Pharmacokinetics-Based Modification of Intravenous Pegylated Asparaginase Dosing in the Context of a “Pediatric-inspired” Protocol in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)
Authors: Douer Dan , Aldoss Ibrahim , Lunning Matthew A , Ramezani Laleh , Burke Patrick , Mark Lisa , Vrona Janice , Park Jae H. , Tallman Martin S , Pullarkat Vinod , Mohrbacher Ann M , Avramis Vassilos I 
Published: October 2019

Abstract
Abstract 1495
Prolonged Asparaginase (ASP) use is standard in all pediatric ALL regimens. In adults ASP is either not used or given for much shorter duration. Recently, several adult ALL protocols adopted pediatric regimens, with long duration of ASP, mostly E. coli, with better outcomes than historically reported. However, optimal implementation of pediatric regimens to adults, especially ASP dosing, has not been studied, considering its potential higher toxicity. We report the results of an ALL protocol adopted from pediatrics, modified by using the long acting pegaspargase (PEG-ASP) with a pharmacokinetics-based dosing strategy, intended for adults with newly diagnosed ALL.

Methods:
We adopted the augmented BFM pediatric protocol (Nachman NEJM 1998) replacing the native E. coli ASP with 6 doses of PEG-ASP. Pediatric and most pediatric-inspired adult protocols use 2,500 u/m2 PEG-ASP at 2 week intervals. Based on our PEG-ASP adult PK and PD data (Douer Blood 2007), the dose was reduced to 2,000 u/m2IV, at intervals no shorter than 4 weeks. Other modifications include 1) Each PEG-ASP dose, having a very long activity (2–4 weeks), was synchronized with the time of myelosuppressive drugs so that there anticipated different serious toxicities are less likely to coincide. 2) Replaced escalated MTX dosing plus E.coli ASP with 4 fixed high doses of MTX, timing PEG-ASP to avoid its overlapping long enzymatic activity with MTX activity. 3) hydrocortisone pre-medication and steroids for 7–14 days after each PEG-ASP dose to prevent allergic reactions. The protocol included 8 cycles of multi-agent chemotherapy, 2-year maintenance and IT MTX CNS prophylaxis. PEG-ASP was given intravenously (IV) once on day 15–17 of induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (# 3 & 6), and two cycles of delayed re-induction (# 5 & 8).

Results:
Between July 2004 and July 2009, 51 (17 women) adults with newly diagnosed previously untreated ALL were enrolled in 2 USC affiliated hospitals. Patient characteristics include: median age - 33 (range18–57) yrs, precursor B cell - 46, T cell-5, Ph+ 11, and median WBC-14,500 (range 800-512, 000)/dL. Total number of PEG-ASP doses was: all 6 doses - 23 pts, 4 doses- 1 pt., 3– 7 pts. 2–9 pts, 1–11pts. Twenty eight (55%) pts. did not complete 6 PEG-ASP doses due to: allogeneic HSCT −8 pts, refusal −1pt., induction failure – 2pts, death in CR −3 pts., relapse- 4 pts; and PEG-ASP related toxicities: 11 (21%) pts: including pancreatitis −7pts, allergy −3 pts, DVT-1 pt (one pt. had pancreatitis and later transplanted). Among 51 pts PEG-ASP related grade 3/4 toxicities were: anaphylaxis-2 pts.(4%); pancreatitis-7 (14%) pts.; thrombosis-8(16%) (5 catheter-related); transaminitis −33(65%); high bilirubin −22 (43%); hyperglycemia-17(33%); high triglycerides −8(16%); fatigue-4(8%). Table I shows the rates of ASP related toxicities in 173 doses. All toxicities were reversible without any PEG-ASP-related deaths. Outcome data is shown in Table 2.
Median follow up – 44 months
Neutralizing antibodies measured in 247 serum samples from 34 pts. (33, 11 & 10 pts. after PEG-ASP doses # 1, 4, and 6 respectively) were detected in 1 patient

Conclusion:
Our rational modification of a pediatric protocol, in adult ALL (age <57 years), is feasible, has very high CR rate (98% by 4 weeks), 58% 7-years DFS, even without HSCT, and in line with reported results of other pediatric-inspired regimens. PEG-ASP toxicities were common but mostly manageable and reversible. Our study suggests the that standard PEG-ASP adult dose can be reduced to 2,000 u/m2 IV at intervals no less than 4 weeks without impairing overall outcome. Steroids may reduce clinical allergies, without masking silent neutralizing antibody formation. The concepts of this study, especially PEG-ASP dosing, could be applied in future ALL protocols.

Disclosures:
Douer: Sigma Tau: Research Funding, Speakers Bureau. Avramis:Sigma Tau: Consultancy.