Incidence of Hypersensitivity Reactions (HSR) Reactions (HSR) to Peg-Asparaginase (PEG-ASP) in 6136 Patients Treated in the AIEOP-BFM ALL 2009 Study Protocol
Authors: Rizzari Carmelo , Moericke Anja , Conter Valentino , Valsecchi Maria Grazia , Zimmermann Martin , Silvestri Daniela , Mann Georg , Niggli Felix , Dalla-Pozza Luciano , Stary Jan , Elitzur Sarah , Cario Gunnar , Locatelli Franco , Boos Joachim , Zucchetti Massimo , Biondi Andrea , Schrappe Martin 
Published: November 2019

Background and aim: The AIEOP-BFM ALL 2009 trial (https://www.clinicaltrials.gov/NCT01117441) is an international collaborative treatment protocol for children and adolescents with acute lymphoblastic leukemia (ALL) wherein PEG-ASP (Oncaspar®, Servier) was used as the front-line ASP product. Since HSR represent the most relevant limitation to the completion of ASP treatment schedules in the context of any study protocol, we evaluated the cumulative incidence of HSR following PEG-ASP treatment for better understanding the impact of this product on the HSR phenomenon in the context of the treatment strategy outlined in the AIEOP-BFM ALL 2009 study protocol.
Patients and Methods: Children with newly diagnosed ALL were enrolled in the AIEOP-BFM ALL 2009 protocol and stratified as Standard (SR), Intermediate (IR) or High-Risk (HR) according to their presenting and response criteria. A first exposure to PEG-ASP, administered I.V. at 2,500 IU/sqm throughout the whole protocol, was scheduled in all patients during induction (phase IA, 2 doses, on day 12 and 26), whilst second or further exposures were scheduled as follows: a. in SR and MR patients during the reintensification (protocol II, 1 dose); and b. in HR patients during each of the three intensive blocks and of the three protocols III (1 dose in each of these phases). In addition, MR patients were randomized (RMR) at the start of reintensification (protocol II) to receive 0 (Standard Arm, SA) vs 9 (Experimental Arm, EA) additional biweekly PEG-ASP doses throughout protocol II and continuation therapy. Therefore, all the SR patients and the MR patients randomized to SA overall received 3 PEG-ASP doses with an 18-week-long interval between doses #1+#2 (induction, first exposure) and dose #3 (reintensification, second exposure) whilst the MR patients randomized to the EA overall received 12 PEG-ASP doses with an 18-week-long interval between doses #1+#2 (induction, first exposure) and doses #3 to #12 (reintensification and continuation therapy, second exposure). HR patients were randomized (RHR) at the start of the consolidation phase (protocol IB) to receive 0 (SA) vs 4 (EA) additional weekly PEG-ASP doses. Therefore, HR patients randomized to the EA received overall 12 PEG-ASP doses (first exposure: #1+#2 in IA; further exposures: #3 to #6 in IB, #7 to #9 in each of the 3 blocks and #10 to #12 in each of the protocols III) without relevant time-intervals among the various doses, whilst HR patients randomized to the SA received overall 8 doses with an 8-week-long interval between the doses #1+#2 (IA, first exposure) and the second and further exposures (3 blocks and 3 protocols III, doses #3 to #8). HSR were recorded by treating physicians and collected in the trial database and cumulative incidence (CI-HSR) was estimated adjusting for competing risks (death for any reasons and leuekemia recurrence).
Results: Between June 01, 2010 and February 28, 2017, 6136 patients were eligible and evaluable in the study and are here reported. An HSR occurred in 468 patients, with a CI-HSR of 7.6% (SE 0.3). In particular, 121 (2.0%) occurred in IA, 20 (0.3%) in IB, 140 (2.3%) in Protocol II, 183 (3.0%) in blocks, 4 (0.07%) in Protocols III and maintenance. According to the stratification group, CI-HSR was 4.9%(0.5) in SR, 4.9% (0.4) in MR and 16.8% (1.0) in HR groups. In the RMR study, the CI-HSR was 3.1% (0.6) vs 4.3% (0.8) in the SA vs the EA, respectively (p-value=0.26), whilst in the RHR study the CI-HSR was 18.3% (1.9) vs 6.1% (1.3) in the SA vs the EA, respectively (p-value<0.001).
Conclusions: In the AIEOP-BFM ALL 2009 trial, the incidence of HSR was much lower with respect of historical experiences of previous AIEOP-BFM ALL protocols wherein the native E.Coli ASP product was used I.V. as first-line product. No difference in terms of HSR was found between patients belonging to the EA and SA of the RMR. As expected, due to the higher number of PEG-ASP doses administered, the cumulative incidence of HSR was much higher in the HR group. Interestingly and in keeping with the concept that continuous and prolonged exposures to PEG-ASP reduce the probability of developing an HSR, patients randomized to receive in the RHR the SA (long interval between the first and subsequent exposures) showed an incidence of HSR much higher (18.3%) than that observed in the EA control arm (6.1%).

Disclosures
Rizzari: Together with study group from Shire, medac , Sigma-Tau, Baxalta, Shire and Servier: Research Funding; JazzPharma, Shire, medac , Sigma-Tau, Baxalta, Shire and Servier: Consultancy, Honoraria. Locatelli:Miltenyi: Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BluebirdBio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boos:medac GmbH: Membership on an entity's Board of Directors or advisory committees, Other: Safety Boards, invited lectures, drug monitoring program; Eusa Pharma: Other: invited lectures, drug monitoring program; Jazz Pharmaceuticals: Other: invited lectures, drug monitoring program; Baxalta: Other: invited lectures, drug monitoring program; Shire: Other: invited lectures, drug monitoring program; Sigma-Tau: Other: invited lectures, drug monitoring program. Zucchetti:Together with study group from medac , Sigma-Tau, Baxalta, Shire and Servier: Research Funding. Schrappe:Together with study group from SHIRE, JazzPharma, Servier, SigmaTau, Amgen, and Novartis.: Research Funding; SHIRE, Servier, and JazzPharma: Honoraria.