Comparative analysis of chromosomal aberrations in children with acute leukemia

2020 ◽  
Vol 5-6 (215-216) ◽  
pp. 7-14
Author(s):  
Zhansaya Nessipbayeva ◽  
◽  
Minira Bulegenova ◽  
Meruert Karazhanova ◽  
Dina Nurpisova ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Chromosomal Aberrations ◽  
Cytogenetic Study ◽  
Normal Karyotype ◽  
Blast Cell ◽  
Bone Marrow Blast ◽  
Scientific Center ◽  
Blast Cells ◽  
Medical Histories

Leukemia is a hematopoetic tissue tumor with a primary lesion of the bone marrow, where the morphological substrate is the blast cell. Chromosomal and molecular genetic aberrations play a major role in the acute leukemia pathogenesis, determing the morphological, immunological and clinical features of the disease. Our study was aimed to to analyze retrospectively the structure and frequency of chromosomal aberrations in children with initially diagnosed acute leukemia. Material and methods. Medical histories retrospective analysis of children charged to oncohematology department of the «Scientific Center of Pediatrics and Pediatric Surgery» in Almaty for the period 2015 - 2017 was carried out. 310 histories with primary diagnosed acute leukemia were studied. Results and discussion. Among 310 patients different chromosome aberrations were isolated in 158 patients (51%) during cytogenetic and molecular cytogenetic (in situ hybridization) studies of bone marrow blast cells. A normal karyotype was observed in 102 patients (33%). Conclusion. The lymphoblastic variant of acute leukemia was determined in 75.5%, that indicates its leading role in AL structure among the children of different ages. AML was determined in 22.6% of all OL cases. The most frequent chromosomal rearrangement in ALL patients was blast cell chromosome hyperdiploidy (10,6%) and t(12;21)(p13;q22)/ETV6-RUNX1,which was detected in 37 (16%) patients. The most frequent AML abberation was t (8;21) (q22;q22)/RUNX1-RUNX1T1, identified in 15 (21.4%) patients. Keywords: acute leukemia, bone marrow, blast cells, karyotype, chromosomal aberrations, cytogenetic study.

The Usefulness of CD71 Expression by Flow Cytometry in the Diagnosis of Acute Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2533-2533 ◽  
Author(s):  
Qian Liu ◽  
Mangju Wang ◽  
Yang Hu ◽  
Haizhou Xing ◽  
Xue Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Clonal Evolution ◽  
Expression Level ◽  
Leukemic Cells ◽  
Bone Marrow Blast ◽  
Blast Cells ◽  
The Mean ◽  
Acute Megakaryocytic Leukemia ◽  
Normal Controls

Abstract Abstract 2533 CD71 (transferring receptor 1) is an integral membrane glycoprotein that plays an important role in cellular uptake of iron. It is well known as a marker for cell proliferation and activation. Although all proliferating cells in hematopoietic system express CD71, however, CD71 has been considered as a useful erythroid-associated antigen. The expression proportion on nucleated red blood cells was significantly higher than other cells, approximately 80% of all CD71 positive cells were of CD71 positive erythroid cells in normal bone marrow. CD71 was usually considered as the representative marker for differentiating erythroblasts and diagnosing acute erythroid leukemia (AEL) by flow cytometry. At the ISAC 2000 Congress, most experts agreed that at least one or more B, T, myeloid, erythroid and megakaryocytic reagents should be included in the essential panel. The reagents recommended for erythroid cells included CD36, CD71 and glycophorin A (GlyA). However, there was no agreement on how to choose and group these antibodies. In the practical analysis of immune phenotypes of leukemic cells we noted that no CD71 expression was detected on blasts of some cases of AEL with typical morphological and cytochemical findings, but other types of acute myeloblastic leukemia (AML) cells may express CD71. Thus, we speculated that CD71 expression may associate with the abnormal antigen expression resulting from hematopoietic disorders. In this study, we evaluated CD71 expression on different acute leukemia cells in association with a variety of other antibodies. In this study we aimed to define CD71 as a flow cytometric marker for the diagnosis of acute leukemia. Bone marrow samples were collected from 82 newly diagnosed acute leukemia patients as well as 13 normal controls. The diagnosis were made according to the WHO 2008 diagnostic criteria. All 6 cases of AEL were erythroid/myeloid subtype (acute erythroid/myeloid leukemia, M6a). The samples were then analyzed using a four-color flow cytometer with antibody panels against a variety of lymphoid, myelomonocytic, erythroid and megakaryocytic antigens. The antibodies included anti-CD3, CD7, CD10, CD11b, CD13, CD14, CD15, CD16, CD19, CD20, CD33, CD34, CD45, CD56, CD61, CD64, CD71, CD117, GlyA, HLA-DR, IgG, IgM, MPO. Subpopulations of bone marrow cells were gated based on CD45 intensities and side scatter (SSC) value to further analyze the expression of antigens in different cell populations. Positive CD71 expression were identified on bone marrow blast cells of 41 (50%) acute leukemia patients and 9 (69.23%) normal controls. The mean expression level on normal controls was 35.99±19.06%. The mean CD71 expression level on blasts of AML with blasts differentiation at early stage of myelopoiesis (including FAB-M0/M1/M2/M4) was significantly higher than AML with partial differentiation of leukemic cells (FAB-M3/M5) and acuteB lymphoblastic leukemia (B-ALL) (p<0.05), with the mean expression level of 38.78±26.65%, 13.25±8.75% and 10.12±11.65%, respectively, and the latter two lower than normal controls (p<0.05). The percentage of CD71 expression level on blasts of acute megakaryocytic leukemia (FAB-M7) was 80.16±8.23%, significantly higher than normal controls, partial differentiation of leukemic cells (FAB-M3/M5), and B-ALL (p<0.05). The percentage of CD71 expression level on blasts of mixed lineage leukemia was 49.66±22.69%, significantly higher than B-ALL (p<0.05). Positive CD71 expression was found on bone marrow blast cells of 4 (66.67%) AEL cases, with the mean level percentage of 25.68±11.63% that was significantly lower than acute megakaryocytic leukemia (FAB-M7) (p<0.05) and was indifferent from normal controls and other types of acute leukemia. Using CD71 expression levels, we identified different abnormal cell clones simultaneously existing within bone marrow of 2 patients of AML with maturation (FAB-M2) and AEL, implicating the clonal evolution process from normal blasts to leukemic cells. CD71 is an important marker for diagnosing acute leukemia, and is useful for distinguishing the differentiation stages of AML. However, CD71 may not be the specific diagnostic marker for AEL. CD71 is also valuable for the observation of clonal evolution process of acute leukemia, which may be informative to the etiology of leukemia. Disclosures: No relevant conflicts of interest to declare.

A Unified Prognostic Model for Myelodysplastic Syndrome and Acute Myeloid Leukaemia Based on Flow Cytometric Blast Count

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1736-1736
Author(s):  
Alexandra Smith ◽  
Simon Crouch ◽  
Dan Painter ◽  
Eve Roman ◽  
Matt Cullen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Cell Count ◽  
Prognostic Model ◽  
Blast Cell ◽  
Bone Marrow Blast ◽  
Flow Cytometric ◽  
Blast Cells ◽  
Blast Count ◽  
Acute Myeloid

Abstract Abstract 1736 The distinction between Acute Myeloid Leukaemia (AML) and Myelodysplastic Syndrome (MDS), together with its prognostic assessment, depends on the proportion of bone marrow blast cells. The International Prognostic Scoring System (IPSS) uses this value to predict survival in conjunction with cytogenetic and blood count parameters. Current practice in most centres is to count blast cells manually on stained smears and to assign patients to one of 4 bands (<5%, 6–10%,11-19% and >20%). This approach has two major disadvantages. Firstly, the evaluation of cellular morphology is subjective and the standard error of a manual count is sufficiently large that many patients cannot be assigned with reasonable accuracy to a category - which can critically impact on their care. Secondly, assigning patients into broad groups, instead of retaining blast cell count as a continuous variable, may be degrading important prognostic information. Modern flow cytometric techniques allow blast cells to be counted with high levels of accuracy. In this study we used a standard five colour assay including CD34, CD117, CD15, CD3, CD19 and physical characteristics to count bone marrow blast cells. Bone marrows from 271 patients with AML/MDS treated with curative intent (median age, 59 yrs; M: F,1.22) and 684 patients treated with supportive therapy (median age, 77 yrs; M: F,1: 1.8) were evaluated. Patients with acute promyelocytic leukaemia (APML), AML with t(8;21) or inv 16 were excluded. All patients were from a population-based cohort (www.hmrn.org), and all diagnostic studies were performed using standard protocols in a single laboratory. A prognostic model was constructed using age, flow cytometric blast cell count and gender. In non-intensively treated patients survival declined rapidly with blast counts up to 10% and then decreases much more slowly. Age had a minimal effect on survival under the age of 70, but prognosis declined rapidly in older patients. Male gender was a significant adverse risk factor (hazard ratio = 1.47). In contrast, patients who were treated intensively showed only a modest relationship between blast count and prognosis but a much more marked effect of age. Survival declined progressively from 20 years with the trend accelerating in those over 60 years. There was also a smaller effect of gender in those receiving intensive treatment (hazard ratio = 1.09). In MDS patients, a complex relationship between blast cell count, standard cytogenetic risk factors and the degree of cytopenia was observed. Using age and flow cytometric blast count as continuous variables, modelled using restricted cubic splines, together with gender enabled more accurate outcome prediction in patients with AML and MDS across the full range of blast counts. This is possible because of the much higher levels of accuracy of flow cytometry compared to manual counting methods. The main practical advantage of a unified prognostic model is that it allows the relative benefits of intensive and non-intensive treatment to be readily compared for an individual patient. The predictive power of this core model can be improved further by the inclusion of additional clinical and molecular data. MDS and most forms of AML are part of a continuous spectrum of disease. A more unified approach to classification avoiding arbitrary subdivision may improve clinical decision making in this complex group of patients. Figure: The interrelationship between survival, age and blast cell count in patients with myelodysplastic syndrome. Figure:. The interrelationship between survival, age and blast cell count in patients with myelodysplastic syndrome. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Blast Cells Count Influences Bleeding Incidence in Acute Leukemia: Preliminary Study in South Kalimantan, Indonesia

2021 ◽  
Vol 9 (B) ◽  
pp. 900-902
Author(s):  
Edward Kurnia Setiawan Limijadi ◽  
Qintani Cantika Ismail ◽  
Dwi Retnoningrum ◽  
Wivina Riza Devi ◽  
Anugrah Riansari
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Medical Records ◽  
Malignant Disease ◽  
Hematopoietic Tissue ◽  
Bone Marrow Blast ◽  
Exact Test ◽  
Risk Of Bleeding ◽  
Blast Cells ◽  
Preliminary Study

Background: Acute leukemia is a malignant disease involving hematopoietic tissue, characterized by abnormal blood cells in bone marrow or called blast cells. The most common complications of acute leukemia is bleeding. A high percentage of blasts has been reported to increase the risk of bleeding in acute leukemia. Preliminary study was needed to investigate relationship between blast cells count and bleeding incidence in acute leukemia. Methods: Crosssectional study with observasional analytic in 18 adult subjects was conducted from November 2019 to March 2020 in Ulin Hospital Banjarmasin South Kalimantan. The data were taken from medical records of acute leukemia patients who met inclusion and exclusion criterias. Data analysis was using Fisher’s exact test. Results: There were 7 men and 11 women in this study. Blast cells count in peripheral with cut off     <50% was 9 (50%) and ≥50% was 9 (50%). It was same for blast cells count in bone marrow. Both of women and men mostly have bleeding in acute leukemia, and bleeding incidence in women is higher than men. Bleeding condition was happened both in peripheral and bone marrow blast cells count with cut of <50% and ≥50%. Significancy of relationship between blast cells count and bleeding incidence was 0.637. Conclusion: There is no significant between blast cells count and the bleeding incidence in acute leukemia. Another parameters that could be influenced bleeding inceidence need to be investigate in acute leukemia.  

NPM-1, but Not FLT3-ITD Mutations Predict Early Blast Cell Clearance and CR Rate in Patients with Normal Karyotype AML or High-Risk Myelodysplastic Syndrome (MDS).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 805-805 ◽  
Author(s):  
Karsten Spiekermann ◽  
Annika Dufour ◽  
Gudrun Mellert ◽  
Evelin Zellmeier ◽  
Jan Braess ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factors ◽  
De Novo ◽  
Blast Cell ◽  
High Dose ◽  
Bone Marrow Blast ◽  
Npm1 Mutation ◽  
Free Survival ◽  
Cell Clearance ◽  
High Dose Cytarabine

Abstract Background: Mutations in the NPM1 gene represent the most frequent alterations in patients with AML and are associated with a favourable clinical outcome. Patients and Methods: We analyzed 803 patients that were treated in the AMLCG2000 study. Patients with de novo or secondary AML or high-risk myelodysplastic syndrome (MDS) were randomly assigned upfront for induction therapy containing one course with standard dose and one course with high-dose cytarabine, or two courses with high-dose cytarabine, and in the same step received postremission prolonged maintenance or busulfan/cyclophosphamide chemotherapy with autologous stem-cell transplantation. At diagnosis mutations in the NPM1 and FLT3 gene were analyzed by routine molecular techniques. Results: The median age of all patients was 60 years and the median observation time 23 months. Results of the mutations status of FLT3 (FLT3-ITD) and NPM1 were available in 761/803 (94,8 %) and 690/803 (85,9 %) patients, respectively. NPM1 and FLT3-ITD mutation were found in 352 (51,1%) and 199 (28,9%), respectively. On the basis of these two molecular markers, patients were grouped in 4 subgroups: 1. NPM1+/FLT3−, N=214 (31%), 2. NPM1+/FLT3+, N=138 (20%); 3. NPM1−/FLT3−, N=276 (40%); NPM1−/FLT3+ (9%). The CR-rates were significantly higher in NPM1+ (74,4%) than in NPM1− (55,9%) patients, but were unaffected by the FLT3-ITD status. Overall survival (OS), event-free survival (EFS) and relapse free survival (RFS) was significantly higher in NPM1 positive and FLT3-ITD negative patients. In a multivariate analysis age, WBC, the presence of the NPM1 mutation and de novo AML were independent prognostic factors for the CR-rate. The NPM1− and FLT3 mutation status, age and LDH were identified as independent prognostic factors for RFS. To further characterize the biological effects of NPM1 and FLT3 mutations, we analyzed the in vivo blast cell clearance measured by the residual bone marrow blast cells one week after the end of the first induction cycle (d+16 blasts). The percentage of patients with adequate blast cell reduction (residual bone marrow blast &lt;10%) was significantly higher in NPM1+ patients (87,3%) compared to NPM1− (65,7%) patients. The presence of a FLT3-ITD mutation had no effect on early blast cell clearance. Conclusions: The presence of a NPM1 mutation represents an independent positive prognostic factor for the CR-rate and RFS/OS. In contrast, FLT3-ITD mutations do not affect the CR-rate, but have a negative prognostic impact on RFS and OS. The higher sensitivity of NPM1-positive blasts towards the induction therapy point to a central role of NPM1 in the regulation of apoptotic cell death in AML.

The Expression and Clinical Significance of PRAME Gene in Acute Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4225-4225
Author(s):  
Rong Fu ◽  
Kai Ding ◽  
Zonghong Shao
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Clinical Significance ◽  
Blood Count ◽  
Mononuclear Cells ◽  
Residual Disease ◽  
White Blood Count ◽  
Gene Expressions ◽  
Healthy Donors ◽  
Blast Cells

Abstract Objective To investigate the expression of PRAME (preferentially expressed antigen of melanoma) gene in acute leukemia and its clinical significance in monitoring prognosis, detecting minimal residual disease (MRD) and gene immunotherapy. Methods The expression of PRAME gene mRNA in bone marrow mononuclear cells is measured by reverse transcriptase polymerase chain reaction in 34 patients with acute leukemia and 12 bone marrow samples of health donors. The relationships between PRAME gene expressions and some clinical data, such as gender, age, white blood count, leukemic immunophenotype, the percentage of blast cells, and the karyotype of chromosome, were also estimated. Results PRAME gene was expressed in 38.2% of all the patients, 40.7% of all the AML patients, which was higher than the 28.6% of ALL patients (p &gt;0.05). There was no expression of PRAME gene in healthy donors. In all the sub phenotypes of AML, the expressive rate of PRAME gene in M3 patients is 80%, which is higher than that in M2 (33.3%) and in M5 (28.6%). The expressive rate of PRAME gene was also positively correlated with the expression of CD15, CD33, and the abnormality in the karyotype of chromosome, but not correlated with age, gender, white blood count and percentage of blast cell in bone marrow. Conclusion PRAME gene is highly expressed in acute leukemia, and could be regarded as a useful tool for monitoring MRD. Differential expression in acute leukemia patients vs. healthy donors suggests that the immunogenic antigens PRAME are potential candidates for immunotherapy in acute leukemia.

Molecular Genetic Characterization of 3'-Deletion of MLL Gene in Infant Acute Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2498-2498
Author(s):  
Grigory Tsaur ◽  
Olga Plekhanova ◽  
Alexander Popov ◽  
Tatyana Gindina ◽  
Yulia Olshanskaya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Molecular Genetic ◽  
Fish Analysis ◽  
Long Distance ◽  
Mll Gene ◽  
Partner Gene ◽  
Genetic Features ◽  
Blast Cells

Abstract Abstract 2498 Background. MLL gene rearrangements are associated with unfavorable outcome in infant acute lymphoblastic leukemia (ALL) and have intermediate prognosis in infant acute myeloid leukemia (AML). Application of fluorescence in-situ hybridization (FISH) allows detecting not only conventional MLL rearrangements, but also concurrent 3'-deletion of MLL gene. However, detailed characteristics of infant leukemia carrying 3' MLL deletion remain unclear. Aim. To investigate molecular genetic features of MLL-rearranged infant acute leukemia with concurrent 3' MLL deletion. Methods. 64 patients (27 boys and 37 girls) aged from 1 day to 11 months (median 6.6 months) including 44 ALL patients, 18 AML patients, 1 patient with acute bilineage leukemia and 1 patient with acute undifferentiated leukemia were enrolled in the current study. Chromosome banding analysis was done according to standard procedure. FISH analysis using LSI MLL Dual Color, Break Apart Rearrangement Probe (Abbott Molecular, USA) was performed on at least 200 interphase nuclei and on all available metaphases. Presence of MLL rearrangements was detected by FISH, reverse-transcriptase PCR. In 29 cases long-distance inverse PCR was additionally performed. In case of MLL rearrangement presence standard FISH pattern was defined as simultaneous detection of 3 different fluorescent signals: 1 fused (orange) signal, 1 green signal derived from 3' part of MLL gene, 1 red signal from 5' end of MLL (1F1G1R). MLL rearrangements with concurrent 3' MLL deletion led to 1F1R FISH pattern formation due to lack of green signal. Results. FISH revealed MLL rearrangements in 73% of ALL cases that was higher than frequency of 11q23 translocations detected by conventional cytogenetics — 55%. In MLL-positive cases we found 38 patients (81%) with standard FISH pattern, 7 ones (15%) with concurrent 3'-deletion of MLL gene and 2 (4%) with complex MLL rearrangements. Among patients with 3' MLL deletions there were 1 case with 5' MLL duplication (1F2R) and 1 case with 5' MLL triplication (1F3R). Frequency of 3'-deletions were similar in ALL and AML patients (13% and 15%, respectively). We did not find more than one FISH pattern in bone marrow blast cells of each patient with 3' MLL deletion. In this cohort of patients all blast cells carried concurrent 3'-deletion of MLL gene. Moreover, percentage of blast cells carrying MLL rearrangements did not differ significantly between patients with standard FISH pattern (median 97%, range 22–100%) and 3'-deletion (median 83%, range 13–99%) (p=0.206). 3'-deletion of MLL was not associated with breakpoint position in MLL gene and type of translocation partner gene. MLL translocation partner genes detected in patients with 3' deletions were as follows AF4(n=2), MLLT3(n= 3), MLLT10(n=2). None of the patients with 3'-deletions had reciprocal fusion gene. Initial patients' characteristics (age, sex, WBC count, immunophenotype, CNS-status, type of MLL partner gene) and treatment response parameters (day 8 peripheral blood blast cell count, day 15 bone marrow status, day 36 remission achievement, minimal residual disease status at time point 4) did not differ significantly between 2 groups. Although cumulative incidence of relapse was lower in patients with 3'-deletion as compared to patients with standard FISH pattern (0.31±0.04 and 0.55±0.01, respectively), difference between these two groups was not statistically significant (p=0.359). Conclusion. In our work we characterized rare subgroup of infant MLL-rearranged acute leukemia carrying concurrent 3' MLL deletion. Our data provide additional information of molecular genetic features of acute leukemia in children younger than one year. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Phase 1 Study of the BET-Bromodomain Inhibitor OTX015 in Patients with Advanced Acute Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 117-117 ◽  
Author(s):  
Hervé Dombret ◽  
Claude Preudhomme ◽  
Céline Berthon ◽  
Emmanuel Raffoux ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Normal Karyotype ◽  
Refractory Anemia ◽  
Phase 1 Study ◽  
Grade 3

Abstract Rationale: BET-bromodomain (BRD) proteins play a major role in the epigenetic regulation of gene transcription, notably of genes with superenhancer promoter regions including many oncogenes, such as MYC. OTX015 is a specific BRD 2, 3 and 4 inhibitor that blocks oncogene transcription, and triggers growth inhibition and apoptosis in acute leukemia cell lines and patient cells in vitro (Braun et al. ASH Annual Meeting 2013). Based on these findings, a Phase 1 study of OTX015 was designed for patients with advanced acute leukemia. Patients & Methods: Patients with various unselected relapsed/refractory leukemia subtypes for which no standard therapy options were available were enrolled in this ongoing Phase 1 study. Patients aged < 60 years had to have failed at least two lines of therapy and those aged >60 years at least one line. At least 5% bone marrow leukemic blasts were required at study entry. OTX015 was given orally, daily for 14 days of 21-day cycles (cy). The dose was escalated from 10 to 160 mg daily (QD) according to a standard 3+3 dose-escalation design, to determine the maximum tolerated dose (MTD) or biologically optimal dose. A BID schedule was tested at dose level (DL) 4 (40 mg x 2) and a continuous schedule at 120 mg. Pharmacokinetics was studied on day 1 and residual concentrations were measured on days 2, 8 and 15. Responses were assessed on blood and bone marrow aspirations at baseline, days 8, 22 and 43. Blasts at baseline and day 8 were stored for pharmacodynamic biomarker evaluation. Cytogenetic and molecular markers were collected based on center practice. Results: From January 2013 to June 2014, 36 patients were treated over 6 dose levels: 33 with acute myeloid leukemia (AML), 2 with acute lymphoblastic leukemia and 1 with refractory anemia with excess blasts. Median age was 70 years (range 19-85), 20 patients were male, 29 patients had ECOG 0-1, and 16 AML patients had normal karyotype. Patients had a median of 2 prior therapy lines (range 1-4). The median number of OTX015 cycles administered was 2 (range 1-14+), including 9 patients with >3 cycles. Among the 28 patients evaluable for dose limiting toxicity (DLT), no DLTs were observed through DL5 (120 mg QD). The MTD was exceeded at DL6 (160 mg QD) with one patient experiencing grade 3 diarrhea and another grade 3 fatigue and anorexia. The main toxicities were non-cumulative grade 1-2 gastrointestinal events (6 patients diarrhea, 3 dysgueusia, 3 abdominal pain, 3 nausea, 1 anorexia), hyperglycemia (3 patients), coagulation factor VII decrease (6 patients) and direct bilirubin increase (3 patients) (two latter AEs asymptomatic). These toxicities were mainly observed at QD doses above 80 mg and with 40 mg BID. Dose proportional plasma concentrations were observed and trough concentrations > 500 nM (in vitro active concentrations) were regularly observed from 80 mg/day. Clinically relevant activity was reported in 5 AML patients treated at 10, 40 and 80 mg, including one sustained CR from cy 4 to cy 12 (40 mg QD) and one CR with incomplete platelet recovery (CRp) from cy 2 to cy 5 (80 mg QD). Two patients (10 mg QD, 40 mg QD) had partial blast clearance (disappearance of peripheral blasts and decrease >50% in bone marrow blast percentage) and the remaining patient (40 mg BID) had gum hypertrophy resolution. Four of these 5 patients had secondary or therapy-related AML, 4 had normal karyotype and 2 had an NPM1 gene mutation. Conclusions: OTX015 single agent exhibits antileukemic activity over a wide range of DLs and plasma concentrations in patients with advanced AML. MTD is exceeded at 160 mg QD. The safe recommended dose and schedule is close to being identified. Central extensive molecular marker analysis is being performed and will be prospectively implemented in an expansion cohort. Updated data will be presented and will include correlations between regimen, pharmacokinetics, clinical activity and molecular profile. Table Dose (Schedule) N pts evaluable Evidence of activity DLT 10 QD (14/21) 3 1 20 QD (14/21) 3 40 QD(14/21) 4 1 (CR) 80 QD(14/21) 3 2 (1 CRp) 40 BID (14/21) 6 1 120 QD (14/21) 3 120 QD (21/21) 3 160 QD (14/21) 3 Diarrhea (1) Anorexia/fatigue (1) Disclosures Dombret: Oncoethix SA: Research Funding. Preudhomme:Oncoethix SA: Research Funding. Berthon:Oncoethix SA: Research Funding. Raffoux:Oncoethix SA: Research Funding. Thomas:Oncoethix SA: Research Funding. Vey:Oncoethix SA: Research Funding. Gomez-Roca:Oncoethix SA: Research Funding. Ethell:Oncoethix SA: Research Funding. Yee:Oncoethix SA: Research Funding. Bourdel:Oncoethix SA: Employee of study CRO Other. Herait:Oncoethix SA: CMO and Shareholder Other. Michallet:Oncoethix SA: Research Funding. Recher:Oncoethix SA: Research Funding. Roumier:Oncoethix SA: Research Funding. Quesnel:Oncoethix SA: Research Funding.

scholarly journals Prediction of Progression from Refractory Cytopenia with Unilineage Dysplasia by Analysis of Bone Marrow Blast Cell Composition

2012 ◽  
Vol 52 (1) ◽  
pp. 63-66 ◽  
Author(s):  
Satoko Oka ◽  
Kazuo Muroi ◽  
Shin-ichiro Fujiwara ◽  
Iekuni Oh ◽  
Tomohiro Matsuyama ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Blast Cell ◽  
Bone Marrow Blast ◽  
Cell Composition

scholarly journals Interleukin-1 alpha also induces granulocyte-macrophage colony- stimulating factor in immature normal bone marrow cells

Blood ◽  
1990 ◽  
Vol 76 (2) ◽  
pp. 307-311 ◽  
Author(s):  
FJ Bot ◽  
P Schipper ◽  
L Broeders ◽  
R Delwel ◽  
K Kaushansky ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Interleukin 1 ◽  
Tnf Alpha ◽  
Normal Bone Marrow ◽  
Bone Marrow Blast ◽  
Gm Csf ◽  
Normal Bone ◽  
Blast Cells ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

The cytokine interleukin-1 (IL-1) plays a role in the regulation of normal as well as leukemic hematopoiesis. In acute myeloid leukemia (AML), IL-1 induces autocrine granulocyte/macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor (TNF) production, and these factors may then synergistically induce proliferation in AML blast cells. In this report, we show that IL-1 stimulates DNA synthesis of highly enriched normal bone marrow blast cells (CD34 positive, adherent cell depleted, CD3/CD14/CD15 negative). The stimulative effect of IL-1 can be blocked with neutralizing anti-TNF alpha and anti-GM-CSF antibodies and, most efficiently, by the combination of anti-TNF alpha and anti-GM-CSF, but not with anti-G-CSF antibody, suggesting that IL-1- induced proliferation was initiated through TNF and GM-CSF release. Concentrations of TNF and GM-CSF increased in the culture medium of normal bone marrow blast cells after IL-1 induction. Of the IL-1- induced cells, 12% were positive for GM-CSF mRNA by in situ hybridization, as opposed to 6% of non-induced cells. Thus, in addition to its effect on leukemic blast cells, IL-1 also acts on normal marrow blast cells. We propose a scheme where IL-1 stimulation of normal bone marrow blast cells leads to the induction of TNF alpha and GM-CSF, which in association stimulate DNA synthesis efficiently according to a paracrine or autocrine mechanism within the marrow blast cell compartment.

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