Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 29 Issue 22 Pg. 4613-4626 (Nov 14 2023) ISSN: 1557-3265 [Electronic] United States
• PMID: 37725576 (Publication Type: Journal Article)
• Copyright: ©2023 American Association for Cancer Research.

Chemical References

• Receptor, Platelet-Derived Growth Factor alpha
• Receptor Protein-Tyrosine Kinases

Topics

• Humans
• Child
• Animals
• Mice
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics)
• Receptor, Platelet-Derived Growth Factor alpha (genetics)
• Mutation
• Receptor Protein-Tyrosine Kinases (genetics)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• T-Lymphocytes