Cytoplasmic localization of wild-type survivin is associated with constitutive activation of the PI3K/Akt signaling pathway and represents a favorable prognostic factor in patients with acute myeloid leukemia

Abstract The Wilms’ tumour 1 (WT1) gene is highly expressed in various types of leukemia, suggesting a role both as a target for immunotherapy and a means for monitoring minimal residual disease. More recently WT1 has been recognised as an important mutational target in normal karyotype (NK) acute myeloid leukemia (AML), with clustering of mutations to exons 7 and 9. In this study, we set out to determine the clinical relevance of these mutations. Diagnostic DNA samples were obtained from peripheral blood or bone marrow of 470 young adult AML patients entered into the UK Medical Research Council AML 10 and 12 trials. Mutation analysis was performed using standard PCR-based direct sequencing and/or high-resolution capillary electrophoresis of exons 7 and 9. Overall, 51 mutations were observed in 47 cases (10%). Of these, 42 cases had 46 frameshift mutations arising from insertions (n=41) or deletions (n=5) of between 1 and 28 bps that would result in disruption of the C-terminal DNA binding domain of the protein. Median mutant level was 45% (range 8–86%). The remaining 5 cases were non-synonymous amino acid substitutions in exon 9, D396N (n=3) which is implicated in Denys-Drash syndrome, and 1 each of H397Y and H397Q that are of unknown functional significance. There was a borderline inverse relationship between the presence of WT1 mutations and NPM1 exon 12 mutations (p=.05), and an increased proportion of FLT3-ITDs in WT1 mutant cases (p=.08). In order to determine the clinical relevance of WT1 mutations we compared patient characteristics between WT1 mutated and WT1 wild-type cases. There was no difference between the 2 groups in age, gender, presenting WBC, or type of AML (de novo/secondary). Patients with WT1 mutations had an inferior response to therapy compared to WT1 wild-type cases (complete remission [CR] 79% Vs 90% respectively, odds ratio [OR] 3.02, 95% confidence intervals [CI] 1.17–7.82, p=.02) which was due to a higher rate of resistant disease (RD) (15% Vs 4%, OR 9.33, CI 2.38–36.6, p=.001). In univariate analysis mutated cases also had a significantly reduced disease free survival (DFS), 22% Vs 44% at 5 years (OR 2.16, CI 1.32–3.55, p=.005) and overall survival (OS), 26% Vs 47%, OR 1.91, CI 1.23–2.95, p=.007). In multivariate analysis considering age, gender, type of leukemia, WBC, FLT3-ITD and NPM1 mutant status, a WT1 mutation remained an independent adverse prognostic factor for both response to therapy (CR: OR 3.19, CI 1.25–8.13, p=.01; RD: OR 4.93, CI 1.58–15.37, p=.006) and survival (DFS: OR 1.60, CI 1.07–2.38, p=.02; OS: OR 1.52, CI 1.05–2.18, p=.03). These results indicate that WT1 mutations are an additional prognostic marker in NK AML and may be suitable for targeted therapy.

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Lack of CD34 Expression in Acute Myeloid Leukemia (AML) Is a Favorable Prognostic Factor in Patients Treated with Stem Cell Transplant Irrespective of the Cytogenetic Risk

Blood ◽

10.1182/blood.v118.21.1894.1894 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1894-1894

Author(s):

Fahed Almhareb ◽

Claudia Ulrike Walter ◽

Randa Nounou ◽

Salem Khalil ◽

Nasir Bakshi ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Prognostic Factors ◽

Prognostic Factor ◽

Myeloid Leukemia ◽

Mutation Status ◽

Allogeneic Hsct ◽

Predicting Outcome ◽

Favorable Prognostic Factor ◽

Cd34 Expression ◽

Acute Myeloid

Abstract Abstract 1894 Background: Most of the studies of prognostic factors in acute myeloid leukemia (AML) are focused on predicting outcome after standard chemotherapy treatment. The studies that looked at the importance of these prognostic variables in predicting outcome after hematopoietic stem cell transplantation (HSCT) are very limited. Considering post-HSCT prognostic factors in stratifying AML patients may add a new level of confidence in any risk stratification of these patients. Toward this goal, we investigated the clinical relevance of CD34 expression in the primary leukemic cells on the outcome of allogeneic HSCT. Methods: Data collected from immunophenotyping of 110 patients with AML who were treated with HSCT was reviewed and the expression of CD34 on the blast population as determined by flow cytometry was correlated with clinical behavior and outcome. All the patients were treated with allogeneic HSCT. The median age of these patients was 24 (range: 14–57) and included 88 patients in the intermediate cytogenetic group and 22 in the adverse cytogenetic group. Of the 110 patients 71, (64.5%) were treated with HSCT in first remission (CR1). Results: Twenty-eight (25%) of all AML patients studied did not express CD34 on the surface of the blasts at diagnosis. Patients with CD34 negative blasts had significantly longer overall survival (OS) (P=0.003) as well as longer event free survival (EFS) (P=0.01) when all patients were considered. In the subgroup of patients who received HSCT in CR1, OS and EFS were significantly longer (P=0.017 and P=0.027, respectively) in the CD34-negative patients (N=20). Furthermore, if we consider only patients in the intermediate cytogenetic group at diagnosis, patients with CD34-negative blasts had significantly longer OS (P=0.007) and EFS (P=0.026). Even in patients with adverse cytogenetic abnormalities, OS and EFS were also significantly longer in the CD34-negative patients (P=0.01 for both). This was true when all patients were considered. The same was true when only patients transplanted in CR1 (P=0.05 for EFS in intermediate cytogenetics and P=0.05 for EFS in patients with adverse cytogenetic) were evaluated. Multivariate analysis including CD34 expression and FLT3 mutation status was carried out on a subset of patients (N=63) and showed CD34 expression was an independent prognostic factor for survival and EFS, while FLT3 mutation status became no longer a predictor. Conclusion: Our data suggests that CD34 expression on the blast cells at the time of AML diagnosis may have an adverse prognostic impact even after allogeneic HSCT. Lack of CD34 expression is a powerful independent favorable prognostic factor for AML patients if these patients are treated with HSCT after induction chemotherapy, irrespective if they were in CR1 or in CR2, and irrespective of their cytogenetic risk at diagnosis. Disclosures: No relevant conflicts of interest to declare.

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