American Association for Cancer Research
ccr-22-2562_supplementary_table_6_suppst6.pdf (759.94 kB)

Supplementary Table 6 from Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma

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posted on 2023-11-14, 08:40 authored by Jonathan Paolino, Boris Dimitrov, Beth Apsel Winger, Angelica Sandoval-Perez, Amith Vikram Rangarajan, Nicole Ocasio-Martinez, Harrison K. Tsai, Yuting Li, Amanda L. Robichaud, Delan Khalid, Charlie Hatton, Riaz Gillani, Petri Polonen, Anthony Dilig, Giacomo Gotti, Julia Kavanagh, Asmani A. Adhav, Sean Gow, Jonathan Tsai, Yen Der Li, Benjamin L. Ebert, Eliezer M. Van Allen, Jacob Bledsoe, Annette S. Kim, Sarah K. Tasian, Stacy L. Cooper, Todd M. Cooper, Nobuko Hijiya, Maria Luisa Sulis, Neerav N. Shukla, Jeffrey A. Magee, Charles G. Mullighan, Michael J. Burke, Marlise R. Luskin, Brenton G. Mar, Matthew P. Jacobson, Marian H. Harris, Kimberly Stegmaier, Andrew E. Place, Yana Pikman

Results of bone marrow and PDX panel sequencing from patient 146.


St. Baldrick's Foundation (SBF)

National Cancer Institute (NCI)

United States Department of Health and Human Services

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Team Crank

Children's Leukemia Research Foundation

Leukemia and Lymphoma Society (LLS)



Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) or lymphoblastic lymphoma (T-LBL) have limited therapeutic options. Clinical use of genomic profiling provides an opportunity to identify targetable alterations to inform therapy. We describe a cohort of 14 pediatric patients with relapsed or refractory T-ALL enrolled on the Leukemia Precision-based Therapy (LEAP) Consortium trial (NCT02670525) and a patient with T-LBL, discovering alterations in platelet-derived growth factor receptor-α (PDGFRA) in 3 of these patients. We identified a novel mutation in PDGFRA, p.D842N, and used an integrated structural modeling and molecular biology approach to characterize mutations at D842 to guide therapeutic targeting. We conducted a preclinical study of avapritinib in a mouse patient-derived xenograft (PDX) model of FIP1L1-PDGFRA and PDGFRA p.D842N leukemia. Two patients with T-ALL in the LEAP cohort (14%) had targetable genomic alterations affecting PDGFRA, a FIP1-like 1 protein/PDGFRA (FIP1L1-PDGFRA) fusion and a novel mutation in PDGFRA, p.D842N. The D842N mutation resulted in PDGFRA activation and sensitivity to tested PDGFRA inhibitors. In a T-ALL PDX model, avapritinib treatment led to decreased leukemia burden, significantly prolonged survival, and even cured a subset of mice. Avapritinib treatment was well tolerated and yielded clinical benefit in a patient with refractory T-ALL. Refractory T-ALL has not been fully characterized. Alterations in PDGFRA or other targetable kinases may inform therapy for patients with refractory T-ALL who otherwise have limited treatment options. Clinical genomic profiling, in real time, is needed for fully informed therapeutic decision making.

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