scholarly journals Cell surface expression of c-kit receptors by childhood acute myeloid leukemia blasts is not of prognostic value: a report from the Childrens Cancer Group

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 847-852 ◽  
Author(s):  
FO Smith ◽  
VC Broudy ◽  
KM Zsebo ◽  
BC Lampkin ◽  
CV Buckley ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Response To Therapy ◽  
Receptor Expression ◽  
Cell Surface Expression ◽  
Cancer Group ◽  
Kit Receptor ◽  
Blast Cells ◽  
Acute Myeloid

Abstract The prognostic significance of c-kit receptor expression on leukemic blast cells was determined in 122 children with acute myeloid leukemia (AML) entered onto Childrens Cancer Group protocol 213. Clinical and laboratory characteristics as well as outcome were analyzed according to the percentage of blast cells expressing c-kit receptors and the relative number of c-kit receptors per cell as determined by indirect immunofluorescence. c-kit receptor expression was strongly associated with the expression of the CD34 antigen. However, contrary to findings in adult patients with AML, c-kit receptor expression by childhood AML blast cells was not predictive of a poor response to therapy.

scholarly journals Cell surface expression of c-kit receptors by childhood acute myeloid leukemia blasts is not of prognostic value: a report from the Childrens Cancer Group

Blood ◽  
1994 ◽  
Vol 84 (3) ◽  
pp. 847-852
Author(s):  
FO Smith ◽  
VC Broudy ◽  
KM Zsebo ◽  
BC Lampkin ◽  
CV Buckley ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Response To Therapy ◽  
Receptor Expression ◽  
Cell Surface Expression ◽  
Cancer Group ◽  
Kit Receptor ◽  
Blast Cells ◽  
Acute Myeloid

The prognostic significance of c-kit receptor expression on leukemic blast cells was determined in 122 children with acute myeloid leukemia (AML) entered onto Childrens Cancer Group protocol 213. Clinical and laboratory characteristics as well as outcome were analyzed according to the percentage of blast cells expressing c-kit receptors and the relative number of c-kit receptors per cell as determined by indirect immunofluorescence. c-kit receptor expression was strongly associated with the expression of the CD34 antigen. However, contrary to findings in adult patients with AML, c-kit receptor expression by childhood AML blast cells was not predictive of a poor response to therapy.

scholarly journals CD33_PGx6_Score Predicts Gemtuzumab Ozogamicin Response in Childhood Acute Myeloid Leukemia: A Report From the Children’s Oncology Group

2019 ◽  
pp. 1-15 ◽  
Author(s):  
Lata Chauhan ◽  
Miyoung Shin ◽  
Yi-Cheng Wang ◽  
Michael Loken ◽  
Jessica Pollard ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Surface ◽  
Clinical Response ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Disease Free Survival ◽  
Gemtuzumab Ozogamicin ◽  
Cell Surface Expression ◽  
Oncology Group ◽  
Acute Myeloid

PURPOSE The US Food and Drug Administration recently announced reapproval of gemtuzumab ozogamicin (GO) for treatment of CD33-positive acute myeloid leukemia (AML), thus opening up opportunities to develop strategies for effective use of GO. In light of our recent report showing prognostic significance of CD33 splicing single nucleotide polymorphisms (SNPs), the objective of this study was to comprehensively evaluate CD33 SNPs for accurate prediction of patients with AML who are more or less likely to respond to GO. PATIENTS AND METHODS We investigated the five new CD33 SNPs (rs2455069, rs35112940, rs61736475, rs1803254, and rs201074739) for association with CD33 leukemic cell surface expression and clinical response in pediatric patients with AML enrolled in the Children’s Oncology Group AAML0531 trial. We further developed a composite CD33 pharmacogenetics (PGx) score using six CD33 SNPs (CD33_PGx6_score) for association with clinical outcome. RESULTS Four CD33 SNPs were associated with cell surface CD33 levels and clinical response in the GO versus no-GO arms. Therefore, the CD33_PGx6_score was built using directional genotype scores for the previously reported splicing SNP and five new SNPs. Patients with a CD33_PGx6_score of 0 or higher had higher CD33 expression levels compared with patients with a score of less than 0 ( P < .001). In addition, patients with a score of 0 or higher demonstrated an improved disease-free survival in the GO versus no-GO arms (62.5% ± 7.8% v 46.8% ± 8.3%, respectively; P = .008) and a reduced risk of relapse (28.3% ± 7.2% v 49.9% ± 8.4%, respectively; P < .001). No improvement from GO was observed in patients with a CD33-PGx6_score of less than 0. Consistent results were observed across the risk groups. CONCLUSION In this study, we report a composite CD33_PGx6_score using directional genotype scores of CD33 SNPs. Once validated, our findings hold promise for use of the CD33_PGx6_score to guide efficient use of GO in patients with AML. In addition, because the CD33_PGx6_score considers SNPs with varying abundance in different ethnic groups, it has potential for global application.

Negative prognostic value of glutathione S-transferase(GSTM1 and GSTT1) deletions in adult acute myeloid leukemia

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2703-2707 ◽  
Author(s):  
Maria Teresa Voso ◽  
Francesco D'Alo' ◽  
Rossana Putzulu ◽  
Luca Mele ◽  
Alessandra Scardocci ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Prognostic Significance ◽  
Response To Therapy ◽  
Induction Treatment ◽  
Chain Reactions ◽  
Response To Chemotherapy ◽  
Homozygous Deletions ◽  
Acute Myeloid

Glutathione S-transferases (GSTs) are enzymes involved in the detoxification of several environmental mutagens, carcinogens, and anticancer drugs. GST polymorphisms resulting in decreased enzymatic activity have been associated with several types of solid tumors. We determined the prognostic significance of the deletion of 2 GST subfamilies genes, M1 and T1, in patients with acute myeloid leukemia (AML). Using polymerase chain reactions, we analyzed theGSTM1 and GSTT1 genotype in 106 patients with AML (median age, 60.5 years; range, 19-76 years). The relevance ofGSTM1 and GSTT1 homozygous deletions was studied with respect to patient characteristics, response to therapy, and survival. Homozygous deletions resulting in null genotypes at theGSTM1 and GSTT1 loci were detected in 45 (42%) and 30 (28%) patients, respectively. The double-null genotype was present in 19 patients (18%). GST deletions predicted poor response to chemotherapy (P = .04) and shorter survival (P = .04). The presence of at least one GST deletion proved to be an independent prognostic risk factor for response to induction treatment and overall survival in a multivariate analysis including age and karyotype (P = .02). GST genotyping was of particular prognostic value in the cytogenetically defined intermediate-risk group (P = .003). In conclusion, individuals with GSTM1 or GSTT1 deletions (or deletions of both) may have an enhanced resistance to chemotherapy and a shorter survival.

scholarly journals Monoclonal antibodies to the human CSF-1 receptor (c-fms proto-oncogene product) detect epitopes on normal mononuclear phagocytes and on human myeloid leukemic blast cells

Blood ◽  
1989 ◽  
Vol 73 (3) ◽  
pp. 827-837 ◽  
Author(s):  
RA Ashmun ◽  
AT Look ◽  
WM Roberts ◽  
MF Roussel ◽  
S Seremetis ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Monoclonal Antibodies ◽  
Myeloid Leukemia ◽  
Mononuclear Phagocytes ◽  
Receptor Expression ◽  
Upstream Region ◽  
Leukemic Blast ◽  
Granulocytic Differentiation ◽  
Blast Cells ◽  
Acute Myeloid

The first monoclonal antibodies (MoAbs) to epitopes in the extracellular domain of the human c-fms proto-oncogene product (receptor for the macrophage colony stimulating factor, CSF-1) were used with flow cytometric techniques to study receptor expression on normal human peripheral blood monocytes, bone marrow cells, and leukemic blasts. On normal cells CSF-1 receptors were restricted in their expression to cells of the mononuclear phagocyte lineage. CSF-1 receptors were detected on leukemic blasts from 15 (30%) of 50 children with acute myeloid leukemia, compared with four (15%) of 26 adults. By contrast, detectable CSF-1 receptors were uniformly absent on blasts from 19 children with acute lymphoblastic leukemia. CSF-1 receptors on normal monocytes and myeloid leukemia cells could be induced to downmodulate by incubation with either human recombinant CSF-1 or phorbol esters, confirming that the receptors had functional ligand- binding sites and responded to transmodulation by inducers of protein kinase C. The numbers of receptors per cell and the percentage of positive cases were highest for leukemic blasts with cytochemical and morphological features of monocytes. However, CSF-1 receptors were also detected on a subset of leukemic blast cells with features of granulocytic differentiation (FAB subtypes M1 through M3). Southern blotting analyses of DNA from 47 cases of acute myeloid leukemia demonstrated no rearrangements within the 32 kb of genomic sequences that contain CSF-1 receptor coding exons or in the 50 kb upstream of the first coding exon. Analysis of the upstream region of the c-fms locus revealed that sequences representing the terminal 112 untranslated nucleotides of c-fms mRNA map 26 kb 5′ to the first coding exon, suggesting that at least one c-fms promoter is separated from the receptor coding sequences by a very long intron. Whereas expression of the CSF-1 receptor in myeloid leukemic blasts is not restricted to cells with monocytic characteristics, the apparently aberrant pattern of receptor synthesis in a subset of cases with granulocytic features appears not to be due to chromosomal rearrangements within 50 kb upstream of sequences encoding the receptor.

Independent Prognostic Significance of Cytogenetics, Immunophenotype, Tumor Burden, and Age in Acute Myeloid Leukemia. Analysis of Patients Treated within PALG 1999 Prospective, Randomized Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4395-4395
Author(s):  
Sebastian Grosicki ◽  
Jerzy Holowiecki ◽  
Sebastian Giebel ◽  
Olga Haus ◽  
Beata Stella-Holowiecka ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Features ◽  
Myeloid Leukemia ◽  
Randomized Study ◽  
Prognostic Significance ◽  
Tumor Burden ◽  
Response To Therapy ◽  
Leukemic Cells ◽  
High Dose ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) refers to a group of distinct diseases that differ with regard to their genetic charakteristics, clinical features, response to therapy, and prognosis. Patients require precise initial evaluation of risk factors including cytogenetics and immunophenotype to plan an optimal treatment program. In this study we analyzed impact of cytogenetics, cell surface marker expression and clinical features on complete remission (CR) rate, leukemia-free survival (LFS) and overall survival (OS). Four-hundred-forty-five AML patients, aged 18–60 years, treated within a multicentre study by the Polish Adult Leukemia Group (PALG 1999 Study) between 1999–2002 were included in the analysis. Induction therapy consisted of daunorubicine+cytarabine+/−cladribine, consolidation included two courses containing high-dose cytarabine (HAM, HD-AraC+/−cladribine). In multivariate analysis the following factors were found to be associated with poor outcome: For CR rate: unfavorable cytogenetics according to CALGB criteria (RR=5,5, p=0,00001), WBC ≥50 x109/L at diagnosis (RR=3,3, p=0,00007), and age ≥50 (RR=1,9, p=0,021). For LFS: unfavorable cytogenetics (RR=1,7, p=0,026), and lack of CD117 expression on leukemic cells (RR=1,8, p=0,026). For OS: unfavorable cytogenetics (RR=1,8, p=0,00002), WBC ≥50 x109/L at diagnosis (RR=1,1, p=0,0007), age ≥50 (RR=1,6, p=0,002), and lack of CD33 expression on leukemic cells (RR=1,7, p=0,014). CONCLUSIONS: In this study we demonstrated that besides cytogenetics, other factors including particular phenotypic features, as well as initial tumor burden, and age independently influence outcome of AML patients. Results of the analysis provide practical information that could be taken into account when planning individualized treatment including indications for high-dose therapy followed by bone marrow transplantation.

Prognostic Significance of Multidrug Resistance Proteins Expression in Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4360-4360
Author(s):  
Oleg D. Zakharov ◽  
Ekaterina U. Rybalkina ◽  
Alla A. Stavrovskaya ◽  
Maya Volkova
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Multidrug Resistance Proteins ◽  
Resistance Proteins ◽  
Blast Cells ◽  
Acute Myeloid

Abstract Background: Conventional induction chemotherapy induces complete remission (CR) in 65–75% of adults with de novo acute myeloid leukemia (AML), and 15–20% of the patients have refractory disease. We investigated the prognostic significance of multidrug resistance proteins (P-glycoprotein (Pgp), BCRP, MRP1 and LRP) expression on AML blast cells before treatment. Methods: We included in analysis 30 patients (pts) with de novo AML. Expression of multidrug resistance proteins (MDR) was detected by indirect immunofluorescence technique and flow cytometry on bone marrow blast cells before chemotherapy. Expression of MDR proteins was considered as positive if at least 25% of the blast cells were stained by anti-MDR protein antibody. All pts received standard induction therapy (cytarabine, etoposide and idarubicin or daunorubicine). Results: Blast cells was defined as Pgp-positive in 64.3% of cases, BCRP+ in 42.9%, MRP1+ in 46.4%, and LRP+ in 64.3% of cases. After induction therapy 20 (66,7%) pts achieved CR and 10 pts (33.3%) were resistant. MDR proteins expression was observed more frequently in resistant group, then in a sensitive one (70% vs 61% for Pgp, 70% vs 33% for MRP1, 100% vs 44% for LRP, 80% vs 22% for BCRP, respectively), difference for LRP and BCRP was statistically significant (p=0.004). Blast cells of all resistant pts expressed 2–4 MDR proteins (all studied proteins − 40%, 3 of them − 40% and 2 proteins − 20%). In a group of pts archived CR the blast cells expressed 3 proteins only in 2 cases (10%), and the expression of all 4 proteins we observed only in 1 patient (5%) with very short CR duration (3 months). Other pts from this group express only one studied protein. According to chromosome analysis 18.2% of pts had favorable, 50% - intermediate and 31.8% unfavorable cytogenetic. Blast cells of all pts in cytogenetically unfavorable group expressed more then 1 protein, 3 or 4 MDR proteins expressed in 71,4% of cases. In favorable and intermediate cytogenetic groups blast cells expressed 1or 2 MDR proteins in 73,2% of cases, 3 or 4 proteins in 20%. Conclusions: The expression of MDR proteins in AML has a prognostic value with respect to CR achievement in pts receiving standard antracycline-Ara-C regimens. The detection of any single protein didn’t have prognostic significance, only co-expression of 2 and more proteins predict unfavorable treatment outcome. We observed a correlation between the cytogenetic and the MDR phenotype.

scholarly journals Monoclonal antibodies to the human CSF-1 receptor (c-fms proto-oncogene product) detect epitopes on normal mononuclear phagocytes and on human myeloid leukemic blast cells

Blood ◽  
1989 ◽  
Vol 73 (3) ◽  
pp. 827-837 ◽  
Author(s):  
RA Ashmun ◽  
AT Look ◽  
WM Roberts ◽  
MF Roussel ◽  
S Seremetis ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Monoclonal Antibodies ◽  
Myeloid Leukemia ◽  
Mononuclear Phagocytes ◽  
Receptor Expression ◽  
Upstream Region ◽  
Leukemic Blast ◽  
Granulocytic Differentiation ◽  
Blast Cells ◽  
Acute Myeloid

Abstract The first monoclonal antibodies (MoAbs) to epitopes in the extracellular domain of the human c-fms proto-oncogene product (receptor for the macrophage colony stimulating factor, CSF-1) were used with flow cytometric techniques to study receptor expression on normal human peripheral blood monocytes, bone marrow cells, and leukemic blasts. On normal cells CSF-1 receptors were restricted in their expression to cells of the mononuclear phagocyte lineage. CSF-1 receptors were detected on leukemic blasts from 15 (30%) of 50 children with acute myeloid leukemia, compared with four (15%) of 26 adults. By contrast, detectable CSF-1 receptors were uniformly absent on blasts from 19 children with acute lymphoblastic leukemia. CSF-1 receptors on normal monocytes and myeloid leukemia cells could be induced to downmodulate by incubation with either human recombinant CSF-1 or phorbol esters, confirming that the receptors had functional ligand- binding sites and responded to transmodulation by inducers of protein kinase C. The numbers of receptors per cell and the percentage of positive cases were highest for leukemic blasts with cytochemical and morphological features of monocytes. However, CSF-1 receptors were also detected on a subset of leukemic blast cells with features of granulocytic differentiation (FAB subtypes M1 through M3). Southern blotting analyses of DNA from 47 cases of acute myeloid leukemia demonstrated no rearrangements within the 32 kb of genomic sequences that contain CSF-1 receptor coding exons or in the 50 kb upstream of the first coding exon. Analysis of the upstream region of the c-fms locus revealed that sequences representing the terminal 112 untranslated nucleotides of c-fms mRNA map 26 kb 5′ to the first coding exon, suggesting that at least one c-fms promoter is separated from the receptor coding sequences by a very long intron. Whereas expression of the CSF-1 receptor in myeloid leukemic blasts is not restricted to cells with monocytic characteristics, the apparently aberrant pattern of receptor synthesis in a subset of cases with granulocytic features appears not to be due to chromosomal rearrangements within 50 kb upstream of sequences encoding the receptor.

scholarly journals Enhancement of Eligibility Guidelines for Gemtuzumab Ozogamicin Therapy for Childhood Acute Myeloid Leukemia: A Report from Children's Oncology Group Protocol AAML0531

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1490-1490
Author(s):  
Laura Pardo ◽  
Lisa Eidenschink Brodersen ◽  
Jatinder K Lamba ◽  
Todd A Alonzo ◽  
Yi-Cheng Wang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Cell Surface ◽  
Myeloid Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Response To Therapy ◽  
Cell Surface Expression ◽  
Oncology Group ◽  
Expression Levels ◽  
Acute Myeloid

Abstract Background: CD33 is variably expressed on leukemia blasts in most patients with acute myeloid leukemia (AML). Efforts to target CD33 therapeutically have focused on gemtuzumab ozogamicin (GO), an antibody-drug conjugate delivering a DNA-damaging calicheamicin derivative. Qualification for GO therapy has been determined by expression of CD33 by multidimensional flow cytometry (MDF); patients with positive CD33 expression receive GO. Previous studies from the AAML0531 protocol demonstrated that the cell surface intensity expression of CD33, determined by MDF, predicts the response to treatment with GO, and that in part this expression is regulated by a pair of CD33 single nucleotide polymorphisms (SNPs) in linkage disequilibrium that also, independently, predict response to therapy. Patients with CC genotype for rs12459419 have lower relapse risk and improved disease-free survival, compared to CT and TT genotypes. Because GO therapy is associated with treatment-related toxicity, it is important to identify biologic variables associated with benefits and risks. To date, there has been no report associating SNP status among CD33 positive versus CD33 negative patients that could assess how the combination of these biomarkers for determining administration of GO therapy could improve patient outcomes. Objective: In an effort to determine which children would benefit most from GO treatment in future prospective pediatric AML protocols, we aimed to elucidate if CD33 SNP genotype status should be combined with quantitative CD33 cell surface antigen expression on the diagnostic leukemia cells (CD33+ versus CD33-) to determine GO eligibility, with a retrospective analysis of children enrolled in Children's Oncology Group AAML0531. Methods: Of 1022 newly diagnosed pediatric patients with de novo AML enrolled on protocol AAML0531, 666 satisfied two criteria for this study: (1) submission of a blood or bone marrow sample for MDF at diagnosis with corresponding CD33 SNP genotype data available, and (2) proper consent for specimen testing. CD33 Expression Levels on Leukemic Blasts The diagnostic AML leukemia population was identified by gating on CD45 versus log-side scatter and CD33 expression levels were determined by measuring the mean fluorescence intensity (MFI) by flow cytometry. For a patient to be considered CD33+ two criteria were required: intensity of CD33 on blasts was at minimum four times the MFI of its correspondent autofluorescent control, and at least 80% of the total blasts were greater than this minimum. Genotyping CD33 SNPs CD33-coding SNP rs12459419-Ala14Val and linked promoter SNP rs3865444 were genotyped using the Sequenome (San Diego, CA) platform at the Biomedical Genomics Center, University of Minnesota. Both SNPs had a call rate of 0.98 and were in Hardy-Weinberg equilibrium (P=0.05). Results: Association of Genotype and cell surface expression of CD33 for AAML0531 patients Of 666 patients, 84% (560/666) were CD33+. CC genotype was observed in 54.5% (305/560) of CD33+ cases, 37.5% (210/560) had CT genotype and 8% (45/560) TT genotype. Of the 16% (106/666) of patients who were CD33 negative, 33% (35/106) had CC genotype, 47% (50/106) CT genotype, and 20% (21/106) had TT genotype. Comprehensively, 340/666 (51%) had CC genotype (51%) and 10% were CD33 negative (35/340). Conversely, out of a total of 66 patients with TT genotype, 45 (68%) were CD33+ and 32% (21/66) were CD33 negative. Conclusions: These results clarify the relationship between the amount of CD33 expressed on AML at diagnosis as measured by MDF and CD33 SNP genotype status. While correlation with clinical outcome analysis is ongoing, these data support inclusion of CD33 SNP genotyping for eligibility of GO therapy. Therefore, the current recommendation for future COG AML clinical protocols is that GO will be administered to patients with CD33 expression as determined by MDF and CC genotype patients regardless of CD33 expression. Disclosures Pardo: Hematologics, Inc: Employment. Eidenschink Brodersen:Hematologics, Inc: Employment. Paine:Hematologics, Inc: Employment. Loken:Hematologics, Inc: Employment, Equity Ownership.

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