Acute erythroleukemia (AEL): Description, Causes and Risk Factors:
AEL is a rare form acute myeloid leukemia (AML)
, comprising less than 5% of cases of adult AML. The definition of AEL has undergone several revisions. Originally designated as M6 in the 1976 French-American-British (FAB) classification, its definition was refined in 1985 as an acute leukemia in which erythroid cells comprised at least 50% of all cells, and myeloblasts comprised at least 30% of the non-erythroid cells. In the 2001 World Health Organization (WHO) classification, the required blast count for all types of AML was lowered from 30% to 20%, which lowered the blast count defining AEL to 20% of the non-erythroid cells. In addition, a rare subcategory of Acute erythroleukemia in which the neoplastic blasts were erythroid (so-called pure erythroid leukemia) was recognized. In the recent 2008 WHO classification of AML, the category of AML with myelodysplasia-related changes (AML-MRC) was proposed. This category includes all cases with blasts comprising 20% or more of all bone marrow cells and the presence of either morphologic evidence of significant multilineage dysplasia, specific myelodysplastic syndrome (MDS)-related cytogenetic abnormalities, or a history of MDS or a myelodysplastic/myeloproliferative neoplasm (MDS/MPN), irrespective of the presence of erythroid hyperplasia. According to this classification scheme, AEL cases with blasts comprising 20% or more of all bone marrow cells and fulfilling these criteria are classified as AML-MRC, whereas cases with blasts comprising less than 20% of all cells but 20% or more of the nonerythroid cells are classified as acute erythroleukemia. Moreover, if bone marrow blasts comprise less than 20% of nonerythroid cells, the case is then classified as MDS, not AEL. In effect, the distinction of AEL from MDS or AML-MRC with erythroid hyperplasia is based solely on the number of blasts, calculated as the proportion of nonerythroid cells in acute erythroleukemia but as the proportion of total bone marrow cells in MDS and AML-MRC. Given our limited understanding of the molecular genetic alterations in these diseases, this classification approach may arbitrarily divide biologically related myeloid neoplasms into different entities.
Because of the relative rarity of AEL, few large studies have examined its clinical and genetic features. Although AEL is now separated from AML-MRC, many publications have emphasized certain similarities between these disease categories, such as the high frequency of a preceding diagnosis of MDS or presence of multilineage dysplasia, as well as similarities in the observed cytogenetic alterations. acute erythroleukemia also has been shown to share similar karyotypic abnormalities with cases of AML with 20-30% blasts, previously categorized as Refractory anemia with excess blasts in transformation (RAEB-t) in the FAB classification of MDS. Indeed, some leukemia experts have voiced concern that the lowered blast count of 20% of nonerythroid elements would lead to cases of MDS with excess blasts and transient erythroid hyperplasia being misdiagnosed as AEL. Acute erythroleukemia has a relatively poor prognosis, with a median survival of 4 to 6 months. Cytogenetics appears to be a major factor in determining survival. Although allogeneic stem cell transplantation improves the outcome of AEL patients, most of these studies were based on AEL as defined by the FAB (? 30% blasts) system. No studies to date have reassessed AEL as currently defined in the 2008 WHO classification.
There is no unique chromosome abnormality described in AEL, however complex karyotypes with multiple structural abnormalities are common. Chromosomes 5 and 7 are the most frequently affected. These findings are also characteristically found in therapy-related AML and MDS, however loss or deletion of 5q is higher in de novo erythroid leukemia whilst loss or deletion of 7q is higher in therapy related AML.
The myeloid blasts express a variety of myeloid markers, similar to other subtypes of AML CD13, CD33, CD117 (c-Kit) and MPO. The erythroblasts lack myeloid antigens but are positive to glycophorin A. Pure erythroleukemia: Erythroid blasts which have differentiated will be positive with glycophorin A but negative with MPO and myeloid markers. The more immature blasts are difficult to identify as erythroid because they are usually negative for glycophorin A. Immature erythroid progenitors may be detected using carbonic anhydrase 1 or CD36. Although CD36 is not specific for erythroid progenitors, negative markers for megakaryocytes and monocytes will aid the diagnosis.
Clinical presentation is non-specific including weakness, pallor, fever and hemorrhages, rarely intracranial hemorrhages. Patients may also present with hepatomegaly, splenomegaly
.Anemia (mean hemoglobin Hb 7.5 g/dL reported in 1 study)and thrombocytopenia are present in all the cases, while the neutrophil count varies from normal-to-low.
A detailed clinical history, laboratory work up, peripheral blood and bone marrow examination, cytochemical, immunohistochemical (IHC), flow cytometry, cytogenetic and molecular studies are required for the diagnosis of AEL.
Patients with AEL may be treated similarly to patients with other types of AML, NOS. Stem cell transplantation seems to be the best treatment approach for now, although the procedure is associated with high morbidity and mortality rate, especially in allogenic bone marrow transplantation. Using HLA identical sibling SCT (stem cell transplant) increases the leukemia-free survival with 60%. Erythropoietin and granulocyte colony stimulating factor have been used to induce clinical remission in elderly patients. One study showed that P-glycoprotein expression correlates with unfavorable cytogenetic abnormalities, poor response to chemotherapy with multi-drug resistance development, and short survival. Cyclosporin A and cyclosporin D analogue PSC-833 (valspodar) are used for clinical drug modulation to overcome multi-drug resistance. These agents can be administered at sufficient doses to achieve effective serum levels, and can be combined with cytotoxic agents without increase of toxicity. Recently, a successful morphologic and cytogenetic remission after sorafenib (NexavarTM
) initiation treatment in a FLT3-ITD (FLT3 internal tandem duplication) positive patient with a refractory acute erythroleukemia and abnormal cytogenetics was reported.
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