Efficacy and Toxicity of Fixed Dose Versus Reduced/PK-Adjusted Dose Pegaspargase in Pediatric Patients with Newly Diagnosed Acute Lymphoblastic Leukemia: Results of DFCI ALL Consortium Protocol 16-001

Background L-asparaginase is an essential component of treatment for acute lymphoblastic leukemia (ALL) but is associated with several treatment-limiting toxicities. Importantly, studies have demonstrated inferior outcomes for patients (pts) unable to tolerate all intended doses (Gupta J Clin Oncol 2020; Silverman Blood 2001). Standard dosing of pegylated E. coli asparaginase leads to prolonged exposure to serum asparaginase activity (SAA) well above levels associated with asparagine depletion (Vrooman J Clin Oncol 2021), possibly contributing to toxicity. To address this clinical challenge, Dana-Farber Cancer Institute ALL Consortium protocol 16-001 (DFCI 16-001) investigated the feasibility, efficacy, and toxicity of reduced/PK-adjusted dosing of pegaspargase (SS-PEG) in children with newly diagnosed ALL. Methods DFCI 16-001 enrolled pts with ALL ages 1 to 21 years from March 2017 until September 2022. All pts received SS-PEG every 2-weeks during post-induction therapy for 15 doses. Pts assigned to the Low, Intermediate and High Risk groups were eligible to participate in a post-induction randomization of standard fixed dose SS-PEG (Arm A, 2500 IU/m2) versus reduced/PK-adjusted dose (Arm B, starting dose 2000 IU/m2). Nadir SAA (NSAA) levels were obtained prior to each dose. For Arm B, SS-PEG dose was adjusted based on NSAA obtained 14 days after the third dose, prior to dose #4, as follows: NSAA <0.4 IU/mL, increase to 2500 IU/m2; NSAA 0.4-0.99 IU/mL, continue 2000 IU/m2, NSAA ≥1.0 IU/mL, decrease to 1750 IU/m2. For any NSAA <0.4 IU/mL on Arm B, SS-PEG was increased 1 dose level to a maximum of 2500 IU/m2. Adverse events were graded according to the CTCAE v.4.0 with attention to asparaginase-related toxicities. Fisher's exact test was used to compare rates, and a log-rank test was used to compare event-free survival (EFS). Results Of 419 eligible subjects, 320 participated in the SS-PEG randomization; 160 each were assigned to Arms A and B. Thirty-one subjects on Arm A and 47 on Arm B discontinued SS-PEG prior to dose #4 due to toxicity, largely hypersensitivity, and were excluded from PK analysis. The median NSAA level prior to dose #4 was 1.31 IU/mL (range 0-2.22 IU/mL; N=123) for Arm A and 1.03 (range 0.56-1.76 IU/mL; N=113) for Arm B. There were statistically significant differences among the distribution of NSAA between the arms, with fewer pts on Arm B having extremely high NSAA levels (≥1.0 IU/mL): On Arm A, 80.5% of subjects pre-dose #4 and 80.6% of subjects pre-dose #15 had NSAA ≥1.0 IU/mL compared with 56.6% and 34.3% of subjects on Arm B at the same timepoints (P<0.0001 at each timepoint). On Arm B, 66 subjects (41.25%) were reduced to 1750 IU/m2 and none required dose re-escalation. No participants on Arm B required escalation to 2500 IU/m2 based on predose #4 NSAA, but 4 pts assigned to 2000 IU/m2 were later escalated to 2500 IU/m2 for NSAA <0.4 IU/mL. Hypersensitivity reaction rates were comparable among the 2 arms (Arm A 26.9% and Arm B 31.3%; P=0.46). Similarly, rates of non-allergic asparaginase-related toxicities were not significantly different between the 2 arms: 43.8% of subjects on Arm A and 46.9% on Arm B experienced at least 1 non-allergic asparaginase-related toxicity (P=0.65). Rates of toxicities were as follows: ≥ Grade 3 hypertriglyceridemia 32.5% on Arm A and 39.4% on Arm B (P=0.24); ≥ Grade 3 hyperbilirubinemia 8.1% on Arm A and 8.8% on Arm B (P>0.99); thromboembolic events 3.8% on Arm A and 8.1% on Arm B (P=0.15); and pancreatitis 10.6% on Arm A and 8.1% on Arm B (P=0.57). Moreover, reduction of SS-PEG on Arm B to 1750 IU/m2 did not result in lower toxicity rates. Of those included in the PK analysis, 12 pts on Arm A and 8 on Arm B discontinued SS-PEG prior to receipt of all 15 intended doses due to asparaginase-related toxicity. With a median follow up of 3.87 years, the 3-year EFS was 95.4% (95%CI 90.6%-97.8%) for Arm A and 93.2% (95%CI 87.6%-96.3%) for Arm B (P=0.91). Conclusions We demonstrate that a reduced/PK-adjusted dose approach for treatment with SS-PEG is feasible in newly diagnosed ALL pts, and preliminary outcome results suggest no decrement in EFS (longer follow-up needed). Despite marked decrease in SAA with reduced/PK-adjusted dosing, rates of non-allergic asparaginase-related toxicities were not reduced compared with standard dosing, suggesting that further investigation of alternative strategies to minimize treatment-limiting toxicities and improve tolerability is warranted.

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