Session: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis III
Hematology Disease Topics & Pathways:
AML, Diseases, Clinically relevant, Myeloid Malignancies
In an international collaborative effort, children and young adults (n=1786; age < 1 month - 29 years, non-APL or Down syndrome) treated on the CCG/COG trials (2961, AAML03P1, AAML0531; n=1472) as well as those treated on the DCOG/BFM/MRC trials (ANLL87, ANLL97, BFM98, BFM04, MRC12, MRC15; n=314) were included in this study. All patients were tested for FLT3/ITD, NPM1, CEBPA, WT1, and NUP98-NSD1 mutations. COG patients underwent either targeted exome or clinical sequencing, while patients in DCOG/BFM/MRC analysis underwent targeted clinical sequencing of hotspot regions in 9 genes. As expected given the heterogeneity of AML, we detected a variety of co-occurring mutations among the ITD+ patients (n=255), ranging from 1-13 (median 2) additional mutations. Overall, we identified 82 different genes with alterations co-occurring with FLT3/ITD mutations. The most prevalent co-occurring mutations were WT1 (26%), NPM1 (21%), NRAS (17%), and CEBPA (6%; Fig 1A). The most common co-occurring fusions were NUP98-NSD1 (18%) and DEK-NUP214 in (6%; Fig 1A). A subset of patients (n=13) harbored FLT3/ITD as well as WT1 and NUP98-NSD1 alternations (ITD+/WT1+/NUP98-NSD1+), referred to as triple positive patients.
We evaluated the prognostic impact of the most common co-occurring mutational profiles as seen in ITD+ children treated on the above cooperative group trials. Clinical outcome of those with FLT3/ITD and favorable (NPM1) or adverse (WT1 or NUP98/NSD1) prognostic factors was contrasted to patients without those risk defining lesions. These presence of the 3 co-occurring mutations added significant prognostic impact when comparing to patients without the 3 mutations (ITD+/other; p<0.001; Fig 1B). Patients with ITD+/other had an event free survival (EFS) of 31% compared to that of 48% in FLT3/ITD negative patients (Fig 1B). Patients with dual ITD/NPM1 mutations (ITD+/NPM1+) had the most favorable outcome with an EFS of 62%, while ITD+ patients harboring either a NUP98-NSD1 and/or WT1 mutation had the most inferior outcome with an EFS of 17%. We sought to further interrogate the effect of the co-occurring mutations in a more homogenously treated cohort of patients treated on COG AAML0531. The ITD+/NPM1+ patients experienced an EFS of 54% which was similar to ITD negative patients. In contrast, ITD+ patients harboring NUP98-NSD1 and/or WT1 experienced an EFS of 24%. Again, the addition of the 3 aberrations to FLT3/ITD demonstrated significant prognostic impact (p<0.001). The triple positive patients experienced an overall survival of <10%. Given the demonstrated significance of AR in risk determination in FLT3/ITD patients, we evaluated the significance of WT1 and NUP98/NSD1 variants in ITD+ patients with a low AR (AR<0.4; n=35). Patients with low AR and WT1 or NUP98/NSD1 variants had a similar dismal outcome as those with higher AR.
Using comprehensive genomic sequencing and outcome evaluation in a large international cooperative study, we found that FLT3/ITD mutations co-occur with a number of other mutations. Importantly, we found that the 3 variants NPM1, WT1, and NUP98-NSD1 can further risk stratify ITD+ patients, regardless of AR. Patients with ITD+/NPM1+ disease experience more favorable outcomes, while ITD+/WT1+ or NUP98-NSD1+ mutant patients do poorly, and triple positive patients have very poor outcomes. This suggests that ITD mutations do not exclusively serve as driving events, rather that co-occurring mutations may impact leukemogenesis and responses to therapy, thus identifying a cohort of patients requiring novel therapeutic approaches to meaningfully improve outcomes.
Disclosures: Gibson: Galen: Research Funding; Pfizer: Research Funding.
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