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

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.
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