Four Additional Doses of PEG-L-Asparaginase During the Consolidation Phase in the AIEOP-BFM ALL 2009 Protocol Do Not Improve Outcome and Increase Toxicity in High-Risk ALL: Results of a Randomized Study

Article

作者: Locatelli, Franco ; Stary, Jan ; Lanvers-Kaminsky, Claudia ; Bodmer, Nicole ; Buldini, Barbara ; Gruhn, Bernd ; Engstler, Gernot ; Elitzur, Sarah ; Silvestri, Daniela ; Niggli, Felix ; Rizzari, Carmelo ; Barbaric, Draga ; Smisek, Petr ; Valsecchi, Maria Grazia ; von Stackelberg, Arend ; Izraeli, Shai ; Matteo, Cristina ; Cazzaniga, Giovanni ; Attarbaschi, Andishe ; Zucchetti, Massimo ; Biondi, Andrea ; Zimmermann, Martin ; Lehrnbecher, Thomas ; Dalla Pozza, Luciano ; Boos, Joachim ; Möricke, Anja ; Cario, Gunnar ; Conter, Valentino ; Schrappe, Martin

PURPOSE The AIEOP-BFM ALL 2009 protocol included, at the end of the induction phase, a randomized study of patients with high-risk (HR) ALL to investigate if an intensive exposure to pegylated L-asparaginase (PEG-ASNASE, 2,500 IU/sqm once a week × 4) on top of BFM consolidation phase IB allowed us to decrease minimal residual disease (MRD) and improve outcome. PATIENTS AND METHODS A total of 1,097 patients presented, from June 2010 to February 2017, with one or more of the following HR criteria: KMT2A::AFF1 rearrangement, hypodiploidy, prednisone poor response, poor bone marrow response at day 15 (Flow MRD ≥10%), or no complete remission (CR) at the end of induction. Of them, 809 (85.1%) were randomly assigned to receive (404) or not receive (405) four weekly doses of PEG-ASNASE. RESULTS By intention to treat (ITT) analysis, there was no significant difference in the proportion of patients with polimerase chain reaction MRD ≥5 × 10−4 at the end of phase IB in the experimental versus control arm (13.9% v 17.0%, P = .25). The 5-year event-free survival (median follow-up 6.3 years) by ITT in the experimental and control arms was 70.4% (2.3) versus 75.0% (2.2; P = .18), and the 5-year overall survival was 81.5% (2.0) versus 84.0% (1.9; P = .25), respectively. The corresponding 5-year cumulative incidence of death in CR was 9.5% (1.5) versus 5.7% (1.2; P = .08), and that of relapse was 17.7% (1.9) versus 17.2% (1.9), respectively ( P = .94). Adverse reactions in phase IB occurred in 22.2% and 8.9% of patients in the experimental and control arm, respectively ( P < .001). CONCLUSION Additional PEG-ASNASE in phase IB did not translate into a benefit for decreasing relapse incidence but was associated with higher toxicity. Further improvements with conventional chemotherapy might be difficult in the context of intensive treatment protocols.

2023-12-31·Hematology

Clinical summary of pediatric acute lymphoblastic leukemia patients complicated with asparaginase-associated pancreatitis in SCCLG-ALL-2016 protocol

Article

作者: Huang, Li-Bin ; Wang, Jian ; Chen, Hui-Qin ; Zhou, Dun-Hua ; Kuang, Wen-Yong ; Wang, Li-Na ; Liao, Ning ; Yang, Li-Hua ; Jia, Wen-Guang

Asparaginase-associated pancreatitis (AAP) is a common and fatal complication after ASNase treatment in acute lymphoblastic leukemia(ALL). Here, a total of 1063 pediatric ALL patients treated with SCCLG-ALL-2016 regimen were collected since October 2016 to June 2020, including 35 patients with AAP. The clinical characteristics of AAP and non-AAP patients were compared. In AAP patients, the possible factors that affected the recurrence of AAP were analyzed, and the possible risk factors related to ALL-relapse were discussed. The results showed that age was a risk factor (P = .017) that affect the occurrence of AAP. In AAP patients, AAP tended to develop after the second use of PEG-ASNase (25.71%). In the follow-up chemotherapy, 17 patients re-exposed to ASNase and 7 cases developed AAP again with a percentage was 41.2%. There were no special factors that related with the recurrence of AAP. This study also found no association between the occurrence of AAP and prognosis of ALL, with the 4-year incidence of ALL relapse in AAP and non-AAP patients were 15.9% v.s.11.7% (HR: 1.009, 95% CI:0.370-2.752, P = .986), and there were no special factors that related with the ALL relapse among AAP patients. Based on the above results, the occurrence of AAP is related to age and should be vigilant after the second use of PEG-ASNase after use in pediatric ALL patients. Moreover, AAP is not associated with ALL relapse, but there is a high AAP recurrence rate when re-exposure to ASNase.

2022-03-01·European Journal of Drug Metabolism and Pharmacokinetics4区 · 医学

Impact of Antibodies Against Polyethylene Glycol on the Pharmacokinetics of PEGylated Asparaginase in Children with Acute Lymphoblastic Leukaemia: A Population Pharmacokinetic Approach

4区 · 医学

Article

作者: Rizzari, Carmelo ; Lanvers-Kaminsky, Claudia ; Würthwein, Gudrun ; Smisek, Petr ; Boos, Joachim ; Alten, Julia ; Nath, Christa E ; Siebel, Christian

BACKGROUND AND OBJECTIVESBesides allergic reactions, antibodies against polyethylene glycol (PEG) have been associated with reduced PEG-asparaginase (PEG-ASNase) activity. Population pharmacokinetics (popPK) allow for an in-depth investigation of the influence of anti-PEG antibodies on PEG-ASNase pharmacokinetics.METHODSPEG-ASNase activity (6261 samples) and anti-PEG antibodies (2082/6412 samples prior to/post administration) in 1444 children with acute lymphoblastic leukaemia treated in the AIEOP-BFM ALL 2009 trial were evaluated. Patients received two doses of PEG-ASNase during induction (2500 U/m², intravenous, biweekly) and a third dose during reinduction treatment. Anti-PEG IgG and IgM measured prior to and post administration were explored for their influence on the initial clearance of PEG-ASNase using a previously established popPK model. Categorical and continuous antibody data, including each isotype individually as well as in combination, were assessed.RESULTSHigh pre-existing levels of anti-PEG antibodies increase the initial drug clearance. Analysed separately, both anti-PEG IgG_prior and IgM_prior were significant covariates; the stronger effect was observed for anti-PEG IgM_prior. Hockey stick models best described the data. For anti-PEG IgM_prior, each additional log unit above the estimated cut point was related to a 41.4% increase in initial clearance after the first dose in induction. Antibody levels below the cut point were not associated with an effect on clearance. The combination of both isotypes did not provide additional information compared to anti-PEG IgM_prior alone. Antibody levels post administration were not associated with an effect on clearance.CONCLUSIONPre-existing antibodies against PEG-ASNase significantly increased the initial clearance in a subgroup of patients showing high antibody levels. (Trial registration: EU clinical trials register; EudraCT No: 2007-004270-43; first registered 23 October 2009.).

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适应症	最高研发状态	国家/地区	公司	日期
肿瘤	临床前	美国	Scorpius Holdings, Inc.	2018-09-01
肿瘤	临床前	中国	默克制药（江苏）有限公司初创企业	2018-09-01
肿瘤	临床前	美国	The University of Texas at Austin	2018-09-01
肿瘤	临床前	荷兰	MedImmune Pharma BV	2018-09-01
肿瘤	临床前	美国	Ikena Oncology, Inc.	2018-09-01