Leucostim®
Treatment with Leukostim® should only be carried out under the supervision of an oncologist or hematologist with experience in the use of G-CSF, if the necessary diagnostic capabilities are available. Cell mobilization and apheresis procedures should be performed at an oncology or hematology center with experience in this field and the ability to adequately monitor hematopoietic progenitor cells.
Infrequent cases of splenic rupture, in some cases with a fatal outcome, have been described during the use of G-CSF (filgrastim). Given these data, careful monitoring of the size of the spleen using clinical examination (palpation) and instrumental methods (for example, ultrasound) is recommended. It is necessary to carry out targeted diagnosis if a splenic rupture or splenomegaly is suspected in case of complaints from patients or healthy donors of pain in the upper quadrant of the abdomen or upper shoulder region.
According to the literature, the presence of sickle cell anemia and a high white blood cell count is an unfavorable prognostic factor. In such patients, blood tests should be performed regularly and the possibility of splenomegaly and vascular thrombosis should be taken into account.
Cases of sickle cell crises have been described during the use of filgrastim, some with a fatal outcome. Caution should be exercised in patients with sickle cell disease when prescribing Leucostim® (filgrastim), carefully assessing the benefits and possible risks.
Due to the frequent incidence of thrombocytopenia in patients treated with filgrastim, careful monitoring of platelet counts is recommended.
Patients with bone tissue pathology, including osteoporosis, receiving continuous treatment with Leucostim® for more than 6 months are advised to monitor bone density.
The effect of Leukostim® in patients with a significantly reduced number of myeloid progenitor cells is unknown. Leukostim® increases the number of neutrophils by acting primarily on neutrophil precursor cells, so in patients with reduced numbers of progenitor cells (for example, those who have undergone intensive radiation or chemotherapy), the degree of increase in the number of neutrophils may be lower.
The effect of Leukostim® on graft-versus-host disease has not been established.
When symptoms such as cough, fever and dyspnea occur, in combination with radiological findings in the form of pulmonary infiltrates and deterioration of lung function, the development of adult respiratory distress syndrome can be assumed. In this case, drug therapy should be discontinued and appropriate treatment should be prescribed.
Growth of malignant cells
The safety and effectiveness of Leukostim® in patients with myelodysplastic syndrome and chronic myeloid leukemia have not been established, therefore it is not indicated for these diseases. Particular attention should be paid to the differential diagnosis between acute myeloid leukemia and blast crisis of chronic myeloid leukemia.
Human G-CSF can stimulate the growth of myeloid cells in vitro
.
Similar effects may be observed in vitro
in some non-myeloid cells. Leukostim® should be used with caution in patients with secondary acute myeloid leukemia, due to limited data on safety and effectiveness in this case.
Safety and efficacy of Leukostim® in patients with de novo
under 55 years of age in the case of prognostically favorable cytogenetic factors (translocations t(8;21), t(l5;17), inv(16)) have not been established.
Patients receiving cytotoxic chemotherapy
Leukocytosis:
in less than 5% of patients receiving Leukostim® in doses of more than 0.3 million units (3 mcg/kg per day), the number of leukocytes increased to 100 x 109/l or more. No side effects directly related to such leukocytosis have been described. However, given the possible risk associated with high leukocytosis, the leukocyte count should be monitored regularly (for example, 2-3 times a week) during treatment with Leukostim®. If, after passing the expected minimum, it exceeds 50 x 109/l, Leucostim® should be discontinued immediately.
If Leucostim® is used to mobilize PSCC, it is discontinued when the leukocyte count exceeds 70 x 109/L.
Risks associated with high-dose chemotherapy:
Particular caution should be exercised when treating patients receiving high-dose chemotherapy, since no improvement in cancer outcome has been observed, while higher doses of chemotherapy have greater toxicity, including skin reactions and side effects from the cardiovascular, nervous and respiratory systems (see instructions for the use of specific chemotherapy drugs).
Monotherapy with Leukostim® does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Due to the possibility of using higher doses of chemotherapy drugs (eg, full doses according to regimens), the patient may be at greater risk of thrombocytopenia and anemia. It is recommended to regularly perform blood tests twice a week to determine the platelet count and hematocrit. Particular caution should be exercised when using single-component or combination chemotherapy regimens that can cause severe thrombocytopenia.
It has been shown that the use of Leukostim® for the mobilization of PSCC leads to a decrease in the degree and duration of thrombocytopenia that develops as a result of myelosuppressive or myeloablative chemotherapy.
Patients with SCN
Transformation into leukemia or preleukemia (myelodysplastic syndrome):
Particular care should be taken when diagnosing severe chronic neutropenia to differentiate it from other hematological diseases such as aplastic anemia, myelodysplasia and myeloid leukemia. Before starting treatment, a detailed blood test should be performed to determine the leukocyte formula and platelet count, as well as examine the morphological picture of the bone marrow and karyotype.
Myelodysplastic syndrome and leukemia have been observed in a small number (3%) of patients with severe congenital neutropenia (Kostmann's syndrome) treated with Leucostim®. Myelodysplastic syndrome and leukemia are natural complications of this disease; their relationship to filgrastim treatment is unclear. Approximately 12% of patients with initially normal cytogenetics were found to have abnormalities upon re-examination, including monosomy 7. If a patient with Kostmann's syndrome develops cytogenetic abnormalities, the benefits and risks of continuing therapy with Leukostim should be carefully assessed. If myelodysplastic syndrome or leukemia develops, Leucostim® should be discontinued. It is unknown whether long-term treatment with Leucostim predisposes patients with severe congenital neutropenia (Kostmann's syndrome) to the development of cytogenetic abnormalities, myelodysplastic syndrome and leukemia. Patients with Kostmann syndrome are recommended to undergo regular (approximately every 12 months) morphological and cytogenetic studies of the bone marrow.
Cytogenetic abnormalities, leukemia and osteoporosis were found with long-term use of filgrastim (>5 years) in patients (9.1%) with severe chronic neutropenia. The connection between these phenomena and the use of the drug has not been clarified.
Blood formula:
The platelet count should be carefully monitored, especially during the first few weeks of treatment with Leukostim®. In case of severe chronic neutropenia, during the first weeks of initial therapy, a clinical blood test and platelet count are determined 2 times a week, if the patient’s condition is stable - once a month. If the patient develops thrombocytopenia (platelet count consistently below 100 x 109/L), temporary discontinuation of the drug or dose reduction should be considered. There are also other changes in the blood count that require careful monitoring, including anemia and a transient increase in the number of myeloid progenitor cells.
Other:
Causes of transient neutropenia such as viral infections should be excluded. Spleen enlargement is a direct consequence of treatment with filgrastim. During clinical studies, 31% of patients with SCN had splenomegaly on palpation. When radiographically, the increase in volume is detected soon after the start of treatment and tends to stabilize. Reducing the dose slows or stops the increase in spleen size; splenectomy may be required in 3% of patients. The size of the spleen should be monitored regularly by palpation.
Hematuria and proteinuria were observed in a small number of patients. To monitor these indicators, urine tests should be performed regularly.
The safety and effectiveness of the drug in newborns and patients with autoimmune neutropenia have not been established.
Patients undergoing PSCC mobilization
After bone marrow transplantation, a blood test is performed and the platelet count is determined 3 times a week.
Mobilization:
The two recommended mobilization methods (filgrastim alone or in combination with myelosuppressive chemotherapy) have not been compared in the same patient population. Direct comparison of results from different studies is difficult due to individual differences between patients and also due to differences between CD34+ values obtained using laboratory tests. Therefore, it is quite difficult to recommend any optimal mobilization method. The choice of mobilization method should be made depending on the overall goals of treatment for a given patient.
Previous treatment with cytotoxic agents:
Patients who have received active myelosuppressive therapy in the past may not sufficiently increase PBMC to the recommended minimum level (≥2.0 x 106 CD34+ cells/kg) or accelerate platelet count normalization.
Some cytostatics are particularly toxic to hematopoietic progenitor cells and may negatively affect their mobilization. The use of drugs such as melphalan, carmustine and carboplatin for a long period before the onset of mobilization can reduce its severity. However, the use of melphalan, carboplatin or carmustine together with the drug Leukostim® is effective in activating PSCC.
If transplantation of PSCC is planned, it is recommended to plan their mobilization at an early stage of the course of treatment. Particular attention should be paid to the number of progenitor cells activated in such patients before high-dose chemotherapy. If mobilization results are insufficient according to the above criteria, alternative treatments that do not require the use of progenitor cells should be considered.
Estimation of the number (“harvest”) of peripheral blood stem cells:
When assessing the number of PSCCs mobilized in patients using the drug Leukostim®, special attention should be paid to the method of quantitative determination. Results from flow cytometric analysis of CD34+ cell counts vary depending on the specific methodology, and data on cell counts based on studies performed in other laboratories should be used with caution.
There is a complex but stable statistical relationship between the number of reinfused CD34+ cells and the rate of platelet count normalization after high-dose chemotherapy. A minimum number of PSCC equal to or greater than 2.0 x 106 CD34+ cells/kg leads to sufficient restoration of hematological parameters. An amount exceeding this value is apparently accompanied by a faster normalization; an amount less than this is accompanied by a slower normalization of the blood picture.
Mobilization of PSCCs in healthy donors
The PSCC mobilization procedure does not directly benefit healthy donors and should only be performed for the purpose of allogeneic transplantation.
Cell mobilization and apheresis procedures should be performed at a center with experience in this field. Mobilization of PSCC is possible only if laboratory parameters, especially hematological parameters of the donor, meet the selection criteria, and special attention should be paid to the presence of infectious diseases.
Transient leukocytosis (leukocytes more than 50 x 109/l) is observed in 41% of healthy donors, more than 75 x 109/l - in 2% of healthy donors. Transient thrombocytopenia (platelet count less than 100 x 109/l) after administration of filgrastim and leukapheresis is observed in 35% of donors. In addition, 2 cases of thrombocytopenia less than 50 x 109/L were noted after the leukapheresis procedure.
If more than one leukapheresis is required, the platelet count should be monitored before each apheresis procedure, especially if the platelet count is less than 100 x 109/L. Leukapheresis is not recommended if the platelet count is less than 75 x 109/L, when anticoagulants are prescribed or when there are known hemostasis disorders.
Leukostim® should be discontinued or its dose reduced if the leukocyte count is more than 70 x 109/L.
In healthy donors, it is necessary to regularly monitor all blood test parameters until they normalize.
Considering isolated cases of splenic rupture after the administration of G-CSF to healthy donors, it is recommended to monitor its size (palpation, ultrasound).
The risk of the emergence of a clone of malignant tumor cells cannot be excluded. It is recommended that the apheresis center systematically monitor the long-term safety of the drug in healthy donors.
The safety and effectiveness of Leukostim® in healthy donors under 16 and over 60 years of age has not been assessed.
Special instructions for recipients of allogeneic PSCC obtained with filgrastim
The use of allogeneic PSCC graft may be associated with an increased risk of acute or chronic graft-versus-host disease compared with bone marrow transplantation.
Neutropenia in HIV patients
With a very rapid positive response to therapy, a significant increase in the number of neutrophils is possible after the administration of initial doses of Leukostim®.
When treating with Leucostim®, it is necessary to regularly conduct a complete blood count (absolute count of neutrophils, red blood cells, platelets, etc.) daily for the first few days, then 2 times a week for the first 2 weeks, and every week or every other week for time of maintenance therapy. When carrying out maintenance therapy of 300 mcg per day according to an alternating regimen, significant fluctuations in the number of neutrophils are possible.
Given fluctuations in the absolute neutrophil count, to determine the true maximum reduction in neutrophil count (nadir), blood sampling should be performed before prescribing the next dose of the drug.
Monotherapy with Leukostim® does not prevent thrombocytopenia and anemia caused by myelosuppressive chemotherapy. Due to the possibility of using higher doses of chemotherapy (eg, full doses according to regimens) or more of them in combination therapy, the patient may be at greater risk of thrombocytopenia and anemia. It is recommended to regularly perform blood tests and determine the platelet count and hematocrit.
In patients with infectious diseases and infiltration of the bone marrow by infectious pathogens (for example, Mycobacterium avium complex) or with a tumor lesion of the bone marrow (lymphoma), filgrastim therapy is carried out simultaneously with therapy directed against these conditions. The effectiveness of Leukostim® in the treatment of neutropenia caused by infiltration of the bone marrow by infectious agents (osteomyelitis) or tumor lesions has not been established.
Instructions for use, handling and disposal
Vigorous shaking should be avoided.
Before administration, the Leucostim® solution should be inspected for the presence of foreign visible particles. It is allowed to administer the solution only without the presence of foreign visible particles.
Vials and pre-filled syringes with Leucostim® are intended for single use only.
The release of medicinal products into the environment should be minimized. Disposal of Leucostim® through wastewater or household waste is not permitted. Where possible, special systems should be used to dispose of medications.
LEUCOSTIM
Directions for use and doses
Leukostim® can be administered both subcutaneously and intravenously.
The route of administration and dose depend on the specific clinical situation and are determined by the attending physician. The preferred route of administration is subcutaneous. If intravenous administration is necessary, the required amount of the drug is injected from a syringe into a vial or plastic container with a 5% dextrose solution, then a 30-minute infusion of the diluted drug is performed. Due to the increased sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy, the use of Leucostim® is not recommended less than 24 hours before the start of chemotherapy and earlier than 24 hours after the end of chemotherapy. Breeding instructions:
Leucostim cannot be diluted with 0.9% sodium chloride solution; the drug is diluted with a 5% dextrose solution. If the drug is diluted to a concentration of less than 15 mcg/ml (less than 1.5 million IU/ml), then human serum albumin should be added to the solution so that the final albumin concentration is 2 mg/ml. For example, with a final solution volume of 20 ml, a total dose of Leucostim® less than 300 mcg (less than 30 million IU) should be administered with the addition of 0.2 ml of a 20% solution of human albumin. Filgrastim should not be diluted to a final concentration of less than 2 mcg/ml (less than 0.2 million IU/ml).
Recommended doses:
For the treatment of neutropenia after a course of cytotoxic chemotherapy
Leucostim® is administered once a day subcutaneously or intravenously at a dose of 5.0 mcg (0.5 million IU) per 1 kg of patient body weight.
In patients receiving cytotoxic chemotherapy, a transient increase in the number of neutrophils is usually observed 1-2 days after the start of treatment with Leukostim®. To assess the effectiveness of treatment, daily counting of the number of neutrophils in peripheral blood is desirable. To achieve a stable therapeutic effect, it is necessary to continue therapy with Leucostim® until the number of neutrophils passes the expected minimum and reaches normal values. Once the absolute neutrophil count exceeds 2.0×109/L, the drug can be discontinued. If necessary, the duration of therapy can be up to 12 days, depending on the severity of the disease and the severity of neutropenia.
After myeloablative chemotherapy followed by bone marrow transplant
Leucostim® is administered subcutaneously or intravenously at the rate of 10 mcg (1.0 million IU) per 1 kg of body weight. The first dose of Leucostim® should be administered no earlier than 24 hours after cytotoxic chemotherapy, and in case of bone marrow transplantation - no later than 24 hours after bone marrow infusion. After the moment of maximum decrease in the number of neutrophils has passed, the daily dose is adjusted depending on the dynamics of their number. If the content of neutrophils in peripheral blood exceeds 1.0 × 109/l for three consecutive days, the dose of Leucostim® is reduced by half (to 5.0 mcg (0.5 million IU) per 1 kg of body weight). Then, if the absolute neutrophil count exceeds 1.0×109/l for three consecutive days, Leucostim® is discontinued. If the absolute number of neutrophils decreases during treatment below 1.0x09/l, the dose of Leucostim® is again increased to 10 mcg (1.0 million IU) per 1 kg of body weight.
To mobilize hematopoietic stem cells
Leucostim® is administered subcutaneously at a daily dose of 5.0 mcg (0.5 million IU) per 1 kg of body weight (in patients after myelosuppressive chemotherapy) or 10 mcg (1.0 million IU) per 1 kg of patient weight (in the absence of chemotherapy) for 5-7 consecutive days (the number of injections depends on the rate of increase in the number of leukocytes in the peripheral blood and the effectiveness of separation). The day before the expected date of the first separation (4th day of administration of the drug Leukostim®) and on the following days (before the day of the last separation), the number of leukocytes and neutrophils in the patient’s peripheral blood is assessed. Cytapheresis is carried out if the number of leukocytes increases to 5×10/l of peripheral blood, starting from the 5th day of administration of the drug Leukostim®. After each separation, the number of nucleated cells and CD34+ cells in the sample intended for cryopreservation is counted. When the number of cryopreserved CD34+ cells is reached, which is sufficient for transplantation (at least 2 × 106 per kg of patient weight), the administration of Leukostim® is stopped.
The effectiveness and safety of Leucostim® in healthy donors under 16 and over 60 years of age have not been studied.
For severe chronic neutropenia (SCN)
Leukostim® should be administered subcutaneously daily until the number of neutrophils stably exceeds 1.5x109/l (for congenital neutropenia - at a dose of 12 mcg (1.2 million IU) per 1 kg of patient weight per day subcutaneously in one or several injections; for idiopathic or periodic neutropenia - 5.0 mcg (0.5 million IU) per 1 kg of body weight per day). After achieving a therapeutic effect, the minimum effective dose to maintain this level of neutrophils must be determined. This requires long-term daily administration of the drug. After 1-2 weeks of treatment, the initial dose can be doubled or halved, depending on the patient's response to therapy. Subsequently, dose adjustments should be made every 1-2 weeks to maintain the neutrophil count in the range of 1.5-10x109/L.
For
neutropenia associated with HIV infection
: initial dose of 1-4 mcg (0.1-0.4 million IU) per 1 kg of body weight per day, once subcutaneously until the number of neutrophils normalizes (>2 × 109/l). Normalization of the number of neutrophils usually occurs after 2 days. If the initial dose is ineffective, it is escalated to 5.0 mcg (0.5 million IU) per 1 kg of body weight per day once subcutaneously. After achieving a therapeutic effect, maintenance therapy with Leukostim® is carried out at a dose of 1-4 mcg (0.1-0.4 million IU) per 1 kg of body weight per day 2-3 times a week. In the future, individual dose adjustment and long-term therapy with Leukostim® may be required to maintain the neutrophil count more than 2.0 × 109/l.
Special dosage instructions
:
When filgrastim was used in pediatric practice in patients with severe chronic neutropenia and cancer, the safety profile of filgrastim did not differ from that in adults. Dosing recommendations for pediatric patients are the same as for adults receiving myelosuppressive or cytotoxic chemotherapy.
Dose adjustment of filgrastim is not required in patients with severe renal or hepatic impairment, since their pharmacokinetic and pharmacodynamic parameters are similar to those in healthy volunteers.
Leucostim, 300 mcg/ml, solution for intravenous and subcutaneous administration, 1 ml, 5 pcs.
Filgrastim is produced by a strain of the bacterium Escherichia coli, into which the human granulocyte colony-stimulating factor gene has been introduced using genetic engineering methods. Leucostim is identical to natural human granulocyte colony-stimulating factor in biological activity, differing from it in the absence of glycosylation and the presence of an additional N-terminal amino acid residue of methionine.
Leucostim accelerates the proliferation of granulocyte precursor cells of the bone marrow neutrophil sprout (CFU-G), differentiation towards mature neutrophils and their release into the peripheral blood from the bone marrow. Causes a dose-dependent increase in the number of neutrophils in peripheral blood. Neutrophils produced in response to the administration of the drug Leucostim have normal or increased chemotactic and phagocytic activity. The use of the drug Leukostim allows you to restore the number of neutrophils in peripheral blood during neutropenia in patients receiving chemotherapy or in patients with chronic neutropenia. The use of Leukostim for preventive purposes can reduce the frequency, severity and duration of neutropenia and febrile neutropenia after chemotherapy. This leads to the prevention of infectious complications, reduction of hospitalization periods and compliance with the intervals between chemotherapy cycles prescribed by treatment regimens.
The use of the drug Leukostim, both after chemotherapy and independently of it, leads to the mobilization of hematopoietic precursor cells into the peripheral blood. These cells can be collected by cytapheresis and injected into the patient after high-dose chemotherapy. The introduction of hematopoietic stem cells makes it possible to restore the hematopoietic and immune systems after myeloablative chemotherapy. After myelosuppressive chemotherapy, the introduction of hematopoietic stem cells accelerates the restoration of hematopoiesis, reducing the frequency and severity of infectious and hemorrhagic complications.
The effectiveness and safety of Leukostim in adults and children receiving cytotoxic chemotherapy are the same.
In children and adults with severe chronic neutropenia, Leucostim consistently increases the number of neutrophils in the peripheral blood, reducing the incidence of infectious complications.
Prescribing Leucostim to patients with HIV infection allows them to maintain normal neutrophil levels and follow the recommended doses of antiretroviral and/or other myelosuppressive therapy. There were no signs of increased HIV replication with filgrastim use.
