scholarly journals Spontaneous apoptosis and BCL2 gene expression as predictors of early death and short overall survival in acute leukemia patients: a prospective, case cohort study

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Huda F. Ebian ◽  
Lobna A. El-korashi ◽  
Ahmed Embaby ◽  
Marwa H. Hussien ◽  
Alshymaa A. Ahmed
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Performance Status ◽  
Early Death ◽  
Spontaneous Apoptosis ◽  
Gene Expressions ◽  
Blood Leukocytes ◽  
Adult Leukemia

Abstract Background Spontaneous apoptosis and expression of MCL1, BCL2, and BCL-XL may be useful prognostic markers in acute leukemia patients. The purpose of this study is to examine the prognosis in adult leukemia patients based on spontaneous apoptosis and anti-apoptosis gene expressions in circulating leukocytes. Results Early, late, and total apoptosis were significantly increased in peripheral blood leukocytes from patients diagnosed with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) compared to controls and in cases of ALL versus AML (P < 0.001). Total apoptosis decreased significantly in AML and ALL patients who died early (ED); P = 0.001 and P = 0.002, respectively. Anti-apoptosis genes MCL1, BCL2, and BCL-XL were upregulated in 62.4%, 64.2%, and 62.4% of the acute leukemia patients, respectively. Among the AML patients, the up-regulation of BCL2 was paradoxically associated with increased apoptosis and low rates of ED. The expression levels of MCL1 and BCL-XL had no significant prognostic values; among patients diagnosed with non-acute promyelocytic leukemia (non-APL-AML), total spontaneous apoptosis, expression of BCL2, and performance status were independent predictors of overall survival (OS). Conclusion Total spontaneous apoptosis and BCL2 gene expression may be valuable independent markers for OS in patients with non-APL-AML. Moreover, in ALL patients decreased levels of spontaneous apoptosis were associated with ED, although this was not a significant predictor of OS.

scholarly journals PIM2 and NF-κβ gene expression in a sample of AML and ALL Egyptian patients and its relevance to response to treatment

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shymaa Kamal El Din Abed El Rahman ◽  
Sanaa Sayed Abd Elshafy ◽  
Mohamed Samra ◽  
Hala Mohammed Ali ◽  
Rabab Afifi Mohamed
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Expression Level ◽  
Response To Treatment ◽  
Control Group ◽  
Poor Overall Survival ◽  
Healthy Control ◽  
Complete Blood Counts

Abstract Background The relation between PIM2 and the transcriptional factor NF κβ have been controversial in literature. The significance of PIM2 and NF-κβ genes expression on the incidence of acute leukemia (AML and ALL) and its relevance to the response rate was evaluated. Sixty de novo acute leukemia patients were stratified in 2 groups: 30 acute myeloid leukemia (AML) and 30 acute lymphoblastic leukemia (ALL) patients and compared to 30 sex- and age-matched controls. The expression level of PIM2 and NF κβ genes was measured using quantitative real-time polymerase chain reaction (QRT-PCR). The patients were followed with clinical examination and complete blood counts. Results The expression level of PIM2 gene was significantly higher in AML patients (P<0.001) compared to the control group. The mean expression level of NF κβ gene was significantly high in AML and ALL patients compared to the healthy control group (P=0.037 and P<0.001; respectively). The overall survival in AML patients was higher in NF κβ gene low expressers compared to high expressers (P=0.047). The number of AML patients who achieved complete remission was significantly higher in PIM2 gene low expressers in comparison to PIM2 gene high expressers (P=0.042). Conclusion PIM2 and NF κβ genes might have a role in the pathogenesis of acute leukemia, poor overall survival, and failure of response to induction therapy.

FLAG/FLAG-IDA regimen for children with relapsed/refractory acute leukemia in the era of targeted novel therapies

2018 ◽  
Vol 25 (8) ◽  
pp. 1831-1838 ◽  
Author(s):  
Omima Mustafa ◽  
Khalid Abdalla ◽  
Aeshah A AlAzmi ◽  
Naglla Elimam ◽  
Mohammed Burhan Abrar ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Bone Marrow Transplantation ◽  
Complete Remission ◽  
Acute Leukemia ◽  
Salvage Therapy ◽  
Marrow Transplantation ◽  
Lymphoblastic Leukemia ◽  
Hematologic Toxicity ◽  
Novel Therapies

Background Outcomes of relapsed/refractory childhood acute leukemia remain poor. We analyzed the safety/efficacy of fludarabine, cytarabine, and granulocyte colony stimulating factor, with/without idarubicin (FLAG ± IDA) as salvage therapy compared with recent published results of novel therapies. Methods This retrospective study included children aged 1 to 15 years with relapsed/refractory acute leukemia who received FLAG ± IDA salvage therapy from January 2000 to December 2014. Patients with infant leukemia, mixed lineage leukemia, Philadelphia-positive acute leukemia, or secondary leukemia were excluded. Result Fifty patients were identified: 25 with acute lymphoblastic leukemia and 25 with acute myeloid leukemia. The median age at initiation of FLAG ± IDA was seven years. Site of relapse was the bone marrow in 29, isolated central nervous system in 11, and combined in 10 patients. FLAG ± IDA was used after first relapse in 68% and after multiple relapses in 32%. Complete remission was achieved in 34 (68%) patients. No variables predictive of complete remission were identified. Grade 3 or greater toxicity was observed in 96% and 6% died from toxicity. Toxicities included hematologic toxicity (96%), infection (52%), and enterocolitis (28%). Twenty-four of 50 (48%) patients achieved a sustained complete remission and survived to bone marrow transplantation. The five-year overall survival was 23.9% ± 6.9%. Patients achieving second complete remission and patients proceeding to bone marrow transplantation following second complete remission demonstrated significantly improved overall survival (p = 0.001). Conclusion Despite a 68% complete remission rate using FLAG ± IDA, only 48% of patients survived to bone marrow transplantation. The regimen was associated with 96% toxicity and only one in four patients was alive at five years. This underscores the need to find more effective lower toxicity salvage regimens.

Gene Expression Profiling Identifies IGFBP7 as a BAALC Co-Expressed Gene with a Functional Role in Acute Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2629-2629
Author(s):  
Sandra Heesch ◽  
Cornelia Schlee ◽  
Martin Neumann ◽  
Andrea Stroux ◽  
Andrea Kühnl ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Acute Leukemia ◽  
Treatment Failure ◽  
Functional Role ◽  
Human Gene ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Insulin Like Growth Factor ◽  
Expression Levels

Abstract Abstract 2629 Poster Board II-605 The human gene BAALC (Brain And Acute Leukemia, Cytoplasmic) is a molecular marker of immature hematopoietic cells. In normal hematopoiesis, BAALC is highly expressed in CD34 positive progenitors and down-regulated with cell differentiation. Moreover, high mRNA expression levels of BAALC have shown to be an adverse risk factor and were associated with chemotherapy resistance in adult patients with cytogenetically normal acute myeloid leukemia (CN-AML) and acute T-lymphoblastic leukemia (T-ALL). While the prognostic value of BAALC expression has been validated, the function of BAALC in leukemia remains unknown. The aim of this study was to identify genes correlated with BAALC to gain further insights into the underlying pathways of the BAALC-associated chemotherapy resistant leukemic phenotype. Therefore, we generated gene expression profiles (GEP) using pre-treatment T-ALL samples (n=86) that differentiated high versus low BAALC expressers (HG-U133 Plus 2.0, Affymetrix). Samples were divided into quartiles (Q1-Q4) according to BAALC expression and QB1-3 was defined as low BAALC and QB4 as high BAALC. Differentially expressed genes between QB1–3 and QB4 were defined by a minimum expression change of three-fold (P'0.05). In order to identify BAALC-associated genes common to T-ALL, CN-AML and normal hematopoiesis we compared these BAALC-derived GEP in T-ALL with BAALC-associated profiles of CN-AML (Langer C et al, Blood 2008) and of normal CD34 positive progenitors (Komor et al, Stem Cells 2005). Only four genes (CD34, CD133, NPR3, IGFBP7) were common to the BAALC-associated GEP of all three entities (T-ALL, CN-AML, and CD34 positive progenitors). Of these genes, the human gene Insulin-like Growth Factor Binding Protein 7 (IGFBP7) was further investigated as the Insulin-like growth factor signaling plays an important role in various human cancers. Next we determined IGFBP7 expression levels by real-time RT-PCR in an independent cohort of 219 adults with newly diagnosed T-ALL, registered within the German Multicenter Acute Lymphoblastic Leukemia Study 06/99 and 07/03 protocols. In T-ALL samples, IGFBP7 showed a heterogeneous expression pattern compared to normal bone marrow (expression range: 0–79.1 vs 0.6–2.3). For correlation of IGFBP7 expression with clinical and molecular features, samples were divided into quartile groups according to IGFBP7 expression and defined as low IGFBP7 with expression levels in QI1 to QI3 (n=158) and as high IGFBP7 with expression levels in QI4 (n=53). High expression levels of IGFBP7 were associated with an immature phenotype of early T-ALL (62% of patients in QI4 showed an early T-ALL immunophenotype as compared to only 15% in QI1–3; P<0.001), high cell surface expression of CD34 (mean: 36% vs 15%; P<0.001) and CD33 (mean: 24% vs 3%; P<0.001). Moreover, high IGFBP7 expression significantly predicted a higher frequency of refractory disease (11% vs 3%; P=0.03) and an inferior overall survival (OS; 4-year OS: IGFBP7 QI4: 42% vs IGFBP7 QI1–3: 55%; P=0.03). In vitro, studies revealed that treatment with rIGFBP7 significantly inhibited proliferation of KG1a leukemic cells (65% reduction of proliferation compared to untreated cells; P<0.001) determined by Cell Proliferation Reagent WST-1. Moreover, a 26% reduction (P<0.001) of the DNA synthesis phase was detected by BrdU incorporation after rIGFBP7 treatment of KG1a cells. Taken together, we identified IGFBP7 as a lineage-independent, BAALC co-expressed gene involved in leukemia. High IGFBP7 expression was associated with stem cell features and treatment failure in T-ALL. In contrast to BAALC which likely represents only a surrogate marker of treatment failure in acute leukemias, IGFBP7 might play functional role and contribute to the molecular basis of BAALC-associated drug resistance. As rIGFBP7 inhibits proliferation of leukemic cells, secreted IGFBP7 protein may therefore promote resistance to cell cycle dependent cytostatic drugs targeting highly proliferate blast cells. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership.

scholarly journals Biology of t(6;11) Fusion Proteins and Their Role in MLL-Rearranged Acute Leukemia Lineage Determination

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5033-5033
Author(s):  
Arpita Kundu ◽  
Eric Kowarz ◽  
Jennifer Reis ◽  
Rolf Marschalek
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Acute Leukemia ◽  
Fusion Proteins ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocation ◽  
Fusion Genes ◽  
Disease Phenotype ◽  
Acute Leukemias

Chromosomal translocations are genetic rearrangements where a chromosomal segment is transferred to a non-homologous chromosome which give rise to novel chimeras. Chromosomal rearrangements play a significant role in the development of acute leukemias (acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML)). Chromosomal translocation events occurring at 11q23 involving the KMT2A or Mixed-Lineage Leukemia (MLL) gene (n=102) can be diagnosed in about 5-10% of all acute leukemia patients (Marschalek Ann Lab Med 2016), especially prevalent in infant acute leukemias (up to 70% of cases). Different chromosomal translocation partner genes (such as AF4, AF6, AF9orENL and ELL) account for the majority of leukemia cases and have their genomic breakpoints within a major breakpoint cluster region (BCR intron 9-11; Meyer et. al. Leukemia 2018). Some rearrangements are specifically associated with particular disease phenotype e.g. the majority of ALL patients (~ 90%) are mainly caused by the following gene fusions, MLL-AF4, MLL-AF9, MLL-ENL. We are interested in a rare but yet drastic chromosomal translocation t(6;11)(q27;q23) which fuses KMT2A/MLL to Afadin (AFDN/AF6) gene. This chromosomal rearrangement has a very poor prognosis (survival-rate is ~10%) and is predominantly diagnosed in patients with high-risk AML. In this project, we investigate the molecular consequences of two different MLL-AF6 fusions and their corresponding reciprocal AF6-MLL fusions. MLL-AF6 fusions are mainly occurring within MLL intron 9 to 11 and are associated with an AML disease phenotype, while the same fusion occurring within the minor breakpoints region in MLL intron 21 until exon (ex) 24 are mainly diagnosed with T-ALL (T-cell acute lymphoblastic leukemia) disease phenotype. The molecular mechanism that determines the resulting disease phenotype is yet unknown. Therefore, we cloned all of these t(6;11) fusion proteins in order to investigate the functional consequences of the two different breakpoints (MLLex1-9::AF6ex2-30, AF6ex1::MLLex10-37; MLLex1-21::AF6ex2-30, AF6ex1::MLLex22-37). All 4 fusion genes were introduced into our inducible Sleeping Beauty system (Ivics et. al. Mobile DNA 2010; Kowarz et. al. Biotechnol J. 2015) and stably transfected reporter cell lines. Basically, these 4 fusion proteins differ only in the presence or absence of their Plant homeodomain 1-3/Bromodomain (PHD1-3/BD) domain (see Figure 1). The PHD domain regulates the epigenetic and transcriptional regulatory functions of wildtype MLL. Subsequently, we analyzed gene expression differences by the MACE-Seq (Massive Analyses of cDNA Ends). MACE data revealed fundamental differences in gene expression profiles when analyzing the two different sets of t(6;11) fusion genes. The resulting profiles have similarities to either AML or T-ALL and might give a rational explanation for the different lineages in these t(6;11) patients. Altogether, these results notably indicate that our study will provide a novel insight into this type of high-risk leukemia and subsequently will be useful for developing of novel and appropriate therapeutic strategies against acute leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Meta-analysis of 1,200 transcriptomic profiles identifies a prognostic model for pancreatic ductal adenocarcinoma

2018 ◽  
Author(s):  
Vandana Sandhu ◽  
Knut Jorgen Labori ◽  
Ayelet Borgida ◽  
Ilinca Lungu ◽  
John Bartlett ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pancreatic Cancer ◽  
Overall Survival ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Prognostic Model ◽  
Meta Analysis ◽  
Early Death ◽  
Receiver Operating Curve ◽  
Ductal Adenocarcinoma ◽  
Survival Predictor

ABSTRACTBackgroundWith a dismal 8% median 5-year overall survival (OS), pancreatic ductal adenocarcinoma (PDAC) is highly lethal. Only 10-20% of patients are eligible for surgery, and over 50% of these will die within a year of surgery. Identify molecular predictors of early death would enable the selection of PDAC patients at high risk.MethodsWe developed the Pancreatic Cancer Overall Survival Predictor (PCOSP), a prognostic model built from a unique set of 89 PDAC tumors where gene expression was profiled using both microarray and sequencing platforms. We used a meta-analysis framework based on the binary gene pair method to create gene expression barcodes robust to biases arising from heterogeneous profiling platforms and batch effects. Leveraging the largest compendium of PDAC transcriptomic datasets to date, we show that PCOSP is a robust single-sample predictor of early death (≤1 yr) after surgery in a subset of 823 samples with available transcriptomics and survival data.ResultsThe PCOSP model was strongly and significantly prognostic with a meta-estimate of the area under the receiver operating curve (AUROC) of 0.70 (P=1.9e-18) and hazard ratio (HR) of 1.95(1.6-2.3) (P=2.6e-16) for binary and survival predictions, respectively. The prognostic value of PCOSP was independent of clinicopathological parameters and molecular subtypes. Over-representation analysis of the PCOSP 2619 gene-pairs (1070 unique genes) unveiled pathways associated with Hedgehog signalling, epithelial mesenchymal transition (EMT) and extracellular matrix (ECM) signalling.ConclusionPCOSP could improve treatment decision by identifying patients who will not benefit from standard surgery/chemotherapy and may benefit from alternate approaches.AbbreviationsAUROCArea under the receiver operating curveGOGene annotationOSOverall survivalPCOSPPancreatic cancer overall survival predictorPDACPancreatic ductal adenocarcinomaTSPTop scoring pairs.

scholarly journals Inotuzumab Ozogamicin (Ino) May Overcome the Impact of Philadelphia Chromosome (Ph)-like Phenotype in Adult Patients (pts) with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1641-1641 ◽  
Author(s):  
Elias Jabbour ◽  
Kathryn G. Roberts ◽  
Koji Sasaki ◽  
Yaqi Zhao ◽  
Chunxu Qu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
The Impact

Background: Ino showed significant activity in phase II trials in pts with R/R ALL, that was subsequently confirmed in Phase III trial where Ino demonstrated higher response rates and superior overall survival vs standard of care chemotherapy (SOC) in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL).Ph-like or BCR-ABL1-like ALL possesses a gene expression profile similar to that of BCR-ABL1 ALL but lacks the BCR-ABL1 fusion protein. It is characterized by increased expression of hematopoietic stem-cell genes, deletion of B-cell lineage genes and kinase-activating alterations. Ph-like ALL is associated with refractoriness to standard induction/consolidation chemotherapy and poor prognosis. Aim: To evaluate the outcomes of pts with R/R Ph-like ALL treated in phase II trial with Ino monotherapy. Methods: We performed an integrated analysis of whole genome sequencing (to identify sequence mutations, structural variations and DNA copy number alterations), and transcriptome sequencing (RNAseq; to quantify gene expression, determine Ph-like gene expression profile and identify fusions) on 53 patients' samples treated with Ino between June 2010 and September 2012. Results: Fifty-three evaluable pts with R/R ALL with stored baseline samples were analyzed. Pts characteristics are summarized in Table 1. Median age was 50 years. Ino was given as Salvage 1, Salvage 2, and Salvage 3 and beyond in 20 (38%), 18 (34%), and 15 (28%) pts, respectively. Figure 1 reflects the different genomic subgroups identified among 53 evaluable pts. Ph-like gene signature was found in 12 pts (22.6%). Among these 12 pts, 6 had IGH-CRLF2, 2 IGH-EPOR, 1 SNX2-ABL1, and 3 had no fusions identified. The overall response rates (ORR) were 54% [complete remission (CR) 20%, CR with partial hematologic recovery (CRh) 32%, and marrow CR (CRi) 2%]. Among pts with morphologic remission, 46% and 82% achieved minimal residual disease (MRD) negativity at CR and at any time, respectively. The ORR for pts with Ph-like ALL, Ph-positive ALL, ALL with KMT2A, and others were 58% (CR=25%; CRh=33%), 42% (CR=8%; CRh=33%), 57% (CR=14%; CRh=29%; CRi=14%), and 56% (CR=26%; CRh=30%), respectively. The respective overall MRD negativity rates were 71%, 100%, 75%, and 83% (Table 1). The median follow-up was 60 months. The median event-free (EFS) and overall survival (OS) were 3.3 and 5.4 months, respectively. There was no difference in EFS and OS between the subgroups analyzed (P=0.464; P=0.824). The median EFS and OS were 4.5 and 4.5 months for pts with Ph-like, 3.1 and 7.2 months for those with Ph-positive ALL, 2.8 and 4.4 months for those with KMT2A, and 2.2 and 4.6 months for others (Table 1). 21 (40%) pts had subsequent allogeneic stem cell transplant; 6 (50%), 3 (25%), 4 (57%), and 8 (36%) in each subgroup, respectively. The rate of VOD was 3 (6%) with no difference among different subgroups. Conclusion: The current analysis suggest that Ino therapy may overcome the impact of Ph-like phenotype in pts with ALL. Confirmation of these findings in a larger cohort and in frontline ALL patients is needed. Disclosures Jabbour: Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Jain:Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Konopleva:Cellectis: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Ablynx: Research Funding; Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding. Mullighan:Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; AbbVie: Research Funding; Loxo Oncology: Research Funding; Amgen: Honoraria, Other: speaker, sponsored travel. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria.

scholarly journals Early Deaths in Pediatric Acute Leukemia; A Challenge in Developing Countries

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5160-5160
Author(s):  
Hanafy Ahmed Hafez ◽  
Rawaa Solaiman ◽  
Dalia Bilal ◽  
Lobna m Shalaby
Keyword(s):  
Developing Countries ◽  
Acute Leukemia ◽  
Supportive Care ◽  
Death Rate ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Early Death ◽  
Response To Therapy ◽  
P Value

Abstract Background and objectives: The survival rates of children with acute leukemia is consistently improving, due to the lower relapse rates in addition to reducing treatment-related mortality, which is mainly a result of infectious causes. The aim of the study is to describe the incidence and risk factors associated with early deaths (first 42 days in treatment) among children with acute leukemia. Methods: This is a retrospective study included newly diagnosed patients with acute leukemia who presented to the National Cancer Institute, Cairo University between Jan. 2011 to Dec. 2013. Patients' data were collected from their files and analyzed for the total and early death rates and proposed causes of death. Results: The study included 370 patients, 253 with acute lymphoblastic leukemia (ALL), 100 with acute myeloid leukemia (AML) and 17 with mixed phenotypic acute leukemia (MPAL). The total death rate among the whole group was 40.5% (n=150) and induction death rate was 19.2% (n=71). AML was accompanied with higher rates of total and induction deaths as they were 58% and 25% respectively, compared to 33.6% and 17.4% in ALL. These early deaths were attributed mostly to infection 64.7% (n=46) and cerebrovascular accidents 18.3% (n=13). Early deaths were significantly higher in patients with age below 2 years old (p. value=0.008), and in those with poor response to therapy (p. value= 0.001). Using enhanced supportive care measures as better infection control, appropriate antibiotic guidelines and available intensive care unit during 2013 had significantly reduced the overall and induction mortality rates (27.8% and 13.8% respectively in 2013 versus 45% and 20.3% in 2011 and 49% and 25% in 2012). Conclusion: Induction deaths in pediatric acute leukemia remain a major challenge in developing countries and constitute an increasing fraction of all deaths. Accordingly, using a well equipped cancer centers with better supportive care guidelines is essential to further improve the survival in these group of patients. Key words: Acute Leukemia- Pediatrics- Early Death- Infection Disclosures No relevant conflicts of interest to declare.

Complications of Hyperleukocytosis and Leukapheresis in Pediatric Acute Leukemias.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1963-1963 ◽  
Author(s):  
Oussama Abla ◽  
M. F. Khanani ◽  
J. K. Hitzler ◽  
L. Sung ◽  
D. Geary ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Sinus Bradycardia ◽  
Lymphoblastic Leukemia ◽  
Femoral Vein ◽  
Early Death ◽  
Acute Leukemias ◽  
Senior Staff ◽  
Vein Thrombosis ◽  
Randomized Evaluation ◽  
Wbc Count

Abstract Leukapheresis is commonly used in children with acute leukemia and hyperleukocytosis (WBC >100 x 109/L). We analyzed the frequency of early complications of hyperleukocytosis in children with acute lymphoblastic leukemia(ALL) and acute myeloid leukemia(AML) and the frequency of complications attributed to leukapheresis. We included all children with acute leukemia and hyperleukocytosis, presenting to HSC between January 1992 and May 2002. ICH/stroke, pulmonary leukostasis, acute renal failure (ARF) and death were considered severe complications of hyperleukocytosis. 61 ALL and 8 AML were reviewed. All children received intravenous hyperhydration, urinary alkalinization and allopurinol. Of 61 ALL children, 16 (26.2%) underwent leukapheresis; median WBC count was 559 x 109/L (range 200–969). Median WBC of non-leukapheresed ALL children was 181 x 109 /L (range 101–392). Five (62.5%) of 8 AML children underwent leukapheresis; median WBC was 376 x 109/L (range 167–470). The remaining 3 had a median WBC of 146 x 109/L (range 114–230). 10/61(16.3%) ALL patients presented with severe complications within 6 to 8 hours of arrival; 9 were leukapheresed. ICH occurred in 2, one of whom failed to receive platelet transfusion at presentation because of a falsely high automated platelet count corrected after 12 hours by more senior staff. Six had respiratory distress thought to be related to pulmonary leukostasis; all but 1 improved after leukapheresis. Three developed ARF due to hyperuricemia pre-leukapheresis. While 2 received leukapheresis, all required dialysis. One early death occurred on day 22 due to enterococcal sepsis. 3/8 (37.5%) AML children developed complications related to hyperleukocytosis: 2 had pulmonary leukostasis, only 1 improved after leukapheresis; 1 died at 72 hours due to stroke. Three non-leukapheresed AML patients remained clinically well with hyperhydration and early chemotherapy. Leukapheresis reduced the WBC by an average of 40–45% in both ALL/AML. Procedural complications secondary to leukapheresis occurred in 18/21(85.7%) children. Femoral vein thrombosis occurred in 5 patients. Five became hypocalcemic; while only one was symptomatic, all were given calcium infusions. Other complications were: coagulopathy(n=6), sinus bradycardia(n=4), hypotension(n=4), hypertension(n=3), hypokalemia(n=4), and hypomagnesemia(n=1). The leukapheresis circuits of 5 children (3 ALL, 2 AML) were primed with undiluted packed RBC; 3 had new or progressive pulmonary leukostasis following leukapheresis, 1 of whom also developed a stroke. In summary, severe complications in children with hyperleukocytosis are common. Leukapheresis reduced WBC in most patients and appeared to improve pulmonary leukostasis in some. However, it did not prevent progression of ARF. Also, procedural-related complications are considerable. We have identified the following sources of potentially preventable morbidity: 1. Calcium infusions during the procedure should be used with extreme caution; 2. Circuits should not be primed with undiluted red blood cells as this may exacerbate hyperviscosity; and 3. Manual platelet counts must be performed in hyperleukocytosis. Furthermore, it is insufficient for these issues to be appreciated by senior staff only. Continuous education of inexperienced staff and leukapheresis team regarding the most appropriate use of this procedure should be emphasized. A randomized evaluation of the benefits versus risks of leukapheresis is needed.

Clinical Outcomes in Patients with Relapsed/Refractory Acute Leukemia Treated with FLAG-IDA Regimen.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4561-4561 ◽  
Author(s):  
Ana L. Basquiera ◽  
M. Virginia Prates ◽  
Ana Gabriela Sturich ◽  
Adriana R. Berretta ◽  
Jorge Milone ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Leukemia ◽  
Median Time ◽  
Chemotherapy Regimen ◽  
Performance Status ◽  
Univariate Analysis ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Transplantation ◽  
High Rate ◽  
Allogeneic Bone

Abstract Background: Patients with Refractory/Relapsed (R/R) acute leukemia (AL) have a poor prognosis. Objective: We aimed to evaluate the chemotherapy regimen fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) in patients with R/R AL. Patients: We studied 16 patients with R/R AL (five female; eleven male). Distribution of the AL subtype was: lymphoblastic n=5 (31%), myeloblastic n=10 (62%) and bifenotipic n=1 (7%). The median of time from diagnosis to the beginning of FLAG-IDA was 320 days. Indication of FLAG-IDA was as follows: relapsed (n=12), refractory (n=2) and consolidation after relapsed (n=1) or refractory (n=1). Before administering FLAG-IDA, six patients were in their first relapse after conventional chemotherapy and six patients had received at least two different chemotherapy protocols (anti-CD33 monoclonal antibody was combined with chemotherapy in 3 of these patients). Two patients were in relapse after autologous peripheral stem cell transplantation and two after related allogeneic bone marrow transplantation. Results: At the beginning of FLAG-IDA, the median age was 29.6 years old (range 11–56) and 5 out of 16 patients (31.2%) had a performance status of ≥2. All patients had at least one episode of febrile neutropenia in a median of 8.5 days (range 3–17) with positive blood cultures in 50% of the events. Grade 5 toxicity occurred in 4 patients resulting in a mortality of 25%. All of the deaths were due to sepsis. In patients with hematological recovery the median time to neutrophils recovery (&gt; 0.5 × 109/l) was 26.5 days (range 17–38); platelet levels of more than 20 × 109/l and 50 × 109/l were reached in a median time of 28 (range 23–44) and 31 days (range 25–51), respectively. Complete remission (CR) was achieved in 7 cases (43%). In the univariate analysis factors significantly associated with CR were the level of hemoglobin in day 0 (CR 10.2 g/dl versus non-CR 7.7 g/dl; p=0.03) and a desfavorable prognostic karyotype at the diagnosis of AL (CR 1/6 versus 5/5 non-CR; p=0.013). After CR, five patients underwent allogeneic transplantation and two patients received a second course of FLAG-IDA. Six out of seven patients (85.7%) who achieved CR with FLAG-IDA relapsed at a median of 248 days (95% CI 22.17 to 473.82 days). Overall survival after FLAG-IDA in the surviving cohort had a median of 131 days (95% CI 121 a 565 days) and one year-survival was 35.71%. We found a significantly better overall survival in patients who received allogeneic transplantation post-FLAG-IDA than those who did not (median 694 vs. 121 days; HR 0.24; 95% CI 0.06 to 0.98; p=0.0157). Conclusions: In our series, FLAG-IDA demonstrated to be an effective salvage chemotherapy regimen but with a high rate of treatment-related deaths probably related to bad performance status. We found that the benefit in survival of this rescue treatment was restrained to patients who underwent allogeneic transplantation.

scholarly journals Expression of MDR1 gene in acute leukemia cells: association with CD7+ acute myeloblastic leukemia/acute lymphoblastic leukemia

Blood ◽  
1993 ◽  
Vol 82 (11) ◽  
pp. 3445-3451 ◽  
Author(s):  
H Miwa ◽  
K Kita ◽  
K Nishii ◽  
N Morita ◽  
N Takakura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
Lymphoblastic Leukemia ◽  
Acute Myeloblastic Leukemia ◽  
Leukemia Cells ◽  
Mdr1 Gene ◽  
Functional Study ◽  
Mdr1 Gene Expression ◽  
Mdr1 Mrna

Abstract MDR1 gene expression was examined in acute leukemia cells from 75 Japanese patients at diagnosis (50 with acute myeloblastic leukemia [AML]: 10 M1, 18 M2, 5 M3, 8 M4, 9 M5; 25 with acute lymphoblastic leukemia [ALL]: 13 B-precursor, 12 T-lineage). The results of MDR1 mRNA expression by reverse transcriptase polymerase chain reaction were confirmed by immunostaining using the anti-P-glycoprotein monoclonal antibody UIC2 and by a functional study using the rhodamine efflux test. Morphologically, AML M1 cases had the highest incidence of MDR1 gene expression (6 of 10 patients). Phenotypically, CD7 and CD34 were the only surface markers that were significantly associated with MDR1 gene expression (P < .01). In CD7+CD4-CD8- ALL, which is thought to originate from the lymphohematopoietic stem cell, expressed the MDR1 gene with a high incidence (six of eight patients), whereas three surface CD3+ and one CD4+CD8+ T-cell ALL (T-ALL) did not have detectable MDR1 transcripts. Only two cases of 13 B-precursor ALL had MDR1 mRNA, one of which had the Philadelphia (Ph1) chromosome. No association was observed between MDR1 gene expression and CD34 positivity in ALL. Our results that MDR1 mRNA was frequently expressed in CD7+ AML and CD7+CD4-CD8- ALL, together with the previous reports indicating clinical similarities between these leukemias, provides a clue to clarify a relationship between CD7+ AML and CD7+CD4-CD8- ALL. In addition, MDR1 expression in CD7+ AML/ALL might be responsible for the poor response to conventional chemotherapies of these types of leukemia.

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