| Patient Education |
|
Click here for patient education.
|
|
You are in: eMedicine Specialties >
Hematology > Stem Cells and Disorders
Erythroleukemia
Article Last Updated: Jul 18, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Beata Holkova, MD, Oncology Fellow, NIH/NCI, National Cancer Institute
Beata Holkova is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, and American Society of Hematology
Coauthor(s):
Kenichi Takeshita, MD, Adjunct Associate Professor, Department of Medicine, Division of Hematology, New York University School of Medicine; Medical Director, Clinical Research and Development, Celgene;
Asher A Chanan-Khan, MD, Assistant Professor, Department of Medicine, Division of Lymphoma and Bone Marrow Transplantation, Roswell Park Cancer Institute, State University of New York at Buffalo
Editors: David Aboulafia, MD, Medical Director, Bailey-Boushay House; Clinical Professor, Department of Medicine, Division of Hematology, University of Washington; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Troy H Guthrie, Jr, MD, Director of Cancer Institute, Baptist Medical Center; Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems; Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Author and Editor Disclosure
Synonyms and related keywords:
erythroleukemia, Di Guglielmo disease, Di Guglielmo syndrome, acute myelogenous leukemia, AML, neoplastic proliferation, erythroid precursor, myeloid precursor, M6 AML
Background
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 acute myelogenous leukemia (AML) in the French-American-British (FAB) classification system based on morphologic and cytochemical criteria.
Pathophysiology
Erythroleukemia is a neoplastic proliferation of erythroid and myeloid precursors of bone marrow hematopoietic stem cells, even though a pure erythroid proliferation may occur on rare occasions.
Frequency
United States
Acute erythroleukemia accounts for 3-5% of all de novo AMLs and 20-30% of secondary leukemias. It is very rare in children.
Race
No racial predilection is known.
Sex
Occurrence has a slight male predominance.
Age
The incidence of erythroleukemia increases in people older than 50 years. Mazzella et al (2000) described 2 peaks, one in the seventh decade of life and a second, smaller peak in the fourth decade of life. Although rare in children, M6 AML has been reported in children from the newborn period through age 7 years.
History
Upon presentation, signs and symptoms of erythroleukemia are usually nonspecific and result from decreased hematopoiesis from the replacement of bone marrow by leukemic cells. This results in anemia, thrombocytopenia, and leukopenia. 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 CNS is present)
- Diffuse joint pain (nonspecific in one third of patients)
Physical
- Pallor (anemia)
- Hemorrhage (thrombocytopenia)
- Ecchymoses or petechiae
- Gum bleeding
- Epistaxis
- Retinal hemorrhage
- Fever and infection (neutropenia): Common sites include the respiratory tract, urinary tract, sinuses, perirectal area, and skin.
- Hepatosplenomegaly (<25% cases)
- Lymphadenopathy
Causes
De novo cases have no identifiable risk factors. The most common predisposing factors in secondary acute erythroleukemia are as follows:
- Myelodysplastic syndrome (MDS) is a predisposing factor.
- Ionizing radiation: Thorotrast, a radiographic contrast medium used in the 1940s, is associated with increased risk of erythroleukemia (latent period of 10-30 y after exposure).
- Prior chemotherapy, such as with alkylating agents, is a predisposing factor. These agents may be used in the treatment of Hodgkin disease, multiple myeloma, bone marrow transplant, ovarian and breast cancer, and nonneoplastic disorders (eg, collagen vascular disease).
- Rare cases of familial erythroleukemia (autosomal dominant with variable penetrance) have been described, which manifest in the sixth decade of life.
Acute Lymphoblastic Leukemia
Acute Myelogenous Leukemia
Myelodysplastic Syndrome
Pernicious Anemia
Other Problems to be Considered
Erythropoietin therapy (may induce increased erythroblasts in bone marrow and, in some situations, may complicate the interpretation of bone marrow morphology)
Lab Studies
- Complete blood cell count
- Most patients present with pancytopenia.
- The WBC count can range from 1000-100,000/mm3.
- Anemia may be mild.
- Peripheral blood smear: Findings may vary and include blasts (may not be present in as many as 50% of cases), macrocytosis, nucleated erythrocytes, schistocytes, and thrombocytopenia.
- Obtain a chemistry profile, liver function tests, and serum electrolytes to assess organ dysfunction resulting from leukemic infiltration. Elevated lactate dehydrogenase (LDH) and uric acid levels may be present.
- Blood and urine cultures should be obtained in patients with fever or signs of infection.
- Rheumatoid factor, antinuclear antibody, Coombs test, and immunoglobulins should be evaluated. Autoantibodies and hypergammaglobulinemia have been reported in patients with erythroleukemia who have joint or bone pain.
- Vitamin B-12 and folate levels should be measured because severe pernicious anemia sometimes mimics acute erythroleukemia.
- For details of the bone marrow examination, see Procedures.
- Flow cytometry
- As a result of the multilineage nature of erythroleukemia, the leukemic cells often express both erythroid and myeloid markers. They are often positive for myeloid markers, such as CD117, CD13, CD33, and MOP, while 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, while the expression of glycophorin A and/or transferrin receptor may be helpful, the absence of erythroid antigens does not exclude erythroleukemia.
- Cytogenetics
- 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 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), or more than 2 cytogenetic abnormalities.
- Prognosis is intermediate with normal karyotype and all other cytogenetic abnormalities.
Imaging Studies
- Echocardiogram or multiple-gated acquisition (MUGA) scan is used to evaluate cardiac function prior to chemotherapy (chemotherapy regimens contain cardiotoxic drugs).
- Normal findings on chest radiograph help exclude potentially complicating factors such as pulmonary infection, cardiomegaly, pulmonary vascular congestion, or pleural effusion.
- Noncontrast CT scan of the head can be used to rule out CNS bleed.
- Perform a CT scan or MRI if neurologic signs are present (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.
Other Tests
- P-glycoprotein (product of MDR1 gene)
- This test should be considered in patients who do not respond to induction chemotherapy.
- P-glycoprotein (Pgp) can be measured by (1) immunohistochemistry (low sensitivity) or (2) flow cytometry with MRK16 or U1C1 antibodies (specific).
Procedures
- 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. This classification does not include cytogenetics. Erythroleukemia is required to have both erythroblastic and myeloblastic components. The assessment of a bone marrow specimen is based on a 500-cell count.
- 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.
- The World Health Organization (WHO) proposed a new subclassification that recognizes 2 subtypes of acute erythroid leukemia:
- Erythroleukemia is 50% or more erythroid precursors in the nucleated cells population and 20% or more nonerythroid elements (ie, myeloblasts I, myeloblasts II, monoblasts).
- In pure erythroid leukemia, the erythroid component seems to be singularly involved. The erythroid component is 80% or more of bone marrow. The myeloblast count is usually less than 30%, and distinguishing the myeloblasts from primitive erythroblasts is difficult. For this reason, Auer rods are never observed in this subtype.
- 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 prior to treatment.
- 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.
- Lumbar puncture
- 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. 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 of higher than 50,000/mm3 or an elevated LDH level.
Histologic Findings
See FAB classification, flow cytometry, and cytogenetics under Procedures.
Medical Care
The approach to the treatment of acute erythroleukemia is similar to the approach used for other subtypes of AML, as described in Acute Myelogenous Leukemia.
- Problems in acute erythroleukemia include primary induction failure, relapse, and the toxicity of chemotherapeutic agents.
- Remission can be achieved in many patients when treated with the standard myeloid protocol (ie, cytosine arabinoside [araC] with anthracycline). Kowal-Vern et al (2000) reported that subtypes characteristic with predominance of proerythroblasts are not targeted by conventional AML protocols and that might relate to the poor outcome observed in these patients.
- 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.
- 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.
Surgical Care
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.
Diet
In a neutropenic diet, fruits and vegetables should be cooked or peeled.
Activity
- 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 IM injections while thrombocytopenic.
- Patients should avoid strenuous physical activity.
- Patients should avoid potted plants and flowers.
The management of AML (including the M6 subtype) usually constitutes induction chemotherapy and postinduction chemotherapy. Cytarabine (Ara-C) 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 and 3 regimen: Ara-C at 100 mg/m2/d IV continuous infusion (CI) on days 1-7 plus anthracycline (idarubicin or daunorubicin) or anthracenedione (mitoxantrone) at 45-60 mg/m2 IV push on days 1-3.
The regimen for postinduction therapy includes 2 options. The high-dose Ara-C (HiDAC) regimen includes Ara-C at 3 g/m2 IV q12h on days 1, 3, and 5. The 5 and 2 regimen includes Ara-C at 100 mg/m2/d IV CI on days 1-5 plus daunorubicin at 45 mg/m2 IV on days 1 and 2.
A bone marrow biopsy should be performed 14-21 days after induction therapy to assess remission status. If persistent blasts are noted, a second course (with dose-reduced 5 and 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.
Drug Category: Antineoplastic agents
Acute erythroleukemia is treated with the same chemotherapeutic regimens as other AMLs, except the M3 variety (acute promyelocytic leukemia). Preferably, all patients should be treated in a tertiary referral center.
| Drug Name | Cytarabine (Cytosar-U) |
|---|
| Description | Cell cycle S phase specific. Blocks the progression from G1 to S phase. Converted intracellularly to active compound cytarabine-5'-triphosphate, which inhibits DNA polymerase. |
|---|
| Adult Dose | 100 mg/m2/d IV for 7 d; alternatively, 3 g/m2 IV q12h on days 1, 3, and 5 |
|---|
| Pediatric Dose | 100-200 mg/m2/d IV for 5-10 d or qd until remission |
|---|
| Contraindications | Documented hypersensitivity |
|---|
| Interactions | Decreases effects of gentamicin and flucytosine; other alkylating agents and radiation increase toxicity; decreases digoxin levels |
|---|
| Pregnancy | D - Unsafe in pregnancy
|
|---|
| Precautions | If significant increase in bone marrow suppression is observed, reduce the number of treatments administered per d; patients with hepatic or renal insufficiencies are at higher risk for CNS toxicity after high-dose therapy (reduce dose) |
|---|
| Drug Name | Daunorubicin (Cerubidine) |
|---|
| Description | Anthracycline antibiotic. Binds to nucleic acids by intercalation between base pairs of DNA, interfering with DNA synthesis. Causes inhibition of DNA topoisomerase II. |
|---|
| Adult Dose | 45-60 mg/m2/d IV 15-30 min infusion for 3 d |
|---|
| Pediatric Dose | 35-45 mg/m2/d IV for 3 d |
|---|
| Contraindications | Documented hypersensitivity; congestive heart failure, arrhythmias, cardiopathy |
|---|
| Interactions | None reported |
|---|
| Pregnancy | D - Unsafe in pregnancy
|
|---|
| Precautions | Extravasation may occur, resulting in severe tissue necrosis; caution in patients with impaired hepatic, renal, or biliary function; assessment of venous patency should be established before infusion; increased incidence of drug-related congestive heart failure in adults at or above total cumulative dose of 550 mg/m2 (monitor cardiac function) |
|---|
| Drug Name | Idarubicin (Idamycin) |
|---|
| Description | Inhibits cell proliferation by inhibiting DNA and RNA polymerase. |
|---|
| Adult Dose | 12 mg/m2 IV qd for 3 d |
|---|
| Pediatric Dose | Not established |
|---|
| Contraindications | Documented hypersensitivity |
|---|
| Interactions | None reported |
|---|
| Pregnancy | D - Unsafe in pregnancy
|
|---|
| Precautions | Extravasation can result in severe tissue necrosis; caution in patients with preexisting cardiac disease and impaired hepatic function |
|---|
| Drug Name | Mitoxantrone (Novantrone) |
|---|
| Description | Inhibits cell proliferation by intercalating DNA and inhibiting topoisomerase II. |
|---|
| Adult Dose | 12 mg/m2 IV push for 3 d |
|---|
| Pediatric Dose | Not established |
|---|
| Contraindications | Documented hypersensitivity |
|---|
| Interactions | None reported |
|---|
| Pregnancy | D - Unsafe in pregnancy
|
|---|
| Precautions | Caution in patients with impaired hepatic function and preexisting cardiac disease (cardiotoxicity is common after cumulative dose of 120-160 mg/m2); perform baseline and follow-up cardiac function tests (2-dimensional echocardiogram and ejection fraction measurements) |
|---|
Further Inpatient Care
- Admit the patient for induction chemotherapy.
- Admit the patient for febrile neutropenia or any grade III or IV chemotherapy-related toxicity.
Further Outpatient Care
- 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.
Deterrence/Prevention
- During chemotherapy, patients should avoid crowded public places and avoid contact with people with infectious diseases.
Complications
- Opportunistic infections and neutropenic fever: Infections, even if properly treated, may be fatal.
- Tumor lysis syndrome (ie, hyperuricemia, hyperkalemia, hyperphosphatemia)
- Recognizing patients who are at risk (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.
- Bleeding
- Patients who have received multiple platelet transfusions may become refractory.
- To reduce alloimmunization, single-donor platelets or HLA-matched platelets with leukocyte reduction filters should be used.
Prognosis
- Prognosis in patients with acute erythroleukemia is poor. Many factors influence patients' responses to chemotherapy and their duration of remission.
- Cytogenetics affects prognosis, as described in Procedures.
- Multidrug resistant phenotype (positive Pgp expression) is associated with poor prognosis.
- Determining the myeloblast-to-erythroblast ratio at diagnosis helps predict prognosis; a higher ratio is associated with favorable prognosis.
Patient Education
- Patients should be educated about the signs of febrile neutropenia and thrombocytopenia.
Medical/Legal Pitfalls
- Failure to clearly explain the long-term adverse effects of chemotherapeutic agents
- Failure to clearly present and discuss issues related to chemotherapy-associated infertility (eg, sperm banking)
- Failure to discuss procedure-related adverse effects and a failure to obtain informed consent
Special Concerns
- Perform a pregnancy test in young females.
- Patients with poor cardiac function may be at increased risk of cardiotoxicity with anthracycline-based chemotherapy regimens.
| Media file 1:
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. |
 |  View Full Size Image | |
Media type: Photo
|
- Bennett JM, Catovsky D, Daniel MT, et al. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French-American-British Cooperative Group. Ann Intern Med. Oct 1985;103(4):620-5. [Medline].
- Cuneo A, Van Orshoven A, Michaux JL, et al. Morphologic, immunologic and cytogenetic studies in erythroleukaemia: evidence for multilineage involvement and identification of two distinct cytogenetic-clinicopathological types. Br J Haematol. Jul 1990;75(3):346-54. [Medline].
- Gozzi TG, Harris NP, McGown IN, et al. Autopsy diagnosis of 21-hydroxylase deficiency CAH in a case of apparent SIDS. Pediatr Dev Pathol. May-Jun 2005;8(3):397-401.
- Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol. Dec 1999;17(12):3835-49. [Medline].
- Jaffe ES, Harris NL, Stein H, Vardiman JW, eds. Acute myeloid leukaemia not otherwise categorised. In: WHO Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon;2001:91-105.
- Kowal-Vern A, Mazzella FM, Cotelingam JD, et al. Diagnosis and characterization of acute erythroleukemia subsets by determining the percentages of myeloblasts and proerythroblasts in 69 cases. Am J Hematol. Sep 2000;65(1):5-13. [Medline].
- Leith CP, Kopecky KJ, Godwin J, et al. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood. May 1 1997;89(9):3323-9. [Medline].
- Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B. N Engl J Med. Oct 6 1994;331(14):896-903. [Medline].
- Mazzella FM, Alvares C, Kowal-Vern A, Schumacher HR. The acute erythroleukemias. Clin Lab Med. Mar 2000;20(1):119-37. [Medline].
- Mazzella FM, Kowal-Vern A, Shrit MA, et al. Effects of multidrug resistance gene expression in acute erythroleukemia. Mod Pathol. Apr 2000;13(4):407-13. [Medline].
- Mazzella FM, Kowal-Vern A, Shrit MA, et al. Acute erythroleukemia: evaluation of 48 cases with reference to classification, cell proliferation, cytogenetics, and prognosis. Am J Clin Pathol. Nov 1998;110(5):590-8. [Medline].
- Mehta J, Powles R, Treleaven J, et al. Long-term follow-up of patients undergoing allogeneic bone marrow transplantation for acute myeloid leukemia in first complete remission after cyclophosphamide-total body irradiation and cyclosporine. Bone Marrow Transplant. Oct 1996;18(4):741-6. [Medline].
- Sonneveld P. Multidrug resistance in haematological malignancies. J Intern Med. May 2000;247(5):521-34. [Medline].
- Thomas ED, Buckner CD, Banaji M, et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood. Apr 1977;49(4):511-33.
- Vardiman J. Proposed WHO Classification of Neoplastic Diseases of Hematopoietic and Lymphoid Tissues (Acute Leukemias and Myeloid Disorders). Am J Surg Path. 1997;21:114-21.
- Willman CL. The prognostic significance of the expression and function of multidrug resistance transporter proteins in acute myeloid leukemia: studies of the Southwest Oncology Group Leukemia Research Program. Semin Hematol. Oct 1997;34(4 Suppl 5):25-33. [Medline].
Erythroleukemia excerpt Article Last Updated: Jul 18, 2006
|
