Erythroleukemia

Giovanni Di Guglielmo first described erythroleukemia in the early twentieth century, and the disorder is often still referred to as acute Di Guglielmo syndrome. It is classified as an M6 subtype of AML in the French-American-British (FAB) classification system on the basis of morphologic and cytochemical criteria.[2]

Acute erythroleukemia has traditionally been recognized as having two subtypes: the more common erythroid/myeloid subtype, defined by the presence of increased erythroid cells and myeloid blasts; and the very uncommon pure erythroid subtype, characterized by expansion of immature erythroid cells only.[3]  The 2016 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia continued to recognize pure erythroid leukemia but eliminated the erythroid/myeloid type of acute erythroleukemia. Cases previously classified as erythroid/myeloid subtype, based on the 2008 WHO classification, are currently categorized either as myelodysplastic syndrome with excess blasts or acute myeloid leukemia, not otherwise specified.[4]  

Erythroleukemia is a neoplastic proliferation of erythroid and myeloid precursors of bone marrow hematopoietic stem cells.[5]  In rare cases, however, a pure erythroid proliferation may occur. Erythroleukemia shares clinical and pathologic features with myelodysplastic syndromes, especially with erythroid-predominant myelodysplastic syndromes.[6]

The leukemic cells in erythroleukemia often carry complex karyotypes and mutations in oncogenes known to be associated with AML. However, on the basis of a study of the genetic and transcriptional landscape of 33 patients with acute erythroleukemia, Fagnan et al propose a transcriptome-based space that helps distinguish acute erythroleukemia from other myeloid leukemias.[7] These researchers describe a spectrum of genetic lesions that can be classified into three distinct molecular subgroups characterized by the following:

• TP53 mutations
• Mutations in epigenetic regulators (eg, DNMT3A, TET2, or IDH2), often accompanied by mutations in splicing factor genes
• Undefined cases with low mutational burden

Further work by Fagnan et al in an animal model found that aberrant expression of oncogenic driver transcription factors results in erythroleukemia by downregulating the GATA1-regulated erythroid epigenome. In vivo work showed that the outcomes of disease (erythroid, myeloid, or both) depend on the driving oncogene and the hematopoietic target cell in which it is aberrantly expressed.[7, 8]

Iacobucci et al studied the genomic features of 159 childhood and adult cases of acute erythroleukemia  and defined five age-related subgroups with distinct transcriptional profiles[9] :

• TP53 mutated (mostly in adults)
• NPM1 mutated
• KMT2A mutated/rearranged
• DDX41 mutated (adult)
• NUP98 rearranged (pediatric)

De novo cases of erythroleukemia are not associated with any identifiable risk factors. The most common predisposing factors in secondary acute erythroleukemia are as follows:

• Myelodysplastic syndrome ( MDS)
• Ionizing radiation - Thorium dioxide suspension (Thorotrast), a radiographic contrast medium used in the 1940s, is associated with increased risk of erythroleukemia (latent period of 10-30 y after exposure).
• Previous exposure to chemotherapy drugs (eg, alkylating agents) - These agents may be used in the treatment of Hodgkin lymphoma, multiple myeloma, bone marrow transplant, ovarian cancer, breast cancer, and nonneoplastic disorders (eg, collagen-vascular disease).
• Rare cases of familial erythroleukemia (autosomal dominant with variable penetrance), manifesting in the sixth decade of life.

Acute erythroleukemia accounts for 3-5% of all de novo AMLs and 20-30% of secondary leukemias. The incidence of erythroleukemia increases in people older than 50 years. Mazzella et al described 2 peaks, one in the seventh decade of life and a second, smaller peak in the fourth decade.[2, 10] Although very rare in children, acute erythroleukemia has been reported in children from the newborn period through age 7 years. Occurrence has a slight male predominance. No racial predilection is known.

Patients with acute erythroleukemia have a poor prognosis. Problems encountered in the treatment of acute erythroleukemia include primary induction failure, relapse, and the toxicity of chemotherapeutic agents.

Many factors influence patients’ responses to chemotherapy and their duration of remission, including the following[11] :

• Findings from cytogenetic evaluation affect the prognosis.
• No specific chromosome abnormalities are associated with this subtype.
• Multidrug resistant phenotype (positive Pgp expression) is associated with a poor prognosis.
• Determining the myeloblast-to-erythroblast ratio at diagnosis helps to predict prognosis; a higher ratio is associated with a favorable prognosis.

A study by Santos et al compared the prognosis in 91 patients with newly diagnosed erythroleukemia with that of patients in a control group suffering from other subtypes of AML.[11] A history of the predisposing factor myelodysplastic syndrome was present in 50% of the patients in the erythroleukemia group and 41% of the patients in the control group. Poor-risk cytogenetics were present in 61% of the erythroleukemia patients and 38% of the control patients. Complete remission rates were 62% in the erythroleukemia group and 58% in the control group. The median period of disease-free survival was 32 weeks for erythroleukemia patients and 49 weeks for control subjects. The median period of overall survival was 36 weeks for erythroleukemia patients and 43 weeks for control subjects.

After carrying out a multivariate analysis, these authors concluded that erythroleukemia is not an independent risk factor in disease-free and overall survival, and that well-known AML prognostic factors should guide treatment decisions.[11]

Remission can be achieved in many patients when treated with the standard myeloid protocol (ie, cytarabine [cytosine arabinoside; ara-C] with an anthracycline). Kowal-Vern et al reported that subtypes characterized by predominance of proerythroblasts are not targeted by conventional AML protocols and suggested that this might be related to the poor outcome observed in these patients.[12]

Multidrug resistance gene (ie, MDR1) expression correlates with unfavorable cytogenetic aberrations and is responsible for poor response to chemotherapy and short survival time. Patients with refractory or relapsed erythroleukemia may be tested for Pgp (ie, MDR1 product). MDR modulators (eg, cyclosporin A, quinidine, verapamil, PSC 833) are being used in a clinical trial setting to overcome this resistance.[10]

A less favorable outcome may be observed in elderly patients, in patients with secondary erythroleukemia (usually after treatment with alkylating agents), and in patients with unfavorable cytogenetics.

Furthermore, patients with the distinct entity of pure erythroid leukemia (PEL) may have an unusually poor prognosis. While the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias includes PEL under a broader category of acute myeloid leukemia with mutated TP53,[13]  the 2016 assigned World Health Organization (WHO) categories fail to capture the distinct features of PEL.[4]  

PEL is characterized as a neoplastic erythroid hyperproliferation with maturation arrest. E-cadherin is the most sensitive and specific marker for immature erythroblasts and is helpful in distinguishing PEL from other erythroid proliferations. The phenotype of PEL correlates with a very complex karyotype and an extremely aggressive clinical course. Median survival has been reported between 1.8 and 3 months with ranges of 0.2-9.3 months.[14, 15]

Iacobucci et al reported an association between genomic features and outcome in acute eyrthroleukemia, with NPM1 mutations and HOXB9 overexpression being associated with a favorable prognosis and TP53, FLT3 or RB1 alterations associated with poor survival. Patients with NPM1-mutated cases had a 5-year survival of 87.5 %, while those with TP53-mutated cases had median survival of 13 months, with no patients surviving at 5 years.[9]

Patients should be educated about the signs of febrile neutropenia and thrombocytopenia. The long-term adverse effects of chemotherapeutic agents must be clearly explained, and issues related to chemotherapy-associated infertility (eg, sperm banking) must be presented and discussed. Procedure-related adverse effects and failure to obtain informed consent should also be addressed.

For patient education information, see the Leukemia Directory.

At presentation, the signs and symptoms of erythroleukemia are usually nonspecific and are attributable to the decreased hematopoiesis resulting from the replacement of bone marrow by leukemic cells. This decrease results in anemia, thrombocytopenia, and leukopenia.[16]

Patients rarely present with symptoms lasting longer than 6 months, and they are usually diagnosed within 1-3 months after the onset of symptoms. The most common presenting symptoms are as follows:

• Fatigue or malaise
• Minimal-to-modest weight loss
• Easy bruising
• Fever
• Bone or abdominal pain
• Dyspnea
• Meningeal signs and symptoms (very rare, only if leukemic involvement of the central nervous system [CNS] is present)
• Diffuse joint pain (nonspecific in one third of patients)

Physical examination findings may include the following:

• Pallor (anemia)
• Hemorrhage (thrombocytopenia) - Ecchymoses or petechiae; gum bleeding; epistaxis; retinal hemorrhage
• Fever and infection (neutropenia) - Respiratory tract, urinary tract, sinuses, perirectal area, or skin
• Hepatosplenomegaly (< 25% of cases)
• Lymphadenopathy

Complications may include opportunistic infections and neutropenic fever, tumor lysis syndrome (ie, hyperuricemia, hyperkalemia, hyperphosphatemia), and bleeding.

Infections, even if properly treated, may be fatal. Recognizing patients who are at risk for tumor lysis syndrome (high tumor burden, elevated uric acid) is important. Intravenous hydration and allopurinol should be started before chemotherapy, and serum electrolytes and renal function should be monitored. Patients who have received multiple platelet transfusions may become refractory. To reduce alloimmunization, single-donor platelets or human leukocyte antigen (HLA)-matched platelets with leukocyte reduction filters should be used.

Workup for erythroleukemia includes blood studies, bone marrow aspiration and biopsy (the definitive diagnostic tests), analysis of genetic abnormalities, and diagnostic imaging.

Findings on blood studies include the following: 

• Complete blood count – Most patients present with pancytopenia. The white blood cell (WBC) count can range from 1000 to 100,000/µL. Anemia may be mild.
• Peripheral blood smear – Findings may vary and include blasts (though these may not be present in as many as 50% of cases), macrocytosis, nucleated erythrocytes, schistocytes, and thrombocytopenia.
• Chemistry profile, liver function tests, and serum electrolytes – Abnormal findings may reflect organ dysfunction resulting from leukemic infiltration. Elevated lactate dehydrogenase (LDH) and uric acid levels may be present.
• Blood cultures – Blood cultures should be obtained in patients with fever or signs of infection.
• Rheumatoid factor, antinuclear antibody, Coombs test, and immunoglobulins – Autoantibodies and hypergammaglobulinemia have been reported in patients with erythroleukemia who have joint or bone pain.
• Vitamin B12 and folate – Severe pernicious anemia sometimes mimics acute erythroleukemia.

Bone marrow aspiration and biopsy are critical in making the diagnosis of acute erythroleukemia. Bone marrow smears from aspirate and touch preparations from biopsy should be stained with Wright-Giemsa and other histochemical stains.

The FAB classification used since 1985 is based on cell morphology to identify the lineage of the blasts, the degree of differentiation, the number of blasts (quantification), and cytochemistry.[17] This classification does not include cytogenetics. Erythroleukemia is required to have both erythroblastic and myeloblastic components (see the image below). The assessment of a bone marrow specimen is based on a 500-cell count.

Bone marrow aspirate showing erythroblasts in a patient with erythroleukemia. Courtesy of Maurice Barcos, MD, PhD, Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY.

FAB criteria require (1) a 50% or more erythroid component in all nucleated cells and (2) at least one of the following: 30% or more nonerythroid blasts, excluding erythroblasts, or less than 30% blasts in all nucleated cells. Nonerythroid blast cells are blast I (ie, myeloblast with no cytoplasmic granules, distinct nucleoli) or blast II (ie, granules, centrally placed nucleus) and monoblast.

Under the 2016 WHO classification, a diagnosis of pure erythroid leukemia requires the following[4, 18] :

• >80% immature erythroid precursors with ≥30% proerythroblasts
• < 20% myeloblasts
• No prior therapy
• No WHO genetic abnormality present

Severe pernicious anemia manifesting with pancytopenia can occasionally mimic erythroleukemia on bone marrow morphology. In such instances, waiting for the results of a complete workup, including cytogenetics and flow cytometry, before initiating treatment is recommended. B-12 and folate levels should similarly be reviewed before treatment.

As a result of the multilineage nature of erythroleukemia,[19] the leukemic cells often express both erythroid and myeloid markers. They are often positive for myeloid markers, such as CD117, CD13, CD33, and MOP, whereas the expression of HLA-DR and CD34 is often decreased or absent. The megakaryocytes antigens CD41 and CD61 can be positive in some cases.

Erythroid markers such as glycophorin A and transferrin receptor (CD71 and CD45) may be increased, but they are negative in many patients with erythroleukemia. Therefore, whereas the expression of glycophorin A and/or transferrin receptor may be helpful, the absence of erythroid antigens does not exclude erythroleukemia.

The assessment of chromosomal abnormalities in patients with erythroleukemia is critical in the diagnosis and prognosis of disease. Multiple chromosomal abnormalities have been described, but none of them is specific for M6 acute myelogenous leukemia (AML).

Results from many studies demonstrate that certain chromosomal abnormalities are associated with different prognoses in all AMLs, including acute erythroleukemia, as follows:

• Prognosis is favorable with t(8;21), inv16/t(16;16), and +14.
• Prognosis is unfavorable with -5/5q, -7/7q-, inv3, 11q, 17p, del20q, +13, t(9;22), FT3 or more than 2 cytogenetic abnormalities.
• Prognosis is intermediate with normal karyotype and all other cytogenetic abnormalities.
• CEBPA associates with longer remission duration
• NPM associates with increased response to chemotherapy

Echocardiography or multiple-gated acquisition (MUGA) scanning is used to evaluate cardiac function before chemotherapy. Chemotherapy regimens contain cardiotoxic drugs.

Chest radiography may be helpful. Normal findings help exclude potentially complicating factors such as pulmonary infection, cardiomegaly, pulmonary vascular congestion, or pleural effusion.

Noncontrast computed tomography (CT) scanning of the head can be used to rule out central nervous system (CNS) bleed. Perform a CT scan or magnetic resonance imaging (MRI) if neurologic signs are present (the fifth and seventh cranial nerves are most commonly involved). The affected cranial nerve may show thickening of the nerve sheath. This can occur even in the absence of CNS involvement.

P-glycoprotein (Pgp) is a product of the MDR1 gene. It can be measured by means of either (1) immunohistochemistry (low sensitivity) or (2) flow cytometry with MRK16 or U1C1 antibodies (specific). This test should be considered in patients who do not respond to induction chemotherapy.

Lumbar puncture (LP) is performed if CNS or meningeal signs are present. LP usually reveals an elevated opening pressure, increased protein, and a low glucose level in the cerebrospinal fluid (CSF). If circulating blasts are present at the time of LP, intrathecal chemotherapy should be administered. LP is also suggested for patients who are asymptomatic but have circulating leukemic cell counts higher than 50,000/µL or an elevated LDH level.

Periodic acid-Schiff (PAS) stain findings are usually positive in erythroblasts and abnormal erythroid precursors and negative in normal erythroid precursors of all stages of maturation.

A pregnancy test should be performed in young females. Fertility counseling should be considered for both male and females.

Urine cultures should be obtained in patients with fever or signs of infection.

The approach to the treatment of acute erythroleukemia is similar to the approach used for other subtypes of acute myelogenous leukemia (AML) (see Acute Myelogenous Leukemia).

Admit the patient for induction chemotherapy. Admit the patient for febrile neutropenia or any grade III or IV chemotherapy-related toxicity. Patients with poor cardiac function may be at increased risk of cardiotoxicity with anthracycline-based chemotherapy regimens.

Placement of an indwelling central venous catheter and/or port for chemotherapy infusion is usually recommended. This access can also be used to draw blood samples for periodic analysis.

The management of AML (including the M6 subtype) usually constitutes induction chemotherapy and postinduction/consolidation chemotherapy. Cytarabine is the most active agent in the management of AML; therefore, various regimens are designed around this agent.

The regimen for induction therapy is the “7 + 3” regimen: Cytarabine at 100 mg/m2/d intravenously (IV) by continuous infusion on days 1-7 plus an anthracycline (idarubicin 12 mg/m2 or commonly used daunorubicin 45-60 mg/ m2) or anthracenedione (mitoxantrone 12 mg/ m2) ( IV) push on days 1-3.[20, 21]

The regimen for consolidation therapy includes 2 options. The high-dose ara-C (HiDAC) regimen includes cytarabine at 3 g/m2 IV q12h on days 1, 3, and 5 for 4 cycles.[22] The “5+2” regimen includes cytarabine at 100 mg/m2/d IV continuously infused on days 1-5 plus daunorubicin at 45 mg/m2 IV on days 1 and 2 for a total of 2 cycles.[23]

A bone marrow biopsy should be performed 14 days after induction therapy to assess remission status. If persistent blasts are noted, a second course (with dose-reduced “5 +2” regimen) is recommended. If marrow is hypoplastic, the second course is delayed until the bone marrow is recovered enough to clearly distinguish the type of recovery (ie, leukemic versus normal).

If the recovering marrow appears to have many immature cells, a wait-and-watch strategy is reasonable for as long as a week. Then, a repeat marrow biopsy is performed to clearly distinguish between relapse and remission.

Patients in whom 2 cycles fail are deemed primary refractory and should be considered for experimental therapeutic approaches.

Supportive care during chemotherapy treatment includes antiemetic prophylaxis, antiviral prophylaxis in herpes simplex – negative patients, and transfusion support.

Less-intensive chemotherapy

Given the poor prognosis for older adults with acute erythroleukemia, the impact of treatment intensity on quality of life should be given consideration. The benefits of less-intensive chemotherapy regimens include fewer adverse events and outpatient administration with less frequent hospitalization.[24]

The American Society of Hematology (ASH) recommends less-intensive therapy with hypomethylating agents (azacitidine and decitabine) for older adults with adverse disease biology, including complex karyotype, history of myelodysplastic syndromes, and TP53 mutations.[25]

Patients should be on a neutropenic diet. All fruits and vegetables should be cooked or peeled.

During the neutropenic phase, all visitors and personnel should wash their hands before entering the patient’s room.

In patients with thrombocytopenia, pay special attention to oral hygiene, with frequent rinsing and brushing of teeth only with a disposable oral swab. Such patients should avoid nonsteroidal anti-inflammatory agents and other medications that can inhibit platelet function. Make sure that these patients do not receive intramuscular injections while thrombocytopenic.

Patients should refrain from strenuous physical activity and should avoid potted plants and flowers. During chemotherapy, they should stay away from crowded public places and avoid contact with people with infectious diseases.

Patients in remission should be examined periodically by their physicians to evaluate their state of health, blood cell counts, and bone marrow, if necessary. The interval between visits may be lengthened, but monitoring should continue indefinitely.

Acute erythroleukemia is treated with the same chemotherapeutic regimens as other acute myelogenous leukemias (AMLs), except the M3 variety (acute promyelocytic leukemia [APL]). Preferably, all patients should be treated in a tertiary referral center.

Class Summary

Antineoplastic agents are used for induction or consolidation therapy. They include cytarabine, daunorubicin, idarubicin, and mitoxantrone.

Cytarabine

Cytarabine is cell cycle S phase specific. It blocks the progression from G1 to S phase. It is converted intracellularly to the active compound cytarabine-5'-triphosphate, which inhibits DNA polymerase.

Daunorubicin (Cerubidine)

Daunorubicin is an anthracycline antibiotic. It binds to nucleic acids by intercalation between base pairs of DNA, interfering with DNA synthesis. It causes inhibition of DNA topoisomerase II.

Idarubicin (Idamycin PFS)

Idarubicin inhibits cell proliferation by inhibiting DNA and RNA polymerase.

Mitoxantrone (Novantrone)

Idarubicin inhibits cell proliferation by inhibiting DNA and RNA polymerase.