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Baseline cytomolecular features and measurable residual disease (MRD) dynamics are both strongly prognostic in acute lymphoblastic leukemia (ALL). Whether early MRD response can overcome the adverse prognosis of high-risk (HR) cytomolecular features is largely unknown. We retrospectively identified 161 patients with newly diagnosed B-cell ALL who underwent MRD assessment with next-generation sequencing (NGS) for IG/TR rearrangements (sensitivity: 1 × 10^-6). Early NGS MRD negativity (i.e. after 1 cycle of induction) was achieved in 33% of patients. Rates of NGS MRD negativity were similar in patients with standard-risk (SR) and HR cytomolecular features. Patients who achieved early NGS MRD negativity had the best outcomes (2-year relapse-free survival (RFS): 94% versus 66% if MRD-positive; P = 0.03). None of the 26 patients with early NGS MRD negativity subsequently relapsed. Early NGS MRD response also identified patients with HR Philadelphia-chromosome (Ph)-negative ALL with low risk of relapse and excellent long-term survival (2-year RFS: 100%); in contrast, the 2-year RFS was 38% for patients with HR ALL who remained MRD-positive after induction (P = 0.01). Outcomes remained poor for HR patients who achieved NGS MRD negativity at later timepoints. In a landmark analysis, allogeneic stem cell transplant (alloSCT) improved outcomes of patients with HR Ph-negative ALL who remained MRD-positive after induction (2-year RFS 80% versus 0% if no alloSCT; P = 0.009). In patients with B-cell ALL, achievement of early NGS MRD negativity is associated with durable remissions, regardless of baseline cytomolecular features. AlloSCT may improve outcomes of patients with HR ALL with suboptimal early MRD dynamics.