Transient abnormal myelopoiesis requiring advanced neonatal intensive care treatment.

AIM: Five to thirty percent of neonates with trisomy 21 develop transient abnormal myelopoiesis (TAM) with a high mortality rate. The aim of the study was to identify contributing factors that determine mortality and need for chemotherapy in this patient group. METHODS: Six-year, single-centre, retrospective study of neonatal TAM cases requiring admission to intensive care. Data were collected from electronic patient records, laboratory and genetic results. The odds ratio was calculated to assess the likelihood of neonates with certain clinical characteristics having short-term mortality and needing chemotherapy. RESULTS: Twenty-one neonates were studied with a mortality rate of 28%. Neonates requiring inotropic support (OR 19, 95% CI: 0.9-399, p = 0.05) and inhaled nitric oxide (iNO) (OR 13, 95% CI: 1.4-124.3, p = 0.03) were less likely to survive to discharge. Neonates needing mechanical ventilation (OR 14, 95% CI: 1.1-185.5, p = 0.04), or a white cell count >50 × 109/L (OR 27, 95% CI: 1.2-605.7, p = 0.04) were more likely to receive chemotherapy. CONCLUSION: A high mortality rate was identified in TAM neonates with symptomatic pulmonary hypertension (PH) needing active treatment strategies, such as inotropes and iNO. The presence of PH should be considered in the clinical management, prognosis and parental counselling.

miR-1202 acts as anti-oncomiR in myeloid leukaemia by down-modulating GATA-1S expression.

Transient abnormal myelopoiesis (TAM) is a Down syndrome-related pre-leukaemic condition characterized by somatic mutations in the haematopoietic transcription factor GATA-1 that result in exclusive production of its shorter isoform (GATA-1S). Given the common hallmark of altered miRNA expression profiles in haematological malignancies and the pro-leukaemic role of GATA-1S, we aimed to search for miRNAs potentially able to modulate the expression of GATA-1 isoforms. Starting from an in silico prediction of miRNA binding sites in the GATA-1 transcript, miR-1202 came into our sight as potential regulator of GATA-1 expression. Expression studies in K562 cells revealed that miR-1202 directly targets GATA-1, negatively regulates its expression, impairs GATA-1S production, reduces cell proliferation, and increases apoptosis sensitivity. Furthermore, data from TAM and myeloid leukaemia patients provided substantial support to our study by showing that miR-1202 down-modulation is accompanied by increased GATA-1 levels, with more marked effects on GATA-1S. These findings indicate that miR-1202 acts as an anti-oncomiR in myeloid cells and may impact leukaemogenesis at least in part by down-modulating GATA-1S levels.

Inherent genome instability underlies trisomy 21-associated myeloid malignancies.

Constitutional trisomy 21 (T21) is a state of aneuploidy associated with high incidence of childhood acute myeloid leukemia (AML). T21-associated AML is preceded by transient abnormal myelopoiesis (TAM), which is triggered by truncating mutations in GATA1 generating a short GATA1 isoform (GATA1s). T21-associated AML emerges due to secondary mutations in hematopoietic clones bearing GATA1s. Since aneuploidy generally impairs cellular fitness, the paradoxically elevated risk of myeloid malignancy in T21 is not fully understood. We hypothesized that individuals with T21 bear inherent genome instability in hematopoietic lineages that promotes leukemogenic mutations driving the genesis of TAM and AML. We found that individuals with T21 show increased chromosomal copy number variations (CNVs) compared to euploid individuals, suggesting that genome instability could be underlying predisposition to TAM and AML. Acquisition of GATA1s enforces myeloid skewing and maintenance of the hematopoietic progenitor state independently of T21; however, GATA1s in T21 hematopoietic progenitor cells (HPCs) further augments genome instability. Increased dosage of the chromosome 21 (chr21) gene DYRK1A impairs homology-directed DNA repair as a mechanism of elevated mutagenesis. These results posit a model wherein inherent genome instability in T21 drives myeloid malignancy in concert with GATA1s mutations.

Myeloid Proliferations Associated with Down Syndrome: Clinicopathologic Characteristics of Forty Cases from Five Large Academic Institutions.

INTRODUCTION: The incidence of myelodysplastic syndrome and acute myeloid leukemia is significantly increased in children with Down syndrome (DS). Within the revised 2016 WHO edition, these entities are jointly classified as myeloid leukemia associated with DS (ML-DS). Additionally, infants with DS may develop transient abnormal myelopoiesis (TAM) which is histomorphologically similar to ML-DS. While TAM is self-limiting, it is associated with an increased risk of subsequently developing ML-DS. Differentiating TAM and ML-DS is challenging but clinically critical. METHODS: We performed a retrospective review of ML-DS and TAM cases collected from five large academic institutions in the USA. We assessed clinical, pathological, immunophenotypical, and molecular features to identify differentiating criteria. RESULTS: Forty cases were identified: 28 ML-DS and 12 TAM. Several features were diagnostically distinct, including younger age in TAM (p < 0.05), as well as presentation with clinically significant anemia and thrombocytopenia in ML-DS (p < 0.001). Dyserythropoiesis was unique to ML-DS, as well as structural cytogenetic abnormalities aside from the constitutional trisomy 21. Immunophenotypic characteristics of TAM and ML-DS were indistinguishable, including the aberrant expression of CD7 and CD56 by the myeloid blasts. DISCUSSION: The findings of the study confirm marked biological similarities between TAM and ML-DS. At the same time, several significant clinical, morphological, and genetic differences were observed between TAM and ML-DS. The clinical approach and the differential diagnosis between these entities are discussed in detail.

Leukemoid reaction in minocycline-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: A brief report.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an idiosyncratic drug reaction hallmarked by cutaneous eruption, fever, lymphadenopathy, multiorgan involvement, and hematological abnormalities, most often eosinophilia and atypical lymphocytosis. Leukemoid reactions have rarely been described in DRESS syndrome and here we describe a 16-year-old male who was admitted to the hospital with DRESS syndrome due to minocycline, who had a severe leukocytosis up to 52.08 K/µL. He improved with cessation of minocycline and initiation of systemic steroids. We report this case to add to the literature on hematological abnormalities in pediatric DRESS syndrome.

A rare case of hepatic sinusoidal occlusive syndrome in a premature neonate with trisomy 21.

Trisomy 21 (Down Syndrome) may lead to multiple hematological and hepatobiliary manifestations including the development of transient abnormal myelopoiesis. While many cases resolve, transient abnormal myelopoiesis may lead to significant morbidity and mortality in a small percentage of patients. This condition may present a diagnostic challenge for physicians and currently there is only limited data on effective treatments, particularly with low blast percent transient abnormal myelopoiesis. We present a case of a neonate with trisomy 21 and multiple congenital anomalies who consequently developed hepatic failure with evidence of non-cirrhotic portal hypertension likely due to transient abnormal myelopoiesis. This clinical scenario highlights the need for additional evaluation for transient abnormal myelopoiesis associated hepatic disorder and possibly hepatic sinusoidal occlusive syndrome among trisomy 21 neonates particularly with low blast percentage.

The circulating cells with blast-like morphology in transient abnormal myelopoiesis of Down syndrome are unique and deserve a specific name: Would the term "megakaryogones" serve this purpose?

No abstract available.

Management of Down Syndrome-Associated Leukemias: A Review.

Importance: Down syndrome (DS), caused by an extra copy of material from chromosome 21, is one of the most common genetic conditions. The increased risk of acute leukemia in DS (DS-AL) has been recognized for decades, consisting of an approximately 150-fold higher risk of acute myeloid leukemia (AML) before age 4 years, and a 10- to 20-fold higher risk of acute lymphoblastic leukemia (ALL), compared with children without DS. Observations: A recent National Institutes of Health-sponsored conference, ImpacT21, reviewed research and clinical trials in children, adolescents, and young adults (AYAs) with DS-AL and are presented herein, including presentation and treatment, clinical trial design, and ethical considerations for this unique population. Between 10% to 30% of infants with DS are diagnosed with transient abnormal myelopoiesis (TAM), which spontaneously regresses. After a latency period of up to 4 years, 20% to 30% develop myeloid leukemia associated with DS (ML-DS). Recent studies have characterized somatic mutations associated with progression from TAM to ML-DS, but predicting which patients will progress to ML-DS remains elusive. Clinical trials for DS-AL have aimed to reduce treatment-related mortality (TRM) and improve survival. Children with ML-DS have better outcomes compared with non-DS AML, but outcomes remain dismal in relapse. In contrast, patients with DS-ALL have inferior outcomes compared with those without DS, due to both higher TRM and relapse. Management of relapsed leukemia poses unique challenges owing to disease biology and increased vulnerability to toxic effects. Late effects in survivors of DS-AL are an important area in need of further study because they may demonstrate unique patterns in the setting of chronic medical conditions associated with DS. Conclusions and Relevance: Optimal management of DS-AL requires specific molecular testing, meticulous supportive care, and tailored therapy to reduce TRM while optimizing survival. There is no standard approach to treatment of relapsed disease. Future work should include identification of biomarkers predictive of toxic effects; enhanced clinical and scientific collaborations; promotion of access to novel agents through innovative clinical trial design; and dedicated studies of late effects of treatment.

Retrospective analysis of leukemoid reactions in extremely preterm infants in a tertiary NICU from 2018-2021.

BACKGROUND: Neonatal leukemoid reaction is associated with higher risk of mortality, chronic lung disease and has been associated with chorioamnionitis. Literature on extremely low birth weight infants with leukemoid reaction is limited. OBJECTIVES: The aim of our study was to characterize the maternal and placental factors associated with neonatal leukemoid reaction and to describe outcomes of these ELBW infants. Our objective was to assess if there were maternal factors that would assist the decision-making process regarding the delivery of preterm infants at risk of chorioamnionitis and the sequelae of this inflammatory process. METHODS: This was a retrospective case-control study performed in a single, tertiary Maternity Hospital in Dublin. Two matched controls were identified for each case based on gestation and year of birth and data was collected on both the infants and their mothers. RESULTS: 7 extremely preterm neonates were identified as having a leukemoid reaction, defined as a total white cell count of >50,000 or in the first seven days of life. Baseline characteristics between the groups were similar. The median gestational age in the cases group was 24 + 4 weeks and in the control group was 24 + 1. The mean birthweight was 650 g in the cases group vs. 655 g in the control group. There was a higher percentage of males in the control group, 42.9% vs 28.6% in the cases. The preterm infants with leukemoid reaction had a longer duration of ventilation with a median of 18 days (7.5-23.5 days) compared to 6.5 days (2.8-24.5 days) in the control group. More infants in the leukemoid reaction group required inotropes for hypotension in the first 72 h after delivery (42.9% vs 7.1% in the controls, p value .169). Death or Bronchopulmonary dysplasia (BPD) occurred in 85.7% of the cases identified with a leukemoid reaction vs 71.4% of the controls matched. Median maternal CRP was higher in cases prior to delivery vs the controls (66 vs 18.1 mg/L, p-value = .2151). There was histological evidence of maternal inflammatory response in all cases with fetal inflammatory response in 71% of cases. CONCLUSIONS: Leukemoid reaction in ELBW infants with evidence of maternal and fetal inflammatory response syndrome on placental histology is associated with a longer duration of initial ventilation, increased need for inotropes in the first 72 h after birth, higher rates of death, and BPD. Prospective studies are required to identify potential biomarkers such as proinflammatory cytokines, IL-6, which might aid the decision-making process in delivery.

Common Blood Test Indices for Predicting Transient Abnormal Myelopoiesis-Related Mortality in Infants with Down Syndrome.

Transient abnormal myelopoiesis (TAM) can cause early death in children with Down syndrome, and liver failure is the most common cause of death. The aim of this single-center retrospective study was to identify a quantitative index for predicting TAM-related mortality at the time of diagnosis. Of the 462 children with Down syndrome admitted to our hospital from 1992 to 2021, we studied 12 infants with TAM-related death and 31 survivors who were diagnosed with TAM. In the death and survival groups, the median gestational ages were 34.9 and 37.1 weeks, respectively (p = 0.12). At diagnosis, the white blood cell (WBC) counts were 99.2 and 36.2 × 109/L (p = 0.011), the hemoglobin concentrations were 131 and 159 g/L (p = 0.009), and the serum albumin concentrations were 23 and 31 g/L (p < 0.001), respectively. The areas under the receiver operating characteristic curve for the abilities of the WBC count, hemoglobin, and serum albumin at diagnosis to predict survival were 0.75, 0.76, and 0.85, respectively. The serum albumin concentration threshold of 28 g/L at diagnosis had sensitivity of 0.79 and specificity of 0.82. Gestational age and serum albumin concentration were entered into a logistic regression model. The serum albumin concentration was an independent indicator of TAM-related death (adjusted odds ratio, 0.78; 95% confidence interval, 0.65-0.93; p = 0.005). In conclusion, a low serum albumin concentration at diagnosis may be a good predictor of TAM-related death.

Bullous eruptions in transient abnormal myelopoiesis with normal phenotype.

Cutaneous lesions are common manifestation of congenital leukaemia especially myeloid type with incidence of 25%-50% in reported cases. It is relatively rare in transient abnormal myelopoiesis (TAM) seen in trisomy 21 (~10%). The rashes seen in leukaemia and TAM are different. We report a case with a rare presentation of confluent bullous eruption in a phenotypically normal neonate with trisomy 21 restricted to haematopoietic blast cells. This rash resolved rapidly after low-dose cytarabine therapy with normalisation of total white cell counts. The risk of Down syndrome-associated myeloid leukaemia in such cases is still high (19%-23%) in first 5 years and rare thereafter.

Pediatric pyoderma gangrenosum associated with leukocyte adhesion deficiency type 1: A case report and review of the literature.

Pyoderma gangrenosum is a rare neutrophilic dermatosis characterized by painful skin ulcers with necrotic, undermined margins. In severe cases, particularly in pediatric patients, work-up for an associated autoimmune, inflammatory, malignant, or genetic disorder should be considered based on the clinical presentation. We report a unique case of pediatric pyoderma gangrenosum with a leukemoid reaction, secondary to an autosomal recessive leukocyte adhesion deficiency type 1.

Paraneoplastic leukemoid syndrome in squamous cell carcinoma of the forearm.

The paraneoplastic leukemoid reaction is a rare haematological paraneoplastic syndrome, which is typically seen with solid tumours and squamous cell carcinomas. As an indication of bone marrow infiltration and malignancy involvement, it indicates a poor outcome and a grave prognosis. We report a woman in her 50s, who presented with an ulcer over the right forearm. Biopsy revealed squamous cell carcinoma. The patient underwent radiological investigations, which showed the presence of metastatic squamous cell carcinoma. Incidentally, the patient was found to have leucocytosis, which was attributed to a paraneoplastic leukemoid reaction, after ruling out all other causes of leukemoid reaction. Due to metastatic disease, the patient was planned for palliative radiotherapy and the best supportive care.

Cytokine alterations during paraneoplastic neutrophilia and leukemoid reaction in patients with advanced melanoma.

BACKGROUND: Paraneoplastic leukemoid reaction (PLR) is a rare phenomenon in metastasized melanoma associated with poor prognosis and rapid disease progression. Currently, no specific therapeutic options exist other than treating the underlying malignancy. METHODS: Five cases of paraneoplastic neutrophilia in patients with advanced-stage IV melanoma were enrolled in our study. Cytokine concentrations in patients' serum samples were analyzed before and during PLR using a multiplex cytokine array. Further, immunohistochemical staining of tumor tissue biopsied during PLR was performed. RESULTS AND CONCLUSIONS: We observed a strong correlation between worsening of tumor burden and aggravation of neutrophilia. Cytokine measurements revealed an increase of proinflammatory cytokines (IL6, IFNγ), proangiogenic cytokines (VEGF) and immune stem cell growth factors (G-CSF) during PLR. Immunohistochemistry confirmed neutrophil infiltration of tumor tissue. The presented cytokine alterations provide a basis for further functional analysis, which is necessary for the development of targeted therapeutic approaches against PLR.

Transient abnormal myelopoiesis in Down syndrome: Experience of long term follow up from a single tertiary center in Thailand.

Transient abnormal myelopoiesis (TAM) is a unique disease occurring in Down syndrome (DS) infants from which most patients have spontaneous remission. This study aimed to evaluate the incidence and outcomes of TAM in a tertiary center in Thailand. We reviewed the records of 997 DS patients diagnosed between June 1993 and October 2019. From the 997 DS patients, 32 had been diagnosed with TAM. The incidence of TAM was 3.2% and an overall survival rate of 87.5%. A total of 2/28 who survived (7.1%) subsequently developed AML-DS at the ages of 2.1 and 4.5 years, respectively. The risk factors related with death included maternal multiparity, sepsis, skin bleeding, subcutaneous nodules, high WBC count, low hemoglobin, and elevated AST level.Abbreviations.

Leukemogenesis in infants and young children with trisomy 21.

Children with Down syndrome (DS) have a greater than 100-fold increased risk of developing acute myeloid leukemia (ML) and an approximately 30-fold increased risk of acute lymphoblastic leukemia (ALL) before their fifth birthday. ML-DS originates in utero and typically presents with a self-limiting, neonatal leukemic syndrome known as transient abnormal myelopoiesis (TAM) that is caused by cooperation between trisomy 21-associated abnormalities of fetal hematopoiesis and somatic N-terminal mutations in the transcription factor GATA1. Around 10% of neonates with DS have clinical signs of TAM, although the frequency of hematologically silent GATA1 mutations in DS neonates is much higher (~25%). While most cases of TAM/silent TAM resolve without treatment within 3 to 4 months, in 10% to 20% of cases transformation to full-blown leukemia occurs within the first 4 years of life when cells harboring GATA1 mutations persist and acquire secondary mutations, most often in cohesin genes. By contrast, DS-ALL, which is almost always B-lineage, presents after the first few months of life and is characterized by a high frequency of rearrangement of the CRLF2 gene (60%), often co-occurring with activating mutations in JAK2 or RAS genes. While treatment of ML-DS achieves long-term survival in approximately 90% of children, the outcome of DS-ALL is inferior to ALL in children without DS. Ongoing studies in primary cells and model systems indicate that the role of trisomy 21 in DS leukemogenesis is complex and cell context dependent but show promise in improving management and the treatment of relapse, in which the outcome of both ML-DS and DS-ALL remains poor.

Epithelioid Inflammatory Myofibroblastic Sarcoma with Leukemoid Reaction.

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is a rare and aggressive inflammatory myofibroblastic tumour (IMT) variant. This report identifies the first case of EIMS with leukemoid reaction. This is also the first case in which pancreatic infiltration occurred from the disease onset. A 14-year male patient presented with an 18×18×10 cm mass at the retroperitoneal space and a white blood cell (WBC) count of 85×109/L. The mass and the invaded tissues were surgically removed with tumour-free margins. Histopathology and bone marrow aspiration confirmed the diagnosis of EIMS with leukemoid reaction. The tumour recurred with hepatic and pulmonary metastasis one month after the surgery. WBC count also increased progressively with the tumour recurrence. There is no consensus on the treatment of EIMS. Since ALK rearrangement presents in all the EIMS cases, surgical resection combined with crizotinib or other targeted drugs may improve the prognosis. Key Words: Sarcoma, Soft tissue neoplasms, Leukemoid reaction, Crizotinib.