Results in pediatric T-ALL patients treated in trial AIEOP-BFM ALL 2009: Prognostic factors in the context of modern risk-adapted therapy

Abstract

To improve the outcome of pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients, the AIEOP-BFM ALL 2009 trial modified T-ALL stratification and treatment based on AIEOP-BFM ALL 2000 and other pediatric ALL groups' results. This report aims to describe the outcome of T-ALL patients in trial AIEOP-BFM ALL 2009 and evaluate prognostic features defined within the end of induction (EOI) therapy, for future protocols stratification and interventions. From 06/2010 to 02/2017, 872 T-ALL patients, aged 1-17, were enrolled. High risk (HR) criteria were prednisone poor response (PPR), Day 15 flow cytometry minimal residual disease (MRD) ≥ 10%, no complete remission at EOI, or polymerase chain reaction (PCR)-MRD ≥ 5 × 10^-4 at end of consolidation (EOC). Three Cox regression models on event-free survival (EFS) evaluated prognostic factors. Overall, 5-year EFS and survival were 79.9% ± 1.4% and 84.9% ± 1.2% with cumulative incidence of relapse (CIR) and death of 13.0% ± 1.2% and 5.9% ± 0.8%. Five-year EFS and CIR were 86.8% ± 1.6% and 8.7% ± 1.3% in non-HR patients (n = 470); 71.9% ± 2.3% and 18.0% ± 1.9% in HR patients (n = 402). High PCR-MRD levels at EOI and EOC were prognostic in all models, with EOC-MRD ≥ 5 × 10^-3 related to a hazard ratio of 6.22 (P < 0.001). When a model considered factors identified at EOI only, central nervous system (CNS)3 (hazard ratio = 2.3, P < 0.001), PPR (hazard ratio = 1.74, P = 0.02), and high EOI-MRD (hazard ratio 4.71 for ≥5 × 10^-2 vs. negative, P < 0.001) significantly impacted EFS. Results of T-ALL patients in AIEOP-BFM ALL 2009 were favorable. While EOC-MRD remained the strongest prognostic predictor, PPR, CNS3 disease, and EOI-MRD showed relevant prognostic value, with CNS3 and EOI-MRD ≥ 5 × 10^-2 being candidate criteria for early stratification and intervention modifications.

Figure 1

Outcome of T‐cell acute lymphoblastic leukemia (T‐ALL) in AIEOP‐BFM ALL 2009 trial. Event‐free survival (EFS) and overall survival (OS) (A); cumulative incidence of relapse (CIR) and cumulative incidence of death (CID) (B) of the cohort of 872 patients. EFS and OS (C); CIR and CID (D) of the sub‐cohort of 470 non‐high risk (HR) patients. EFS and OS (E); CIR and CID (F) of the sub‐cohort of 402 HR patients.

Figure 2

Event‐free survival (EFS) of AIEOP‐BFM ALL 2009 T‐cell acute lymphoblastic leukemia (T‐ALL) patients by polymerase chain reaction minimal residual disease (PCR‐MRD) response. Outcome by PCR‐MRD at end of induction (EOI) on the cohort of 746 patients with PCR‐MRD stratification (A). Outcome by PCR‐MRD at end of consolidation (EOC) on the cohort of 746 patients with PCR‐MRD stratification (B). Outcome by PCR‐MRD at EOC on the subset of 90 patients with PCR‐MRD at EOI ≥ 5 × 10⁻² (C).

Figure 3

Results of three different Cox regression models on event‐free survival in the AIEOP‐BFM ALL 2009 T‐cell acute lymphoblastic leukemia (T‐ALL) patients with available data on regression variables (complete cases). Model A includes polymerase chain reaction minimal residual disease (PCR‐MRD) at end of induction (EOI) only, Model B includes PCR‐MRD at EOI and end of consolidation (EOC) separately, and Model C includes the dynamic of PCR‐MRD at EOI and EOC. All three models include as regression variables age, central nervous system (CNS) status and white blood cell (WBC) count at diagnosis, prednisone response at Day +8, flow cytometry minimal residual disease (FCM‐MRD) at Day +15. MRD dynamics from EOI to EOC—low–low: MRD levels were low (neg or <5 × 10⁻⁴) at EOI and EOC; high–low: MRD levels from high at EOI (≥5 × 10⁻⁴ and <5 × 10⁻²) became low at EOC (neg or <5 × 10⁻⁴); very high–low: from very high at EOI (≥5 × 10⁻²) became low at EOC; high/very high–high: from high or very high levels at EOI were subsequently high (≥5 × 10⁻⁴ and <5 × 10⁻³) at EOC; high/very high–very high: from high or very high levels at EOI were subsequently very high (≥5 × 10⁻³) at EOC. One patient was excluded from this model as the MRD dynamic with increasing MRD from EOI to EOC did not fit with any of the categories described.