TEL-AML1 fusion transcript designates a favorable outcome with an intensified protocol in childhood acute lymphoblastic leukemia

Abstract

CORRESPONDENCE TEL-AML1 fusion transcript designates a favorable outcome with an intensified protocol in childhood acute lymphoblastic leukemia TO THE EDITORDespite the striking success that has been achieved in the treatment of acute lymphoblastic leukemia (ALL), 20-25% of children eventually relapse. 1 Several well-accepted clinical and biological features are of prognostic value: age between 1 and 10 years, leukocyte count of less than 50 000/ l, and hyperdiploid content (DNA index у1.16Ͻ1.60) all predictive of a good outcome. 1 The presence of translocations t(4;11) and t(9;22) confer a poor prognosis and the cryptic translocation t(12;21)(p12;q22), a good prognosis. 2 The t(12;21)(p12;q22) translocation fuses the TEL gene on 12p and the AML1 gene on 21q. 3,4 The predicted hybrid protein includes the region of TEL that is thought to interact with other proteins and to possess transactivating properties together with the DNA binding and transactivating motifs of AML1. In addition, the unrearranged TEL allele is lost in some cases. 5 Several studies have determined that t(12;21) is involved exclusively in B-lineage ALL, mostly in children, and is associated with an excellent prognosis. [6][7][8][9] Recently, however, Borkhardt et al 10 reported that even though patients with the positive chimeric transcript are good responders and achieve CCR, they may develop late relapses. Therefore it is of the utmost importance to identify, at diagnosis, patients in the standard risk group with the tendency to relapse.In the present study, we analyzed 98 B-lineage childhood ALL patients for the TEL-AML1 fusion transcript at diagnosis and correlated the findings with duration of remission according to treatment protocol.Twenty-four of the 98 patients (24%) studied at diagnosis were positive for the TEL-AML1 transcript. The clinical features of the children who were positive or negative for the TEL-AML1 fusion transcript are summarized in Table 1. There were no significant differences between the groups in age, DNA index (DI), leukocyte count, phenotype (CD10 + vs CD10 − ) or response to therapy. Seventy-five percent of the positive patients peaked at age 2-6 although only 38% of the negative patients were in this age group. A recent study showed that the age distribution of TEL-AML1-positive patients peaked at 2-4 years. 11 Eighty-four percent had a leukocyte count of less than 50 000/ l ( Table 1). The majority had a diploid DNA content, generally associated with a less favorable prognosis. Good response to therapy, defined as the achievement of remission by day 23 or before, was noted in 87% of the TEL-AML1-positive children compared to 65% of the TEL-AML1-negative children (P = 0.06).Relapse occurred in 12.5% (3/24) of the positive group and 22% (16/74) of the negative group. The median duration of remission was 56 months and 19 months in the positive and negative groups, respectively.

Outcome of ETV6/RUNX1‐positive childhood acute lymphoblastic leukaemia in the NOPHO‐ALL‐1992 protocol: frequent late relapses but good overall survival

“…Shurtleff et al (1995) suggested that this ALL subgroup was characterized by an excellent prognosis, although the 5‐year event‐free survival (EFS) was not significantly better than for the t(12;21)‐negative cases. Similar data indicating a favourable outcome for this patient cohort have since come from several retrospective studies (McLean et al , 1996; Borkhardt et al , 1997; Avigad et al , 1999; Maloney et al , 1999; Jamil et al , 2000; Uckun et al , 2001) as well as from a recent prospective study in which the survival rate was significantly better for BCP ALLs with ETV6/RUNX1 than for those without this fusion (Loh et al , 2006). However, many investigators have not observed any statistically significant survival differences between t(12;21)‐positive and ‐negative ALLs (Lanza et al , 1997; Takahashi et al , 1998; Kempski et al , 1999; Codrington et al , 2000; Hann et al , 2001; Hubeek et al , 2001; Pajor et al , 2001).…”

TEL/AML1 rearrangement and the prognostic significance in childhood acute lymphoblastic leukemia in Hong Kong

“…With the sensitivity level of 10 −4 in the nested RT-PCR employed in this study, rapid clearance of the TEL/ AML1 fusion gene on completion of the induction therapy in 50% of the patients suggested that TEL/ AML1+ leukemic clones were highly sensitive to chemotherapy. Many reports suggest excellent prognosis for patients with the TEL/AML1 rearrangement and propose that the TEL/AML1 fusion gene is an independent favorable prognostic factor in childhood ALL [14,28,[33][34][35]. However, some recent conflicting reports challenged the prognostic impact of the TEL/AML1 rearrangement [20,21].…”

Determination of ETV6‐RUNX1 genomic breakpoint by next‐generation sequencing

“…ETV6-RUNX1 fusion protein is expressed in 25% of childhood B-lineage ALL cases and is associated with favorable prognosis following conventional therapeutic strategies [23][24][25][26][27][28]. However, some patients relapse at a late stage during therapy or after therapy, while they could also achieve sustained second remission.…”