Survival outcomes of myeloid leukemia associated with Down syndrome and de novo acute myeloid leukemia in children: Experience from a single tertiary center in Thailand.

Few studies have reported the survival outcomes of myeloid leukemia associated with Down syndrome (DS) in resource-limited countries. This study aimed to compare characteristics and survival outcomes of children with acute myeloid leukemia (AML) between those with and without DS in Thailand. The medical records of AML patients aged 0-15 years treated in a major tertiary center in Southern Thailand between October 1978 and December 2019 were reviewed retrospectively. The overall (OS) and event-free survivals (EFS) rates were calculated using the Kaplan-Meier method. A total of 362 AML patients were included, of which 41 (11.3%) had DS. The mean age at diagnosis of the DS patients was 2.5 ± 1.9 years and most of them (90.2%) were under the age of five. The DS patients had lower initial white blood cell counts and peripheral blasts compared to the non-DS patients. The AML-M7 subtype was more common in the DS than in the non-DS patients (80.5% vs. 9.1%, p < 0.01, respectively). The 5-year OS and EFS rates of the DS patients were lower compared to the non-DS patients (12.9% vs. 20.5%, p = 0.05 and 13.7% vs. 18.4%, p = 0.03, respectively). DS patients had a significantly higher rate of early and treatment-related deaths compared to non-DS patients (30.3% vs. 13.5%, p < 0.01 and 39.4% vs. 19.5%, p = 0.02, respectively). Over the study period, there were a decrease in early death rate and an increase in survival rates of DS patients, which suggests that chemotherapy regimens and supportive care have improved over time.

[Chronic neutrophilic leukemia/chronic eosinophilic leukemia].

Chronic neutrophilic leukemia (CNL) is a clonal disorder that is characterized by increasing mature neutrophils. Colony stimulating factor 3 receptor (CSF3R) T618I mutation was frequently identified in patients with CNL and is defined as a molecular marker of the disease. Ruxolitinib, a JAK2 inhibitor, provided a promising therapeutic effect in a phase II study. In particular, ruxolitinib was more efficient for patients with CSF3R mutation. Allogeneic stem cell transplantation (Allo-SCT) may be a curative treatment for CNL. On the other hand, further studies are needed to define the optimal method of transplantation, source of donor, conditioning therapy, and timing of transplantation. Chronic eosinophilic leukemia (CEL) is a clonal disorder that is characterized by increasing eosinophils. In the World Health Organization Classification 5th edition, diagnostic criteria for CEL are renewed. Because the new criteria will be more specific for CEL than criteria in the older edition, "not otherwise specified (NOS) " is removed from the name of the disease. Anti-CD52 antibody, alemtuzumab, or anti-IL-5 antibody, mepolizumab, are promising drugs to control symptoms that are associated with hypereosinophilic syndrome. Allo-SCT is anticipated as a curative treatment for CEL, but the evidence of Allo-SCT for CEL is still limited. Further study is required to define the treatment strategy.

[Posterior reversible encephalopathy syndrome during nilotinib treatment for chronic myeloid leukemia].

Here we present the case of a 50-year-old woman with chronic myeloid leukemia who received nilotinib as initial treatment. After about 2 years of nilotinib therapy, she developed headache, blurred vision, impaired consciousness, and marked hypertension. Posterior reversible encephalopathy syndrome (PRES) was diagnosed, and was strongly suspected to be a vascular adverse event caused by nilotinib. Nilotinib was withheld and the patient was treated with antihypertensive drugs under ventilator management. Her symptoms resolved quickly. The most likely cause of PRES is systemic arterial hypertension and endothelial dysfunction due to direct injury leading to dysfunction at the level of the blood-brain barrier, along with the resultant vasogenic edema. PRES has been reported with some tyrosine kinase inhibitors, but this is the first case of PRES during nilotinib treatment.

"TAM"ing of the shrew-challenges in the diagnosis of Neonatal leukemia with Down's syndrome -A case report with literature review.

The latest WHO (2017) classification describes the hematological abnormalities of Down's syndrome as a separate entity under 'Myeloid proliferations associated with Down's syndrome'. It includes Transient Abnormal Myelopoiesis and Myeloid leukemia of Down's syndrome. Here we report a case of a 3 days old neonate with Down's syndrome, presenting with a leukemic blood picture. The baby had icterus, fever and hepatosplenomagaly. Peripheral blood showed megakaryoblasts and giant platelets. A diagnosis of transient abnormal myelopoiesis was made by confirming with karyotyping and immunophenotyping. We attempt to address all the diagnostic challenges faced by a clinician and pathologist same, upon encountering such a case,by following an algorithmic approach. The mandatory need for follow up and cytogenetic studies in identifying high risk cases that will become myeloid leukemia of Down's syndrome are stressed. Our case also throws light upon the significance of identification of GATA1 mutation in diagnosing and prognostication of such cases.

Germline GATA1s-generating mutations predispose to leukemia with acquired trisomy 21 and Down syndrome-like phenotype.

Individuals with Down syndrome are at increased risk of myeloid leukemia in early childhood, which is associated with acquisition of GATA1 mutations that generate a short GATA1 isoform called GATA1s. Germline GATA1s-generating mutations result in congenital anemia in males. We report on 2 unrelated families that harbor germline GATA1s-generating mutations in which several members developed acute megakaryoblastic leukemia in early childhood. All evaluable leukemias had acquired trisomy 21 or tetrasomy 21. The leukemia characteristics overlapped with those of myeloid leukemia associated with Down syndrome, including age of onset at younger than 4 years, unique immunophenotype, complex karyotype, gene expression patterns, and drug sensitivity. These findings demonstrate that the combination of trisomy 21 and GATA1s-generating mutations results in a unique myeloid leukemia independent of whether the GATA1 mutation or trisomy 21 is the primary or secondary event and suggest that there is a unique functional cooperation between GATA1s and trisomy 21 in leukemogenesis. The family histories also indicate that germline GATA1s-generating mutations should be included among those associated with familial predisposition for myelodysplastic syndrome and leukemia.

Prognostic significance of long non coding maternally expressed gene 3 in pediatric acute myeloid leukemia.

ABSTRACT: The purpose of this study was to evaluate the correlation of long non-coding RNA maternally expressed gene 3 (Lnc-MEG3) with disease features, treatment response, and survival in pediatric acute myeloid leukemia (AML) patients.Among 92 de novo pediatric AML patients (before treatment and after 1 course of induction) and 40 controls, bone marrow mononuclear cells were obtained. Then, Lnc-MEG3 expression was determined by reverse transcription quantitative polymerase chain reaction. After 1 course of standard induction therapy of pediatric AML patients, complete remission (CR) was assessed. Furthermore, event-free survival (EFS) and overall survival (OS) were determined according to follow-up data.Lnc-MEG3 was reduced in pediatric AML patients compared with controls. In pediatric AML patients, Lnc-MEG3 was correlated with French-American-Britain subtypes and lower Chinese Medical Association risk stratification, while it was not associated with cytogenetic features, FLT3-ITD mutation, CEBPA mutation, NPM1 mutation, WT1 mutation, or National Comprehensive Cancer Network risk stratification. After 1 course of treatment, Lnc-MEG3 exhibited an up-regulation trend. Furthermore, Lnc-MEG3 was of no difference before treatment between patients with and without CR, while elevated Lnc-MEG3 and change of Lnc-MEG3 after 1 course of treatment were associated with increased CR rate. Additionally, increased Lnc-MEG3 expression before treatment was associated with longer EFS but not OS, while enhanced Lnc-MEG3 expression after 1 course of treatment was correlated with both prolonged EFS and OS.Lnc-MEG3 may have clinical significance as a biomarker for assisting with disease management, treatment optimization, and prognosis improvement in pediatric AML patients.

High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial.

Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children's Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (<0.05%) and did not receive the historically administered HD-AraC course. Interim analysis of 114 SR patients revealed a 2-year EFS of 85.6% (95% confidence interval [CI], 75.7-95.5), which was significantly lower than for MRD- patients treated with HD-AraC on AAML0431 (P = .0002). Overall survival at 2 years was 91.0% (95% CI, 83.8-95.0). Twelve SR patients relapsed, mostly within 1 year from study entry and had a 1-year OS of 16.7% (95% CI, 2.7-41.3). Complex karyotypes were more frequent in SR patients who relapsed compared with those who did not (36% vs 9%; P = .0248). MRD by error-corrected sequencing of GATA1 mutations was piloted in 18 SR patients and detectable in 60% who relapsed vs 23% who did not (P = .2682). Patients with SR ML-DS had worse outcomes without HD-AraC after risk classification based on flow cytometric MRD.

Serum Aspergillus galactomannan lateral flow assay for the diagnosis of invasive aspergillosis: A single-centre study.

BACKGROUND: Aspergillus species meet the most important group of invasive fungal diseases (IFD) in immunosuppressed patients. Galactomannan is a polysaccharide antigen located in the wall structure of Aspergillus. The most commonly used method for antigen detection is enzyme-linked immunoassay (ELISA). Aspergillus galactomannan lateral flow assay (LFA) constitutes one of the new methods in the diagnosis of invasive aspergillosis (IA). The goal of this study was to demonstrate efficacy of LFA in our patients and to compare it to synchronous ELISA results. METHODS: Galactomannan antigen was examined using both LFA and ELISA in serum samples taken from patients who were followed up in our haematology clinic. All patients are classified in subgroups as 'proven', 'probable' and 'possible' patients according to the last EORTC / MSG guideline. Patients who met the 'proven' IA criteria were included in the study as the gold standard. RESULTS: A total of 87 patients were included in the study. Majority of patients had acute myeloid leukaemia (AML) (56.3%). Eleven (12.6%) were in 'proven' IA group. LFA test showed a superior diagnostic performance compared with ELISA (LFAAUC  = 0.934 vs ELISAAUC  = 0.545; p < .001). The LFA had a sensitivity of 90.9% and a specificity of 90.8% for '0.5 ODI' in predicting IA (PPV = 55.8%; NPV = 98.6%; p < .001). CONCLUSION: The most important finding of this study is that the specificity of LFA was found to be higher for cut-off value of 0.5. It is recommended to combine the methods in many studies to provide a better early diagnosis for IA.

Erdheim-Chester disease.

Erdheim-Chester disease (ECD) is characterized by the infiltration of tissues by foamy CD68+CD1a- histiocytes, with 1500 known cases since 1930. Mutations activating the MAPK pathway are found in more than 80% of patients with ECD, mainly the BRAFV600E activating mutation in 57% to 70% of cases, followed by MAP2K1 in close to 20%. The discovery of BRAF mutations and of other MAP kinase pathway alterations, as well as the co-occurrence of ECD with LCH in 15% of patients with ECD, led to the 2016 revision of the classification of histiocytoses in which LCH and ECD belong to the "L" group. Both conditions are considered inflammatory myeloid neoplasms. Ten percent of ECD cases are associated with myeloproliferative neoplasms and/or myelodysplastic syndromes. Some of the most striking signs of ECD are the long bone involvement (80%-95%), as well as the hairy kidney appearance on computed tomography scan (63%), the coated aorta (40%), and the right atrium pseudo-tumoral infiltration (36%). Central nervous system involvement is a strong prognostic factor and independent predictor of death. Interferon-α seems to be the best initial treatment of ECD. Since 2012, more than 200 patients worldwide with multisystem or refractory ECD have benefitted from highly effective therapy with BRAF and MEK inhibitors. Targeted therapies have an overall, robust, and reproducible efficacy in ECD, with no acquired resistance to date, but their use may be best reserved for the most severe manifestations of the disease, as they may be associated with serious adverse effects and as-yet-unknown long-term consequences.

A Case of Granulocytic Sarcoma of the Lung in Acute Myeloid Leukemia.

BACKGROUND: Granulocytic sarcoma in the lung is a rare presentation of acute myeloid leukemia (AML). Here, we describe a rare case of granulocytic sarcoma of the lung in a 56-year-old male patient with AML. METHODS: Hematologic investigation, bone marrow aspirate, cytogenetic analysis, chest computed tomography (CT), and pulmonary biopsy were performed. RESULTS: The patient achieved complete remission (CR) after induction therapy, but the patient refused further treatment and was lost to follow-up. CONCLUSIONS: Pulmonary biopsy and bone marrow aspirate are important to confirm a correct diagnosis. Pulmo-nary granulocytic sarcoma as a prognostic factor needs further studies.

Quantitative Lipidomics in Pulmonary Alveolar Proteinosis.

Rationale: Pulmonary alveolar proteinosis (PAP) is characterized by filling of the alveolar spaces by lipoprotein-rich material of ill-defined composition, and is caused by molecularly different and often rare diseases that occur from birth to old age.Objectives: To perform a quantitative lipidomic analysis of lipids and the surfactant proteins A, B, and C in lavage fluids from patients with proteinosis of different causes in comparison with healthy control subjects.Methods: During the last two decades, we have collected BAL samples from patients with PAP due to autoantibodies against granulocyte-macrophage colony-stimulating factor; genetic mutations in CSF2RA (colony-stimulating factor 2 receptor α-subunit), MARS (methionyl aminoacyl-tRNA synthetase), FARSB (phenylalanine-tRNA synthetase, ß-subunit), and NPC2 (Niemann-Pick disease type C2); and secondary to myeloid leukemia. Their lipid composition was quantified.Measurements and Main Results: Free cholesterol was largely increased by 60-fold and cholesteryl esters were increased by 24-fold. There was an excessive, more than 130-fold increase in ceramide and other sphingolipids. In particular, the long-chain ceramides d18:1/20:0 and d18:1/24:0 were elevated and likely contributed to the proapoptotic environment observed in PAP. Cellular debris lipids such as phosphatidylethanolamine and phosphatidylserine were only moderately increased, by four- to sevenfold. The surfactant lipid class phosphatidylcholine expanded 17-fold, lysophosphatidylcholine expanded 54-fold, and the surfactant proteins A, B, and C expanded 144-, 4-, and 17-fold, respectively. These changes did not differ among the various diseases that cause PAP.Conclusions: This insight into the alveolar lipidome may provide monitoring tools and lead to new therapeutic strategies for PAP.

Acute myeloid leukemia with t(8;21)(q22;q22.1)/RUNX1-RUNX1T1 and KIT Exon 8 mutation is associated with characteristic mastocytosis and dismal outcomes.

KIT mutations are observed in about 20-40% of acute myeloid leukemia with t(8;21)(q22;q22.1)/RUNX1-RUNX1T1 [abbreviated AML t(8;21) here] with mutations involving exon 17 being the most common. Despite high frequencies of KIT mutations in both AML t(8;21) and systemic mastocytosis (SM), AML t(8;21) associated with SM is uncommon, and restricted to KIT exon 17 mutated cases. In this study, we report two cases of AML t(8;21) associated SM that KIT mutation occurred in exon 8 (T417_D419delinsY). In both patients, the bone marrow displayed increased round/ovoid mast cells with bilobated nuclei and absence of CD2 and CD25 expression. RUNX1/RUNX1T1 fusion was shown in both myeloblasts and mast cells by FISH. Patient #1 was refractory to induction chemotherapy and died at day 50; patient #2 had residual AML, marked SM, and persistent RUNX1/RUNX1T1 fusion after induction therapy.

Neutrophilic Dermatoses Associated with Myeloid Malignancies.

Neutrophilic dermatoses (ND) are a group of conditions characterized by an aseptic accumulation of polymorphonuclear leukocytes in the skin. Occurrence of ND in association with myeloid malignancies, mainly myelodysplastic syndrome and myelogenous acute leukemia, is not rare and is often associated with a poor prognosis. Recent findings have improved understanding of the pathophysiology of myeloid malignancy-associated ND. We review the clinical spectrum of myeloid malignancy-associated ND with an emphasis on recently identified mechanisms. Myeloid leukemia cells retain the potential for terminal differentiation into polymorphonuclear leukocytes in the skin. Many studies suggest a clonal link between myeloid malignancies and ND. Activation of autoinflammatory pathways (NOD-like receptor family pyrin domain-containing-3, Familial Mediterranean Fever Gene) in the clonal cells of myeloid disorders may also be involved in this setting.

Vemurafenib-induced histiocytoid neutrophilic panniculitis simulating myeloid leukaemia cutis.

Neutrophilic panniculitis is an infrequent but characteristic adverse event under therapy with BRAF inhibitors (BRAFi). Since the approval of vemurafenib for treatment of metastatic melanoma in 2011, only two cases of neutrophilic panniculitis in malignancies other than melanoma have been published. Histiocytoid infiltrates of immature neutrophils resembling histiocytes or myelocytes have been reported in Sweet's syndrome and rarely in other neutrophilic dermatoses. We describe a novel variant of neutrophilic panniculitis with histiocytoid myeloid cells in an early lesion from a patient treated with vemurafenib in combination with an anti-EGFR (epidermal growth factor receptor) agent for metastatic colon carcinoma, three weeks after initiation of therapy. Recognizing this variant of panniculitis associated to BRAFi can avoid misinterpretation of the atypical subcutaneous infiltrate as myeloid leukaemia cutis.