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    Home > Active Ingredient News > Blood System > Chemotherapy drug-allergic ALL patients new hope Eryaspas can be used for second-line treatment of acute lymphoblastic leukemia patients allergic to asparaginase

    Chemotherapy drug-allergic ALL patients new hope Eryaspas can be used for second-line treatment of acute lymphoblastic leukemia patients allergic to asparaginase

    • Last Update: 2022-06-18
    • Source: Internet
    • Author: User
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    Asparaginase is one of the main chemotherapy drugs for the treatment of acute lymphoblastic leukemia (ALL), which helps to prolong the survival of patients, but it is highly toxic
    .

    Interruption of therapy due to asparaginase-related hypersensitivity reactions can lead to shortened event-free survival in patients with ALL
    .

    Therefore, the use of other asparaginase preparations to replace asparaginase in the treatment of ALL is critical
    .

    Eryaspase is a novel drug that encapsulates L-asparaginase in allogeneic red blood cells, prolonging the half-life of asparaginase, reducing allergic reactions and asparaginase-related toxicity
    .

    The encapsulated asparaginase prevents the asparaginase epitope from being recognized by the host immune system
    .

    Patients can be re-exposed to eryaspas even if they develop a severe allergic reaction while on asparaginase therapy
    .

    Therefore, we conducted a multicenter, single-arm, phase II clinical trial to investigate the pharmacological profile and associated toxicity of eryaspas in PEG-asparaginase-allergic ALL patients
    .

    Study methods Enrollment criteria: (1) Age: 1-45 years old; (2) Diagnosed as first-line, non-high-risk, Philadelphia chromosome negative, B lymphocyte precursor or T cell ALL; (3) PEG-asparagine Patients with a history of allergy to enzymes (first-line therapy) who have been treated with the Nordic Cooperation Group (NOPHO) ALL2008 program (NCT00819351) or the ALLTogether pilot program (NCT04307576)
    .

    In the NOPHO ALL2008 regimen, 5 doses of PEG-asparaginase (1000 IU/m²/dose, intramuscularly) were administered to non-high-risk patients at 2-week intervals during the consolidation phase, starting on day 30 of treatment, followed by delayed intensive chemotherapy.
    and 3 additional doses of PEG-asparaginase every 6 weeks during the first maintenance phase
    .

    In the ALLTogether pilot protocol, PEG-asparaginase injections (<16 years: 1500 IU/m² and >16 years: 1000 IU/m², IV) were administered starting on day 4 of induction therapy
    .

    Non-high-risk patients were assigned to standard-risk, intermediate-low-risk, or intermediate-high-risk groups on day 29 of treatment, and were injected with 4, 5, or 8 doses of PEG-asparaginase, respectively, after a 2-week interval
    .

    Allergic reactions to PEG-asparaginase treatment were included in the study, and eryaspas (150 U/kg) were used to replace the remaining doses of PEG-asparaginase
    .

    Treatment was started after a 2- or 6-week interval, depending on the treatment regimen and time of enrollment
    .

    Results 1 Patient Baseline Characteristics From August 2017 to July 2020, a total of 55 patients were included in the study, including 53 children (96.
    4%) and 2 adults (3.
    6%), with a median age of 6.
    1 years (quartile).
    Difference [IQR]: 3.
    5-10.
    6)
    .

    Patients were enrolled when the median dose of PEG-asparaginase was 3 (range: 2-6)
    .

    Of the enrolled patients, 53 patients (96.
    4%) had clinical hypersensitivity reactions to PEG-asparaginase, and 46 of 53 patients (87%) had confirmed PEG-asparaginase in 2 or more test samples inactivated
    .

    Among the patients with clinical anaphylaxis: 31 patients (58.
    5%) had severe anaphylaxis and 22 patients (41.
    5%) had mild anaphylaxis
    .

    Two patients (3.
    6%) had silent inactivation
    .

    The baseline characteristics of the patients are shown in Table 1
    .

    Table 1 Patient baseline characteristics 2 Pharmacokinetics and pharmacodynamics A total of 1665 samples from 53 patients were included in the pharmacokinetic analysis
    .

    Of 53 patients, 49 patients (92.
    5%) had asparaginase enzyme activity (AEA) ≥100 IU/L 14±2 after the first eryaspase infusion (median AEA: 511 IU/L, IQR: 291-780 IU/L); 9 patients tested AEA after the 4th infusion, of which 6 patients (66.
    7%) had AEA ≥ 100 IU/L (median AEA: 932 IU/L, IQR: 496- 163 IU/L)
    .

    The change trend of AEA after the first and fourth doses of eryaspase infusion is shown in Figure 1
    .

    AEA ≥ 100 IU/L in 109 of 151 samples from 37 patients (median AEA: 422 IU/L, IQR: 252-732 IU/L); 42 ± 5 days after eryaspase infusion, AEA ≥ 100 IU/L in 41 (41.
    4%) of 99 samples from 37 patients (median AEA: 261 IU/L) L, IQR: 146-482 IU/L)
    .

    Figure 1 Changes in AEA after the first and fourth doses of eryaspase infusion The mean terminal elimination half-life (t1/2) and standard deviation (SD) after the first infusion was 15.
    3 ± 15.
    5 days
    .

    The mean clearance (CL) was 0.
    01 L/day/kg and was highly variable (coefficient of variation [CV]: 80.
    5%)
    .

    The mean t1/2 and SD after the 4th infusion were 13.
    2 ± 11.
    2 days and were highly variable (CV: 84.
    8%)
    .

    Thirty-two patients (60.
    4%) developed asparaginase-directed antibodies during eryaspase treatment
    .

    In addition, 4 of the 5 patients with asparaginase-related allergy tested positive for antibodies at the time of anaphylaxis and asparaginase inactivation
    .

    164 cerebrospinal fluid samples from 49 patients were tested, and AEA measurements were consistent (±48h) in 110 samples
    .

    Cerebrospinal fluid asparaginase concentrations decreased with increasing AEA
    .

    3 Safety Clinical allergic reactions occurred in 10 patients after eryaspase infusion, of which 2 patients were severely allergic, which led to the discontinuation of eryaspase treatment
    .

    Among the 2 patients, 1 patient developed mild allergy after the first infusion, and severe allergy at the fourth infusion after continuing treatment, and retrospective analysis showed that the patient had a low AEA value; Severe hypersensitivity developed at 4 infusions, and this patient had an AEA above threshold
    .

    However, both patients developed allergies during treatment after a 6-week interval
    .

    Of the 8 mild allergic patients, 3 patients had AEA < 100 IU/L 14 days after infusion
    .

    One patient had AEA < 100 IU/L 14 days after injection (3 doses, 6 weeks apart) but no clinical symptoms
    .

    Grade 2 osteonecrosis was reported in 1 patient
    .

    No patients developed thromboembolism or pancreatitis
    .

    Most (15/23) adverse events were grade 2 or less
    .

    One patient died, which was judged to be unrelated to eryaspase
    .

    All patients were followed up for 1 year after the last treatment
    .

    Fifty-three patients (96.
    4%) achieved complete remission at the end of follow-up
    .

    One patient died of hemophagocytic lymphohistiocytosis unrelated to eryaspase during follow-up
    .

    One patient developed CNS ALL recurrence during follow-up
    .

    Conclusion Eryaspase is well tolerated, and most patients can complete asparaginase therapy
    .

    After the 1st to 4th infusions, most patients had AEA levels above the therapeutic target
    .

    Based on the half-life of eryaspase, a 2-week eryaspase treatment plan is suitable for ALL patients
    .

    References Lynggaard, LS, Vaitkeviciene G, Langenskiöld, C, et al , Asparaginase encapsulated in erythrocytes as second-line treatment in hypersensitive patients with acute lymphoblastic leukaemia.
    Br J Haematol.
    2022; 00: 1– 10.
    https://doi .
    org/10.
    1111/bjh.
    18152.
    Editor: Wenting Reviewer: Quinta Typesetting: Youshi Execution: Youshi pokes "read the original text", let's make progress together
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