Against the background of treatment with asparaginase, the following life threatening complications may occur: anaphylaxis; Hyperglycemic conditions that can be treated with insulin; bleeding disorders requiring replacement therapy with fresh frozen plasma to reduce the risk of bleeding.
Recommended follow-up examinations and precautions
Before the start of treatment, it is necessary to conduct a study of kidney function and determine the concentration of electrolytes, transaminases, glucose and protein in the blood.
After the initiation of treatment with asparaginase, regular blood testing with blood counting, control of electrolytes, urinary excretion, glucose in the blood and urine, hemostasis parameters (activated partial thromboplastin time (APTT), prothrombin time, antithrombin concentration and D- dimer), amylase and lipase of blood, alkaline phosphatase, bilirubin, ammonia, triglycerides, cholesterol, if necessary - very low density lipoproteins (VLDL) and lipoproteins low (LDL) from the start of therapy to the complete normalization of these indicators.
Control of blood form factors and physical examination should be performed every 4 weeks during the first year after completion of therapy, quarterly for the 2nd and 3rd year, then every six months.
The risk of developing hypersensitivity reactions increases with the increase in the number of doses administered. However, in rare cases, allergic reactions can occur with the first administration of asparaginase.
In some patients, the formation of antibodies to asparaginase, which neutralizes its effect, can occur without clinical manifestations of hypersensitivity. However, the presence of such antibodies can lead to accelerated inactivation and accelerated elimination of asparaginase from the body ("silent inactivation" of asparaginase). To detect hypersensitivity or reduce the effectiveness of therapy due to "silent inactivation" during treatment, it is recommended to periodically perform a determination of the concentration of asparaginase in the blood, for example, using the MAAT test system (medac Asparaginase Activity Test). Negative results of the intradermal tests performed before the start of treatment do not exclude the possibility of the development of anaphylactic reactions.
Depending on the clinical course of the disease, additional studies may be required.
Immune system disorders
In case of appearance during the therapy with Asparaginase medak symptoms of allergic reactions treatment with the drug should be stopped immediately. Depending on the severity of the developed allergic reactions, it is necessary to conduct appropriate therapeutic measures: administration of antihistamines, glucocorticosteroids and, if necessary, drugs that stabilize hemodynamics. In most cases, treatment can be continued by switching to another asparaginase preparation.
Effect on hemopoiesis
Asparaginase can cause from mild to moderate severity myelosuppression of all three hematopoiesis germs; in general, it does not have any clinical significance for the treatment.
Blood clotting disorders
The risk of thrombosis increases with increasing time after completion of treatment. It should be borne in mind that the cause of the above disorders in the blood clotting system, in addition to asparaginase, may be concomitant treatment with other myelosuppressive drugs, as well as the disease itself.
An increased risk of thrombosis has been reported in children with clotting factor V mutations, resistance to activated protein C, or a decreased concentration of protein S, antithrombin III, or protein C in serum. In such patients, central venous catheters should be avoided whenever possible, as this may increase the risk of thromboembolic complications. When conducting induction therapy in patients with acute lymphoblastic leukemia, the central venous catheter, if possible, should be established after asparaginase treatment is completed.
When laboratory monitoring of blood coagulability is performed, it is possible to detect signs of disturbance of the blood coagulation system and fibrinolysis, for example, reduction of fibrinogen concentration, coagulation factors IX, XI, antithrombin III, protein C and plasminogen, as well as an increase in the concentration of von Willebrand factor, inhibitor of plasminogen activator type 1 , fragments 1 and 2 of prothrombin, and fibrinogen cleavage products (D-dimers). Fibrinogen can be considered as an indicator of control of the pro- and anticoagulant system.If the concentration of fibrinogen or antithrombin III is significantly reduced, the need for selective substitution therapy should be assessed. Antithrombin III Assign in the form of infusion at a dose of 100% minus the current concentration in the blood serum, measured in percent, multiplied by the body weight in kg. Fibrinogen is introduced in the form of fresh-frozen plasma at a dose of 10-15 ml / kg body weight.
Thrombocytopenia and sepsis increase the risk of bleeding.
Influence on the nervous system
In rare cases, it is possible to develop a reversible leukoencephalopathy syndrome. Symptoms of leukoencephalopathy syndrome are mainly manifested in the form of increased blood pressure, seizures, headache, changes in mental state and acute visual impairment (mainly cortical blindness or cortical hemianopia). Treatment of leukoencephalopathy syndrome is symptomatic. The main measures in these cases are antihypertensive therapy and arresting seizures with antiepileptic drugs. It is also recommended to reduce the dose or interrupt immunosuppressive drug therapy.
Disorders from the gastrointestinal tract
There are separate reports on the formation of pseudocyst pseudocysts (for up to 4 months after the end of treatment). In this regard, patients need to conduct appropriate examinations (eg, ultrasound) within 4 months after the last injection of asparaginase. Since the exact pathogenesis of pseudocyst formation is not known, in such cases only symptomatic treatment can be recommended.
In the literature, 2 cases of mumps not associated with pancreatitis were reported; After stopping the injection of asparaginase, mumps symptoms resolved within a few days.
Disorders from the endocrine system
Often observed changes in the endocrine function of the pancreas are manifested mainly in the form of violations of glucose metabolism. In this case, both diabetic ketoacidosis and hyperosmolar hyperglycemia can develop, which are usually amenable to treatment with insulin preparations. Risk factors for developing hyperglycemia include age over 10 years, overweight, Down's syndrome. Violation of the exocrine function of the pancreas can cause diarrhea.
Metabolic disorders
The change in the concentration of serum lipids can be caused by the concomitant administration of glucocorticoids.
With a significant increase in these indicators (for example, at a triglyceride concentration> 2000 mg / dL), careful monitoring is recommended because of the increased risk of developing pancreatitis.
Common violations
A rise in body temperature, in most cases passing spontaneously, can be observed after 2-5 hours after the administration of asparaginase. Often observed pain in the joints, back, in the abdomen, is usually associated with allergic reactions and pancreatitis. In very rare life-threatening hyperpyrexia.
Disorders from the hepatobiliary system
Violation of protein synthesis can lead to a decrease in the concentration of whey proteins. In the majority of patients, the development of a dose-dependent decrease in serum albumin concentration is possible during treatment. Most violations affect the α2 and β fractions of albumin, while the α1 fraction remains unchanged. Since the concentration of serum albumin is essential for the binding and transport of certain drugs,Serum albumin control is necessary, especially in combination chemotherapy. As a result of hypoalbuminemia, edema can develop. During or after the treatment with asparaginase, the serum amylase concentration may increase. In such cases, further treatment with asparaginase should be suspended. During therapy with the drug and within 3 months after its completion, patients should abstain from sexual activity or use reliable contraceptive measures.