A phase 2 study evaluating the safety and efficacy of first line asparaginase recombinant erwinia asparaginase (Rylaze) during pediatric-inspired regimen in high-risk adults with newly diagnosed ALL or lbl

Abstract Background and Significance: Pegaspargase-based therapy for acute lymphoblastic leukemia (ALL) offers well-established benefits but treatment-related toxicity precludes its widespread adoption. Obesity (defined as body mass index [BMI] >30 mg/m²) and older age (≥40 years) are risk factors linked to high-grade asparaginase toxicity, with hepatotoxicity often emerging early in induction, following the initial dose of pegaspargase. Beyond hepatotoxicity, advanced age and/or elevated BMI are also associated with increased risk of asparaginase-induced thrombosis and pancreatitis. Given the rising national prevalence of obesity, this patient subgroup presents a unique and increasingly relevant clinical concern, warranting the development of alternative asparaginase formulations to mitigate toxicity risks. Erwinia-based asparaginase is approved for patients who experience hypersensitivity to E. coli-derived formulations. Recombinantly produced asparaginase Erwinia (Rylaze) has a short half-life compared to pegaspargase, and it has demonstrated efficacy in depleting asparagine among hypersensitive patients. Studies examining Erwinia-based asparaginase as a second-line therapy reveal a low incidence of high-grade hepatotoxicity and generally reduced toxicity compared to other formulations. We propose evaluating recombinant Erwinia asparaginase during induction in newly diagnosed adults with ALL who are at high risk for asparaginase-related toxicities. This approach aims to enhance safety and broaden the use and tolerability of pediatric-inspired regimens. Eligible patients will include obese or older AYA individuals who are often under-dosed or not offered asparaginase containing regimens due to toxicity concerns. Given its short half-life, recombinant Erwinia asparaginase may result in shorter biochemical toxicity duration. As newly diagnosed ALL patients are typically hospitalized during early induction, frequent dosing is unlikely to pose a significant burden. We hypothesize that this regimen will offer a more favorable toxicity profile than pegaspargase, while maintaining comparable efficacy. Study Design and Methods: This study (NCT06918431) is a prospective, non-randomized, two-stages, single arm, multi-center (City of Hope, University of Chicago, Memorial Sloan Kettering, Cleveland Clinic, University of Cincinnati) phase 2 clinical trial. We will utilize recombinant Erwinia asparaginase (7 doses, 25 mg/m2 per dose every 48 hours intramuscular) as part of the C10403 induction regimen in order to assess safety, tolerability and response in high-risk newly diagnosed adults with B/T ALL and lymphoblastic lymphoma (LBL) who are either obese (age 18-39 and BMI ≥30) or older (age 40-54, regardless of BMI). A single dose level and a single cycle (28-day induction cycle 1) safety lead-in (SLI) phase will ensure there are no above-threshold unacceptable toxicities (UT) encountered at the FDA approved dose. The SLI phase will enroll 6-12 patients. If the number of UTs is below the rule-based threshold, then an expansion cohort will assess the primary endpoint - grade 3 or higher hepatotoxicity at least possibly related to the study drug and not recovered to grade 1 within 14 days of occurrence. The study will evaluate key secondary endpoints including rates of complete remission (CR)/CR with incomplete count recovery (CRi), undetected minimal residual disease, other asparaginase-related toxicities and maintaining adequate 48 hours nadir serum asparaginase activity. Enrolled patients who achieve CR after induction may receive recombinant Erwinia asparaginase during consolidation at the discretion of the treating physician. The study aims to accrue a total of 50 patients assuming 40% hepatotoxicity (grade 3 or higher) rate and 80% average CR/CRi rate for the tested therapy. If our study demonstrates the tolerability and safety of using frontline recombinant Erwinia asparaginase during induction in high-risk adults with ALL, this approach could potentially establish it as the first-line asparaginase in this population and support its use in subsequent treatment cycles. Acknowledgements:This study is financially supported by Jazz Pharmaceuticals, which also conducted a courtesy medical review of this abstract.