Blinatumomab during Consolidation in High-Risk Philadelphia Chromosome (Ph)-Negative B-Cell Precursor (BCP) Acute Lymphoblastic Leukemia (ALL) Adult Patients: A Two-Cohort Comparison within the Graall-2014/B Study

Introduction

ALL with unfavorable biology and/or high minimal residual disease (MRD) levels are at high-risk of disease recurrence. Based on the GRAALL-2005/B analysis (Beldjord K et al, Blood 2014), Ph-negative BCP-ALL patients enrolled in the GRAALL-2014/B trial were classified at high-risk (HR) if presenting KMT2A-rearrangement (KMT2A-r), IKZF1 intragenic deletion (IKZF1del), and/or IG/TR post-induction MRD1 ≥ 10^-4 (including the need of a salvage course to reach a first complete remission [CR]). In the nested phase 2 QUEST sub-study (initiated by amendment during the GRAALL-2014/B course), those patients were offered to receive blinatumomab during consolidation and maintenance or as bridge to allogeneic hematopoietic stem cell transplantation (HSCT). The aim of the present report is to compare their outcome to that of similar patients treated in the same GRAALL-2014/B trial but without frontline blinatumomab.

Patients and methods

Between December 2015 and December 2020, the GRAALL-2014/B trial included 489 patients with Ph-negative BCP-ALL. Among these patients, 266 presented with HR features as defined above. The QUEST study amendment occurred in October 2018. QUEST eligibility was HR patients with no CNS involvement at baseline who started consolidation 2 at week 12 in continuous CR. Blinatumomab was given as bridge to transplant for patients with MRD1 ≥ 10^-3 and/or with post-consolidation 1 MRD2 ≥ 10^-4 with an available matched sibling or unrelated donor (10/10 or 9/10). Other patients received up to 5 cycles of blinatumomab during consolidation and maintenance phases. A total of 95 patients, including 94 evaluable patients, were included in QUEST between October 2018 and December 2020. A total of 104 control patients treated in the GRAALL-2014/B met the QUEST eligibility criteria but were not included in this sub-study, either before QUEST activation (n=92), or during accrual (n=6), or after accrual completion (n=6). The QUEST cohort (n=93) was compared to the control cohort (n=104) for disease-free survival (DFS, primary endpoint), MRD evolution, relapse, and overall survival (OS).

Results

Patients from both QUEST and control cohorts had similar baseline characteristics (Table 1). Notably, there was no differences in terms of HR features, including KMT2A-r and IKZF1del rates. As per protocol, all patients were in CR with no difference in terms of second induction requirement to reach CR. Both cohorts had comparable MRD1 and MRD2 levels. Patients included in the QUEST study reached lower MRD3 (post-consolidation 2) levels. Among patients with MRD2 ≥ 10^-4, undetectable MRD was achieved at MRD3 in 23/41 (56%) after blinatumomab versus 4/29 (14%) after chemotherapy alone (p<0.001). The rate of HSCT in first CR did not statistically differ among both cohorts. QUEST patients, who received blinatumomab, had a lower cumulative incidence of relapse (CIR; SHR 0.48, 95% CI [0.28-0.83]; p=0.009) and a prolonged disease-free survival (DFS; HR 0.59, 95% CI [ 0.37-0.96]; p=0.03), with no difference in terms of overall survival (OS; HR 0.67, 95% CI [0.36-1.25], p=0.21) (Table 1, Figure 1). These differences were also observed after censoring patients at the time of allo-HSCT, or when excluding from the control group patients not enrolled in the QUEST study during accrual period.

Conclusion

With the limitations of a non-controlled study but in patients all enrolled in the same prospective GRAALL-2014/B trial, this observation suggests that blinatumomab in consolidation benefits to HR Ph-negative BCP-ALL patients by markedly reducing the risk of relapse. Phase 3 studies are ongoing or about to start to confirm this observation.