Acute Leukemias - Republican Scientific Medical Library

a 23.9 · Neurological Complications 285
23.8 L-Asparaginase and Coagulopathy
L-asparaginase (L-asp), an enzyme from bacteria that
destroys the amino acid asparagine, required primarily
by leukemic cells, is an important component of combination
chemotherapy for ALL. L-asp can produce depletion
of many of the hemostatic, anticoagulant, and fibrinolytic
factors such as fibrinogen, factors IX, XI, antithrombin
III, proteins C and S, and plasminogen with
an associated risk of thrombosis and hemorrhage [59–
61]. These effects are likely due to the decreased protein
synthesis by the liver, rather than clotting factor consumption
or the production of the abnormal molecules
[60, 62, 63]. This reduction of the synthesis of the clotting
factors appears to be proportional to the elimination
of asparagine from the plasma, and normalizes as
soon as L-asp is discontinued [64].
Although marked reductions in fibrinogen and factors
IX and XI due to L-asp occurs frequently, excessive
bleeding is rare [60]. There is no prospective data to
suggest a fibrinogen level at which replacement is required.
It is reasonable to temporarily discontinue the
L-asp when fibrinogen level decreases to 50–70 mg/dl.
However, in general, we do not recommend fibrinogen
replacement therapy in an asymptomatic patient regardless
of fibrinogen level. When clinically significant
bleeding occurs or a patient is required to undergo a
surgical procedure, therapy with cryoprecipitate or
FFP is usually successful in correcting the hemostatic
defect [65].
The concentration of the anticoagulant proteins AT
III, protein C, and protein S can decrease to 30% of normal
level in patients treated with L-asp, levels low enough
to predispose to thrombosis. The low level of circulating
fibrinogen does not appear to offset the risk of
thrombosis, since cases of severe central nervous system
(CNS) thrombosis are reported in patients with a fibrinogen
level of 29 mg/dl [66]. Prophylactic use of FFP
was ineffective in preventing the decrease in antithrombin
III level induced by L-asp [67].
In a setting of L-asp therapy, the presence of an inherited
hypercoagulable state such as Factor V Leiden,
or the prothrombine gene mutation was shown to increase
the risk of thrombosis in some studies [68],
but not in others [69]. The presence of the antiphospholipid
antibody increases the risk of thrombosis in patients
treated with L-asp [69].
CNS thrombosis occurs in approximately 4% of
adult patients with ALL, usually 2–3 weeks after the
initiation of therapy with L-asp. Although most patients
recover without significant neurological consequences,
death and permanent neurological defects
have been reported [70–72]. While the risk of thrombosis
is greatest during the remission induction phase
of chemotherapy with L-asp, it may occur at any stage
of therapy [73].
Pegaspargase, a modified form of native E. coli asparaginase,
has been reported to cause hypofibrinogenemia
in more than 50% of patients, however the clinical
evidence of thrombosis were rarely encountered [73a,
73b]. Pancreatitis was reported in approximately 15%
of patients treated with E. coli L-asparaginase and in
1–4% of patients receiving pegaspargase [73c]. Hepatotoxicity
and hyperbilirubinemia are common complications
of asparaginase therapy, although typically are
grades 1–2 and are reversible with the discontinuation
of therapy [73b]. However, in one study grade 4 hyperbilirubinemia
was reported in 54% of patients who received
1–4 doses of pegasparaginase [73a]. The rate of
allergic reaction appears to be less frequent in patients
receiving pegasparaginase compared to ones treated
with E. coli L-asparaginase [73d].
23.9 Neurological Complications
Five to ten percent of adult patients with ALL may present
with clinically significant neurological findings related
to the leukemic infiltration of CNS [74]. CNS involvement
may manifest as generalized headache and
papilledema from raised intracranial pressure, blindness
due to the bilateral optic nerve infiltration, trigeminal
neuralgia secondary to 7th cranial nerve infiltration
and lymphomatous meningitis, transverse myelopathy,
and epidural spinal cord compression [75–78].
Significance of such symptoms must be recognized
immediately and chemotherapy with systemic and intrathecal
methotrexate or cytarabine, steroids, and radiation
therapy should be administered promptly in
hopes to prevent permanent damage.
In a study of 36 patients with leukemic involvement
of the nervous system (46 episodes of CNS involvement)
21.7% of the episodes involved the cranial nerve, most
commonly the bulbar motor, facial, and optic nerves
[79]. Although CNS involvement is likely to require radiation
therapy, the optimal protocol for radiation administration
is yet to be determined. Patients with
symptomatic cranial nerve palsy are recommended to