Key toxicities related to treating acute lymphoblastic leukemia (ALL) with asparaginase, specifically pancreatitis and osteonecrosis, are associated with increases in asparaginase enzyme activity, suggesting that patients at risk for those toxicities would benefit from therapeutic drug monitoring, according to new research.
In the study, published Oct. 8 in Blood Advances, increased asparaginase enzyme activity was not significantly associated with overall asparaginase toxicity. However,“ the authors concluded.
“The [findings are] new, and we have included patients from a quite big cohort, which is unique,” coauthor Birgitte Klug Albertsen, MD, PhD, associate clinical professor with Aarhus (Denmark) University Hospital, told this news organization.
Therapeutic drug monitoring already is widely used during treatment with asparaginase, the standard of care treatment for ALL; however, the focus of this monitoring has typically been on clinical effectiveness, as levels of asparaginase enzyme activity can indicate hypersensitivity reactions, while the absence of such activity can suggest inferior outcomes.
Meanwhile, drug monitoring is not normally used to assess the risk of treatment-related toxicities. This has been due to a lack of evidence regarding asparaginase enzyme activity and toxicity risk, which, if severe enough, can prevent further treatment.
To investigate the relationship with toxicities, Dr. Albertsen and colleagues evaluated data from seven countries in Europe on 1,155 children between the ages of 1 and 17.9 who were diagnosed with ALL and treated with asparaginase, according to the Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol between July 2008 and March 2016.
Blood samples drawn approximately 14 days after asparaginase administration showed that some level of asparaginase enzyme activity was measurable in 955 patients (82.7%), while 200 patients (17.3%) had asparaginase inactivation. Overall, there were 159 asparaginase-associated toxicities of pancreatitis, thromboembolism, or osteonecrosis among the 955 patients with measurable asparaginase enzyme activity.
There were no significant differences in median asparaginase enzyme activity levels between those who did and did not experience toxicities (224 IU/L vs. 221 IU/L, respectively; P = .1), and the results did not change after adjustment for age and sex. However, the risk of pancreatitis was found to increase with a hazard ratio (HR) of 1.40 for each 100 IU/L increase in the median asparaginase enzyme activity level (P = .002).
Likewise, an increase in risk was observed for osteonecrosis (HR 1.36; P = .02) per 100 IU/L increase in median asparaginase enzyme activity. However, the HR for the risk of thromboembolism, the most common of asparaginase-related toxicities, was not significant (HR 0.99; P = .96).
Dr. Albertsen said the etiology behind the occurrence of osteonecrosis is not well understood.
“We know that steroids, especially dexamethasone, are a risk factor,” she said. “We believe that asparaginase may play a role too, but a clear association has not been demonstrated.”
In the NOPHO ALL2008 protocol used in the study, dexamethasone is used in the same time periods as PEG-asparaginase treatment for patients receiving 15 doses.
The finding of only a nonsignificant trend between asparaginase enzyme activity with overall toxicities may have reflected the low dose that was used, Dr. Albertsen added.
“In the NOPHO ALL2008 protocol, we used quite a low dose of PEG-asparaginase, and the risk may be higher in protocols using higher doses,” she said.
Relapse reduction
Notably, the study showed that asparaginase enzyme elevations were, in fact, not significantly associated with a reduction in the risk of leukemic relapse (HR .88 per 100 IU/L increase; P = .35).
Those findings suggest that measurable asparaginase enzyme activity levels, and thus asparaginase depletion, “may be sufficient to ensure an antileukemic effect,” the authors noted.
“Therapeutic drug monitoring of asparaginase enzyme activity is indicated mainly to detect inactivation, but [it] may be further explored for dose reduction to reduce some specific toxicities,” they concluded.
Dr. Albertsen disclosed being sponsor of the investigator-initiatied NOR-GRASPALL 2016 trial.