Serum asparaginase activities and asparagine concentrations in the cerebrospinal fluid after a single infusion of 2,500 IU/m(2) PEG asparaginase in children with ALL treated according to protocol COALL-06-97.

BACKGROUND AND PROCEDURE: Pharmacological surrogate parameters are considered a useful tool in estimating the treatment intensity of asparaginase (ASNase) preparations. When a pegylated ASNase (single infusion of 2,500 IU/m(2) polyethylene glycol (PEG)-ASNase, Oncaspar) was introduced into the treatment protocols of the German Cooperative Acute Lymphoblastic Leukaemia (COALL) study group, this was accompanied by a drug monitoring programme measuring serum ASNase activity and asparagine (ASN) concentrations in the cerebrospinal fluid (CSF) in 70 children. RESULTS: Four hundred fifty-nine serum samples from 67 evaluable patients showed medians of ASNase activity of 1,189.5, 824.5, 310.5, 41 and 4 U/l on day 7 +/- 1, 14 +/- 1, 21 +/- 1, 28 +/- 1 and 35 +/- 1 respectively. One hundred eighty-four samples from 59 patients were evaluable for ASN concentrations in the CSF. The medians of ASN concentration were <0.2, 0.2, 0.9 and 3.2 microM on day 14 +/- 1, 21 +/- 1, 28 +/- 1 and 35 +/- 1 respectively. When relating CSF ASN levels to the serum ASNase activity measured on the same day, a median of 1.2 microM CSF ASN was associated with values of serum ASNase activity between > or =2.5 and <100 U/l. Serum ASNase activity values > or =100 U/l were associated with a median CSF ASN of <0.2 microM, with 13/27 samples being incompletely depleted. CONCLUSIONS: The treatment intensity achieved with PEG ASNase in the present study appears to be acceptable based on the surrogate of serum ASNase activity. However, the pharmacological objective of ASNase treatment, that is, complete CSF ASN depletion with an ASNase activity >100 U/l, was not ensured. Nevertheless, one must also be aware that the minimum ASN concentration required for leukaemic cell growth is yet to be established.

Asparagine concentration in plasma after 2,500 IU/m(2) PEG-asparaginase i.v. in children with acute lymphoblastic leukemia.

UNLABELLED: Polyethylene glycol conjugated asparaginase (PEG-ASNase) can be substituted in cases of hypersensitivity to native Escherichia coli asparaginase. We measured asparagine (asn) levels in plasma after a single dose of 2,500 IU/m(2) i.v. PEG-ASNase (Oncaspar) in consolidation treatment of ALL and compared those with data from the previous protocol COALL-05-92. This protocol was similar to COALL-06-97, except that children had been given 45,000 IU/m(2) C-ASNase instead of PEG-ASNase. PATIENTS AND METHODS: Between May 2000 and December 2001 seventy-one children (38 boys, 33 girls) with newly diagnosed ALL treated according to the multicenter protocol COALL-06-97 were investigated in this study. Four hundred and seventy-four plasma samples (71 patients) were analysed by ion exchange chromatography after column derivatization with o-phthaldialdehyde. For comparison data (350 plasma samples) from 51 patients treated according to the protocol COALL-05-92 were available. The same method for detection of asn in plasma was used. RESULTS: The median asparagine level in plasma after 2,500 IU/m(2) PEG-ASNase i.v. was below the limit of detection for at least 5 weeks in 81 % of the patients. When divided into high risk (HR) and low risk (LR) group, HR patients who had previously received one dose more of C-ASNase showed a markedly shorter depletion than the LR patients compatible with a higher risk of antibody formation and consequent silent inactivation after a higher number of exposures to ASNase. In the previous protocol COALL-05-92 median asn levels in plasma after 45,000 IU/m(2) native C-ASNase i.v. were below the limit of detection for at least 5 weeks in 65 % of the patients. CONCLUSIONS: 2,500 IU/m(2) PEG-ASNase led to an equally long depletion of asn in plasma as did 45,000 IU/m(2) native C-ASNase i.v. used in COALL-05-92.

Drug monitoring of PEG-asparaginase treatment in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma.

This is an updated review of the pharmacokinetic profile of PEG-asparaginase (PEG-ASNase) in childhood acute lymphoblastic leukemia (ALL) or non-Hodgkin's lymphoma (NHL). In a total of 271 children undergoing ALL/NHL or relapsed ALL treatment according to the Berlin-Frankfurt-Münster (BFM) protocols, drug monitoring of ASNase serum activity was performed after PEG-ASNase infusions. From December 1996 to July 2000, 1667 samples after 362 intravenous administrations of either 500, 750, 1000 or 2500 IU/m2 PEG-ASNase were analyzed. Three weeks after infusion when relating the ASNase activity to the four-dose levels significant differences were not observed. Large interpatient variability was seen at each dose level resulting in a relevant number of patients not achieving adequate treatment intensity. Neither the extent of ASNase pre-treatment nor a prior event of a hypersensitivity reaction against unmodified ASNase had any impact on PEG-ASNase pharmacokinetics. It is concluded that escalation of the dose of PEG-ASNase did not result in a significant prolongation of time with activity values considered therapeutic. Depending on the desired endpoint, a second administration of PEG-ASNase seems to be more favorable than increasing the dose. For a safer recommendation, further investigations assessing the pharmacodynamic profile are required. Drug monitoring is advisable for early detection of patients with rapid elimination in order to ensure maximum treatment intensity.

Drug monitoring of low-dose PEG-asparaginase (Oncaspar) in children with relapsed acute lymphoblastic leukaemia.

Use of asparaginase (ASNase) in the treatment of relapsed childhood acute lymphoblastic leukaemia (ALL) is associated with a high rate of hypersensitive reactions. 'Silent' inactivation may additionally reduce treatment intensity. Therefore, PEG-ASNase (Oncaspar), a polyethylene glycol conjugate of the native Escherichia coli-ASNase, was introduced into the Berlin-Frankfurt-Münster (BFM) 96 treatment protocol for relapsed ALL under drug monitoring conditions. A single i.v. dose of 500 IU/m2 PEG-ASNase, substituted for the native ASNases, was administered to supply a plasma activity of 100 IU/l for 1 week. From November 1997 to March 2000, 35 patients from 23 BFM-associated hospitals, with or without a previous allergic reaction to one or both native preparations, underwent monitoring. After 82 applications, a total of 270 samples were submitted to be tested for ASNase activity. The ASNase activity on the day of the administration and the following day ranged between < 20 and 693 IU/l, with a median of 413 IU/l (53 samples). The median on d 7 +/- 1 was 199 IU/l (range <20--421 IU/l; 41 samples) and on d 14 +/- 1, 105 IU/l (range <20--188 IU/l; 19 samples). An ASNase activity of > 100 IU/l was seen on d 7 in 36 activity time courses of 52 interpretable applications (69%). Intraindividual variability of activity time courses was low. However, a rapid decrease in ASNase activity after repeated applications was observed in 4 out of 20 children. Previously experienced allergic reactions to native ASNases did not influence PEG-ASNase pharmacokinetics. PEG-ASNase is a useful alternative to the native ASNases in children with relapsed ALL. Whenever possible, drug monitoring should be performed to identify patients with 'silent' inactivation.

Pharmacokinetic dose adjustment of Erwinia asparaginase in protocol II of the paediatric ALL/NHL-BFM treatment protocols.

Native forms of asparaginase stem from different biological sources. Previously reported data from children treated with Erwinase showed significantly lower trough levels and pharmacokinetic dose intensity than after E. coli-derived preparations. Hence, schedule optimization was initiated to achieve relevant serum activities. 21 children on reinduction therapy received Erwinase on Mondays, Wednesdays and Fridays for 3 weeks (9 x 20000 IU/m2 i.v.) instead of 4x 10 000IU/m2 of E. coli asparaginase (twice weekly for 2 weeks). Asparaginase trough activities were measured as the primary parameter, targeting 100-200 IU/I after 2 d and >50 IU/l after 3 d. Concurrently, asparagine trough concentrations were monitored. The mean trough activity was 156+/-99 IU/l, with 2/108 samples showing no detectable activity. Regarding trough levels per individual (three or more measurements/patient), means ranged from 52+/-29 to 276+/-114 IU/l (20 patients, 106 samples), with nine, six, and five children inside, below, and above the target range, respectively. The mean 3 d trough activity was 50+/-39 IU/l (20 patients, 51 samples). In 11 of these samples no activity was measurable. Mean trough activities calculated per individual ranged from < 20-84+/-30 IU/l (14 patients, 42 samples) with seven children below the target limit of 50 IU/l and asparagine concentrations <0.2 - 1.5microM. We concluded that an increased dose of 9x20000 IU/m2 of Erwinia asparaginase within 3 weeks resulted in a pharmacokinetic dose intensity comparable to former observations made with 4 x 10 000IU/m2 of the E. coli product Crasnitin which is no longer marketed. High interindividual variability and the phenomenon of 'silent' inactivation necessitate monitoring wherever possible.