Characteristics and Outcome of Early T Cell Precursor ALL (ETP-ALL) Patients Treated with High-Risk Spanish Pethema Protocols
Authors: Genesca Eulalia , Morgades Mireia , Montesinos Pau , Barba Pere , Gil Cristina , Guàrdia Ramon , Moreno Maria Jose , Martínez-Carballeira Daniel , García-Cadenas Irene , Vives Susana , Ribera Jordi , González-Campos José , Diaz-Beyá Marina , Mercadal Santiago , Artola Maria Teresa , Cladera Antonia , Tormo Mar , Bermudez Arancha , Vall-Llovera Ferran , Martinez Pilar , Amigo María-Luz , Bergua Juan-Miguel , Calbacho María , Hernández-Rivas Jesús-María , Monsalvo Silvia , Novo Andrés , Cervera Marta , Garcia-Guiñon Antonio , Junca Jordi , Ciudad Juana , Orfao Alberto , Ribera Josep-Maria 
Published: October 2019

Abstract

Background:
ETP-ALL was included as a provisional identity in the 2016 WHO classification of ALL. This subtype was first identified by Coustan-Smith et al. in 2009. However, this immunophenotype-based classification does not fully enclose all ETP-ALL cases identified by gene expression profile (GEP). Although early studies in small series of ETP-ALL suggested a very poor outcome for ETP ALL more recent and larger series have showed improvement in outcome treating children with a contemporary protocol based on chemotherapy schedules, or after allogeneic stem cell transplantation (allo-SCT) in adults.
Aim:
To investigate the clinical and biological features of ETP-ALL cases in the Spanish cohort of adult T-cell ALL (T-ALL) patients and to assess the potential impact of high-risk therapy on their outcome.
Method:
One hundred eighty-five adults with T-ALL treated according to two consecutive MRD-oriented high-risk adult PETHEMA protocols -ALL-HR-2003 (NCT00853008) and ALL-HR-11 (NCT01540812; still ongoing)- were included in this study. The EGIL criteria were used to define the immunologic subtype of T-ALL after central review of immunophenotype reports, and the criteria proposed by Zuurbier et al. (Zuurbier L. et al. Haematologica 2014; 99:94-102) were used to define ETP-ALL. These later criteria consist of a combination of immunophenotypic markers (absence of CD1a-/CD4-/CD8-, cut-off <10%, and expression of the stem cell marker CD34+and/or at least one myeloid marker such as CD13+or CD33+, cut-off >25%), that resemble those published by Coustan-Smith, with the advantage that include most ETP-ALL cases, as identified by GEP, avoiding the use of partial expression of CD5 marker to immuno-classify these patients.
Results:
Thirty-four out of 167 evaluable patients (20%) with T-ALL showed an ETP-ALL immunophenotype. Patients with ETP-ALL were older (mean 39 [SD 12] vs. 33 [12] yr; p=0.011), showed more frequently lymph node involvement (79% vs. 56%; p=0.021) and lower WBC counts at diagnosis (mean, 72 [155] vs. 97 [112] x109/L; p=0.004). At genetic level, ETP-ALL patients were associated with the absence of deletions in CDKN2A/B gene cluster (91% vs. 26%; p<0.001) (10/11 cases) and with the absence of bi-allelic deletions in TCRG gene (67% vs. 5%; p=0.001) (6/9 cases). In turn, ETP-ALL patients showed poorer response to induction therapy: 82% of ETP-ALL had poorer early cytologic response (>10% BM blasts on day+14) vs. 37% of non-ETP (p<0.001), and 23% of ETP-ALL patients did not reach CR vs. 6% non-ETP T-ALL cases (p=0.005). Flow-MRD data at CR (available in 141/167 patients) showed MRD levels ≥0.1% in 65% of ETP-ALL vs. 18% of non-ETP ALL (p<0.001), and MRD level ≥0.01% in 85% vs. 37%, respectively (p<0.001). Forty-six percent of ETP-ALL patients required a second induction treatment compared to 8% of non-ETP-ALL (p<0.001). Consequently, more ETP-ALL patients underwent allo-SCT (70% vs. 21%, p<0.001). The OS of ETP-ALL patients was poorer after censoring or not the follow-up at the time of transplant (Figures 1A and B).
Conclusions:
ETP-ALL accounts for 20% of adult T-ALL in the PETHEMA cohort and it is associated with a poorer initial response to treatment (lower CR rate, poorer MRD clearance) than the remaining T-ALL patients. Such poorer outcome is not overcome by allo-SCT in our series.
Supported by grants from: Asociación Española Contra el Cáncer, AECC (GC16173697BIGA), Instituto Carlos III (PI14/01971 FI), 2017-SGR288 (GRC), CERCA Program from Generalitat de Catalunya, and "La Caixa" Foundation.
Figure 1. Figure 1.

Disclosures
Montesinos: Daiichi Sankyo: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.