Paper Details

ABSTRACT

Background: Despite pediatric-inspired therapy, adults with high-risk T-cell acute lymphoblastic leukemia (T-ALL) remain at substantial risk of relapse. In the GRAALL-2014/T trial, high-risk disease was defined by post-induction IG/TR measurable residual disease (MRD) ≥10?4 and/or an unfavorable NOTCH1/FBXW7/RAS/PTEN classifier. The phase 2 ATRIALL substudy evaluated the addition of nelarabine (NELA) during frontline consolidation and maintenance.

Methods: Between November 2015 and May 2022, the GRAALL-2014/T enrolled 325 patients with T-ALL. ATRIALL was a multicenter, open-label, single-arm phase 2 substudy activated in April 2017. Patients aged 18-59 years with newly diagnosed high-risk T-ALL in first complete remission (CR1) and no baseline central nervous system (CNS) involvement were enrolled at the start of consolidation 2 (week 12) and scheduled to receive 5 NELA courses: 2 during consolidation and 3 during the first year of maintenance. Patients with very-high-risk (VHR) disease, defined by MRD1 ≥10^-3 and/or MRD2 ≥10^-4, were eligible for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in CR1 after 1 NELA course. The primary phase 2 endpoint was 4-year disease-free survival (DFS), with a prespecified target of improving the historical estimate from 50% to 65%. Overall, 113 CNS-negative patients were enrolled; 7 additional CNS-positive patients were subsequently included following a protocol amendment. The comparative analysis included the 113 CNS-negative ATRIALL patients and 41 CNS-negative high-risk GRAALL-2014/T patients who started consolidation 2 without receiving NELA. Outcomes were measured from the start of consolidation 2. MRD was assessed by clone-specific IG/TR PCR at the end of induction (MRD1), after consolidation 1 and before NELA initiation (MRD2), and after consolidation 2 and 1 NELA course (MRD3).

Results: In the 113-patient primary efficacy population, median follow-up was 5.4 years (95% CI, 5.2-5.7). Four-year DFS was 65.1% (95% CI, 55.5-73.2), 4-year cumulative incidence of relapse (CIR) was 28.6% (95% CI, 21.1-37.9), and 4-year overall survival (OS) was 70.4% (95% CI, 61.0-78.0).

The internal control cohort comprised 41 patients, of whom 21 were enrolled before ATRIALL activation, 18 during ATRIALL recruitment, and 2 after ATRIALL closure. Baseline characteristics were similar between groups, including age, white blood cell count, 4-gene classifier, number of treatment courses required to achieve CR1, and MRD1. VHR disease was present in 46% of NELA-treated patients and 40% of controls (P=.32). After consolidation 2, MRD3 was undetectable in 75% of NELA-treated patients versus 53% of controls (P=.019). Four-year DFS was 53.6% (95% CI, 37.3-67.4) in controls, with no significant difference between patients exposed or not exposed to NELA (HR, 0.72; 95% CI, 0.41-1.24; P=.23).

In exploratory subgroup analyses, NELA was associated with lower risk of DFS events in non-VHR patients (HR, 0.46; 95% CI, 0.23-0.95; P=.036), but not in VHR patients (HR, 1.23; 95% CI, 0.52-2.93; P=.64). Similarly, NELA was associated with better DFS in non-early T-cell precursor (non-ETP) ALL (HR, 0.43; 95% CI, 0.22-0.85; P=.016), but not in ETP-ALL (HR, 1.57; 95% CI, 0.62-4.02; P=.344; interaction P=.026). CIR was also significantly inferior after NELA in the non-VHR (SHR, 0.45; 95% CI, 0.22-0.92; P=.03) and non-ETP subgroups (SHR, 0.36; 95% CI, 0.17-0.76; P=.007). No OS difference was observed; however post-relapse survival was shorter after prior NELA exposure (median, 4.8 vs 19.1 months; P=.034). Within the NELA cohort, persistent MRD3 was strongly associated with inferior DFS (HR, 2.92; 95% CI, 1.47-5.78; P=.002).

Conclusions: NELA-based consolidation was associated with improved MRD response and outcome in adults with high-risk T-ALL. In this nonrandomized comparison, greater benefit was observed in non-ETP patients and in non-VHR patients, who were also more exposed to NELA. The optimal integration of NELA into frontline T-ALL therapy and its potential impact on outcomes after relapse require further investigations.