Abstract
Rationale. Young adults with Philadelphia chromosome–negative (Ph-negative) B-cell acute lymphoblastic leukemia (B-ALL) have benefited from intensified frontline strategies, but still face a 30–40% relapse risk and increased toxicity. Blinatumomab, a bispecific T-cell engager, was recently approved for frontline consolidation based on two key studies: the phase 3 ECOG-E1910 trial, showing benefit in patients with favorable measurable residual disease (MRD) response to chemotherapy, and the phase 2 BLAST study, supporting use in poor MRD responders. The phase 2 GRAALL-2014/B-QUEST study, nested within the GRAALL-2014/B trial, evaluated blinatumomab consolidation in high-risk patients defined by poor end-of-induction (EOI) MRD1 response (≥10-4), or presence of KMT2A rearrangement (KMT2A-r) or IKZF1 intragenic deletion (IKZF1del). This final report also includes a non-randomized comparison with high-risk patients from GRAALL-2014/B not enrolled in QUEST.
Patients and methods. Between December 2015 and December 2020, the GRAALL-2014/B trial enrolled 489 patients aged 18–59 with Ph-negative B-ALL. Of these, 455 (93.1%) achieved complete remission (CR), including 259 classified as high-risk (HR). The QUEST substudy began in October 2018, enrolling HR patients without central nervous system involvement at diagnosis and in sustained CR at the start of consolidation 2 (week 12). Blinatumomab was given as a bridge to allogeneic hematopoietic stem cell transplant (allo-HSCT) in very high-risk (VHR) patients (MRD1 ≥10-3 and/or MRD2 ≥10-4 before consolidation 2), or as up to five cycles during consolidation and maintenance in those not eligible for transplant. The primary objective was to improve 3-year disease-free survival (DFS) from 50% to 65% (alpha 5%, power 90%). Ninety-five patients were enrolled in QUEST between October 2018 and December 2020, with 94 evaluable. An internal control cohort included 90 similar patients treated before QUEST activation (December 2015–October 2018) without blinatumomab.
Results. Baseline characteristics were comparable between the QUEST and control cohorts, including the frequency of KMT2A-r (17% vs 23%, p=0.36), IKZF1del (40% vs 39%, p=0.99), and MRD1 ≥10-4 (73% vs 70%, p=0.29). By design, all patients were in continuous CR at the start of consolidation 2, with no difference between groups in the proportion requiring a second induction to achieve CR. The rate of MRD2 ≥10-4 prior to consolidation 2 was also similar (45% vs 39%, p=0.54). However, the rate of complete MRD response at the end of consolidation 2 was significantly higher in the blinatumomab-treated group (72% vs 55%, p=0.041). The primary endpoint was met, with a 3-year disease-free survival (3y-DFS) of 70% (95%CI[60–78], lower limit above 50%). In contrast, the control cohort demonstrated a 3y-DFS of 48% (95% CI[38–58]), consistent with the historical benchmark used for comparison. Following blinatumomab, the 5-year cumulative incidence of relapse (CIR), DFS, and overall survival (OS) were 23% (95% CI: 16–33), 68% (95% CI: 58–76), and 79% (95% CI: 69–86), respectively, significantly better than outcomes in the control cohort (CIR: SHR 0.41, 95% CI: 0.25–0.68; DFS: HR 0.48, 95% CI: 0.31–0.75; OS: HR 0.54, 95% CI: 0.32–0.93). DFS benefit was consistent across subgroups defined by age (<45 vs ≥45 years), gender, and white blood cell count (<30 G/L, ≥30 G/L). Among HR features, a benefit in DFS was observed in patients with MRD1 ≥10-4 and IKZF1del, while no significant benefit was seen in those with KMT2A-r. Although the proportion of allo-HSCT–eligible patients was similar between groups (50/94 [53%] vs 51/90 [57%], p=0.66), significantly more patients received a transplant after blinatumomab (88% [44/50] vs 65% [33/51], p=0.009). Overall, blinatumomab consolidation improved outcomes in VHR patients (DFS: HR 0.54, 95% CI: 0.31–0.95). Whether this benefit stems from blinatumomab itself, increased transplant rates, or a combination of both remains to be clarified.
Conclusion. In conclusion, this study supports the use of blinatumomab consolidation in high-risk Ph-negative B-ALL patients. Building on these findings and to further refine risk-adapted treatment strategies, the ongoing GRAALL-2024 trial prospectively randomizes allo-HSCT in patients with poor oncogenic characteristics or EOI MRD response, but who achieve undetectable MRD after blinatumomab.
