scholarly journals Clinical Significance of CD33 Non-Synonymous Single Nucleotide Polymorphisms (SNPs) in Pediatric Patients with Acute Myeloid Leukemia Treated with Gemtuzumab Ozogamicin-Containing Chemotherapy,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3489-3489
Author(s):  
Jatinder Lamba ◽  
Leslie J. Mortland ◽  
Amit Mitra ◽  
Roland B. Walter ◽  
Jessica A. Pollard ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Risk Group ◽  
Gemtuzumab Ozogamicin ◽  
Phase Iii ◽  
Nucleotide Polymorphisms ◽  
Newly Diagnosed ◽  
Single Nucleotide ◽  
Expression Levels ◽  
Pediatric Aml ◽  
White Patients

Abstract Abstract 3489 Introduction: Acute myeloid leukemia (AML) remains a difficult-to-treat disease, and outcome with standard conventional chemotherapeutics is often poor. An emerging approach uses monoclonal antibodies as a means to deliver targeted therapy. The antigen currently most exploited is CD33, in particular with gemtuzumab ozogamicin (GO), an immunoconjugate with a toxic calicheamicin derivative that causes DNA strand breaks, apoptosis, and cell death. However, while efficacious in some patients with untreated or relapsed/refractory disease, clinical response to GO is heterogeneous, emphasizing the need for studies to determine the subsets of patients that will benefit from GO. Although response to therapy is generally multi-factorial in origin, there is often a significant contribution of host genetic factors. Since GO targets CD33, we sought to determine the clinical impact of CD33 single nucleotide polymorphisms (SNPs) in a larger cohort of pediatric AML patients enrolled on Children's Oncology Group (COG) AAML03P1 pilot Phase III study, which explored the safety of GO addition to standard induction chemotherapy for newly-diagnosed AML. Methods: We genotyped four CD33 SNPs [rs35112940 (G>A; Arg304Gly), rs12459419 (C>T; Ala14Val), rs2455069 (A>G; Arg69Gly), and rs1803254 (G>C; 3'UTR)] occurring with an allelic frequency greater than 10% in genomic DNA samples in 242 pediatric AML patients. These were treated on trial COG-AAML03P1, and determined the associations between CD33 SNPs with CD33 protein expression levels in diagnostic leukemic cells and clinical outcome. Results: CD33 coding SNPs, rs35112940 (G>A; Arg304Gly) and rs12459419 (C>T; Ala14Val), and the 3'UTR SNP rs1803254 demonstrated significant associations with outcome or CD33 expression levels. Specifically, among white patients (which consisted of the major group 166/242=68.6%) homozygous for wild-type allele (GG) for the SNP rs35112940, a lower 3-year relapse risk from the end of course 1 was observed as compared to other genotypes (GG vs. AG vs. AA; 24±9% vs. 41±17% vs. 67±38%; p=0.018 Figure. 1A). Similarly, the 3-year overall survival from end of course 1 for among white patients homozygous for G allele in complete remission was 84±8% versus 68±15% for other genotypes (p=0.036; Figure. 1B). Patients homozygous for variant allele (TT) for SNP rs12459419 had a 3-year overall survival of 88±13% compared to 69±6% for other genotypes (p=0.056). Among white patients, the homozygous TT genotype also had a lower mean CD33 expression compared to other genotypes at this SNP (mean fluorescence intensity, 42 vs. 145, p=<0.001). Additionally, we observed an increased proportion of patients homozygous for variant allele (TT) for rs12459419 in the favorable risk group compared to genotypes CC and CT (52% vs. 31 %, p=0.034). Conclusion: In conclusion, our findings suggest that CD33 SNPs are associated with clinical disease features such as CD33 expression levels and risk group as well as outcome after GO-containing chemotherapy in patients with newly diagnosed AML. The recently completed COG-AAML0531 randomized Phase III trial will allow validation of our findings. If their usefulness as a prognostic marker for treatment outcome of GO-based therapy is confirmed in an independent cohort, CD33 SNPs may serve to optimize the clinical use of this immunoconjugate; by extrapolation, prognostic information provided by CD33 SNPs may also be applicable to novel, second-generation CD33-targeting immuno-conjugates that have entered preclinical and clinical testing. Disclosures: No relevant conflicts of interest to declare.

Sequential Combination of Gemtuzumab Ozogamicin and Standard Chemotherapy in Older Patients With Newly Diagnosed Acute Myeloid Leukemia: Results of a Randomized Phase III Trial by the EORTC and GIMEMA Consortium (AML-17)

2013 ◽  
Vol 31 (35) ◽  
pp. 4424-4430 ◽  
Author(s):  
Sergio Amadori ◽  
Stefan Suciu ◽  
Roberto Stasi ◽  
Helmut R. Salih ◽  
Dominik Selleslag ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Phase Iii ◽  
Newly Diagnosed ◽  
Standard Chemotherapy ◽  
Sequential Combination ◽  
Grade 3 ◽  
Acute Myeloid

Purpose This randomized trial evaluated the efficacy and toxicity of sequential gemtuzumab ozogamicin (GO) and standard chemotherapy in older patients with newly diagnosed acute myeloid leukemia (AML). Patients and Methods Patients (n = 472) age 61 to 75 years were randomly assigned to induction chemotherapy with mitoxantrone, cytarabine, and etoposide preceded, or not, by a course of GO (6 mg/m2 on days 1 and 15). In remission, patients received two consolidation courses with or without GO (3 mg/m2 on day 0). The primary end point was overall survival (OS). Results The overall response rate was comparable between the two arms (GO, 45%; no GO, 49%), but induction and 60-day mortality rates were higher in the GO arm (17% v 12% and 22% v 18%, respectively). With median follow-up of 5.2 years, median OS was 7.1 months in the GO arm and 10 months in the no-GO arm (hazard ratio, 1.20; 95% CI, 0.99 to 1.45; P = .07). Other survival end points were similar in both arms. Grade 3 to 4 hematologic and liver toxicities were greater in the GO arm. Treatment with GO provided no benefit in any prognostic subgroup, with the possible exception of patients age < 70 years with secondary AML, but outcomes were significantly worse in the oldest age subgroup because of a higher risk of early mortality. Conclusion As used in this trial, the sequential combination of GO and standard chemotherapy provides no benefit for older patients with AML and is too toxic for those age ≥ 70 years.

Large Interindividual Differences in In Vitro Calicheamicin Sensitivity May Underly Gemtuzumab Ozogamicin Resistance in Acute Myeloid Leukemia (AML).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 107-107
Author(s):  
Bianca F. Goemans ◽  
Gertjan J.L. Kaspers ◽  
Susanne J.H. Vijverberg ◽  
Anne H. Loonen ◽  
Ursula Creutzig ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Drug Sensitivity ◽  
Gemtuzumab Ozogamicin ◽  
Cross Resistance ◽  
Newly Diagnosed ◽  
Primary Resistance ◽  
In Vitro Sensitivity ◽  
Resistant Patient ◽  
Pediatric Aml

Abstract Gemtuzumab ozogamicin (GO or Mylotarg®) is increasingly being used in the treatment of AML. GO consists of a cytotoxic drug - calicheamicin which is conjugated to an anti-CD33 antibody. Most AML patients highly express CD33 on their blasts. Studies relating CD33 expression to response to GO have failed to show an association. Although 30–50% of patients respond to Mylotarg®, the causes of primary resistance to this drug remain unclear. Previous reports have studied P-gp status and CD33 expression as a cause of resistance to GO. Another factor that might determine response to GO is cellular drug resistance to calicheamicin. In this study we examined in vitro resistance to calicheamicin in 90 initially diagnosed and 32 relapsed pediatric AML samples using the 4 day MTT assay (concentration range 0.000004 – 0.4 μg/ml). The LC50 value, the drug concentration at which 50% of the cells is killed by the drug, is used as a measure of sensitivity. In addition to calicheamicin, some samples were also tested successfully for in vitro sensitivity to etoposide, cytarabine, daunorubicin, idarubicin, mitoxantrone, 6-thioguanine, vincristine and L-asparaginase. The characteristics of the 122 pediatric AML samples included are as follows: 62% boys, median age 9.6 years, median WBC 53.0*109/L, FAB types M0 n=9, M1 n=10, M2 n=18, M3 n=9, M4 n=33, M5 n=24, M7 n=3, unknown n=16. There was a more than 100,000 fold difference in calicheamicin sensitivity between the most sensitive and the most resistant patient samples. FAB M2 samples taken at initial diagnosis (n=13) were significantly more resistant to calicheamicin compared to the other FAB types (Resistance Ratio (RR)=2.5, median LC50 0.033 vs. 0.013 μg/ml, p=0.008). Newly diagnosed AML samples were significantly more sensitive to calicheamicin compared to relapsed AML samples (RR=0.68, median LC50 0.023 vs. 0.034 μg/ml, p=0.042) (although these patients had not been treated with calicheamicin). There was strong cross-resistance between calicheamicin and the anthracyclines idarubicin (Spearmans rho = 0.73, p&lt;0.0001, n=23), daunorubicin (rho=0.61, p&lt;0.0001, n=103) and mitoxantrone (rho=0.52, p=0.039, n=16). In addition, there was moderate cross-resistance with etoposide (rho=0.42, p&lt;0.0001, n=101). No cross-resistance was observed between calicheamicin and cytarabine (rho=0.11, p=0.28, n=106), 6-thioguanine (rho=0.20, p=0.054, n=97), vincristine (rho=0.12, p=0.44, n=46) or L-asparaginase (rho=0.21, p=0.16, n=45). In conclusion, the interpatient differences in calicheamicin sensitivity are the largest differences in in vitro drug sensitivity we have ever observed in pediatric AML. FAB M2 samples are 2.5 fold more resistant to calicheamicin than samples with other FAB types. Initially diagnosed pediatric AML samples are 1.5 fold more sensitive to calicheamicin than relapsed AML samples. There is marked cross-resistance between calicheamicin and the related anthracyclin compounds. Given the large differences in sensitivity to calicheamicin in pediatric AML samples, it is likely that calicheamicin resistance plays a role in resistance to Mylotarg®.

High Transcription Levels Of S100A8 and S100A9 In Acute Myeloid Leukemia Are Predictors For Poor Overall Survival

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2610-2610 ◽  
Author(s):  
Shao-yan Hu ◽  
Ming-ying Zhang ◽  
Shui-yan Wu ◽  
Dong Wu ◽  
Neetika Ashwani ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Group ◽  
High Expression ◽  
Intermediate Risk ◽  
Newly Diagnosed ◽  
Transcription Level ◽  
Expression Levels ◽  
De Novo Aml ◽  
Low Expression

Abstract S100A8 and S100A9 are two members of the S100 calcium-binding protein family, preferentially form functional heterodimers of S100A8/S100A9, and have been increasingly recognized as biomarkers in malignancies. Recent proteomic studies revealed that S100A8 and S100A9 played pivotal roles in hematologic malignancies and elevated expression of S100A8/S100A9 implicated in glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia (ALL). In addition, S100A8 proteomic expression in leukemic cells was reported to predict survival in AML patients. However, information on the gene expression level of S100A8 and S100A9 and their clinical correlation in acute myeloid leukemia (AML) is lacking. Using the real-time quantitative RT-PCR, we analyze the transcription levels of S100A8 and S100A9 in AML patient leukemic specimens underwent pre-planned induction chemotherapy. A total of 189 patient cases at different stages of AML (excluding acute promyelocytic leukemia [APL]), including 91 newly diagnosed AML, 64 patient remission marrow specimens and 34 patient specimens as well as 20 controls without leukemia were included in the study collected from the period between 2007 and 2011. Among the cohort of 91 newly diagnosed AML, the over all median OS was 20 months, and the median follow-up for survivors was 24 months (range: 17 to 60 months). There were significant positive correlations of transcription levels between S100A8 and S100A9 in AML patients from different stages. The expression levels of S100A8 and S100A9 in newly diagnosed and relapsed AML patients revealed no significant difference, but were both lower than those in complete remission and control group. Patients with high transcription level of S100A8 and S100A9 were predominantly in AML with myelo-monocytic differentiation (M4, M5) whereas those with low transcription level of S100A8 and S100A9 often showed more immature cytomorphology (M0, M1), erythrocytic or megakaryocytic differentiation. The subgroup of patient with high transcription level of S100A8 could be a predictor for inferior overall survival (OS) (P = 0.0012). High levels of transcription for both S100A8 and S100A9 in de novo AML patients could predict shorter OS than those with low levels after adjustment on their ages at diagnosis (P = 0.003). In a multivariate analysis for OS, high S100A8 transcription was a significant prognostic factor (P =0.001) after analysis adjustment for age (P = 0.019), bone marrow blast percentage (P = 0.04) and cytogenetic classification (P = 0.05) at diagnosis. Using a combination of S100A8 transcription level and cytogenetic risk classification, survival analysis gave result that the new stratification was highly correlated with the OS (P < 0.0001). With significantly different OS, patients from the intermediate-risk group can be divided into two subgroups (IH = cytogenetically intermediate-risk with S100A8 high transcription and IL = cytogenetically intermediate-risk with S100A8 low transcription). Patients from group IL emerged with a probability of OS similar to the cytogenetically favorable-risk group, whereas the survival curve of IH subgroup was close to the unfavorable-risk group. (Figure)FigureRisk stratification of de novo AML patients by a combination of age and cytogenetic characteristics with S100A8 expression levels. 1H = cytogenetically favorable-risk with S100A8 high expression, 1L = cytogenetically favorable-risk with S100A8 low expression, 2H = cytogenetically intermediate-risk with S100A8 high expression, 2L = cytogenetically intermediate-risk with S100A8 low expression, 3H = cytogenetically unfavorable-risk with S100A8 high expression, 3L = cytogenetically unfavorable-risk with S100A8 low expression.Figure. Risk stratification of de novo AML patients by a combination of age and cytogenetic characteristics with S100A8 expression levels. 1H = cytogenetically favorable-risk with S100A8 high expression, 1L = cytogenetically favorable-risk with S100A8 low expression, 2H = cytogenetically intermediate-risk with S100A8 high expression, 2L = cytogenetically intermediate-risk with S100A8 low expression, 3H = cytogenetically unfavorable-risk with S100A8 high expression, 3L = cytogenetically unfavorable-risk with S100A8 low expression. In conclusion, the transcription levels of S100A8 and S100A9 were significantly associated with development and prognosis of AML. Both S100A8 and S100A9 expression levels provided useful clinical information, and more importantly, S100A8 expression level significantly correlates with prognosis in addition to well-known cytogenetic risk factors, and could potentially further refine current stratification of de novo AML patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CD33 Splicing Polymorphism Determines Gemtuzumab Ozogamicin Response in De Novo Acute Myeloid Leukemia: Report From Randomized Phase III Children’s Oncology Group Trial AAML0531

2017 ◽  
Vol 35 (23) ◽  
pp. 2674-2682 ◽  
Author(s):  
Jatinder K. Lamba ◽  
Lata Chauhan ◽  
Miyoung Shin ◽  
Michael R. Loken ◽  
Jessica A. Pollard ◽  
...  
Keyword(s):  
Single Nucleotide Polymorphism ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gemtuzumab Ozogamicin ◽  
Phase Iii ◽  
Oncology Group ◽  
Nucleotide Polymorphism ◽  
Single Nucleotide ◽  
Relapse Risk ◽  
Acute Myeloid

Purpose Gemtuzumab ozogamicin (GO), a CD33-targeted immunoconjugate, is a re-emerging therapy for acute myeloid leukemia (AML). CD33 single nucleotide polymorphism rs12459419 C>T in the splice enhancer region regulates the expression of an alternatively spliced CD33 isoform lacking exon2 (D2-CD33), thus eliminating the CD33 IgV domain, which is the antibody-binding site for GO, as well as diagnostic immunophenotypic panels. We aimed to determine the impact of the genotype of this splicing polymorphism in patients with AML treated with GO-containing chemotherapy. Patients and Methods CD33 splicing single nucleotide polymorphism was evaluated in newly diagnosed patients with AML randomly assigned to receive standard five-course chemotherapy alone (No-GO arm, n = 408) or chemotherapy with the addition of two doses of GO once during induction and once during intensification (GO arm, n = 408) as per the Children’s Oncology Group AAML0531 trial. Results The rs12459419 genotype was CC in 415 patients (51%), CT in 316 patients (39%), and TT in 85 patients (10%), with a minor allele frequency of 30%. The T allele was significantly associated with higher levels of D2-CD33 transcript ( P < 1.0E−6) and with lower diagnostic leukemic cell surface CD33 intensity ( P < 1.0E−6). Patients with the CC genotype had significantly lower relapse risk in the GO arm than in the No-GO arm (26% v 49%; P < .001). However, in patients with the CT or TT genotype, exposure to GO did not influence relapse risk (39% v 40%; P = .85). Disease-free survival was higher in patients with the CC genotype in the GO arm than in the No-GO arm (65% v 46%, respectively; P = .004), but this benefit of GO addition was not seen in patients with the CT or TT genotype. Conclusion Our results suggest that patients with the CC genotype for rs12459419 have a substantial response to GO, making this a potential biomarker for the selection of patients with a likelihood of significant response to GO.

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