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 sig-nificance, 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. System-atic integration of precision medicine efforts can inform therapy. We report the feasibility of identify-ing targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1424-1439 |
| Number of pages | 16 |
| Journal | Cancer Discovery |
| Volume | 11 |
| Issue number | 6 |
| DOIs | |
| State | Published - 2021 |
All Science Journal Classification (ASJC) codes
- Oncology
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In: Cancer Discovery, Vol. 11, No. 6, 2021, p. 1424-1439.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Matched targeted therapy for pediatric patients with relapsed, refractory, or high-risk leukemias
T2 - A report from the leap consortium
AU - Pikman, Yana
AU - Tasian, Sarah K.
AU - Sulis, Maria Luisa
AU - Stevenson, Kristen
AU - Blonquist, Traci M.
AU - Apsel Winger, Beth
AU - Cooper, Todd M.
AU - Pauly, Melinda
AU - Maloney, Kelly W.
AU - Burke, Michael J.
AU - Brown, Patrick A.
AU - Gossai, Nathan
AU - McNeer, Jennifer L.
AU - Shukla, Neerav N.
AU - Cole, Peter D.
AU - Kahn, Justine M.
AU - Chen, Jing
AU - Barth, Matthew J.
AU - Magee, Jeffrey A.
AU - Gennarini, Lisa
AU - Adhav, Asmani A.
AU - Clinton, Catherine M.
AU - Ocasio-Martinez, Nicole
AU - Gotti, Giacomo
AU - Li, Yuting
AU - Lin, Shan
AU - Imamovic, Alma
AU - Tognon, Cristina E.
AU - Patel, Tasleema
AU - Faust, Haley L.
AU - Contreras, Cristina F.
AU - Cremer, Anjali
AU - Cortopassi, Wilian A.
AU - Garrido Ruiz, Diego
AU - Jacobson, Matthew P.
AU - Dharia, Neekesh V.
AU - Su, Angela
AU - Robichaud, Amanda L.
AU - Saur Conway, Amy
AU - Tarlock, Katherine
AU - Stieglitz, Elliot
AU - Place, Andrew E.
AU - Puissant, Alexandre
AU - Hunger, Stephen P.
AU - Kim, Annette S.
AU - Lindeman, Neal I.
AU - Gore, Lia
AU - Janeway, Katherine A.
AU - Silverman, Lewis B.
AU - Tyner, Jeffrey W.
AU - Harris, Marian H.
AU - Loh, Mignon L.
AU - Stegmaier, Kimberly
N1 - Funding Information: We are grateful to the patients and families who participated in this clinical trial. We are grateful to the late Dr. Frank Kuo for his hard work in establishing and validating the targeted sequencing panel, Rapid Heme Panel, which was used in this study. We are grateful to Dr. Marilyn Li and the Children’s Hospital of Philadelphia Division of Genomic Diagnostics for assistance with clinical genetic testing. This work is supported by a St. Baldrick’s Foundation Consortium grant and Hannah’s Heroes. N.V. Dharia is a Julia’s Legacy of Hope St. Baldrick’s Foundation Fellow. This work was additionally supported by the following grants: Wong Family Fund for Translational Research (Y. Pikman), R35 CA210030 (K. Steg-maier), K08 CA222684 (Y. Pikman), 1K08CA184418 (S.K. Tasian), 1U01CA232486 (S.K. Tasian), Alex’s Lemonade Stand Foundation (L. Gore), P30 CA046934 (LG), 1R01CA214428-01A1 (C.E. Tognon), the Children’s Leukemia Research Foundation (K. Stegmaier), Pan-Mass Challenge Team Crank (K. Stegmaier), and the 4C’s Fund (K. Stegmaier). M.L. Loh is the Benioff Chair of Children’s Health and the Deborah and Arthur Ablin Endowed Chair for Pediatric Molecular Oncology at Benioff Children’s Hospital. Biobanking and PDX modeling studies at the Children’s Hospital of Philadelphia were also supported by the SchylerStrong Foundation in memory of Schyler Anna Herman, the Simutis family childhood leukemia research fund in memory of Andrew David Simutis, and the Viands family childhood leukemia research fund in honor of Nathaniel J Viands (S.K. Tasian). S. Lin is a Fellow of the Leukemia and Lymphoma Society. We are grateful to the Seattle Children’s Tumor Bank for supporting this study. A. Puissant is a recipient of support from the ATIP/ AVENIR French research and the ERC Starting program (758848), and is supported by the St Louis Association for leukemia research, the LNCC, and the Emergence 2017 Program from the city of Paris. Funding Information: We are grateful to the patients and families who participated in this clinical trial. We are grateful to the late Dr. Frank Kuo for his hard work in establishing and validating the targeted sequencing panel, Rapid Heme Panel, which was used in this study. We are grateful to Dr. Marilyn Li and the Children’s Hospital of Philadelphia Division of Genomic Diagnostics for assistance with clinical genetic testing. This work is supported by a St. Baldrick’s Foundation Consortium grant and Hannah’s Heroes. N.V. Dharia is a Julia’s Legacy of Hope St. Baldrick’s Foundation Fellow. This work was additionally supported by the following grants: Wong Family Fund for Translational Research (Y. Pikman), R35 CA210030 (K. Steg-maier), K08 CA222684 (Y. Pikman), 1K08CA184418 (S.K. Tasian), 1U01CA232486 (S.K. Tasian), Alex’s Lemonade Stand Foundation (L. Gore), P30 CA046934 (LG), 1R01CA214428-01A1 (C.E. Tognon), the Children’s Leukemia Research Foundation (K. Stegmaier), Pan-Mass Challenge Team Crank (K. Stegmaier), and the 4C’s Fund (K. Stegmaier). M.L. Loh is the Benioff Chair of Children’s Health and the Deborah and Arthur Ablin Endowed Chair for Pediatric Molecular Oncology at Benioff Children’s Hospital. Biobanking and PDX modeling studies at the Children’s Hospital of Philadelphia were also supported by the SchylerStrong Foundation in memory of Schyler Anna Herman, the Simutis family childhood leukemia research fund in memory of Andrew David Simutis, and the Viands family childhood leukemia research fund in honor of Nathaniel J Viands (S.K. Tasian). S. Lin is a Fellow of the Leukemia and Lymphoma Society. We are grateful to the Seat3tle Children’s Tumor Bank for supporting this study. A. Puissant is a recipient of support from the ATIP/ AVENIR French research and the ERC Starting program (758848), and is supported by the St Louis Association for leukemia research, the LNCC, and the Emergence 2017 Program from the city of Paris. Funding Information: of the study. S.K. Tasian reports grants from Incyte Corporation, Gilead Sciences, and MacroGenics, Inc., and personal fees from Aleta Biotherapeutics outside the submitted work. T.M. Blonquist reports grants from St. Baldrick’s Foundation Consortium during the conduct of the study. T.M. Cooper reports grants from St. Baldricks, during the conduct of the study; other support from Juno/Celgene outside the submitted work. M. Pauly reports grants from St. Baldrick’s Foundation Consortium during the conduct of the study. P.A. Brown reports grants from St. Baldrick’s Foundation during the conduct of the study. J.M. Kahn reports grants from St. Baldrick’s Foundation Consortium Grant and a grant from the NIH (KL2TR001874) during the conduct of the study. J.A. Magee reports grants from St. Baldrick’s Foundation, NHLBI, Alex’s Lemonade Stand Foundation, and Hyundai Hope on Wheels during the conduct of the study. A.A. Adhav reports grants from St. Baldrick’s Foundation Consortium during the conduct of the study. S. Lin reports grants from Leukemia and Lymphoma Society during the conduct of the study. A. Cremer reports grants from German Cancer Aid during the conduct of the study. M.P. Jacobson reports personal fees from Schrodinger, Relay Therapeutics, Circle Pharmaceuticals, and Cedilla Therapeutics outside the submitted work. N.V. Dharia reports grants from St. Baldrick’s Foundation during the conduct of the study; other from Genentech, Inc., a member of the Roche Group outside the submitted work. A. Puissant reports grants from ATIP/AVENIR French Research Program and EHA Research Grant for Non-Clinical Advanced Fellow during the conduct of the study. S.P. Hunger reports other support from Amgen and personal fees from Amgen and Novartis outside the submitted work. A.S. Kim reports personal fees from LabCorp, Inc and grants from Multiple Myeloma Research Foundation outside the submitted work. L. Gore reports grants from St. Baldrick’s Foundation Consortium during the conduct of the study, University of Colorado Cancer Center, NCI, and Alex’s Lemonade Stand outside the submitted work; and serves or has served as an unpaid member of data safety and monitoring committees and scientific advisory boards for Amgen, Celgene, Cura Oncology, Novartis, Pfizer, Roche/Genentech, Syndax on studies related to pediatric oncology products and protocols. L. Gore is a member of the Scientific Advisory Board for OnKure Therapeutics. L.B. Silver-man reports personal fees from Syndax, Servier, and Takeda outside the submitted work. J.W. Tyner reports grants from Aptose, Array, AstraZeneca, Constellation, Genentech, Gilead, Incyte, Janssen, Petra, Seattle Genetics, Syros, Takeda, Tolero, and Agios outside the submitted work. M.H. Harris reports grants from St. Baldrick’s Foundation during the conduct of the study. M.L. Loh reports personal fees from MediSix Therapeutics outside the submitted work. K. Stegmaier reports grants from St. Baldrick’s Foundation– Hannah’s Heroes, NIH R35 CA210030, and Children’s Leukemia Research Foundation, other support from 4C’s Fund and Pan-Mass Challenge Team Crank during the conduct of the study; personal fees from Rigel Therapeutics, KronosBio, and Bristol Myers Squibb, personal fees and other support from Auron Therapeutics, and grants from Novartis outside the submitted work. No other disclosures were reports. Funding Information: Y. Pikman reports grants from St. Baldrick’s Foundation, Wong Family Fund for Translational Research, and NCI during the conduct Publisher Copyright: © 2021 American Association for Cancer Research.
PY - 2021
Y1 - 2021
N2 - 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 sig-nificance, 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. System-atic integration of precision medicine efforts can inform therapy. We report the feasibility of identify-ing targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations.
AB - 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 sig-nificance, 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. System-atic integration of precision medicine efforts can inform therapy. We report the feasibility of identify-ing targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations.
UR - http://www.scopus.com/inward/record.url?scp=85107440371&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85107440371&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-20-0564
DO - 10.1158/2159-8290.CD-20-0564
M3 - Article
C2 - 33563661
AN - SCOPUS:85107440371
SN - 2159-8274
VL - 11
SP - 1424
EP - 1439
JO - Cancer Discovery
JF - Cancer Discovery
IS - 6
ER -