Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma.
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Paolino Jonathan, Dimitrov Boris, Apsel Winger Beth, Sandoval-Perez Angelica, Rangarajan Amith Vikram, Ocasio-Martinez Nicole, Tsai Harrison K, Li Yuting, Robichaud Amanda L, Khalid Delan, Hatton Charlie, Gillani Riaz, Polonen Petri, Dilig Anthony, Gotti Giacomo, Kavanagh Julia, Adhav Asmani A, Gow Sean, Tsai Jonathan, Li Yen Der, Ebert Benjamin L, Van Allen Eliezer M, Bledsoe Jacob, Kim Annette S, Tasian Sarah K, Cooper Stacy L, Cooper Todd M, Hijiya Nobuko, Sulis Maria Luisa, Shukla Neerav N, Magee Jeffrey A, Mullighan Charles G, Burke Michael J, Luskin Marlise R, Mar Brenton G, Jacobson Matthew P, Harris Marian H, Stegmaier Kimberly, Place Andrew E, Pikman Yana
Аннотация
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.