EARLY T-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDHOOD

Abstract

Early T-cell precursor (ETP) ALL accounts for 10% to 15% of T-ALL, which arises from an early T-cell lineage clone with aberrant expression of myeloid and/or early progenitor cell markers (1,2). ETPs are a subset of thymocytes representing recent immigrants from the bone marrow to the thymus, they retain multilineage differentiation potential, suggesting their direct derivation from hematopoietic stem cells (3). ETP-ALL, which was first reported by Coustan-Smith in 2009, largely overlaps with the pro-T subtype of the EGIL classification; its special diagnostic criteria in immunophenotypic screening are the absence of CD1a and CD8 expression, the absence or weak expression of CD5, and the presence of strong positive for at least one of CD34, CD117, HLADR, CD13, CD33, CD11b, and CD65 (2,4-6). In case of strong positivity of CD5, at least two of the latter must be strong positive (6). There is also novel evidence that the myeloid marker CD371 may be positive in ETP (6).The genetic features of ETP-ALL are similar to those of hematopoietic stem cells and myeloid progenitor cells. The genomic mutations of ETP-ALL are enriched in hematopoietic transcriptional regulators (such as BCL11B, ETV6, RUNX1, biallelic WT1, and GATA3), epigenetic factors (such as histone modification, including PHF6, CTCF, EED, EZH2, SUZ12, and SETD2), and signaling genes (such as activation JAK-STAT, IL-7R and RAS signaling pathway, including JAK1, JAK3, IL7R, SH2B3, NRAS, KRAS, FLT3, NF1, and PTPN11). ETP-ALL has a lower frequency of classical T-ALL genetic alterations such as NOTCH1/FBXW7/CDKN2A mutations and a higher prevalence of FLT3, NRAS/KRAS, DNMT3A, IDH1, IDH2, JAK3, and ETV6 mutations (1,2,5).ETP-ALL was initially thought to have a poor prognosis, but the opinions on it vary (2,3,7). ETP ALL is often corticosteroid resistant and a high percentage of ETP ALL patients have detectable MRD at day 29 including many induction failures (1,2,7,8). No difference in OS was observed in the COG AALL0434 study and UKALL 2003 trial between the patients with ETP-ALL and typical T-ALL (4,9). Therefore, it is important to continue with conventional therapy in ETP-ALL patients who have poor end-induction response; MRD based therapeutic approach is recommanded (7,10). Patients with ETP-ALL had high risk of hematological relapse treated at St Jude Children's Research Hospital (3). For relapsed and refractory patients, the use of acute myeloid leukemia-oriented therapies such as FLAG-IDA regimen or targeted agents may be of benefit for some patients, including FLT3 inhibitors, tyrosine kinase inhibitors, BCL-2 inhibitors such as venetoclax, or JAK/STAT inhibitors in patients with JAK mutations or fusions (1,2,4,5,7).