Prevention and treatment of myelotoxic agranulocytosis in cancer patients

Myelotoxicity is the damaging effect of chemotherapy drugs on the hematopoietic tissue of the bone marrow. According to the criteria of the US National Cancer Institute, there are 4 degrees of suppression of each of the hematopoietic germs.

National Cancer Institute Myelotoxicity Criteria

	Neutrophils	Hemoglobin	Platelets
Degree 1	<2000-1500 per µl	<120-100 g/l	<150,000-75,000 per µl
Degree 2	<1500-1000 per µl	<100-80 g/l	<75,000-50,000 per µl
Degree 3	<1000-500 per µl	<80-65 g/l	<50,000-25,000 per µl
Degree 4	<500 per µl	<65 g/l	<25,000 per µl

Neutropenia is a serious manifestation of myelosuppression due to the high mortality from infectious complications that develop against its background. In this regard, the main task of an oncologist is to prevent the development of febrile neutropenia while maintaining the maximum intensity of chemotherapy. Currently, this can be achieved using cytokines G-CSF or filgrastim.

The administration of G-CSF (filgrastim) is the only way to reduce the duration and depth of myelotoxic neutropenia, as well as the development of febrile neutropenia. The administration of G-CSF before the first course of chemotherapy is called primary prevention of neutropenia, which is indicated for patients with the risk factors listed in the table.

Risk factors for the development of febrile neutropenia

Peculiarities of the patient's condition	Features of the underlying disease	Associated diseases	Features of therapy
Age >65 years	Tumor lesion of bone marrow	COPD	History of severe neutropenia following similar courses of chemotherapy
Female gender	Common stages of the tumor process	Cardiovascular diseases	Use of anthracyclines
Cachexia	Elevated LDH levels (in lymphomas)	Liver diseases	Planned relative dose intensity >80%
Immunodeficiency states	Oncohematological disease	Diabetes mellitus	Baseline neutropenia <1000/µL or lymphocytopenia
	Lung cancer	Low hemoglobin	History of multiple chemotherapy courses
		Open wound surfaces	Concurrent or prior use of radiation therapy to areas containing hematopoietic tissue
		Foci of infection

Prescription of G-CSF preparations to patients with a history of prolonged profound neutropenia or an episode of febrile neutropenia after previous similar courses of chemotherapy is called secondary prevention. The MASSC screening system can be used to predict the outcome of febrile neutropenia in order to prescribe the most intensive etiotropic therapy and G-CSF preparations.

Screening system MASSC

Absence or mild symptoms of the disease	5
No hypotension	5
No COPD	4
Solid tumor with no history of fungal infections	4
No dehydration	3
Moderate symptoms of the disease	3
Outpatient regime	3
Age <60 years	2

Patients with a score of less than 21 are considered to be at high risk of adverse outcomes of febrile neutropenia. G-CSF preparations must be prescribed if neutropenia lasts more than 10 days, the neutrophil count is less than 100 per μl, and in patients over 65 years of age with progressive cancer, pneumonia, hypotension, sepsis, and invasive fungal infections. In addition, an absolute indication for G-CSF is hospitalization of a patient due to febrile neutropenia.

The standard dosage regimen of filgrastim for the prevention and treatment of myelotoxic neutropenia is 5.0 mcg/kg once daily intravenously or subcutaneously.

To achieve a stable therapeutic effect, it is necessary to continue G-CSF therapy until the absolute neutrophil count exceeds the expected minimum and does not exceed 2.0x10 ⁹ /l. If necessary, the duration of the therapy course can be up to 12 days, depending on the severity of the disease and the severity of neutropenia. During the administration of cytokines, regular monitoring of the number of neutrophils in the patient's peripheral blood is necessary. It is important to administer G-CSF preparations at intervals of one day before or after taking antitumor cytostatic drugs due to the high sensitivity of actively proliferating myeloid cells to them.

G-CSF preparations are indicated for the treatment of neutropenia developing after high-dose myeloablative chemotherapy with autologous hematopoietic stem cell transplantation. In these cases, filgrastim is administered at a dose of 10 mcg/kg. After the moment of maximum decrease in the neutrophil count has passed, the daily dose is adjusted depending on the dynamics of their count. If the neutrophil content in the peripheral blood exceeds 1.0x10 ⁹ /l for three consecutive days, the filgrastim dose is reduced by 2 times (to 5 mcg/kg). Then, if the absolute neutrophil count exceeds 1.0x10 ^{9 /l for three consecutive days, filgrastim is discontinued. If the absolute neutrophil count decreases below 1.0x109} /l during treatment, the drug dose is again increased to 10 mcg/kg.

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