Erythroleukemia
Synonyms and keywords:Pure erythroid leukemia,  FAB ( French-American-British)  M6, acute erythroid leukemia, Di Guglielmos disease

# Overview
Erythroleukemia was first discovered by M. Copelli, in 1912. In 1917, Di Guglielmo, Italian hematologist, described leukemic nature of the erythroleukemia. Erythroleukemia accounts for < 5 % of acute myeloid leukemia (AML). Erythroleukemia may be classified into 2 groups: De novo cases of erythroleukemia and secondary erythroleukemia. Erythroleukemia may be classified according to previous version WHO into 2 sub-types : The erythroid/myeloid type and the pure type. Erythroleukemia is the neoplastic proliferation of myeloid and erythroid precursors of bone marrow hematopoietic stem cells. A pure erythroid proliferation may also occur. The erythroblasts do not stain with myeloperoxidase (MPO). Markers of myeloid lineage can not be expressed on the erythroblasts. Leukemic cells are positive for myeloid markers such as CD117, CD13, CD33, andmyeloperoxidase (MPO). Megakaryocytes antigens can be positive in some cases of erythroleukemia, such as CD41 and CD61. Erythroleukemia may be caused by translocation t(1;16) generating the fusion gene NFIA/CBFA2T3. Erythroleukemia must be differentiated from MDS with erythroid predominance, other types of AML with increased erythroid precursors, AML with myelodysplasia-related changes. Non-neoplastic disorders that can cause erythroid predominance in the bone marrow such as megaloblastic anemia due to vitamin B12 or folate deficiency, heavy metal intoxication such as arsenic, drug effects (such as antineoplastic agents or chloramphenicol) are other differential diagnoses. The incidence of erythroleukemia is approximately 0.077 per 100,000 individuals worldwide. Erythroleukemia commonly affects individuals older than 50 years of age with a median age of 65. There is no racial predilection to erythroleukemia. Men are more commonly affected by erythroleukemia than women. The male to female ratio is approximately 2 to 1. There are no established risk factors for de novo cases of erythroleukemia. The most potent risk factor in the development of secondary erythroleukemia is previous myelodysplastic syndrome (MDS). There is insufficient evidence to recommend routine screening for erythroleukemia. If left untreated, patients with erythroleukemia may progress to develop bleeding due to disseminated intravascular coagulation (DIC). Common complications of erythroleukemia include infection and bleeding. Therapy related complications are rash, cardiomyopathy and cerebellar toxicity. Prognosis is generally poor. Median survival ranges from 3 - 9 months after the initial diagnosis. A high proerythroblast/myeloblast ratio correlates with worse outcome. The diagnosis of erythroleukemia is based on the 2016 version of WHO classification for AML. History and symptoms include fatigue, Malaise, bone pain, abdominal pain, weight loss, Easy bruising, Fever, and Dyspnea. Patients with erythroleukemia usually appear anemic.  Physical examination of patients with erythroleukemia may include Ecchymoses or petechiae, Hepatomegaly, Splenomegaly, Lymphadenopathy, and headache. Laboratory findings include Pancytopenia, few peripheral blood blasts, Dysplasia in bone marrow and peripheral blood, dysplastic PAS positive erythroblasts with overexpression of the multidrug resistance (MDR) gene product P-glycoprotein, and high frequency of mutations, especially of TP53. Electrocardiogram is useful for the assessment of QT interval prior to starting chemotherapy. An x-ray may be helpful in the diagnosis of complications of erythroleukemia management which include infection, volume overload. Chest x-ray is also useful for venous catheter placement for chemotherapy. An echocardiogram is helpful for assessing cardiac function (ejection fraction) in patients with acute myeloid leukemia before and after receiving anthracycline chemotherapy. An ultrasound is useful for the diagnosis of lower extremity thrombosis, which commonly occurs in patients with acute myeloid leukemia. Abdominal and chest CT scan may be helpful in the diagnosis of acute myeloid leukemia. Findings on CT scan suggestive of acute myeloid leukemia include lymphadenopathy, hepatomegaly, splenomegaly and pulmonary embolism because of deep venous thrombosis. Brain MRI is helpful in the diagnosis of CNS bleeding in acute myeloid leukemia (AML). There are no other imaging findings associated with erythroleukemia. Other diagnostic studies include cytogenetics and flow cytometry. Pharmacologic medical therapy is recommended for patients with erythroleukemia who are not candidates for intensive chemotherapy or allogenic hematopoietic stem cell transplantation. Pharmacologic medical therapies for erythroleukemia include hypomethylating agents (HMA) such as azacitidine and Decitabine. Surgical interventions include allogenic hematopoietic stem cell transplantation (Allo-SCT). There are no established measures for the primary prevention of erythroleukemia. Effective measures for the secondary prevention of erythroleukemia include maintenance of remission treatment post-transplant.

# Historical Perspective
- Erythroleukemia was first discovered by M. Copelli, in 1912.
- In 1917, Di Guglielmo, Italian hematologist, described leukemic nature of the erythroleukemia. Erythroblasts may have vacuolization in the cytoplasm surrounding the nucleus (pearl necklace).

# Classification
- Erythroleukemia accounts for < 5 % of acute myeloid leukemia (AML).
- Erythroleukemia may be classified into 2 groups: De novo cases of erythroleukemia and secondary erythroleukemia.
- Erythroleukemia may be classified according to previous version WHO into 2 sub-types : The erythroid/myeloid type and the pure type.
- Diagnosis of erythroid/myeloid type, based on previous version WHO:
- Erythroid precursors more than 50% of the cells in bone marrow
The blasts comprise of 20% or more of the non-erythroid cells
- Erythroid precursors more than 50% of the cells in bone marrow
- The blasts comprise of 20% or more of the non-erythroid cells
2016 version of WHO classification for AML (erythroid/myeloid type) :
- 20% or more blasts in bone marrow irrespective of the number of erythroid precursors
- Diagnosis of pure erythroid leukemia:
- Erythroblasts (at the stage of pronormoblast > 80% of the marrow cells in patients without exposure to cytotoxic agent and without AML genetic abnormalities). Erythroblasts may have vacuolization in the cytoplasm surrounding the nucleus (pearl necklace).
- Erythroblasts (at the stage of pronormoblast > 80% of the marrow cells in patients without exposure to cytotoxic agent and without AML genetic abnormalities). Erythroblasts may have vacuolization in the cytoplasm surrounding the nucleus (pearl necklace).

# Pathophysiology
- Erythroleukemia is the neoplastic proliferation of myeloid and erythroid precursors of bone marrow hematopoietic stem cells.
- Erythroleukemia accounts for 3 - 5% of all AML cases.
- A pure erythroid proliferation may also occur.
- The erythroblasts do not stain with myeloperoxidase (MPO).
- Markers of myeloid lineage can not be expressed on the erythroblasts.
Microscopic Examanination:
- Erythroblasts may have vacuolization in the cytoplasm surrounding the nucleus (pearl necklace).
Immunohistochemistry
Leukemic cells are positive for myeloid markers such as:
- CD117
- CD13
- CD33
- Myeloperoxidase (MPO)
Megakaryocytes antigens can be positive in some cases of erythroleukemia, such as:
- CD41
- CD61

# Causes
Erythroleukemia may be caused by translocation t(1;16) generating the fusion gene NFIA/CBFA2T3.

# Differentiating Erythroleukemia from Other Diseases
- Erythroleukemia must be differentiated from MDS with erythroid predominance, other types of AML with increased erythroid precursors, AML with myelodysplasia-related changes.
- Non-neoplastic disorders that can cause erythroid predominance in the bone marrow such as megaloblastic anemia due to vitamin B12 or folate deficiency, heavy metal intoxication such as arsenic, drug effects (such as antineoplastic agents or chloramphenicol) are other differential diagnoses.

# Epidemiology and Demographics
- The incidence of erythroleukemia is approximately 0.077 per 100,000 individuals worldwide.
- Erythroleukemia commonly affects individuals older than 50 years of age with a median age of 65.
- There is no racial predilection to erythroleukemia.
- Men are more commonly affected by erythroleukemia than women. The male to female ratio is approximately 2 to 1.

# Risk Factors
- There are no established risk factors for de novo cases of erythroleukemia.
- The most potent risk factor in the development of secondary erythroleukemia is previous myelodysplastic syndrome (MDS).
- Other risk factors include:
- Ionizing radiation such as Thorium dioxide suspension (Thorotrast)
Previous use of chemotherapy drugs such as alkylating agents
Familial erythroleukemia, autosomal dominant disorder
- Ionizing radiation such as Thorium dioxide suspension (Thorotrast)
- Previous use of chemotherapy drugs such as alkylating agents
- Familial erythroleukemia, autosomal dominant disorder

# Screening
There is insufficient evidence to recommend routine screening for erythroleukemia.

# Natural History, Complications, and Prognosis
- If left untreated, patients with erythroleukemia may progress to develop bleeding due to disseminated intravascular coagulation (DIC).
- Common complications of erythroleukemia include infection and bleeding. Therapy related complications are rash, cardiomyopathy and cerebellar toxicity.
- Prognosis is generally poor.
- Median survival ranges from 3 - 9 months after the initial diagnosis.
- A high proerythroblast/myeloblast ratio correlates with worse outcome.

# Diagnosis

## Diagnostic Study of Choice
The diagnosis of erythroleukemia is based on the 2016 version of WHO classification for AML:
- AML (erythroid/myeloid type): 20% or more blasts in the bone marrow irrespective of the number of erythroid precursors
- Pure erythroid leukemia: Erythroblasts, at the stage of pronormoblast, more than 80% of the marrow cells in patients without exposure to cytotoxic agent and without AML genetic abnormalities. Erythroblasts may have vacuolization in the cytoplasm surrounding the nucleus (pearl necklace).

## History and Symptoms
- Fatigue
- Malaise
- Bone pain
- Abdominal pain
- Weight loss
- Easy bruising
- Fever
- Dyspnea
Less common symptoms of erythroleukemia include diffuse joint pain.

## Physical Examination
Patients with erythroleukemia usually appear anemic. Physical examination of patients with erythroleukemia may include:
- Ecchymoses or petechiae
- Hepatomegaly
- Splenomegaly
- Lymphadenopathy
- Headache

## Laboratory Findings
- Pancytopenia
- Few peripheral blood blasts
- Dysplasia in bone marrow and peripheral blood
- Dysplastic PAS positive erythroblasts with overexpression of the multidrug resistance (MDR) gene product P-glycoprotein
- High frequency of mutations, especially of TP53

## Electrocardiogram
- Electrocardiogram is useful for the assessment of QT interval prior to starting chemotherapy.
- It is also useful for assessing arrhythmias induced by anthracycline chemotherapy.
- For more information, click here.

## X-ray
- An x-ray may be helpful in the diagnosis of complications of erythroleukemia management which include infection, volume overload.
- Chest x-ray is also useful for venous catheter placement for chemotherapy.

## Echocardiography or Ultrasound
- An echocardiogram is helpful for assessing cardiac function (ejection fraction) in patients with acute myeloid leukemia before and after receiving anthracycline chemotherapy. 
- An ultrasound is useful for the diagnosis of lower extremity thrombosis, which commonly occurs in patients with acute myeloid leukemia.

## CT scan
- Abdominal and chest CT scan may be helpful in the diagnosis of acute myeloid leukemia.
- Findings on CT scan suggestive of acute myeloid leukemia include lymphadenopathy, hepatomegaly, splenomegaly and pulmonary embolism because of deep venous thrombosis.
- Non contrast brain CT scan is useful to rule out CNS bleed.

## MRI
Brain MRI is helpful in the diagnosis of CNS bleeding in acute myeloid leukemia (AML).

## Other Imaging Findings
There are no other imaging findings associated with erythroleukemia.

## Other Diagnostic Studies
- The myeloid blasts are often postive for myeloid marker such as CD117, CD13, CD33 and MPO.
- The erythroblasts lack myeloid antigens. They are postive for glycophorin A.
- Loss of all or part of the long arm (q) of chromosomes 5 and/or 7. 

# Treatment

## Medical Therapy
- Pharmacologic medical therapy is recommended for patients with erythroleukemia who are not candidates for intensive chemotherapy or allogenic hematopoietic stem cell transplantation.
- Pharmacologic medical therapies for erythroleukemia include hypomethylating agents (HMA) such as:
- Azacitidine
Decitabine
- Azacitidine
- Decitabine
For more information about acute myeloid leukemia (AML) medical therapy, click here.

## Surgery
- Allo-SCT (Allogenic hematopoietic stem cell transplantation)

## Primary Prevention
There are no established measures for the primary prevention of erythroleukemia.

## Secondary Prevention
Effective measures for the secondary prevention of erythroleukemia include maintenance of remission treatment post-transplant.