Acute Leukemias - Republican Scientific Medical Library

a 10.6 · CALGB Study 9251 141
agine. Because asparaginase is not markedly myelosuppressive,
it is easily added to combination chemotherapy
regimens.
Three preparations of asparaginase are available.
One preparation is derived from Escherichia coli (E.
coli) and is commercially available for use in the USA.
A second preparation is derived from Erwinia carotovora
and is commercially available in Europe; it can
be ordered in the USA only for patients with allergy
to E. coli asparaginase. PEG-asparaginase is derived
from E. coli L-asparaginase by covalently conjugating
units of polyethylene glycol (PEG) to the protein. Differences
between PEG-asparaginase and the other two
forms of the drug include decreased immunogenicity
and a longer half-life. The half-life of E. coli asparaginase
is 1.2 days, Erwinia asparaginase 0.7 days, and
PEG-asparaginase 5.7 days [10]. Currently, PEG-asparaginase
is indicated for use in adult patients with hypersensitivity
to native E. coli asparaginase at a dose of
2000 U/m 2 every 14 days.
The optimal dosing schedule of PEG-asparaginase
in adults remains to be determined. Studies in children
have shown that a dose of 2000 U/m 2 delivered every 2
weeks produced asparagine depletion for 14 days in
more than 70% of patients despite inclusion of some patients
with neutralizing antibodies [11]. We therefore
chose initially to test a dose of 2000 U/m 2 (maximum,
3750 U) administered SC or IM once during each of
the first three courses of therapy in newly diagnosed patients
[12]. PEG-asparaginase was given on day 5 during
Course I and day 15 during Courses IIA and IIB (Table
9.1). Pharmacokinetic studies of asparaginase levels
were also done. Asparaginase levels provided a surrogate
measure of asparagine depletion since levels
> 0.03 U/ml produce complete asparagine depletion.
The frequency of antiasparaginase neutralizing antibodies
was also measured using an enzyme-linked immunoassay
(ELISA) method.
Pharmacokinetic sampling of the first 21 patients
studied in this trial showed that asparaginase levels
were >0.03 U/ml in all 21 patients at 7 days and in 16
of 20 patients (80%) at 14 days but in only 5 of 20
(25%) at 24 days after the initial dose of PEG-asparaginase
[12, 13]. When the second dose was given on day 15
of the second chemotherapy course, 16 of 18 evaluable
patients (83%) had complete asparagine depletion 7
days later, and 12 of the 18 (67%) had depletion at 14
days. A third dose was given on day 15 of the third chemotherapy
course, and 14 of 16 patients (85%) had de-
pletion at 7 days and 13 of 16 (79%) at 14 days following
this final dose. Therefore, through all three doses, 67–
80% of patients maintained sufficient asparaginase
levels to deplete asparagine for 2 weeks. Antibodies to
PEG-asparaginase developed in three patients but none
before the end of the third course. No grade 3 or 4 allergic
reactions or pancreatitis were observed. Hyperglycemia
was reported in 38% of patients. Four patients
(15%) had grade 3 phlebitis or thrombosis, and one
patient had a deep vein thrombosis of the leg with embolization
to the lung.
Preliminary retrospective analyses in pediatric ALL
populations have suggested that the longer periods of
asparagine depletion that result from the use of E. coli
asparaginase are associated with better outcomes than
the shorter periods of depletion that result from the
use of Erwinia asparaginase. Therefore, a second cohort
of patients was treated on the 9511 trial, and a second
dose of PEG-asparaginase was added on day 22 of the
induction course to extend the duration of asparagine
depletion [13]. Pharmacokinetic analyses of this cohort
of patients showed asparagine depletion in 18 of 20 patients
(90%) at 14 days and 10 of 14 (71%) at 31 days.
Further analyses are pending.
10.6 CALGB Study 9251
Patients with mature B-cell ALL (Burkitt-type, ALL-L3,
surface immunoglobulin positive, t(8q24)) fare poorly
with conventional ALL chemotherapy approaches. Early
CALGB data for patients with the t(8;14) showed that
none of those patients were long-term disease-free survivors.
Of the eight patients with the L3 subtype enrolled
on CALGB 8811, two failed to achieve CR and five
relapsed after a median remission duration of only 3
months; all five developed CNS involvement.
CALGB study 9251 was derived from a series of reports,
both in children and adults, which highlight a different
approach to the treatment of these diseases. Repeated
short courses of cyclophosphamide and highdose
methotrexate led to CR rates of 85–95% and impressive
long-term DFS in a large number of patients
with Burkitt-type leukemia or lymphoma. All regimens
contained aggressive CNS prophylaxis and some included
an initial cytoreduction using modest doses of
cyclophosphamide and corticosteroids. In CALGB
9251, therapy was given over an 18-week period of time
[14, 15]. We used a regimen similar to that used success