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 on the basis of morphologic and cytochemical criteria.[1]
Pathophysiology
Erythroleukemia is a neoplastic proliferation of erythroid and myeloid precursors of bone marrow hematopoietic stem cells. On rare occasions, however, a pure erythroid proliferation may occur.
Etiology
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:
- 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 disease, 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.
Epidemiology
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.[1, 2] Although very rare in children, M6 AML has been reported in children from the newborn period through age 7 years. Occurrence has a slight male predominance. No racial predilection is known.
Prognosis
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[3] :
- 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.
In a study of 91 patients with newly diagnosed erythroleukemia, Santos et al compared the disease’s prognosis with that of patients in a control group suffering from other subtypes of AML.[3] A history of the predisposing factor MDS 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, the report’s 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.
Remission can be achieved in many patients when treated with the standard myeloid protocol (ie, cytarabine [cytosine arabinoside; ara-C] with 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.[4]
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.[2]
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. 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 newly assigned World Health Organization (WHO) categories fail to capture the distinct features of PEL; the phenotype of PEL correlates with a very complex karyotype and an extremely aggressive clinical course. Among 18 patients with PEL, median survival was only 3 months (range 1-7 mo).[5]
Patient Education
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.
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].
Santos FP, Faderl S, Garcia-Manero G, Koller C, Beran M, O'Brien S, et al. Adult acute erythroleukemia: an analysis of 91 patients treated at a single institution. Leukemia. Sep 10 2009;[Medline].
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].
Liu W, Hasserjian RP, Hu Y, Zhang L, Miranda RN, Medeiros LJ, et al. Pure erythroid leukemia: a reassessment of the entity using the 2008 World Health Organization classification. Mod Pathol. Mar 2011;24(3):375-83. [Medline].
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].
Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Geneva, Switzerland: WHO Press; 2008.
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].
McHayleh W, Sehgal R, Redner RL, Raptis A, Agha M, Natale J, et al. Mitoxantrone and etoposide in patients with newly diagnosed acute myeloid leukemia with persistent leukemia after a course of therapy with cytarabine and idarubicin. Leuk Lymphoma. Oct 8 2009;[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].
Wiernik PH, Banks PL, Case DC Jr, et al. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. Jan 15 1992;79(2):313-9. [Medline].
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