Depletion of d‐ and l‐asparagine in cerebrospinal fluid in acute lymphoblastic leukemia during PEGasparaginase therapy. Issue 11 (26th July 2022)

• Record Type: Journal Article
• Authors: Brigitha, Leiah J.; Pieters, Rob; Struys, Eduard A.; Bakkali, Abdellatif; van der Sluis, Inge M.
• Is Part Of: Pediatric blood & cancer. Volume 69:Issue 11(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-07-26
• Subjects: acute lymphoblastic leukemia -- asparaginase -- cerebrospinal fluid -- d‐asparagine -- l‐asparagine -- pediatric ALL; Tumors in children -- Periodicals; Blood -- Diseases -- Periodicals; Cancer in children -- Periodicals; 618.92
• DOI: 10.1002/pbc.29865
• Languages: English
• ISSNs: 1545-5009

Abstract

Abstract: Background: l ‐Asparaginase hydrolyzes l ‐asparagine and not its enantiomer d ‐asparagine. Unlike l ‐asparagine, d ‐asparagine is nonessential for the survival of acute lymphoblastic leukemia (ALL) cells. Studies showed that serum asparagine is depleted below 0.5 μM in ≥96% of the patients during pegylated Escherichia coli l ‐asparaginase (PEGasparaginase) treatment; however, cerebrospinal fluid (CSF) asparagine levels are depleted in only 20%–30% of the patients. Thus far, studies only reported the total CSF asparagine (sum of d ‐ and l ‐asparagine) concentrations. Data on the pharmacological goal, which is l ‐asparagine depletion, are lacking. Method: Therefore, we studied this in 30 patients (95 samples) with newly diagnosed ALL. They received two doses of PEGasparaginase on day 4 and 18 in induction. Results: Median age at diagnosis was 5.7 years (range 1.5–17.1 years). d ‐Asparagine and l ‐asparagine concentrations (median (range)) before PEGasparaginase treatment were 0.038 (0.0–0.103) μM and 6.1 (1.82–11.5) μM, respectively. CSF l ‐asparagine concentrations were reduced by 85% (76%–100%) and approximately one‐third of the patients (32%) had CSF l ‐asparagine depletion below 0.5 μM 11 days after the second PEGasparaginase dose administration. CSF d ‐asparagine and l ‐glutamine levels remained stable before and after administration of PEGasparaginase. The percentage of d ‐asparagine as a fraction of total asparagine (sum of d ‐ and l ‐asparagine) was 0.62% before and 4.5% after PEGasparaginase treatment. No correlation was found between higher serum PEGasparaginase activity and CSF l ‐asparagine concentration. Conclusion: l ‐Asparagine is not a better parameter than total asparagine in CSF due to the negligible amount of d ‐asparagine in the CSF before and after PEGasparaginase treatment.