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BACKGROUND: Patients with FMS like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML) have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (HCT). METHODS: Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were used to evaluate 511 adult patients with de novo AML who underwent HCT during 2008 through 2011 to determine whether FLT3 mutations had an impact on HCT outcomes. RESULTS: In total, 158 patients (31%) had FLT3 mutations. Univariate and multivariate analyses revealed an increased risk of relapse at 3 years in the FLT3 mutated group compared with the wild-type (WT) group (38% [95% confidence interval (CI), 30%-45%] vs 28% [95% CI, 24%-33%]; P = .04; relative risk, 1.60 [95% CI, 1.15-2.22]; P = .0048). However, FLT3 mutation status was not significantly associated with nonrelapse mortality, leukemia-free survival, or overall survival. Although more patients in the FLT3 mutated group died from relapsed primary disease compared with those in the WT group (60% vs 46%), the 3-year overall survival rate was comparable for the 2 groups (mutated group: 49%; 95% CI, 40%-57%; WT group: 55%, 95% CI, 50%-60%; P = .20). CONCLUSIONS: The current data indicate that FLT3 mutation status did not adversely impact overall survival after HCT, and about 50% of patients with this mutation who underwent HCT were long-term survivors. Cancer 2016;122:3005-3014. © 2016 American Cancer Society.

Abstract 294 T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic tumor associated with poor prognosis. Over the last decade, microarray gene expression studies have shown that T-ALL encompasses distinct molecular groups defined by characteristic gene expression signatures and molecular studies have uncovered major mechanisms of T-cell transformation and numerous oncogenes and tumor suppressors involved in the pathogenesis of T-ALL. This molecular and genetic heterogeneity suggests that distinct groups of T-ALL may respond differently to chemotherapy. However, today there are no well established prognostic markers for patient stratification in this disease and all T-ALL patients are treated under the same therapeutic scheme. To overcome this obstacle here we performed a comprehensive analysis of the prognostic significance of molecular groups defined gene microarray expression profiling, copy number alterations identified by array-Comparative Genomic Hybridization, immunophenotypic markers and mutation analysis of all major adult T-ALL oncogenes (NOTCH1, IL7R, FLT3, NRAS) and tumor suppressor genes (FBXW7, PTEN, DNM2, PHF6, BCL11B, WT1, EZH2, ETV6, IDH1, IDH2, DNMT3A, GATA3 and RUNX1) in a clinical series of 53 primary leukemia samples uniformly treated according to the Eastern Cooperative Oncology Group (ECOG) E2993 protocol. Unsupervised analysis of gene expression oligonucleotide microarrays in this series revealed the presence of 2 stable gene expression clusters corresponding to early immature (n = 28) and cortical/mature (n = 25) adult T-ALLs respectively. Early immature T-ALLs show gene expression signatures related to hematopoietic stem cells and myeloid progenitors and are associated with poor prognosis and reduced overall survival compared with cortical/mature adult T-ALLs (P = 0.011). Immunophenotypic analysis showed that CD13 expression was strongly associated with poor survival in our patient series (P=0.002), whereas other early immature or myeloid antigens including CD34 and CD33 showed no clinical impact. Array comparative genomic hybridization (aCGH) analysis in this series identified absence of biallelic deletion of TCRγ, a cytogenetic feature associated with early induction failure and inferior overall survival rates in pediatric T-ALL (Gutierrez et al., JCO, 2010), in 27 out of 53 (51%) adult T-ALL samples analyzed. Notably, 22 of 27 T-ALLs with absence of biallelic deletion of TCRγ were found in the early immature adult T-ALL group, and as in pediatric T-ALL, this molecular marker was associated with inferior overall survival (P = 0.022). In addition, heterozygous deletions of the short arm of chromosome 17 encompassing the TP53 tumor suppressor gene predicted for worse clinical outcome (P = 0.0005); while, homozygous deletions of the CDKN2A/CDKN2B locus on the short arm of chromosome 9 was associated with favorable prognosis (P = 0.012). Most notably, the favorable prognostic effect of homozygous CDKN2A/CDKN2B deletions in our series was restricted to the good prognostic subtype of leukemia samples with a mature/cortical gene expression profile. Finally, comprehensive mutation analysis of adult T-ALL oncogenes and tumor suppressors demonstrated a favorable prognosis for patients with activation of NOTCH1 signaling as result of mutations in NOTCH1 and/or FBXW7 (P = 0.021) and for those harboring heterozygous inactivating mutations or deletions in the BCL11B tumor suppressor gene (P = 0.041). In contrast, somatic mutations in genes targeting the epigenetic regulators DNMT3A (P = 0.003) and IDH1/2 (P = 0.011) were associated with adverse prognosis. Multivariate analyses highlighted the association of NOTCH1 and/or FBXW7 mutations with favorable outcome and that of TP53 deletions and DNMT3A mutations with poor prognosis in adult T-ALL. Importantly, homozygous CDKN2A/CDKN2B deletions and CD13 expression may serve as prognostic markers to further stratify low-risk cortical/mature adult T-ALL leukemias, whereas DNMT3A mutations might be useful for risk stratification within high-risk early immature adult T-ALLs. Overall, our comprehensive analysis of molecular prognostic markers identify for the first time a subset of adult T-ALLs with very poor response to intensified chemotherapy, highlighting the need to introduce alternative therapies aiming to improve the therapeutic outcome in this group. Disclosures: No relevant conflicts of interest to declare.

Adults with relapsed/refractory acute lymphoblastic leukemia have an unfavourable prognosis, which is influenced by disease and patient characteristics. To further evaluate these characteristics, a retrospective analysis of 1,706 adult patients with Ph-negative relapsed/refractory B-precursor acute lymphoblastic leukemia diagnosed between 1990-2013 was conducted using data reflecting the standard of care from 11 study groups and large centers in Europe and the United States. Outcomes included complete remission, overall survival, and realization of stem cell transplantation after salvage treatment. The overall complete remission rate after first salvage was 40%, ranging from 35%-41% across disease status categories (primary refractory, relapsed with or without prior transplant), and was lower after second (21%) and third or greater (11%) salvage. The overall complete remission rate was higher for patients diagnosed from 2005 onward (45%, 95% CI: 39%-50%). One- and three-year survival rates after first, second, and third or greater salvage were 26% and 11%, 18% and 6%, and 15% and 4%, respectively, and rates were 2%-5% higher among patients diagnosed from 2005. Prognostic factors included younger age, longer duration of first remission, and lower white blood cell counts at primary diagnosis. This large dataset can provide detailed reference outcomes for patients with relapsed/refractory Ph-negative B-precursor acute lymphoblastic leukemia. clinicaltrials.gov identifier: 02003612.