Paper Details

ABSTRACT

Introduction: The ECOG-ACRIN E1910 clinical trial evaluated the effect of blinatumomab and chemotherapy (blin) when compared to chemotherapy alone (chemo) on relapse-free (RFS) and overall survival (OS) in adults with BCR::ABL1-negative precursor B-cell acute lymphoblastic leukemia (B-ALL) in remission.  The addition of blin in patients (pts) with no evidence of flow cytometry-based (Flow) measurable residual disease (MRDf) after intensification (course 3) of E1910 therapy significantly improved both RFS and OS, leading to FDA approval of blin in adults with newly diagnosed B-ALL (Litzow et al, NEJM 2024;391:320) in remission. MRDf-negativity was defined as <0.01% leukemic cells in bone marrow prior to randomization. We examined associations between levels of MRD measured by antigen receptor sequencing (clonoSEQ) in MRDf-negative patients and RFS/OS in the blin versus chemo-treated patients.

Methods: ClonoSEQ was performed for bone marrow samples at baseline and pre-randomization for 176 of the 224 pts (78.6%) who had achieved MRDf negativity. Analytic sensitivity (limit of detection, LOD) was 1 cell per million (10^-6). The effects of molecular MRD (MRDm) on OS and RFS at thresholds of 10^-4, 10^-5 and 10^-6 were analyzed. Samples with analyzed DNA equivalent to less than 1 million cells were considered indeterminate at 10^-6 (or 10^-5 if less than 500,000 cells) and deemed negative at those levels if no residual dominant clonal sequence was detected. Genomic subtypes were determined as described in the primary manuscript. Estimates of RFS and OS were calculated using the Kaplan-Meier method. Comparison of RFS and OS between treatment arms was conducted using the two-sided log-rank test. Hazard ratios and 95% confidence intervals were estimated using the Cox proportional hazards model.

Results: MRDm analysis identified a median of 3 (range 1-10) trackable distinct sequences in 176 baseline samples, the number of which varied by B-ALL genomic subtype. MRDm was successfully measured in MRDf-negative pre-randomization samples for 85/112 and 91/112 pts who received blin and chemo, respectively. At a median follow up of 53.7 months, 58.0% of pts (102/176) were MRDm negative (MRDm-neg) at LOD of 10^-6 of which 26.5% (13/49) chemo treated and 9.43% (5/53) blin treated patients relapsed or died. Of MRDm-positive pts (MRDm-pos) at 10^-6, 50% (21/42) of chemo treated pts and 25% (8/32) of blin-treated pts relapsed or died. Of those who were MRDm-pos at 10^-5, 50% of chemo-treated pts (9/18) and 18.8% of blin-treated pts relapsed or died (3/16). At the 10^-4 MRDm-pos level 66.6% (6/9) of chemo and 50% (2/4) of blin-treated pts relapsed or died. OS (HR 0.31, 95% CI (0.10,0.98), P=0.046) and RFS (HR 0.33 (0.12,0.91), P=0.033) were superior in MRDm-neg pts treated with blin when compared to chemo. OS (HR 0.31 (0.12,0.76), P=0.011) and RFS (HR 0.37 (0.17,0.85), P=0.018) were superior in pts who were MRDm-pos at 10^-6 treated with blin when compared to chemo.  Stratifying by genomic subtype, 49.3% (33/67) of patients with high-risk genomic subtypes were MRDm-negative 63.0% (51/81) of patients with low/intermediate-risk subtypes.  RFS in high-risk MRDm-neg pts was superior with blin treatment (HR 0.14 (0.03,0.70), P=0.016).  In low/intermediate risk MRDm-neg pts RFS was not statistically different (HR 0.21(0.02,1.82) P=0.16) comparing blin and chemo treated patients. 

Conclusions: In the E1910 trial, MRDm predicted relapse risk in pts who were MRDf-negative. In the presence of quantifiable MRDm to 10^-6, blin treatment was associated with a reduced risk of relapse and prolonged OS compared to chemo. In MRDm-negative patients, blin significantly improved RFS and OS when compared to chemo. These data indicate that there is no level of MRDm negativity that eliminates the risk of relapse or eliminates the clinical utility of blin in consolidation. Overall, these results confirm the benefit of blin consolidation in MRD negative patients measured by flow cytometry or molecular testing.