pure red cell leukemia



Overview of acute myeloid leukemia

Acute myeloid leukemia is a kind of acute myeloid leukemia, the bone marrow in the red lineage cell significant proliferation of the main manifestations of weakness, panic, dizziness and other symptoms of anemia, some patients may be combined with bleeding, infection chemotherapy and allogeneic hematopoietic stem cell transplantation is the main therapeutic approach chemotherapy is less effective, the prognosis is poor, as early as possible for allogeneic hematopoietic stem cell transplantation may be able to improve prognosis

Definition

Pure erythroid leukemia is a specific type of acute myeloid leukemia World Health Organization (WHO) typology, which is mainly characterized by a significant proliferation of red lineage cells in the bone marrow.

Previously, pure erythroleukemia and red leukemia were collectively referred to as acute red lineage leukemia, but because most cases of acute red lineage leukemia have less than 20% of primitive cells, in 2016, the WHO classified most of these cases as myelodysplastic syndromes (MDS). The revision retained only pure erythroleukemia.

Pure erythroid leukemia has a proportion of naïve red blood cells in the bone marrow of >80% of all nucleated cells, and of these, ≥30% are primitive naïve cells and <20% are primitive granulocytes.

The disease is clinically rare. The patient is markedly anemic, with moderate or large naïve red cells with one or more nucleoli visible in the bone marrow. Nucleated erythrocytes are seen in the peripheral blood with rapid clinical progression.

Pathogenesis

Pure erythroid leukemia is clinically rare, accounting for less than 1% of acute myeloid leukemias, and there are no accurate epidemiological data in China [1-2].

Etiology

The etiology and pathogenesis of pure erythroleukemia are not fully understood and may be similar to leukemia.

Causes

The etiology of pure erythroleukemia is unknown, and may be similar to that of leukemia. Ionizing rays, chemicals, viral infections, and heredity cause DNA mutations in normal hematopoietic stem/progenitor cells through different mechanisms, which ultimately cause malignant proliferation of hematopoietic stem/progenitor cells and lead to leukemia.

Ionizing radiation

Including X-rays, γ-rays, etc. Studies have shown that large area and high dose irradiation can lead to bone marrow suppression and decrease of body immunity, DNA mutation, breakage and recombination, and then cause leukemia.

Chemical factors

Chemical substances

Benzene and organic solvents containing benzene: Benzene is a volatile organic solvent with strong fat solubility, which is easy to enter the body through the skin and lungs, and accumulates in fat and brain tissues, with significant chromosomal aberration-causing and leukemia-causing effects.

Smoking: Tobacco contains potential leukemia-causing chemicals, such as benzene, urethane, nitrosamines, and radioactive substances, etc. The incidence of acute leukemia in long-term heavy smokers is relatively high.

Drugs

Anti-tumor drugs: mainly alkylating agents and topoisomerase II inhibitors, such as cyclophosphamide, phenylbutyric acid nitrogen mustard, leucovorin, etc., which can cause gene mutation and lead to the occurrence of leukemia.

Other drugs: such as flavonoids, catechols, caffeine, quinolones, etc. Exposure to these drugs during pregnancy can lead to an increased risk of leukemia in the fetus.

Genetic factors

Leukemia is not a genetic disease, but it has been reported in the literature that family history of leukemia in leukemia patients accounts for 8.1%.

In monozygotic twins, if one person has leukemia, the other person has a 20% chance of developing leukemia, and twins can have homozygous leukemia.

People with certain congenital disorders such as Down syndrome and Fanconi anemia are 20 times more likely to develop leukemia than the general population.

Other blood disorders

Myelodysplastic syndromes, myeloproliferative disorders, and aplastic anemia can develop into leukemia.

High risk factors

Long-term heavy smoking and alcohol consumption.

Long-term exposure to ionizing radiation such as living in nuclear radiation areas, working with radiation, etc.

Long-term exposure to benzene and its derivatives, gasoline, rubber, paint, preservatives, pesticides, etc.

History of hematologic diseases such as myelodysplastic syndrome, aplastic anemia, etc.

Have a history of malignant tumors and long-term chemotherapy or radiotherapy.

There are leukemia patients in the direct line such as parents, children or collateral line within 3 generations such as brothers, sisters, uncles and other relatives.

Marriage of close relatives.

Pathogenesis

The pathogenesis of pure erythroleukemia is not completely clear. Leukemia cells have enhanced self-renewal, uncontrolled proliferation, impaired differentiation, and impaired apoptosis, while stagnating at different stages of cell development, and ultimately inhibiting normal hematopoiesis and infiltration of other tissues, which may be specifically related to the following mechanisms.

Transformation of proto-oncogenes

There are proto-oncogenes in the human chromosome genome, and under normal conditions, their main function is to participate in the regulation of cell proliferation, differentiation, and aging and death.

Under the action of oncogenic factors, proto-oncogenes can undergo point mutation, chromosomal rearrangement or gene amplification, and be transformed into oncogenes, thus leading to the occurrence of leukemia.

Oncogene aberrations

When the oncogenes in the body undergo mutation, deletion and other variations, they lose their oncogenic activity, resulting in the abnormal proliferation of leukemia cells and the development of leukemia.

It has been found that mutation of oncogene TP53 is common in pure erythroleukemia patients.

Impaired apoptosis

Apoptosis is a process of cellular active self-death under gene regulation, and it is a normal pathway of cell removal in human tissue and organ development.

When apoptosis is inhibited or blocked, cells continue to proliferate without normal apoptosis, resulting in mutations.

The “second strike” theory

The above genetic alterations may be based on certain genetic abnormalities, which together may lead to blocked or disrupted differentiation of hematopoietic cells [1-4].

Symptoms

The symptoms of pure erythroleukemia are similar to those of other types of acute leukemia. The leukemia cells inhibit the normal hematopoietic function of the bone marrow, causing a decrease in blood cells and infiltration of extramedullary tissues and organs, resulting in the corresponding manifestations.

Main symptoms

Anemia

Anemia is the most obvious symptom of pure red blood cell leukemia, which is mostly manifested as pale face, generalized weakness, panic, chest tightness, shortness of breath, dizziness and other symptoms.

With acute onset, anemia is progressive.

Bleeding

Mainly skin and mucous membrane bleeding, such as skin hemorrhages, petechiae, nosebleeds, gum bleeding and oral blisters.

Bleeding from deep organs, such as gastrointestinal tract, respiratory tract, urinary tract, uterus, fundus of the eye and even central nervous system can also be seen, which can be life-threatening in severe cases.

The bleeding manifestations of pure red cell leukemia are less severe.

Fever

Most of the patients may have fever, which is mostly irregular, or as high as 39～40℃ or above, accompanied by chills and sweating, etc. If persistent high fever occurs, it suggests that the patient has a fever.

If there is persistent high fever, it suggests that there may be a combination of infection, with various sites of infection, mainly oral infection, which may rapidly develop into bacteremia or sepsis.

The most common pathogenic bacteria are gram-negative bacilli, long-term application of antibiotics and granulocyte deficiency can be fungal infections, some patients with immune deficiency, easy to combine with viral infections.

Infiltration symptoms

Liver and spleen enlargement

Early stage of pure red cell leukemia, liver and spleen enlargement are not obvious, but later stage of the disease, liver and spleen enlargement may be obvious.

If the splenomegaly exceeds 5 cm below the rib cage, it should be considered that it may be secondary to myelodysplastic syndrome.

Others

In some patients, the white blood cell count is significantly elevated at the onset of the disease, and there may be pressure pain in the lower part of the sternum caused by leukocyte stasis. Bone pain and arthralgia may be caused by leukemia cells invading the periosteum.

Very few patients may present with skin lumps, swollen gums or even neurologic infiltration manifested by blurred vision and convulsions.

Very few patients may present with enlarged lymph nodes [1-2].

Seek medical attention.

Seek medical attention at the hematology department when symptoms of anemia such as dizziness and weakness, pallor, etc. occur.

Department of Medicine

Department of Hematology

Hematology is the first choice when symptoms such as pallor, fatigue, dizziness, headache, and recurrent bleeding from the skin and mucous membranes occur.

Emergency Department

If there is severe bleeding or infection resulting in unstable vital signs, consult the Emergency Department first.

Preparation for medical treatment

Preparation for medical treatment: registration, preparation of documents, and common problems.

Tips for seeking medical treatment

If your vital signs are unstable, call 120 and go to the hospital.

It is recommended to wear loose-fitting clothes to facilitate the doctor’s physical examination.

Do not wear makeup, lipstick, nail polish, etc. to avoid interfering with the doctor’s judgment.

If the patient’s symptoms are obvious, it is recommended to have a family member accompany the patient during the visit.

Preparation Checklist

Symptom list

Pay particular attention to the time of onset of symptoms, special manifestations, etc.

Are there any symptoms such as generalized weakness, chest tightness, panic or dizziness?

Are there any bleeding spots on the skin, blood blisters on the oral mucosa, etc.?

Are there nosebleeds, vomiting blood, black stools, etc.? What is the approximate amount of bleeding each time?

Are there any prolonged menstrual periods or increased menstrual flow?

Is there any bone pain, joint pain?

Is there any fever? What is the highest temperature? Are there any chills or chills before the onset of fever?

Are there any symptoms of infection such as cough, sputum, abdominal pain, diarrhea, etc.?

List of medical history

Is there any history of other hematologic disorders such as myelodysplastic syndrome, aplastic anemia, etc.?

Any history of other malignant tumors? Has he/she received anti-tumor treatment such as radiotherapy, chemotherapy, etc.?

Any long-term exposure to toxic and harmful chemicals such as pesticides, rubber, gasoline, etc.?

Is there any long-term exposure to radiation or other radiation?

Are there other relatives in the family with leukemia?

Have you been smoking or drinking alcohol for a long time? Or mother smoked or drank during pregnancy?

Checklist

Test results for the last six months, which can be brought to the doctor’s office

Recent hematology results such as routine blood tests, peripheral blood smears, blood biochemistry, etc.

Imaging results such as chest CT, abdominal ultrasound, etc.

Bone marrow findings such as bone marrow smear, bone marrow biopsy, chromosomes, flow cytometry, etc [5-6].

Diagnosis

The diagnosis of pure red cell leukemia is mainly based on the results of bone marrow smear and other examinations.

Diagnosis is based on

Medical history

History of other hematologic disorders such as myelodysplastic syndrome, aplastic anemia, paroxysmal sleep hemoglobinuria, etc.

Received radiation or chemotherapy treatment for malignant tumors.

Have a history of long-term exposure to chemicals or ionizing radiation.

Have a family history of leukemia.

The mother has not quit smoking or alcohol during pregnancy.

Clinical manifestations

Anemia: generalized weakness, panic, chest tightness and dizziness.

Bleeding: skin bleeding spots, nosebleeds, gastrointestinal bleeding, etc.

Infection: fever, cough, dyspnea, diarrhea, etc.

Infiltration: patients may have liver and spleen enlargement, sternal pressure pain and other manifestations.

Physical examination

Vital Signs: Anemia may be severe with elevated heart rate, infection may have elevated body temperature, and severe bleeding may have decreased blood pressure.

Visual examination: to see whether there is pallor, skin bleeding spots, blood blisters in the mouth.

Palpation: to clarify whether there is enlarged liver, spleen, lymph nodes and sternal pressure pain, etc.

Auscultation: If there is lung infection, lung rales can be heard.

Laboratory tests

Blood tests

Hemoglobin and red blood cell counts are decreased, and the degree of anemia varies, with most being normocytic and a few being microcytic hypochromic.

The white blood cell count is usually low, but may be normal or elevated in a few cases.

Platelet counts are often decreased, and a few may be normal.

Peripheral blood smear

Young red blood cells in all stages are seen with morphological abnormalities, with a predominance of primitive red blood cells.

Blood biochemistry

Some patients may have elevated serum lactate dehydrogenase (LDH).

Those with high white blood cell counts may have elevated uric acid.

Bone marrow smear

It is the most important test for the diagnosis of pure erythroid leukemia, and most often shows:

marked or extremely active bone marrow proliferation.

In pure erythroid leukemia, the proportion of naïve red blood cells in the bone marrow is >80% of all nucleated cells and includes ≥30% of primitive naïve cells and <20% of primitive granulocytes.

Bone marrow staining

Myeloperoxidase (MPO) and Sudan black B (SBB) stains are negative, whereas α-naphthol acetate lyase, acid phosphatase, and peroxynitrite Schiff (PAS) stains are positive in the bone marrow of pure erythroid leukemia.

Bone marrow biopsy

Bone marrow tissue sections showed abnormally active bone marrow proliferation with little or no adipocytes.

Flow cytology

PURPOSE: Flow cytometry is mainly used to detect molecular markers on the surface of individual cells within the bone marrow for typing and diagnosis of leukemia.

Results: Well-differentiated primitive (red) cells in the bone marrow of pure erythroid leukemia express hemoglobin A and blood group glycoproteins, while MPO and other myeloid markers are negative, CD34 and HLA-DR are usually negative, but CD117 can be positive; poorly differentiated blood group glycoproteins are also negative or only weakly positive.

Chromosomal and molecular biology

There are no specific cytogenetic abnormalities in pure erythroleukemia. Some cases are associated with complex karyotypes with multiple chromosomal structural abnormalities, such as -5/del (5q), -7/del (7q), and +8, which are most often transformed from myelodysplastic syndromes.

TP53 mutations are common.

Imaging

Chest CT: Cases with combined lung infection mostly have changes of lung inflammation.

Abdominal ultrasound: it can determine whether there is hepatomegaly and splenomegaly.

Differential diagnosis

Megaloblastic anemia

Both have pathological hematopoiesis of the red lineage, and it is sometimes difficult to distinguish between them. However, megaloblastic anemia mostly has a history of malnutrition and malabsorption disorders, and there is no abnormal proliferation of the granulomatous lineage or pathological hematopoiesis in the bone marrow, and it is usually treated effectively with folic acid and vitamin B12.

Hemolytic anemia

Pure erythrocyte leukemia is easy to be confused with hemolytic anemia because of the extreme hyperplasia of the red lineage in the bone marrow smear. However, hemolytic anemia can be distinguished from hemolytic anemia because of the presence of hemoglobinuria, elevated bilirubin, and abnormal hemolysis-related indexes.

Myelodysplastic syndrome

Pure erythroid leukemia can progress from myelodysplastic syndromes, and it is sometimes difficult to distinguish them, but in myelodysplastic syndromes, <20% of the bone marrow is primitive [1,7-8].

Treatment

Aim of treatment: to remove leukemia cells from the body so that hematopoietic function can be restored.

Treatment principle: there is no standard treatment plan for pure red cell leukemia. Chemotherapy is the main treatment method, while chemotherapy strengthens supportive treatment, prevents bleeding and infection, and hematopoietic stem cell transplantation can be chosen for patients with conditions.

Symptomatic treatment

General supportive treatment

Attention to rest: patients should reduce activities, and those with respiratory difficulties need to strengthen oxygen or assist ventilation.

During chemotherapy: patients should live in laminar flow wards or sterile wards, and the wards should be sterilized with ultraviolet rays every day.

Enhance self-protection: pay attention to personal hygiene, wash hands frequently every day, rinse mouth frequently after meals and before going to bed, and take sitz bath with potassium permanganate twice a day.

Dietary precautions: all food and drinks must be warmed up before consumption, pay attention to the cleanliness of tableware, do not eat too cold or too hot food, and try to keep the bowel movement as smooth as possible. Anti-leukemia treatment can cause patients with digestive tract mucosal damage and functional disorders, attention should be paid to supplemental nutrition, maintain water and electrolyte balance, can eat high protein, high calorie, easy to digest food, if necessary, through the vein supplemental nutrition.

Correcting anemia

Anemia is the most common manifestation of pure red cell leukemia.

If the hemoglobin is <60g/L or the symptoms of anemia are severe during chemotherapy, red blood cell transfusion can be used to improve the symptoms of anemia.

If hemoglobin decreases during chemotherapy, erythropoietin can be given to raise red blood cells.

Anti-infection

Severe infections can be life-threatening.

Once there are signs of fever and infection, relevant body fluid specimens should be collected immediately for microbial culture, and antibiotics should be used empirically for treatment, and then the medication can be adjusted according to the results of microbial culture.

Due to the patient’s low immune function, high-dose gammaglobulin can be injected intravenously if the treatment of severe bacterial and viral infections is ineffective.

For severe granulocytopenia after chemotherapy, granulocyte colony-stimulating factor should be given to elevate white blood cells.

Hemostasis

For those with thrombocytopenia and bleeding, hemostasis can be performed with drugs such as hemagglutinin and aminoglutethic acid.

Platelet transfusion can be used prophylactically if the platelet count drops rapidly to <20×109/L as a result of chemotherapy.

Platelet transfusion is feasible for those with platelet count <40×109/L and active bleeding that cannot be stopped by conventional methods.

For thrombocytopenia after chemotherapy, interleukin-11 can be given to elevate platelet therapy.

Prevention of chemotherapy side effects

During chemotherapy, due to the disintegration of leukemia cells, a large amount of cell contents are released, which can lead to the elevation of uric acid, and in severe cases, acute renal failure may be caused, so it is necessary to strengthen the treatment of controlling uric acid and alkalizing urine, and pay attention to strengthening the intake of fluids.

Due to the damage of chemotherapeutic drugs to the liver, hepatoprotective drugs should also be given to protect the liver during treatment.

Long-term use of anthracycline-based chemotherapeutic drugs can produce a certain degree of toxicity to the heart, regular monitoring of heart function is required, and cardioprotective drugs should be used when necessary.

Anti-leukemia treatment

There is no standard treatment for pure erythroleukemia, and chemotherapy is the main treatment strategy. Anti-leukemia treatment is usually divided into 2 phases, the first phase is induction of remission treatment and the second phase is post remission treatment.

Induction of remission

Purpose: Usually a combination of multiple chemotherapeutic agents is used with the goal of rapidly killing leukemia cells and achieving a state of complete remission.

Complete remission: refers to the disappearance of signs and symptoms of leukemia, no primitive cells in peripheral blood, no extramedullary leukemia; recovery of hematopoiesis in the three lineages of bone marrow, with primitive cells <5%; peripheral blood neutrophils >1.0~109/L, platelets >100×109/L.

Commonly used chemotherapeutic drugs: desmethoxazole erythromycin, decitabine, cytarabine, hypertriglyceride, etc.

Post-remission treatment

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be chosen for treatment of pure erythroleukemia after remission, but the efficacy of allo-HSCT has to be further evaluated due to the fact that most of the patients respond poorly to chemotherapy, and it is difficult for chemotherapy to achieve a state of complete remission [2-3,9].

Prognosis

The current prognosis of pure red cell leukemia is poor due to the lack of standard and effective treatment options.

Cure

Pure erythroid leukemia is usually incurable and responds poorly to chemotherapy, resulting in a poor treatment outcome and a poorer prognosis than other types of leukemia, with a shorter median survival time of only a few months.

Prognostic factors

Several studies have shown that patients with chromosomal abnormalities secondary to myelodysplastic syndromes, myeloproliferative disorders, aplastic anemia, etc. or in combination with complex chromosomal abnormalities tend to have a poorer prognosis. Older individuals, those with elevated white blood cells at the time of initial diagnosis, and those who tolerate chemotherapy poorly usually have a poorer prognosis as well.

Patients with no previous history of blood disorders and normal chromosomal test results may have a better prognosis. Early allogeneic hematopoietic stem cell transplantation may also improve the prognosis of patients to some extent [9].

Daily

Patients with pure erythrocyte leukemia should pay attention to symptoms such as anemia and bleeding on a daily basis, and return to the hospital regularly to review the relevant indicators.

Daily management

Dietary management: diet should be rich in high protein, high calories, high vitamins, light, easy to digest, less residue soft food, avoid spicy stimulation, prevent oral mucosal damage. Drink more water, eat more vegetables and fruits to keep the bowel movement smooth.

Life management: pay attention to rest in normal life, avoid strenuous exercise, prevent bumping, prevent bleeding. Pay attention to personal hygiene, go to less crowded places, keep indoor ventilation and disinfection in the place of residence, and wear masks when going out according to the norms.

Psychological support: patients should maintain a positive and optimistic mindset, establish confidence in treatment, and strictly follow the doctor’s instructions for standardized treatment [10].

Follow-up review

In the course of treatment, regular review of blood routine, biochemistry and other tests should be conducted according to the condition of the patient, and the treatment is feasible only after the relevant indexes mentioned above reach the standard before each chemotherapy.

After chemotherapy or post-transplantation, patients should return to the hospital for regular blood tests, blood biochemistry, bone marrow smear and other tests in strict accordance with medical advice.

Prevention

At present, there is no accurate and effective prevention method for pure red cell leukemia, but taking the following measures may reduce its incidence.

Lifestyle habits: Strengthen physical exercise in life, avoid staying up late and working hard, and quit smoking and drinking. Do not smoke or drink alcohol during pregnancy.

Environmental factors: Try to avoid contact with X-rays, gamma rays and other ionizing radiation, and personnel engaged in radiation-related work need to do a good job of personal protection. Try to stay away from gasoline, pesticides, hair dyes, formaldehyde and other chemical substances, if you need to use these substances, try to do a good job of protection.

Disease factors: Patients with myelodysplastic syndromes and aplastic anemia need regular review and strict monitoring.