Achievement of therapeutic levels using dose-reduced peg-asparaginase in adult patients with acute lymphoblastic leukemia.

Abstract

6530 Background: Peg-asparaginase (PEG) doses range from 2000-2500 IU/m2 in pediatric-inspired regimens for acute lymphoblastic leukemia (ALL). Pediatric PEG dosing in adolescents and young adults (AYAs) has resulted in improved outcomes, but PEG-associated toxicities increase with age and often limit its use. Therapeutic dosing is determined by asparagine (ASP) depletion for 14 days after dose; L-asparaginase levels can act as a surrogate marker of ASP depletion. We previously showed dose reduced PEG (defined as <2000 IU/m2) results in high rates of therapeutic L-asparaginase 7 days post PEG (Derman et al, Leuk Lymphoma 2020). Here we describe prolonged duration of ASP depletion and comparable toxicities after dose reduced PEG in adults with ALL. Methods: Patients ≥18 years with ALL or lymphoblastic lymphoma (LBL) who received PEG from 1/1/2008 to 9/28/2023 were identified for retrospective chart review. Those with ≥1 PEG trough level (defined as 10-20 days after dose) were included. The primary endpoint was therapeutic PEG levels (≥0.1IU/mL L-asparaginase) at 7 and 14 days post administration, with secondary endpoint being induction grade 3+ toxicities (CTCAE v.5.0). Results: 49 patients met inclusion criteria, of which 48 received PEG during induction. Median age was 34.7 (range 18-66), 67% were male and 53% had B-cell ALL. 17 (35%) received an induction dose ≤ 500 IU/m2, 22 (46%) received 501 to ≤1000 IU/m2 and 9 (19%) received >1000 IU/m2. Induction median dose was 1000 IU/m2. Among those with PEG trough levels, 79% were therapeutic after induction; of note, 4 patients were transitioned from PEG to Erwinia asparaginase due to silent inactivation. During induction, 23 (48%) patients had ≥1 grade 3+toxicity, including 5 (10%) with hepatotoxicity, 1 (2%) with pancreatitis, and 2 (4%) with a thrombotic event. There was no statistical relationship between dose level and toxicities (p=.8). Conclusions: This study demonstrates durability of therapeutic L-asparaginase levels and ASP depletion that persists 14 days despite dose reduction. There were decreased rates of hepatotoxicity and comparable rates of pancreatitis and thrombotic events compared to rates reported in CALBG 10403 (C10403) (Stock et al, Blood 2019), which utilized standard pediatric dosing. In addition, our cohort’s median age was significantly older than those treated on C10403. This suggests PEG dose reduction may offer similar therapeutic ASP depletion with comparable or reduced toxicities. Dose reduction should be studied prospectively in AYAs with ALL. [Table: see text]