scholarly journals Wilms Tumor 1 Mutations Are Independent Poor Prognostic Factors in Pediatric Acute Myeloid Leukemia

2021 ◽  
Vol 11 ◽  
Author(s):  
Yin Wang ◽  
Wen-Jun Weng ◽  
Dun-Hua Zhou ◽  
Jian-Pei Fang ◽  
Srishti Mishra ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factors ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Event Free Survival ◽  
Free Survival ◽  
Wilms Tumor 1 ◽  
Pediatric Aml ◽  
Acute Myeloid

The prognostic impact of Wilms tumor 1 (WT1) mutations remains controversial for patients with acute myeloid leukemia (AML). Here, we aimed to determine the clinical implication of WT1 mutations in a large cohort of pediatric AML. The clinical data of 870 pediatric patients with AML were downloaded from the therapeutically applicable research to generate effective treatment (TARGET) dataset. We analyzed the prevalence, clinical profile, and prognosis of AML patients with WT1 mutations in this cohort. Our results showed that 6.7% of total patients harbored WT1 mutations. These WT1 mutations were closely associated with normal cytogenetics (P<0.001), FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) mutations (P<0.001), and low complete remission induction rates (P<0.01). Compared to the patients without WT1 mutations, patients with WT1 mutations had a worse 5-year event-free survival (21.7 ± 5.5% vs 48.9 ± 1.8%, P<0.001) and a worse overall survival (41.4 ± 6.6% vs 64.3 ± 1.7%, P<0.001). Moreover, patients with both WT1 and FLT3/ITD mutations had a dismal prognosis. Compared to chemotherapy alone, hematopoietic stem cell transplantation tended to improve the prognoses of WT1-mutated patients. Multivariate analysis demonstrated that WT1 mutations conferred an independent adverse impact on event-free survival (hazard ratio 1.910, P = 0.001) and overall survival (hazard ratio 1.709, P = 0.020). In conclusion, our findings have demonstrated that WT1 mutations are independent poor prognostic factors in pediatric AML.

scholarly journals Wilms Tumor 1 Mutations are Independent Poor Prognostic Factors in Pediatric Acute Myeloid Leukemia

2020 ◽  
Author(s):  
Yin Wang ◽  
Wen-Jun Weng ◽  
Dun-Hua Zhou ◽  
Jian-Pei Fang ◽  
Li Chai ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factors ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Event Free Survival ◽  
Free Survival ◽  
Wilms Tumor 1 ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Background: The role of Wilms tumor 1 (WT1) mutations remains controversial for patients with acute myeloid leukemia (AML) with regard to the prognostic impact. Here, we aimed to determine the clinical implication of WT1 mutations in a large cohort of pediatric AML. Methods: The clinical data of 870 pediatric patients with AML were downloaded from the therapeutically applicable research to generate effective treatment (TARGET) dataset. We analyzed the prevalence, clinical profile and prognosis of WT1 mutations in these patients. Results: WT1 mutations were founded in 6.7% of total patients. WT1 mutations were closely associated with normal cytogenetics (P<0.001), FMS-like tyrosine kinase 3/internal tandem duplication (FLT3/ITD) mutations (P<0.001), and low complete remission induction rates (P<0.01). Compared to patients without WT1 mutations, patients with WT1 mutations had worse 5-year event-free survival (21.7±5.5% vs 48.9±1.8%, P<0.001) and overall survival (41.4±6.6% vs 64.3±1.7%, P<0.001). Moreover, patients with both WT1 and FLT3/ITD mutations had a dismal prognosis. Compared to chemotherapy alone, hematopoietic stem cell transplantation had a tendency to improve prognoses of WT1-mutated patients. In multivariate analysis, WT1 mutations conferred an independent adverse impact on event-free survival (hazard ratio 1.910, P = 0.001) and overall survival (hazard ratio 1.709, P = 0.020). Conclusion: Our findings demonstrate that WT1 mutations are independent poor prognostic factors in pediatric AML.

scholarly journals MicroRNA Expression-Based Model Indicates Event-Free Survival in Pediatric Acute Myeloid Leukemia

2017 ◽  
Vol 35 (35) ◽  
pp. 3964-3977 ◽  
Author(s):  
Emilia L. Lim ◽  
Diane L. Trinh ◽  
Rhonda E. Ries ◽  
Jim Wang ◽  
Robert B. Gerbing ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Oxidative Phosphorylation ◽  
Treatment Failure ◽  
Myeloid Leukemia ◽  
Outcome Prediction ◽  
Classification Scheme ◽  
Event Free Survival ◽  
Free Survival ◽  
Pediatric Aml ◽  
Acute Myeloid

Purpose Children with acute myeloid leukemia (AML) whose disease is refractory to standard induction chemotherapy therapy or who experience relapse after initial response have dismal outcomes. We sought to comprehensively profile pediatric AML microRNA (miRNA) samples to identify dysregulated genes and assess the utility of miRNAs for improved outcome prediction. Patients and Methods To identify miRNA biomarkers that are associated with treatment failure, we performed a comprehensive sequence-based characterization of the pediatric AML miRNA landscape. miRNA sequencing was performed on 1,362 samples—1,303 primary, 22 refractory, and 37 relapse samples. One hundred sixty-four matched samples—127 primary and 37 relapse samples—were analyzed by using RNA sequencing. Results By using penalized lasso Cox proportional hazards regression, we identified 36 miRNAs the expression levels at diagnosis of which were highly associated with event-free survival. Combined expression of the 36 miRNAs was used to create a novel miRNA-based risk classification scheme (AMLmiR36). This new miRNA-based risk classifier identifies those patients who are at high risk (hazard ratio, 2.830; P ≤ .001) or low risk (hazard ratio, 0.323; P ≤ .001) of experiencing treatment failure, independent of conventional karyotype or mutation status. The performance of AMLmiR36 was independently assessed by using 878 patients from two different clinical trials (AAML0531 and AAML1031). Our analysis also revealed that miR-106a-363 was abundantly expressed in relapse and refractory samples, and several candidate targets of miR-106a-5p were involved in oxidative phosphorylation, a process that is suppressed in treatment-resistant leukemic cells. Conclusion To assess the utility of miRNAs for outcome prediction in patients with pediatric AML, we designed and validated a miRNA-based risk classification scheme. We also hypothesized that the abundant expression of miR-106a could increase treatment resistance via modulation of genes that are involved in oxidative phosphorylation.

scholarly journals Myeloid sarcoma is associated with superior event-free survival and overall survival compared with acute myeloid leukemia

Cancer ◽  
2008 ◽  
Vol 113 (6) ◽  
pp. 1370-1378 ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
Hagop M. Kantarjian ◽  
Sijin Wen ◽  
Michael J. Keating ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Myeloid Sarcoma ◽  
Event Free Survival ◽  
Free Survival ◽  
Acute Myeloid

scholarly journals High Expression of Myocyte Enhancer Factor 2C (MEF2C) Is Associated with Adverse Risk Features and Poor Outcome in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2570-2570
Author(s):  
George S. Laszlo ◽  
Todd A. Alonzo ◽  
Chelsea J. Gudgeon ◽  
Kimberly H. Harrington ◽  
Alex Kentsis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Event Free Survival ◽  
Free Survival ◽  
Expression Levels ◽  
Acute Myeloid ◽  
Enhancer Factor

Abstract Background: Myocyte enhancer factor 2C (MEF2C) was initially identified as essential transcription factor for cardiac muscle development. However, subsequent studies have indicated that MEF2C plays a much broader biological role, including in the normal hematopoietic system. Recent studies have now identified MEF2C as cooperating oncogene in acute myeloid leukemia (AML) and suggested a contribution to the aggressive nature of at least some subtypes of AML. These findings raised the possibility that MEF2C could serve as marker of poor-risk disease and, therefore, have prognostic significance in AML. To test this hypothesis, we retrospectively quantified MEF2C expression in participants of the AAML0531 trial and correlated expression levels with disease characteristics and clinical outcome. Patients and Methods: AAML0531 (NCT00372593) was a multicenter phase 3 study that determined the addition of gemtuzumab ozogamicin to intensive chemotherapy among 1,022 eligible patients aged <30 yearswith newly diagnosed de novo non-APL AML, excluding those with bone marrow failure syndromes, juvenile myelomonocytic leukemia, or Down syndrome (if ≤3 years of age) between 2006 and 2010. Cryopreserved pretreatment ("diagnostic") specimens from patients enrolled on AAML0531 who consented to the biology studies and had bone marrow samples were available were included in this study. Total RNA from unsorted specimens was extracted, quantified, and subjected to quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) using TaqMan primers to determine expression of MEF2C and, for normalization, the housekeeping gene, β-glucuronidase (GUSB). Patient samples were run in duplicate, and the ΔΔCT method quantified as 2(-ΔΔCT) was used to determine the expression levels of MEF2C relative to GUSB. Results: In all 751 available patient specimens, MEF2C mRNA was detectable and varied >3,000-fold relative to GUSB (0.0091-29.1272 [median: 0.7978]). Patients with the highest relative MEF2C expression (4th quartile) less likely achieved a complete remission after one course of chemotherapy than the other patients (67% vs. 78%, P=0.005). They also had an inferior overall survival (P=0.014; at 5 years: 55±8% vs. 67±4%), inferior event-free survival (P<0.001; at 5 years: 38±7% vs. 54±4%), and higher relapse risk than patients within the lower 3 quartiles of MEF2C expression (P<0.001; at 5 years: 53±9% vs. 35±5%). Of note, exploratory multiple cutpoint analyses for overall and event-free survival indicated that the most statistically significant results were centered around the Q4 cutpoint region, supporting our approach of comparing patients with the highest quartile of relative MEF2C expression with those having lower relative MEF2C expression. Importantly, MEF2C expression was strongly associated with cytogenetic and molecular abnormalities. Specifically, patients with high MEF2C expression less likely had CBF translocations (inv(16): P=0.007, and t(8;21): P<0.001) or normal karyotype AML (P<0.001); conversely, they were more likely to have leukemia with monosomy 7 (P<0.001) and abnormalities involving 11q23 (P<0.001). Furthermore, patients with high MEF2C less likely had a FLT3/ITD (P =0.018) or a mutation in either NPM1 (P=0.010) or CEBPA (P =0.002). Consistently, patients with high MEF2C expression less likely had low-risk disease (16% vs. 46%, P<0.001) and more likely had standard-risk disease (68% vs. 42%, P <0.001) than those with lower MEF2C expression. Indeed, after adjustment for disease risk, age, FAB category, and treatment arm, high MEF2C expression was no longer statistically significantly associated with inferior overall survival (hazard ratio [HR]=0.99 [95% confidence interval: 0.72-1.36], P=0.929), inferior event-free survival (HR: 1.14 [0.86-1.49], P=0.365), or higher relapse risk (HR: 1.32 [0.91-1.92], P=0.137), suggesting that MEF2C cooperates with additional pathogenic abnormalities. Conclusion: High MEF2C expression identifies a subset of AML patients with adverse-risk disease features and poor outcome. These findings provide the rationale for therapeutic targeting of MEF2C transcriptional activation in AML. Disclosures Walter: AstraZeneca, Inc.: Consultancy; Covagen AG: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen, Inc.: Research Funding; Pfizer, Inc.: Consultancy; Amphivena Therapeutics, Inc.: Consultancy, Research Funding.

Response Rate, Event-Free Survival, and Overall Survival in Newly Diagnosed Acute Myeloid Leukemia: US Food and Drug Administration Trial-Level and Patient-Level Analyses

2021 ◽  
Author(s):  
Kelly J. Norsworthy ◽  
Xin Gao ◽  
Chia-Wen Ko ◽  
E. Dianne Pulte ◽  
Jiaxi Zhou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Strong Association ◽  
Intensive Chemotherapy ◽  
Newly Diagnosed ◽  
Event Free Survival ◽  
Free Survival ◽  
Patient Level ◽  
Acute Myeloid

PURPOSE To explore trial-level and patient-level associations between response (complete remission [CR] and CR + CR with incomplete hematologic [CRi] or platelet [CRp] recovery), event-free survival (EFS), and overall survival (OS) in newly diagnosed acute myeloid leukemia (AML) trials of intensive chemotherapy. METHODS We identified data from eight randomized, active-controlled trials of intensive chemotherapy submitted to the US Food and Drug Administration for treatment of newly diagnosed AML (N = 4,482). Associations between trial-level odds ratios (ORs) for CR and CR + CRi or CRp, and hazard ratios (HRs) for EFS and OS were analyzed using weighted linear regression models. We performed patient-level responder analyses to compare OS by response using pooled data from all studies. RESULTS In trial-level analyses, association between HR for OS and OR for CR was moderate (R2 = 0.49; 95% CI, 0.05 to 0.86), as was the association with OR for CR + CRi or CRp (R2 = 0.48; 95% CI, 0.05 to 0.99). For OS versus EFS, a strong association was observed (R2 = 0.87; 95% CI, 0.47 to 0.98) when EFS definitions were harmonized across trials using raw data. In the patient-level responder analyses, patients who achieved CR had better OS compared with CRi or CRp responders (0.73; 95% CI, 0.64 to 0.84) and nonresponders (HR, 0.33; 95% CI, 0.31 to 0.37). CONCLUSION On a trial level, there is a moderate association between OS and CR rate. A strong association between EFS and OS was observed. However, CIs were wide, and results became moderate using alternative definitions for EFS. Patient-level analyses showed CR responders have better OS compared with CRi or CRp responders and nonresponders. A therapy in newly diagnosed AML with benefit in EFS or substantial benefit in CR rate would be likely to have an OS effect.

scholarly journals Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine

Blood ◽  
2012 ◽  
Vol 119 (23) ◽  
pp. 5367-5373 ◽  
Author(s):  
Thomas Pabst ◽  
Edo Vellenga ◽  
Wim van Putten ◽  
Harry C. Schouten ◽  
Carlos Graux ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Favorable Effect ◽  
Remission Induction ◽  
Event Free Survival ◽  
Entire Study ◽  
Free Survival ◽  
Acute Myeloid

Abstract The clinical value of chemotherapy sensitization of acute myeloid leukemia (AML) with G-CSF priming has remained controversial. Cytarabine is a key constituent of remission induction chemotherapy. The effect of G-CSF priming has not been investigated in relationship with variable dose levels of cytarabine. We randomized 917 AML patients to receive G-CSF (456 patients) or no G-CSF (461 patients) at the days of chemotherapy. In the initial part of the study, 406 patients were also randomized between 2 cytarabine regimens comparing conventional-dose (199 patients) versus escalated-dose (207 patients) cytarabine in cycles 1 and 2. We found that patients after induction chemotherapy plus G-CSF had similar overall survival (43% vs 40%, P = .88), event-free survival (37% vs 31%, P = .29), and relapse rates (34% vs 36%, P = .77) at 5 years as those not receiving G-CSF. However, patients treated with the escalated-dose cytarabine regimen benefited from G-CSF priming, with improved event-free survival (P = .01) and overall survival (P = .003), compared with patients without G-CSF undergoing escalated-dose cytarabine treatment. A significant survival advantage of sensitizing AML for chemotherapy with G-CSF was not apparent in the entire study group, but it was seen in patients treated with escalated-dose cytarabine during remission induction. The HOVON-42 study is registered under The Netherlands Trial Registry (www.trialregister.nl) as #NTR230.

scholarly journals Wilms’ tumor gene 1 is an independent prognostic factor for pediatric acute myeloid leukemia following allogeneic hematopoietic stem cell transplantation

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dao-Xing Deng ◽  
Juan-Juan Wen ◽  
Yi-Fei Cheng ◽  
Xiao-Hui Zhang ◽  
Lan-Ping Xu ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Disease Free Survival ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Pediatric Aml ◽  
Disease Free ◽  
Tumor Gene ◽  
Acute Myeloid

Abstract Background Sequential monitoring of Wilms’ tumor gene 1 (WT1) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) could predict relapse in adult acute myeloid leukemia (AML). However, the prognostic role of WT1 in pediatric AML after allo-HSCT is unclear. Thus, we determined to see whether sequential monitoring of WT1 after allo-HSCT could predict relapse in AML children. Methods Pediatric AML patients receiving allo-HSCT from January 21, 2012 to December 20, 2018 at the Peking University Institute of Hematology were included in this study. WT1 expression level was determined by TaqMan-based reverse transcription-polymerase chain reaction. WT1 sequential monitoring was performed 1, 2, 3, 4.5, 6, 9, and 12 months post-transplantation and at 6-month intervals thereafter. The primary end point was relapse. The secondary end points included disease-free survival (DFS), overall survival (OS), and non-relapse mortality (NRM). Kaplan–Meier analysis was used for DFS and OS estimates, while competing risk analysis was used for estimating relapse and NRM. Results Of the 151 consecutive patients included, the median age was 10 years (range, 1–17). The optimal cutoff value of WT1 within 1 year after allo-HSCT to predict relapse was 0.8% (80 WT1 copies/104 ABL copies), with a sensitivity of 60% and specificity of 79%. Compared with WT1 expression < 0.8%, WT1 expression ≥0.8% indicated significantly higher 5-year cumulative incidence of relapse (CIR, 35.1% vs. 11.3%; P = 0.001), lower 5-year disease-free survival (DFS, 60.4% vs. 80.8%; P = 0.009), and lower 5-year overall survival (OS, 64.9% vs. 81.6%; P = 0.038) rates. Multivariate analyses showed that WT1 was an independent risk factor for relapse (HR 2.89; 95% confidence interval (CI), 1.25–6.71; P = 0.014). Both the CIR (5-year CIR: 8.3% vs. 11.3%; P = 0.513) and DFS (5-year DFS: 91.7% vs. 80.8%; P = 0.208) were comparable between patients achieving minimal residual disease (MRD) negativity after preemptive interferon-α (IFN-α) treatment and those without MRD after allo-HSCT, which were better than those of MRD-positive patients without preemptive therapies. Conclusions Sequential monitoring of WT1 could predict relapse in pediatric AML after allo-HSCT. WT1-directed immunotherapy may have the potential to prevent relapse and improve survival.

A Prospective Randomized Comparison of Idarubicin and High-Dose Daunorubicin in the Induction Chemotherapy for Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2535-2535 ◽  
Author(s):  
Je-Hwan Lee ◽  
Hawk Kim ◽  
Young-Don Joo ◽  
Won Sik Lee ◽  
Sung Hwa Bae ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
High Dose ◽  
Event Free Survival ◽  
Consolidation Chemotherapy ◽  
Free Survival ◽  
Acute Myeloid

Abstract Introduction: We conducted a randomized trial comparing two different doses of daunorubicin as induction chemotherapy in young adults with acute myeloid leukemia (AML) and showed intensification of induction therapy using a high daily dose of daunorubicin (90 mg/m2/d x 3d) improved both complete remission (CR) rate and survival duration compared to standard daunorubicin dose (45 mg/m2/d x 3d) (Lee JH et al. Blood 2011;118:3832). As it is necessary to compare the effects of high-dose daunorubicin with that of other agents, especially idarubicin, we performed another randomized trial comparing two induction regimens in young adults with AML: idarubicin vs. high-dose daunorubicin (ClinicalTrials.gov #NCT01145846). Here, we present final results of the study. Methods: Between May 2010 and March 2014, a total of 316 patients (65 years or younger) with newly diagnosed AML except acute promyelocytic leukemia were registered in this study. Seventeen patients were removed from the study (change of diagnosis in 11, patient's refusal to be randomized in 3 and other in 3) and the remaining 299 patients were analyzed. After random assignments, 149 patients received idarubicin (AI, 12 mg/m2/d x 3d) and 150 patients received high-dose daunorubicin (AD, 90 mg/m2/d x 3d) in addition to cytarabine (200 mg/m2/d x 7d) for induction of CR. Patients with persistent leukemia received the second attempt of induction chemotherapy, consisting of idarubicin (AI, 12 mg/m2/d x 2d) or daunorubicin (AD, 45 mg/m2/d x 2d) plus cytarabine (5d). Patients who attained CR received 4 cycles of high-dose cytarabine (3 g/m2 x 6 doses) in patients with good- or intermediate-risk cytogenetics and 4 cycles of cytarabine (1 g/m2 x 6d) plus etoposide (150 mg/m2 x 3d) in those with high-risk cytogenetics. Hematopoietic cell transplantation (HCT) was performed according to attending physician's discretion after one or two cycles of consolidation chemotherapy in most transplant cases. Results: CR was induced in 232 (77.6%) of 299 patients. Reasons for induction failure were resistant disease in 50, hypoplastic death in 5, and indeterminate cause in 12. As postremission therapy, 3 patients received no further treatment, 71 received consolidation chemotherapy without HCT, 137 underwent allogeneic HCT, and 21 underwent autologous HCT. The CR rates were not significantly different between two arms: 80.5% (120 of 149, AI) vs. 74.7% (112 of 150, AD) (P=0.224). With a median follow-up of 1046 days, overall survival probabilities at 4 years were 51.1% in AI vs. 54.7% in AD (P=0.756). The probabilities at 4 years for relapse-free survival were 63.5% in AI vs. 74.2% in AD (P=0.181) and those for event-free survival were 44.8% in AI vs. 50.7% in AD (P=0.738). Toxicity profiles were similar between two arms. Interestingly, overall and event-free survivals of 44 patients with FLT-ITD mutants (27 in AI and 17 in AD) were significantly different according to the induction regimens (AI vs AD; overall survival, 30.8% vs. 61.9%, P=0.030; event-free survival, 31.4% vs. 61.9%, P=0.025). Conclusions: The results of this phase 3 trial, which compared idarubicin (12 mg/m2/d x 3d) with high-dose daunorubicin (90 mg/m2/d x 3d), did not show significant differences between two arms in the outcomes of patients in terms of CR rates and overall, relapse-free or event-free survivals. In subset analysis, high-dose daunorubicin seems to be more effective than idarubicin in patients with FLT-ITD mutants. Disclosures Kim: Celgene: Research Funding; Alexion Pharmaceuticals: Research Funding; Il-Yang: Research Funding; Novartis: Research Funding.

High ROBO3 expression predicts poor survival in non-M3 acute myeloid leukemia

2021 ◽  
pp. 153537022098824
Author(s):  
Zhimei Cai ◽  
Jifeng Wei ◽  
Ze Chen ◽  
Haiqing Wang
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Signaling Pathway ◽  
Myeloid Leukemia ◽  
Remission Induction ◽  
Intensive Chemotherapy ◽  
Event Free Survival ◽  
Free Survival ◽  
Receptor Proteins ◽  
Acute Myeloid

Roundabout guidance receptor proteins are crucial components of the SLIT/ROBO signaling pathway. This pathway is important for the nervous system and in embryonic development. Recently, increasing evidence has shown that roundabout guidance receptor proteins and the SLIT/ROBO signaling pathway also participate in tumorigenesis. Here, by analyzing transcriptome data from the TCGA and GEO databases, we found that ROBO3 is highly expressed in non-M3 acute myeloid leukemia. High ROBO3 expression was associated with increased age at diagnosis and poorer risk classification (both P <  0.01). Patients with high ROBO3 expression had higher rates of TP53 and RUNX1 mutations (both P <  0.05). Significantly worse overall survival and event-free survival were observed in high ROBO3 expression patients compared with low ROBO3 expression patients (OS: P =  0.004; EFS: P= 0.012). High ROBO3 expression was also associated with poorer overall survival and event-free survival in a subgroup of patients who received intensive chemotherapy (OS: P =  0.024; EFS: P =  0.040). Moreover, multivariate analysis indicated that high ROBO3 expression was an independent risk factor for poor overall survival in non-M3 acute myeloid leukemia patients who are younger than 60 and received intensive chemotherapy during remission induction. Bioinformatics analysis by Kyoto Encyclopedia of Genes and Genomes and Gene Ontology revealed that high ROBO3 expression significantly altered cell adhesion and extracellular matrix-related pathways (adjusted P <  0.05). Taken together, the data demonstrate that ROBO3 is upregulated in non-M3 acute myeloid leukemia and may be a potent biomarker of inferior prognosis.

scholarly journals A 16-Gene Signature Associated with High Levels of Wilms Tumor-1 (WT1) Expression Is an Adverse Prognostic Factor in Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1021-1021
Author(s):  
Ahmadreza Niavarani ◽  
Tobias Herold ◽  
Yasmin Reyal ◽  
Erin Currie ◽  
Stuart Horswell ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
The Netherlands ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Gene Signature ◽  
Free Survival ◽  
Lower Upper ◽  
Wilms Tumor 1 ◽  
Acute Myeloid

Abstract Wilms Tumor-1 (WT1) expression level has long been found to be implicated in acute myeloid leukemia (AML) prognosis, though this is not reflected in current AML risk stratification. We hypothesized that a gene expression profile (GEP) associated with WT1expression could be of prognostic value. We analyzed two publically available AML GEP series in order to identify a gene signature associated with high-WT1 expression (hi-WT1). The first, herein called Netherlands series, comprised of 524 younger adult patients who have been treated according to sequential Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for Clinical Cancer Research (HOVON/SAKK) AML-04, 04A, 29, 32, 42, and 43 protocols (GSE14468). The second series, herein called Germany series, consisted of 562 younger and older AML patients who were treated in the German AMLCG 1999 trial (GSE37642). We identified the hi-WT1 gene sets by comparing GEP among the highest and lowest quartiles of WT1 expression in both AML studies. About 62% of the probe sets in the Netherlands hi-WT1 set were found to be common with the Germany hi-WT1 set; 97% differed in the same direction. Moreover, a high degree of correlation of the fold differences was found among the two hi-WT1 sets (r2 = 0.81, p < 10-18), collectively suggesting a biological relevance for hi-WT1gene sets. In order to assess the prognostic implication of the hi-WT1 set, we used K-Nearest Neighborhood algorithm to generate various lists of hi-WT1 probe sets predicting event-free survival (EFS) as the favorable, and all others (dead, no remission, progressive disease/relapse) as the unfavorable events in the Netherlands series. Stepwise screening of the lists of 10 to 100 probe sets by Cox Regression identified a 16-gene subset of hi-WT1 set with distinct GEP and as the optimal predictor of overall survival (OS) and EFS in the Netherlands series. It comprised of GPR56, FAM30A, NGFRAP1, WBP5, LTK, PTP4A3, CD109, ZC3H12C, PYGB, CHIC1, HAVCR2, TMEM110, HAL, HDAC4, BLVRA, and P2RY2. In this series, the hi-WT1 cluster of patients showed lower 5y-probability of OS (10% vs 44%) and EFS (6% vs 38%) as compared to the remaining clusters. Accordingly, the hi-WT1 cluster showed shorter median OS (8.3 [CI 6.7-9.9] vs 31.3 [CI 17.1-45.5] months, P = 6 x 10-18) and EFS (4.9 [CI 3.2-6.5] vs 14.5 [CI 9.4-19.5] months, P = 3 x 10-16). Although the hi-WT1 cluster was associated with some of the cytogenetic and molecular aberrations including FLT3-ITD, it remained significant for both OS (P = 3 x 10-5) and EFS (P = 3 x 10-6) after adjustment for known AML risk factors. In order to validate our findings, we performed a supervised clustering of the Germany AML series using the 16-gene signature. The hi-WT1 cluster predicted both adverse OS and relapse-free survival (RFS) (Fig. 1), which remained statistically significant after adjustment for known AML risk factors (Table 1). The median OS was 7.1 (CI 5.7-8.5) months for the hi-WT1 cluster as compared to 20.1 (CI 15.2- 25.0) months for other cases (P = 2 x 10-13), and the median RFS was 5.8 (CI 4.8-6.8) vs 20.3 (CI 10.6-30.0) months, respectively (P = 2 x 10-11). Moreover, the rate of complete remission was significantly lower in hi-WT1 cluster as compared to other clusters (42% vs 61%, P = 2 x 10-5). The positive (PPV) and negative predictive value (NPV) of the marker for prediction of adverse OS were 90% and 34%, respectively. These values were found to be 88% and 38%, respectively, for prediction of adverse RFS. MetaCore analysis identified the Antigen Presentation by MHC-II as the most implicated biological pathway in hi-WT1sets, with many genes downregulated in the pathway. In brief, we identified a 16-gene signature associated with WT1 expression and demonstrated its adverse and independent prognostic impact in adult AML patients. These promising results should be validated in further trials and provide new clues to the molecular mechanisms underlying WT1regulation. Figure 1 Figure 1. Kaplan-Meier analysis of OS and RFS in the Germany series separated by WT1-related 16-gene signature. Table 1. Multivariate analysis of OS and RFS in the Germany AML series. Variable OS RFS P val HR 95% CI for HR P val HR 95% CI for HR Lower Upper Lower Upper WT1 signature .001 1.485 1.186 1.860 .000 1.834 1.326 2.536 Age .000 1.291 1.197 1.391 .001 1.198 1.081 1.327 ELN2 .000 2.395 1.743 3.291 .000 3.147 2.124 4.663 ELN3 .000 2.395 1.732 3.312 .000 2.153 1.405 3.299 ELN4 .000 3.306 2.376 4.599 .000 6.401 4.027 10.175 Disclosures No relevant conflicts of interest to declare.

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