Low Levels of Mir-151-5p and Mir-451 Predict Relapse in Pediatric B-Lineage Acute Lymphoblastic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2507-2507
Author(s):  
Smadar Avigad ◽  
Iedan RN Verly ◽  
Gertjan J.L. Kaspers ◽  
Jacqueline Cloos ◽  
Anat Ohali ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Standard Group ◽  
Cox Regression Analysis ◽  
Increased Risk ◽  
Low Levels ◽  
B Lineage ◽  
Group Stratification ◽  
Low Expression

Abstract Abstract 2507 Aim: microRNAs (miRNAs) have been implicated in many malignancies. Our aim was to identify specific miRNAs that can predict risk of relapse in pediatric acute lymphoblastic leukemia (ALL) patients treated according to BFM protocols already at diagnosis. The current risk group stratification is based on the amount of minimal residual disease (MRD) assessed at specific time points by real time quantitative PCR (RQ-PCR). Material and methods: Following miRNA expression analysis, we decided to focus on miR-151-5p and miR-451 that significantly correlated with known prognostic factors in ALL. Validation was performed by measuring the expression levels of miR-151-5p and miR-451 by RQ-PCR on bone marrow samples at diagnosis of 101 B-lineage ALL patients excluding Philadelphia positive patients. Results: Low expression of miR-151-5p, miR-451 or of both together resulted in significantly worse relapse free survival (RFS) (43%, 58% and 38%, respectively) compared to RFS rates when either or both miRNAs were highly expressed (81%, 75% and 75%, respectively) (p=0.001, 0.044 and 0.001, respectively). Moreover, following PCR-MRD stratification, low expression of miR-451 or both miRNAs remained significant within the PCR-MRD medium risk group (p=0.00001) and within the standard group for both miRNAs (p=0.024). Multivariate Cox regression analysis identified low expression of both miRNAs as an independent prognostic marker with 11.7 fold increased risk for relapse (p=0.002). After excluding patients harboring the adverse genetic markers Ikaros deletion and P2RY8-CRLF2 rearrangement, a patient expressing low levels of both miRs had a 35 fold risk to relapse (p=0.005). Analyzing a non-BFM treated B-lineage ALL cohort from The Netherlands, both miRNAs significantly correlated with outcome (p=0.003). Conclusion: Our results identify miR-151-5p and miR-451 as novel biomarkers for outcome in pediatric B-lineage ALL patients, regardless of treatment protocol. This may allow earlier and improved risk group stratification already at diagnosis, enabling exploration of early therapeutic interventions. Disclosures: No relevant conflicts of interest to declare.

Prediction of Relapse By microRNA Expression in Pediatric B-Lineage Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3793-3793
Author(s):  
Isaac Yaniv ◽  
Asaf Lebel ◽  
Keren Shichrur ◽  
Oshrit Kordi ◽  
Anat Ohali ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Prognostic Marker ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Microrna Expression ◽  
Increased Risk ◽  
Low Levels ◽  
B Lineage ◽  
Group Stratification ◽  
Low Expression

Abstract Aim: microRNAs (miRs) have been implicated in many malignancies. Our aim was to identify specific miRNAs that can predict risk of relapse in pediatric acute lymphoblastic leukemia (ALL) patients treated on BFM protocols, better than the current risk group stratification. Currently, the main method for risk group stratification is based on the amount of minimal residual disease (MRD) assessed at specific time points by real time quantitative PCR (RQ-PCR). Material and methods: Following microRNA expression analysis performed on 48 bone marrow samples at diagnosis, we focused on several miRs that correlated with at least 3 of the established prognostic markers in ALL to be validated in a cohort of 138 B-lineage ALL samples. Of the miRs studied, down regulated miR-151-5p and miR-451 and upregulated miR-1290 significantly correlated with outcome. Results: Low expression of miR-151-5p, miR-451 or of both together resulted in significantly worse relapse free survival (RFS) (56%, 63% and 47%, respectively) compared to RFS rates when either or both miRs were highly expressed (80%, 78% and 78%, respectively) (p=0.007, 0.042 and 0.002, respectively). High expression of miR-1290 resulted in worse RFS compared to those that expressed low levels (54% versus 81%; p=0.014). When combining the 3 miRs, a patient expressing low levels of both miRs and/or high levels of miR-1290 had a RFS of 54% (p=0.004). Furthermore, the expression of the 3 miRs could distinguish within the TEL-AML1 negative cohort two groups; one with 80% and the other with 44% RFS (p=0.004). Multivariate Cox regression analysis identified low expression of both miRs and/or high expression of miR-1290 as an independent prognostic marker in the PCR-MRD non-high risk cohort. Patients expressing abnormal levels of the 3 miRs had a 4.47-fold increased risk for relapse (p=0.037). Deletion of IKZF1 gene is a known adverse prognostic marker in B-lineage ALL. In 85 patients, IKZF1 status was analyzed and 9 patients were found to harbor the deletion. The expression of the 3 miRs could still identify an adverse group of patients with 69% RFS within the group with no deletion (p=0.004). When adding IKZF1 and TEL-AML1 status to the Multivariate analysis in addition to PCR-MRD, the expression of the 3 miRs remained a significant independent marker with a 24 fold increased risk for relapse (p=0.011). Figure 1 Figure 1. Conclusion: Our results identify the combination of miR-151-5p, miR-451 and miR-1290 as a novel biomarker for outcome in pediatric B-lineage ALL patients, already at time of diagnosis. This may lead to improved risk group stratification and enable early therapeutic intervention that may result in better RFS. Disclosures No relevant conflicts of interest to declare.

Intensification of Mercaptopurine/Methotrexate Maintenance Chemotherapy May Increase the Risk of Relapse for Some Children With Acute Lymphoblastic Leukemia

2003 ◽  
Vol 21 (7) ◽  
pp. 1332-1339 ◽  
Author(s):  
Kjeld Schmiegelow ◽  
Olle Björk ◽  
Anders Glomstein ◽  
Göran Gustafsson ◽  
Niels Keiding ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Maintenance Therapy ◽  
Cox Regression ◽  
Lymphoblastic Leukemia ◽  
Tpmt Activity ◽  
Control Group ◽  
Cox Regression Analysis ◽  
Cell Counts ◽  
Increased Risk ◽  
Risk Of Relapse

Purpose: Thioguanine nucleotides (TGNs) mediate the cytotoxicity of mercaptopurine (MP). Methylated MP metabolites (formed by thiopurine methyltransferase [TPMT]) and methotrexate (MTX) polyglutamates can inhibit de novo purine synthesis. We explored whether dose adjustment of MP and MTX by erythrocyte (E) levels of TGN and MTX (including polyglutamates) could improve outcome in childhood acute lymphoblastic leukemia (ALL). Patients and Methods: A total of 538 children with ALL were randomly assigned to have their oral MP/MTX maintenance therapy adjusted by white cell counts (WBC), E-TGN, and E-MTX (pharmacology group), or by WBC only (control group). Results: After a median follow-up of 7.8 years, 79 patients had relapsed. Cox regression analysis showed an increased risk of relapse for boys (P = .00003), high WBC at diagnosis (P = .03), pharmacology arm (6.6 times increased relapse hazard for girls), high TPMT activity (P = .002), and high average neutrophil counts during maintenance therapy (P = .0009), with a significant interaction between sex and randomization group (P = .0007). For girls, the relapse risk was 5% in the control group and 19% in the pharmacology group (P = .001) because of an increased relapse hazard during the first year after cessation of therapy. TPMT activity was the most significant predictor of relapses among girls in the pharmacology arm (P < .0001). Overall, the TPMT activity was higher for patients who relapsed after cessation of therapy compared with those who stayed in remission (girls 19.5 v 17.4 U/mL, P = .03; boys 19.3 v 18.0 U/mL, P = .04). Conclusion: Adding pharmacologically guided treatment intensification to dose adjustments by blood counts may not be warranted for girls, whereas new approaches to optimize maintenance therapy are needed for boys.

Validation of a Predictive Model for Indentifying An Increased Risk for Thromboembolism in Children with Acute Lymphoblastic Leukemia: Results of a Multicenter Cohort Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 524-524
Author(s):  
Silke Flege ◽  
Lesley Mitchell ◽  
Gili Kenet ◽  
Christine Heller ◽  
Michael Fruhwald ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Predictive Model ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Low Risk ◽  
Carrier Status ◽  
Central Venous ◽  
Increased Risk ◽  
Genetic Abnormalities

Abstract Children with acute lymphoblastic leukemia (ALL) are at increased risk for venous thromboembolism (VTE), however, not all children experience a VTE. Developing a predictive model for determining children at increased risk would be beneficial in targeting interventional studies to only high risk groups. A recent meta-analysis of studies in VTE in children with ALL identified four potential risk factors: treatment with Escherichia coli asparaginase (CASP), concomitant use of steroids, presence of central venous lines and thrombophilic genetic abnormalities. As VTE in childhood ALL is well recognized as serious clinical problem and due to the lack of studies on prevention, the standard of practice varies and some centres use enoxaparin prophylaxis for these children. However, the risks and benefits of the intervention are unknown. The aim of the study was to develop a simple model for predicting ALL-chemotherapy-associated VTE using baseline clinical and laboratory variables, and to evaluate, on an explorative basis, the increasing off-label use of enoxaparin for VTE prophylaxis in ALL children. For development of the risk model the predictive variables were scored as follows: treatment with CASP (5000–10000/m2) in combination with prednisone or dexamethasone, presence of central venous lines, thrombophilic genetic abnormalities, e.g. positive family history for VTE or identification of a single thrombophilic trait (1 point each), or carrier status of combined thrombophilic traits (2 points). A definition of VTE risk by score was low (1–2) and high (□ 3). The risk score was than prospectively validated in an independent cohort of 136 newly recruited patients enrolled into the German database. Seven patients were excluded (lost to follow-up n=2; death n=2, secondary malignancy, VTE before ALL-onset, infant &lt; 12 months of age: each n=1). The cumulative VTE rates at 3.5 months in the validation cohorts were 3.6% (95% CI 1%–9%) in the low-risk group (4 of 112), and 47% (95%CI 23%–72%) in the high-risk category (8 of 17). In multivariate analysis [Cox regression] the high risk group was significantly associated with VTE when compared to the low risk group even after adjusting for age at ALL-onset, duration of CASP administration, steroid administered (prednisone/dexamethasone), and presence or absence of enoxaparin prophylaxis [hazard/95%CI: 4.16/1.13–15.34]. The negative predictive value for VTE was 96.3% [95%CI: 92.9–99.8]. Early enoxaparin prophylaxis reduced the absolute VTE-risk about 60% [95%CI: 23–96]. Therefore, the model can identify ALL-children with an increased risk for symptomatic VTE.

Utilization of Ig heavy chain variable, diversity, and joining gene segments in children with B-lineage acute lymphoblastic leukemia: implications for the mechanisms of VDJ recombination and for pathogenesis

Blood ◽  
2004 ◽  
Vol 103 (12) ◽  
pp. 4602-4609 ◽  
Author(s):  
Aihong Li ◽  
Montse Rue ◽  
Jianbiao Zhou ◽  
Hongjun Wang ◽  
Meredith A. Goldwasser ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Heavy Chain ◽  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Tumor Biology ◽  
Vdj Recombination ◽  
Childhood All ◽  
Increased Risk ◽  
B Lineage

Abstract Sequence analysis of the immunoglobulin heavy chain genes (IgH) has demonstrated preferential usage of specific variable (V), diversity (D), and joining (J) genes at different stages of B-cell development and in B-cell malignancies, and this has provided insight into B-cell maturation and selection. Knowledge of the association between rearrangement patterns based on updated databases and clinical characteristics of pediatric acute lymphoblastic leukemia (ALL) is limited. We analyzed 381 IgH sequences identified at presentation in 317 children with B-lineage ALL and assessed the VHDHJH gene utilization profiles. The DHJH-proximal VH segments and the DH2 gene family were significantly overrepresented. Only 21% of VH-JH joinings were potentially productive, a finding associated with a trend toward an increased risk of relapse. These results suggest that physical location at the VH locus is involved in preferential usage of DHJH-proximal VH segments whereas DH and JH segment usage is governed by position-independent molecular mechanisms. Molecular pathophysiology appears relevant to clinical outcome in patients who have only productive rearrangements, and specific rearrangement patterns are associated with differences in the tumor biology of childhood ALL. (Blood. 2004;103:4602-4609)

Residual disease at the end of induction therapy as a predictor of relapse during therapy in childhood B-lineage acute lymphoblastic leukemia.

1992 ◽  
Vol 10 (12) ◽  
pp. 1879-1888 ◽  
Author(s):  
R Wasserman ◽  
N Galili ◽  
Y Ito ◽  
J H Silber ◽  
B A Reichard ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Induction Therapy ◽  
Clinical Remission ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cells ◽  
Induction Phase ◽  
Increased Risk ◽  
B Lineage ◽  
Wbc Count

PURPOSE More than 95% of children with B-lineage acute lymphoblastic leukemia (ALL) achieve a clinical remission after the induction phase of chemotherapy (first 28 days) as evaluated by morphologic criteria. However, relapse occurs in approximately 30% of these children. The objective of this study was to determine whether the outcome of patients in clinical remission at the end of induction therapy could be predicted using a highly sensitive method to detect residual disease. PATIENTS AND METHODS All children diagnosed with B-lineage ALL at the Children's Hospital of Philadelphia during a 2-year period were eligible. The extent of residual leukemia was quantitated in remission marrow samples obtained at the end of induction therapy in 44 children using a phage clonogenic assay in association with complementarity-determining-region 3 (CDR3)-polymerase chain reaction (PCR). RESULTS Residual disease was a significant predictor of outcome independent of WBC count, age, or sex. The estimated relapse-free survival (RFS) during therapy was 50.4% (+/- 12.6%) for patients with high residual disease (> or = 0.6% leukemia cells among total marrow B cells) versus 91.9% (+/- 5.5%) for those with lower levels (P < .002). There were no significant differences in off-treatment RFS between patients with high or low residual disease who completed therapy in continuous remission (P = .82). The overall estimated RFS was 32.3% (+/- 11.6%) for patients with high residual disease versus 62.6% (+/- 10.7%) for patients with lower levels of residual leukemia cells, with a median follow-up of 5.3 years for patients in continuous remission (P < .008). CONCLUSION PCR detection of high residual disease at the end of induction therapy identifies patients at increased risk for relapse during therapy.

scholarly journals Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations

Haematologica ◽  
2020 ◽  
pp. 0-0
Author(s):  
Željko Antić ◽  
Jiangyan Yu ◽  
Simon V. Van Reijmersdal ◽  
Anke Van Dijk ◽  
Linde Dekker ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Clinical Relevance ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Ras Pathway ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Genomic Studies ◽  
Hotspot Mutations ◽  
Molecular Inversion Probe ◽  
Group Stratification

Genomic studies of pediatric acute lymphoblastic leukemia (ALL) have shown remarkable heterogeneity in initial diagnosis, with multiple (sub)clones harboring lesions in relapse-associated genes. However, the clinical relevance of these subclonal alterations remains unclear. We assessed the clinical relevance and prognostic value of subclonal alterations in the relapse-associated genes IKZF1, CREBBP, KRAS, NRAS, PTPN11, TP53, NT5C2, and WHSC1 in 503 ALL cases. Using Molecular Inversion Probe sequencing and breakpoint-spanning PCR we reliably detected alterations below 1% allele frequency. We identified 660 genomic alterations in 285 diagnosis samples of which 495 (75%) were subclonal. RAS pathway mutations were common, particularly in minor subclones, and comparisons between RAS hotspot mutations revealed differences in their capacity to drive clonal expansion in ALL. We did not find an association of subclonal alterations with unfavorable outcome. Particularly for IKZF1, an established prognostic marker in ALL, all clonal but none of the subclonal alterations were preserved at relapse. We conclude that, for the genes tested, there is no basis to consider subclonal alterations detected at diagnosis for risk group stratification of ALL treatment.

scholarly journals Down syndrome childhood acute lymphoblastic leukemia has a unique spectrum of sentinel cytogenetic lesions that influences treatment outcome: a report from the Children's Oncology Group

Blood ◽  
2010 ◽  
Vol 116 (7) ◽  
pp. 1045-1050 ◽  
Author(s):  
Kelly W. Maloney ◽  
William L. Carroll ◽  
Andrew J. Carroll ◽  
Meenakshi Devidas ◽  
Michael J. Borowitz ◽  
...  
Keyword(s):  
Overall Survival ◽  
Down Syndrome ◽  
Acute Lymphoblastic Leukemia ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Oncology Group ◽  
Blood Cell Count ◽  
Childhood All ◽  
Children With Down Syndrome ◽  
Increased Risk

Abstract Children with Down syndrome (DS) have an increased risk of acute lymphoblastic leukemia (ALL) and an inferior outcome. We reviewed data from 2811 children with ALL enrolled in Children's Oncology Group P9900, which included prospective testing for the major cytogenetic lesions in childhood ALL: ETV6-RUNX1, TCF3-PBX1, BCR-ABL1, and MLL translocations and trisomies of chromosomes 4 and 10. Eighty (3%) B-precursor ALL patients had DS. Age, sex, white blood cell count, and risk group were similar between DS-ALL and non–DS-ALL but significantly more patients with DS-ALL were white (91.2% vs 76.4%, P = .001). Children with DS-ALL had lower rates of the favorable cytogenetic lesions ETV6-RUNX1 (2.5% vs 24%, P < .001) and trisomies 4 and 10 (7.7% vs 24%, P < .001). Five-year event-free (EFS) and overall survival (OS) were inferior in children with DS-ALL: 69.9% ± 8.6% versus 78.1% ± 1.2% (P = .078), and 85.8% ± 6.5% versus 90.0% ± 0.9% (P = .033). However, when children with MLL translocations, BCR-ABL1, ETV6-RUNX1, and trisomies 4 and 10 were excluded, the EFS and OS were similar for children with and without DS (EFS 68.0 %± 9.3% vs 70.5% ± 1.9%, P = .817; and OS 86.7% ± 6.7% vs 85.4% ± 1.5%; P = .852), both overall and adjusted for race. DS-ALL displays a unique spectrum of biologic subtypes with different frequencies of sentinel cytogenetic lesions having a large influence on outcome.

Cytogenetics and Outcome Of Infants With Acute Lymphoblastic Leukemia and Absence Of MLL Rearrangements

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1349-1349
Author(s):  
Christine J Harrison ◽  
Anthony V. Moorman ◽  
Paola de Lorenzo ◽  
Rob Pieters ◽  
Zoann E. Dreyer ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Older Children ◽  
Childhood All ◽  
Poor Risk ◽  
Risk Patients ◽  
Flt3 Expression ◽  
Good Risk ◽  
Low Expression

Abstract Acute lymphoblastic leukemia (ALL) in infants less than one year of age is characterized by a high frequency of rearrangements of the MLL gene (MLL-R) and poor prognosis. Infants with no MLL rearrangements (MLL-G) have a better outcome than those with MLL-R. To better understand the association of chromosomal abnormalities and outcome among MLL-G infants, we carried out a detailed cytogenetic investigation of patients from two infant ALL trials: Interfant-99 and Children’s Oncology Group (COG)-P9407. Among 162 MLL-G patients, an abnormal karyotype was detected in 90/128 (70%) patients with a successful result. They were categorised according to cytogenetic risk group (good, intermediate and poor) as previously defined for childhood ALL. Compared with childhood ALL (1-18 years) using data from the UKALL97/99 treatment trial, the frequency of good risk cytogenetic abnormalities among MLL-G infants was significantly lower (12% v 60%, p<0.01), while the frequency of poor risk abnormalities (excluding MLL translocations) was similar (8% v 10%). While ETV6-RUNX1 fusion is present in 25% of childhood ALL, no ETV6-RUNX1 cases were found among 75 patients tested by FISH or RT-PCR. High hyperdiploidy was the most prevalent abnormality, although the frequency was also much lower than childhood ALL (12% v 38%, p<0.01). Other established translocations were observed in a small number of cases: t(9;22)(q34;q11)/BCR-ABL1 (n=2), t(1;19)(q23;p13)/TCF3-PBX1 (n=3) and the infant specific, t(7;12)(q36;p13)/ETV6-HLXB9 fusion (n=1). Interestingly the incidence of t(9;22) and t(1;19) among MLL-G infants was not markedly different from childhood ALL: 1.6% v 2.6% and 2.3% v 3.5%, respectively. Abnormalities of the short arm of chromosome 9 (9p) were observed in 14 (11%) cases at a similar incidence to childhood ALL. Chromosome 15 abnormalities were found in 12 patients. This more frequent occurrence of 15q abnormalities in infant ALL has been previously noted. It is well established that MLL-R infants are younger than their MLL-G counterparts. Classification of MLL-G patients by cytogenetic risk group showed further correlation with age. The majority of cytogenetic good risk and all poor risk patients were >9 months old, whereas half of the cytogenetic intermediate risk patients were <9 months. In addition, there was evidence of outcome heterogeneity according to cytogenetic risk group. Event free survival at 4 years was 93% (SE 6.9), 66% (SE 4.7) and 50% (SE 15.8) for good, intermediate and poor risk groups, respectively, similar to that observed in childhood ALL when the same cytogenetic classification was applied. Low FLT3 expression has been associated with an excellent outcome in infants with ALL treated on COG-P9407, and the majority (10/11) of cases with low expression were MLL-G. However, low FLT3 expression was not simply a reflection of MLL-G status, as 7 MLL-G patients had high FLT3 expression. We have shown that low expression in MLL-G patients is not associated with a particular cytogenetic risk group. Interestingly, none of the MLL-G patients with low expression had an event, whereas all 5 of the events occurred in the high expressers. We have confirmed a unique cytogenetic profile among infants with MLL-G ALL. We demonstrate that the MLL-G infants share the same cytogenetic abnormalities as older children with ALL, but the distribution of abnormalities differs. Generally infants with MLL-G ALL are older, have low FLT3 expression and have an improved outcome compared to their MLL-R counterparts. Despite small numbers of MLL-G infants, when classified into the same good, intermediate and poor risk cytogenetic subgroups as childhood ALL, their pattern of outcome was very similar to that observed in older children. However, their overall worse outcome likely reflects the differences in distribution of good and poor risk abnormalities: lower incidence of the good risk abnormality: high hyperdiploidy, absence of ETV6-RUNX1, and higher incidence of poor risk abnormalities. Nevertheless, these data suggest that some MLL-G infants, especially those with good risk cytogenetics, may benefit from treatment on childhood protocols, which are generally less intensive and less toxic than infant ALL regimens. Disclosures: No relevant conflicts of interest to declare.

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