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Acute Myeloid Leukemia (acute + myeloid_leukemia)
Kinds of Acute Myeloid Leukemia Terms modified by Acute Myeloid Leukemia Selected AbstractsSecondary clonal cytogenetic abnormalities following successful treatment of acute promyelocytic leukemia,AMERICAN JOURNAL OF HEMATOLOGY, Issue 11 2009Crisoula Batzios To identify patients who developed secondary clonal cytogenetic aberrations (CCA) following therapy for acute promyelocytic leukemia (APL), we retrospectively analyzed cytogenetic results from 123 patients diagnosed with APL between 1995 and 2007, who had ongoing cytogenetic analysis undertaken in our laboratory. During follow-up for APL we identified 12 patients (9.8%) who developed CCA, not detected at diagnosis of APL and unrelated to their original APL karyotype. All patients had received all-trans retinoic acid (ATRA) and chemotherapy and were in complete remission for APL when secondary CCA were identified. The median latency period between diagnosis of APL and emergence of secondary CCA was 27.5 months (range: 2,54 months). To date, four patients with CCA have been diagnosed with therapy-related myelodysplastic syndrome (t-MDS)/acute myeloid leukemia (t-AML), giving a median t-MDS/AML free survival of 78 months, with follow-up ranging between 20 and 136 months from APL diagnosis. Three patients have died: two patients died of t-AML and another developed relapsed APL with persistence of his secondary clone but no diagnosis of t-MDS/AML and died from transplant-related complications. Two patients are alive with t-MDS. Seven patients with CCA are alive with no morphological evidence of MDS at the time of their last known follow-up; thus median survival has not been reached. The appearance of these abnormalities in the absence of morphological evidence of MDS in the majority of patients is unusual, and highlights the importance of continued cytogenetic follow-up in these patients. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc. [source] Hematological malignancies in the island of Sardinia, 1974,1993: age and sex distributions and temporal changes in incidenceHEMATOLOGICAL ONCOLOGY, Issue 3 2004G. Broccia Abstract We have collected, by an active retrospective survey, all the cases of hematologic malignancies (HM) newly diagnosed during the time period 1974,1993 in the resident population of Sardinia. Diagnosis was deemed valid, after consultation of clinical records, in more than 90% of the 7264 collected cases. The number of newly diagnosed cases by year more than doubled during the 20-year period investigated. This striking increase can be only partially accounted for by ageing of population. Indeed, age-specific and age-adjusted rates of most of HM increased during this period, although Hodgkin Disease (HD), Chronic Myeloid Leukemia (CML) and Acute Lymphoblastic Leukemia (ALL) were notable exceptions. The observed increase in rates is likely, in a large part, to be fictitious, due to easier access to a health care system, which in the meantime, improved its diagnostic efficiency. This was particularly evident for Chronic Lymphocytic Leukemia (CLL), Multiple Myeloma (MM) and some others myelo- and lympho-proliferative disorders, but its relevance declined after 1984,1989. A likely true increase in occurrence was evidenced for Non-Hodgkin Lymphomas (NHL) and similarly, although to a lesser extent and more doubtful, for Myelodysplasias (MDS) and Acute Myeloid Leukemia (AML). At the end of the studied period each type of HM presented age and sex distributions and age-adjusted rates that show only minor differences from those reported for other western countries. No argument emerged to suggest that any genetic peculiarities of the Sardinian population might have affected the occurrence of HM. The confounding effects of improved diagnostic efficiency have prevented a reliable assessment of influence on incidences of environmental and socio-economic changes that, in relatively recent times, have occurred in Sardinia. Copyright © 2005 John Wiley & Sons, Ltd. [source] Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2009Yuichi Ishikawa Abstract Acute myeloid leukemia (AML) has been thought to be the consequence of two broad complementation classes of mutations: class I and class II. However, overlap-mutations between them or within the same class and the position of TP53 mutation are not fully analyzed. We comprehensively analyzed the FLT3, cKIT, N-RAS, C/EBPA, AML1, MLL, NPM1, and TP53 mutations in 144 newly diagnosed de novo AML. We found 103 of 165 identified mutations were overlapped with other mutations, and most overlap-mutations consisted of class I and class II mutations. Although overlap-mutations within the same class were found in seven patients, five of them additionally had the other class mutation. These results suggest that most overlap-mutations within the same class might be the consequence of acquiring an additional mutation after the completion both of class I and class II mutations. However, mutated genes overlapped with the same class were limited in N-RAS, TP53, MLL -PTD, and NPM1, suggesting the possibility that these irregular overlap-mutations might cooperatively participate in the development of AML. Notably, TP53 mutation was overlapped with both class I and class II mutations, and associated with morphologic multilineage dysplasia and complex karyotype. The genotype consisting of complex karyotype and TP53 mutation was an unfavorable prognostic factor in entire AML patients, indicating this genotype generates a disease entity in de novo AML. These results collectively suggest that TP53 mutation might be a functionally distinguishable class of mutation. [source] microRNAs in acute myeloid leukemia: Expression patterns, correlations with genetic and clinical parameters, and prognostic significanceGENES, CHROMOSOMES AND CANCER, Issue 3 2010Rotraud Wieser Acute myeloid leukemia (AML) is a malignant disease of hematopoietic cells whose emergence, course, and prognosis is affected by specific recurrent genetic alterations like chromosome aberrations and point mutations, as well as by changes in the expression of certain genes. In the past 2 years, microRNAs (miRNAs),a novel class of small RNA molecules involved in posttranscriptional gene regulation,have also been shown to be aberrantly expressed in AML. Furthermore, specific miRNA expression patterns were found to be associated with certain genetic and cytogenetic alterations in this disease, and two studies identified miRNAs whose expression levels were predictive of survival. Interestingly, the results of these analyses showed only very limited congruence. This review summarizes published reports on the expression patterns of miRNAs in AML, and discusses possible reasons for the differences in their results. © 2009 Wiley-Liss, Inc. [source] Identification of genes with abnormal expression changes in acute myeloid leukemiaGENES, CHROMOSOMES AND CANCER, Issue 1 2008Derek L. Stirewalt Acute myeloid leukemia (AML) is one of the most common and deadly forms of hematopoietic malignancies. We hypothesized that microarray studies could identify previously unrecognized expression changes that occur only in AML blasts. We were particularly interested in those genes with increased expression in AML, believing that these genes may be potential therapeutic targets. To test this hypothesis, we compared gene expression profiles between normal hematopoietic cells from 38 healthy donors and leukemic blasts from 26 AML patients. Normal hematopoietic samples included CD34+ selected cells (N = 18), unselected bone marrows (N = 10), and unselected peripheral bloods (N = 10). Twenty genes displayed AML-specific expression changes that were not found in the normal hematopoietic cells. Subsequent analyses using microarray data from 285 additional AML patients confirmed expression changes for 13 of the 20 genes. Seven genes (BIK, CCNA1, FUT4, IL3RA, HOMER3, JAG1, WT1) displayed increased expression in AML, while 6 genes (ALDHA1A, PELO, PLXNC1, PRUNE, SERPINB9, TRIB2) displayed decreased expression. Quantitative RT/PCR studies for the 7 over-expressed genes were performed in an independent set of 9 normal and 21 pediatric AML samples. All 7 over-expressed genes displayed an increased expression in the AML samples compared to normals. Three of the 7 over-expressed genes (WT1, CCNA1, and IL3RA) have already been linked to leukemogenesis and/or AML prognosis, while little is known about the role of the other 4 over-expressed genes in AML. Future studies will determine their potential role in leukemogenesis and their clinical significance. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat. © 2007 Wiley-Liss, Inc. [source] Differential expression of specific microRNA and their targets in acute myeloid leukemia,AMERICAN JOURNAL OF HEMATOLOGY, Issue 5 2010Giuseppe Cammarata Acute myeloid leukemia (AML) the most common acute leukemia in adults is characterized by various cytogenetic and molecular abnormalities. However, the genetic etiology of the disease is not yet fully understood. MicroRNAs (miRNA) are small noncoding RNAs which regulate the expression of target mRNAs both at transcriptional and translational level. In recent years, miRNAs have been identified as a novel mechanism in gene regulation, which show variable expression during myeloid differentiation. We studied miRNA expression of leukemic blasts of 29 cases of newly diagnosed and genetically defined AML using quantitative reverse transcription polymerase chain reaction (RT-PCR) for 365 human miRNA. We showed that miRNA expression profiling reveals distinctive miRNA signatures that correlate with cytogenetic and molecular subtypes of AML. Specific miRNAs with consolidated role on cell proliferation and differentiation such as miR-155, miR-221, let-7, miR-126 and miR-196b appear to be associated with particular subtypes. We observed a significant differentially expressed miRNA profile that characterizes two subgroups of AML with different mechanism of leukemogenesis: core binding factor (CBF) and cytogenetically normal AML with mutations in the genes of NPM1 and FLT3- ITD. We demonstrated, for the first time, the inverse correlation of expression levels between miRNA and their targets in specific AML genetic groups. We suggest that miRNA deregulation may act as complementary hit in the multisteps mechanism of leukemogenesis offering new therapeutic strategies. Am. J. Hematol. 2010. © 2010 Wiley-Liss, Inc. [source] Successful cell-mediated cytokine-activated immunotherapy for relapsed acute myeloid leukemia after hematopoietic stem cell transplantationAMERICAN JOURNAL OF HEMATOLOGY, Issue 3 2009Benjamin Gesundheit Acute myeloid leukemia (AML) is an extremely aggressive disease with a high relapse rate even after allogeneic hematopoietic stem cell transplantation (HSCT). We report the successful outcome of cell-mediated cytokine-activated immunotherapy in a high-risk pediatric AML patient who relapsed shortly after allogeneic HSCT. Donor lymphocyte infusion along with interferon induced a graft-versus-leukemia effect, presenting as a reversible episode of graft-versus-host disease, which led to stable complete donor chimerism and total eradication of AML for over 24 months, at the time of this report. The curative potential of immunotherapy in hematological malignancies is discussed. Am. J. Hematol., 2009. © 2008 Wiley-Liss, Inc. [source] Acute myeloid leukemia, the 3q21q26 syndrome and diabetes insipidus: A case presentationASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY, Issue 2 2010Cameron CURLEY Abstract Diabetes insipidus (DI) is a rare presenting complication of acute myeloid leukaemia (AML). Typically, the combination of DI and AML is associated with structural abnormalities of the neurohypophysis. We present a case of AML and DI presenting without any abnormalities of the neurohypophysis on radiological scanning and with normal cerebrospinal fluid examination. The AML karyotype at presentation was characterized by the presence of a t(3; 3)(q21; q26) translocation and monosomy 7. After treatment with induction chemotherapy, the patient achieved a complete remission and his DI resolved. At subsequent AML relapse, characterized by a complex karyotype without the t(3; 3)(q21; q26) translocation or monosomy 7, DI did not recur. Our case provides clinical support to the hypothesis that the t(3; 3)(q21; q26) translocation and/or monosomy 7 in AML may directly result in dysregulation of transcription factors resulting in development of DI in AML patients. [source] Positive selection for CD90 as a purging option in acute myeloid leukemia stem cell transplants,CYTOMETRY, Issue 1 2008Nicole Feller Abstract Background: Several studies showed the benefit of purging of acute myeloid leukemia (AML) stem cell transplants. We reported previously that purging by positive selection of CD34+ and CD133+ cells resulted in a 3,4 log tumor cell reduction (TCR) in CD34, and/or CD133, AML, but has been shown to be potentially applicable in only about 50% of cases. Similar to CD34 and CD133, CD90 marks the hematopoietic CD34 positive stem cells capable of full hematopoietic recovery after myeloablative chemotherapy, and therefore, in the present study, we explored whether a similar purging approach is possible using CD90. Methods: CD90 expression was established by flowcytometry in diagnosis AML on the clonogenic AML CD34+ blast population by flow cytometry. Positivity was defined as >3% CD90 (CD34+) expression on blasts. For the calculation of the efficacy of TCR by positive selection, AML blasts were recognized by either prelabeling diagnosis blasts with CD45-FITC in spiking model experiments or using expression of leukemia associated marker combinations both in spiking experiments and in real transplants. Results: In 119 patients with AML and myelodysplastic syndrome, we found coexpression of CD34 and CD90 (>3%) in 42 cases (35%). In AML patients 60 years or younger, representing the patients who are eligible for transplantation, only 23% (16/69) of the patients showed CD90 expression. Positive selection for CD90 in transplants containing CD90 negative AML resulted in a 2.8,4 log TCR in the models used. Conclusions: Purging by positive selection using CD90 can potentially be applied effectively in the majority of AML patients 60 years or younger. © 2007 Clinical Cytometry Society [source] Multiparametric analysis of normal and postchemotherapy bone marrow: Implication for the detection of leukemia-associated immunophenotypes,CYTOMETRY, Issue 1 2008D. Olaru Abstract Background: The knowledge of normal marrow is mandatory to assess the malignant counterpart of normal cells and define leukemia-associated immunophenotypes (LAIPs). In this study, the expression of a variety of antigens expressed in normal and postchemotherapy bone marrow (BM) was analyzed to provide a frame of reference for the identification of myeloid LAIPs. Methods: Multiparameter four- and six-color flow cytometry was used to define antigen combinations totally absent or present at very minimal levels in marrow cells of normal individuals (n = 20) and patients receiving chemotherapy for acute lymphoblastic leukemia (n = 20). Immature (blast) cells were gated according to CD45/SSC properties. Fifty-three acute myeloid leukemia (AML) samples were studied in six-color combinations. Results: In six-color flow cytometry, 47 phenotypes were totally absent from blast gate in all normal samples. Forty-one other phenotypes were identified in less than 0.05% of blast cells. There was no difference between normal and postchemotherapy BMs. The four-color panel allowed to identify only 30 phenotypes present at a frequency <0.05%. Using the six-color panel, 58% of the absent or infrequent phenotypes in normal BM were found in at least one of 53 AML samples. All AML cases exhibited at least one LAIP. Conclusion: Our results show that the ability to distinguish leukemic from healthy cells is considerably increased by a six-color approach. Furthermore, these absent or infrequent phenotypes in normal BM are identified in AML and can be utilized for minimal residual disease study. © 2007 Clinical Cytometry Society [source] Remission induction chemotherapy induces in vivo caspase-dependent apoptosis in bone marrow acute myeloid leukemia blast cells and spares lymphocytesCYTOMETRY, Issue 3 2006J.-P. Vial Abstract Background The goal of new therapeutic strategies is to adapt the treatment of acute myeloid leukemia (AML) patients to the prognostic and/or to the hematological response. Methods We analyzed in vivo apoptosis induction in blast cells and in lymphocytes of AML patients receiving remission induction treatment. Results We show, on 12 peripheral blood samples, that the increase of peripheral apoptotic blast cells cannot be considered as the earliest marker of the treatment efficiency, because the significant increase of apoptosis followed the white blood cell and the peripheral blast cell count reductions, probably due to an efficient clearance of circulating apoptotic cells. Furthermore, the study of 65 bone marrow samples at d15 showed that the treatment induced apoptosis of blast cells while sparing the lymphocytes. This apoptosis was evidenced both at the caspase and at the membrane levels using respectively fmk-VAD-FITC and Annexin V binding assays. We found that less than 50% of apoptosis, measured with the fmk-VAD-FITC, in the d15 residual bone marrow blast cells, correlated with lower disease-free survival probability. Conclusion More studies are needed in larger series and earlier during the remission induction treatment to confirm the possible prognostic significance of in vivo apoptosis induction. © 2006 International Society for Analytical Cytology [source] JC-1, a sensitive probe for a simultaneous detection of P-glycoprotein activity and apoptosis in leukemic cellsCYTOMETRY, Issue 3 2006Driss Chaoui Abstract Background JC-1 probe has been successfully used for the analysis of either apoptosis or P-glycoprotein (P-gp) activity. Therefore, we wanted to see if JC-1 could also simultaneously assess both, P-gp activity and apoptosis, in acute myeloid leukemia (AML) cells. Methods P-gp activity was measured using JC-1 and compared to the results of the Rhodamine 123 (Rh 123) assay in P-gp negative and P-gp positive cell lines, and 12 AML samples. For apoptosis, spontaneous apoptosis, as well as, apoptosis induced by Cytosine Arabinosine and Homoharringtonine were analyzed. Both mitochondrial red fluorescence and cytoplasmic green fluorescence of JC-1 with and without a P-gp inhibitor (Cyclosporine A : CsA) were used for the identification of apoptotic cells, and this was compared to Annexin V/PI staining. Results (1) We found a good correlation between JC-1 and Rh 123 in viable cells. Even in a small population of viable cells, P-gp positive cells emitting low red fluorescence, gained on red fluorescence after P-gp inhibition with CsA permitting an evaluation of P-gp activity. (2) We found a good correlation between the Annexin V/PI staining and JC-1 (P < 0.0001) in the assessment of apoptotic cells. Most importantly, the apoptotic cells could be distinguished by the loss of red fluorescence and the increase of green fluorescence without any change after P-gp inhibition with CsA. Conclusions JC-1 can simultaneously evaluate two important parameters involved in drug resistance in AML cells, P-gp activity and apoptosis. © 2006 International Society for Analytical Cytology [source] C-Kit receptor (CD117) expression on myeloblasts and white blood cell counts in acute myeloid leukemiaCYTOMETRY, Issue 1 2004Jolanta Wo Abstract Background The c-Kit receptor is considered to play a crucial role in hematopoiesis. Induction of mobilization of hematopoietic cells in the bone marrow requires cooperative signaling through c-Kit and c-Kit ligand pathway, and these interactions are important in the retention of stem cells within the bone marrow. Therefore, we analyzed c-Kit density on the leukemic myeloblasts of patients with acute myeloid leukemia (AML) in relation to white blood cell count (WBC) in the peripheral blood. Methods Bone marrow aspirates collected from patients with AML and bone marrow aspirates and leukapheresis products after granulocyte colony-stimulating factor blood mobilization from adult volunteers were studied. To determine the level of c-Kit receptor expression, we applied quantitative (relative fluorescence intensity and antibody binding per cell) cytometric methods. Results Our data showed negative correlation between the level of c-Kit expression intensity on myeloblasts and the number of leukocytes in blood of AML patients. The c-Kit receptor density on myeloblasts in patients with low WBC was significantly stronger than that on myeloblasts in patients with high WBC. In the latter patient group, the density c-Kit receptor on myeloblasts was similar to that on CD34+ cells in mobilized peripheral blood. Conclusions The obtained data suggest an involvement of c-Kit receptor in the regulation of leukemic myeloblasts egress to the peripheral blood. © 2004 Wiley-Liss, Inc. [source] The clinical pharmacology of therapeutic monoclonal antibodiesDRUG DEVELOPMENT RESEARCH, Issue 3 2004Lorin K. Roskos Abstract Seventeen monoclonal antibodies are currently approved in the United States for therapeutic use in organ transplantation, percutaneous coronary intervention, prophylaxis of respiratory syncytial virus disease, rheumatoid arthritis, Crohn's disease, asthma, chronic lymphocytic leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, breast cancer, and colorectal cancer. All approved antibodies are of the IgG class. Thirteen are unconjugated intact antibodies, three are intact immunoconjugates, and one is a Fab fragment. Three of the antibodies are murine, five are chimeric, eight are humanized, and one is a fully human antibody generated by phage display technology. The antigen target and the structural and binding characteristics of the antibody determine the antibody's mechanism of action, pharmacokinetics, safety, and immunogenicity. Antibodies act through multiple mechanisms that include functional modulation of the antigen, recruitment of ADCC and CDC, and delivery of radionuclide or toxin payloads to target cells. Antibody half-life is usually governed by interaction with the FcRn receptor. In some cases, the antigen may act as a sink for antibody elimination. Safety profiles are determined by the pharmacology and tissue distribution of the target antigen, antibody isotype, the antibody payload, cytokine release, hypersensitivity reactions to xenogeneic protein, and immunogenicity. Fully human antibody technology may allow development of antibodies that have reduced risks of hypersensitivity reactions and immunogenicity, thereby enhancing safety and efficacy. The exquisite target specificity of antibodies, improvements in antibody engineering technology, and the wide availability of novel and validated therapeutic targets provide many current and future opportunities for the clinical development of therapeutic antibodies. Drug Dev. Res. 61:108,120, 2004. © 2004 Wiley-Liss, Inc. [source] Determinants of urinary 8-hydroxy-2,-deoxyguanosine in Chinese children with acute leukemiaENVIRONMENTAL TOXICOLOGY, Issue 5 2009You Yang Abstract The 8-hydroxy-2,-deoxyguanosine (8-OHdG), an oxidized nucleoside of DNA, not only is a widely used biomarker for the measurement of endogenous oxidative DNA damage, but might also be a risk factor for many diseases including cancer. Elevated level of urinary 8-OHdG has been detected in patients with various malignancies. In the present study, the level of urinary 8-OHdG was examined in 116 Chinese children with acute leukemia (94 acute lymphoid leukemia, ALL, 22 acute myeloid leukemia, AML), and its correlation with urinary metal elements was investigated. Our result showed that the level of urinary 8-OHdG in children with acute leukemia before treatment was significantly elevated compared with that in normal controls (11.92 ± 15.42 vs. 4.03 ± 4.70 ng/mg creatinine, P < 0.05). In particular, urinary 8-OHdG was higher in children with acute leukemia aged under 3 years (20.86 ± 21.75 ng/mg creatinine) than in those aged 3,15 years (8.09 ± 9.65 ng/mg creatinine), whereas no differences were shown in terms of gender, parental smoking and education, household income, place of residence, and use of paracetamol. In addition, urinary 8-OHdG levels were similar among different subtypes of acute lymphoid leukemia (ALL) patients. Furthermore, linear regression analysis revealed a significant correlation between urinary 8-OHdG and urinary Cr, but not Fe or As, in group aged <3 years compared with group aged 3,15 years (P = 0.041), indicating that the metal elements may be involved in increasing urinary 8-OHdG level in younger children with acute leukemia. Our results suggest that children with acute leukemia undergo an increased risk of oxidative DNA damage, which may be correlated with high level of Cr exposure in Chinese children with acute leukemia. © 2008 Wiley Periodicals, Inc. Environ Toxicol, 2009. [source] Therapy-related leukemia following chemoradiotherapy for esophageal cancerEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2010Naoya Mimura Abstract Chemoradiotherapy has improved the outcome of patients with esophageal cancer. Although a sufficiently long-time survival has resulted in the increase of several treatment-related late toxicities, little is still known about the incidence of secondary malignancies. In our hospital, 348 patients with esophageal cancer received chemotherapy consisting of nedaplatin and 5-fluorouracil and concurrent irradiation. Median and average follow-up durations were 8 and 21 months (1,92), respectively. Four patients developed leukemia after 19,48 months of follow-up. Two patients were diagnosed with overt leukemia from myelodysplastic syndrome presenting a complex karyotype, including the deletion of chromosome 5 or 7. Notably, one patient showed an additional chromosomal abnormality with t(9;22)(q34;q11). Other patients developed acute myeloid leukemia with t(9;22)(q34;q11) and Burkitt leukemia with t(8;14)(q24;q32). All patients eventually succumbed to leukemia. Platinum and fluorouracil have shown relatively lower risks for secondary malignancies in comparison with alkylating agents and topoisomerase II inhibitors. Especially, nedaplatin has never been described to introduce secondary neoplasms. Our report supports the idea that the concurrent administration of radiotherapy with these agents affects the risk of leukemia. Interestingly, rare balanced chromosomal abnormalities were observed in the present cases, thus providing new insights into the leukemogenesis of therapy-related leukemia. [source] Epigenetic therapy in myelodysplastic syndromesEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2010Caterina Musolino Abstract The wide spectrum of clonal hematopoietic disorders that fall under the broad diagnostic category of myelodysplastic syndromes (MDS) consist of a family of bone marrow malignancies , with ineffective, inadequate, and dysplastic hematopoiesis, and with an increased risk of life-threatening infections, bleeding, and progression to acute myeloid leukemia (AML) , that are characterized by a deep heterogeneity on the clinical, biologic and prognostic level. The intrinsic complexity of this group of disorders and the frequent association with one or more comorbidities have limited for many years the number of effective treatment options available: most patients are, indeed, still managed by supportive care measures, with just a minority of them being eligible for allogeneic stem cell transplantation, which is still the only potentially curative modality. In the last two decades, the progressively better understanding of MDS biology has shown how an abnormal epigenetic modulation might play a crucial part in the pathogenesis and in the process of biologic evolution of these disorders. Moreover, pharmacological agents that target the so-called epigenome have shown a significant clinical activity for diverse hematologic malignancies, including MDS. The aim of this review is to highlight recent developments within the context of current knowledge of MDS and its altered epigenetic regulation and to recall the experimental steps that have brought to the clinical development and application of epigenetic modifiers, such as azacytidine and decitabine, trying to explain the biologic rationale for their use in this setting. [source] Chromosome 1 abnormalities in myeloid malignancies: a literature survey and karyotype,phenotype associationsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2010Domenica Caramazza Abstract Chromosome 1 is the largest human chromosome and contains over 1600 known genes and 1000 novel coding sequences or transcripts. It is, therefore, not surprising that recurrent chromosome 1 abnormalities are regularly encountered in both neoplastic and non-neoplastic medical conditions. The current review is focused on myeloid malignancies where we summarize the relevant published literature and discuss specific karyotype,phenotype associations. We show that chromosome 1 abnormalities are most frequent in BCR-ABL -negative classic myeloproliferative neoplasms (MPN): polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Specific abnormalities include duplications (e.g. 1q12,1q32 in PV, 1q21,32,1q32,44 in post-PV MF or PMF), deletions (e.g. 1p13,36,pter in PV or PMF, 1q21 in PMF) and unbalanced translocations involving chromosome 6, such as der(6)t(1;6)(q21,25;p21.3,23), and other partner chromosomes involving 1q10/1p11 and 1q21,25 breakpoints. Although occasionally seen in chronic phase MPN, unbalanced 1;7 translocations, e.g. der(1;7)(q10;p10), are usually seen in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and post-MPN AML/MDS. These observations suggest that certain chromosome 1 regions, especially 1q21,1q32 and 1p11,13, might harbor oncogenes or tumor suppressor genes that are pathogenetically relevant to both chronic and advanced phases of MPN. [source] Voriconazole as primary antifungal prophylaxis in patients with neutropenia after hematopoietic stem cell transplantation or chemotherapy for acute myeloid leukemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2010Antonio Torres No abstract is available for this article. [source] Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2009Yuichi Ishikawa Abstract Acute myeloid leukemia (AML) has been thought to be the consequence of two broad complementation classes of mutations: class I and class II. However, overlap-mutations between them or within the same class and the position of TP53 mutation are not fully analyzed. We comprehensively analyzed the FLT3, cKIT, N-RAS, C/EBPA, AML1, MLL, NPM1, and TP53 mutations in 144 newly diagnosed de novo AML. We found 103 of 165 identified mutations were overlapped with other mutations, and most overlap-mutations consisted of class I and class II mutations. Although overlap-mutations within the same class were found in seven patients, five of them additionally had the other class mutation. These results suggest that most overlap-mutations within the same class might be the consequence of acquiring an additional mutation after the completion both of class I and class II mutations. However, mutated genes overlapped with the same class were limited in N-RAS, TP53, MLL -PTD, and NPM1, suggesting the possibility that these irregular overlap-mutations might cooperatively participate in the development of AML. Notably, TP53 mutation was overlapped with both class I and class II mutations, and associated with morphologic multilineage dysplasia and complex karyotype. The genotype consisting of complex karyotype and TP53 mutation was an unfavorable prognostic factor in entire AML patients, indicating this genotype generates a disease entity in de novo AML. These results collectively suggest that TP53 mutation might be a functionally distinguishable class of mutation. [source] Quantitative assessment of WT1 gene expression after allogeneic stem cell transplantation is a useful tool for monitoring minimal residual disease in acute myeloid leukemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2009Anna Candoni Abstract Introduction:,WT1 overexpression is described in several oncological diseases including acute myeloid leukemia (AML). Quantification of WT1 in bone marrow samples may be useful as a marker of minimal residual disease (MRD) and may predict the relapse of AML after allogeneic hematopoietic stem cell transplant (HSCT). Methods and results:, The quantitative expression of WT1 was measured in 38 AML patients (16 males and 22 females) at diagnosis, at the time of transplant and after the allogeneic HSCT (at precise time points). All cases showed high WT1 expression levels at diagnosis with a mean of 4189 (SD 3325) and a median of 3495 (range 454,13923) copies WT1/104Abl. At transplant, 25 patients (66%) were in complete cytologic remission (CcR) and 13 (34%) had refractory or relapsed AML. Bone marrow samples from patients transplanted in CcR showed significantly lower WT1 expression levels during HSCT compared with the samples from patients with a relapsed or refractory AML (P = 0.004). After HSCT, a rapid decline in WT1 expression levels was observed in all patients who attained or maintained a condition of CcR. Six of 38 patients (13%) relapsed after HSCT and all of them had an increase in WT1 expression at/or before relapse. Five of these six patients died of leukemia and one was successfully reinduced with donor lymphocyte infusion (DLI) + chemotherapy with a rapid reduction of WT1 levels. Besides, we found a complete concordance between WT1 expression levels and other disease markers (when available). Conclusions:, In our experience, there was a complete concordance between WT1 expression levels (measured by quantitative RT-PCR at precise time points) and status of AML before and after allogeneic HSCT. WT1 may be useful as a non-specific leukemia marker for monitoring MRD and as a predictor of AML clinical relapse. Based on these results, cases with increase of WT1 levels after HSCT and without graft vs. host disease may be candidate to discontinuation of immunosuppression and/or DLI therapy. [source] Invasive fungal infections in patients with acute myeloid leukemia and in those submitted to allogeneic hemopoietic stem cell transplant: who is at highest risk?EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2008Morena Caira No abstract is available for this article. [source] The expression of cytosolic phospholipase A2 and biosynthesis of leukotriene B4 in acute myeloid leukemia cellsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2007Gudmundur Runarsson Abstract Leukotrienes (LT) exert stimulatory effects on myelopoiesis, beside their inflammatory and immunomodulating effects. Here, we have studied the expression and activity of the enzymes involved in the synthesis of leukotriene B4 (LTB4) in acute myeloid leukemia (AML) cells (16 clones) and G-CSF mobilized peripheral blood CD34+ cells. CD34+ cells from patients with non-myeloid malignancies expressed cytosolic phospholipase A2 (cPLA2), 5-lipoxygenase activating protein (FLAP), and leukotriene A4 (LTA4) hydrolase but not 5-lipoxygenase (5-LO). The enzyme cPLA2 was abundantly expressed in AML cells and the activity of the enzyme was high in certain AML clones. The expression of 5-LO, FLAP, and LTA4 hydrolase in AML clones was in general lower than in healthy donor polymorphonuclear leukocytes (PMNL). The calcium ionophore A23187-induced release of [14C] arachidonic acid (AA) in AML cells was low, compared with PMNL, and did not correlate with the expression of cPLA2 protein. Biosynthesis of LTB4, upon calcium ionophore A23187 activation, was only observed in five of the investigated AML clones and only three of the most differentiated clones produced similar amounts of LTB4 as PMNL. The capacity of various cell clones to produce LTs could neither be explained by the difference in [1 , 14C] AA release nor 5-LO expression. Taken together, these results indicate that LT synthesis is under development during early myelopoiesis and the capacity to produce LTs is gained upon maturation. High expression of cPLA2 in AML suggests a putative role of this enzyme in the pathophysiology of this disease. [source] Mesothelin, a possible target for immunotherapy, is expressed in primary AML cellsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 4 2007Daniel Steinbach Abstract Background:, Mesothelin is a promising candidate for tumor-specific therapy because of its limited expression in normal tissues and high expression in several cancers. The expression of the protein mesothelin in hematological malignancies has not yet been analyzed. SS1(dsFv)PE38 is a recombinant anti-mesothelin immunotoxin which is undergoing clinical evaluation in patients with mesothelin-expressing tumors. Methods and Results:, In this study we show that the mesothelin protein is expressed in leukemic cells from children with acute myeloid leukemia (AML). This finding was confirmed by western blot, immunocytochemistry and real time polymerase chain reaction (PCR). Despite the expression of mesothelin, the patient samples were not sensitive to immunotoxin SS1(dsFv)PE38 in MTT assays. Conclusions:, Primary AML cells express mesothelin but SS1(dsFv)PE38 is not active in killing these cells. Other approaches that utilize mesothelin as a target might be more effective and should be tested against AML cells. [source] Redefining monosomy 5 by molecular cytogenetics in 23 patients with MDS/AMLEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 6 2007Angèle Herry Abstract Deletion of the long arm of chromosome 5 [del(5q)] or loss of a whole chromosome 5 (,5) is a common finding, arising de novo in 10% of patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) and in 40% of patients with therapy-related MDS or AML. We investigated by molecular cytogenetics 23 MDS/AML patients for whom conventional cytogenetics detected a monosomy 5. Monosomy 5 was redefined as unbalanced or balanced translocation and ring of chromosome 5. Loss of 5q material was identified in all 23 patients, but one. One copy of EGR1(5q31) or CSF1R(5q33,34) genes was lost in 22 of the 23 patients. Chromosome 5p material was a constant chromosomal component of derivative chromosomes or rings in all patients, but one. Sequential fluorescent in situ hybridization studies with whole chromosome paints and region-specific probes, used as a complement to conventional cytogenetic analysis, allow a better interpretation of karyotypes in MDS/AML patients. [source] Graft rejection and hyperacute graft-versus-host disease in stem cell transplantation from non-inherited maternal antigen complementary HLA-mismatched siblingsEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 2 2007Hirokazu Okumura Abstract Human leukocyte antigen (HLA)-mismatched stem cell transplantation from non-inherited maternal antigen (NIMA)-complementary donors is known to produce stable engraftment without inducing severe graft-versus-host disease (GVHD). We treated two patients with acute myeloid leukemia (AML) and one patient with severe aplastic anemia (SAA) with HLA-mismatched stem cell transplantation (SCT) from NIMA-complementary donors (NIMA-mismatched SCT). The presence of donor and recipient-derived blood cells in the peripheral blood of recipient (donor microchimerism) and donor was documented respectively by amplifying NIMA-derived DNA in two of the three patients. Graft rejection occurred in the SAA patient who was conditioned with a fludarabine-based regimen. Grade III and grade IV acute GVHD developed in patients with AML on day 8 and day 11 respectively, and became a direct cause of death in one patient. The findings suggest that intensive conditioning and immunosuppression after stem cell transplantation are needed in NIMA-mismatched SCT even if donor and recipient microchimerisms is detectable in the donor and recipient before SCT. [source] Zoledronate-induced remission of acute panmyelosis with myelofibrosisEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2004I. Español Abstract:, Acute panmyelosis with myelofibrosis is a rare and aggressive form of acute myeloid leukemia. We describe a new case with a huge proliferation of megakaryocytes, blast cells and reticulin fibers. The patient was treated with zoledronate, a third-generation bisphosphonate, and a gradual recovery from pancytopenia was observed. A new bone marrow biopsy performed 4 months later showed a surprising disappearance of the leukemic infiltration. Ten months after the diagnosis, the patient is still in healthy condition. This may support the recently described anti-tumor activity of zoledronate. [source] A multicenter, open, non-comparative, phase II study of the combination of cladribine (2-chlorodeoxyadenosine), cytarabine, and G-CSF as induction therapy in refractory acute myeloid leukemia , a report of the Polish Adult Leukemia Group (PALG)EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 3 2003A. Wrzesie Abstract: Objectives: To evaluate the efficacy and toxicity of cladribine (2-chlorodeoxyadenosine, 2-CdA), cytarabine (Ara-C), and granulocyte-colony stimulating factor (G-CSF) (CLAG) regimen in refractory acute myeloid leukemia (AML) in the multicenter phase II study. Methods: The induction chemotherapy consisted of 2-CdA 5 mg/m2, Ara-C2 g/m2, and G-CSF. In the case of partial remission (PR), a second CLAG was administered. Patients in complete remission (CR) received two consolidation courses based on HD Ara-C, mitoxantrone or idarubicine, with or without 2-CdA. Results: Fifty-eight patients from 11 centers were registered; 50 primary resistant and eight early relapsed (CR1 < 6 months). CR was achieved in 29 (50%) patients, 19 (33%) were refractory, and 10 (17%) died early. Forty of 50 primary resistant patients received daunorubicin (DNR) and Ara-C as the first-line induction therapy (DA-7), 10 received additional 2-CdA (DAC-7). The CR rates after CLAG were 58% and 10%, respectively in each group (P = 0.015). Five of six patients with myelodysplastic syndrome (MDS)/AML achieved CR. Hematologic toxicity was the most prominent toxicity of this regimen. The overall survival (OS, 1 yr) for the 58 patients as a whole, and the 29 patients in CR were 42% and 65%, respectively. Disease-free survival (DFS, 1 yr) was 29%. Only first-line induction treatment with DA-7 significantly influenced the probability of CR after CLAG. None of the analyzed factors significantly influenced DFS and OS. Conclusion: CLAG regimen has significant anti-leukemic activity and an acceptable toxicity in refractory AML. The addition of 2-CdA to the first-line induction treatment may worsen the results of salvage with CLAG. The high CR rate in patients with MDS preceding AML deserves further observation. [source] Chronic basophilic leukemia: a distinct clinico-pathologic entity?EUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2003Animesh D. Pardanani Abstract: Objective: We sought to better define a group of rare and poorly understood myeloproliferative disorders that are characterized by prominent chronic basophilia in the absence of the Philadelphia chromosome (Ph) or its molecular equivalent. Methods: We screened our institution's electronic database from 1975 onwards, and identified four such cases. Clinical data and bone marrow pathology were carefully reviewed for these patients. Results: Two patients had prominent manifestations of basophil mediator-release and another presented with pituitary dysfunction. Bone marrow examination uniformly revealed trilineage hyperplasia with basophilia and eosinophilia, dysplastic megakaryocytic hyperplasia, and the absence of megakaryocyte clustering. An abnormal pattern of atypical mast cells was noted in two cases. While disease palliation was effectively achieved with hydroxyurea for one patient, transformation to acute myeloid leukemia was eventually observed in this case. Another patient has achieved long-term disease-free survival after undergoing allogeneic stem cell transplantation. Conclusions: Our observations reveal a striking pathologic similarity among all four cases, and suggest this disease, which may be aggressive with the potential to transform into acute leukemia, to possibly represent a distinct clinico-pathologic entity (chronic basophilic leukemia). [source] Penile chloroma in a patient with secondary acute myeloid leukemiaEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2002Árpád Szomor No abstract is available for this article. [source] | |||||||||||||||||||||||||||||||