scholarly journals TEL-AML1 Fusion Transcript in Relapsed Childhood Acute Lymphoblastic Leukemia

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1716-1722 ◽  
Author(s):  
Karlheinz Seeger ◽  
Hans-Peter Adams ◽  
Dirk Buchwald ◽  
Birgit Beyermann ◽  
Bernhard Kremens ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Fusion Transcript ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Long Term Results ◽  
Childhood All ◽  
Cryptic Translocation

The cryptic translocation t(12;21)(p13;q22) has been recently recognized as the most common genetic rearrangement in B-lineage childhood acute lymphoblastic leukemia (ALL). The resulting fusion transcript, termed TEL-AML1, has been associated with an excellent prognosis at initial ALL diagnosis. Hence, we postulated that the incidence of TEL-AML1 fusion should be lower in patients with ALL relapse. To address this assumption and to investigate the prognostic significance of TEL-AML1 expression in relapsed childhood ALL, bone marrow samples of 146 children were analyzed by reverse-transcriptase (RT)-polymerase chain reaction (PCR). All children were treated according to Berlin-Frankfurt-Münster (BFM) ALL relapse trial protocols (ALL-REZ BFM 90-96). Their clinical features and outcome were compared with those of 262 patients who could not be tested due to lack of bone marrow samples. Thirty-two of 146 children with relapsed ALL were TEL-AML1–positive. Four of the negative patients had T-lineage and nine Philadelphia chromosome (Ph1)-positive leukemia. Thus, the incidence ofTEL-AML1 in relapsed Ph1-negative, B-cell precursor ALL is 32 of 133 (24%). The 32 TEL-AML1–positive and 101 negative patients differed significantly with respect to duration of last remission (42.5 v 27 months; P = .0001) and age at initial diagnosis (53.5 v 74 months;P = .0269). At a median follow-up time of 21.5 months, children positive for TEL-AML1 had a significantly (P = .0011) higher probability of event-free survival (EFS; 0.79 v 0.33). The predominant majority of patients had been treated for initial ALL according to German multicenter BFM (108 of 133) or Cooperative ALL study group (CoALL) (19 of 133) frontline protocols. The comparison of tested and not-tested (N = 262) patients showed no significant difference.TEL-AML1 positivity predicted a favorable short-term outcome; long-term results are unknown. Screening for TEL-AML1 should become routine at relapse diagnosis and might be used for therapy stratification in future trials.

scholarly journals TEL-AML1 Fusion Transcript in Relapsed Childhood Acute Lymphoblastic Leukemia

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1716-1722 ◽  
Author(s):  
Karlheinz Seeger ◽  
Hans-Peter Adams ◽  
Dirk Buchwald ◽  
Birgit Beyermann ◽  
Bernhard Kremens ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Fusion Transcript ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Long Term Results ◽  
Childhood All ◽  
Cryptic Translocation

Abstract The cryptic translocation t(12;21)(p13;q22) has been recently recognized as the most common genetic rearrangement in B-lineage childhood acute lymphoblastic leukemia (ALL). The resulting fusion transcript, termed TEL-AML1, has been associated with an excellent prognosis at initial ALL diagnosis. Hence, we postulated that the incidence of TEL-AML1 fusion should be lower in patients with ALL relapse. To address this assumption and to investigate the prognostic significance of TEL-AML1 expression in relapsed childhood ALL, bone marrow samples of 146 children were analyzed by reverse-transcriptase (RT)-polymerase chain reaction (PCR). All children were treated according to Berlin-Frankfurt-Münster (BFM) ALL relapse trial protocols (ALL-REZ BFM 90-96). Their clinical features and outcome were compared with those of 262 patients who could not be tested due to lack of bone marrow samples. Thirty-two of 146 children with relapsed ALL were TEL-AML1–positive. Four of the negative patients had T-lineage and nine Philadelphia chromosome (Ph1)-positive leukemia. Thus, the incidence ofTEL-AML1 in relapsed Ph1-negative, B-cell precursor ALL is 32 of 133 (24%). The 32 TEL-AML1–positive and 101 negative patients differed significantly with respect to duration of last remission (42.5 v 27 months; P = .0001) and age at initial diagnosis (53.5 v 74 months;P = .0269). At a median follow-up time of 21.5 months, children positive for TEL-AML1 had a significantly (P = .0011) higher probability of event-free survival (EFS; 0.79 v 0.33). The predominant majority of patients had been treated for initial ALL according to German multicenter BFM (108 of 133) or Cooperative ALL study group (CoALL) (19 of 133) frontline protocols. The comparison of tested and not-tested (N = 262) patients showed no significant difference.TEL-AML1 positivity predicted a favorable short-term outcome; long-term results are unknown. Screening for TEL-AML1 should become routine at relapse diagnosis and might be used for therapy stratification in future trials.

scholarly journals TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4252-4258 ◽  
Author(s):  
TW McLean ◽  
S Ringold ◽  
D Neuberg ◽  
K Stegmaier ◽  
R Tantravahi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocation ◽  
Fusion Transcript ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Childhood All ◽  
Polymerase Chain ◽  
B Lineage

Abstract Polymerase chain reaction-based screening of childhood acute lymphoblastic leukemia (ALL) samples showed that a TEL/AML1 fusion transcript was detected in 27% of all cases, representing the most common known gene rearrangement in childhood cancer. The TEL/AML1 fusion results from a t(12;21)(p13;q22) chromosomal translocation, but was undetectable at the routine cytogenetic level. TEL/AML1-positive patients had exclusively B-lineage ALL, and most patients were between the ages of 2 and 9 years at diagnosis. Only 3/89 (3.4%) adult ALL patients were TEL/AML1-positive. Most importantly, TEL/AML1-positive children had a significantly lower rate of relapse compared with TEL/AML1-negative patients (0/22 v 16/54, P = .004). Co- immunoprecipitation experiments demonstrated that TEL/AML-1 formed homodimers in vitro, and heterodimerized with the normal TEL protein when the two proteins were expressed together. The elucidation of the precise mechanism of transformation by TEL/AML1 and the role of TEL/AML1 testing in the treatment of childhood ALL will require additional studies.

CD34+CD38-CD58- leukemia-Propagating Cells at Diagnosis Could Identify Patients at High-Risk for Relapse in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3795-3795
Author(s):  
Yuan Kong ◽  
Lan-Ping Xu ◽  
Yan-Rong Liu ◽  
Ya-Zhen Qin ◽  
Yu-Qian Sun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Hematopoietic Stem Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Hematopoietic Stem ◽  
Peking University

Abstract Background: Relapse of Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ALL) may result from the persistence of leukemia stem cells sometimes termed leukemia-propagating cells (LPCs). We recently found that Ph+ALL LPCs are enriched in the CD34+CD38-CD58- fraction using anti-CD122-conditioned NOD/SCID xenograft assay by intra-bone marrow injection, which translating to adverse clinical outcomes (Kong Y, et al. Leukemia 2014. accepted). Despite the widespread use of abelson tyrosine kinase inhibitors (TKIs) in Ph+ALL, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the best curative option. However, whether the prognostic significance of the identified LPCs phenotype to identify patients at high risk for relapse could retain in Ph+ALL after allo-HSCT, if any, is unknown. Aims: To investigate the prognostic significance of the candidate CD34+CD38-CD58- LPCs in Ph+ALL subjects underwent allo-HSCT. Methods: A total of 80 consecutive adults (18-60 years) with Ph+ALL underwent allo-HSCT were eligible for the study at Peking University Institute of Hematology from January 1, 2009 to December 31, 2013. Imatinib was routinely administered in subjects pre- and post-HSCT as previously reported. A multi-parameter flow cytometry analysis of CD58-FITC/CD10-PE/CD19-APC-Cy7/CD34-PerCP/CD45-Vioblue/ CD38-APC on gated leukemia blasts of bone marrow was performed at diagnosis. Furthermore, minimal residual disease (MRD) was monitored by BCR/ABL transcripts in bone marrow samples at diagnosis, directly before transplantation, as well as serially at 1, 2, 3, 6, 9, 12,24,36,60 months post-HSCT and at relapse using real-time quantitative polymerase chain reaction. Cumulative incidences of relapse (CIR) and non-relapse mortality were calculated using the Kalbfleisch and Prentice method. Leukemia-free survival (LFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Factors at a level of P<0.1 were included as variables in the multivariate Cox regression model. The study was approved by the Ethics Committee of Peking University People’s Hospital. Results: On the basis of blasts phenotypes at diagnosis, subjects were stratified into CD34+CD38-CD58- group (N=15) and other phenotype group (N=65). The demographic and clinical characteristics showed no significant difference between the two phenotype groups. Median follow-up was 25.5 mo (range, 6-65 mo) for all subjects and 33 mo (range, 6-65 mo) for survivors. During the MRD monitoring, significantly higher levels of BCR/ABL transcripts were detected in subjects in CD34+CD38-CD58- group than persons in other phenotype group especially at 3 mo post-HSCT [0.12(0-152.4)% vs. 0(0-100)%, P=0.001]. Additionally, CD34+CD38-CD58- LPCs phenotype directly correlated with higher 3-year CIR (63.2% [58.2-68.1%] vs. 5.3% [5.1-5.5%]; P<0.0001), worse LFS (30.2% [8.1-56.6%] vs. 78.7% [64.5-87.7%]; P=0.001) and OS (37.7% [12.6-63.2%] vs. 82.3% [68.5-90.4%]; P=0.0004). Multivariate analyses indicated that CD34+CD38-CD58- LPCs phenotype at diagnosis and BCR-ABL reduction at 3 mo post-HSCT were independent risk factors for relapse, LFS and OS in adults with Ph+ALL underwent allo-HSCT. Summary/Conclusion: Our data suggest that a candidate CD34+CD38-CD58- LPCs phenotype at diagnosis allows rapid identification of high-risk patients for relapse even after allo-HSCT. Risk-stratification post-HSCT therapy incorporating analysis of CD34+CD38-CD58- LPCs phenotype at diagnosis promises to benefit the adults with Ph+ALL in the future. Acknowledgment: Supported by the National Natural Science Foundation of China (grant nos. 81370638&81230013), the Beijing Municipal Science and Technology Program (grant no. Z141100000214011), and Peking University People’s Hospital Research and Development Funds (grant no. RDB2012-23). Disclosures No relevant conflicts of interest to declare.

scholarly journals Prognostic implications of cytogenetic studies in an intensively treated group of children with acute lymphoblastic leukemia

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2130-2135 ◽  
Author(s):  
JA Fletcher ◽  
VM Kimball ◽  
E Lynch ◽  
M Donnelly ◽  
K Pavelka ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Leukemia Cell ◽  
Treated Group ◽  
Childhood All ◽  
Number Of Children ◽  
Prognostic Implications

Abstract We assessed the prognostic significance of leukemia cell cytogenetics by analyzing bone marrow aspirates obtained at time of diagnosis in 165 children on a single protocol for acute lymphoblastic leukemia (ALL). These children were assigned to six mutually exclusive cytogenetic categories as follows: (1) hyperdiploid, with 50 or more chromosomes (n = 35); (2) hyperdiploid, with 47 to 49 chromosomes (n = 11); (3) diploid (n = 42); (4) pseudodiploid (n = 34); (5) hypodiploid (n = 9); and (6) insufficient data (n = 34). At a median follow-up of 5 years, there were no statistically significant differences between any of these cytogenetic categories in either event-free or overall survival. Those children with chromosomal translocations (n = 26) appeared to fare the same as those lacking translocations (n = 105). The absence of karyotypic prognostic significance was observed not only within the overall group, but also when the results were stratified by standard- risk and high-risk status. Of the specific structural chromosome changes that we studied, only the Philadelphia chromosome (Ph) appeared to confer a poor prognosis, although there were too few such cases to achieve statistical significance. Although we did not detect the event- free survival differences that have been described previously in hyperdiploid, hypodiploid, and pseudodiploid childhood ALL, our findings must be viewed as preliminary given the small number of children in some of the cytogenetic categories. We think that the prognostic implications of these cytogenetic features might have been nullified by improvements in therapy.

scholarly journals Prognostic significance of day 14 bone marrow evaluation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia

Cancer ◽  
2016 ◽  
Vol 122 (24) ◽  
pp. 3812-3820 ◽  
Author(s):  
Nicholas J. Short ◽  
Hagop M. Kantarjian ◽  
Koji Sasaki ◽  
Jorge E. Cortes ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Bone Marrow Evaluation

scholarly journals TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4252-4258 ◽  
Author(s):  
TW McLean ◽  
S Ringold ◽  
D Neuberg ◽  
K Stegmaier ◽  
R Tantravahi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocation ◽  
Fusion Transcript ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Childhood All ◽  
Polymerase Chain ◽  
B Lineage

Polymerase chain reaction-based screening of childhood acute lymphoblastic leukemia (ALL) samples showed that a TEL/AML1 fusion transcript was detected in 27% of all cases, representing the most common known gene rearrangement in childhood cancer. The TEL/AML1 fusion results from a t(12;21)(p13;q22) chromosomal translocation, but was undetectable at the routine cytogenetic level. TEL/AML1-positive patients had exclusively B-lineage ALL, and most patients were between the ages of 2 and 9 years at diagnosis. Only 3/89 (3.4%) adult ALL patients were TEL/AML1-positive. Most importantly, TEL/AML1-positive children had a significantly lower rate of relapse compared with TEL/AML1-negative patients (0/22 v 16/54, P = .004). Co- immunoprecipitation experiments demonstrated that TEL/AML-1 formed homodimers in vitro, and heterodimerized with the normal TEL protein when the two proteins were expressed together. The elucidation of the precise mechanism of transformation by TEL/AML1 and the role of TEL/AML1 testing in the treatment of childhood ALL will require additional studies.

scholarly journals Prognostic implications of cytogenetic studies in an intensively treated group of children with acute lymphoblastic leukemia

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2130-2135
Author(s):  
JA Fletcher ◽  
VM Kimball ◽  
E Lynch ◽  
M Donnelly ◽  
K Pavelka ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Leukemia Cell ◽  
Treated Group ◽  
Childhood All ◽  
Number Of Children ◽  
Prognostic Implications

We assessed the prognostic significance of leukemia cell cytogenetics by analyzing bone marrow aspirates obtained at time of diagnosis in 165 children on a single protocol for acute lymphoblastic leukemia (ALL). These children were assigned to six mutually exclusive cytogenetic categories as follows: (1) hyperdiploid, with 50 or more chromosomes (n = 35); (2) hyperdiploid, with 47 to 49 chromosomes (n = 11); (3) diploid (n = 42); (4) pseudodiploid (n = 34); (5) hypodiploid (n = 9); and (6) insufficient data (n = 34). At a median follow-up of 5 years, there were no statistically significant differences between any of these cytogenetic categories in either event-free or overall survival. Those children with chromosomal translocations (n = 26) appeared to fare the same as those lacking translocations (n = 105). The absence of karyotypic prognostic significance was observed not only within the overall group, but also when the results were stratified by standard- risk and high-risk status. Of the specific structural chromosome changes that we studied, only the Philadelphia chromosome (Ph) appeared to confer a poor prognosis, although there were too few such cases to achieve statistical significance. Although we did not detect the event- free survival differences that have been described previously in hyperdiploid, hypodiploid, and pseudodiploid childhood ALL, our findings must be viewed as preliminary given the small number of children in some of the cytogenetic categories. We think that the prognostic implications of these cytogenetic features might have been nullified by improvements in therapy.

Peripheral blast counts at diagnosis of late isolated bone marrow relapse of childhood acute lymphoblastic leukemia predict response to salvage chemotherapy and outcome. Berlin-Frankfurt-Münster Relapse Study Group.

1996 ◽  
Vol 14 (10) ◽  
pp. 2812-2817 ◽  
Author(s):  
C Bührer ◽  
R Hartmann ◽  
R Fengler ◽  
B Rath ◽  
M Schrappe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Cranial Irradiation ◽  
Salvage Chemotherapy ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
High Dose ◽  
Study Group ◽  
Childhood All ◽  
The Impact

PURPOSE In newly diagnosed childhood acute lymphoblastic leukemia (ALL), a high tumor burden indicates a poor prognosis, while no such link has been established yet after relapse. The impact of the absolute peripheral blast count (PBC) at the time of relapse on the response to salvage chemotherapy after a late isolated bone marrow (BM) relapse is the subject of this prospective analysis. PATIENTS AND METHODS Since 1983, 260 children with a first isolated BM relapse of ALL that occurred 6 months or later after elective cessation of front-line therapy were enrolled onto four consecutive multicenter trials of the Berlin-Frankfurt-Münster (BFM) Relapse Study Group. All patients received intensive multiagent induction and consolidation chemotherapy for 6 months, followed by maintenance therapy with methotrexate (MTX) and thioguanine for 2 years. Treatment of subclinical meningeal leukemia consisted of high-dose intravenous MTX and intrathecally administered cytostatic drugs, which was augmented by cranial irradiation since 1988. RESULTS At the time relapse was diagnosed, PBC varied considerably among patients (median, 1,060/microL; range, 0 to 106,800/microL). Achievement of a second complete remission (CR) was not significantly different in children without detectable circulating blasts at relapse (37 of 38) and those with moderate (1 to 9,999/microL) PBC (165 of 171). In contrast, only 42 of 51 children with high PBC (> or = 10,000/microL) achieved a second CR (P = .0015). At a median follow-up time of 40 months, the 10-year event-free survival (EFS) probability was significantly (P = .0001) higher in children without circulating blasts (.64) than in children with moderate PBC (.32) or high PBC (.10). There was a preponderance of boys in the group without detectable circulating blasts, while the three PBC-defined groups did not differ with respect to frontline treatment, age at initial diagnosis, age at relapse, time off therapy, or salvage treatment protocol. On sequential univariate and multivariate analysis, only duration of first remission > or = 48 months was an additional independent indicator of adverse prognosis, while preventive cranial irradiation improved outcome independently of PBC. CONCLUSION The absence of blasts on peripheral-blood smears at the time of a first late isolated BM relapse of childhood ALL is associated with a favorable response and prognosis in chemotherapy-treated children, who should be regarded as ineligible for bone marrow transplantation (BMT) unless a second round of chemotherapy has failed to produce a response.

scholarly journals 12p Abnormalities and the TEL Gene (ETV6) in Childhood Acute Lymphoblastic Leukemia

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4559-4566 ◽  
Author(s):  
S.C. Raimondi ◽  
S.A. Shurtleff ◽  
J.R. Downing ◽  
J. Rubnitz ◽  
S. Mathew ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Genetic Material ◽  
Fusion Transcript ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Similar Distribution ◽  
Event Free Survival ◽  
Childhood All ◽  
Free Survival ◽  
The Status

Abstract Although abnormalities involving the short arm of chromosome 12 (12p) are one of the most frequently observed rearrangements in childhood acute lymphoblastic leukemia (ALL), little is known about the frequency of different structural abnormalities and their relationship to the status of the ETV6 (also named TEL) gene in this region. Of 815 children with newly diagnosed ALL, 94 (11.5%) had a total of 104 cytogenetic 12p abnormalities. Loss of genetic material was observed in 67 (64%) of these abnormalities. Cases with 12p alterations had a much lower frequency of hyperdiploidy greater than 50 (7%) than did the ALL population in general, but these cases had a similar distribution of immunophenotype and similar 5-year event-free survival (70% ± 5% SE v 64% ± 2%, P = .64). Rearrangement of the ETV6 gene was identified in 36 (56%) of 64 cases evaluated. The ETV6-CBFA2 (TEL-AML1) fusion transcript was found in 25 (66%) of 38 cases evaluated, and all but one of these showed ETV6 rearrangement. Importantly, ETV6 rearrangement was associated with a favorable prognosis (5-year event-free survival: 89% ± 6% v 60% ± 1%, P < .01). We conclude that most but not all 12p cytogenetic abnormalities in childhood ALL involve ETV6, and that rearrangement of ETV6 is associated with a favorable treatment outcome.

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