An unusual case of pure erythroid leukemia with normal karyotype and NPM1 mutation.

Pure erythroid leukemia (PEL) is an extremely rare subtype of acute myeloid leukemia (AML). Although not specific, PEL is almost uniformly associated with complex karyotype and TP53 mutations. Given the rarity of the disease, our understanding of its cytogenetic and molecular features deems incomplete. We aim to complement existing literature by presenting an unusual case of PEL. The case is comprehensively worked up with multiple modalities. We present for the first time a case of PEL with unusual cytogenetic and molecular features: normal karyotype with absence of TP53 mutations and presence of NPM1 and NRAS mutations. This is a valuable addition to literature, expanding our understanding of molecular and cytogenetic spectra of PEL.

Acute Erythroid Leukemia: From Molecular Biology to Clinical Outcomes.

Acute Erythroid Leukemia (AEL) is a rare and aggressive subtype of Acute Myeloid Leukemia (AML). In 2022, the World Health Organization (WHO) defined AEL as a biopsy with ≥30% proerythroblasts and erythroid precursors that account for ≥80% of cellularity. The International Consensus Classification refers to this neoplasm as "AML with mutated TP53". Classification entails ≥20% blasts in blood or bone marrow biopsy and a somatic TP53 mutation (VAF > 10%). This type of leukemia is typically associated with biallelic TP53 mutations and a complex karyotype, specifically 5q and 7q deletions. Transgenic mouse models have implicated several molecules in the pathogenesis of AEL, including transcriptional master regulator GATA1 (involved in erythroid differentiation), master oncogenes, and CDX4. Recent studies have also characterized AEL by epigenetic regulator mutations and transcriptome subgroups. AEL patients have overall poor clinical outcomes, mostly related to their poor response to the standard therapies, which include hypomethylating agents and intensive chemotherapy. Allogeneic bone marrow transplantation (AlloBMT) is the only potentially curative approach but requires deep remission, which is very challenging for these patients. Age, AlloBMT, and a history of antecedent myeloid neoplasms further affect the outcomes of these patients. In this review, we will summarize the diagnostic criteria of AEL, review the current insights into the biology of AEL, and describe the treatment options and outcomes of patients with this disease.

A History and Current Understanding of Acute Erythroid Leukemia.

Acute erythroid leukemia (AEL) is a highly aggressive subtype of acute myeloid leukemia. Since the first recognition of an erythroid-predominant hematologic malignancy in the early 20th century, AEL has gone through a turnstile of changing definitions and nomenclature, including eritoleucemia, erythremic myelosis, AML-M6 and pure erythroid leukemia. Ever-changing diagnostic criteria and under recognition have stifled our understanding of, and therapeutic options for, this rare erythroid-predominant myeloid neoplasm. It is now well-documented that true AEL, which is characterized primarily by immature erythroid proliferation, often harbors highly complex cytogenetic changes and multiple, deleterious TP53 mutations. These cytogenetic and molecular characteristics render current treatment approaches largely ineffective, and signal an urgent need for novel therapeutic modalities. Due to its rarity and aggressive nature, concerted collaborative efforts must be undertaken in order to improve the outcomes and treatment options for patients with AEL.

[Molecular pathogenesis and therapeutic targets in acute erythroid leukemia].

Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by erythroid predominance and dysplasia. It is classified into two subtypes: pure erythroid (PEL) and erythroid/myeloid (EML) phenotypes. To understand the mechanism of the erythroid dominant phenotype of AEL and identify potential therapeutic targets for AEL, we analyzed 105 AEL and 214 non-AEL cases using whole-genome/exome and/or targeted-capture sequencing, with SNP probes for detecting copy number abnormalities. We also performed a transcriptome analysis of 12 AEL samples. Combining publicly available sequencing data, AEL was genetically clustered into four groups according to mutational status in TP53, STAG2, and NPM1 genes. Conspicuously, highly recurrent gains and amplifications affecting EPOR, JAK2, and/or ERG/ETS2 were recurrently detected in AEL cases, almost exclusively found in TP53-mutated cases. Among these, gains/amplifications of EPOR/JAK2 were more highly enriched in PEL than EML cases. Along with the activated STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism, and they showed high sensitivity to ruxolitinib in in vitro and in xenograft models, highlighting the potential role of JAK2 inhibition in AEL therapeutics.

Erythroleukemia: an Update.

PURPOSE OF THE REVIEW: Acute erythroleukemia (AEL) is a rare form of acute myeloid leukemia recognized by erythroblastic proliferation. Many controversies remain around diagnosis influencing prognostic and therapeutic implications relating to this unique leukemia subset. RECENT FINDINGS: The 2016 WHO classification includes more clear and restrictive diagnostic criteria for AEL. Primary acute erythroid leukemia is associated with complex and high-risk karyotypes including chromosomes 5q and 7q abnormalities. Mutational data shows that AEL is characterized by far lower NPM1 and FLT3-ITD mutation rates and higher mutational rates in TP53 compared with other AML subtypes. Hypomethylating agents have shown therapeutic value in AEL. In this article, we discuss the evolving diagnostic concepts of erythroleukemia, genomics, clinical outcome, and promising therapeutic targets through an appraisal of the current literature.

Pure erythroid leukemia subsequent to acute myelomonocytic leukemia: A case report.

RATIONALE: Pure erythroid leukemia is a rare subcategory of acute myeloid leukemia characterized by predominant immature erythroid population. Its occurrence subsequent to acute myelomonocytic leukemia has not been reported before. We reported this rare case to call attention because it may pose a diagnostic challenge. PATIENTS CONCERNS: A 54-year-old female patient presented to our hospital in March 2018 with symptoms of easy fatigability. DIAGNOSIS: Bone marrow aspiration was hypercellular showing 67.2% blasts mainly including moderate myeloblasts and monoblasts. There was mild dysplasia with some cells having round, oval, or bizarre nuclei which containing 1 to 3 nucleolus. Erythroid lineage was hypoplasia and mature erythrocytes were generally normal. Conventional cytogenetics of bone marrow cells revealed complex karyotype (44, XX, del (5) (q14q34) del (5) (q14q34), del (14) t (11;14) (q10; q10), -16, del (17), -18[10]). INTERVENTIONS: The patient was treated with second line chemotherapy but did not respond. QUTCOMES: She died of cardiopulmonary failure 19days after starting of therapy. LESSONS: This unexpected and relatively uncommon occurrence was associated with a universally rapid and fatal clinical course with survival measured in <2 months despite intensive chemotherapy. We call attention to this rare phenomenon because it may pose a diagnostic challenge.

To bi or not to bi: Acute erythroid leukemias and hematopoietic lineage choice.

Acute erythroid leukemia (AEL) is an acute leukemia characterized by erythroid lineage transformation. The World Health Organization (WHO) 2008 classification recognized two subtypes of AEL: bilineage erythroleukemia (erythroid/myeloid leukemia) and pure erythroid leukemia. The erythroleukemia subtype was removed in the updated 2016 WHO classification, with about half of cases reclassified as myelodysplastic syndrome (MDS) and half as acute myeloid leukemia (AML). Diagnosis and classification are currently based on morphology using standard blast cutoffs, without integration of underlying genomic and other molecular features. Key outstanding questions are therefore whether AEL can be accurately diagnosed based solely on morphology or whether genetic or other molecular criteria should be included in its classification, and whether considering AEL as an entity distinct from AML and MDS is clinically relevant. We discuss recent work on the molecular basis of AEL, including the identification of mutations causative of AEL and of transcriptional and epigenetic features that can be used to distinguish AEL from MDS and nonerythroid AML, and the prognostic value of these molecular features.

E-Cadherin Expression in Blastic Plasmacytoid Dendritic Cell Neoplasms: An Unrecognized Finding and Potential Diagnostic Pitfall.

E-cadherin is expressed in hematopoietic erythroid precursors, but to our knowledge, its expression in blastic plasmacytoid dendritic cell neoplasm (BPDCN) has not been described. We report a case of BPDCN showing strong expression of E-cadherin, arising in a patient with history of primary myelofibrosis. Four more cases of BPDCN tested all showed strong expression of E-cadherin. Lack of awareness of this pattern of expression may lead to erroneous diagnosis of acute erythroid leukemia. It is increasingly becoming important to correctly identify this group of neoplasms, as approved new anti-CD123-targeted therapies are becoming available.

Anti-CD71 antibody immunohistochemistry in the diagnosis of acute myeloid leukemia, subtype acute erythroid leukemia with erythroid dominance (AML M6-Er), in a retrovirus-negative cat.

CD71 is an immunohistochemical marker used in diagnosing acute myeloid leukemia (AML) M6-Er in humans; however, to our knowledge, it has not been reportedly used for immunohistochemistry in veterinary medicine. We evaluated the pathologic features of AML M6-Er in a retrovirus-negative cat and used CD71 to support the diagnosis. A 4-y-old spayed female Scottish Fold cat was presented with lethargy, anorexia, and fever. Whole-blood PCR assay results for pro feline leukemia virus/pro feline immunodeficiency virus and feline vector-borne diseases were negative. Early erythroid precursors were observed in the peripheral blood smear. Fine-needle aspiration of the enlarged spleen and splenic lymph node showed many early erythroid precursors. Bone marrow aspirate smears revealed erythroid hyperplasia with 68.4% erythroid lineage and 3.6% rubriblasts. Dysplastic cells infiltrated other organs. The patient was diagnosed with myelodysplastic syndrome, progressing to the early phase of AML M6-Er. The patient died on day 121 despite multidrug treatments. Postmortem examination revealed neoplastic erythroblasts infiltrating the bone marrow and other organs. Neoplastic cells were immunopositive for CD71 but immunonegative for CD3, CD20, granzyme B, von Willebrand factor, CD61, myeloperoxidase, and Iba-1. Although further studies are necessary for the application of CD71, our results supported the morphologic diagnosis of AML M6-Er.

Acute erythroid leukemia is enriched in NUP98 fusions: a report from the Children's Oncology Group.

Acute erythroid leukemia (AEL) is a rare subtype of acute myeloid leukemia (AML) primarily affecting older adults and was previously classified into erythroid/myeloid and pure erythroid subtypes. In this pediatric AEL study, we evaluated morphologic, immunophenotypic, cytogenetic, molecular, and clinical data of 24 (1.2%) cases from all cases undergoing central pathology review in Children's Oncology Group trials AAML0531 and AAML1031. Of 24 cases, 5 had a pure erythroid phenotype, and 19 had an erythroid/myeloid phenotype. NUP98 fusions were highly enriched in patients with AEL, occurring in 7 of 22 cases for which molecular data were available (31.8% vs 6.7% in other AML subtypes). Of 5 cases of pure erythroid leukemias (PELs), 3 had NUP98 fusions, and 4 had complex karyotypes. Erythroid/myeloid leukemias were reclassified by using the 2017 World Health Organization hematopathology classification as: myelodysplastic syndrome (MDS) with excess blasts-1 (n = 3), MDS with excess blasts-2 (n = 7), AML (nonerythroid, n = 5), and unknown MDS/AML (n = 4); the 5 cases of nonerythroid AML included 1 with an NUP98-NSD1 fusion, 2 with myelodysplasia-related changes, and 1 with a complex karyotype. Three cases of MDS with excess blasts-2 also had NUP98 rearrangements. WT1 mutations were present in 5 of 14 cases, all erythroid/myeloid leukemia. Outcomes assessment revealed statistically poorer overall survival (5-year, 20% ± 36% vs 66% ± 23%; P = .004) and event-free survival (5-year, 20% ± 36% vs 46% ± 23%; P = .019) for those with PEL than those with erythroid/myeloid leukemia. Our study supports that AEL is a morphologically and genetically heterogeneous entity that is enriched in NUP98 fusions, with the pure erythroid subtype associated with particularly adverse outcomes.

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.