Eritroleucemias: Recategorización según criterios de la organización mundial de la salud / Erythroleukemias. Recategorization according to the World Health Organization's criteria

La leucemia aguda es la enfermedad oncológica más frecuente en la infancia. La leucemia linfoblástica aguda representa el 75% y la mieloblástica aguda el 25% de ellas. La eritroleucemia es una entidad infrecuente, representando menos del 5% de las leucemias mieloblásticas agudas. Su definición ha variado a lo largo del tiempo. La OMS en 2017 define el subtipo de eritroleucemia cuando el porcentaje de eritroblastos representa el 80% de la celularidad total de la médula ósea. El presente trabajo, de tipo analítico, retrospectivo, tuvo como finalidad revisar los hallazgos de morfología, citometría de flujo, citogenética, respuesta al tratamiento y evolución de los casos previamente definidos como eritroleucemia, en nuestro centro, en los últimos 25 años y reclasificar aquellos que no cumplían con los nuevos criterios de la OMS 2017. Entre enero de 1990 y diciembre de 2015, se diagnosticaron 576 casos de leucemia mieloblástica aguda siendo 11 (1.9%) de ellos clasificados como eritroleucemia. Resultaron evaluables 10 casos. La distribución por sexo fue 1:1 y la edad mediana fue 5 (rango: 0.9-14) años. Seis pacientes presentaban antecedentes de síndrome mielodisplásico. Según los nuevos criterios, ninguno de los casos analizados puede ser actualmente definido como eritroleucemia. De acuerdo a la recategorización, fueron definidos como leucemias de subtipos de mal pronóstico, como leucemia aguda indiferenciada, sin diferenciación y megacarioblástica. Solo dos pacientes se encuentran libres de enfermedad, probablemente debido a estos subtipos desfavorables, sumado al antecedente frecuente de mielodisplasia.

Acute leukemia is the most frequent malignant disease in childhood. Acute lymphoblastic leukemia represents 75% and acute myeloblastic leukemia 25% of them. Erythroleukemia is a rare entity, corresponding to less than 5% of acute myeloblastic leukemia. Its definition has changed over the time. WHO in 2017 defines erythroleukemia when the percentage of erythroblasts represent 80% of the total cellularity of the bone marrow aspirate. This analytical and retrospective study was performed with the aim of reviewing morphology, flow cytometry and cytogenetic features, response to treatment and outcome of cases previously defined as erythroleukemia in our center during the last 25 years and, in addition to reclassify those cases which do not meet the new WHO 2017 criteria. From January 1990 to December 2015, 576 patients were diagnosed as acute myeloblastic leukemia and 11 (1.9%) of them were classified as erythroleukemia. Ten cases were evaluable. Sex distribution was 1:1 and the median age at diagnosis was 5 (range: 0.9-14) years. Six of them had presented with previous myelodysplastic syndrome. None of the analyzed cases can be currently defined as erythroleukemia, according to the new criteria. When reclassified, the cases were defined as leukemias of subsets with poor prognosis such as acute undifferentiated leukemia, without differentiation and megakaryoblastic leukemia. Only 2 patients remain leukemia-free and this could be explained both by the unfavorable prognosis of these leukemia subtypes, and the antecedent of myelodysplastic syndrome in most of the cases.

[Erythroleukemias. Recategorization according to the World Health Organization's criteria]. / Eritroleucemias. Recategorización según criterios de la Organización Mundial de la Salud.

Acute leukemia is the most frequent malignant disease in childhood. Acute lymphoblastic leukemia represents 75% and acute myeloblastic leukemia 25% of them. Erythroleukemia is a rare entity, corresponding to less than 5% of acute myeloblastic leukemia. Its definition has changed over the time. WHO in 2017 defines erythroleukemia when the percentage of erythroblasts represent 80% of the total cellularity of the bone marrow aspirate. This analytical and retrospective study was performed with the aim of reviewing morphology, flow cytometry and cytogenetic features, response to treatment and outcome of cases previously defined as erythroleukemia in our center during the last 25 years and, in addition to reclassify those cases which do not meet the new WHO 2017 criteria. From January 1990 to December 2015, 576 patients were diagnosed as acute myeloblastic leukemia and 11 (1.9%) of them were classified as erythroleukemia. Ten cases were evaluable. Sex distribution was 1:1 and the median age at diagnosis was 5 (range: 0.9-14) years. Six of them had presented with previous myelodysplastic syndrome. None of the analyzed cases can be currently defined as erythroleukemia, according to the new criteria. When reclassified, the cases were defined as leukemias of subsets with poor prognosis such as acute undifferentiated leukemia, without differentiation and megakaryoblastic leukemia. Only 2 patients remain leukemia-free and this could be explained both by the unfavorable prognosis of these leukemia subtypes, and the antecedent of myelodysplastic syndrome in most of the cases.

Re-evaluation of acute erythroid leukemia according to the 2016 WHO classification.

In the recent update of WHO classification, the definition of myeloid neoplasms with erythroid predominance has been modified shifting the main criteria for calculating blast percentage from non-erythroid cells (NEC) to all nucleated marrow cells (ANC). Thus, the cases previously classified as erythroid/myeloid subtype of acute erythroid leukemia (AEL) based on the 2008 WHO will now be categorized either as myelodysplastic syndrome with excess blasts (MDS-EB) or acute myeloid leukemia, not otherwise specified (AML-NOS). However, the clinical significance of this new classification has not been demonstrated. Thus, we reviewed a leukemia database and reclassified 38 cases previously diagnosed as AEL, erythroid/myeloid subtype, with the consideration of 2016 revision criteria. Twenty seven (71%) of them had >20% blasts in NEC but less than 20% blasts in ANC, and 11 (29%) had >20% in both NEC and ANC. There was no significant difference in overall survivals (OS) among AEL, MDS-EB, and AML-NOS (non-erythroid predominance, NEP). However, AML with myelodysplasia-related changes showed significant shorter OS than AEL, MDS-EB and AML-NOS (NEP). Our results indicate that in myeloid neoplasm with erythroid predominance, patients with >20% blasts, of either NEC or ANC, share similar clinical laboratory features and survival outcomes with AML-NOS.

The uniqueness of morphological features of pure erythroid leukemia in myeloid neoplasm with erythroid predominance: A reassessment using criteria revised in the 2016 World Health Organization classification.

We reviewed 97 consecutive cases of myeloid neoplasm with erythroid predominance (MN-EP) between 2000 and 2015. Following 2016 WHO classification, MN-EP patients were classified into four groups. Eight pure erythroid leukemia (PEL) (including t-MN and AML-MRC morphologically fulfilled criteria for PEL) patients had dismal outcomes (median OS: 1 month) and showed more bone marrow fibrosis, worse performance status (PS) and higher serum lactate dehydrogenase (LDH) at diagnosis than the other groups. In the univariate analysis, risks of death in MN-EP patients included the morphologic features of PEL, very poor cytogenetic risk by IPSS-R, bone marrow fibrosis, leukocytosis, anemia, hypoalbuminemia, high LDH, and poor PS. In the multivariate analysis, independent predictors of death were morphologic features of PEL (adjusted hazards ratio [HR] 3.48, 95% confidence interval [CI] 1.24-9.74, p = 0.018), very poor cytogenetic risk by IPSS-R (adjusted HR 2.73, 95% CI 1.22-6.10, p = 0.015), hypoalbuminemia (< 3.7 g/dl) (adjusted HR 2.33, 95% CI 1.10-4.91, p = 0.026) and high serum LDH (≥ 250 U/L) (adjusted HR 2.36, 95% CI 1.28-4.36, p = 0.006). Poor or unfavorable risk in different cytogenetic risk systems independently predicted death and UKMRC-R was the best model.

Pure erythroid leukemia.

The category of acute erythroid leukemia was significantly revised in the recently published 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms. In the previous 2008 WHO classification, acute erythroid leukemia was categorized into two subtypes: erythroleukemia and pure erythroid leukemia (PEL), whereas in the 2016 WHO update, erythroleukemia was merged into myelodysplastic syndrome, and PEL becomes the only type of acute erythroid leukemia. PEL is a rare and aggressive form of acute leukemia whose biology remains poorly characterized. In this review, we discuss the clinicopathologic features, diagnosis, putative pathogenesis, and molecular biology of PEL, with an overview of novel concepts and future directions in this area.

Erythroleukemia shares biological features and outcome with myelodysplastic syndromes with excess blasts: a rationale for its inclusion into future classifications of myelodysplastic syndromes.

Erythroleukemia was considered an acute myeloid leukemia in the 2008 World Health Organization (WHO) classification and is defined by the presence of ≥50% bone marrow erythroblasts, having <20% bone marrow blasts from total nucleated cells but ≥20% bone marrow myeloblasts from nonerythroid cells. Erythroleukemia shares clinicopathologic features with myelodysplastic syndromes, especially with erythroid-predominant myelodysplastic syndromes (≥50% bone marrow erythroblasts). The upcoming WHO revision proposes to eliminate the nonerythroid blast cell count rule and to move erythroleukemia patients into the appropriate myelodysplastic syndrome category on the basis of the absolute blast cell count. We conducted a retrospective study of patients with de novo erythroleukemia and compared their clinico-biological features and outcome with those of de novo myelodysplastic syndromes, focusing on erythroid-predominant myelodysplastic syndromes. Median overall survival of 405 erythroid-predominant myelodysplastic syndromes without excess blasts was significantly longer than that observed in 57 erythroid-predominant refractory anemias with excess blasts-1 and in 59 erythroleukemias, but no significant difference was observed between erythroid-predominant refractory anemias with excess blasts-1 and erythroleukemias. In this subset of patients with ≥50% bone marrow erythroblasts and excess blasts, the presence of a high-risk karyotype defined by the International Prognostic Scoring System or by the Revised International Prognostic Scoring System was the main prognostic factor. In the same way, the survival of 459 refractory anemias with excess blasts-2, independently of having ≥20% bone marrow blasts from nonerythroid cells or not, was almost identical to the observed in 59 erythroleukemias. Interestingly, 11 low-blast count erythroleukemias with 5 to <10% bone marrow blasts from total nucleated cells showed similar survival than the rest of erythroleukemias. Our data suggest that de novo erythroleukemia is in the spectrum of myelodysplastic syndromes with excess blasts and support its inclusion into future classifications of myelodysplastic syndromes.

Acute erythroid leukemia with <20% bone marrow blasts is clinically and biologically similar to myelodysplastic syndrome with excess blasts.

In acute erythroleukemia, erythroid/myeloid subtype, blasts usually comprise 5-19% of total bone marrow cells, similar to the myelodysplastic syndrome subtype refractory anemia with excess blasts; recent studies have raised the question if acute erythroleukemia should be considered as a myelodysplastic syndrome subtype. We reviewed 77 de novo acute erythroleukemia and 279 de novo refractory anemia with excess blasts from three large medical centers. Compared to refractory anemia with excess blasts, acute erythroleukemia patients had higher total bone marrow blasts, lower platelets, hemoglobin, and absolute neutrophil counts, with more patients being assigned a very-poor-karyotype risk and very-high Revised International Prognostic Scoring System score. Induction chemotherapy was administered to 55% of acute erythroleukemia patients, but was not associated with longer overall survival compared to acute erythroleukemia patients treated with lower-intensity therapies or supportive care (P=0.44). In multivariable analysis of all patients, Revised International Prognostic Scoring System very high (P<0.0001) or high (P=0.005) risk, but not a diagnosis of acute erythroleukemia (P=0.30), were independent risk factors for shorter overall survival. Our data show that acute erythroleukemia patients have similar risk-adjusted outcome to refractory anemia with excess blasts patients and do not appear to gain survival advantage with acute myeloid leukemia-type induction chemotherapy. These data suggest that acute erythroleukemia, erythroid/myeloid subtype with <20% blasts may be more appropriately classified as refractory anemia with excess blasts rather than as an acute myeloid leukemia subtype.

Acute Erythroleukemias, Acute Megakaryoblastic Leukemias, and Reactive Mimics: A Guide to a Number of Perplexing Entities.

OBJECTIVES: At the 2013 Society for Hematopathology/European Association for Hematopathology Workshop, 36 cases were submitted to the session that covered acute erythroid leukemia (AEL), acute megakaryoblastic leukemia (AMKL), and reactive mimics. METHODS: Cases were reviewed by the session chairs and workshop panel to reach a consensus diagnosis. RESULTS: For acute erythroleukemia, erythroid/myeloid type, discussion acknowledged overlapping features between AEL and myelodysplastic syndromes. Cases submitted as pure erythroid leukemia had distinctive morphology and immunophenotype, complex karyotypes, and aggressive clinical behavior, illustrating certain diagnostic features not currently captured by the current World Health Organization (WHO) definition. In Down syndrome, there were striking similarities between transient abnormal myelopoiesis and AMKL. Most cases of AMKL in adults would be classified as acute myeloid leukemia with myelodysplasia-related changes according to the WHO classification, but this approach deemphasizes their unique clinical, morphologic, and immunophenotypic features. CONCLUSIONS: The broad spectrum of cases illustrated the difficulties and complex issues involved in establishing a diagnosis of these entities and the need for better disease definitions.

Clinicopathologic features and outcome of acute erythroid leukemia based on 2008 revised World Health Organization classification.

We report 67 patients with acute erythroid leukemia (erythroleukemia) based on the World Health Organization (WHO) 2008 classification. Reviewing the clinicopathologic features, cytogenetics and outcomes, the characteristics of erythroleukemia resembled myelodysplastic syndromes (MDS). Patients with poor performance status, advanced anemia and poor-risk cytogenetics had significantly inferior outcomes. The International Prognostic Scoring System (IPSS) for MDS is useful to differentiate the prognosis of erythroleukemia.

Erythroid proliferations in myeloid neoplasms.

Prominent erythroid proliferations (in which erythroid elements comprise ≥50% of total bone marrow cells) can be seen in various hematopoietic stem cell neoplasms. The myeloproliferative neoplasm polycythemia vera exhibits effective, overexuberant erythropoiesis resulting in an increased red blood cell mass; in contrast, most other diseases characterized by erythroid predominance exhibit ineffective hemopoiesis. The latter include acute erythroid leukemia (erythroid-myeloid and pure erythroid leukemia subtypes) as well as some cases of myelodysplastic syndromes, acute myeloid leukemia with myelodysplasia-related changes, and therapy-related myeloid neoplasms. Some nonneoplastic reactive conditions may also manifest a striking bone marrow erythroid predominance. In this article, we review the literature relevant to this group of diseases for a better understanding of their clinicopathologic features and surrounding controversies. We also examine the position of neoplastic erythroid proliferations in the current 2008 World Health Organization Classification of Myeloid Neoplasms and provide recommendations as to how to approach the differential diagnosis of this group of diseases.

Pure erythroid leukemia: a reassessment of the entity using the 2008 World Health Organization classification.

Pure erythroid leukemia (PEL) is rare, characterized by a neoplastic proliferation of erythroblasts. Given recent incorporation of molecular genetic findings and clinical features in the revised 2008 World Health Organization classification scheme of acute myeloid leukemia, we questioned if PEL still remains as a distinct subtype of acute myeloid leukemia. In this retrospective study, we identified 18 cases of acute leukemia with morphologic and immunophenotypic features of PEL. Following the current World Health Organization classification algorithm, these cases were classified as: 13 acute myeloid leukemia with myelodysplasia-related changes, 3 therapy-related acute myeloid leukemia, and 1 chronic myelogenous leukemia blast crisis, and one unclassifiable due to insufficient clinical information. All 16 cases with cytogenetic data harbored an extremely complex karyotype and the median overall survival of the 18 patients was 3 months (range, 1-7 months). This survival was significantly shorter than that of patients with acute erythroid leukemia, erythroid/myeloid subtype, or acute myeloid leukemia with myelodysplasia-related changes with erythroid predominance (P<0.001). PEL is characterized as a neoplastic erythroid hyperproliferation with maturation arrest. E-cadherin emerged as the most sensitive and specific marker for immature erythroblasts, and was helpful in distinguishing PEL from other erythroid proliferations. Our study showed that the criteria for acute myeloid leukemia in the 2008 World Health Organization system facilitate reclassification of PEL cases into other acute myeloid leukemia categories, mainly of acute myeloid leukemia with myelodysplasia-related changes. These new assigned categories fail to capture the distinct features of PEL, where the phenotype of PEL correlates with a very complex karyotype and an extremely aggressive clinical course.

Acute erythroid leukemia.

CONTEXT: Acute erythroid leukemia (AEL) is an uncommon type of acute myeloid leukemia (AML), representing less than 5% of all cases. Acute erythroid leukemia is characterized by a predominant erythroid proliferation, and in the current World Health Organization (WHO) classification scheme there are 2 subtypes: erythroleukemia (erythroid/myeloid leukemia) and pure erythroid leukemia. Morphologic findings are most important for establishing the diagnosis. The erythroleukemia subtype, which is most common, is defined as the presence of 50% or more erythroid precursors and 20% or more blasts in the nonerythroid component. The pure erythroid leukemia subtype is composed of 80% or more immature erythroblasts. Although these morphologic criteria appear straightforward, AEL overlaps with other types of AML and myelodysplastic syndrome that are erythroid rich. OBJECTIVE: To provide an update of AEL, including clinical presentation, morphologic features, immunophenotype, and cytogenetic and molecular data. As the erythroleukemia subtype is most common, the literature and this review are biased towards this subtype of AEL. DATA SOURCES: Clinicopathologic, cytogenetic, and molecular information were extracted from our review of pertinent literature and a subset of AEL cases in the files of The University of Texas M. D. Anderson Cancer Center (Houston) and University of South Alabama (Mobile). CONCLUSIONS: The current WHO criteria for establishing the diagnosis of AEL reduce the frequency of this entity, as cases once classified as the erythroleukemia subtype are now reclassified as other types of AML, particularly AML with myelodysplasia-related changes and therapy-related AML. This reclassification also may have prognostic significance for patients with the erythroleukemia subtype of AEL. In contrast, the current WHO criteria appear to have little impact on the frequency and poor prognosis of patients with the pure erythroid leukemia subtype of AEL. Molecular studies, preferably using high-throughput methods, are needed for a better understanding of the pathogenesis of AEL, and for developing diagnostic and prognostic markers.

Acute erythroid leukemia: a reassessment using criteria refined in the 2008 WHO classification.

Acute erythroid leukemia (AEL) is a rare type of acute myeloid leukemia (AML) for which diagnostic criteria have been refined in the 2008 World Health Organization (WHO) classification of AML. The relationship of AEL to myelodysplastic syndromes (MDSs) and to AML with myelodysplasia-related changes (AML-MRC) is not clearly defined. We conducted a retrospective, multi-institutional study of patients with AEL and compared them with patients with MDS or AML-MRC with erythroid hyperplasia (> or = 50% erythroid cells). Among a total of 124 patients with AEL, 32% had a history of MDS or chronic cytopenia, 32% had therapy-related disease, and 35% had de novo disease. Sixty-four percent of patients had unfavorable AML risk-group karyotypes. FLT3 and RAS mutations were infrequent, occurring in 6% and 2%, respectively. The median overall survival (OS) of all AEL patients was 8 months, comparable with that of patients with MDS or AML-MRC with erythroid hyperplasia. The OS was related to cytogenetic risk group, but not blast count or morphologic dysplasia. Our findings suggest that AEL is in the continuum of MDS and AML with erythroid hyperplasia, where karyotype rather than an arbitrary blast cutoff represents the most important prognostic factor.

Sub classification and clinico-hematological correlation of 40 cases of acute erythroleukemia - can proerythroblast/myeloblast and proerythroblast/total erythroid cell ratios help subclassify?

The clinico-hematological profile of 40 cases of acute erythroleukemia (AEL) was evaluated. These were subclassified into three types, namely AML M6a, M6b and M6c based on the myeloblast and proerythroblast percentages. The proerythroblast percentage has been shown to be a prognostic indicator by several studies. As AEL is biologically an "erythroid predominant" disease, two ratios (PE/MB, PE/TEC) with proerythroblasts as numerator have been formulated. An attempt has been made to assess the difference in these ratios in subclassified AEL. There were 29 M6a, 2M6b,and 9 M6 c patients, which were subclassified using the criteria proposed by Mazzella et al. The incidence of AEL in our study was 3.7%, predominantly affecting males with a predilection to younger age in contrast to Western studies. Both PE/MB and PE/TEC ratios were higher in M6b and M6c in comparison to M6a. The subclassification of AEL becomes essential especially in the era of lineage-targeted therapies, which can lead to the development and use of erythroid specific treatments in the near future.

Recommendation of the use of myeloblast percentage among non-erythroid cells instead of percentage among total nucleated cells for therapeutic response assessment in acute erythroid leukemia.

The diagnostic criteria of acute erythroid leukemias (AEL) has been revised by WHO in 2001. The National Cancer Institute (NCI) published a set of standardized diagnostic and response criteria for acute myeloid leukemia in 1990, which was revised in 2003. The aim of the present study was to establish the best criteria for therapeutic response assessment in the newly classified AEL and evaluate patient outcomes. Fifty-two patients with AEL as defined by the new WHO criteria were evaluated in this study. The following seven indices for therapeutic response assessment were evaluated: (i) NCI criteria (myeloblast percentage among total nucleated cells (TNC) and cellularity); (ii) myeloblast percentage among non-erythroid cells (NEC) and cellularity; (iii) erythroid series percentage among TNC; (iv) pronormoblast percentage among erythroid cells; (v) ratio of pronormoblasts and blasts; (vi) maturation arrest index; and (vii) disappearance of erythroid dysplasia. Complete remission (CR) patients with <5% of myeloblast/NEC (NEC-CR) showed significantly longer overall survival periods (mean 55.8 months) compared to CR patients with >5% myeloblast/NEC (mean 11.7 months, P = 0.006). NEC-CR patients also had longer event-free survival (median 16.4 months) compared to patients with >5% and <20% of myeloblast/NEC (median 6.2 months) (P = 0.044). The other indices for therapeutic response assessment are not significant for predictability of relapse and outcomes. Therefore, we recommend that the myeloblast percentage among NEC be used instead of myeloblast percentage among TNC for therapeutic response assessment in AEL.