Asparaginase toxicity: Issues and potential solutions

Asparaginase (asp) is a key part of the treatment of acute lymphoblastic leukemia (ALL) in both adult and pediatric patients. However, up to 20% of patients experience toxicity associated with asp treatment, such as hypersensitivity reactions which may lead to silent inactivation. Other toxicities include osteonecrosis, thromboembolism, and pancreatitis. During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, four talks examining asp-induced toxicities and possible solutions, were presented.

Asp toxicity

Asp enzyme activity does not predict toxicity

Asp enzyme activity (AEA) levels are frequently measured in patients with ALL to determine in which patient’s asp activity has been inactivated. However, it is not common to use AEA to measure if a patient has high-levels and if this has any association with the severity of and risk of asp-toxicity. Line Stensig Lynggaard spoke on this subject at the 62nd ASH Annual Meeting and Exposition, regarding a study that followed the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol.¹

After analyzing 6,929 samples from 1,155 patients ≤ 18 years with non-high-risk ALL, 328 asp-toxicity events were recorded following administration of pegylated asp (peg-asp). AEA was measured from two or more blood samples drawn 14 days after administration and before first toxicity was recorded. Patients who experienced toxicities were significantly more likely to be older, with 67% of the 10- to 17-year-old group experiencing toxicity events compared with 33% of the 0- to 9-year-old cohort (p < 0.001). Patients who had no or low AEA levels (< 100 U/L) showed a significantly increased incidence of hypersensitivity reactions (149/152 events). By contrast, no significant difference was found between high-level AEA (> 250 U/L), therapeutic level AEA (100–250 U/L), and low-level AEA in terms of asp-induced pancreatitis, thromboembolism, or osteonecrosis. Also, no difference in the 5-year survival was found in the different AEA groups. Therefore, there is no therapeutic advantage in monitoring patients with high-level AEA as they are not associated with more toxicity and different outcome.

Asp rechallenging is feasible after hypersensitivity reactions

One possibility for patients with hypersensitivity reactions to Escherichia coli-derived peg-asp, is using Erwinia-asp. However, the dosing schedule is more demanding, and it can be difficult to source. Rechallenging with E. coli-derived peg-asp may be viable in some patients. Lynda Vrooman presented a talk at the 62nd ASH Annual Meeting and Exposition, examining the results in patients with ALL who were rechallenged with peg-asp following a Grade II hypersensitivity reaction.² AEA was monitored, and patients were given premedication (premed) at rechallenge. Patients (N = 317) were eligible for inclusion in the Dana-Farber Cancer Institute (DFCI) 16-001 protocol if they were newly diagnosed with ALL and age 1 to < 22 years old. Peg-asp was given at induction and during consolidation (every 2 weeks, up to 15 doses) and administered intravenously without premed over 1−2 hours.

Out of the 299 patients who were evaluable, 81 patients experienced an allergic reaction (Grade 2 in 68, and Grade ≥ 3 in 13). 50 patients with Grade 2 allergic reaction were rechallenged with peg-asp while 13 patients with Grade 3 allergic reaction were switched to Erwinia-asp. In this prospective study, patients who were rechallenged received peg-asp at a slower infusion rate and were administered acetaminophen, diphenhydramine, and hydrocortisone as premed. A total of 25 patients (50%) were successfully rechallenged with peg-asp while the other half, either failed to achieve adequate AEA (n = 6), had reactions at rechallenge (n = 17) or both (n = 2). Patients who failed rechallenge were switched to Erwinia-peg-asp. Using this protocol requires less Erwinia-peg-asp and limits the amount of premed exposure in patients to only a small cohort.

High rates of Asp-induced osteonecrosis in adolescent and young adult patients

In a talk presented by Yannis Valtis, the problem of osteonecrosis following asp treatment in adolescents and young adults (AYA) with ALL as experienced on DFCI ALL consortium trials, was examined.³ AYA patients with ALL fare better on pediatric regimens compared with adult protocols but their risk of osteonecrosis has not been assessed so far. However, these pediatric regimens rely on corticosteroids and asp, which can lead to osteonecrosis and fractures along with increased risk of thrombosis, liver toxicity, and pancreatitis. Glucocorticoids are known to interfere with osteoblast differentiation and cause ischemia while asp can cause hypercoagulability. Toxicities have been seen to affect older children and adults disproportionately.

DFCI ALL consortium protocols (2000−2019) were used; the earlier protocols mostly relied on E. coli-asp, whereas the later ones used peg-asp. With a median follow-up of around 5 years for all studies, out of 367 patients examined, 17% (95% CI, 13–22%) experienced osteonecrosis and 12% (95% CI, 9–16%) suffered fractures. Of the patients experiencing osteonecrosis, 46% required surgery. Age and use of peg-asp were risk factors for developing osteonecrosis. Younger patients, < 30 years old, were more likely to experience osteonecrosis (HR 2.58 [1.26−5.30]; p = 0.010). The later peg-asp based protocols that used dexamethasone also resulted in higher rates of orthopedic toxicities (HR 5.08 [2.12−12.16]; p < 0.001). In conclusion, as AYA patients face an increased risk of osteonecrosis compared with children, especially when treated with peg-asp, novel treatment protocols need to take this into account.

Reduced toxicity with erythrocyte-encapsulated asp

A second talk presented by Line Stensig Lynggaard at the 62nd ASH Annual Meeting and Exposition, investigated the use of erythrocyte-encapsulated asp (eryaspase) as part of the NOR-GRASPALL 2016 multinational, single arm phase II study (NCT03267030) treating newly diagnosed patients with non-high-risk ALL aged 1−45 years.⁴ This method of asp delivery is intended to prolong the half-life, as well as reducing asp-toxicity. Patients (N = 55) were included in the study following hypersensitivity reactions (53 patients) or silent inactivation (two patients) after treatment with peg-asp in the screening phase. Eryaspase (150 U/kg) was given every 2 weeks for up to seven doses and patients were followed for toxicity for 30 days.

With a medium of five doses of eryaspase administered per patient, 18 patients experienced adverse events related to the study drug, with five experiencing a severe adverse event (allergy) and 11 patients experiencing mild adverse events (rash, temperature rise, hyperlipidemia, liver toxicity, and osteonecrosis). Overall, eryaspase was well tolerated with no cases of pancreatitis and few liver toxicities. However, the two patients with severe allergic reaction to eryaspase were unable to complete the full asp treatment.

AEA level was measured and the therapeutic target of > 100 U/L was achieved in 98.1% of patients after the first dose. The one patient who did not achieve this on the first dose, reached > 100 U/L after subsequent doses.

In conclusion, these data show that sustained therapeutic AEA is achieved after first administration of eryaspase while the risk of toxicity, especially hypersensitivity, is low.

Conclusion

Asp toxicity continues to be a problem for the treatment of ALL with significant morbidity caused by side effects such as severe allergic reactions, osteonecrosis, and fractures. Keeping these adverse advents in mind when deciding on treatment regimens is advisable, especially for the use of pediatric protocols in AYA patients. High rates of hypersensitivity reactions remain a challenge for asp treatment. However, recent efforts have shown that even patients who experience Grade 2 hypersensitivity reactions from peg-asp may be able to derive benefit from rechallenge. In those patients who cannot tolerate peg-asp, a new option may be offered by eryaspase which shows low rates of toxicity and good AEA after only one infusion.