marrow samples from an 11-year-old patient with suspected post-alloHCT relapse of AML, we interrogated three methods of sample processing, 1) RBC lysis, 2) Ficoll-centrifugation, and 3) Ficoll-centrifugation combined with CD34+ immunomagnetic selection. The samples were further split to separately capture the 3' or 5' end of polyadenylated transcripts. The six resulting libraries were sequenced using standard short-read sequencing, and reads were demultiplexed and counted using common workflows. Data from the samples were combined, and sub-populations were visualized using UMAP (see Figure). This study demonstrated the feasibility of real-time single-cell sequencing for clinical utility. It is possible to process, capture, and sequence a patient's sample in approximately three working days (A). By integrating our data with single-cell expression profiles from an atlas of healthy human bone marrow, we were able to identify cells with gene-expression programs distinct from those of normal hematopoietic cells (B). With these integrated data, we could clearly identify populations of cells that embed away from healthy atlas cells (yellow circle, B), defining a different than normal single-cell profile. This "malignant" profile also included several genes whose expression is usually restricted to healthy hematopoietic progenitors (Panel C), suggesting these cells had a severely dysregulated transcriptome. As this patient was post-alloHCT, we interrogated the abundance of single-nucleotide-polymorphisms (SNPs) in the sequence data. We quantified these SNPs in single cells to distinguish each cell as either of donor or recipient origin using a method we have previously validated for genotyping RNA sequence in single cells. We clearly demonstrate that those cells identified as "different than normal" have a distinct SNP profile suggesting they are of recipient origin. Further analysis revealed that this malignant population was highly enriched for a population of cells expressing a previously described set of "AML-restricted genes" (Huang, B. et al., ASH 2021). (Panel E). Finally, from the Ficoll-processed sample, we quantified a level of 9.8% residual disease (243 malignant cells from a total of 2487). Notably, the number of abnormal myeloid progenitors determined by MFC was 2.0% which increased to 13% on a subsequent marrow sample drawn one week later. Incidentally, we observed only minimal differences across the two single-cell sequencing chemistries (3' vs. 5'). Taken together, our data strongly argue that droplet-based, single-cell RNA sequencing is a feasible and powerful tool for the ascertainment of residual disease in AML. Given the robust nature of the platform and the ability to incorporate SNP integration into the analytic pipeline, it allows confident detection of residual disease in the post-alloHCT setting. By combining genomic quantification of transcripts with the power of SNP-based genotyping all at the level of the single cells, we believe this technology can substantially improve our diagnosis of post-alloHCT AML relapse. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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- 2021
37. A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML
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Laura Martin, David W. Lee, John D. Carpten, Aru Narendran, Philip Barnette, Winnie S. Liang, Soheil Meshinchi, Todd M. Cooper, Bodour Salhia, Frank Alvaro, Robert J. Arceci, Daniel H. Wai, Lia Gore, Jessica Pollard, Margaret E. Macy, Jessica Boklan, Christophe Legendre, Jason E. Farrar, Timothy J. Triche, Gerald C. Gooden, and Carola A.S. Arndt
- Subjects
0301 basic medicine ,Male ,Oncology ,lcsh:Medicine ,Pediatrics ,Epigenesis, Genetic ,law.invention ,chemistry.chemical_compound ,0302 clinical medicine ,Randomized controlled trial ,AML ,law ,Child ,Promoter Regions, Genetic ,Genetics (clinical) ,Etoposide ,0303 health sciences ,DNA methylation ,Cytarabine ,Combination chemotherapy ,Induction Chemotherapy ,3. Good health ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Tolerability ,Child, Preschool ,030220 oncology & carcinogenesis ,Azacitidine ,Female ,Deoxycytidine ,Epigenetics ,medicine.drug ,medicine.medical_specialty ,Adolescent ,lcsh:QH426-470 ,Decitabine ,Neutropenia ,03 medical and health sciences ,Internal medicine ,Genetics ,medicine ,Humans ,Pharmacokinetics ,Adverse effect ,Molecular Biology ,030304 developmental biology ,business.industry ,Research ,Daunorubicin ,lcsh:R ,Infant ,Induction chemotherapy ,medicine.disease ,Clinical trial ,lcsh:Genetics ,030104 developmental biology ,chemistry ,Pharmacodynamics ,Immunology ,business ,Developmental Biology - Abstract
BackgroundDecitabine is a deoxycytidine nucleoside derivative inhibitor of DNA-methyltransferases, which has been studied extensively and is approved for myelodysplastic syndrome in adults but with less focus in children. Accordingly, we conducted a phase 1 multicenter, randomized, open-label study to evaluate decitabine pre-treatment before standard induction therapy in children with newly diagnosed AML to assess safety and tolerability and explore a number of biologic endpoints.ResultsTwenty-four patients were fully assessable for all study objectives per protocol (10 in Arm A, 14 in Arm B). All patients experienced neutropenia and thrombocytopenia. The most common grade 3 and 4 non-hematologic adverse events observed were gastrointestinal toxicities and hypophosphatemia. Plasma decitabine PK were similar to previously reported adult data. Overall CR/CRi was similar for the two arms. MRD negativity at end-induction was 85% in Arm A versus 67% in Arm B patients. DNA methylation measured in peripheral blood over the course of treatment tracked with blast clearance and matched marrow aspirates at day 0 and day 21. Unlike end-point marrow analyses, promoter methylation in blood identified an apparent reversal of response in the lone treatment failure, one week prior to the patient’s marrow aspirate confirming non-response. Decitabine-induced effects of end-induction marrows in Arm A were reflected by changes in DNA methylation and gene expression comparison with matched paired marrow diagnostic aspirates.ConclusionsThis first-in-pediatrics trial demonstrates that decitabine prior to standard combination chemotherapy is feasible and well tolerated in children with newly diagnosed AML. Pre-treatment with decitabine may represent a newer therapeutic option for pediatric AML, especially as it appears to induce important epigenetic alterations. The novel biological correlates studied in this trial offer a clinically relevant window into disease progression and remission. Additional studies are needed to definitively assess whether decitabine can enhance durability responses in children with AML. This trial was registered at www.clinicaltrials.gov as NCT01177540.
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- 2017
38. Venetoclax Alone or in Combination with Chemotherapy: Responses in Pediatric Patients with Relapsed/Refractory Acute Myeloid Leukemia with Heterogeneous Genomic Profiles
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Seth E. Karol, Arnaud Petit, Fengjiao Dunbar, Daniel Morgenstern, Seong Lin Khaw, Henrique Bittencourt, Tammy Palenski, Giridharan Ramsingh, Deeksha Vishwamitra, Kristina Unnebrink, Andrew E. Place, Margaret E. Macy, Betty Prine, Bo Tong, and Todd M. Cooper
- Subjects
Oncology ,medicine.medical_specialty ,education.field_of_study ,business.industry ,Venetoclax ,Immunology ,Population ,Decitabine ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Charitable contribution ,Discontinuation ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Ven ,medicine ,business ,education ,Febrile neutropenia ,Progressive disease ,medicine.drug - Abstract
Introduction: Pediatric acute myeloid leukemia (AML) is a molecularly heterogeneous group of diseases lacking therapy options that would improve overall survival. Venetoclax (VEN) is an oral inhibitor for selective targeting of B-cell lymphoma 2 (BCL2), which is highly expressed in most patients (pts) with AML and has demonstrated promising efficacy in pediatric pts with AML when combined with chemotherapy (CTx) (Karol SE, et al. Lancet Oncol. 2020;21:551-560). Here, we present safety, efficacy, and preliminary genomic results from pediatric pts with relapsed/refractory (R/R) AML receiving VEN + CTx. Methods: This phase 1 open-label, 2-part, multicenter study (NCT03236857) enrolled pts Results: As of June 2020, 36 pts with R/R AML were enrolled and received VEN monoTx (n=3) and VEN + CTx (n=33: VEN + decitabine [VEN-DEC, n=5], azacitidine [VEN-AZA, n=19], or low- [VEN-LDAC, n=1] or high-dose cytarabine [VEN-HDAC, n=8]) (Table). The primary reason for VEN discontinuation was progressive disease (n=19); median duration of VEN therapy was 3.1 months (range 0.2-9.3). All pts experienced adverse events (AEs); 3 pts (n=1 VEN-DEC, n=2 VEN-AZA) had fatal AEs considered unrelated to VEN. The most common grade 3/4 AEs were febrile neutropenia (58%) and hypokalemia (33%). The overall objective response rate (ORR) was 25% (9/36); median duration of response was 0.8 month (95% CI, 0.5, 3.6). The best ORR was seen with VEN-HDAC (4/8, 50%) with 1 complete response (CR), 1 CR without platelet recovery, 1 CR with incomplete marrow recovery (CRi), and 1 partial response (PR); 2 pts achieved minimal residual disease negativity and 2 pts proceeded to transplant. The ORR with VEN-AZA was 26% (5/19), with 3 CR/CRi and 2 PR. No responses were seen with VEN monoTx or VEN + other CTx. The genomic landscape of biomarker-evaluable pts was highly heterogeneous (Figure A). Mutations of genes involved in epigenetic modification (MYH11, IDH2, ASXL1, SETBP1, TET2, and NSD1) and transcription regulation (GATA1, WT1, RUNX1, and CEBPA) were the most common, in 58% and 48% of pts, respectively. Analysis of the recurring mutations found in ≥2 pts revealed that responses to VEN-AZA were seen in pts with IDH2 (1/4), MYH11 (2/6), RUNX1 (1/3), or FLT3 (1/3) mutations, and responses to VEN-HDAC were seen in pts with JAK2 (1/4) or GATA1 (1/3) mutations. Pts with WT1 (3/6) and PTPN11 (3/4) mutations responded to both regimens. Pts with TP53 (n=2) or ETV6 (n=3) mutations and PML-RARA (n=2) or KMT2A rearrangements (n=8) did not respond to any treatment. Gene expression profiling revealed that BCL-xL expression was significantly higher compared with BCL2;MCL1 levels were the highest (Figure B). There was no association between expression of these genes and response. Mutations were seen in BCL2 and MCL1 (n=1 each), but not in BCL-xL. Conclusions: VEN + CTx was well tolerated in pediatric pts with R/R AML, with no unexpected toxicities. Preliminary efficacy was seen in pts receiving VEN-AZA or VEN-HDAC: ORR 26% and 50%, respectively. VEN + CTx resulted in responses in pts harboring mutations across a range of functional classifications; however, some alterations may confer resistance. Due to the limited number of pts harboring each mutation and the overall heterogeneity of the genomic landscape, these findings need to be evaluated in a larger population, and warrant further investigation. Disclosures Karol: AbbVie Inc.: Other: Unrelated to this study, St. Jude has received a charitable contribution from AbbVie, Inc. The charitable contribution is not being used for clinical or research activities, including any activities related to this study. . Bittencourt:Jazz Pharmaceuticals: Consultancy, Other: travel, accommodations, expenses; Novartis: Consultancy. Morgenstern:EUSA Pharma: Consultancy, Other: travel support; Bayer: Consultancy; Clarity Pharmaceuticals: Consultancy; BMS: Other: Institutional Research Funding; Boehringer Ingelheim: Consultancy; Roche: Consultancy. Macy:Merck: Other: Institutional Research Funding; Pfizer: Other: Institutional Research Funding; Bayer: Other: Institutional Research Funding; AbbVie Inc.: Other: Institutional Research Funding; Roche: Other: Institutional Research Funding; Johnson & Johnson: Current equity holder in publicly-traded company. Khaw:Amgen: Other: Institutional Research Funding; Bristol-Myers Squibb: Other: Institutional Research Funding; AbbVie Inc.: Other: Institutional Research Funding; Novartis: Other: travel, accommodation, expenses; Walter and Eliza Hall Institute of Medical Research.: Patents & Royalties: Recipient of a share in royalty payments . Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019). Ramsingh:Genentech: Current Employment, Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Tong:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Unnebrink:AbbVie: Current Employment, Other: may hold stock or other options. Vishwamitra:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Dunbar:Abbvie: Current Employment, Current equity holder in publicly-traded company. Prine:AbbVie: Current Employment, Other: may hold stock or other options. Palenski:AbbVie: Current Employment, Other: may hold stock or other options. Place:Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA approved for some indications. Venetoclax for treatment of pediatric AML is not an approved indication.
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- 2020
39. Characteristics and Prognostic Effects of IDH Mutations across the Age Spectrum in AML: A Collaborative Analysis from COG, SWOG, and ECOG
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Soheil Meshinchi, Selina M. Luger, Richard Aplenc, Alan S. Gamis, Ehab Atallah, Frederick R. Appelbaum, Jerald P. Radich, Mark R. Litzow, Matthew A. Kutny, Amanda R. Leonti, Martin S. Tallman, Todd A. Alonzo, Era L. Pogosova-Agadjanyan, Todd M. Cooper, Harry P. Erba, Megan Othus, Ross L. Levine, Derek L. Stirewalt, Katherine Tarlock, Yi-Cheng Wang, Anders Kolb, Rhonda E. Ries, Kristen M. O'Dwyer, Zhuoxin Sun, Omar Abdel-Wahab, and Sara Zarnegar-Lumley
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Oncology ,medicine.medical_specialty ,Cog ,business.industry ,Internal medicine ,Immunology ,Medicine ,Cell Biology ,Hematology ,business ,Biochemistry ,health care economics and organizations - Abstract
Background: Somatic mutations in the IDH genes are common in acute myeloid leukemia (AML). Mutations occur at active site arginine residues in IDH1 (R132) and IDH2 (R140, R172). IDH inhibitors, ivosidenib (IDH1) and enasidenib (IDH2), have shown improved clinical outcomes in patients with relapsed/refractory IDH-mutant AML and are approved for use in this setting, while investigations in combination with chemotherapy are underway in de novo AML. The prognostic significance of IDH mutations remains controversial. We hypothesize that refining our understanding of IDH-mutated AML will contribute to risk-adapted treatment strategies, including optimal use of IDH-targeted agents. The objective of our study was to identify characteristics that affect outcome in de novo IDH-mutated AML across the age spectrum utilizing a large cohort of patients enrolled on several pediatric and adult trials. Methods: The total cohort (N=3588) included patients age Results: The prevalence of IDH mutations among the entire cohort was 8.6% (N=276). Analysis according to mutation type demonstrated that IDH2 mutations comprised 57% (N=158) and IDH1 mutations 43% (N=118). The prevalence of IDH mutations was strongly correlated with increased age (Fig 1A); according to the age-defined cohorts was 4.0% (N=82) in younger, 15.2% (N=126) in intermediate, and 20.3% (N=65) in older patients (p Conclusion: Analysis of this large patient cohort provides the most comprehensive description of IDH mutations in AML across the age spectrum. We confirm age-associated prevalence of IDH mutations and frequent co-occurrence with NPM1 mutation in all ages and in further combination with DNMT3A mutation in intermediate-aged adults. We definitively demonstrate that IDH mutation status is not an independent prognostic determinant of outcome in any age group. Co-occurrence of NPM1 and IDH mutations favorably impacts outcome in patients < 60 years of age with AML, particularly in the absence of DNMT3A mutation. Our data support that IDH inhibitors may be of particular interest in older adults and in patients Disclosures Othus: Marck: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Membership on an entity's Board of Directors or advisory committees. Radich:Jazz: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy. Abdel-Wahab:Merck: Consultancy; Janssen: Consultancy; Envisagenics Inc.: Current equity holder in private company; H3 Biomedicine Inc.: Consultancy, Research Funding. Tallman:UpToDate: Patents & Royalties; ADC Therapeutics: Research Funding; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Research Funding; Rafael: Research Funding; Amgen: Research Funding; Bioline rx: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Cellerant: Research Funding; Orsenix: Research Funding. Atallah:Jazz: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Novartis Pharmaceutical Corporation: Consultancy. Luger:Daiichi-Sankyo: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Acceleron: Honoraria; Agios: Honoraria; Loxo Oncology: Honoraria; Onconova: Research Funding; Kura: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Hoffman La Roche: Research Funding. Levine:Novartis: Consultancy; Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy; Astellas: Consultancy; Janssen: Consultancy; Prelude Therapeutics: Research Funding; Amgen: Honoraria; Gilead: Honoraria; Lilly: Consultancy, Honoraria; Qiagen: Current equity holder in publicly-traded 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; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019).
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- 2020
40. Pediatric Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia Harboring Heterogeneous Genomic Profiles Respond to Venetoclax in Combination with Chemotherapy
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Nicolas U. Gerber, Christopher J. Forlenza, Deeksha Vishwamitra, Andrew E. Place, Maureen M. O'Brien, Dirk Reinhardt, Bo Tong, Giridharan Ramsingh, Fengjiao Dunbar, Betty Prine, Seth E. Karol, Marion Gambart, Phillip Barnette, Chris Fraser, Todd M. Cooper, Tammy Palenski, Mignon L. Loh, Kristina Unnebrink, and Gunnar Cario
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Oncology ,medicine.medical_specialty ,Vincristine ,business.industry ,Venetoclax ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Charitable contribution ,Discontinuation ,chemistry.chemical_compound ,chemistry ,Internal medicine ,Ven ,medicine ,Cytarabine ,business ,Febrile neutropenia ,Progressive disease ,medicine.drug - Abstract
Introduction: Venetoclax (VEN) is an orally administered selective inhibitor of the B-cell lymphoma 2 (BCL2) antiapoptotic protein. VEN combined with chemotherapy (CTx) has demonstrated encouraging responses in a variety of hematologic malignancies. Here, we present safety, efficacy, and preliminary genomics results from our phase 1 study of VEN administered with CTx in pediatric patients (pts) with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). Methods: This open-label, phase 1, 2-part study enrolled pts Results: As of June 2020, 25 pts with ALL were enrolled and received VEN + CTx; CTx regimens included dexamethasone and/or vincristine and/or peg-asparaginase (D/V/P, n=16) or cytarabine and/or etoposide and/or peg-asparaginase (C, n=9). Pts had a median of 3.5 (range 1.0-9.0) prior therapies; the median duration of VEN therapy was 2.1 mo (range 0.4-4.6). Most common reasons for VEN discontinuation were progressive disease (28%; D/V/P: n=1; C: n=6) or continuation to transplant (28%; D/V/P: n=6; C: n=1). Eight (32%; D/V/P: n=4; C: n=4) pts had fatal adverse events (AEs), all unrelated to VEN. Most common grade 3/4 AEs were febrile neutropenia (52%) and anemia (44%); 1 pt (D/V/P)completed ramp up, but reported laboratory tumor lysis syndrome with CTx combination. A best objective response rate (ORR) of 56% was seen with VEN + D/V/P: 4 complete responses (CR), 4 CR with incomplete marrow recovery (CRi), and 1 CR without platelet recovery (CRp). ORR of 11% (CRi: n=1) was seen with VEN + C (Table). In pts who achieved CR/CRi/CRp, MRD Genetic analysis of evaluable pts (VEN + D/V/P: n=12; VEN + C: n=6) demonstrated a highly heterogeneous genomic landscape (Figure A) including a range of somatic mutations and structural variants, comprising translocations, rearrangements, and chromosomal abnormalities. Analysis of mutations found in ≥2 pts revealed that responses were seen in VEN + D/V/P-treated pts with CREBBP, KMT2A, KMT2D, RB1, PTPN11, and PDGFRB mutations. Of the pts who had CREBBP mutations, 2/3 obtained CR. Pts with mutations in RB1, PTPN11, and PDGFRB (n=2 each) also achieved CR or CRi. Of the pts with KMT2A or KMT2D mutations detected by our sequencing platform, 1/2 and 2/4 achieved CR, respectively. Furthermore, of the 6 pts with KMT2A translocations identified locally, 3 obtained CR with VEN + D/V/P. Baseline gene expression profiling revealed that BCL-xL and MCL1 levels were slightly higher in comparison to BCL-2 (Figure B). There was no significant correlation between these gene expression levels and response. No mutations were detected in BCL2, BCL-xL, or MCL1. Conclusions: VEN + CTx was well tolerated, with no unexpected toxicities in pediatric pts with R/R ALL. Promising preliminary efficacy was observed in these refractory pts receiving VEN + D/V/P (ORR 56%). Our genomic profiling suggests that responses with VEN + CTx occur in pediatric ALL with a variety of mutations, including those with KMT2A rearrangements. However, due to the limited sample size and the overall heterogeneity, further investigation in a larger pt cohort is warranted to determine which mutations confer resistance or sensitivity to VEN. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Karol:AbbVie: Other: Unrelated to this study, St. Jude has received a charitable contribution from AbbVie, Inc. The charitable contribution is not being used for clinical or research activities, including any activities related to this study. . Gambart:Jazz Pharmaceuticals: Other: travel, accommodations, expenses; Eisai: Other: travel, accommodations, expenses. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019). Fraser:Novartis, Amgen: Consultancy. Cario:Jazz Pharmaceuticals: Consultancy, Other: travel support; Novartis: Consultancy, Other: travel support. O'Brien:Celgene: Research Funding; Jazz: Research Funding; Amgen: Research Funding; BMS: Research Funding; AbbVie: Research Funding; Pfizer: Honoraria, Research Funding; Incyte: Research Funding. Gerber:AbbVie, Loxo, Novartis: Other: Institutional Research Funding. Reinhardt:Behring: Other: Institutional Research Funding; Novo Nordisk: Other: Institutional Research Funding; Biotest: Other: Institutional Research Funding; Roche: Consultancy, Other: Institutional Research Funding; bluebird bio: Consultancy; Celgene: Consultancy, Other: Institutional Research Funding; Jazz: Consultancy, Other: Institutional Research Funding; Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Ramsingh:Genentech: Current Employment, Current equity holder in publicly-traded company; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Tong:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Unnebrink:AbbVie: Current Employment, Other: may hold stock or other options. Vishwamitra:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Dunbar:Abbvie: Current Employment, Current equity holder in publicly-traded company. Prine:AbbVie: Current Employment, Other: may hold stock or other options. Palenski:AbbVie: Current Employment, Other: may hold stock or other options. Loh:Pfizer: Other: Institutional Research Funding; Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA approved for some indications. Venetoclax for treatment of pediatric ALL is not an approved indication.
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- 2020
41. Venetoclax Crosses the Blood Brain Barrier: A Pharmacokinetic Analysis of the Cerebrospinal Fluid in Pediatric Leukemia Patients
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Todd M. Cooper, Tammy Palenski, Andrew E. Place, Rajeev M. Menon, Su Young Kim, Richard Arrendale, Ahmed Salem, Sara M. Federico, and Mohamed Badawi
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Oncology ,medicine.medical_specialty ,Chemotherapy ,Acute leukemia ,business.industry ,Venetoclax ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,chemistry.chemical_compound ,Cerebrospinal fluid ,chemistry ,Pharmacokinetics ,Internal medicine ,medicine ,Rituximab ,Methotrexate ,business ,medicine.drug - Abstract
Introduction: Venetoclax is a selective BCL2 inhibitor approved for the treatment of CLL and AML in adults and is currently being evaluated in several hematologic and solid malignancies. While plasma pharmacokinetics (PK) of venetoclax is well documented, data regarding the accumulation of venetoclax into the central nervous system (CNS) are limited. Venetoclax has a molecular weight of 868.44 which was hypothesized to limit its passage through the tight junctions of the blood brain barrier (BBB). Moreover, venetoclax is a substrate of the P- glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters, expressed by endothelial cells at the BBB, which presents an extra hurdle for penetration into the CNS. In this analysis we characterized the passage of venetoclax into the CNS using PK samples collected during a phase 1 study (NCT03236857) of pediatric patients with relapsed and refractory acute leukemia receiving venetoclax in combination with chemotherapy. Methods: PK samples from cerebrospinal fluid (CSF) were collected at screening and if a lumbar puncture was performed as standard of care during treatment. Plasma PK samples were collected throughout the study. CSF and plasma concentrations of venetoclax were determined using liquid-liquid extraction followed by liquid chromatography (LC) with tandem mass spectrometric detection (MS/MS). The lower limit of quantitation for venetoclax was 2.14 ng/mL in plasma and 0.1ng/mL in CSF. Results: There was a total of 66 samples from 33 patients with relapsed or refractory AML or ALL. The venetoclax concentration in CSF ranged between Conclusion: To our knowledge this is the first study reporting venetoclax CSF pharmacokinetics in the AML and ALL setting. The lower disposition observed in humans is contrary to our expectation, given the significantly higher expression of P-gp in mice BBB compared to humans and suggests that other factors are involved in venetoclax disposition to the CSF. The ability of venetoclax to cross the blood brain barrier may explain the reported activity of venetoclax in treatment of hematologic malignancies with CNS involvement1,2. References: Reda G, Cassin R, Dovrtelova G, et al. Venetoclax penetrates in cerebrospinal fluid and may be effective in chronic lymphocytic leukemia with central nervous system involvement. Haematologica. 2019;104(5):e222-e223. doi:10.3324/haematol.2018.213157 Beziat G, Gauthier M, Protin C, et al. Venetoclax with high-dose methotrexate and rituximab seem effective and well-tolerated in the treatment of central nervous system involvement of chronic lymphocytic leukemia: A case report. Clin Case Rep. 2020;8(2):269-273. Published 2020 Jan 10. doi:10.1002/ccr3.2580 Disclosures Salem: AbbVie Inc.: Current Employment, Other: may hold stock or other options. Badawi:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Place:Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Palenski:AbbVie: Current Employment, Other: may hold stock or other options. Arrendale:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Kim:AbbVie, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: may hold stock or other options. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019). Menon:AbbVie Inc.: Current Employment, Other: may hold stock or other options.
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- 2020
42. The Molecular Characteristics and Clinical Relevance of NUP98-Other Translocations in Pediatric Acute Myeloid Leukemia
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Soheil Meshinchi, Betsy A. Hirsch, Eline J.M. Bertrums, Jenny L. Smith, Rhonda E. Ries, Gertjan J.L. Kaspers, Alan S. Gamis, Edward A. Kolb, Todd A. Alonzo, Richard Aplenc, Fabiana Ostronoff, Christian M. Zwaan, Henrik Hasle, Todd M. Cooper, Susana C. Raimondi, and Bianca F. Goemans
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Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,Pediatric acute myeloid leukemia ,medicine ,Chromosomal translocation ,Clinical significance ,Cell Biology ,Hematology ,business ,Biochemistry - Abstract
Background Cytogenetic and molecular aberrations are important prognostic factors in pediatric acute myeloid leukemia (AML). NUP98 translocations with more than 30 different partner genes have been identified in pediatric AML. The 2 most common fusions, NUP98-NSD1 and NUP98-KDM5A, have been shown to have distinct characteristics and are both associated with adverse outcomes. Although NUP98 fusions with less common fusion partners have been identified, the biological and clinical implications of these variants are unknown. Methods To determine the biological and clinical implications of the less common "other" NUP98 translocations (NUP98-X), we evaluated the clinical characteristics and transcriptome and genome sequencing data from 2396 children and young adults with AML within 4 consecutive Children's Cancer Group (CCG) and Children's Oncology Group (COG) trials CCG-2961, AAML03P1, AAML0531 and AAML1031. All NUP98-X translocations were confirmed by RNA sequencing. Results Of the 2396 patients screened, 164 patients (6.8%) had a NUP98 translocation. We identified 20 patients with a NUP98-X fusion (0.83%) and compared them with those with NUP98-NSD1 (n=110, 4.5%), NUP98-KDM5A(n=34, 1.4%), and a reference cohort without NUP98 translocations (n=2232). Translocation partners identified in the NUP98-X group were HOXA9 (n=4), HOXD13 (n=3), PHF15 (n=2), PHF23 (n=2), and single cases of BPTF, BRWD3, DDX10, HMGB3, HOXA13, KAT7, PRRX1, SET and TOP1. Besides the distinct characteristics of NUP98-NSD1 and NUP98-KDM5A, the NUP98-X group showed high inter-patient variance in clinical characteristics compared to our reference cohort. NUP98-X patients showed a clear bimodal age distribution with half of the patients being in the older age category and a similar number in the category We evaluated the impact of NUP98-X translocations in response to the initial induction therapy. The morphological complete remission (CR) rate after course 1 was 65% in the NUP98-X cohort versus 76% in the reference cohort (p=0.266). NUP98-NSD1 patients had an inferior CR rate (36%, p Conclusion NUP98-X translocated pediatric AML patients represent a rare cohort with a high variability in both translocation partners and other clinical characteristics. Despite this heterogeneity, the OS of these patients is comparable to high-risk pediatric AML patients, which justifies a high-risk stratification of these patients and emphasizes the need for developing new treatment strategies. Further research within large patient cohorts is needed to investigate the biologic and clinical characteristics of these rare translocations and potential differences between the different NUP98-X fusion partners. Disclosures Kaspers: AbbVie: Ended employment in the past 24 months; Helsinn Healthcare: Ended employment in the past 24 months; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Ended employment in the past 24 months. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019).
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- 2020
43. Integrated Stem Cell Signature and Cytomolecular Risk Determination in Pediatric Acute Myeloid Leukemia
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Jenny L. Smith, Lisa Wei, Xiaotu Ma, Todd M. Cooper, Todd A. Alonzo, Edward A. Kolb, Timothy J. Triche, Robert B. Gerbing, Jason E. Farrar, Timothy I. Shaw, Amanda R. Leonti, Rhonda E. Ries, Soheil Meshinchi, Yi-Cheng Wang, Benjamin J. Huang, Erin L. Crowgey, and Scott N. Furlan
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Oncology ,medicine.medical_specialty ,biology ,business.industry ,Proportional hazards model ,Immunology ,Myeloid leukemia ,Cell Biology ,Hematology ,Disease ,Biochemistry ,KMT2A ,medicine.anatomical_structure ,Internal medicine ,Cohort ,medicine ,biology.protein ,Population study ,Bone marrow ,Young adult ,business - Abstract
Acute myeloid leukemia (AML) remains a therapeutic challenge with high mortality rates despite intensive and myeloablative therapies. Structural and sequence alterations have been linked to outcomes in pediatric AML and have been used for risk-based therapy allocation with modest success. Given the vast heterogeneity of AML, conventional cytogenetic and mutational (cytomolecular) biomarkers have not yielded a robust prognostic model: nearly one-third of pediatric patients deemed "low risk" relapse and, inversely, approximately one-third of those in "high risk" categories have favorable outcomes. AML studies in adults previously identified a leukemia stem cell score (LSC17) that was highly prognostic across five independent cohorts comprised of adult patients with diverse AML subtypes (n = 908). We reasoned that incorporating a similar scoring system in pediatric AML would lead to improved prognostic risk models. To assess for the effects of LSC17 on pediatric AML, we leveraged transcriptome sequencing data from bone marrow aspirates and peripheral blood collected from 1,503 children, adolescents, and young adults with AML at the time of diagnosis. Patients were enrolled on one of three upfront phase III Children's Oncology Group trials spanning the past three decades: CCG-2961, AAML0531, and AAML1031. In aggregate, patients with a high LSC17 score had an event free survival (EFS) of 36.9 ± 3.5% at 5 years from diagnosis compared to 55.3 ± 3.7% for those with low LSC17 scores (p < 0.0001). (Figure 1A) LSC17 scores were also associated with adverse overall survival (OS): 51.9 ± 3.9% versus 73.8 ± 3.5% (p < 0.0001) (data not shown). Intriguingly, we found that LSC17 scores significantly cluster within fusion groups and that median LSC17 scores closely correlate with survival based on fusion status (Figure 1B). Thus, when the impact of LSC17 scores was evaluated in the context of established cytomolecular risk groups, LSC17 scores were no longer predictive of outcome (Figure 1C). We then asked whether LSC gene expression data could be utilized to generate a more robust risk classification schema in the context of disease defining structural variants. Importantly, AMLs diagnosed in children, adolescents, and young adults are associated with frequent driver gene fusion alterations that also play an important role in risk stratification and transcriptional landscape (Figure 1D). We went on to confirm that AML fusion groups occupy distinct transcriptional stages of hematopoietic stem cell and myeloid progenitor maturation based on gene set enrichment analysis (GSEA) using normal hematopoiesis transcriptome experiments as their reference (data not shown). To develop more predictive biomarkers related to stemness, we used the 54 original LSC genes identified by Ng S, et al. and performed linear regression based on a least absolute shrinkage and selection operator (LASSO) algorithm to fit a Cox regression model for patients within each fusion group. The study population was divided into discovery (n = 752) and validation (n = 752) cohorts using stratified randomization based on fusion status (RUNX1-RUNX1T1, CBFB-MYH11, KMT2A, NUP98, CBFA2T3-GLIS2, and Other/None). In the discovery cohort, we identified distinct LSC signatures that best distinguished outcome cohorts in patients with conventional high/standard risk disease (KMT2A, NUP98, and Other/None fusions) (Figure 1E). For patients deemed favorable risk (RUNX1-RUNX1T1 and CBFB-MYH11 or core binding factor/CBF), LSC signatures were not reliably predictive based on "leave one out" cross validation. Therefore, we performed multivariable analysis incorporating clinical, mutational, and transcriptional signatures to determine the factors that best discriminated outcomes with CBF AML, and found GLIS2-like transcriptional signatures were most predictive. These cytomolecular and LSC (CM-LSC) biomarkers were then combined to build a robust risk determination model that was then validated in an independent cohort (Figure 1F). This study demonstrates that a 54 LSC gene expression panel can enhance the predictive power of conventional cytomolecular markers and can more effectively partition patients into risk groups. Figure 1 Disclosures Cooper: Celgene: Other: Spouse was an employee of Celgene (through August 2019).
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- 2020
44. Feasibility of pevonedistat combined with azacitidine, fludarabine, cytarabine in pediatric relapsed/refractory AML: Results from COG ADVL1712
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Terzah M. Horton, Sharon Bergeron, Emasenyie Isikwei, Joel M. Reid, Charles G. Minard, Sarah Menig, Brenda J. Weigel, Elizabeth Fox, Xiaowei Liu, Katherine Tarlock, and Todd M. Cooper
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Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Azacitidine ,Fludarabine ,Cog ,Refractory ,Internal medicine ,Relapsed refractory ,Cytarabine ,Medicine ,business ,medicine.drug - Abstract
10018 Background: Outcomes for children with relapsed/refractory (R/R) AML and MDS are poor and new therapies are needed. Pevonedistat is an inhibitor of the NEDD-8 activating enzyme, a key regulator of the ubiquitin proteasome system that is responsible for protein turnover, cell growth and survival. In preclinical models, pevonedistat was synergistic with cytarabine (AraC) and azacitidine (aza). The combination of pevonedistat + aza in adults with AML demonstrated improved responses compared to either single agent. We evaluated the feasibility, toxicity and pharmacokinetics (PK) of pevonedistat in combination with aza, fludarabine, AraC (Aza-FLA) in children with R/R AML and MDS. Methods: Pevonedistat 20 mg/m2, IV days 1, 3, 5, the recommended adult dose, was administered in combination with aza (75 mg/m2, days 1-5), fludarabine (30 mg/m2, days 6-10), and AraC (2000 mg/m2, days 6-10). Intrathecal AraC was administered at the start of therapy and additional doses given to patients with CNS leukemia. If < 33% of the initial 6 enrolled patients experienced dose limiting toxicity (DLT) during cycle 1 the regimen would be considered tolerable and 6 additional patients could enroll to further assess tolerability and PK. Pevonedistat PK was determined during cycle 1 following doses 1 and 5. Response was evaluated after cycle 1. Results: A total of 12 patients were enrolled, median age was 13 years (range 1-21). All patients received prior chemotherapy, median number of prior regimens was 2 (range 1-5) and 3 (25%) patients had prior hematopoietic stem cell transplant. Diagnoses were AML NOS (n = 10, 83%), acute monocytic leukemia (n = 1), and therapy related AML (n = 1). One of the initial 6 patients had DLTs (hypertension, GGT elevation, and proteinuria); pevonedistat 20 mg/m2 + Aza-FLA was considered tolerable. Six additional patients were enrolled, two had DLTs (weight loss, hypoxia). Overall, 3/12 (25%) of patients experienced DLTs. As expected, using the intensive Aza-FLA backbone, myelosuppression, electrolyte abnormalities, and hepatic transaminase elevation were common. Day 1 PK parameters (n = 12, mean±SD) were: Cmax= 223±91 ng/mL, AUC0-24h= 892±216 ng/hr/mL, T1/2=4.3±1.2 hours, CL = 23.2±6.9 L/hr/m2. PK parameters were similar following doses 1 and 5, for patients < 12 (n = 6) and ≥ 12 (n = 6) years, and to adult PK profiles. Ten patients were evaluable for response. The overall response rate was 30% (95% CI: 7,75) with 3 patients achieving a CR with incomplete hematologic recovery (CRi). Conclusions: Pevonedistat 20 mg/m2 combinedwith Aza-FLA was tolerable in children with R/R AML. The toxicity of the regimen was similar to other intensive AML regimens. PK parameters were similar among the two age groups and were comparable to adults. Within the confines of a phase I study, there was limited anti-leukemic activity of the combination of pevonedistat +Aza-FLA in R/R AML. Clinical trial information: NCT03813147.
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- 2021
45. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia
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Rupert Handgretinger, Phillip Barnette, Benoit Brethon, Chiara Messina, Christian M. Zwaan, Franco Locatelli, Steven G. DuBois, Lia Gore, Peter Bader, Gérard Michel, Kuolung Hu, Carmelo Rizzari, Paul G. Schlegel, James A. Whitlock, Maureen M. O'Brien, Min Zhu, Tanya M. Trippett, Todd M. Cooper, Deepa Bhojwani, Gerhard Zugmaier, Susan R. Rheingold, Arend von Stackelberg, Arndt Borkhardt, Pediatrics, Von Stackelberg, A, Locatelli, F, Zugmaier, G, Handgretinger, R, Trippett, T, Rizzari, C, Bader, P, O'Brien, M, Brethon, B, Bhojwani, D, Schlegel, P, Borkhardt, A, Rheingold, S, Cooper, T, Zwaan, C, Barnette, P, Messina, C, Michel, G, Dubois, S, Hu, K, Zhu, M, Whitlock, J, and Gore, L
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Cancer Research ,bispecific ,Pharmacology ,Gastroenterology ,Antineoplastic Agent ,0302 clinical medicine ,blinatumomab ,Antibodies, Bispecific ,antibodies ,Single-Blind Method ,Infusions, Intravenou ,Infusions, Intravenous ,Child ,adolescent ,antibodies, bispecific ,antineoplastic agents ,child ,disease-free survival ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Hypokalemia ,Treatment Outcome ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Oncology ,Child, Preschool ,030220 oncology & carcinogenesis ,Blinatumomab ,Survival Analysi ,medicine.symptom ,Human ,medicine.drug ,medicine.medical_specialty ,Adolescent ,Maximum Tolerated Dose ,Anemia ,Antineoplastic Agents ,Disease-Free Survival ,Drug Administration Schedule ,Follow-Up Studie ,03 medical and health sciences ,Refractory ,Internal medicine ,medicine ,Humans ,Adverse effect ,Survival analysis ,Dose-Response Relationship, Drug ,business.industry ,Complete Minimal Residual Disease Response ,medicine.disease ,Survival Analysis ,Respiratory failure ,business ,Follow-Up Studies ,030215 immunology - Abstract
Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m2/d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m2/d for the first 7 days, followed by 15 µg/m2/d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.
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- 2016
46. Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy
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Hannah Brakke, Olivia Finney, Kasey J. Leger, Juliane Gust, Todd M. Cooper, Rebecca Gardner, Daniel H. Li, Julie Rivers, Corinne Summers, Julie R. Park, Francesco Ceppi, Michael C. Jensen, Agne Taraseviciute, Colleen Annesley, and Katherine Tarlock
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0301 basic medicine ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Adoptive cell transfer ,Adolescent ,medicine.medical_treatment ,Immunology ,Antigens, CD19 ,Receptors, Antigen, T-Cell ,Antibodies, Monoclonal, Humanized ,Biochemistry ,Immunotherapy, Adoptive ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Tocilizumab ,Therapeutic index ,Adrenal Cortex Hormones ,T-Lymphocyte Subsets ,Internal medicine ,Precursor B-Cell Lymphoblastic Leukemia-Lymphoma ,medicine ,Humans ,Child ,Dose-Response Relationship, Drug ,business.industry ,Incidence ,Infant ,Cell Biology ,Hematology ,Immunotherapy ,medicine.disease ,Chimeric antigen receptor ,Cytokine release syndrome ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Child, Preschool ,Monoclonal ,Cytokines ,Female ,Neoplasm Grading ,business ,Cytokine Release Syndrome ,CD8 - Abstract
Immunotherapy with the adoptive transfer of T cells redirected with CD19-specific chimeric antigen receptors (CARs) for B-lineage acute lymphoblastic leukemia (ALL) can salvage >80% of patients having relapsed/refractory disease. The therapeutic index of this emerging modality is attenuated by the occurrence of immunologic toxicity syndromes that occur upon CAR T-cell engraftment. Here, we report on the low incidence of severe cytokine release syndrome (CRS) in a subject treated with a CAR T-cell product composed of a defined ratio CD4:CD8 T-cell composition with a 4-1BB:zeta CAR targeting CD19 who also recieved early intervention treatment. We report that early intervention with tocilizumab and/or corticosteroids may reduce the frequency at which subjects transition from mild CRS to severe CRS. Although early intervention doubled the numbers of subjects dosed with tocilizumab and/or corticosteroids, there was no apparent detrimental effect on minimal residual disease-negative complete remission rates or subsequent persistence of functional CAR T cells compared with subjects who did not receive intervention. Moreover, early intervention therapy did not increase the proportion of subjects who experience neurotoxicity or place subjects at risk for infectious sequelae. These data support the contention that early intervention with tocilizumab and/or corticosteroids in subjects with early signs of CRS is without negative impact on the antitumor potency of CD19 CAR T cells. This intervention serves to enhance the therapeutic index in relapsed/refractory patients and provides the rationale to apply CAR T-cell therapy more broadly in ALL therapy. This trial was registered at www.clinicaltrials.gov as #NCT020284.
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- 2019
47. CPX-351 Population Pharmacokinetics in Pediatric and Adult Patients with Acute Myeloid Leukemia (AML)
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Michael J. Absalon, Nathalie H. Gosselin, Qi Wang, Grygoriy Vasilinin, J.F. Marier, E. Anders Kolb, Todd A. Alonzo, and Todd M. Cooper
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Volume of distribution ,Body surface area ,medicine.medical_specialty ,education.field_of_study ,Creatinine ,Daunorubicin ,business.industry ,Immunology ,Population ,Renal function ,Cell Biology ,Hematology ,Biochemistry ,Gastroenterology ,chemistry.chemical_compound ,Pharmacokinetics ,chemistry ,Internal medicine ,medicine ,Cytarabine ,business ,education ,medicine.drug - Abstract
CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of daunorubicin and cytarabine at a 1:5 synergistic ratio, is approved by the US FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Recently, CPX-351 was used in pediatric patients (pts) with relapsed AML (JCO 2020, ASH 2019, ASH 2018). A population pharmacokinetic (PK) analysis of plasma concentrations of cytarabine and daunorubicin following IV administration of CPX-351 was performed to assess sources of variability in PK and to determine if age-based dose adjustments may be warranted, particularly in pediatric pts. The PK population consisted of 250 pts with advanced hematologic malignancies from 7 studies and included 46 (18%) pediatric pts (1-17 y) and 204 (82%) adults (≥18 y). The population included 148 (59%) males, mainly of white origin (82%). Nonlinear mixed-effect modeling was performed using NONMEM®. Model evaluation and selection were assessed using a standard model discrimination process that included statistical criteria (eg, objective function value) and pertinent graphical representations of goodness-of-fit. Separate PK models were developed for cytarabine and daunorubicin; intrinsic and extrinsic factors were evaluated as covariates. The intrinsic factors included body weight, body mass index, age, sex, race, white blood cell count, and markers of renal function (creatinine clearance, serum creatinine) and hepatic function (bilirubin, aspartate and alanine aminotransferases, alkaline phosphatase). The extrinsic factors included study type (adult vs pediatric/young adult) and formulation (frozen vs lyophilized). Based on previous population PK models developed for adults, the PK models for cytarabine and daunorubicin used 2-compartment structural models, with drug input into the central compartment, first-order distribution between the central and peripheral compartments, and first-order elimination from the central compartment. Two-compartment structural models with body surface area (BSA) as an allometric scalar provided minimum bias in estimates of systemic clearance (CL) and volume of distribution for the central compartment (Vc). Based on the final population PK models, the estimates of CL and Vc in adults were 0.101 L/h and 4.76 L, respectively, for cytarabine and 0.140 L/h and 4.04 L for daunorubicin. The population estimates of CL and Vc for cytarabine in children, adolescents, and young adults ( All tested covariates were eventually excluded from the population PK models, except BSA, bilirubin, study type, and formulation, which have a small effect on PK and are not expected to result in detectable changes in clinical safety or efficacy. Age was evaluated both as a continuous and categorical variable (1-5, 6-11, and 12-17 y) and was not a significant covariate for cytarabine and daunorubicin CL and Vc. Study type was identified as a significant covariate for CL and Vc for cytarabine and daunorubicin, which was possibly due to a change in analytical site for pediatric studies. Mean AUC0-48 values of cytarabine in pts aged 1-5, 6-11, and 12-17 y (135 U/m2) were similar (2767, 2783, and 2806 μg·h/mL, respectively) and approximately 40% higher than that observed in pts ≥18 y (100 U/m2, 1928 μg·h/mL), proportional to the 35% higher dose in pediatric pts. Mean AUC0-48 values of daunorubicin in pts aged 1-5, 6-11, and 12-17 y (135 U/m2) were similar (967, 896, and 982 μg·h/mL, respectively) and approximately 40% higher than that observed in pts ≥18 y (100 U/m2, 615 μg·h/mL), proportional to the 35% higher dose in pediatric pts. The results of this population PK analysis indicated exposures to CPX-351 in pediatric pts were not affected by age and were similar to those in adults when administered at the same BSA-normalized dose. Disclosures Wang: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019). Absalon:Jazz Pharmaceuticals: Research Funding. OffLabel Disclosure: Yes, in this study, CPX-351 was also evaluated in pediatric AML
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- 2020
48. Newly Diagnosed Childhood AML Patients Treated with Bortezomib Show Superior Survival If CD74 Is Expressed: A Report of 991 Patients from the Children's Oncology Group AAML1031 Protocol
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Robert B. Gerbing, Michael R. Loken, Laura Pardo, Loren L. Lott, Jessica A. Pollard, Richard Aplenc, E. Anders Kolb, Lisa Eidenschink Brodersen, Chad A. Hudson, Timothy P. Singleton, Todd M. Cooper, Soheil Meshinchi, Fan Chi Hsu, Fangyan Dai, Keely Ghiradelli, Amanda R. Leonti, and Todd A. Alonzo
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Oncology ,medicine.medical_specialty ,Chemotherapy ,Bortezomib ,business.industry ,medicine.medical_treatment ,Standard treatment ,Immunology ,Hazard ratio ,Cell Biology ,Hematology ,Hematopoietic stem cell transplantation ,medicine.disease ,Biochemistry ,Leukemia ,Internal medicine ,Statistical significance ,medicine ,business ,Multiple myeloma ,medicine.drug - Abstract
Introduction: CD74 is a type II transmembrane protein expressed on antigen-presenting cells and an MHC class II chaperone. It has been associated with tumor progression and metastasis in solid tumors, and its expression has been suggested to serve as a prognostic factor in many cancers, with higher relative expression associated with oncogenesis. As the expression of CD74 has been associated with response to bortezomib in multiple myeloma, we inquired whether such correlation might be seen in pediatric AML. We prospectively evaluated CD74 expression by difference from normal (ΔN) flow cytometry and correlated expression with clinical characteristics and outcome as part of Children's Oncology Group protocol AAML1031 that randomized patients younger than 30 years of age with de novo AML to standard treatment with (Arm B) or without (Arm A) bortezomib. The addition of bortezomib to standard chemotherapy increased toxicity but did not improve survival. Given the association of CD74 with B-lymphoid neoplasms and bortezomib's known efficacy in B-cell neoplasms and multiple myeloma, we hypothesized that within Arm B, the patients with CD74 expression would have a more favorable outcome. Methods: In total, 1,139 newly diagnosed pediatric patients with de novo AML were randomized to standard chemotherapy (n=561, Arm A) or standard chemotherapy with bortezomib (n=578, Arm B). All patients received the identical chemotherapy backbone with either four intensive chemotherapy courses or three courses followed by allogeneic hematopoietic stem cell transplantation for high-risk patients. To qualify for this correlative study, 991 patients satisfied 2 criteria: (1) submitting a bone marrow aspirate for ΔN at diagnosis and (2) providing consent for correlative biology studies. All diagnostic specimens were centrally and prospectively evaluated for the expression of CD74 by ΔN. AML was considered to be CD74-positive if the MFI was more than two times above background autofluorescence and more than 40% of the leukemia was above background autofluorescence. Results: Among 991 patients, 263 were CD74-positive (26.5%) by ΔN, with similar prevalence in Arm A (27.9%) and Arm B (25.2%). Correlation of CD74 expression with clinical characteristics showed that those with CD74 expression had higher median age (p For patients in Arm A (no bortezomib), the differences in OS (66.1% vs 61.0%, p=0.138) and EFS (48.9% vs 41.7% p=0.088) were not significant between those that were CD74-positive and those that were CD74-negative (Figure 1). However, patients in Arm B receiving bortezomib that were CD74-positive showed a significant improvement in OS (75.3% vs 62.5%, p=0.006) and EFS (53.6% vs 44.3%, p=0.028) compared to those who were CD74-negative (Figure 1). Comparison of the outcomes for CD74-positive patients with and without bortezomib exposure showed a difference in OS of 66.1% vs. 75.3% for those in Arm A vs. Arm B but did not reach significance (p=0.155). Multivariable analysis for OS yielded a hazard ratio of 0.67 (95% CI: 0.44 - 1.02) and p=0.061, approaching, but not reaching, statistical significance. Conclusions: These data demonstrate that CD74 expression is associated with more favorable disease characteristics and survival. Patients receiving bortezomib that were CD74-positive showed a superior response to therapy compared to patients who did not express CD74, by both OS and EFS, suggesting that CD74-positive childhood AML patients stand to benefit from bortezomib therapy. Bortezomib may induce a mechanistic response in CD74-positive AMLs similar to that in bortezomib-treated B-cell neoplasms and/or multiple myeloma, where bortezomib has proven to be beneficial. Disclosures Cooper: Celgene: Other: Spouse was an employee of Celgene (through August 2019). Pollard:Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.
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- 2020
49. CPX-351 Exposure-Response Analyses for Efficacy and Safety in Pediatric Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML)
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Stefan Faderl, Todd M. Cooper, Qi Wang, Todd A. Alonzo, Nathalie H. Gosselin, E. Anders Kolb, Michael J. Absalon, and J.F. Marier
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Oncology ,education.field_of_study ,medicine.medical_specialty ,business.industry ,Daunorubicin ,Immunology ,Population ,Cmax ,Area under the curve ,Cell Biology ,Hematology ,Odds ratio ,medicine.disease ,Biochemistry ,Refractory ,Internal medicine ,medicine ,Cytarabine ,education ,business ,Progressive disease ,medicine.drug - Abstract
CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of daunorubicin and cytarabine at a synergistic 1:5 molar ratio, is approved by the US FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Separate studies at Cincinnati Children's Hospital (CCH) and by the Children's Oncology Group (COG) evaluated the efficacy and safety of CPX-351 in pediatric patients (pts). CPX-351 was administered by IV infusion on Days 1, 3, and 5 for the first induction only. The CCH study included 2 dose levels, 100 and 134 units/m2, with 100 units/m2 identified as the recommended phase 2 dose (RP2D); pts with multiple relapsed or refractory AML were included in the exposure-response (E-R) analyses. The COG study established an RP2D of 135 units/m2; the majority of pts in the E-R analyses had first-relapsed AML. E-R analyses were conducted to evaluate the relationship between plasma exposures to CPX-351 and efficacy or safety endpoints. Plasma PK parameters of cytarabine and daunorubicin, including area under the curve up to 48 h post dose on Day 5 Cycle 1 (AUC48), maximum concentration on Day 5 Cycle 1 (Cmax), and concentration at 48 h post dose on Day 5 Cycle 1 (C48), were derived from a previously developed population PK model for pediatric and adult pts. The efficacy endpoints were complete remission (CR), CR+CRp (partial platelet count recovery), or CR+CRp+CRi (incomplete hematologic recovery). Age, sex, bone marrow blast, white blood cell, and platelet counts at baseline were included in the covariate analysis. The safety endpoints included grade ≥3 TEAEs. From the studies, both pediatric and adult pts were included in the E-R analyses for efficacy. Overall, the E-R efficacy population included 43 (53%) pediatric pts (1-17 y) and 38 (47%) adults (≥18 y); the majority were male (57%) and of white origin (63%). Of the 81 pts included in the analysis, 28 (31%), 16 (25%), and 1 (2%) pt achieved CR, CRp, and CRi, respectively; 39 (48%) pts had progressive disease or no response. Various models were used to describe the relationship between probability of response (CR, CRi, or CRp) and exposure parameters (AUC48, Cmax, and C48). C48 of cytarabine was associated with the best statistical goodness-of-fit in the logistic regression model. The effect of cytarabine C48 on the probability of response was statistically significant (P = 0.0144; odds ratio = 1.057). These results suggest the odds of response increased by ~6% for each 1-unit increment of cytarabine C48 (ie, 1 μg/mL). The estimated probability of response was separated into exposure quartiles: 33% for Q1, 49% for Q2, 59% for Q3, and 83% for Q4. The cytarabine C48 was mainly observed in Q1 and Q2 for the 100 units/m2 dose and in Q3 and Q4 for the 134-135 units/m2 doses. In a covariate analysis, none of the covariates tested explained the variability in response. AUC48 of cytarabine and daunorubicin and C48 of daunorubicin were also significantly correlated with probability of response to CPX-351. This was expected, as the PK of daunorubicin and cytarabine are highly correlated when administered as CPX-351. Logistic models were also developed to describe the relationship between probability of response and exposure parameters. Similarly, cytarabine C48 was a significant predictor of the probability of CR or CRi. However, no logistic models were found to describe the relationship of probability of CR+CRp (or CR only) and exposure parameters. Although pt populations of the CCH and COG studies were different, a similar correlation was shown for exposures and efficacy in the CCH study, where higher exposures were associated with higher response rates. Grade ≥3 TEAEs observed in pediatric pts were separated into exposure quartiles for Cmax of cytarabine or daunorubicin. The probabilities of grade ≥3 TEAEs for quartiles of cytarabine Cmax were 77% for Q1, 85% for Q2, 85% for Q3, and 71% for Q4. Similar results were observed with daunorubicin. In these post hoc E-R analyses, higher CPX-351 doses were associated with higher plasma exposures, which led to a higher probability of response (CR+CRp+CRi) in pediatric pts with relapsed or refractory AML. There was no correlation of plasma exposures to grade ≥3 TEAEs. These analyses should be interpreted with caution due to the small sample size; however, they support use of the higher dose of 135 units/m2. Disclosures Wang: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Absalon:Jazz Pharmaceuticals: Research Funding. Faderl:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019). OffLabel Disclosure: Yes, in these studies, CPX-351 was evaluated in pediatric AML
- Published
- 2020
50. Early T-Cell Precursor Acute Lymphoblastic Leukemia in an Infant With anNRASQ61R Mutation and Clinical Features of Juvenile Myelomonocytic Leukemia
- Author
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Todd M. Cooper, Himalee S. Sabnis, Silvia T. Bunting, John Dallas Scarborough, Sunil S. Raikar, Frank G. Keller, Brent L. Wood, David Wu, and John Bergsagel
- Subjects
0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,T cell ,medicine.medical_treatment ,Population ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Monocytosis ,hemic and lymphatic diseases ,medicine ,Missense mutation ,education ,Mutation ,education.field_of_study ,Chemotherapy ,Juvenile myelomonocytic leukemia ,business.industry ,Hematology ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Immunology ,business - Abstract
Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a subtype of T-acute lymphoblastic leukemia (T-ALL) arising from a primitive precursor. We present a unique case of an infant with ETP-ALL with a missense NRAS mutation in codon 61 (c.182A>G, p.Q61R). The patient also had a minor population of non-ETP T-ALL blasts and clinical features typically associated with juvenile myelomonocytic leukemia (JMML), namely, absolute monocytosis, splenomegaly, and elevated hemoglobin F. The treatment was initiated with chemotherapy, followed by cord blood transplantation. The patient achieved remission, but unfortunately died from transplant-related complications. This case highlights an NRAS mutation in ETP-ALL with JMML-like phenotype.
- Published
- 2016
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