TY - JOUR
T1 - Integration of Genomic Sequencing Drives Therapeutic Targeting of PDGFRA in T-Cell Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma
AU - Paolino, Jonathan
AU - Dimitrov, Boris
AU - Winger, Beth Apsel
AU - Sandoval-Perez, Angelica
AU - Rangarajan, Amith Vikram
AU - Ocasio-Martinez, Nicole
AU - Tsai, Harrison K.
AU - Li, Yuting
AU - Robichaud, Amanda L.
AU - Khalid, Delan
AU - Hatton, Charlie
AU - Gillani, Riaz
AU - Polonen, Petri
AU - Dilig, Anthony
AU - Gotti, Giacomo
AU - Kavanagh, Julia
AU - Adhav, Asmani A.
AU - Gow, Sean
AU - Tsai, Jonathan
AU - Li, Yen Der
AU - Ebert, Benjamin L.
AU - Van Allen, Eliezer M.
AU - Bledsoe, Jacob
AU - Kim, Annette S.
AU - Tasian, Sarah K.
AU - Cooper, Stacy L.
AU - Cooper, Todd M.
AU - Hijiya, Nobuko
AU - Sulis, Maria Luisa
AU - Shukla, Neerav N.
AU - Magee, Jeffrey A.
AU - Mullighan, Charles G.
AU - Burke, Michael J.
AU - Luskin, Marlise R.
AU - Mar, Brenton G.
AU - Jacobson, Matthew P.
AU - Harris, Marian H.
AU - Stegmaier, Kimberly
AU - Place, Andrew E.
AU - Pikman, Yana
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023
Y1 - 2023
N2 - 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-a (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.
AB - 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-a (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.
UR - http://www.scopus.com/inward/record.url?scp=85176974112&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-22-2562
DO - 10.1158/1078-0432.CCR-22-2562
M3 - Article
C2 - 37725576
AN - SCOPUS:85176974112
SN - 1078-0432
VL - 29
SP - 4613
EP - 4626
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -