scholarly journals Evaluation of Therapeutic Results of A Series of Moroccan Patients Aged 20 To 60 Years Treated According To The Acute Myeloid Leukaemia 03 Protocol At The Paediatric Haematology Oncology Centre In Casablanca

2021 ◽  
Author(s):  
Marielle IGALA ◽  
Mouna LAMCHAHAB ◽  
Siham CHERKAOUI ◽  
Nisrine Khoubila ◽  
Bouchra OUKKACHE ◽  
...  
Keyword(s):  
De Novo ◽  
Maintenance Phase ◽  
Inclusion Criteria ◽  
Paediatric Haematology ◽  
Single Center Study ◽  
Therapeutic Results ◽  
Blast Cells ◽  
De Novo Aml ◽  
Oncology Centre ◽  
Moroccan Patients

Abstract Acute Myeloblastic Leukaemia (AML) is a malignant haemopathy characterized by infiltration and accumulation in the bone marrow by myeloblastic-type blast cells causing medullary insufficiency. At the global level, the search for improved AML treatment is a long-standing concern.PurposeTo evaluate a new protocol AML MA 2003 its therapeutic results and tolerance in de novo AML patients.MethodsIt was a prospective and descriptive unicentre study carried out from January 2003 to December 2010. It included adults of 20 to 60 years with a diagnosis of de novo AML except a promyelocytic leukemia and without treatment by hydroxyurea.ResultsA total of 962 AMLs were diagnosed, 438 met the inclusion criteria, 48.4% women and 51.6% men with a median age of 39.8 years. 36.1% received hydroxyurea in pre-induction. 96.3% patients were induced, 76 (18%) died. A total of 178 (40.6%) of the 438 evaluable patients reached the maintenance phase. The overall survival of all patients was 32.4% at 5 years. Survival without event was 17.6% for all patients.ConclusionThe results of this single-center study illustrate the difficulty of treating AML patients despite the use of drugs recognised for their effectiveness in appropriate doses.

Myeloid Blasts in Transformed JAK2-V617F Positive Myeloproliferative Disorders Are Frequently Negative for the JAK2-V617F Mutation.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 375-375 ◽  
Author(s):  
Alexandre Theocharides ◽  
Marjorie Boissinot ◽  
Richard Garand ◽  
François Girodon ◽  
Soon-Siong Teo ◽  
...  
Keyword(s):  
De Novo ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Jak2 V617f Mutation ◽  
Jak2 Mutation ◽  
Allelic Ratio ◽  
Pcr Products ◽  
Blast Cells ◽  
V617f Mutation ◽  
De Novo Aml

Abstract Acute myeloid leukemia (AML) is a common complication of myeloproliferative disorders (MPDs). The role of the JAK2-V617F mutation in this process is unknown. We performed a retrospective analysis of DNA samples from MPD patients with secondary AML. We analysed DNA samples taken at the time of transformation to AML from 54 MPD patients (24 PV, 21 ET, 9 IMF). In addition, DNA samples taken at diagnosis of MPD were obtained in 21 of these patients. DNA was extracted from bone marrow or peripheral blood films, purified granulocytes or frozen cells. FACS sorting of blast cells, T cells and neutrophils was performed in some of the samples. The allelic ratio of JAK2-V617F was determined by allele-specific quantitative PCR (AS-PCR). We obtained AS-PCR data on 52/54 samples taken at the time of transformation (96%), whereas 2 samples did not yield PCR products: 24/52 samples were negative for JAK2-V617F (46%) and 28/52 were positive (54%). For 14/24 negative patients (58%) we had additional DNA samples taken at the time of MPD diagnosis and interestingly, 5 of these 14 patients (36%) were positive for JAK2-V617F at this earlier time point before AML transformation. This suggests that in these patients the JAK2-V617F positive clone was lost during the evolution to AML. Furthermore, comparison of the JAK2-V617F allelic ratios with the percentage of blast cells in patient samples positive at transformation revealed 8/28 cases where the JAK2-V617F allelic ratio was markedly lower than the percentage of blasts, e.g. 8%T-allele and 52% myeloid blast cells. In these patients a JAK2-V617F negative AML clone most likely co-exists with a JAK2-V617F positive MPD clone. To address the question whether the AML clone arose independently from the JAK2-V617F clone, we analyzed loss of heterozygosity on chromosome 9p (9pLOH) in one informative patient who displayed a high allelic ratio of mutant JAK2 at diagnosis (94%T). The CD15+ cells from this patient showed 9pLOH at diagnosis, as demonstrated with two independent microsatellite markers. In contrast, the FACS sorted blast cells at the time of transformation contained both parental alleles in the 9p region and were JAK2-V617F negative by AS-PCR. This excludes the possibility that the AML clone lost the JAK2V617F in the process of undergoing mitotic recombination at a stage heterozygous for JAK2-V617F. Analysis of additional patients is under way. In summary, we found in a cohort of 54 MPD patients, 13 patients initially positive for JAK2-V617F that transformed into JAK2-V617F negative AML. Although not confirmed in the one patient analyzed, we cannot exclude that other patients the JAK2-V617F positive MPD clone lost the JAK2 mutation during the process of transformation. Alternatively, the AML clone could have developed de novo from a JAK2-V617F negative progenitor or stem cell. The latter model has difficulties explaining the high incidence of de novo AML (8/54 patients), unless the JAK2-V617F negative progenitor already carried an as yet unknown mutation and was part of the MPD clone.

Impact of Post-Remission Treatments in Patients Aged 65–70 Years with De Novo AML: A Comparison of Two Concomitant Randomized ALFA Trials with Overlapping Age Inclusion Criteria

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 557-557
Author(s):  
Raphael Itzykson ◽  
Claude Gardin ◽  
Cécile Pautas ◽  
Xavier Thomas ◽  
Pascal Turlure ◽  
...  
Keyword(s):  
Risk Factor ◽  
De Novo ◽  
Univariate Analysis ◽  
Significant Risk ◽  
High Dose ◽  
Inclusion Criteria ◽  
Aged Patients ◽  
Ambulatory Treatment ◽  
De Novo Aml ◽  
The Impact

Abstract Background: The outcome of older patients with AML treated with intensive chemotherapy remains poor. No standard of treatment for post-remission therapy been demonstrated in these patients, and repeated high-dose cytarabine (AraC) post-remission courses have only been shown of benefit in patients aged of 50 years or less. Objective: To compare the overall outcome and the impact of post-remission strategies in patients with newly-diagnosed AML aged 65 to 70 years and enrolled during the same period (12/1999 to 10/2006) in two concomitant randomized ALFA trials with overlapping age inclusion criteria. The ALFA-9803 study (Gardin et al, Blood, 2007) was designed for elderly patients (65y+ with de novo or post-MDS AML) while the ALFA-9801 trial was designed for middle-aged patients (50–70y with de novo AML) (Pautas et al. ASH 2007 #162). All other inclusion criteria were similar among the two trials. Patients and Treatments: Analysis was restricted to the 211 patients aged 65–70y with de novo AML. A frontline randomization between idarubicin (IDA) and daunorubicin (DNR) was included in the two trials, with a total IDA/DNR dose of 36/180 mg and 36–48/240 mg during induction, for the 9803 and 9801 trial respectively. After induction, both trials essentially differed by the post-remission chemotherapy, which comprised two intermediate-dose cytarabine (IDAC) cycles in the 9801 trial and a second randomization between one repeated 3+7 like cycle and six 1+5 anthracycline-based ambulatory consolidations in the 9803 trial. Only two patients received a stem cell transplantation in first CR (1 allogeneic, 1 autologous). In both studies, the initial randomization between IDA and DNR had no impact on OS. Nevertheless, all analyses were stratified on IDA/DNR randomization arm. Results: Seventy-six patients were treated in the 9801 trial and 135 in the 9803 trial. Median age was 67 years and M/F sex ratio was 110/101. Median WBC was 7.4 G/L. Cytogenetic risk was favorable in 9 (4%), intermediate in 118 (56%) and unfavorable in 54 (26%) patients, respectively. Ninety-five and 116 patients were randomized to receive DNR and IDA, respectively. Aside from median age (67 vs 68 years in 9801 and 9803, respectively; P<.001), patient characteristics were similar between the two protocol subgroups, in terms of inclusion date, sex, PS, FAB, cytogenetics, and WBC. The overall CR rate was 62%. In univariate analysis, there was a trend for a higher CR rate in the younger 9801 trial (70 vs 57%; p=.17). As expected, cytogenetics was identified as the sole significant risk factor for CR achievement (89% in favorable, 68% in intermediate, and 44% in unfavorable-risk; p=0.03). Median follow-up, OS, RFS, and EFS were 35, 14, 12 and 6.5 months, respectively. In univariate analysis, the trial did not influence OS (3-year OS, 20 vs 17% in the 9801 and 9803 trial, respectively; p=.71), RFS or EFS. Again, the only identified risk factor for OS and EFS was high-risk cytogenetics. After CR achievement, 44 9801-patients (58%) received the planned IDAC consolidation, while 30 (22%) and 33 (24%) 9803-patients received the planned 3+7 like or ambulatory consolidation, respectively. In these patients, no significant differences in CR duration (median CR duration: 12.4, 14.8 and 11.9 months with IDAC, 3+7 like, and ambulatory consolidation, respectively; p=0.57) was observed among these three different post-remission strategies. In multivariate analysis, only unfavorable cytogenetics affected OS (HR=1.8 [95% CI 1.3–2.6], p=10-3) and EFS (HR=2.0 [1.4–2.8], p<10-4), with a trend for adverse RFS (HR=1.6 [.99–2.7], p=.055). Conclusion: In patients aged 65–70 years with de novo AML, more intensive post-remission therapy containing IDAC does not appear to significantly improve EFS, RFS, or OS, as compared to less intensive consolidation or even repeated anthracyclin-based ambulatory treatment. The poor early outcome of those with unfavorable cytogenetics justifies the evaluation of new global therapeutic approaches in this patient subset.

scholarly journals Reductive regulation of BECN1 gene in adult Egyptian patients with do novo AML

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Manal Fawzy Ghozlan ◽  
Botheina Ahmed Thabet Farweez ◽  
Nesma Ahmed Safwat ◽  
Noha Bassiouny Hassan ◽  
Walaa Ali Elsalakawy
Keyword(s):  
Gene Expression ◽  
Bone Marrow ◽  
Peripheral Blood ◽  
De Novo ◽  
Quantitative Polymerase Chain Reaction ◽  
Control Group ◽  
Significant Difference ◽  
Egyptian Patients ◽  
Blast Cells ◽  
De Novo Aml

Abstract Background Acute myeloid leukaemia (AML) is a clonal haematopoietic disease characterized by the proliferation of immature blast cells in the bone marrow and peripheral blood. Autophagy is an inherent cellular route by which waste macromolecules are engulfed within autophagosomes prior to their fusion with cytoplasmic lysosomes for degradation. The BECN1 gene encodes the Beclin-1 protein, which regulates autophagy. Few reports have investigated BECN1 gene expression and its value in AML patients. Results This randomized case-control study included 50 newly diagnosed AML patients, in addition to 20 subjects as a control group. BECN1 gene expression was assessed using real-time quantitative polymerase chain reaction (qRT-PCR). The median level of BECN1 gene expression in AML patients was 0.41 (IQR 0.29–1.03) in comparison to 1.12 (IQR 0.93–1.26) in the control group (P = 0.000). Seventy-two percent of AML patients showed reduced BECN1 gene expression, which was highly significantly associated with intermediate and adverse cytogenetic risk. Reduced BECN1 gene expression was associated with older age, higher total leukocyte counts, the presence of peripheral blood blast cells, a higher percentage of bone marrow blast cells, and higher expression of CD34 and CD117. FLT3-ITD mutation was detected in 14 patients (38.9%), all of whom showed reduced BECN1 gene expression (P = 0.006). BECN1 gene expression was also reduced in non-responder AML patients, with a highly statistically significant difference (P = 0.002). Conclusion A reduction in BECN1 gene expression might indicate a poor prognosis in adult Egyptian patients with de novo AML. Decreased BECN1 gene expression is associated with a higher risk of resistance to treatment. Targeting autophagy pathways may help in the treatment of AML patients.

The Intention To Treat Analysis of the Different Post Remission Therapy Modalities in AML Patients with the “Intermediate Risk Group (IPG)” Based on Cytogenetics.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4563-4563
Author(s):  
Yeung-Chul Mun ◽  
S.M. Lee ◽  
S.H. Park ◽  
E.K. Cho ◽  
J.H. Lee ◽  
...  
Keyword(s):  
Statistical Power ◽  
De Novo ◽  
Treatment Modalities ◽  
Inclusion Criteria ◽  
Secondary Aml ◽  
Intention To Treat ◽  
Cardiac Ejection Fraction ◽  
De Novo Aml ◽  
Grade 3 ◽  
Treat Analysis

Abstract The results of cytogenetics are one of the most important prognostic factors in the prognosis of AML. Three different post remission therapies were given with the IPG based on the MRC definitions using the cytogenetics results. The inclusion criteria included age<65, PS<3 with reasonable organ functions, cardiac ejection fraction>50%, bilirubin<2.0mg/dl, creatinine<2mg/dl in de novo AML and secondary AML. The aims of this prospective intention to treat analysis were to compare the CR, recovery kinetics, DFS and OS in IPG based on cytogenetics with 3 different consolidation treatment modalities described as follows. Three plus seven(Idarubicin 12mg/m2, D1-D3; Ara-C 100mg/m2, D1–D7) were given to de novo AML and secondary AML. HDAC followed by three times of post remission therapy or auto PBPCT followed by two times of post remission therapy was given to IPG. If an HLA-identical sibling were available, then allo BMT was tried after 1st post-remission therapy. The median age of the cohort(Total 194) is 42.5(±17.6) (HDAC(n:89) : 47.6, auto PBPCT(n:51) : 46.6, and allo BMT(n:54) : 30.5). The median days for ANC >500/μl and platelet>20k/μl during induction were 22 days and 21 days respectively. Grade 3~4 toxicities were found in 34.1%, 27.7% and 47.2% during HDAC, auto PBPCT and allo BMT, respetively(p<0.05). The relapse rate and the toxic death rate were 25.8%, 27.5% and 29.6%(p=0.24) and 9.1%, 5.5% and 16.6%(p<0.05) in HDAC, auto PBPCT and allo BMT, respectively. So far, this trial seems to be tolerable in terms of toxicities, during induction and post remission therapies. Among IPG, the auto PBPCT arm had a tendency of superior median survival over the HDAC or allo BMT in terms of OS and LFS without statistical differences(HDAC:17m and 8m, auto-PBPCT:18m and 12m, allograft:15m and 8m). This intention to treat trial, which started in Jan, 2000, has proceeded until now in order to have better statistical power for the subset analysis.

scholarly journals Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML

Blood ◽  
2016 ◽  
Vol 127 (7) ◽  
pp. 893-897 ◽  
Author(s):  
Terrence N. Wong ◽  
Christopher A. Miller ◽  
Jeffery M. Klco ◽  
Allegra Petti ◽  
Ryan Demeter ◽  
...  
Keyword(s):  
Induction Therapy ◽  
De Novo ◽  
Rapid Expansion ◽  
Key Points ◽  
De Novo Aml

Key Points Hematopoietic populations unrelated to the AML founding clone often expand after induction therapy, resulting in oligoclonal hematopoiesis.

Diagnoses and mortality in a population without acute myocardial infarction, but with elevated highsensitive troponin I – a retrospective register-based single center study

2021 ◽  
Vol 20 (1) ◽  
pp. 18-24
Author(s):  
Rasmus Søgaard Hansen ◽  
◽  
Jesper Revsholm ◽  
Daniel Pilsgaard Henriksen ◽  
Lars Christian Lund Lund ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Troponin I ◽  
Inclusion Criteria ◽  
Danish Population ◽  
Medical Observation ◽  
Single Center Study ◽  
One Year ◽  
High Sensitive Troponin ◽  
Center Study

Aim: To explore, which differential diagnoses to consider in individuals with elevated troponins without acute myocardial infarction (AMI), and the mortality for those individuals. Methods: Retrospective, register-based study on a representative sample of the Danish population with the following inclusion criteria: High-sensitive troponin I (hs-TnI) ≥25 ng/L, age ≥18 years, and exclusion of AMI. Results: 3067 individuals without AMI but increased hs-TnI were included. Most frequent discharge diagnoses: Pneumonia (12.8%), Aortic valve disorder (11.3%), Medical observation (10.9%) and Heart failure (8.9%). The 30-days and one-year mortality was 15.8% and 32.0%, respectively. Conclusions: A selected number of alternative diagnoses must be considered in individuals with increased hs-TnI. Due to high mortality it is crucial to carefully evaluate these individuals despite the absence of AMI.

Antileukemic activity of rapamycin in acute myeloid leukemia

Blood ◽  
2005 ◽  
Vol 105 (6) ◽  
pp. 2527-2534 ◽  
Author(s):  
Christian Récher ◽  
Odile Beyne-Rauzy ◽  
Cécile Demur ◽  
Gaëtan Chicanne ◽  
Cédric Dos Santos ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Mammalian Target Of Rapamycin ◽  
Cell Types ◽  
Mtor Inhibition ◽  
Growth And Survival ◽  
Clinical Responses ◽  
De Novo Aml ◽  
Acute Myeloid

AbstractThe mammalian target of rapamycin (mTOR) is a key regulator of growth and survival in many cell types. Its constitutive activation has been involved in the pathogenesis of various cancers. In this study, we show that mTOR inhibition by rapamycin strongly inhibits the growth of the most immature acute myeloid leukemia (AML) cell lines through blockade in G0/G1 phase of the cell cycle. Accordingly, 2 downstream effectors of mTOR, 4E-BP1 and p70S6K, are phosphorylated in a rapamycin-sensitive manner in a series of 23 AML cases. Interestingly, the mTOR inhibitor markedly impairs the clonogenic properties of fresh AML cells while sparing normal hematopoietic progenitors. Moreover, rapamycin induces significant clinical responses in 4 of 9 patients with either refractory/relapsed de novo AML or secondary AML. Overall, our data strongly suggest that mTOR is aberrantly regulated in most AML cells and that rapamycin and analogs, by targeting the clonogenic compartment of the leukemic clone, may be used as new compounds in AML therapy.

scholarly journals Two distinct clinical patterns of checkpoint inhibitor-induced thyroid dysfunction

2020 ◽  
Vol 9 (4) ◽  
pp. 318-325 ◽  
Author(s):  
Anna Olsson-Brown ◽  
Rosemary Lord ◽  
Joseph Sacco ◽  
Jonathan Wagg ◽  
Mark Coles ◽  
...  
Keyword(s):  
Thyroid Dysfunction ◽  
De Novo ◽  
Clinical Phenotype ◽  
Checkpoint Inhibitors ◽  
Hormone Replacement ◽  
World Population ◽  
Inclusion Criteria ◽  
Antibody Titres ◽  
Clinical Patterns ◽  
Regional Cancer Centre

Introduction Immune checkpoint inhibitors can lead to thyroid dysfunction. However, the understanding of the clinical phenotype of ICI-induced thyroid dysfunction in the real-world population is limited. The purpose of this study was to characterise the clinical patterns of dysfunction and evaluate the demographic, biochemical and immunological features associated with this patient cohort. Materials and methods To characterise the longitudinal clinical course of thyroid dysfunction in patients from a single, UK regional cancer centre, a retrospective review of patients was conducted. Inclusion criteria included all patients treated with antiPD-1 checkpoint inhibitors (ICI), either as monotherapy (pembrolizumab/nivolumab) or in combination with a CTLA-4 inhibitor (ipilimumab). Patterns of toxicity were evaluated together with assessment of antibody titres. Results Over 16 months, thyroid dysfunction was seen in 13/90 and 3/13 patients treated with anti-PD1 monotherapy and in combination with ipilimumab, respectively. Patients either developed hyperthyroidism followed by hypothyroidism (12/16) or de novo hypothyroidism (4/16). Most patients were female (n = 11). All patients required thyroid replacement therapy. There was no relationship between clinical pattern of dysfunction and the presence of thyroid autoantibodies. Conclusions There are two distinct patterns of thyroid dysfunction in ICI-treated patients. Patients with thyroiditis develop subsequent hypothyroidism in the vast majority of cases. The potential benefit from steroids or other therapy to manage the hyperthyroid phase remains unclear. Early detection of these patients through appropriate monitoring will improve clinical management and early hormone replacement, reducing the symptomatic burden of hypothyroidism.

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