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

Abstract

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. 1 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). 1,2 In turn, ETP-ALL frequently shows myeloid-associated gene alterations such as FLT3, NRAS/KRAS, DNMT3A, IDH1 and IDH2 mutations, 3,4 with lower frequencies of other T-ALL-associated mutations (e.g., NOTCH1 and CDKN2A/B gene mutations). 5,6 The World Health Organization (WHO) 2016 classification of ALL included ETP-ALL for the first time, as a provisional entity, 7 but it failed to establish robust diagnostic criteria. Thus, after the first immunophenotypic characterization of ETP-ALL by Coustan-Smith et al. 1 the proposed criteria did not allow identification of all ETP-ALL cases as detected by gene expression profiling. 2 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. 2 From the clinical point of view early studies based on limited numbers of pediatric patients indicated that ETP-ALL was associated with a very poor outcome. 1,8,9 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. 10 In contrast, limited data have been reported for adult ETP-ALL, with conflicting results. 11,12 In one study, adult ETP-ALL was associated with a worse prognosis following different frontline chemotherapy schedules. 11 The

The Physiopathology of T- Cell Acute Lymphoblastic Leukemia: Focus on Molecular Aspects

“…in T-ALL, higher than those used in B-cell ALL (19). As regards ETP-ALL, a Spanish multicentre study showed the worse prognosis to be ascribed to a lower response to induction therapy than to an increased relapse rate, suggesting that use of different schedules, such as fludarabine, cytarabine, G-CSF, idarubicin (FLAG-IDA), and other more myeloid-oriented chemotherapies, or FLT3targeted therapies, may play an advantage in this subcategory of patients (20). Current consolidation strategies comprise a delayed intensification including drugs used in induction phase, followed by a 2-year maintenance with 6-mercaptopurine and methotrexate, pulses of vincristine and steroids, and additional IT CNS prophylaxis.…”

“…Allocation to alloHSCT may vary among study groups, but generally speaking, failure to achieve CR after induction therapy, high white cell count at presentation, high risk cytogenetics/immunophenotype, and MRD persistence at defined timepoints can all be used to allocate to transplant (11,24,25). As regards the subcategory of ETP-ALL, two trials demonstrated improvement in survival in ETP-ALL patients transplanted early in case of treatment resistance (20). Considered its better prognosis, consolidation with alloHSCT is not considered necessary in T-LBL, unless suggested by an adverse course of the disease (26).…”

Early precursor T-cell acute lymphoblastic leukemia: current paradigms and evolving concepts

“…As noted previously, a recent retrospective analysis by Genescà and colleagues included 34 patients with ETP-ALL, and, despite treatment intensification with alloHSCT, a significant improvement on OS was not attained. 49 The 4-years OS was 36% for ETP-ALL patients when censoring occurred at alloHSCT and 33% without censoring for alloHSCT. On the other hand, non-ETP-ALL patients exhibited a 4-years OS 49% when censoring at alloHSCT and 51% without censoring for alloHSCT.…”

“…The authors pointed out that the OS for the patients who underwent alloHSCT was lower compared with other studies, and that the inferior outcomes of ETP-ALL patients may be secondary to lower CR rates. 49 Another recent report by Zhu and colleagues (based on abstract available in English) explored the efficacy and outcomes of alloHSCT in 23 patients with ETP-ALL from 2010 to 2018. 59 The patients were diagnosed following WHO criteria.…”

“…The authors pointed out that the OS for the patients who underwent alloHSCT was lower compared with other studies, and that the inferior outcomes of ETP-ALL patients may be secondary to lower CR rates. 49 …”