Low frequency of TEL-AML1 in relapsed acute lymphoblastic leukemia supports a favorable prognosis for this genetic subgroup

Rubnitz, Jeffrey E.; Behm, Frederick G.; Wichlan, David; Ryan, Ciara; Sandlund, John T.; Ribeiro, Raul C.; Rivera, Gaston K.; Hancock, Michael L.; Relling, Mary V.; Evans, William E.; Pui, Ching Hon; Downing, James R.

doi:10.1038/sj.leu.2401257

Cited by 73 publications

(54 citation statements)

References 13 publications

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“…However, none of the major studies disputed better outcome of TEL/AML1-positive patients. [2][3][4] In this respect, disturbing phenomenon emerged in retrospective studies on relapsed ALL. Not only do the TEL/AML1-positive leukaemias relapse but in some studies their relapse rate appears to be unexpectedly high.…”

Section: To the Editormentioning

confidence: 99%

Significantly lower relapse rate for TEL/AML1-positive ALL

et al. 1999

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CORRESPONDENCE Significantly lower relapse rate for TEL/AML1-positive ALL TO THE EDITORWe read with interest an updated analysis of TEL/AML1 incidence in relapsed ALL patients by Seeger et al. 1 Several reports have been published recently concerning the issue of prognostic impact of TEL/AML1. However, none of the major studies disputed better outcome of TEL/AML1-positive patients. [2][3][4] In this respect, disturbing phenomenon emerged in retrospective studies on relapsed ALL. Not only do the TEL/AML1-positive leukaemias relapse but in some studies their relapse rate appears to be unexpectedly high. 5 Prospective studies based on large cohorts of patients will contribute to disclosure of a real clinical significance of TEL/AML1 fusion gene. The major drawback of retrospective studies resides in a possible selection bias due to low availability of samples from a defined population.Present Seeger's data are based on testing 268 patients with relapsed B cell precursor (BCP) ALL while only 178 cases are included in the declared prospective study. Unfortunately, the proportion of evaluated samples is not mentioned. Moreover, only BCP ALL relapses are considered. In our opinion, exclusion of subgroups that are seemingly irrelevant for analysis (T lineage and mature B ALL) has no effect on the possible overall selection bias.In our updated analysis (October 1994-April 1999) the incidence of TEL/AML1 among relapsed ALL patients is 12.1% (7/58), slightly higher than in our original report (8.9%, 4/45). 6 The incidence within BCP ALL increased from 11.8% (4/34) to 15.2% (7/46). However, in comparison to the incidence of TEL/AML1 positivity at diagnosis (59/241, 24.5%), the difference is statistically significant (12.1% vs 24.5%, P = 0.026). The significant level is reached even when we take into account only patients with BCP immunophenotype (15.2% (7/46) vs 29% (59/203), P = 0.037). Unfortunately, this kind of data is not provided by Seeger et al. Assuming a similar proportion of TEL/AML1-positive cases among newly diagnosed patients we can speculate that a comparable difference exists in the German population.Among published studies, our cohort of relapsed patients is the most precisely defined and the possibility of bias is minimised. We are aware that the size of our cohort is markedly lower than that described by Seeger et al. Nevertheless, present updated analysis of TEL/AML1 incidence among Czech children with ALL at relapse is based on 58 patients. It is the second largest cohort published to date. TEL/AML1-positive relapses are characterised by a long duration of first remission (11-89, median 34 months for positive vs 2-149, median 18 months for negative children; P = 0.016 in our study). We completely agree with Seeger et al that a long follow-up is necessary to establish the true relapse rate of TEL/AML1-positive ALL. Two studies with a long median follow-up (8.3 and 8.4 years) 2,3 documented highly significant differences in disease-free survival (DFS) between TEL/AML1-positive and negative patients (P = 0....

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Section: To the Editormentioning

confidence: 99%

Significantly lower relapse rate for TEL/AML1-positive ALL

et al. 1999

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“…6 Investigators from St. Jude and from the DFCI also demonstrated a very low frequency of TEL-AML1 in patients with relapsed ALL, consistent with the excellent outcome of patients with this translocation. 7,8 Despite the plethora of studies that suggest that TEL-AML1 is an independent favorable predictor of outcome and should be used in risk classification, questions remain regarding its true impact. 9 For example, some reports demonstrated a high incidence (20% to 24%) of the TEL-AML1 fusion in relapsed cases of ALL, thereby casting doubt as to the prognostic significance of this genetic alteration.…”

Section: Introductionmentioning

confidence: 99%

Prospective Analysis of TEL Gene Rearrangements in Childhood Acute Lymphoblastic Leukemia: A Children's Oncology Group Study

Rubnitz

Wichlan

Devidas

et al. 2008

JCO

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Purpose-To prospectively determine the prognostic significance of the TEL-AML1 fusion in children with acute lymphoblastic leukemia (ALL).Patients and Methods-TEL gene status was determined for 926 patients with B-precursor ALL enrolled on the Pediatric Oncology Group ALinC 16 trials and patients were followed for a median time of eight years.Results-Rearrangements of the TEL gene were detected in 244 (26%) patients. The estimated 5-year event-free survival rate (± SE) for patients with TEL rearrangements was 86% ± 2%, compared with 72% ± 2% for those with germline TEL (p<0.0001). TEL rearrangements were associated with a superior outcome among patients with standard-risk ALL, high-risk ALL, and rapid early responses to therapy. In a multivariate analysis that included risk group, sex, and day 15 marrow status, TEL status was an independent predictor of outcome (p=0.0002).Conclusion-We conclude that TEL gene status should be incorporated into risk classification schemes and suggest that patients who have the TEL-AML1 fusion and rapid early responses to therapy should be treated with antimetabolite-based therapy designed to maintain their high cure rates and avoid late effects.

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“…high initial WBC, early relapse and death) are general features of this subgroup. In fact they seem to differ from the characteristics of TEL/AML1-positive patients generally described in the literature (Nakao et al, 1996;Borkhardt et al, 1997;Loh et al, 1998;Seeger et al, 1998;Rubnitz et al, 1999;Zuna et al, 1999). However, studies describing the incidence of the TEL/AML1 fusion transcript in relapsed ALL patients did not analyse these characteristics.…”

Section: Discussionmentioning

confidence: 77%

“…Selection bias in our study may be a cause of this discrepancy. But other studies also reported a normal incidence of about 20± 24% Seeger et al, 1998) or a slightly lower incidence of 19% (Nakao et al, 1996;Rubnitz et al, 1999;Zuna et al, 1999) of TEL/AML1 fusion in relapsed patients. In these studies, the analyses were mainly carried out on leukaemic cells collected at relapse and the translocation may have occurred during therapy; at initial diagnosis, the leukaemic cells might have been negative for a TEL/AML1 fusion transcript.…”

Section: Discussionmentioning

confidence: 92%

Minimal residual disease studies are beneficial in the follow‐up of TEL/AML1 patients with B‐precursor acute lymphoblastic leukaemia

et al. 2000

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Summary. The t(12;21)(p13;q22) translocation has been identified as the most common chromosomal abnormality in childhood acute lymphoblastic leukaemia (ALL). Initially, several investigators reported an excellent prognosis in paediatric leukaemias with this translocation, but other studies showed a 20% incidence in relapsed ALL. We performed an extensive analysis of 90 ALL patients. In 17 (19%) cases a TEL/AML1 fusion was found. However, this group was not representative as it included a high number of relapsed patients compared with the normal incidence in B-precursor ALL [54 in continuous complete remission (CCR) and 36 relapsed patients] and only a slightly better prognosis for TEL/AML1-positive patients was found (not significant) (four relapses in 17 TEL/AML1-postive patients vs. 32 relapses in 73 TEL/AML1-negative patients).Comparison of known prognostic factors (age, sex, ploidy, white blood cell count and immunophenotype) between relapsed TEL/AML1-positive and TEL/AML1-positive patients in CCR did not reveal differences, except that the white blood cell count was significantly higher in the relapsed group (P 0´001). Time between diagnosis and relapse was not different for the relapsed TEL/AML1-positive group vs. the relapsed TEL/AML1-negative group. In 11 TEL/AML1-positive patients, the minimal residual disease (MRD) level at the end of induction therapy was quantified in a limiting dilution assay using IGH or TCRD junctional regions as polymerase chain reaction (PCR) targets. In all four relapsed patients, the level of MRD at the end of induction therapy was high (range 0´24±1´2%), whereas in all seven CCR patients, the MRD level was extremely low (0´02 to , 0´001%). In agreement with previous studies in which MRD levels at the end of induction therapy were found to be the strongest risk factor independent of other risk factors, in the present study we show that the MRD level remains a risk factor independent of the presence of a TEL/ AML1 fusion gene.

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Low frequency of TEL-AML1 in relapsed acute lymphoblastic leukemia supports a favorable prognosis for this genetic subgroup

Cited by 73 publications

References 13 publications

Significantly lower relapse rate for TEL/AML1-positive ALL

Significantly lower relapse rate for TEL/AML1-positive ALL

Prospective Analysis of TEL Gene Rearrangements in Childhood Acute Lymphoblastic Leukemia: A Children's Oncology Group Study

Minimal residual disease studies are beneficial in the follow‐up of TEL/AML1 patients with B‐precursor acute lymphoblastic leukaemia

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