Acute erythroid leukemia in a child: insights from a rare case.

PCYT1A Is a Metabolic Vulnerability in Monocytic Acute Myeloid Leukemia

Novel Molecular Pathogenesis and Therapeutic Target in Acute Erythroid Leukemia

Is Acute Erythroid Leukemia a Transitional Stage from MDS to AML?: A Study by Fluorescence in Situ Hybridization and Cytogenetics

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.

The XPO7/Npat Axis Is a Potential Therapeutic Target for TP53-Mutated AML

The World Health Organization separates acute erythroid leukemia (erythropoiesis in ≥50% of nucleated bone marrow cells; ≥20% myeloblasts of non-erythroid cells) from other entities with increased erythropoiesis - acute myeloid leukemia with myelodysplasia-related changes (≥20% myeloblasts of all nucleated cells) or myelodysplastic syndromes - and subdivides acute erythroid leukemia into erythroleukemia and pure erythroid leukemia subtypes. We aimed to investigate the biological/genetic justification for the different categories of myeloid malignancies with increased erythropoiesis (≥50% of bone marrow cells). We investigated 212 patients (aged 18.5-88.4 years) with acute myeloid leukemia or myelodysplastic syndromes characterized by 50% or more erythropoiesis: 108 had acute myeloid leukemia (77 with acute erythroid leukemia, corresponding to erythroid/myeloid erythroleukemia, 7 with pure erythroid leukemia, 24 with acute myeloid leukemia with myelodysplasia-related changes) and 104 had myelodysplastic syndromes. Morphological and chromosome banding analyses were performed in all cases; subsets of cases were analyzed by polymerase chain reaction and immunophenotyping. Unfavorable karyotypes were more frequent in patients with acute myeloid leukemia than in those with myelodysplastic syndromes (42.6% versus 13.5%; P<0.0001), but their frequency did not differ significantly between patients with acute erythroid leukemia (39.0%), pure erythroid leukemia (57.1%), and acute myeloid leukemia with myelodysplasia-related changes (50.0%). The incidence of molecular mutations did not differ significantly between the different categories. The 2-year overall survival rate was better for patients with myelodysplastic syndromes than for those with acute myeloid leukemia (P<0.0001), without significant differences across the different acute leukemia subtypes. The 2-year overall survival rate was worse in patients with unfavorable karyotypes than in those with intermediate risk karyotypes (P<0.0001). In multivariate analysis, only myelodysplastic syndromes versus acute myeloid leukemia (P=0.021) and cytogenetic risk category (P=0.002) had statistically significant effects on overall survival. The separation of acute myeloid leukemia and myelodysplastic syndromes with 50% or more erythropoietic cells has clinical relevance, but it might be worth discussing whether to replace the subclassifications of different subtypes of acute erythroid leukemia and acute myeloid leukemia with myelodysplasia-related changes by the single entity, acute myeloid leukemia with increased erythropoiesis ≥50%.

Introduction/Objective Acute erythroid leukemia (AEL) is a rare (&amp;lt;1%) and highly aggressive subtype of acute myeloid leukemia (AML), characterized by predominant erythroid precursor proliferation. The 2022 WHO defines AEL as a distinct entity, whereas the ICC includes it under AML with mutated TP53. AEL frequently harbors complex karyotypes and biallelic TP53 alterations, and exhibits marked chemoresistance. The transformation from polycythemia vera (PV) to PEL is exceedingly rare, with only very few cases described in the literature with absence of prior radiation or alkylator exposure. Methods/Case Report We report a 71-year-old woman with a 8-year history of JAK2 V617F-mutated PV, treated with hydroxyurea and phlebotomy, who developed anemia, thrombocytopenia, and 50% circulating blasts. Bone marrow biopsy revealed 70% CD34-positive blasts, fibrosis, and a complex monosomal karyotype. Molecular testing showed JAK2 and TP53 mutations. Despite treatment with azacytidine and venetoclax, her disease progressed. Repeat marrow showed &amp;gt;30% proerythroblasts positive for CD71, CD117, and E-cadherin, consistent with AEL. Results NA Conclusion This case illustrates the rare evolution of PV to AEL in the absence of prior chemotherapy and highlights the need for comprehensive morphologic and molecular assessment in high-risk PV. Early recognition of AEL is critical due to its poor prognosis and limited therapeutic options.

Background: Acute erythroid leukemia (AEL) is a rare subtype of acute myeloid leukemia (AML) characterized by erythroid predominant proliferation and classified into two subtypes with pure erythroid (PEL) and erythroid/myeloid (EML) phenotypes based on the degree of erythroid hyperplasia. Despite an intensive mutational analysis, the mechanism of erythroid hyperplasia in AEL is still poorly understood and so are feasible therapeutic targets. Aims: To understand the mechanism of erythroid dominant phenotype of AEL and identify potential therapeutic targets for AEL. Methods: We analyzed a total of 124 adult AEL cases, where whole genome/exome sequencing of 35 cases were followed by targeted-capture sequencing in all cases. RNA sequencing was also performed in 23 cases. The mutational profile of AEL cases was compared to that of 409 cases with non-erythroid AML (non-AEL). Patient-derived xenograft (PDX) mouse models of AEL with JAK2 and/or EPOR amplification were established from 6 AEL patients with these abnormalities. These models were tested for their response to JAK1/2 inhibitor. Results: In accordance with a recent report, AEL cases were classified into 4 genomic groups (A-D), which are characterized by biallelic TP53 mutations and complex karyotype (Group-A), mutated NPM1 (Group-B) and STAG2 (Group-C), and other mutations in histone modifiers and transcription factors (Group-D). In particular, all but one PEL cases belonged to Group-A. Also found in non-AEL cases, these group-defining lesions in AEL were uniquely associated with focal gains/amplifications of EPOR, JAK2, and/or ERG/ETS2 loci (Group-A), PTPN11 mutations (Group-B), and KMT2A-PTD (Group-C), which might be responsible for the AEL phenotype. Highly enriched in PEL cases (7/13), EPOR/JAK2 focal gains/amplifications were implicated in their extreme erythroid hyperplasia and associated with particularly poor prognosis, even compared to other Group-A cases, who had shorter survival than those in other groups. As expected, JAK2/EPOR-amplified cases showed upregulated STAT5 signaling compared to non-AEL cases, which however, was also observed in other AEL cases, suggesting that upregulated STAT5 signaling is a hallmark of AEL. Based on these findings, we tested the effect of JAK2 inhibition on cell growth of EPOR/JAK2-amplified AEL cells in in vitro culture and xenograft model. Of interest, ruxolitinib-mediated JAK2 inhibition resulted in significantly suppressed in vitro cell growth of EPOR/JAK2-amplified AEL cells and prolonged overall survival in 4 PDX models with phospho-STAT5 downregulation, although other 2 models were resistant to JAK2 inhibition with persistent STAT5 activation. Summary/Conclusion: AEL is a heterogenous subgroups of AML characterized in common by upregulated JAK/STAT5 signaling. Gains/amplifications of JAK2/EPOR are frequent in TP53-mutated cases, particularly those with the PEL phenotype, and could be exploited as potential therapeutic targets using JAK2 inhibitors.

Simple SummaryPure erythroid leukemia (PEL), a rare subtype of acute myeloid leukemia (AML), is characterized by the proliferation of malignant erythroid precursors. To understand the status of PEL at the population level, a retrospective analysis was conducted using the Surveillance Epidemiology and End Results (SEER) database from 2000 to 2019. The study included 968 patients with a confirmed diagnosis of PEL, with a median age of 68 years and a higher proportion of males (62%). Among the patients, 62.5% received chemotherapy. The overall survival (OS) rates varied significantly based on age, with better outcomes seen in younger age groups. Chemotherapy was associated with improved OS both in adults and children. However, there were no significant differences in OS based on sex, race, ethnicity, or median household income. Over the two decades of the study, there was no notable improvement in OS, indicating poor outcomes with current chemotherapeutic agents. The study underscores the urgent need for investigational agents that are capable of inducing remission. Background: Acute erythroid leukemia (AEL), also known as pure erythroid leukemia, is a rare subtype of acute myeloid leukemia (AML) characterized by the proliferation of malignant erythroid precursors. Outcome data at the population level are scarce. Methods: We performed a retrospective analysis of the Surveillance Epidemiology and End Results (SEER) database. All cases with a histologically confirmed diagnosis of acute (pure) erythroid leukemia during the period of 2000–2019 were included in the study. The Kaplan–Meier method was used to perform survival analysis. The significance of differences between overall survival (OS) was analyzed using the log-rank test. Results: In total, 968 patients were included in the study. The median age was 68 years (range 0–95), 62% of patients were males, and 62.5% (n = 605) were treated with chemotherapy. The median OS for <18, 18–49, 50–64, 65–79 and 80+ age groups was 69, 18, 8, 3 and 1 month, respectively (p < 0.0001). Patients who received chemotherapy had significantly improved OS compared to patients who did not, among both adults (p < 0.0001) and children (p = 0.004). There were no significant differences in OS based on sex, race, ethnicity and median household income. Median OS for adults diagnosed in 2000–2004, 2005–2009, 2010–2014, 2015–2019 was 4, 6, 6 and 3 months, respectively, with no significant differences in OS between these groups. Conclusion: AEL occurs in all age groups but is most common in the elderly. Outcomes are poor with current chemotherapeutic agents, with no improvement in the last two decades. This study stresses the urgent need for investigational agents.

This Good Practice Paper was compiled according to the BSH process (https://b-s-h.org.uk/media/19922/bsh-guidance-development-process-july-2021.pdf). The British Society for Haematology (BSH) produces Good Practice Papers to recommend good practice in areas where there is a limited evidence base but for which a degree of consensus or uniformity is likely to be beneficial to patient care. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org.

The XPO7/Npat Axis Inactivation Is a Therapeutic Vulnerability for TP53-Mutated AML

Survival after acute paediatric (014 years), adolescent (15-19 years) and young adult (20-39 years) leukaemia has improved substantially over the last five decades, particularly for acute lymphoblastic leukaemia (ALL) and acute promyelocytic leukaemia, a subtype of acute myeloid leukaemia. This progress represents one of the most successful achievements in the history of medicine and has been attributed to the development of effective chemotherapy regimens, improvement in supportive care, better risk stratification, use of targeted therapies, and advances in haematopoietic stem cell transplantation. Currently, long-term survival for children diagnosed with acute lymphoblastic leukaemia is 80%-90% in developed countries. Strikingly, survival among adolescents and young adults with this disease is about 60% and 40% respectively. In addition, in these countries, 5-year survival for young patients with acute myeloid leukaemia (excluding acute promyelocytic leukaemia) remains approximately 60% in the modern era of treatment. This project aimed to evaluate how survival and, when appropriate, early death (death occurring within 30 days of diagnosis) after acute leukaemia varied during almost 25 years in California, the most populous and racially/ethnically diverse state in the United States (US). A second aim was to investigate the association between sociodemographic and selected clinical factors and outcomes. Using high-quality data from the California Cancer Registry, I evaluated survival trends from acute lymphoblastic leukaemia among patients aged 0-19 years, and survival and early death trends after acute myeloid leukaemia among patients aged 0-39 years. I also investigated whether early death has decreased among young patients after the approval by the US Food and Drug Administration of all-trans retinoic acid (ATRA) for the treatment of acute promyelocytic leukaemia. The overall results of this thesis showed improvement in survival over time for all age groups and subtypes of leukaemia. Early death after acute promyelocytic and myeloid leukaemias declined during the study period. However, these outcomes varied widely by age at diagnosis and were associated with sociodemographic and clinical factors. Racial/ethnical survival inequalities were identified and found to persist even after adjustment for other covariates. These inequalities were more marked among patients of Hispanic (acute lymphoblastic leukaemia) and black race/ethnicity (for acute lymphoblastic and myeloid leukaemias). Patients living in lower socioeconomic neighbourhoods had worse survival than those living in higher socioeconomic neighbourhoods (for acute lymphoblastic and myeloid leukaemias). Early death and worse survival were associated with initial care at hospitals not affiliated with National Cancer Institute-designated cancer centres (for acute myeloid leukaemia) and lack of health insurance (for acute myeloid and promyelocytic leukaemias). Intriguingly, over the 25-year study period, adolescents and young adults with acute leukaemia continued to have worse survival than children. These results suggest that lack of timely access to treatment and suboptimal care have influenced outcome among vulnerable patients. In conclusion, survival and early death after acute leukaemia has greatly improved among young patients in California. However, inequalities in outcomes remain and are likely a result of multiple factors. My studies highlight the importance of population-based data to reveal the actual burden of the disease in this population and help clinicians, policy makers, government, and researchers better understand the predictors of outcomes. I expect my work to contribute to the development of strategies aimed at improving survival from acute leukaemia, especially among

Pitfalls in the diagnosis of childhood leukaemia.

Erythroid Leukemia Is Increased at High Altitude (4000 m)

Exome Sequencing Identifies Highly Recurrent Somatic GATA2 and CEBPA Mutations in Acute Erythroid Leukemia