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CD117 Expression Is Associated with Cytogenetic and Molecular Profiles and Outcome in Pediatric Acute Myeloid Leukemia
- Source :
- Blood. 134:2699-2699
- Publication Year :
- 2019
- Publisher :
- American Society of Hematology, 2019.
-
Abstract
- Cell surface antigen expression in AML is becoming focus of investigation as it relates to prognostic impact as well as potential therapeutic implications. The CD117 (c-KIT) receptor tyrosine kinase is expressed on the cell surface of hematopoietic stem cells and its signaling is important in cell survival, proliferation and differentiation. CD117 is expressed in a majority of AML cases. In addition, mutations in c-KIT have been identified in a subset of patients, specifically those with CBF AML (inv(16)/t(16;16) and t(8;21)). As there is increasing interest in using tyrosine kinase inhibitors with anti-KIT activity based on surface CD117 expression as treatment in AML, we sought to evaluate the association of CD117 expression with biologic and clinical features in pediatric and young adult (YA) AML. A total of 1803 pediatric and YA patients (ages 0.01-29.2 years) treated on the Children's Oncology Group (COG) phase III trials AAML0531 (n=762) and AAML1031 (n=1041) with complete cyto/molecular and outcome data available were included in the analysis. The primary aim of AAML0531 evaluated the addition of gemtuzumab ozogamicin to a 5-course MRC-based backbone, while AAML1031 evaluated the addition of bortezomib to a similar 4-course backbone. Outcomes between the 2 primary randomized arms on each trial were similar and thus were included together for each trial. Multidimensional flow cytometry was used to determine the CD117 mean fluorescence intensity (MFI) of myeloid progenitor cells as defined by CD45 low and side scatter using a CD117-PE antibody with stable intensity detection since 2002. Patients were divided into quartiles based on CD117 expression and clinical characteristics and outcome were evaluated across the quartiles. CD117 MFI distribution was similar across both trials (Fig 1A). Analysis of CD117 expression with cytogenetics demonstrated that t(8;21) was significantly associated with higher CD117 (p Outcome analysis demonstrated that CD117 surface expression was not associated with CR, with similar CR rates across the quartiles (p=0.726). In a univariate analysis, overall survival (OS) was associated with higher CD117 expression (p We show here that CD117 expression was higher in patients with favorable risk CBF AML and inversely associated with KMT2A rearrangements, which are generally considered to be neutral or unfavorable depending on the specific translocation partner. Higher CD117 expression was associated with improved outcomes, which may in part be explained by the association with CBF and inverse association with KMT2A. Although patients with higher CD117 MFI generally have favorable risk genomic alterations, the strategy of c-KIT inhibition warrants further investigation in AML given the potential for facilitating de-escalation of conventional therapeutics with significant toxicity in future clinical trials if found to be safe and effective. Disclosures Eidenschink Brodersen: Hematologics, Inc: Employment. Pardo:Hematologics, Inc: Employment. Dai:Hematologics, Inc: Employment. Loken:Hematologics, Inc: Employment, Equity Ownership.
- Subjects :
- Oncology
Univariate analysis
medicine.medical_specialty
biology
Bortezomib
business.industry
CD117
Immunology
Pediatric acute myeloid leukemia
Cytogenetics
Signs and symptoms
Chromosomal translocation
Cell Biology
Hematology
Biochemistry
digestive system diseases
CCAAT/enhancer binding protein alpha
Internal medicine
medicine
biology.protein
business
medicine.drug
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 134
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi...........2f8aab265c149e1c5fb17fbcbe21f318