Pediatric-inspired intensified therapy of adult T-ALL reveals the favorable outcome of NOTCH1/FBXW7 mutations, but not of low ERG/BAALC expression: a GRAALL study

Abstract

Despite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/B low ) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/B low in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatricinspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/B low and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatricinspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup. (Blood. 2011;118(19):5099-5107) IntroductionThe outcome of acute lymphoblastic leukemia (ALL) has been considerably improved in pediatric cases, with 5-year overall survival (OS) rates now reaching Ͼ 80%. 1 In adults with Philadelphia chromosome (Ph)-negative ALLs, even if the complete remission (CR) rate reaches 90%, long-term therapeutic results remain less satisfactory, with a 5-year OS rate of 45%. 1 The Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study group recently reported a significant improvement in the outcome of Ph-negative adult ALL using a pediatric-inspired, intensified treatment protocol. 2 T-ALL corresponds to a heterogeneous group of acute leukemias, which account for 35% of Ph-negative adult ALLs. The classic initial prognostic factors used for ALL therapeutic stratification are predominantly clinical: age, WBC count, and CNS involvement. 3 These undoubtedly identify prognostically distinct subgroups among patients with B lineage ALL, but they are less appropriate for the stratification of T-ALL.Although recent advances have led to spectacular progress in the understanding of T-ALL oncogenesis, 4 the large number of molecular markers identified in this process and the fact that most are only present in minor subgroups limit their use for therapeutic stratification. Recognized oncogenic pathways in T-ALL include transcriptional activation of several proto-oncogenes, submicroscopic deletions of tumor suppressor genes, and NOTCH1 and/or FBXW7 mutations. 5,6 The NOTCH1 signaling pathway has been shown to be an essential factor in normal and pathologic T lymphoid development. 7,8 In T-ALL, NOTCH1 abnormalities The online v...

Immature MEF2C-dysregulated T-cell leukemia patients have an early T-cell precursor acute lymphoblastic leukemia gene signature and typically have non-rearranged T-cell receptors

“…40 Although none of these mutations have previously been explicitly associated with outcome in our relatively limited number of patient samples, additional mutation screens using an expanded series of patient samples are required to determine whether our immature cluster/ETP-ALL samples differ from the spectrum of mutations identified in the St. Jude's and COG patient samples. 11,12 In contrast to adult T-ALL studies, [34][35][36] we did not observe low ERG or low BAALC expression in our immature cluster/ETP-ALL samples in line with results for adult T-ALL patients that enrolled on GRAALL protocols. 36 With respect to our immature T-ALL cluster, we previously identified a variety of distinct genetic rearrangements that result in the activation of oncogenes (e.g.…”

“…11,12 In contrast to adult T-ALL studies, [34][35][36] we did not observe low ERG or low BAALC expression in our immature cluster/ETP-ALL samples in line with results for adult T-ALL patients that enrolled on GRAALL protocols. 36 With respect to our immature T-ALL cluster, we previously identified a variety of distinct genetic rearrangements that result in the activation of oncogenes (e.g. NKX2-5, PU.1, and MEF2C), RUNX1, or ETV6 fusion products, all of which converge on the activation of MEF2C.…”

“…Although the expression of LYL1 was higher in the ABD cases than in the non-ABD ETP-ALL cases, significance was lost following correction for multiple testing. ERG1 or BAALC levels, previously linked to adult immature T-ALL/ETP-ALL and poor outcome in some, 34,35 but not all, 36 studies were not significantly elevated in our pediatric ETP-ALL series.…”

Toward aNOTCH1/FBXW7/RAS/PTEN–Based Oncogenetic Risk Classification of Adult T-Cell Acute Lymphoblastic Leukemia: A Group for Research in Adult Acute Lymphoblastic Leukemia Study

“…1 Recognized T-ALL oncogenic pathways include proto-oncogene activation, tumor suppressor gene deletion, and activation of the Notch1 pathway by NOTCH1/FBXW7 (N/F) mutations, 2,3 leading to various combinations of gene alterations and complex oncogenic networks. [4][5][6][7][8] N/F mutations involve either the heterodimerization domain, probably facilitating cleavage of the NOTCH receptor, and/or the negative regulatory PEST domain, 9 increasing the halflife of intracellular NOTCH.…”

The prognosis of CALM-AF10-positive adult T-cell acute lymphoblastic leukemias depends on the stage of maturation arrest

“…1,2 Although its outcome has improved significantly with current therapy, relapses are frequent and are associated with a poor prognosis .3,4 The prediction of relapsing T-ALL remains challenging and few of the classical initial prognostic factors appropriate for therapeutic stratification in B-lineage ALL apply. [5][6][7] Currently recognized predictors of poor outcome include the absence of NOTCH1 and/or FBXW7 mutation in adult T-ALL 8 and an early T-cell precursor (ETP) phenotype in pediatric T-ALL, defined as CD1a -, CD8…”