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Abstract Although acute lymphoblastic leukemia (ALL) is most common in pediatric and adolescent and young adult (AYA) patients, 20% of cases are diagnosed in patients ≥ 55 years old. Use of intensive pediatric regimens in AYA populations has demonstrated excellent tolerability and significant improvements in event‐free survival (EFS) and overall survival (OS). The backbone of pediatric regimens includes asparaginase and corticosteroids, both of which are associated with more toxicity in older patients and those with body mass index (BMI) ≥ 30 kg/m which leads to poor tolerance of these regimens. We tested the safety and efficacy of a dose‐modified The Cancer and Leukemia Group B 10403 regimen using reduced doses of pegylated (PEG)‐asparaginase (ASP) and corticosteroids (RD‐10403) in 30 patients with Philadelphia‐chromosome negative ALL who were ≥50‐year‐old and younger adults with significant metabolic or hepatic co‐morbidities. The complete remission rate on day 28 was 77%, 3‐year EFS was 54%, and estimated 3‐year OS was 55%. Grade 3+ toxicity was noted in 40% of patients during induction, and induction‐related mortality was 3%. Additional prospective evaluation of RD‐10403 is merited to determine efficacy and safety of this regimen and to serve as a framework for chemoimmunotherapy combination therapy.