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Functional Properties of KIT Mutations Are Published OnlineFirst June 10, 2019; DOI: 10.1158/1078-0432.CCR-18-1897 Clinical Trials: Targeted Therapy Clinical Cancer Research Functional Properties of KIT Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia Katherine Tarlock1,2,Todd A. Alonzo3,4,Yi-Cheng Wang4, Robert B.Gerbing4, Rhonda Ries1, Michael R. Loken5, Laura Pardo5, Tiffany Hylkema1, Jason Joaquin1, Leela Sarukkai1, Susana C. Raimondi6, Betsy Hirsch7, Lillian Sung8, Richard Aplenc9, Irwin Bernstein1,2, Alan S. Gamis10, Soheil Meshinchi1,2, and Jessica A. Pollard11,12 Abstract þ Purpose: KIT mutations (KIT ) are common in core bind- (10%) both exons, and 3 (5%) alternative exons. Functional ing factor (CBF) AML and have been associated with varying studies demonstrated that E17, but not E8, mutations result prognostic significance. We sought to define the functional in aberrant KIT phosphorylation and growth. TKI exposure and clinical significance of distinct KIT mutations in CBF significantly affected growth of E17, but not E8, transfected þ pediatric AML. cells. Patients with KIT CBF AML had overall survival similar À Patients and Methods: Following transfection of exon 17 to those with KIT (78% vs. 81%, P ¼ 0.905) but higher þ (E17) and exon 8 (E8) mutations into HEK293 and Ba/F3 relapse rates (RR ¼ 43% vs. 21%; P ¼ 0.005). E17 KIT À cells, KIT phosphorylation, cytokine-independent growth, outcomes were inferior to KIT patients [disease-free survival andresponsetotyrosinekinaseinhibitors(TKI)wereeval- (DFS), 51% vs. 73%, P ¼ 0.027; RR ¼ 21% vs. 46%, P ¼ uated. Clinical outcomes of patients treated on COG 0.007)], although gemtuzumab ozogamicin abrogated this AAML0531 (NCT01407757), a phase III study of gemtuzu- negative prognostic impact. E8 mutations lacked significant mab ozogamicin (GO), were analyzed according to muta- prognostic effect, and GO failed to significantly improve þ À tion status [KIT vs. wild-type KIT (KIT )] and mutation outcome. location (E8 vs. E17). Conclusions: E17 mutations affect prognosis in CBF AML, Results: KIT mutations were detected in 63 of 205 patients as well as response to GO and TKIs; thus, clinical trials using þ (31%); 22 (35%) involved only E8, 32 (51%) only E17, 6 both agents should be considered for KIT patients. (RTK; refs. 5–7). Mutations in KIT serve as potent oncogenic Introduction events in a number of malignancies, namely gastrointestinal The cytogenetic abnormalities t(8;21)(q22;q22) and inv(16) stromal tumors (GIST), melanomas, and mastocytosis (8–10). (p13.1q22)/t(16;16)(p13.1;q22) [hereafter referred to as inv Oncogenic mutations often effect domains critical to RTK activity, (16)], commonly referred to as core binding factor (CBF) such as the juxtamembrane domain (JMD) in exon 11 as seen in acute myeloid leukemia (AML), are observed in 20%–30% GIST, or the tyrosine kinase domain (TKD), and result in ligand- of pediatric AML cases and confer favorable outcome with overall independent activation (7, 11, 12). Among malignancies with þ survival (OS) in the range of 85% (1, 2). However, disease KIT mutations (KIT ), inhibition of aberrantly activated KIT has outcomes with initial therapy are not favorable in all cases (1, 3, 4), been achieved with a subset of tyrosine kinase inhibitors (TKI) thus efforts continue to further risk stratify such patients to with KIT-targeting potential; these medications have proven to be improve clinical response. The KIT proto-oncogene encodes a quite effective and, in some cases, are considered the first-line transmembrane glycoprotein type III receptor tyrosine kinase therapeutic approach for KIT-mutated disease (13, 14). 1Clinical Research Division, Fred Hutchinson Cancer Research Center, Note: Supplementary data for this article are available at Clinical Cancer Seattle, Washington. 2Division of Hematology/Oncology, Seattle Children's Research Online (http://clincancerres.aacrjournals.org/). 3 Hospital, University of Washington, Seattle, Washington. University of S. Meshinchi and J.A. Pollard contributed equally to this article. Southern California Keck School of Medicine, Los Angeles, California. 4Children's Oncology Group, Monrovia, California. 5Hematologics, Inc, Corresponding Author: Katherine Tarlock, Seattle Children's Hospital, 4800 Seattle, Washington. 6St Jude Children's Research Hospital, Memphis, Sand Point Way NE, M/S MB.8.501, PO Box 5371, Seattle, WA 98145-5005. Tennessee. 7University of Minnesota Cancer Center, Minneapolis, Minne- Phone: 206-987-6018; Fax: 206-667-7084; E-mail: sota. 8The Hospital for Sick Children, Toronto, Ontario, Canada. 9The [email protected] 10 Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Children's Clin Cancer Res 2019;XX:XX–XX Mercy Hospitals and Clinics, Kansas City, Missouri. 11Pediatric Oncology, doi: 10.1158/1078-0432.CCR-18-1897 Dana-Farber Cancer Institute, Boston, Massachusetts. 12Harvard Medical School, Boston, Massachusetts. Ó2019 American Association for Cancer Research. www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst June 10, 2019; DOI: 10.1158/1078-0432.CCR-18-1897 Tarlock et al. study if written consent for biology studies was obtained. The trial Translational Relevance was conducted in accordance with the Declaration of Helsinki. Patients with core binding factor (CBF) AML generally have The institutional review boards of all participating institutions a good prognosis, whereas co-occurrence of KIT mutations in approved the clinical protocol and this study was approved by this group has been associated with varying prognostic signif- the COG Myeloid Disease Biology Committee. Details of the icance. This study evaluated the functional properties of KIT treatment protocol have been described previously (1). Patients mutations occurring in the immunoglobulin (IgG) and tyro- with CBF AML enrolled on AAML0531 were randomly assigned to sine kinase domains (TKD) and their prognostic impact. We one of the two treatment arms—arm A (no GO), which was found that mutations in the IgG domain (exon 8) have no conventional chemotherapy only, and arm B (GO), which includ- functional or prognostic impact. In contrast, mutations in the ed a dose of GO (3 mg/m2) on day 6 of induction I and day 7 of TKD (exon 17) resulted in aberrant KIT phosphorylation and intensification II. Given the historically favorable outcome of CBF were associated with inferior clinical outcomes. Importantly, AML (1), patients with CBF enrolled on the study received 5 cycles exon 17 mutations also conferred sensitivity to KIT-directed of chemotherapy and the first-line use of hematopoietic stem cell tyrosine kinase inhibitors (TKI) in vitro. Moreover, when exon transplant was prohibited. 17–positive patients received gemtuzumab ozogamicin in Cytogenetic data were available for 949 of 1,022 (93%) combination with chemotherapy, their negative prognostic patients enrolled on AAML0531. A diagnosis of CBF AML was impact was abrogated. Patients with exon 17–mutated CBF made if either t(8;21)(q22;22) or inv(16)(p13;q22)/t(16;16) AML represent a higher-risk subgroup of CBF AML and may (p13;q22) was detected in diagnostic bone marrow (BM) or benefit from TKI or CD33-targeted therapy. peripheral blood (PB) specimens by either conventional cytoge- netics and/or FISH techniques. Karyotype was confirmed by central review in 100% of cases. KIT mutations are enriched in CBF AML and published adult KIT mutational analysis series report a prevalence of 12%–46% in t(8;21) and 9%–53% in Samples from diagnostic and remission BM or PB underwent þ inv(16) AML (15–19). Within pediatric CBF AML, KIT disease is DNA extraction using the AllPrep Extraction Kit (Qiagen). The seen in approximately 20%–40% of patients (2, 17, 19–22). We integrity of the samples was confirmed by visualization on a 0.8% previously screened CBF AML samples from pediatric patients agarose gel. All samples then underwent targeted exome capture enrolled on serial trials and identified KIT mutations in approx- sequencing, which included the entire coding region of KIT,as imately 20% of patients. Within that heterogeneously treated described previously (31). Samples from relapse specimens þ population, KIT disease lacked prognostic significance overall underwent analysis of mutations of exon 8 and 17 using ampli- and within cytogenetic subtypes (19). Data regarding the prog- fication by genomic PCR as described previously (19). þ nostic significance of KIT CBF AML is conflicting, particularly in children. While some pediatric and dual adult/pediatric studies CD117 expression analysis have failed to show a prognostic impact (2, 20, 21, 23, 24), other Flow cytometry was used to determine the CD117 (KIT) mean pediatric series and meta-analyses dispute such findings, suggest- fluorescence intensity (MFI) of myeloid progenitor cells, as ing prognostic impact may differ in the context of certain KIT defined by CD45 low and side scatter. BM cells were incubated mutations or cytogenetic subgroups (15, 17, 22, 25–27). with CD117-PE (clone 104D2; BD Biosciences), C45-peridinin Given this discrepancy and the uncertainty regarding the func- chlorophyll protein (clone 2D1; BD Biosciences), and CD34- tional significance of KIT mutations, we sought to investigate allophycocyanin (clone HPCA-2; BD Biosciences). Cells were the functional impact of distinct mutation subsets as well as then incubated followed by red cell lysis
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