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Acute Lymphoblastic Leukemia
Combinatorial efficacy of entospletinib and chemotherapy in patient-derived xenograft models of infant acute lymphoblastic leukemia
Ferrata Storti Foundation
Haematologica 2021 Volume 106(4):1067-1078
Joseph P. Loftus,1* Anella Yahiaoui,2* Patrick A Brown,3 Lisa M. Niswander,1 Asen Bagashev,1 Min Wang,2 Allyson Shauf,2 Stacey Tannheimer2
and Sarah K. Tasian1,4
1Division of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA; 2Gilead Sciences, Foster City, CA; 3Department of Pediatrics, Division of Pediatric Hematology/Oncology, Johns Hopkins University and Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD and 4Department of Pediatrics and Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
*JPL and AY contributed equally as co-first authors.
ABSTRACT
Survival of infants with KMT2A-rearranged acute lymphoblastic leukemia (ALL) remains dismal despite intensive chemotherapy. We observed constitutive phosphorylation of spleen tyrosine kinase (SYK) and associated signaling proteins in infant ALL patient-derived xenograft (PDX) model specimens and hypothesized that the SYK inhibitor entosple- tinib would inhibit signaling and cell growth in vitro and leukemia prolifera- tion in vivo. We further predicted that combined entospletinib and chemotherapy could augment anti-leukemia effects. Basal kinase signaling activation and HOXA9/MEIS1 expression differed among KMT2A- rearranged (KMT2A-AFF1 [n=4], KMT2A-MLLT3 [n=1], KMT2A-MLLT1 [n=4]) and non-KMT2A-rearranged [n=3] ALL specimens and stratified by genetic subgroup. Incubation of KMT2A-rearranged ALL cells in vitro with entospletinib inhibited methylcellulose colony formation and SYK pathway signaling in a dose-dependent manner. In vivo inhibition of leukemia prolif- eration with entospletinib monotherapy was observed in RAS-wild-type KMT2A-AFF1, KMT2A-MLLT3, and KMT2A-MLLT1 ALL PDX models with enhanced activity in combination with vincristine chemotherapy in several models. Surprisingly, entospletinib did not decrease leukemia burden in two KMT2A-AFF1 PDX models with NRAS or KRAS mutations, suggesting potential RAS-mediated resistance to SYK inhibition. As hypothesized, superior inhibition of ALL proliferation was observed in KMT2A-AFF1 PDX models treated with entospletinib and the MEK inhibitor selumetinib versus vehicle or inhibitor monotherapies (P<0.05). In summary, constitutive acti- vation of SYK and associated signaling occurs in KMT2A-rearranged ALL with in vitro and in vivo sensitivity to entospletinib. Combination therapy with vincristine or selumetinib further enhanced treatment effects of SYK inhibition. Clinical study of entospletinib and chemotherapy or other kinase inhibitors in patients with KMT2A-rearranged leukemias may be warranted.
Introduction
B-cell acute lymphoblastic leukemia (B-ALL) is the most common childhood can- cer and is characterized by recurrent somatic cytogenetic and molecular abnormal- ities. While modern risk-adapted chemotherapy regimens for children and adoles- cents/young adults (AYA) have achieved overall survival rates exceeding 90%,1,2 optimal salvage therapy for the 10-15% of children and >60% of adults with B-ALL who relapse remains a major unmet medical need.3-5
Patients with B-ALL harboring rearrangements in lysine-specific methyltrans-
Correspondence:
SARAH K. TASIAN
tasians@chop.edu
Received: October 28, 2019. Accepted: May 8, 2020. Pre-published: May 15, 2020.
https://doi.org/10.3324/haematol.2019.241729
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