Unique clinico-biological, genetic and prognostic features of adult early T-cell precursor acute lymphoblastic leukemia

Early T-cell precursor (ETP) acute lymphoblastic leukemia (ALL), was first identified within cases of childhood T-ALL based on its unique immunophenotypic and genetic features of limited (early) T-cell differentiation associated with (some) myeloid and stem cell features. Thus ETP-ALL blasts express CD7, dim CD5 (<75% positive cells), in the absence of CD1a and CD8, and positivity for ≥1 myeloid/stem cell related markers (i.e., CD34, CD13 or CD33). In turn, ETP-ALL frequently shows myeloid-associated gene alterations such as FLT3, NRAS/KRAS, DNMT3A, IDH1 and IDH2 mutations, with lower frequencies of other T-ALL-associated mutations (e.g., NOTCH1 and CDKN2A/B gene mutations). The World Health Organization (WHO) 2016 classification of ALL included ETP-ALL for the first time, as a provisional entity, but it failed to establish robust diagnostic criteria. Thus, after the first immunophenotypic characterization of ETP-ALL by Coustan-Smith et al. the proposed criteria did not allow identification of all ETP-ALL cases as detected by gene expression profiling. In addition, the “partial CD5 expression” criterion had a negative impact on the reproducibility of ETP-ALL diagnoses because of the lack of standardization of the method used for its assessment. Because of this, Zuubier et al. proposed refined immunophenotypic criteria by excluding CD5 expression while adding negativity for CD4. From the clinical point of view early studies based on limited numbers of pediatric patients indicated that ETPALL was associated with a very poor outcome. More recent data, based on larger series of children treated with more intensive therapy, showed no significant differences in outcome for ETP-ALL vs. other T-ALL cases. In contrast, limited data have been reported for adult ETP-ALL, with conflicting results. In one study, adult ETP-ALL was associated with a worse prognosis following different frontline chemotherapy schedules. The GRAALL 2003 and 2005 trials showed that treatment intensification with allogeneic hematopoietic stem cell transplantation (HSCT) in ETP-ALL with early treatment resistance could improve survival. Here we retrospectively analyzed the frequency, clinico-biological and prognostic features of adult ETP-ALL vs. other T-ALL cases in a series of 185 adults with T-ALL treated within two consecutive minimal residual diseaseoriented trials by the Programa Español de Tratamientos en Hematología (PETHEMA): ALL-HR-2003 (NCT00853008) and ALL-HR-11 (NCT01540812), the latter still ongoing). All 185 patients were diagnosed with T-ALL using the WHO criteria. The treatment protocol schedules have been described previously elsewhere. The patients’ characteristics at diagnosis and at follow-up are summarized in Table 1. The immunological T-ALL subtype was defined according to the European Group for the Immunological Characterization of Leukemias (EGIL) criteria after centralized review of immunophenotypic reports. In turn, the criteria proposed by Zuurbier et al. were used to define ETP-ALL. The combination of markers used (<5% CD1a, CD8 and CD4; >25% CD34 and/or CD33/CD13), resembles that proposed by CoustanSmith et al., while dim CD5 expression (<75% positive cells) was not considered. The inclusion of negativity for CD4 instead of dim CD5 expression as an immunophenotypic criterion, allows identification of most ETP-ALL cases identified by gene expression profiling (increased sensitivity of immunophenotyping to detect ETP-ALL cases). Clinical data were obtained in accordance with the principles of the Declaration of Helsinki and Spanish legislation, after written informed consent had been provided by each patient. The study was approved by the Institutional Review Board of the Hospital Germans Trias i Pujol (Badalona, Spain). Comparisons between ETP-ALL and other T-ALL cases were performed with the χ test, Fisher exact test, and the median test, as appropriate. Event-free survival and overall survival curves were plotted using the Kaplan-Meier method and compared by the log-rank test. A secondary