Occurrence Of Acute Myeloid Leukemia Research Articles

Association between direct acting agents used for chronic hepatitis C virus infection and the occurrence of acute leukaemia – A disproportionality analysis

BACKGROUND AND AIMSA recent single-center study reported a significant increase in acute myeloid leukaemia (AML) cases, including mixed-phenotype acute leukaemia (MPAL), after exposure to direct acting agents (DAA). We investigated whether DAA use increased the risk of AML in patients with chronic hepatitis C virus (HCV) infection. METHODSWe conducted a disproportionality analysis of the WHO Pharmacovigilance database Vigibase up to 2020. Queries focused on all DAAs, subclasses, combinations or each DAA separately as well as interferon and ribavirin as negative controls. The primary outcome was AML. Secondary outcomes were AML without MPAL, MPAL, acute lymphoid leukemia (ALL) and acute leukemia (AL, high-level term encompassing AML, ALL, MPAL and unspecified acute leukemia [UAL]). The information component (IC0.25) and proportional reporting ratio (PRR0.25) were computed to assess a potential pharmacovigilance signal. RESULTSWe identified 49 notifications reporting any AL occurrence after anti-HCV treatments from June 1997 to December 2020: 23 (47%) involved a DAA, 24 (49%) interferon and 12 (24%) ribavirin. The DAAs sofosbuvir and ledipasvir were suspected in 74% (n = 17) and 39% (n = 9) of cases. The events reported were AML (n = 22), ALL (n = 11), AML and ALL (n = 1) and UAL (n = 15) and no MPAL. DAA, interferon or ribavirin were not significantly associated with AML, ALL or AL. CONCLUSIONThis study did not find any association between DAA exposure and the occurrence of AML. Nevertheless, vigilance should remain, particularly for MPAL, which may not have been well captured in our study because of its rareness and high risk of misclassification.

KLK2 single-nucleotide polymorphism rs198977 is associated with increased susceptibility and hyperleukocytosis in AML.

Introduction: Acute myeloid leukemia (AML) is a heterogeneous myeloid malignancy with abnormal molecular diversity. Tissue kallikrein 2 (KLK2) is a kind of serine protease, and has a close relationship with the occurrence and development of malignant tumors. Single nucleotide polymorphism (SNP) of various genes are associated with susceptibility, treatment and survival of AML. Methods: We investigated the association of KLK2 SNPs rs198977 and rs2664155 with AML. We recruited 284 AML patients and 280 healthy controls from the Han population and genotyping KLK2 SNPs rs198977 and rs2664155 by MassARRAY system. Results: Using clinical data from AML patients and controls, including AML susceptibility, blood count, risk stratification, response to induced chemotherapy and survival, our results showed an increased risk of AML susceptibility with KLK2 rs198977 TT genotype in the recessive model. Regarding white blood cell counts in AML patients, the results showed an increased risk of hyperleukocytosis with the TT genotype of KLK2 rs198977 in a codominant model. Moreover, in the recessive model, AML with KLK2 SNPs rs198977 TT genotype had an increased risk of hyperleukocytosis. No significant correlation was found between KLK2 rs2664155 and AML. Discussion: This study suggests that KLK2 rs198977 may be an important genetic factor in the occurrence of AML and hyperleukocytosis in AML, providing a new perspective for disease progression and new therapeutic targets.

Simultaneous Occurrence of Acute Myeloid Leukemia and Chronic Lymphocytic Leukemia: A Case Report

Simultaneous Occurrence of Acute Myeloid Leukemia and Chronic Lymphocytic Leukemia: A Case Report

Systematic Construction and Validation of an RNA-Binding Protein-Associated Prognostic Model for Acute Myeloid Leukemia.

Background: The abnormal expression of RNA-binding proteins (RBPs) in various malignant tumors is closely related to the occurrence and development of tumors. However, the role of RBPs in acute myeloid leukemia (AML) is unclear.Methods: We downloaded harmonized RNA-seq count data and clinical data for AML from UCSC Xena, including The Cancer Genome Atlas (TCGA), The Genotype-Tissue Expression (GTEx), and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) cohorts. R package edgeR was used for differential expression analysis of 337 whole-blood data and 173 AML data. The prognostic value of these RBPs was systematically investigated by using univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO)–Cox regression analysis, and multivariate Cox regression analysis. C-index and calibration diagram were used to judge the accuracy of the model, and decision curve analysis (DCA) was used to judge the net benefit. The biological pathways involved were revealed by gene set enrichment analysis (GSEA). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and the protein–protein interaction (PPI) network performed lateral verification on the selected gene set and LASSO results.Results: A prognostic model of 12-RBP signature was established. In addition, the net benefit and prediction accuracy of the prognostic model and the mixed model based on it were significantly higher than that of cytogenetics. It is verified in the TARGET cohort and shows good prediction effect. Both the selection of our gene set and the LASSO results have high credibility. Most of these pathways are involved in the development of the disease, and they also accumulate in leukemia and RNA-related pathways.Conclusion: The prognosis model of the 12-RBP signature found in this study is an optimized biomarker that can effectively stratify the risk of AML patients. Nomogram based on this prognostic model is a reliable method to predict the median survival time of patients. This study expands our current understanding of the role of RBPs in the occurrence of AML and may lay the foundation for future treatment of the disease.

Simultaneous Occurrence Of Multiple Myeloma and Acute Myeloid Leukemia: A Dual Malignancy Of The Hematopoietic System

The occurrence of acute myeloid leukemia (AML) after the treatment for multiple myeloma (MM) is well described in several cases. The simultaneous presentation of MM and AML is very rare, with only 17 cases reported in articles found at PubMed.A 69 years old woman was sent at our institution for consultation due to pancitopenia at check-up. Past medical history was irrelevant. The CBC reported Hb 11.3 g/dL, Htc 33.8 %, ESR 32 mm/hr, Rouleaux formation +++, WBC 24.5 K/µL; differential showing nuetrophils 0.748 K/μL, lymphocytes 2.2 K/μL and myeloid blasts 20.1 K/µL, platelets 23.4 K/µL. The bone marrow aspiration was hypercellular with infiltration by myeloid blasts counting 95 %, and plasma cells with neoplastic morphology counting the remaining 5 %, no normal hematopoietic cells were observed. Hematological malignancy work up, also for MM, was performed, including flow cytometry (FC) and G band karyotype (GBK). FC revealed three populations: 1) representing 82.9 % that expressed CD11b +, CD13 ++, CD33 +, CD34 +, CD 38 +, HLA-DR + and MPO +; 2) representing 4.6 % and expressed CD38 +++, CD56 +, CD138 +++, kappa ++; 3) mixed population of normal B and T cells, representing 12.5 %. GBK showed 18 normal metaphases and 2 metaphases with t(11:14) (q13:q32) and del(13q). Stratification tests reported creatinin 2.3 mg/dL, , Ca 10.15 mg/dL, us-CRP 23 mg/dL, β-2-microglobulin 7.751 mg/L, albumin 2.35 g/dL, globulin 5.75 g/dL, serum protein electrophoresis with M-spike in the gamma region with 4.12 g/dL, positive Bence Jones protein, X-ray from the skull showed multiple lytic lesions. High risk MM and AML M4 were diagnosed. The patient did not accept any treatment and died few days later due a pulmonary hemorrhage.There is no pathophysiologic mechanism that explains the simultaneous occurrence. MM is a slowly disease, it may lead to chromosomal instability and immunosuppression with failure to eliminate clones of leukemic cells. No effective treatment is currently available, allogeneic stem cell transplantation is the best option. [Display omitted] [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Interesting and Rare Case of Central Diabetes Insipidus in a Patient With Acute Myeloid Leukemia

Introduction: Central Diabetes Insipidus (CDI) is the lack of antidiuretic hormone (ADH) leading to impaired urinary concentration and manifests with extreme thirst and excessive urination. Patients unable to drink fluids are at risk of severe dehydration and hypernatremia. CDI can be a rare complication of acute myeloid leukemia (AML). The occurrence of AML with CDI is extremely rare with only few case reports published. This combination of AML with CDI has been reported to be associated with monosomy 7 and inversion (3) (q21q26) and portends an overall a very poor treatment response resulting in poor outcomes.Case Presentation: 66-year-old female with hypertension, polycythemia vera diagnosed in 2006 with transformation to AML in 2020. FISH studies revealed monosomy 7. Cytogenetic studies showed inv (3)(q21q26.2). Remission induction chemotherapy was initiated. Subsequently, neutropenic fever and sepsis secondary to Clostridium difficile colitis lead to hospitalization. Her sodium (Na) level gradually trended up and reached a peak of 157 mmol/l (range 136-145) and elevated serum osmolality at 311 mOsm/K with low urine osmolality 135 mOsm/K, low urine sodium at 13 and low urine specific gravity 1.006 concerning for CDI. She developed polyuria and received desmopressin (DDAVP) leading to improvements in urine osmolality to 267 mOsm/K, 30 minutes indicating CDI diagnosis. Her Na gradually normalized to 144 mmol/l, urine osmolality improved to 580 mOsm/K and urine specific gravity to 1.025. She is now on DDAVP 0.05 mg oral twice daily and her Na is in normal range. MRI pituitary did not show any evidence of metastatic lesion with intact pituitary bright spot. Her other pituitary hormonal workup was normal except for hypogonadotropic hypogonadism.Discussion: The pathophysiology of AML and CDI is unclear. Leukemic cells infiltration of the neurohypophysis; thrombosis of small vessels in hypothalamic nuclei and the posterior pituitary; alterations of the neutrophil migration placed on the chromosome 7 leading to glycoprotein gp 130 production, a cell surface marker on granulocytes are some of hypothesis suggested. CDI has a variable onset in the course of myeloid malignancies. MRI pituitary can be normal in most of the cases.

First Description of Upfront Target Therapy Treating AML and Bcll Presented Simultaneously As First Line

INTRODUCTION: The occurrence of acute myeloid leukemia (AML) and chronic lymphoid leukemia (B-CLL) simultaneously is rarely described. We describe a case report of AML and B-CLL, diagnosed simultaneously, without any previous treatment for any of the hematological neoplasms [1]. The patient received low-dose cytarabine (ARA-C) and Venetoclax, which is medically indicated on label for both hematological neoplasms. CASE REPORT: A 75-year-old male, presented with edema and joint pain one month before hospital admission, showing pancytopenia on a complete blood count and presence of blasts in peripheral blood. The patient was then referred to the hematology service. The morphological analysis of the bone marrow aspirate showed 67.7% of myeloblasts, compatible with AML. Bone marrow immunophenotyping was performed, which identified 34.10% of myeloblasts, compatible with AML and 50.48% of monoclonal B lymphocytes (chronic B-cell lymphoproliferative disease). In flow cytometry there were two distinct populations of myeloblasts. Type 1 myeloblasts labeling CD7 +, CD13 +, CD34 ++, CD38 ++, CD45 ++, CD56 ++, CD117 ++, CD123 +, HLA-DR +++ and MPO + / ++. The second population marked CD13 + / ++, CD34 + / ++, CD38 ++, CD45 +, CD117 ++, CD123 +, HLA-DR ++ / +++ and MPO + (30%). Monoclonal lymphocytes showed CD11c + / ++ (70%), CD19 ++, CD20 + / ++ (84%), CD22 + (39%), CD23 + / ++, CD25 +, CD31 +/-, CD43 ++, CD45 ++ / +++, CD81 + (38%), CD200 + (85%) and Lambda +. The molecular study was negative for genetic abnormalities: FLT3, KIT and NPM, configuring the patient as an intermediate risk for AML. In the cytogenetic analysis there was no growth of metaphases. Patient received simultaneous diagnosis of AML and B-CLL. As he was ineligle to intensive chemotherapy (IC), we started original protocol Subcutaneous Cytarabin+venetoclax(VIALE C). The patient had grade 2-3 AE(neutropenia managed with GCSF) ending the fourth cycle in July 2020. The evolution of hematimetric parameters and diseases are described in graphics. DISCUSSION: This is the first described case in our knowledge treated upfront with bcl2-inh target therapy for two absolutely different hematological neoplasms: AML and BCLL. Nowadays we are experiencing a new therapeutic model in oncohematology, in which the targeted therapy is gaining ground in relation to IC with excellent results. In this way, the importance of comprehension of the pathophysiological mechanism of the neoplasms and the way we can stop the disease proliferation is progressively guiding the new protocols. Elderly patients are more likely to have early treatment-related death and exhibit therapeutic resistance, limiting alternatives. We decided to start first-line treatment with ARA-C and Venetoclax [2]. Venetoclax associated with ARA-C has a manageable safety profile, producing quick and durable remissions in elderly people with AML ineligible for IC, as well as in B CLL, being the best therapeutic alternative for the case, in our opinion. Venetoclax belongs to a group of drugs called Bcl-2 inhibitors, an anti-apoptotic protein, which works by blocking this protein in the body, causing apoptosis of both neoplastic cells. The high rate of remission and low early mortality, combined with fast and durable remission, make Venetoclax and ARA-C a new and attractive treatment for the elderly [2]. In our case, the intention of the product in the first line was not B-CLL, but it would certainly be a good option for this profile of elderly patients. CONCLUSION: We report the first description of simultaneous diagnosis of AML and B CLL treated with a Bcl-2 inhibitor, demonstrating that antitumor mechanisms can be extremely effective in completely different diseases. We have a long way to go in the search for full knowledge of oncohematological diseases and targeted therapies. However, this case report shows that we are on the right track.

Double trouble: A case of synchronous presentation of acute myeloid leukaemia and multiple myeloma

Malignancies following successful chemotherapy for various malignant diseases, including multiple myeloma (MM), are well known and documented. The occurrence of acute myeloid leukaemia (AML) after chemotherapy for MM with alkylating agents is well described; however, simultaneous occurrence of the two entities with no prior therapy is extremely rare. We describe a case of an elderly patient with no previous exposure to chemotherapy, who was diagnosed with both MM and AML concurrently. Very few similar cases have been described in the literature.

Meta-analysis of case-control studies to examine the relationship between occupational pesticide exposure and risk of acute myeloid leukemia.

7540 Background: Occupational pesticide exposure (OPE) is associated with the risk of developing lymphoid malignancies, but less information is available on large cohorts about the risk of occurrence of acute myeloid leukemia (AML). To answer this question, we performed a meta-analysis including relevant adult case-control studies which reported OPE. Methods: Following PRISMA and MOOSE guidelines, two investigators performed a systematic search in PubMed and Cochrane databases for case-control studies evaluating the association between OPE and AML between 1946 and August 28, 2018. In order to identify the maximum number of studies, keywords related to demographical, pesticides and chemicals data exposures were used. Studies reporting AML diagnosis based only on death certificates, controls from cancer databases and pediatric cases (<15 years-old) were not included. Statistical analyses were performed with R software and the ‘mefafor’ package. Results: Fifteen studies which included 4,068 AML patients and 250,975 control subjects were included. Using a random effects model, the overall analysis showed a significant adverse association between OPE and AML with OR=1.49 (95%CI: 1.10-2.01), and a significant heterogeneity between studies ( I² =0.73, p<0.001). The robustness was checked after sequential exclusion of one study at a time which did not influence the overall OR estimate. A publication bias underestimating the OR was suggested by an asymmetrical funnel plot. Using trim-and-fill method, hypothetical missing studies were added studies in order to adjust the OR (OR=1.76 [95%CI: 1.30-2.38]. A stratified analysis showed that the association was significant in Asian populations (OR=1.74; 95%CI: 1.32-2.30) and upon exposure to insecticides (OR=1.45; 95%CI: 1.16-1.81), yet partly influenced by other factors, since most of the studies reported unadjusted results (n=8, 53%). Data on biological characteristics were unavailable to stratify patients according to AML molecular or cytogenetic characteristics. Conclusions: From this new extensive review and analysis, it clearly appears that AML should be considered as occupational illness in patients with demonstrated OPE. Further studies will have to focus on the biological effects of individual and pesticides cocktails in order to determine the pathogenesis mechanisms involved in leukemogenesis, and to improve individual protection.

RUNX1 variant as a genetic predisposition factor for acute myeloid leukemia

Acute myeloid leukemia (AML) is the most common hematological malignancy among adults and is characterized by accumulation of immature myeloid cells. Different genetic factors have role in the occurrence of AML. Among different proteins, RUNX1 and BAALC are involved in the development AML. It has been shown that BAALC overexpression is a factor that indicate shorter disease free survival in a subset of AML patients. RUNX1 has been implicated in the development of breast, prostate, lung, and skin cancers. The aim of this study is determination of the prevalence of common polymorphisms in BAALC (rs6999622 and rs62527607) and RUNX1 (rs13051066 and rs61750222) in AML patients compared with healthy subjects. A total of 100 AML patients and 100 healthy control subjects were included in our study. Genomic DNA was isolated from peripheral blood and the polymorphisms were genotyped by applying ARMS and PCR-RFLP methods. Finally, data was analyzed using SPPSS software. Our results demonstrate a significant association between the RUNX1 rs13051066 and AML in the co-dominant (odd ratio = 6.66, 95% Cl = 1.85–25, p = .006) and dominant (GT + TT versus GG: odd ratio = 6.15, 95% CI = 1.73–21.87, p = .002) models. The RUNX1 rs13051066 polymorphism is associated with risk of AML in Iranian population. Future studies should consider larger sample size for assessment of RUNX1 gene polymorphisms, and employ cytogenetic and molecular analyses in AML patients from different ethnic origins.

Acute Myeloid Leukemia in Patients Living with HIV Infection: Several Questions, Fewer Answers.

Both human immunodeficiency virus (HIV) infection and acute myeloid leukemia (AML) may be considered relatively uncommon disorders in the general population, but the precise incidence of AML in people living with HIV infection (PLWH) is uncertain. However, life expectancy of newly infected HIV-positive patients receiving anti-retroviral therapy (ART) is gradually increasing, rivaling that of age-matched HIV-negative individuals, so that the occurrence of AML is also expected to progressively increase. Even if HIV is not reported to be directly mutagenic, several indirect leukemogenic mechanisms, mainly based on bone marrow microenvironment disruption, have been proposed. Despite a well-controlled HIV infection under ART should no longer be considered per se a contraindication to intensive chemotherapeutic approaches, including allogeneic hematopoietic stem cell transplantation, in selected fit patients with AML, survival outcomes are still generally unsatisfactory. We discussed several controversial issues about pathogenesis and clinical management of AML in PLWH, but few evidence-based answers may currently be provided, due to the limited number of cases reported in the literature, mainly as case reports or small retrospective case series. Prospective multicenter clinical trials are warranted to more precisely investigate epidemiology and cytogenetic/molecular features of AML in PLWH, but also to standardize and further improve its therapeutic management.

The intriguing occurrence of Acute Myeloid Leukemia in a case of Acute Lymphoblastic leukemia:Report of two cases

The aim of this study is to study the two cases of acute lymphoblastic leukemia (ALL) who relapsed as acute myeloid leukemia (AML). Presented here are reports of two cases of pediatric ALL who developed change of lineage to AML at relapse. This change in phenotype, which involves the conversion of one phenotype to other phenotype during the course of disease or at relapse is a rare phenomenon rarely described in literature. The immunophenotypic and molecular findings are described. The present study emphasizes the need of immunophenotyping and molecular workup at relapse. Also adds to the repertoire of the published literature on this rare entity.

Formaldehyde Exposure and Acute Myeloid Leukemia: A Review of the Literature.

Background and objective: The aim of the present study was to evaluate associations between cumulative and peak formaldehyde exposure and occurrence of acute myeloid leukemia. Material and Methods: A comprehensive search was performed using the PubMed and Embase databases. We included studies presenting information about the role of formaldehyde in leukemic occurrence and mortality risk. Then, full texts of the selected references were assessed, and references of included studies were checked to identify additional articles. Result: The information was then summarized and organized in the present review. A total of 81 articles were obtained from the search. Conclusion: Findings from the review of the literature do not support the hypothesis that formaldehyde is a cause of acute myeloid leukemia.

Augmentation of the Acute Myeloid Leukemia-Composite Model (AML-CM) with Performance Status and Secondary Leukemia

Background:To help optimize decision-making for acute myeloid leukemia (AML) treatment in the clinic, risk models comprising different variables were developed. A Treatment-Related Mortality (TRM) model was developed to predict 28-day mortality. The TRM model includes age, performance status, platelet count, albumin, secondary AML, peripheral white blood cell count, peripheral blood blast percentage, and creatinine (Walter et al, 2011 Nov 20; 29(33): 4417-4424). More recently, an AML-specific composite model (AML-CM) introduced the combination of cytogenetic/molecular risks per European Leukemia Network (ELN) classification with burdens of increasing age and comorbidities. The AML-CM can predict both early and late mortality after diagnosis of AML (Sorror et al, 2017; 3(12):1675-1682). All factors within the TRM model were tested during the development of the AML-CM, except for the impacts of Karnofsky Performance Status (KPS), and presence of secondary AML. To this end, we explored the possibility of augmenting the AML-CM by testing the prognostic value added by including KPS and presence of secondary AML.Methods:The study comprises two cohorts from two different institutions: 311 patients (pts) to be used for development of new scores and 187 pts to be used for independent validation. Both cohorts were seen for initial therapy for AML between 2008 and 2017. We collected patients' demographics and comorbidity information through patient charts. We defined secondary AML as an occurrence of AML after a previous malignancy or after hematological abnormalities for at least one month. Afterwards, Cox regression models were designed to test whether KPS and secondary AML have independent prognostic impacts that could be added to the AML-CM. Prediction of eight-week and one-year mortality were compared between the original versus augmented AML-CM using c-statistics and area under the curve (AUC) of the receiver-operator characteristic curve (ROC) in the independent validation cohort from the different institution.Results:In a multivariate model, after adjusting for AML-CM variables, both secondary AML (hazard ratio [HR] =2.19, p=0.0001) and worse KPS percentages (KPS 80-75%: HR=1.53, p=0.06; KPS ≤70%: HR=2.60, p=0.0001) were significantly associated with one-year mortality. Using the same equation used in the development of the AML-CM, we assigned 1 point to KPS 80-75%, 2 points to KPS ≤70% and 2 points to secondary AML. These points were added to those of age, comorbidities and ELN risks in order to calculate the augmented AML-CM scores.In the validation set, the augmented AML-CM had a c-statistic estimate of 0.71 vs. 0.69 for the original AML-CM. The true AUC for prediction of 1-year mortality was 0.75 vs. 0.72 while the AUC for prediction of 8-week mortality was 0.83 vs. 0.79 for the augmented AML-CM and original AML-CM, respectively.Figure 1 shows the discrimination of four risk groups per the new augmented AML-CM scores. Patients with scores of 1-3, 4-6, 7-9, and ≥10 had 1-year survival rates of 91%, 76%, 46% and 37%, respectively.Conclusions:In this study we found that worse KPS percentages add prognostic value to those of age and comorbidities, while secondary AML adds prognostic value to that of ELN cytogenetic/molecular risks for prediction of early (8-week) and late (1-year) mortality after diagnosis of AML. This suggests that KPS provides prognostic information above what is provided by age and comorbidities alone. Similarly, the classification of a patient's AML as secondary AML provides prognostic information beyond what is understood about the patient's disease risk as indicated by the ELN cytogenetic/molecular risk category.Combining these five factors: age, comorbidity burden, performance status, disease risk, and presence of secondary AML results in an augmented AML-CM that can be used in the clinic for improved risk-assessment before treatment decisions. [Display omitted] DisclosuresBecker:GlycoMimetics: Research Funding.

H2O2/Peroxynitrite-Activated Hydroxamic Acid HDAC Inhibitor Prodrugs Show Antileukemic Activities against AML Cells.

Occurrence of acute myeloid leukemia (AML) results in abundant endogenous reactive oxygen species (ROS)/reactive nitrogen species (RNS) in AML cells and in disease-relevant microenvironments. Histone deacetylase inhibitor (HDACi) prodrug approach was designed accordingly by masking the hydroxamic acid zinc binding group with hydrogen peroxide (H2O2)/peroxynitrite (PNT)-sensitive, self-immolative aryl boronic acid moiety. Model prodrugs 5-82 and 5-23 were activated in AML cells to release cytotoxic HDACis, evidenced by inducing acetylation markers and reducing viability of AML cells. Intracellular activation and antileukemic activities of prodrug were increased or decreased by ROS/PNT inducers and scavengers, respectively. Prodrugs 5-82 and 5-23 also enhanced the potency of chemotherapy drug cytarabine, supporting the potentials of this prodrug class in combinatorial treatment.

A Subset of MicroRNAs and Genes Involved in AML Has a Pivotal Role in the in Vitro differentiation of Hematopoietic Stem Cell Precursors

Abstract 1290After the finding of a set of transcription factors capable of reprogram any somatic cell into an embryonic stem-like cell by Yamanaka's group a lot of effort has been put to differentiate and produce in-vitro engraftable cells that could replace and fix damaged tissues. One of the most attractive and promising fields is the differentiation towards blood, considering it is a tissue without a complex tridimensional structure and that the phenotypes of the different sublineages are already well characterized. Nonetheless, so far there are no reports of successful differentiation into blood progenitors which are able to completely recover functionally in vivo blood-depleted mice. We previously reported the differentiation from induced pluripotent stem cells (iPS) towards hematopoietic cells capable of distinguish into sub lineages in in vitro assays, while another group obtained blood precursors by transdifferentiation of fibroblasts; however a complete recovery of the hematopoietic lineages in vivo was not seen. Our hypothesis is that the gap missing in the current protocols to obtain repopulating blood stem cells can be filled by the microRNA profiling of Cord Blood (CB) progenitors, in order to find the key players in the maintenance of blood stemness. In particular, it has been shown that population with the highest capacity to be engrafted in mice is the CD34+/CD90+ from CB. Our preliminary results depict a set of miRNAs that are specifically overexpressed in the CD34+/CD90+ population from CB cells when compared against a less specific CD34+ population. These miRNAs are currently being tested as a tool to improve the efficiency of iPS differentiation and fibroblasts conversion towards blood progenitors by means of lentiviral infection of the miRNA precursors. Interestingly, we have found that these miRNAs have been previously reported to have a main role in the occurrence of Acute Myeloid Leukemia in humans and mice. These results led us to look for genes that are highly expressed in blood progenitors but also have been shown to be correlated with AML.As a safety study, we are currently evaluating the effect of overexpressing AML related factors (miRNAs and genes) when added to the established protocols to obtain blood progenitors from iPS and fibroblasts. Surprisingly, our initial results show that the overxpression of the above mentioned genes and miRNAs have an intrinsic potential to induce in vitro differentiation or conversion from iPS and fibroblasts towards blood progenitors. Disclosures:No relevant conflicts of interest to declare.

Expression and clinical significance of MN1 and PTEN gene in patients with acute myeloid leukemia

The aim of our study was to explore the correlations between both the genes, evolution and prognosis of the disease by detecting the expression of MN1 (meningioma 1) gene and PTEN (phosphatase and tensin homolog) gene in patients with acute myeloid leukemia (AML). MN1 and PTEN mRNA were detected by reverse transcription-PCR in mononuclear cells of 38 patients with AML and 13 patients with normal bone marrow. Positive rates of MN1 and PTEN genes were 76.3% and 60.5% respectively in bone marrow mononuclear cells. The expression level of MN1 mRNA for the de novo group increased comparing with that for normal control group (P < 0.05), the expression level of PTEN mRNA for de novo group decreased obviously comparing with that for normal control group (P < 0.01), MN1 mRNA level decreased in remission group, while PTEN mRNA level increased comparing with that in de novo group (P < 0.05). MN1 mRNA level increased and PTEN mRNA decreased in relapsed group comparing with that in control group, and their difference was statistical significance (P < 0.05). The two genes’ levels had negative correlations in acute myeloid leukemia (r = −0.314, P < 0.05). There is close correlations between expression of MN1 and PTEN genes and the prognosis and occurrence of acute myeloid leukemia, and their expression can be taken as significant indexes to access the de novo, relapse and prognosis of acute myeloid leukemia.

Comparative Effectiveness of Azacitidine Versus Decitabine for the Treatment of Myelodysplastic Syndromes

AbstractAbstract 3995 Background:Azacitidine (5-AzaC) and decitabine (DAC) are two hypomethylating agents commonly used in treatment of Myelodysplastic Syndromes (MDS). The comparative effectiveness of 5-AzaC versus DAC is not known. Both agents have been tested against supportive care in controlled settings, but not head-to-head. The most comprehensive assessment of the efficacy of 5-AzaC versus DAC was done by Kumar et al. (Haematologica95: 340-2) by performing an indirect meta-analysis using data from controlled trials, RCTs. The real world effectiveness of the 5-Aza-C versus DAC has not been evaluated. In response, we have performed a comparative effectiveness study of 5-AzaC versus DAC for treatment of MDS. Methods:All MDS patients treated with 5-AzaC or DAC at Moffitt Cancer Center from December 1999 to December 2009 were included in the analysis. Benefits and harms associated with 5-AzaC and DAC were assessed. The primary outcome was overall survival, OS. The secondary outcomes were progression free survival (PFS), defined as progression to Acute Myeloid Leukemia (AML), response rate evaluated according to IWG 2006 criteria, reduction in IV antibiotic use and transfusion dependence. For harms assessment, we extracted data on grade 3/4 toxicities and treatment related mortalities (TRM). OS and PFS were estimated using the Kaplan-Meier method and difference between treatments was calculated using the log-rank test. Cox proportional hazard model was used to estimate hazard ratios. Competing risk regression was applied in estimating PFS for time to AML or death, since the occurrence of AML may be unobservable due to patients' death. Covariate matching analysis (CMA) was applied for the outcomes of OS and PFS to estimate differences in treatment due to the non-random nature of the data. Each patient was matched to four other patients on prognostically significant covariates of age, MDS type, IPSS score, and FAB class. Differences in treatment effects for dichotomous outcomes were assessed using Mann-Whitney test. Results:One hundred seventy four MDS patients met the inclusion criteria (121 patients treated with 5-AzaC and 53 with DAC). Patient characteristics are summarized in table below. The unadjusted results showed a statistically significant OS benefit with 5-AzaC versus DAC (hazard ratio (HR) was 1.496 (95% Confidence Interval (CI), 1.005 to 2.226; p=0.047). However, the CMA showed a statistically non-significant gain of 1.088 months of survival with use of 5-AzaC versus DAC (95% CI, -4.219 to 6.395; p=0.688). For PFS, a statistically significant benefit was associated with 5-AzaC versus DAC (unadjusted HR=1.471 (95% CI 1.000 to 2.165; p=0.049). Nevertheless, CMA results showed a statistically non-significant gain of 1.060 months of PFS with use of 5-AzaC versus DAC (95% CI, -4.391 to 6.512; p=0.703). The overall response rate (20.0% vs 6.3%; p=0.029) and hematological response rate (24.4% vs 6.0%; p=0.006) was significantly better with 5-AzaC versus DAC. However, differences in cytogenetic response rate (23.4% vs 33.3%; p=0.398), bone marrow blast response rate (43.3% vs 54.5%; p=0.370), reduction of IV antibiotic drug use (9.5% vs 12.0%; p=0.780), and RBC (15.3% vs 12.2%; p=0.609) or platelet (5.0% vs 9.8%; p=0.291) transfusion requirements were statistically non-significant with 5-AzaC versus DAC. There was a statistically non-significant difference in occurrence of grade 3/4 toxicity (24.6% vs 37.6%; p=0.094) or TRM (1.0% vs 0.0%; p=.512) between patients treated with 5-AzaC versus DAC. Conclusions:Results from first retrospective population based study assessing the effectiveness of 5-AzaC versus DAC for treatment of MDS showed no significant difference in OS and PFS. However, 5-AzaC was associated with higher overall response rates compared with DAC with no significant difference in harms associated with the two treatments. Due to the limitations of retrospective analysis, these results warrant a prospective direct comparison of 5-AzaC versus DAC in a RCT.VariableNo. of Patients (%)5Aza-CDACOverall12153Age at Treatment≤6545 (37)14 (26)>6576 (63)39 (74)GenderMale81 (67)34 (64)Female40 (33)19 (36)MDS Type11952Primary87 (73)47 (90)Secondary32 (27)5 (10)IPSS Class9830Low-risk21 (21)6 (20)Int-1 Risk27 (28)12 (40)Int-2 Risk38 (39)7 (23)High-risk12 (12)5 (17)FAB10949RA25 (23)5 (10)RARS7 (6)4 (8)RAEB52 (48)24 (49)RAEB-t7 (6)2 (4)CMML18 (17)14 (29) Disclosures:Lancet:Eisai: Consultancy; Celgene: Honoraria.

Simultaneous occurrence of acute myeloid leukaemia with mutated nucleophosmin (NPM1) in the same family

Simultaneous occurrence of acute myeloid leukaemia with mutated nucleophosmin ( NPM1 ) in the same family

Occurrence of Acute Myeloid Leukemia in Young Pregnant Women

Although acute leukaemia is rare in pregnancy its importance lies in its life-threatening potential, both to the child and the mother. The possibility of vertical transmission of leukemic cells increases the attention devoted to these patients and their offspring. Three cases of pregnant young women (15-17 years of age) with AML are presented. This series of cases is the first report where gene abnormalities such as ITD mutations of the FLT3 gene and AML1/ETO fusion genes were screened in pregnant AML patients and their babies, so far. Unfortunately, very poor outcomes have been associated to similar cases described in literature, and the same was true to the patients described herein. Although very speculative, we think that the timing and possible similar exposures would be involved in all cases.