scholarly journals Detection of the WT1 transcript by RT-PCR in complete remission has no prognostic relevance in de novo acute myeloid leukemia

Leukemia ◽  
1998 ◽  
Vol 12 (12) ◽  
pp. 1886-1894 ◽  
Author(s):  
A Gaiger ◽  
D Schmid ◽  
G Heinze ◽  
B Linnerth ◽  
H Greinix ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Rt Pcr ◽  
Prognostic Relevance ◽  
Acute Myeloid

The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML

Blood ◽  
2011 ◽  
Vol 117 (7) ◽  
pp. 2137-2145 ◽  
Author(s):  
Sabine Kayser ◽  
Konstanze Döhner ◽  
Jürgen Krauter ◽  
Claus-Henning Köhne ◽  
Heinz A. Horst ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Topoisomerase Ii ◽  
De Novo ◽  
Negative Impact ◽  
Primary Malignancy ◽  
De Novo Aml ◽  
The Impact ◽  
Acute Myeloid

Abstract To study the characteristics and clinical impact of therapy-related acute myeloid leukemia (t-AML). 200 patients (7.0%) had t-AML and 2653 de novo AML (93%). Patients with t-AML were older (P < .0001) and they had lower white blood counts (P = .003) compared with de novo AML patients; t-AML patients had abnormal cytogenetics more frequently, with overrepresentation of 11q23 translocations as well as adverse cytogenetics, including complex and monosomal karyotypes, and with underrepresentation of intermediate-risk karyotypes (P < .0001); t-AML patients had NPM1 mutations (P < .0001) and FLT3 internal tandem duplications (P = .0005) less frequently. Younger age at diagnosis of primary malignancy and treatment with intercalating agents as well as topoisomerase II inhibitors were associated with shorter latency periods to the occurrence of t-AML. In multivariable analyses, t-AML was an adverse prognostic factor for death in complete remission but not relapse in younger intensively treated patients (P < .0001 and P = .39, respectively), relapse but not death in complete remission in older, less intensively treated patients (P = .02 and P = .22, respectively) and overall survival in younger intensively treated patients (P = .01). In more intensively treated younger adults, treatment-related toxicity had a major negative impact on outcome, possibly reflecting cumulative toxicity of cancer treatment.

scholarly journals Prognostic Impact of the Interaction between DNMT3A mutation and Internal Tandem Duplication of the FLT3 Gene (FLT3-ITD) in Patients with De Novo Mutated NPM1 (NPM1mut) acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1492-1492
Author(s):  
Guadalupe Oñate ◽  
Ana Garrido ◽  
Jordi Esteve ◽  
Rosa Coll ◽  
Montserrat Arnan Sangerman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Mutational Status ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction The association of NPM1mut and FLT3-ITD in de novo acute myeloid leukemia (AML) with intermediate-risk cytogenetics has different prognostic impact depending on the FLT3 allelic burden. Previous studies published by our cooperative group showed that patients with de novo AML of intermediate-risk cytogenetics with NPM1mut and FLT3-ITD low ratio (<0.5, FLT3low) at diagnosis presented an overall survival and relapse rate similar to those with NPM1mut and FLT3wt. Therefore, in the CETLAM-2012 protocol, patients with FLT3low NPM1mut AML are not considered for allogenic hematopoietic stem cell transplant (allo-HSCT) in first complete remission (CR1). Recent studies suggest that the co-occurrence of DNMT3A mutation in FLT3-ITD NPM1mut AML patients confers a worse prognosis regardless of FLT3-ITD ratio. We analysed our data to determine whether these findings were confirmed in our cohort, specifically in the low FLT3-ITD ratio patients, since this could have therapeutic implications. Methods and patients A total of 163 patients with de novo AML, intermediate-risk cytogenetics and NPM1mut were analysed (median age 53 years (18-72); male:female 72:91 (0.79)). Eighty patients (49%) harboured an FLT3-ITD, with a high allelic ratio in 42 of 76 patients with available ITD/wt ratio (55%). They were included in the AML-2003 (n=49) and AML-2012 (n=114) CETLAM protocols. Proportion of patients undergoing alloHSCT in CR1 is detailed in table 1. Bone marrow samples from diagnosis were studied for DNMT3A mutations as previously described. The definition of complete remission (CR), overall survival (OS), leukemia-free survival (LFS) and risk of relapse (RR) followed recommended ELN criteria. The Kaplan-Meier method was used to estimate the distribution of LFS and OS, for RR cumulative incidence was used. Results Out of the 163 patients with AML of intermediate risk cytogenetics and NPM1mut, 78 presented DNMT3A mutations (48%). Of these, 62 (79%) presented mutations in codon R882 or corresponded to DNA insertions/deletions while 16 (21%) harboured missense mutations. Presence of DNMT3A mutation did not associate with FLT3-ITD (ITD/85 DNMT3Awt vs ITD/78 DNMT3Amut, p=0.394). In the entire cohort, 5-year OS, LFS and RR were 58±4.5%, 59±4.6% and 27±13.9%. FLT3-ITD ratio confirmed its prognostic impact when analysing FLT3wt (n=83) vs FLT3low (n=34) vs FLT3high (n=42) patients (5-year OS of 68±6% vs 62±8.7% vs 37±8.6%; p=0.002; and 5-year RR of 18±9.4% vs 27±16.1% vs 41±23.2%; p=0.023). On the contrary, DNMT3Amut did not exert any effect on overall outcome (5-yr OS DNMT3Awt vs DNMT3Amut 61±6.2% vs 55±6.2%; p=0.234) When DNTM3A mutational status was considered, the impact of FLT3-ITD on outcome was mitigated in wild-type DNMT3A population. Thus, we found that DNMT3Awt patients presented no statistical differences in OS according to FLT3 mutational status or ratio: FLT3wt (n=46) vs FLT3-ITD (n=39) was 67±8.5% vs 57±8.2%; p=0.122, whereas FLT3wt (n=46) vs FLT3low (n=18) vs. FLT3high (n=19) was 67±8.5% vs. 66±11.5% vs 46±11.8%; p=0.088 (image 1A).This was also seen in relation to LFS and RR according to FLT3 ratio: 5-yr LFS of FLT3wt vs FLT3low vs FLT3high was 72±7.9% vs 61±12.6% vs 51±13.4%; p=0.244 and 5-year RR of the same groups: 19±8.8% vs 26±12.5% vs 27±21.9%; p=0.724 (image 2A). In the DNMT3Amut group, patients with FLT3-ITD (n=41) presented shorter OS than those with FLT3wt (n=37) with an OS of 37±10.7% vs 69±7.8%; p=0.028. When FLT3 ratio was considered, FLT3wt (n=37) vs FLT3low (n=16) vs FLT3high (n=23) showed an OS of 69±7.8% vs. 58±13.2% vs 27±13.1%; p=0.038 (image 1B). Similar results were seen in LFS according to FLT3 ratio (FLT3wt (n=29) vs FLT3low (n=16) vs FLT3high (n=20) 71±8.6% vs 53±12.9% vs 18±13.8%; p=0.012). Finally, we observed significant differences in the 5-year RR when considering DNMT3Amut patients in relation to FLT3 ratio (FLT3wt vs FLT3low vs FLT3high 18±10.6% vs 27±20% vs 54±28.8%; p=0.021)(image 2B). Conclusions In this study, patients with NPM1mut and FLT3-ITDlow presented a similar outcome to patients with NPM1mut and FLT3wt regardless of DNMT3A mutational status. These results support the modification of alloHCST policy in CR1 in CETLAM-2012, which do not consider alloHSCT for patients with FLT3low. On the other hand, concurrence of DNMT3A mutation may have an added negative effect in patients with NPM1mut and FLT3-ITDhigh, which should be further confirmed in larger studies. Disclosures No relevant conflicts of interest to declare.

Homoharringtonine-Based Induction Regimens for Patients with De Novo Acute Myeloid Leukemia: A Multicenter Randomized Controlled Phase 3 Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 45-45 ◽  
Author(s):  
Jie Jin ◽  
Jianxiang Wang ◽  
Feifei Chen ◽  
Depei Wu ◽  
Jiong Hu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Phase 3 ◽  
Free Survival ◽  
Cytogenetic Profile ◽  
To Receive ◽  
Acute Myeloid

Abstract Abstract 45 Background Homoharringtonine-based induction regimens have been widely used in China for patients with acute myeloid leukemia (AML), which have shown to improve the rate of complete remission (CR) and long-term survival. We aimed to further evaluate its efficacy and safety in treatment of de novo AML. Methods This phase 3 study was done in 17 institutions in China. Patients between the age of 14 and 59 with untreated AML were randomly assigned to receive HAA (homoharringtonine 2 mg/m2/day, days 1–7; cytarabine 100 mg/m2/day, days 1–7, aclarubicin 20 mg/day, days 1–7), HAD (homoharringtonine 2 mg/m2/day, days 1–7; cytarabine 100 mg/m2/day, days 1–7; daunorubicin 40 mg/m2/day, days 1–3) or DA (daunorubicin 40–45 mg/m2/day, days 1–3; cytarabine 100 mg/m2/day, days 1–7) regimen as induction therapy. Patients who achieved partial remission or had a decrease of blast ¡Ý60% could receive a same second induction course. All patients who had a complete remission were offered the same consolidation chemotherapy according to the cytogenetic-risk. The primary endpoints were CR and event-free survival (EFS). The trial is registered in Chinese Clinical Trial Register, number ChiCTR-TRC-06000054. Results 620 patients were randomly assigned to receive HAA (n=207), HAD (n=206) and DA (n=207) regimens. HAA or HAD regimen, as compared with DA regimen, resulted in a higher rate of CR in the first course of induction therapy (67.5% vs. 54.0%, P=0.005; 64.9% vs. 54.0%, P=0.026, respectively). The overall CR rate remained significantly higher in the HAA arm as compared with DA arm (75.0% vs. 61.9%, P=0.005). HAA or HAD regimen has similar rates of adverse events as compared with DA regimen, but was associated with significantly increased risk of induction death (5.8% vs. 1.0%, P=0.007; 6.6% vs. 1.0%, P=0.003, respectively). The EFS was greatly improved in the HAA arm (3-year EFS 35.4±3.5% vs.23.1±3.1%, P=0.002), while not significantly in the HAD arm (3-year EFS 32.7±3.5% vs.23.1±3.1%, P=0.078) as compared with the DA arm. Overall survival (OS) and relapse-free survival (RFS) did not differ significantly in the HAA or HAD arm as compared with DA arm, but an OS and RFS advantage of the HAA arm over the DA arm was observed in patients with favorable or intermediate cytogenetic profile (OS: P=0.014; RFS: P=0.022, respectively). Patients in the HAD arm with NPM1 but not FLT3ITD mutations, as compared with the patients in the DA arm, had an improved EFS (P=0.038). In intermediate cytogenetic profile, patients with mutant CEBPA had prolonged RFS in the HAA arm as compared with the DA arm (P=0.045). Conclusions Homoharringtonine-based induction regimens are associated with a higher rate of CR and improved survival as compared with DA regimen in AML. The toxicity is mild with the exception of a higher rate of induction death. Disclosures: No relevant conflicts of interest to declare.

Morphologic Dysplasia in De Novo Acute Myeloid Leukemia (AML) Is Related to Unfavorable Cytogenetics but Has No Independent Prognostic Relevance Under the Conditions of Intensive Induction Therapy: Results of a Multiparameter Analysis From the German AML Cooperative Group Studies

2003 ◽  
Vol 21 (2) ◽  
pp. 256-265 ◽  
Author(s):  
Torsten Haferlach ◽  
Claudia Schoch ◽  
Helmut Löffler ◽  
Winfried Gassmann ◽  
Wolfgang Kern ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Who Classification ◽  
De Novo ◽  
World Health ◽  
Prognostic Impact ◽  
Cooperative Group ◽  
Prognostic Relevance ◽  
Health Organization ◽  
Acute Myeloid

Purpose: On the basis of cytomorphology according to the French-American-British (FAB) classification, we evaluated the prognostic impact of dysplastic features and other parameters in de novo acute myeloid leukemia (AML). We also assessed the clinical significance of the recently introduced World Health Organization (WHO) classification for AML, which proposed dysplasia as a new parameter for classification. Patients and Methods: We analyzed prospectively 614 patients with de novo AML, all of whom were diagnosed by central morphologic analysis and treated within the German AML Cooperative Group (AMLCG)-92 or the AMLCG-acute promyalocytic leukemia study. Results: Patients with AML M3, M3v, or M4eo demonstrated a better outcome compared with all other FAB subtypes (P < .001); no prognostic difference was observed among other FAB subtypes. The presence or absence of dysplasia failed to demonstrate prognostic relevance. Other prognostic markers, such as age, cytogenetics, presence of Auer rods, and lactate dehydrogenase (LDH) level at diagnosis, all showed significant impact on overall and event-free survival in univariate analyses (P < .001 for all parameters tested). However, in a multivariate analysis, only cytogenetics (unfavorable or favorable), age, and high LDH maintained their prognostic impact. Dysplasia was not found to be an independent prognostic parameter, but the detection of trilineage dysplasia correlated with unfavorable cytogenetics. Conclusion: Our results indicate that cytomorphology and classification according to FAB criteria are still necessary for the diagnosis of AML but have no relevance for prognosis in addition to cytogenetics. Our results suggest that the WHO classification should be further developed by using cytogenetics as the main determinant of biology. Dysplastic features, in particular, have no additional impact on predicting prognosis when cytogenetics are taken into account.

Towards individualized follow-up in adult acute myeloid leukemia in remission

Blood ◽  
2011 ◽  
Vol 117 (9) ◽  
pp. 2577-2584 ◽  
Author(s):  
Peter Hokland ◽  
Hans Beier Ommen
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Disease Recurrence ◽  
Clinical Implementation ◽  
Rt Pcr ◽  
Traditional Concept ◽  
Promising Alternative ◽  
Acute Myeloid

Abstract An increasing body of data has demonstrated that the traditional concept of morphologic complete remission in acute myeloid leukemia, in which less than 5% myeloblasts is regarded as a sufficient response criterion, is not biologically sound. Fortunately, the quantitative reverse-transcribed polymerase chain reaction (RT-PCR) method seems to be a promising alternative because of its high degree of preclinical standardization and extreme sensitivity on the background of an accurate day-to-day estimate of sample quality. Widespread implementation of this has, however, to some extent been hampered by the lack of knowledge of how and when to measure minimal residual disease levels and, even more importantly, how to react preemptively on a molecular relapse defined by a PCR reversal. Thus, only few prospective studies have been published to date to clinically validate this assay. Here, we discuss outstanding issues in the clinical implementation of RT-PCR for fusion transcripts, mutated and overexpressed genes in acute myeloid leukemia patients in complete remission, and propose a set of guidelines, which can be used when designing prospective trials aimed at validating the use of RT-PCR as well as for following these patients based on mathematical models for disease recurrence recently developed in our laboratory.

scholarly journals FLAG-IDA As First Line Induction Treatment for Children De Novo AML

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4900-4900
Author(s):  
Xiaoqin Feng ◽  
Chunfu Li ◽  
Lan He
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Primary Study ◽  
Induction Treatment ◽  
First Line ◽  
Acute Myeloid

Abstract Objective: The complete remission after induction therapy is very important for the prognosis of AML. Fludarabine, cytarabine, granulocyte colony-stimulating factor (G-CSF), and idarubicin (FLAG-IDA) regimen has been proven to be an effective chemotherapy for relapsed or refractory acute myeloid leukemia. The aim of this study was to evaluate complete remission rate and toxicity in children with de novo acute myeloid leukemia (none APL) who received the FLAG-IDA regimen as induction therapy. Method: Between March 2014 and July 20015, 14 children with de novo acute myeloid leukemia (none APL) were received FLAG-IDA regimen as first line induction treatment in our center. The regimen including: Fludarabine 30 mg/(m2.d), PI 0.5hr, qd, d2-6; Ara-C 2g/(m2.d), PI 3hr, d2-6; Ida (Idarubicin) mg/(m2.d), PI 1hr, qd, d4-6; G-CSF 5μg/(Kg.d), s.c./i.v. qd,d1-7. Of the 14 children, age 1-13 years old (median age 7 years old), including 2 (14.3%) children with favorable gene, 4 (28.6%) children with high risk gene. 3(21.4%) children received 1 cycle, 11 (78.6%) received 2 cycles of FLAG-IDA regimen. The CR rate and toxicity in total 25 cycles were evaluated. Result: After 25 cycles of FLAG-IDA regimen, only 1 child (7.1%) did not get CR, 13/14 (92.9%) got CR after 1 or 2 cycles of FLAG-IDA induction treatment. In 25 FLAG-IDA cycles, the neutropenic time was from 13-43 days (mean 24.8 days). In the induction period, 2(14.3%) children suffered sepsis, 3 children (21.4%) had proven invasive fungal infection. Of 14 children, 2 children(14.3%) combined with cutaneous anaphylaxis, 2 children combined with transient fever after venous transfusion of chemicals. None obvious cardiac toxicity (arrhythmia or heart failure) was proved. One child died of ARDS in the neutropenic period after 2nd FLAG-IDA cycle. Of 14 children, 12 children (85.7%) got continues CR with the follow up 1-19 months (median 8 months). Discussion: Our primary study showed quite high CR rate combined with quite toxicity but can be tolerated using the FLAG-IDA regimen as first line induction treatment. Comprehensive supportive care should be given during the induction therapy. The LFS and OS need to be feedback after long time follow up. Disclosures No relevant conflicts of interest to declare.

Impact of Leukemia Stem Cells Phenotype Expression on Response to Induction Therapy in Acute Myeloid Leukemia Patients

2020 ◽  
Vol 20 (2) ◽  
pp. 145-151 ◽  
Author(s):  
Faez Almohsen ◽  
Subh S. Al-Mudallal
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Laboratory Data ◽  
Leukemic Stem Cells ◽  
Color Flow ◽  
Acute Myeloid

Background: Laboratory data suggest that acute myeloid leukemia AML originates from a rare population of cells, termed Leukemic Stem Cells (LSCs) or leukemia-initiating cells, which are capable of self-renewal, proliferation and differentiation into malignant blasts. There is a universal agreement that LSCs lie within the CD34+ compartment of hemopoietic cells and most of leukemic stem cells express the interleukin-3 alpha chain receptor, CD123 and lack CD38. This study aimed to estimate the expression of LSC phenotype in AML patients and to correlate it with response to induction therapy. Methods: A cohort of 41 patients older than 15 years with newly diagnosed de novo AML were enrolled in this study. They were obtained from the National center of hematology in Baghdad and Baghdad teaching hospital between February and July 2013. The expression of CD34, CD38 and CD123 was assessed by multi-color flow cytometry. LSC positive (LSC+) samples must express CD34 and CD123 and lack the expression of CD38 in >1% of cells. French American British (FAB) classification system was used in this study. : After four weeks of induction therapy; three groups were found: those who reached the Complete morphological Remission (CR), those who failed to reach CR and those who died before the assessment of morphological remission. The last two groups were merged for statistical purposes. Results: After the course of induction therapy, 41.46% of patients had complete morphological remission while 58.54% of the studied patients failed to reach complete remission. The Complete Remission (CR) rate was higher (53.33%) in patients who were negative for LSC phenotype than patients who were positive for LSC phenotype (34.61%). Conclusions: LSCs were expressed in 63.41% of AML cases and were in approximate distribution in FAB M3 and non-M3 patients. The expression of LSC phenotype was associated with poor response to induction therapy in AML patients.

Adhesion Of Acute Myeloid Leukemia Blasts To E-Selectin In The Vascular Niche Enhances Their Survival By Mechanisms Such As Wnt Activation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 61-61 ◽  
Author(s):  
Sylvia Chien ◽  
Siraj U. Haq ◽  
Matthew Pawlus ◽  
Randall T. Moon ◽  
Elihu H. Estey ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Rt Pcr ◽  
Selectin Ligand ◽  
Acute Myeloid

Abstract Background Adhesion within the bone marrow microenvironment enhances leukemia survival and chemoresistance. Both normal hematopoietic stem cells and cancer cells are known to express E-selectin ligands, and adhesion of colon carcinoma cells to E selectin activates survival pathways such as NFκB (Porquet et al., BMC Cancer 11:285, 2011). E-selectin within the bone marrow vascular niche induces proliferation of normal hematopoietic stem cells (HSC), and a selectin inhibitor enhances HSC quiescence and self-renewal (Winkler et al., Nat Med 18:1651, 2012). We therefore initiated a study of E-selectin ligand expression and function by acute myeloid leukemia (AML) blasts to elucidate the potential role of E-selectin in AML biology and chemotherapy resistance. Methods Primary AML blasts and leukemia stem cells (LSCs) (CD34+CD38-CD123+) obtained with informed consent from 40 patients were analyzed for E-selectin ligands by flow cytometry for binding of E-selectin-Fc chimera or by labeling with the HECA452 antibody. Primary AML blasts were engrafted in NODscid IL2Rgc-/- mice for studies of E-selectin inhibitors in combination with chemotherapy. Human Stem Cell Signaling, Leukemia, Apoptosis, and NFκB PCR Arrays (SA Biosciences) were used to analyze gene expression by quantitative RT-PCR after adhesion of primary AML patient blasts to E-selectin coated plates, compared to bovine serum albumin (BSA) coated plates. The activation of the Wnt pathway was studied by luciferase reporter assay. Results We find that the majority of primary patient acute myeloid leukemia blasts and leukemia stem cells express an E-selectin ligand, as demonstrated by flow cytometry by binding of E-selectin-Fc chimera and by staining with HECA-452 antibody [that recognizes hematopoietic cell E-/L-selectin ligand (HCELL) and cutaneous lymphocyte antigen (CLA)], as well as by binding to E-selectin coated plates. Flow cytometry analysis reveals that the mean percent binding of E-selectin-Fc chimera is 28% ± 24% (SD) by AML blasts, the mean % staining by the HECA-452 antibody 51% ± 35% (SD). De novo patients tended to have smaller mean fluorescence intensity (MFI) values than relapsed/refractory patients, as follows: for blasts, de novo mean 1441 ± 1127 (SD) vs. relapsed/refractory 4488 ± 4920 (SD) (Wilcoxon p=0.024), and for LSCs, de novo mean 1578 ± 1560 (SD) vs. relapsed/refractory 6601 ± 8498 (SD) (Wilcoxon p=0.061), suggesting upregulation of expression of E-selectin ligand for relapsed as compared to newly diagnosed patients. The specific E-selectin small molecule inhibitor GMI-1271 is able to overcome adhesion mediated chemotherapy resistance of AML in vitro and reduce the leukemia burden of primary AML engrafted NODscid IL2Rgc-/- mice in combination with chemotherapy agents daunorubicin and cytarabine. Addition of GMI1271 to chemotherapy in this xenograft model reduced the spleen burden at 2 weeks post treatment from 17.1 ± 10.4 X 106 hCD45+ cells/spleen to 7.6 ± 5.8 (p=0.04). To assess the molecular mechanism by which adhesion to E-selectin might protect AML blasts, we first screened with quantitative RT-PCR arrays. We found that adhesion to E-selectin caused upregulation of members of the Wnt and sonic hedgehog pathways for primary AML patient blasts grown on E-selectin vs. BSA coated plates, as well as members of other pathways critical to leukemia such as GM-CSF and IL-3 receptors and Fos. We then confirmed adhesion to E-selectin by AML blasts from 4 different patients enhanced activity of Wnt target genes by Wnt reporter assays. The Wnt reporter assay demonstrated 2-3 fold enhanced activity of Wnt target genes for AML blasts on E-selectin as compared to those on BSA, which increased to 3.3-4.5 fold with addition of Wnt3a. The inhibitor GMI-1271 reduced Wnt activity to 1.4-2.5 fold, similar to XAV939, an inhibitor of the Wnt/β catenin pathway that reduced activity to 1.1-1.8 fold. Similar reduction of Wnt pathway gene expression by GMI-1271 was also observed by the quantitative RT-PCR assay. Conclusion These data support a critical role for E-selectin, likely in the vascular bone marrow niche, that promotes survival of AML, that can be targeted with therapeutic intent, and suggests that GMI-1271 should be explored as a treatment for AML in combination with chemotherapy. Disclosures: Chien: GlycoMimetics, Inc.: Research Funding. Haq:GlycoMimetics, Inc.: Research Funding. Magnani:GlycoMimetics, Inc.: Employment, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees. Becker:GlycoMimetics, Inc.: Research Funding.

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