List of Abbreviations
CRA – cancer-related anemia
ACD – anemia of chronic disease
ID – iron deficiency
SI – serum iron concentration
ZNO – malignant neoplasms
BM – bone marrow
TSAT – transferrin saturation
TIBC – total iron-binding capacity
RNA – ribonucleic acid
rhEPO – recombinant human erythropoietin
SF – serum ferritin
FID – functional iron deficiency
CT – chemotherapy
CNS – central nervous system
EPO – erythropoietin
EPOR – erythropoietin receptors
ESAs – erythropoiesis-stimulating agents (ATC: Antianemic preparations (B03) or (B03XA): Other antianemic preparations)
IFN-ɣ – interferon gamma
IL-1 – interleukin 1
IL-6 – interleukin 6
Hb – hemoglobin
Ht – hematocrit
TNF-α – tumor necrosis factor alpha
Terms and Definitions
Cancer-related anemia (CRA) is a variant of anemia of chronic disease, the development of which is based on a multifactorial process triggered by the interaction between the tumor cell population and the immune system, resulting in the production of a number of cytokines responsible for the relative insufficiency of erythropoiesis.
Erythropoiesis-stimulating agents (ESAs, B03XA: Other antianemic preparations) are a group of medicinal products that stimulate the formation of red blood cells in the bone marrow, used for the treatment of anemias.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Cancer-related anemia is a variant of anemia of chronic disease (ACD). Its development is based on a multifactorial process triggered by the interaction between the tumor cell population and the immune system, resulting in the production of a number of cytokines responsible for the relative insufficiency of erythropoiesis [1].
The consequences of anemia may include an impaired response to cancer treatment and decreased overall survival (OS), even if a direct causal relationship has not been established [61,62], as well as a decrease in patients' quality of life due to varying degrees of impaired exercise tolerance and symptoms associated with anemia.
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
The pathogenesis of anemia in children with malignant neoplasms (MN) is quite complex and is associated with both direct and indirect effects of the tumor process on the body. These include: bleeding, bone marrow (BM) infiltration by tumor cells, myelotoxic effects of chemotherapy (CT), excessive production of pro-inflammatory cytokines, and associated disorders of iron metabolism and erythropoiesis. The combination of these pathophysiological reactions, expressed to varying degrees, leads to impaired proliferation, differentiation, and maturation of bone marrow erythroid committed precursors [2].
The pathogenesis of cancer-related anemia (CRA) can be divided into three main aspects: anemia as a manifestation of the paraneoplastic process; chemotherapy-induced anemia; and anemia caused by other reasons [3].
The paraneoplastic process is characterized by increased production of a number of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukins (IL-1, IL-6), and interferons (IFN-ɣ), which are responsible for the development of anemia against the background of a malignant tumor process [4]. Characteristic pathophysiological features of CRA are:
shortening of erythrocyte lifespan associated with the indirect action of TNF-α and IL-1 [2,5];
disorders of iron metabolism due to increased production of hepcidin, which reduces iron absorption in the gastrointestinal tract and impairs its reutilization from cells of the mononuclear phagocyte system [5-6];
suppression of erythroid precursors caused by the action of IL-1, TNF-α, IFN-ɣ [5,7];
decreased production of erythropoietin (EPO) in the kidneys due to the direct inhibitory effect of TNF-α and IL-1 [6-7].
The results of studies postulate defective erythropoiesis as the main cause of anemia in cancer patients [8-9]. In children with acute leukemias, research results demonstrate preserved adequate EPO production relative to the severity of anemia [10-14].
Most CT regimens suppress the proliferation of hematopoietic precursor cells in the BM. A number of cytostatic drugs (ATX Antineoplastic agents (L01): cisplatin**, carboplatin**) directly and selectively suppress EPO production in the kidneys, reducing the sensitivity of peritubular fibroblasts to hypoxia. Some antineoplastic agents that block ribonucleic acid (RNA) synthesis (ATX anthracyclines and related substances (L01DB), cyclophosphamide**, ifosfamide**) or protein secretion (vincristine**) cause suppression of EPO synthesis [15-19].
Other causes of anemia in patients with MN may include:
bleeding (exogenous bleeding, intratumoral hemorrhage);
hemolysis (autoimmune, microangiopathic);
displacement of normal hematopoiesis germs in the BM by tumor cells in hemoblastoses or metastases of solid tumors;
deficiency of iron, folates, vitamin B12;
renal dysfunction;
intercurrent diseases [20].
Thus, the pathogenesis of anemia in patients with malignant neoplasms is quite complex and is associated with both direct and indirect effects of the tumor process on the body, as well as with the potential suppressive effect of antineoplastic treatment on erythroid hematopoietic cells in a number of cases [63].
1.3 Epidemiology of the Disease or Condition
Anemia is one of the most frequent problems during the treatment of children with MN and is often already present at the time of diagnosis. Anemia and iron deficiency (ID) are common complications in patients with malignant neoplasms, especially those receiving antineoplastic drugs [64]. According to the European Cancer Anemia Survey (ECAS), among 15,000 analyzed cancer patients at the time of diagnosis, the incidence of anemia was 39.3%, and the administration of specialized therapy increased the incidence of anemia in these patients to 67.0% [65].
A European analysis covering 18 major pediatric oncology centers and including data on 25,093 patients showed that among children with MN, regardless of tumor type, more than 80% are anemic, whereas in children with acute leukemia, anemia is recorded in 97% of cases. During intensive antineoplastic therapy, the prevalence of anemia in this patient group increases significantly, while the severity of anemia and, accordingly, the need for red blood cell transfusion therapy increase with higher CT intensity [21]. Thus, anemia is one of the typical manifestations of the malignant neoplastic process in children and a frequent complication of their chemotherapy treatment.
1.4 Features of Coding the Disease or Condition
D63.0 – Anemia in neoplastic disease
1.5 Classification of the disease or condition
According to the WHO criteria, the severity of anemia is classified as follows [66]:
mild - Hb concentration above 90 g/L;
moderate - Hb concentration within 90-70 g/L;
severe - Hb concentration less than 70 g/L.
1.6 Clinical presentation of the disease or condition
Clinical manifestations of CRA are usually non-specific and depend on the severity of anemia. Anemic syndrome of varying severity (weakness, decreased exercise tolerance, tachycardia, shortness of breath, dizziness, and/or headache). Anemia is often associated with fatigue, impaired physical function, and reduced quality of life [67-69].
2. Diagnostics, medical indications and contraindications for diagnostic methods
Many recommended methods for diagnosing the disease and related conditions have a limited evidence base (according to the grading scales for the levels of evidence and confidence of recommendations) due to the lack of clinical studies dedicated to them. Despite this, they are necessary elements of patient evaluation for establishing a diagnosis and choosing treatment tactics, as more effective and proven methods have not yet been developed.
The diagnosis of anemia in MN can be suspected based on anamnestic data and physical examination results; it is established based on laboratory test results.
The main diagnostic criterion for anemia is a persistent decrease in hemoglobin concentration below 120 g/L in females and below 130 g/L in males [85].
2.1 Complaints and Anamnesis
It is recommended to conduct a detailed questioning of complaints and collection of medical history in all patients with suspected CRA to assess the patient's condition and to identify potential alternative causes of anemia [63].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: when collecting patient complaints, the presence of the following symptoms is ascertained: palpitations, shortness of breath worsening with physical exertion; dizziness, tinnitus; weakness, fatigue. When taking the patient's history, potential alternative causes of anemia are investigated: bleeding (acute and chronic); hemolysis (autoimmune, microangiopathic); intercurrent diseases (infectious and inflammatory, kidney diseases); deficiency of iron, folates, vitamin B12 (dietary factor, impaired absorption, ongoing specific therapy).
2.2 Physical Examination
It is recommended to perform a visual examination, general physical examination, palpation (of peripheral lymph nodes, mesenteric lymph nodes, spleen), percussion (of the spleen, intrathoracic lymph nodes, thymus gland) in diseases of the hematopoietic and blood organs at every medical appointment for all patients with suspected CRA and all patients with an established diagnosis of CRA in order to assess the severity of the condition and identify signs of the underlying disease [63].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: general physical examination implies the assessment of the patient's general condition using the Eastern Cooperative Oncology Group scale – ECOG (Appendix G1), the presence of hypoxia symptoms, and the degree of compensation of the anemic syndrome. General examination implies the assessment of general physical condition, symptoms ofemic hypoxia, and potential signs of anemic syndrome decompensation. During the physical examination, attention is paid to identifying the following signs: pallor of the skin and visible mucous membranes (yellowish discoloration of the skin and mucous membranes in hemolysis); tachycardia, tachypnea; muffled heart sounds, systolic murmur at the apex of the heart and over large vessels; lethargy.
It should be noted that most complaints and symptoms are non-specific signs of anemia that overlap with the symptoms of the underlying disease, tumor intoxication, and side effects of ongoing CT.
In addition, it should be kept in mind that children may be more tolerant of anemia than adults. This is partly due to greater cardiopulmonary reserve and the absence of coronary artery disease, as well as relatively rapid compensation for the loss of oxygen-transport capacity (shift of the oxygen dissociation curve to the right and decreased hemoglobin affinity for oxygen). Thus, compensatory mechanisms of chronic anemia in children ensure tolerance to very low Hb concentrations with few or no symptoms, especially if anemia develops slowly over weeks or months.
However, many factors can provoke decompensation in a child with anemia and lead to life-threatening tissue and organ hypoxia.
Causes of chronic anemia decompensation: increased oxygen demand due to infection, pain, or fever; further impairment of tissue oxygen delivery due to acute blood loss or pneumonia.
Early signs of decompensation: labored, rapid breathing with intercostal, subcostal, and suprasternal retractions (respiratory distress); increased use of abdominal muscles for breathing; nasal flaring.
Signs of acute decompensation: forced ("grunting") expiration (respiratory distress); altered mental status; weak peripheral pulses; congestive heart failure; hepatomegaly; poor peripheral perfusion (capillary refill time greater than 2 seconds).
A child presenting with these clinical signs urgently requires medical intervention due to the high risk of mortality associated with impaired oxygen-carrying capacity.
2.3 Laboratory Diagnostics
It is recommended that all patients with suspected anemia of chronic disease (ACD) and all patients with a confirmed diagnosis of ACD undergo laboratory and instrumental examinations to detect anemia, determine its type, assess its severity, and identify the leading etiological factors [63]. The diagnosis of anemia and the identification of its causes should be performed prior to blood transfusion (unless there are emergency indications) or the administration of erythropoiesis-stimulating agents (ESAs; V03XA: Other antianemic preparations) and iron preparations [27,63].
Level of Evidence: 5Level of Recommendation C (Level of Evidence – 5)
It is recommended that all patients with ACD undergo a complete blood count (CBC) with differential, including the assessment of total blood hemoglobin level, red blood cell and reticulocyte counts, hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) [70].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the primary diagnostic criterion for anemia is a decrease in blood Hb concentration to less than 110 g/L. ACD typically presents as hypoproliferative, normocytic, and normochromic [2,22].
It is recommended that all patients with ACD undergo iron panel testing (serum iron, serum ferritin, serum transferrin, total iron-binding capacity, and transferrin saturation) and serum C-reactive protein (CRP) testing to determine the type of anemia and perform differential diagnosis with iron deficiency anemia [24,70-72].
Level of Evidence CGrade of Recommendation 5Level of Evidence C (reliability of evidence – 5)
Comments: when evaluating children with malignancies, it must be considered that iron deficiency can be absolute (serum ferritin <100 mcg/L) or functional, characterized by impaired iron mobilization from macrophages with a preserved storage pool (transferrin saturation <20%, serum ferritin <100 mcg/L) [23]. Elevated serum ferritin concentration, commonly observed in children with malignancies, is driven by a combination of factors, most importantly a prominent inflammatory process as a manifestation of the underlying disease, as well as infectious complications frequently seen in pediatric oncology patients.
In patients presenting with clinical and laboratory features suggestive of hemolytic anemia, it is recommended to perform hemolysis tests (total bilirubin, free (unconjugated) and conjugated bilirubin, lactate dehydrogenase (LDH) activity, and haptoglobin in the blood [73-75].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: some malignancies can be accompanied by hemolysis, renal impairment, or bleeding. General laboratory characteristics of hemolytic anemias include reticulocytosis (relative and absolute), elevated bilirubin levels due to the indirect fraction, elevated LDH levels, and decreased serum haptoglobin. Bone marrow examination in hemolytic anemias reveals erythroid hyperplasia [74].
It is recommended that all patients with ACD undergo a direct antiglobulin test (direct Coombs test) and an indirect antiglobulin test (indirect Coombs test) to detect an immune-mediated mechanism of hemolytic anemia [22,75].
GRC CLEL 4Grade of Recommendation C (Level of Evidence – 4)
Comments: some malignancies may be accompanied by autoimmune hemolysis. In cases of autoimmune hemolysis, the direct Coombs test is positive.
In patients presenting with clinical and laboratory features suggestive of vitamin B12- or folate-deficiency anemia, it is recommended to measure vitamin B12 (cyanocobalamin) and serum folic acid levels [63,76,77].
Level of Evidence: 5Level of Recommendation C (Level of Evidence – 5)
Comments: vitamin B12- and folate-deficiency anemias are characterized by macrocytosis and erythrocyte hyperchromia, normal or decreased reticulocyte counts, megaloblastic erythropoiesis in the bone marrow, decreased platelet and leukocyte counts (up to severe pancytopenia), neutrophil hypersegmentation, and laboratory signs of hemolysis. Vitamin B12 deficiency is characteristically associated with neurological disorders [78,79].
In patients presenting with clinical and laboratory features suggestive of occult gastrointestinal bleeding, it is recommended to perform a fecal occult blood test [70].
Level of Evidence: 5Level of Recommendation C (Level of Evidence – 5)
Comments: upper gastrointestinal bleeding (from the esophagus, stomach, and duodenum) may present with the following signs: vomiting of fresh blood or "coffee-ground" emesis; melena—tarry, dark stools with a sharp, foul odor. Lower gastrointestinal bleeding presents with: bright red blood mixed in the stool; rectal bleeding; "raspberry jelly" stools; melena. General signs associated with blood loss include: progressive weakness; dizziness, tinnitus, visual floaters, disorientation, and syncope; oliguria—decreased urine output; thirst. With mild bleeding, symptoms may be entirely absent. Sometimes patients experience mild weakness, dizziness, general malaise, along with symptoms of the underlying pathology: abdominal pain, dyspepsia, heartburn, nausea, pain during defecation, etc. In massive bleeding, especially from large-caliber vessels, and severe blood loss, loss of consciousness and even death are possible.
In patients presenting with clinical and laboratory features suggestive of myelodysplastic syndrome or impaired renal erythropoietin production, it is recommended to measure blood erythropoietin levels [73].
Level of Evidence: 5Level of Recommendation C (Level of Evidence – 5)
Comments: myelodysplastic syndrome is a group of clonal hematopoietic stem cell disorders characterized by cytopenia, bone marrow dysplasia, and a high risk of transformation into acute leukemia. The presence of refractory anemia (after exclusion of other etiologies) combined with thrombocytopenia and/or leukopenia raises suspicion for myelodysplastic syndrome. Anemia in myelodysplastic syndrome is typically normocytic (macrocyctic in certain subtypes), with a normal or decreased reticulocyte count. Iron metabolism parameters reveal a pattern of tissue iron overload: serum ferritin >300 ng/mL, transferrin saturation >45%, decreased serum transferrin concentration, and decreased total iron-binding capacity (TIBC) [80].
2.4 Instrumental Diagnostics
In patients with a confirmed diagnosis of iron deficiency anemia occurring against the background of a malignant neoplasm, it is recommended to perform endoscopic examinations of the upper and lower gastrointestinal tract (esophagogastroduodenoscopy, colonoscopy) to rule out bleeding and take measures to stop it [63,70,86].
Level of Evidence: 5Level of Recommendation C (Level of Evidence – 5)
Comment: the diagnosis of anemia and the identification of its causes should be performed prior to blood transfusion (unless there are emergency indications for transfusion) or the administration of erythropoiesis-stimulating agents (ESAs; V03XA1 and V03XA2) and iron preparations.
2.5 Other Procedures
In patients with suspected anemia caused by impaired bone marrow hematopoiesis, bone marrow metastases, or causes other than the underlying malignancy, it is recommended to perform a bone marrow examination [60].
Level of Evidence: 5Level of Recommendation C (Level of Evidence – 5)
Comments: bone marrow aspiration (obtaining a bone marrow cytological specimen via puncture) for cytological examination of a bone marrow smear (myelogram) and/or trephine biopsy (obtaining a histological bone marrow specimen) for pathomorphological examination of bone marrow biopsy (surgical) material may be performed as indicated.
All patients with ACD are recommended to undergo ABO blood grouping and Rhesus (Rh factor) D antigen typing [83].
Level of Evidence: 5Level of Recommendation C (Level of Evidence – 5)
Comments: determination of major blood groups using the ABO system, determination of the D antigen of the Rhesus system (Rh factor), determination of the phenotype by C, c, E, e, Cw, K, and k antigens, and determination of anti-erythrocyte antibodies, as well as other tests as clinically indicated.
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
For patients with a hemoglobin concentration below 70 g/L and/or with clinical manifestations of anemic hypoxia (including at higher hemoglobin levels), blood transfusion of donor red blood cell components (leukocyte-depleted red blood cell suspension, red blood cell suspension obtained by apheresis, etc.) is recommended [24-28,60,63,81].
Level of Evidence: 5Level of Recommendation C (Level of Evidence – 5)
Comments: blood transfusions are prescribed based on clinical indications, and the hemoglobin level serves as one of the reference points. Thus, transfusions of donor red blood cell components may be indicated in milder anemia with a hemoglobin level of 80–100 g/L if extensive surgery is planned, if anemia leads to hypoxic symptoms, etc.
Replacement transfusions of donor red blood cell components are a traditional method for correcting decreased Hb and life-threatening situations associated with acute blood loss (extensive surgeries). However, for the treatment of anemia associated with a tumor process (tumor breakdown, intoxication) and antineoplastic treatment, blood transfusions are not a unambiguously safe and effective method. Thus, blood transfusions may be accompanied by hemolytic reactions, including fatal ones (frequency 1:1,000), transfusion-related acute lung injury (frequency 1:5,000), bacterial contamination, including fatal sepsis (frequency 1:10,000), transmission of hepatitis B virus (frequency 1:30,000), hepatitis C, and human immunodeficiency virus (frequency 1:1,000,000) [31,83]. In addition, many potentially dangerous viral infections are currently not tested in donors. Along with the above, immunosuppression induced by blood transfusion leads to an increased risk of thrombosis, infectious complications, and a decrease in disease-free and overall survival in a number of tumor diseases (colorectal cancer, bladder cancer) [33,82]. The increase in Hb concentration after blood transfusions is short-lived, and to maintain its normal value, they need to be repeated. Therefore, the WHO recommends strictly regulating replacement transfusions in cancer patients and using alternative methods of Hb correction.
Blood transfusions for a decrease in Hb concentration <70–80 g/L are indicated only in cases of acute posthemorrhagic anemia with a simultaneous decrease in hematocrit to ≤ 25%. In chronic anemia, the main task is to eliminate the cause of anemia, and blood transfusions are prescribed only to correct clinically significant symptoms caused by hypoxia due to decreased Hb that do not respond to pathogenetic therapy. Thus, the Hb concentration in isolation cannot serve as an absolute criterion for the necessity of blood transfusions; therefore, the decision must always be the result of the attending physician's clinical judgment, and should be based primarily on objective signs of hypoxia, taking into account concomitant risk factors (bleeding, intercurrent infections, upcoming chemo/radiotherapy, etc.).
Transfusions may not be required for well-compensated patients recovering from chemotherapy-induced aplasia [24-27]. However, in the case of upcoming intensive chemotherapy, transfusions in the absence of clinical manifestations are justified [24,28-29].
All pediatric oncology patients should receive irradiated, leukocyte-depleted red blood cell suspension [30]. Leukoreduction has been shown to significantly reduce the risk of febrile non-hemolytic transfusion reactions, as well as the transmission of infectious pathogens, in particular, cytomegalovirus (CMV) [31,32]. Irradiation of the red blood cell suspension prevents the development of transfusion-associated graft-versus-host disease in immunocompromised patients [33,34].
A general rule for deciding on the need for blood transfusion in pediatric practice is to focus primarily on clinical indicators, such as:
clinical symptoms and functional indicators of anemia (primarily the rate of its progression);
presence or absence of cardiovascular and/or respiratory symptoms, anemic hypoxia, CNS disorders;
physical condition and activity of the child;
absence of alternative therapy methods.
Hb concentration in isolation cannot serve as an absolute criterion for the necessity of blood transfusions. Therefore, the decision must always be the result of the attending physician's clinical judgment, and should be based primarily on objective signs of hypoxia, taking into account concomitant risk factors (bleeding, intercurrent infections, upcoming chemo/radiotherapy, etc.) [28,35-36].
The usual dose of red blood cell suspension transfusion is 10-15 mL/kg. Transfusion of red blood cell suspension to children in a volume of 10 mL/kg increases the hemoglobin concentration by an average of 10-20 g/L. In case of an inadequately low increase in hemoglobin concentration, the following conditions should be taken into account:
hidden bleeding;
repeated blood sampling for laboratory tests;
fever;
hypersplenism;
primary and secondary immunological causes;
mechanical or other type of hemolysis [28,37-38].
The disadvantages of blood transfusion therapy are the short duration of the achieved result, the risk of developing a number of acute and delayed reactions and complications [28,30,39].
For patients with anemia of chronic disease in the presence of absolute or relative contraindications to transfusions of donor red blood cell components, pharmacotherapy with erythropoiesis-stimulating agents (ESAs, B03XA1 and B03XA2) as monotherapy or in combination with iron preparations is recommended [24,30,42-51,57-60,63].
LoE CGoE 3Level of Evidence C (Grade of Recommendation – 3)
Comments: data from randomized trials indicate the efficacy and safety of ESA therapy in children with malignancies [20,42-51]. Despite the data from these studies, recombinant human erythropoietin (rhEPO) is not recommended for routine use in children with malignancies. This is primarily due to the lack of a scientifically sound evidence base regarding the effect of ESA therapy on the quality of life and survival of children with cancer, as well as emerging contradictions regarding the effect of ESA therapy on the survival of adult patients with malignancies. The results of several randomized trials showed lower overall survival rates among adult patients with malignancies receiving ESAs compared to patients receiving placebo. Although most of these studies had methodological problems, their results prompted a cautious attitude towards the use of ESAs in cancer patients [52,53]. In addition, a number of preclinical studies indicate the presence of erythropoietin receptors (EPOR) on certain tumor cells, through which ESAs can potentially influence the processes of proliferation and apoptosis of EPOR-expressing tumor cells [54-56]. Most recent studies indicate that the expression of erythropoietin receptors on malignant cells does not lead to a tumor-stimulating effect and does not protect them from drug-induced apoptosis. The results of large controlled trials published over the past few years evaluating the effect of ESA therapy on adult patient survival rates do not support the hypothesis of ESA-induced tumor progression and/or reduced survival [57]. To date, there is no reliable data on the effect of ESA therapy on the survival of children with malignancies. Isolated publications evaluating the survival of small groups of children with malignancies receiving ESA therapy have not revealed any negative impact [20,58].
The use of rhEPO in children with malignancies is currently experimental in nature and should be carried out within the framework of large controlled randomized trials.
However, in certain cases, with relative contraindications to red blood cell suspension transfusions (acute liver failure, circulatory decompensation, severe cerebrovascular disorders, thrombophilic/thromboembolic states), in the case of a rare blood group or alloimmunization, or if the patient/parents refuse transfusions for religious reasons, anemia correction may be performed using recombinant human erythropoietin (rhEPO) with iron supplements. In addition, such therapy is justified for patients receiving palliative care. ESA therapy may be administered only during chemotherapy and only with the informed consent of the parents/legal guardians or the patient themselves if they have reached the age of 16 [58,59].
The use of rhEPO for the prevention of anemia is not recommended [57].
Before starting EPO therapy, any other causes of anemia (other than tumor-related) should be identified and eliminated.
RhEPO therapy should be initiated at Hb < 100 (110) g/L, depending on the symptoms of anemia. INN: Epoetin beta** is administered intravenously at a dose of 600 IU/kg once a week. Subcutaneous administration of INN: Epoetin beta** is permissible in the absence of venous catheters. A starting single dose of 600 IU/kg is used. In the absence of a complete therapeutic response after 4 weeks of administration of INN: Epoetin beta** , defined as an increase in hemoglobin level by 20 g/L from baseline in the absence of packed red blood cell transfusions, the single dose of the drug is increased by 100 IU/kg. Subsequent dose increases of INN: Epoetin beta** are provided every 2 weeks by 100 IU/kg, provided that the rate of hemoglobin increase is insufficient (< 5 g/L per week), up to a maximum of 900 IU/kg. If a dose of 900 IU/kg is ineffective, further therapy with INN: Epoetin beta** is inappropriate.
When treating cancer-related anemia, one should not strive for a significant increase in hemoglobin concentration (above 110–120 g/L), even despite the lack of data on the development of thromboembolic complications in children receiving rhEPO therapy. When evaluating the efficacy of recombinant human erythropoietin therapy, the most important significance should be given not to achieving the target hemoglobin level, but to maintaining a satisfactory quality of life for the patient. For adult cancer patients, the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH), as well as the National Comprehensive Cancer Network (NCCN), consider the elimination of anemia symptoms and the prevention of transfusions to be the main goals of ESA therapy [60,61].
If Hb increases excessively rapidly (by more than 20 g/L per week) or if its concentration is ≥ 120 g/L, administration of the drug should be discontinued. Administration of the drug is resumed when Hb decreases to ˂ 100 (110) g/L, depending on the symptoms of anemia.
Contraindications to the use of ESAs (B03XA1, B03XA2):
known hypersensitivity to ESAs or their components;
uncontrolled arterial hypertension;
high risk of thromboembolic complications (history of thrombosis, extensive surgery, prolonged immobilization or activity restriction, treatment with lenalidomide** in combination with doxorubicin** and glucocorticoids; data on the role of prophylactic use of ATC antithrombotic agents are absent).
Considering the development of functional iron deficiency (FID) in all patients receiving ESA therapy, a universal rule during ESA therapy is the prescription of iron supplements.
Patients with proven absolute iron deficiency are recommended to receive iron preparations in accordance with iron deficiency anemia treatment protocols [13,19,40].
CR CLEL 5Level of Evidence C (Level of Likelihood of Evidence – 5)
Comments: in a number of patients, against the background of intensified erythropoiesis resulting from ESA therapy (B03XA1 or B03XA2), absolute iron deficiency develops, which necessitates monitoring iron metabolism parameters in patients with cancer-related anemia both initially and dynamically. The laboratory criterion for absolute iron deficiency is a decrease in transferrin saturation (TSAT) to less than 20%, and serum ferritin (SF) to less than 100 ng/mL.
The choice of the preferred dosage form (oral or parenteral) and the dose of the iron preparation depends on a number of factors: the severity of anemia, the presence of concomitant inflammation (in particular, against the background of the tumor process), ongoing blood loss, as well as individual tolerance to various forms of iron preparations.
In the case of mild or moderate anemia, in the absence of ongoing bleeding and normal CRP values, it is advisable to correct iron deficiency with iron preparations in an oral dosage form, in doses for children in accordance with the clinical guidelines for the treatment of iron deficiency anemia (IDA) – until the laboratory picture of IDA regresses (ferritin 40-60 ng/mL with CRP <5 ng/mL).
In severe anemia, ongoing bleeding (which cannot be stopped by surgical and/ch or conservative methods), as well as with an increase in CRP >5 ng/mL (against the background of the tumor process), it is advisable to treat with parenteral iron preparations used in children in doses in accordance with the clinical guidelines for the treatment of IDA (INN ferric carboxymaltose** or INN: Iron [III] hydroxide sucrose complex** or Iron [III] hydroxide dextran).
In the presence of infectious complications, the use of both oral and intravenous iron preparations is postponed until the infectious process is resolved.
Due to the potential interaction of iron and certain antineoplastic agents (anthracyclines and related compounds, platinum preparations), administration of iron preparations should be avoided on the days of administration of antineoplastic agents. Recommended doses and regimens of parenteral administration of iron preparations are presented in Table 2 (see Appendix A3).
Patients who develop autoimmune hemolytic anemia against the background of malignant neoplasms are recommended to receive therapy in accordance with the treatment protocols for autoimmune hemolytic anemias [41,42].
LEL 2Level of Evidence B (Level of Likelihood of Evidence – 2)
Comments: in some cases, the development of autoimmune hemolysis, for example, in lymphoproliferative disorders, is an indication for specific chemotherapy.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
Specific methods of rehabilitation and sanatorium-respiratory treatment for patients with cancer-related anemia have not been developed. Rehabilitation of patients with cancer-related anemia should be carried out in accordance with an individually developed rehabilitation program for each patient, taking into account other complications of the oncological disease. Such a program is developed by a physical and rehabilitation medicine physician, a medical psychologist with the participation of an oncologist, hematologist, pediatric oncologic-hematologist based on the International Classification of Functioning, Disability and Health. In addition, the rehabilitation program should take into account the social and psychological problems of the patient and include (as indicated) social workers and psychologists.
5. Prevention and Dispensary Observation
Specific preventive measures regarding patients with anemia of malignant neoplasms have not been developed. For the timely detection of cancer-related anemia, regular monitoring of the complete blood count during therapy and dispensary observation for the underlying disease (malignant neoplasm) are necessary.
6. Organization of Medical Care
Considering that anemia is a typical complication of both the oncological disease itself and the chemotherapy treatment being administered, its correction is carried out as part of the treatment of the underlying disease.
In the case of outpatient chemotherapy, indications for hospitalization will include severe anemia (Hb ≤ 70 g/L, Ht ≤ 25-30%), or the presence of symptoms and signs of anemic hypoxia even at higher Hb concentration values.
Indications for discharging a patient from a medical organization:
1) resolution of anemia (increase or normalization of hemoglobin level during ongoing treatment);
2) resolution of symptoms of anemic hypoxia.
7. Additional Information
At the clinical level, the relationship between anemia and fatigue is considered well-established. In adults, a direct effect of Hb levels on fatigue and other quality of life parameters has been proven. In children, especially younger ones, quality of life assessment is associated with technical difficulties, as it requires questionnaires to be filled out by the children themselves and their parents. According to quality of life studies in children with malignant neoplasms, fatigue has also been identified by children and adolescents as one of the most distressing symptoms they experience [38]. In addition, children of different ages interpret the sensation of fatigue differently: children 7-12 years old emphasize physical fatigue, while adolescents 13-18 years old also note a mental sensation of fatigue [39]. There are isolated publications showing an improvement in the quality of life of children with malignant neoplasms, correlating with an increase in Hb concentration during ESA therapy.
Despite this, fatigue is rarely noted in the complaints of patients and their parents, leading to an underestimation of this condition.
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Evaluation of compliance (yes/no) |
|---|---|---|
1 | A complete (clinical) blood count was performed, differential, with determination of hematocrit and reticulocytes (upon diagnosis establishment, during follow-up studies) | Yes / No |
2 | Serum iron level determination, blood ferritin level testing, and transferrin iron saturation testing were performed when iron deficiency was suspected (upon establishing the diagnosis). | Yes / No |
3 | Ultrasound examination was performed when internal bleeding was suspected (depending on the expected localization of the bleeding source). | Yes / No |
4 | Endoscopic examination was performed when internal bleeding was suspected (depending on the expected localization of the bleeding source). | Yes / No |
5 | Red blood cell suspension transfusion was performed in the presence of indications and the absence of contraindications. | Yes / No |
6 | X-ray examination was performed when internal bleeding was suspected (depending on the expected localization of the bleeding source). | Yes / No |
7 | ATC therapy was administered: Antianemic preparations (B03) or (B03XA): Other antianemic preparations (erythropoiesis-stimulating agents) in children with malignant neoplasms in the presence of absolute or relative contraindications to blood transfusions. | Yes / No |
8 | Iron supplement therapy was administered in the presence of absolute iron deficiency. | Yes / No |
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Appendix A1. Working Group Composition
Aleksandr Grigoryevich Rumyantsev – Doctor of Medical Sciences, Professor, Academician of the RAS, Member of the Russian Society of Pediatric Oncologists and Hematologists; President of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.
Nataliya Sergeyevna Smetanina – Doctor of Medical Sciences, Professor, Member of the National Hematological Society, Member of the Russian Society of Pediatric Oncologists and Hematologists, Member of the European Hematology Association, Member of the International Bioiron Society; Deputy General Director – Director of the Department for Planning and Strategic Development of Pediatric Oncology and Hematology Services, Deputy Director of the Institute of Hematology, Immunology and Cell Technologies of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.
Svetlana Rafaelevna Varfolomeeva – Doctor of Medical Sciences, Professor, President of the Russian Society of Pediatric Oncologists and Hematologists; Director of the L.A. Durnov Research Institute of Pediatric Oncology and Hematology of the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Professor of the Department of Pediatric Oncology of the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.
Mariya Anatolyevna Lunyakova – Candidate of Medical Sciences, Member of the Russian Society of Pediatric Oncologists and Hematologists; Chief Physician of the Scientific and Clinical Center of Hematology, Oncology and Immunology of the Ryazan State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health.
Pavel Evgenyevich Trakhtman – Doctor of Medical Sciences, Associate Professor, Member of the Russian Society of Pediatric Oncologists and Hematologists, Member of the Russian Association of Transfusiologists; Head of the Department of Transfusion Medicine, Harvesting and Processing of Hematopoietic Stem Cells of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.
Yury Aleksandrovich Shifrin – Candidate of Medical Sciences, Member of the Russian Society of Pediatric Oncologists and Hematologists; Junior Researcher at the Department of Molecular and Clinical Pharmacology, Clinical Pharmacologist at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.
Andrey Borisovich Abrosimov – Candidate of Medical Sciences, Head of Department - Hematologist at the Department of Treatment and Rehabilitation of Patients with Immunohematological Profiles and Stem Cell Recipients, Senior Researcher at the Laboratory of Pharmacology and Health Technology Assessment of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.
Conflict of interest: None.
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience of these clinical guidelines:
Hematologists
Pediatric oncologists.
Pediatricians
Pediatric oncologists-hematologists.
Medical students, residents, postgraduate students
Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
|---|---|
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual studies with reference standard control or individual randomized controlled trials and systematic reviews of studies of any design, except randomized controlled trials, with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard not independent of the test method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case report |
5 | Only justification of mechanism of action or expert opinion is available |
Table 2. Levels of Evidence (LE) rating scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)
LoE | Definitions |
|---|---|
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design except RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | Only justification of the mechanism of action of the intervention (preclinical studies) or expert opinion is available |
Table 3. Scale for grading grades of recommendation (GoR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)
GoR | Definition |
|---|---|
A | Strong recommendation (all considered efficacy criteria (outcomes) are important, all studies are of high or acceptable methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered efficacy criteria (outcomes) are important, not all studies are of high or acceptable methodological quality, and/or their conclusions on the outcomes of interest are inconsistent) |
C | Weak recommendation (lack of adequate quality evidence (all considered efficacy criteria (outcomes) are unimportant, all studies are of low methodological quality, and their conclusions on the outcomes of interest are inconsistent) |
Procedure for updating clinical guidelines.
The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
Table 1. Recommended doses of erythropoiesis-stimulating agents and principles of their correction in adult cancer patients receiving chemotherapy
Parameters | Epoetin alfa**1 | Epoetin beta**1 | Darbepoetin alfa**1 |
|---|---|---|---|
Initial dose | 150 IU/kg × 3 times/week [44,63] #40,000 IU × 1 time/week [63] | 450 IU/kg × 1 time/week [87] | 2.25 mcg / kg × once a week #200 mcg × 1 time every 2 weeks [63] #300 mcg × 1 time every 3 weeks [63] #500 mcg × 1 time every 3 weeks [63] |
Dose reduction upon reaching the target hemoglobin level2 | 25–50% of the dose | ||
Treatment interruption | When Hb > 130 g/L, administration of the drug should be suspended until Hb drops below < 120 g/L | ||
Drug discontinuation | Completion of chemotherapy or lack of response after 8 weeks of treatment (need for blood transfusions persists) | ||
1All rhEPO products (ATC: Antianemic preparations (B03) or (B03XA): Other antianemic preparations) are administered subcutaneously.
2Achieving an Hb level of 120 g/L or an Hb increase of more than 20 g/L over 2 weeks.
Table 2. Recommended intravenous administration regimens for iron preparations
Drug | Route of administration and dosage | Test dose |
|---|---|---|
Iron [III] hydroxide sucrose complex**1 |
| Intravenously slowly (over 1–2 min) 20 mg – for adults and children with a body weight of more than 14 kg; for children with a body weight of less than 14 kg – 1.5 mg/kg; waiting time – 15 min; in the absence of adverse events, administration of the full dose at the recommended speed is possible [63] |
Gland carboxymaltose**1 |
| No |
Iron [III] hydroxide dextran1 | Depends on the exact type of dextran, see instructions for use. Minimum infusion time 240 – 360 min (4 – 6 h). | Intravenous slow (over 1–2 min) 25 mg or 0.5 ml of the drug; waiting time – 15 min; in the absence of adverse events, administration of the full dose at the recommended speed is possible |
1Iron preparations must not be administered on the days of anti-tumor drug administration.
Appendix B. Physician Action Algorithms
Appendix C. Patient Information
Anemia frequently accompanies the course of malignant neoplasms in children as a consequence of suppressed erythropoiesis in the bone marrow caused by the tumor or ongoing chemotherapy.
Anemia is a frequent symptom of malignant neoplasms themselves, as well as a common complication of anti-tumor treatment (drug therapy and radiation therapy). The main cause of anemia in malignant neoplasms is the suppression of erythropoiesis and erythrocyte maturation processes in the patient's bone marrow, but anemia can also result from other causes (blood loss, erythrocyte destruction, etc.).
Anemia negatively impacts the patient's quality of life and the efficacy of anti-tumor treatment (due to the inability to administer cycles of drug therapy and radiation therapy at optimal doses and within optimal timeframes — when anemia develops, it becomes necessary to reduce the calculated drug dose and increase the interval between cycles of drug therapy and radiation therapy).
Among the main symptoms of anemia are pallor of the skin and mucous membranes, tachycardia, shortness of breath upon minor physical exertion and at rest, dizziness, tinnitus, a feeling of weakness, and increased fatigue, which worsen with physical exertion.
The main clinical and laboratory test for detecting anemia is the complete blood count, which evaluates blood hemoglobin levels and hematocrit.
Correction of anemia in malignant neoplasms can be carried out through replacement blood transfusions – transfusion of red blood cell-containing blood components, or through the use of medications from the ATC group: Antianemic preparations (B03) or (B03XA): Other antianemic preparations (erythropoiesis-stimulating agents), iron preparations, etc. The choice of optimal treatment tactics is determined by the attending physician.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
Appendix G1. ECOG/WHO Scale for assessing the general condition of the patient
Russian title: Eastern Cooperative Oncology Group Performance Status scale.
Original title (if applicable): The ECOG Scale of Performance Status.
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP: Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982, 5(6):649-655.
Type: rating scale.
Purpose: clinical assessment of the patient's general condition.
Content (template) and key (interpretation):
Score | Description |
|---|---|
0 | Fully active, able to carry on all pre-disease performance without restriction |
1 | Patient is unable to do heavy work, but can carry out light or sedentary work (e.g., light housework or office work) |
2 | The patient is ambulatory, capable of self-care, but unable to work. Spends more than 50% of waking hours active in an upright position. |
3 | The patient is capable of only limited self-care, confined to a bed or chair more than 50% of waking hours |
4 | Completely disabled; cannot carry on any self-care; totally confined to bed or chair |
5 | Dead |
Notes: none.
Appendix G2. Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 scale
Russian title: CTCAE toxicity grading scale.
Original title (if applicable): Common Terminology Criteria for Adverse Events (CTCAE) v 5.0.
Source: Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 Publish Date: November 27, 2017 (http://ctep.cancer.gov).
Type: rating scale.
Purpose: assessment of adverse event severity.
Content (template) and key (interpretation)
Severity grade | Hb level (g/L) | Comments |
|---|---|---|
1 | <100 g/L | |
2 | 80–100 g/L | |
3 | <80 g/L | Blood transfusion indicated |
4 | Life-threatening condition, urgent medical intervention required | |
5 | Dead |