The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group

We report the nonrandom occurrence, frequency, and degree of immunophenotype association of the t(1;14)(p34;q11) in children with acute lymphoblastic leukemia (ALL). This chromosomal abnormality occurred in leukemia cells from 5 of 1,630 (0.3%) consecutive children with newly diagnosed ALL who were entered on a single Pediatric Oncology Group classification study (POG 8600) between January 1986 and February 1989. The frequency of the t(1;14) was 3% (5 of 168 cases) in children with T-cell ALL. All five cases had pseudodiploid karyotypes, and in 3 cases the t(1;14) was accompanied by a deletion of the long arm of chromosome 6. This translocation is of special interest because the breakpoint on chromosome 14 in band q11 corresponds to the assigned locus of the T-cell receptor alpha/delta chain gene. All five of our patients and three cases reported previously have had T-cell ALL. These findings, considered together, suggest that this translocation is specific for T-cell ALL and that a gene in the 1p34 region may play an important role in malignant transformation of thymocytes.

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Role of cranial radiotherapy for childhood T-cell acute lymphoblastic leukemia with high WBC count and good response to prednisone. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster groups.

Journal of Clinical Oncology ◽

10.1200/jco.1997.15.8.2786 ◽

1997 ◽

Vol 15 (8) ◽

pp. 2786-2791 ◽

Cited By ~ 61

Author(s):

V Conter ◽

M Schrappe ◽

M Aricó ◽

A Reiter ◽

C Rizzari ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Lymphoblastic Leukemia ◽

Group Versus ◽

Rank Test ◽

Intrathecal Methotrexate ◽

Intrathecal Therapy ◽

Cell Acute Lymphoblastic Leukemia ◽

Wbc Count ◽

The Impact

PURPOSE The ALL-BFM 90 and AIEOP-ALL 91 studies share the same treatment backbone and have 5-year event-free survival (EFS) rates close to 75%. This study evaluated the impact of differing presymptomatic CNS therapies in T-cell acute lymphoblastic leukemia (T-ALL) patients with a good response to prednisone (PGR) according to WBC count and Berlin-Frankfurt-Münster (BFM) risk factor (RF). PATIENTS A total of 192 patients (141 boys; median age, 7.5 years) with T-ALL, PGR, RF less than 1.7, and no CNS leukemia diagnosed between 1990 and 1995 were enrolled onto the ALL-BFM 90 (n = 123) or AIEOP-ALL 91 (n = 69) study. Presymptomatic CNS therapy consisted of cranial radiation (CRT) and intrathecal methotrexate (I.T. MTX) (11 doses) in the BFM study and of extended triple intrathecal therapy (T.I.T.) (17 doses) in the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) study. Patients were divided into a low-WBC group (WBC count < 100,000/microL) and a high-WBC group (WBC count > 100,000/microL). EFS was compared using the log-rank test. RESULTS For patients treated with CRT and I.T. MTX (BFM group), the 3-year EFS rate was 89.8% (SE = 3.5) for 99 patients in the low-WBC group versus 81.9% (SE = 8.2) in the high-WBC group (difference not significant). Conversely, for patients treated with T.I.T. alone (AIEOP group), the EFS rate was 80.6% (SE = 5.6) in 55 patients with a low WBC count versus 17.9% (SE = 11.0) in 14 patients with a high WBC count (P < .001). CONCLUSION These data suggest that CRT may not be necessary in PGR T-ALL patients with a WBC count less than 100,000/microL; on the contrary, in patients with a high count, extended T.I.T. may be inferior to CRT and I.T. MTX.

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High Mir-221 Expression Is Associated with Poorer Treatment Outcome of Patients with T-Cell Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v118.21.1439.1439 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1439-1439 ◽

Cited By ~ 1

Author(s):

Hamilton L. Gimenes-Teixeira ◽

Guilherme A. dos Santos ◽

Dalila L. Zanette ◽

Priscila S Scheucher ◽

Luciana Correa Oliveira de Oliveira ◽

...

Keyword(s):

Treatment Outcome ◽

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Mirna Expression ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Disease Free Survival ◽

Cell Counts ◽

Cell Acute Lymphoblastic Leukemia ◽

The Impact

Abstract Abstract 1439 T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of immature T cells that accounts about 15% of pediatric and 25% of adult ALL cases. In the last years, several clinical and laboratory features have been described as prognostic markers; nevertheless, with intensification of therapy most of them have lost their predictive value. MicroRNA (miRNA) expression analysis has proved to be an useful tool for identifying specific subsets of cancer patients with relevant cytogenetic, laboratorial and clinical features. The aim of the present study was to determine if miRNAs may be useful markers in T-ALL. First, we performed a supervised analysis comparing the miRNA expression profile of T-ALL blasts from 36 T-ALL/CD56− and 12 T-ALL/CD56+. We selected CD56 as prognostic marker based on our previous report showing that the disease-free survival (DFS) of T-ALL/CD56+ patients was of 28.5 months compared to 69.8 in the CD56− group. Also patients tended to be older and to present normal platelet counts in the T-LLA/CD56+ group. We used the Taqman MicroRNA Assay Human Panel (Applied Biosystems) to perform a screening of 164 knowledge mature miRNA sequences using specific primers and probes according to manufacturer instructions. Total RNA input was normalized based on the geometric means of Ct values obtained from four endogenous RNAs. All reactions were run in duplicate and a coefficient of variation greater than 5% was used as an exclusion factor (seven miRNAs were excluded). The fold change was calculated using comparative 2−δCt method. We have identified a set of 14 miRNAs differentially expressed, of which miR-374 and miR-221 best distinguished T-ALL/CD56+ from T-ALL/CD56− blasts. Based on this profile, we selected miR-221 and miR-374 as potential markers and quantified their expression in the same samples using RQ-PCR. Patients were stratified as high and low expression using the median value as cut off. We detected a significant association between the miR-221 high expression and poorer treatment outcome. On the contrary, miR-374 expression levels were not associated with treatment outcome. We evaluate the impact of age, white blood cell counts, CD56 and miR221 expression on overall survival (OS). Age and miR-221 were the only ones found to be significant. The estimate 5-year OS (mean and confidence interval 95%) was of 67.0 ± 10.3% in the group of patients expressing miR-221 below the cut-off value, whereas this value was of 28.5 ± 14.5% in the alternative group. Even among T-ALL/CD56− patients, the higher expression of miR-221 was significantly associated with poorer outcome. Our data suggest that miR-221 play an important role in T-ALL and its regulation may represent a potential therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.

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Effects of cranial radiation in children with high risk T cell acute lymphoblastic leukemia: a Pediatric Oncology Group report

Leukemia ◽

10.1038/sj.leu.2401693 ◽

2000 ◽

Vol 14 (3) ◽

pp. 369-373 ◽

Cited By ~ 16

Author(s):

JH Laver ◽

JC Barredo ◽

M Amylon ◽

M Schwenn ◽

J Kurtzberg ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

High Risk ◽

Pediatric Oncology ◽

Lymphoblastic Leukemia ◽

Oncology Group ◽

Cranial Radiation ◽

Group Report ◽

Pediatric Oncology Group ◽

Cell Acute Lymphoblastic Leukemia

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Does activation of the TAL-1 gene occur in a majority of patients with T-cell acute lymphoblastic leukemia? A pediatric oncology group study

Molecular Medicine Today ◽

10.1016/s1357-4310(95)93701-3 ◽

1995 ◽

Vol 1 (8) ◽

pp. 352-353

Author(s):

R.O. Bash

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Pediatric Oncology ◽

Lymphoblastic Leukemia ◽

Oncology Group ◽

Oncology Group Study ◽

Pediatric Oncology Group ◽

Cell Acute Lymphoblastic Leukemia

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Clinical features and outcome of T-cell acute lymphoblastic leukemia in childhood with respect to alterations at the TAL1 locus: a Pediatric Oncology Group study

Blood ◽

10.1182/blood.v81.8.2110.2110 ◽

1993 ◽

Vol 81 (8) ◽

pp. 2110-2117 ◽

Cited By ~ 82

Author(s):

RO Bash ◽

WM Crist ◽

JJ Shuster ◽

MP Link ◽

M Amylon ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Clinical Features ◽

Pediatric Oncology ◽

Lymphoblastic Leukemia ◽

Genetic Defect ◽

Gene Rearrangements ◽

Oncology Group ◽

Pediatric Oncology Group ◽

Cell Acute Lymphoblastic Leukemia

Abstract Alteration of the TAL1 locus is the most common nonrandom genetic defect in childhood T-cell acute lymphoblastic leukemia (T-ALL). To determine if rearrangements of the TAL1 proto-oncogene confer a distinct leukemic phenotype, we studied leukemic peripheral blood or bone marrow samples from 182 children with newly diagnosed T-ALL enrolled on Pediatric Oncology Group treatment protocols. Forty-eight (26%) of the samples had a local rearrangement of the TAL1 locus. Demographic and clinical features were compared for patient subgroups with and without TAL1 rearrangements. The only clinical correlates that were significantly associated with TAL1 gene rearrangements were higher white blood cell count (P = .017) and higher hemoglobin (P = .007) at diagnosis. Immunophenotypically, samples with altered TAL1 were more likely to be CD2+ (P = .001) and lack CD10 (cALLa) expression (P = .007) than those without the rearrangement. There was a trend toward improved event-free survival (EFS) in patients with TAL1 rearrangements (4-year EFS was 44% +/- 7% for patients without the rearrangements v 59% +/- 11% for those with rearrangements), but the difference was not significant (P = .34). The role of TAL1 in leukemogenesis has yet to be clearly defined, and the prognostic significance of TAL1 gene rearrangements in T-ALL deserves further study.

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Pilot Study of Nelarabine in Combination With Intensive Chemotherapy in High-Risk T-Cell Acute Lymphoblastic Leukemia: A Report From the Children's Oncology Group

Journal of Clinical Oncology ◽

10.1200/jco.2011.40.8724 ◽

2012 ◽

Vol 30 (22) ◽

pp. 2753-2759 ◽

Cited By ~ 56

Author(s):

Kimberly P. Dunsmore ◽

Meenakshi Devidas ◽

Stephen B. Linda ◽

Michael J. Borowitz ◽

Naomi Winick ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Chemotherapy Regimen ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Poor Response ◽

Early Response ◽

Oncology Group ◽

Significant Difference ◽

Cell Acute Lymphoblastic Leukemia

Purpose Children's Oncology Group study AALL00P2 was designed to assess the feasibility and safety of adding nelarabine to a BFM 86–based chemotherapy regimen in children with newly diagnosed T-cell acute lymphoblastic leukemia (T-ALL). Patients and Methods In stage one of the study, eight patients with a slow early response (SER) by prednisone poor response (PPR; ≥ 1,000 peripheral blood blasts on day 8 of prednisone prephase) received chemotherapy plus six courses of nelarabine 400 mg/m2 once per day; four patients with SER by high minimal residual disease (MRD; ≥ 1% at day 36 of induction) received chemotherapy plus five courses of nelarabine; 16 patients with a rapid early response (RER) received chemotherapy without nelarabine. In stage two, all patients received six 5-day courses of nelarabine at 650 mg/m2 once per day (10 SER patients [one by MRD, nine by PPR]) or 400 mg/m2 once per day (38 RER patients; 12 SER patients [three by MRD, nine by PPR]). Results The only significant difference in toxicities was decreased neutropenic infections in patients treated with nelarabine (42% with v 81% without nelarabine). Five-year event-free survival (EFS) rates were 73% for 11 stage one SER patients and 67% for 22 stage two SER patients treated with nelarabine versus 69% for 16 stage one RER patients treated without nelarabine and 74% for 38 stage two RER patients treated with nelarabine. Five-year EFS for all patients receiving nelarabine (n = 70) was 73% versus 69% for those treated without nelarabine (n = 16). Conclusion Addition of nelarabine to a BFM 86–based chemotherapy regimen was well tolerated and produced encouraging results in pediatric patients with T-ALL, particularly those with a SER, who have historically fared poorly.

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Activating NOTCH1 Mutations Are Associated with Good Treatment Response in Childhood T-Cell Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v106.11.1444.1444 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1444-1444

Author(s):

Stephen Breit ◽

Martin Stanulla ◽

Thomas Flohr ◽

Martin Schrappe ◽

Wolf-Dieter Ludwig ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Confidence Interval ◽

Treatment Response ◽

Lymphoblastic Leukemia ◽

Wild Type ◽

Cell Acute Lymphoblastic Leukemia ◽

The Impact ◽

Notch1 Mutations

Abstract T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10–15 % of pediatric ALL. Very rare cases of T-ALL (< 1 %) harbor the chromosomal translocation t(7;9) that involves NOTCH1, a gene encoding a single-pass, heterodimeric transmembrane receptor. NOTCH1 has an essential function in early intrathymic T-cell development. Recently, it has been demonstrated that more than 50 % of childhood T-ALLs carry activating mutations within the NOTCH1 gene (Weng et al., Science 2004). In the present study, we systematically analyzed the impact of activating NOTCH1 mutations on treatment response in 108 pediatric T-ALLs, registered in the ongoing ALL-BFM 2000 trial. In 56 cases (51.8%) activating NOTCH1 mutations were identified, located either in the heterodimerization (38/56 mutations; 65.5%), in the PEST (10/56; 17.9%) or in both domains (8/56; 14.3%). The presence of activating NOTCH1 mutations was significantly correlated with good prednisolone (p = 0.001, c2 or Fisher’s exact test) and MRD response (p = 0.002). T-ALLs with NOTCH1 mutations were 3.7 times more likely to show a good prednisolone response (95% confidence interval = 1.64–8.33; p = 0.002) and 4.8 times more likely to show a favorable MRD response (95% confidence interval = 2.04–11.11; p = 0.0003) when compared to patients with wild type NOTCH1. Patients with mutated NOTCH1 were thus underrepresented in the high risk group of the ALL-BFM 2000 protocol. This influence of NOTCH1 mutational status on risk stratification was independent from other commonly used criteria, like age and initial white blood cell count (WBC) at the time of diagnosis. Considering the impact of NOTCH1 mutations on long term prognosis, we analyzed those 49 patients of this cohort with a median follow-up of > 4 years. Eight patients relapsed within this follow-up period, 2 patients with mutated and 6 with wild type NOTCH1. With this small number of relapses, this trend towards a favorable influence of activating NOTCH1 mutations on EFS did not reach statistical significance. In conclusion, T-ALLs with NOTCH1 mutations are demonstrated to be more sensitive than those without to the ALL-BFM 2000 treatment strategy and may show a lower rate of relapse.

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