First name
Susana
Middle name
C
Last name
Raimondi

Title

Gemtuzumab Ozogamicin Improves Event-Free Survival and Reduces Relapse in Pediatric -Rearranged AML: Results From the Phase III Children's Oncology Group Trial AAML0531.

Year of Publication

2021

Number of Pages

JCO2003048

Date Published

2021 May 28

ISSN Number

1527-7755

Abstract

<p><strong>PURPOSE: </strong>We investigated the impact of the CD33-targeted agent gemtuzumab ozogamicin (GO) on survival in pediatric patients with -rearranged (-r) acute myeloid leukemia (AML) enrolled in the Children's Oncology Group trial AAML0531 (NCT01407757).</p>

<p><strong>METHODS: </strong>Patients with -r AML were identified and clinical characteristics described. Five-year overall survival (OS), event-free survival (EFS), disease-free survival (DFS), and relapse risk (RR) were determined overall and for higher-risk versus not high-risk translocation partners. GO's impact on response was determined and outcomes based on consolidation approach (hematopoietic stem cell transplant [HSCT] chemotherapy) described.</p>

<p><strong>RESULTS: </strong>Two hundred fifteen (21%) of 1,022 patients enrolled had -r AML. Five-year EFS and OS from study entry were 38% and 58%, respectively. EFS was superior with GO treatment (EFS 48% with GO 29% without, = .003), although OS was comparable (63% 53%, = .054). For patients with -r AML who achieved complete remission, GO was associated with lower RR (40% GO 66% patients who did not receive GO [No-GO], = .001) and improved 5-year DFS (GO 57% No-GO 33%, = .002). GO benefit was observed in both higher-risk and not high-risk -r subsets. For patients who underwent HSCT, prior GO exposure was associated with decreased relapse (5-year RR: 28% GO and HSCT 73% No-GO and HSCT, = .006). In multivariable analysis, GO was independently associated with improved EFS, improved DFS, and reduced RR.</p>

<p><strong>CONCLUSION: </strong>GO added to conventional chemotherapy improved outcomes for -r AML; consolidation with HSCT may further enhance outcomes. Future clinical trials should study CD33-targeted agents in combination with HSCT for pediatric r AML.</p>

DOI

10.1200/JCO.20.03048

Alternate Title

J Clin Oncol

PMID

34048275

Title

Acute erythroid leukemia is enriched in NUP98 fusions: a report from the Children's Oncology Group.

Year of Publication

2020

Number of Pages

6000-6008

Date Published

2020 Dec 08

ISSN Number

2473-9537

Abstract

<p>Acute erythroid leukemia (AEL) is a rare subtype of acute myeloid leukemia (AML) primarily affecting older adults and was previously classified into erythroid/myeloid and pure erythroid subtypes. In this pediatric AEL study, we evaluated morphologic, immunophenotypic, cytogenetic, molecular, and clinical data of 24 (1.2%) cases from all cases undergoing central pathology review in Children's Oncology Group trials AAML0531 and AAML1031. Of 24 cases, 5 had a pure erythroid phenotype, and 19 had an erythroid/myeloid phenotype. NUP98 fusions were highly enriched in patients with AEL, occurring in 7 of 22 cases for which molecular data were available (31.8% vs 6.7% in other AML subtypes). Of 5 cases of pure erythroid leukemias (PELs), 3 had NUP98 fusions, and 4 had complex karyotypes. Erythroid/myeloid leukemias were reclassified by using the 2017 World Health Organization hematopathology classification as: myelodysplastic syndrome (MDS) with excess blasts-1 (n = 3), MDS with excess blasts-2 (n = 7), AML (nonerythroid, n = 5), and unknown MDS/AML (n = 4); the 5 cases of nonerythroid AML included 1 with an NUP98-NSD1 fusion, 2 with myelodysplasia-related changes, and 1 with a complex karyotype. Three cases of MDS with excess blasts-2 also had NUP98 rearrangements. WT1 mutations were present in 5 of 14 cases, all erythroid/myeloid leukemia. Outcomes assessment revealed statistically poorer overall survival (5-year, 20% ± 36% vs 66% ± 23%; P = .004) and event-free survival (5-year, 20% ± 36% vs 46% ± 23%; P = .019) for those with PEL than those with erythroid/myeloid leukemia. Our study supports that AEL is a morphologically and genetically heterogeneous entity that is enriched in NUP98 fusions, with the pure erythroid subtype associated with particularly adverse outcomes.</p>

DOI

10.1182/bloodadvances.2020002712

Alternate Title

Blood Adv

PMID

33284945

Title

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

Year of Publication

2017

Number of Pages

JCO2016712513

Date Published

2017 Jun 23

ISSN Number

1527-7755

Abstract

<p>Purpose Gemtuzumab ozogamicin (GO), a CD33-targeted immunoconjugate, is a re-emerging therapy for acute myeloid leukemia (AML). CD33 single nucleotide polymorphism rs12459419 C&gt;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 &lt; 1.0E(-6)) and with lower diagnostic leukemic cell surface CD33 intensity ( P &lt; 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 &lt; .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.</p>

DOI

10.1200/JCO.2016.71.2513

Alternate Title

J. Clin. Oncol.

PMID

28644774

Title

Ethnic variation of TET2 SNP rs2454206 and association with clinical outcome in childhood AML: a report from the Children's Oncology Group.

Year of Publication

2015

Number of Pages

2424-6

Date Published

2015 Dec

ISSN Number

1476-5551

DOI

10.1038/leu.2015.171

Alternate Title

Leukemia

PMID

26126966

Title

Gemtuzumab Ozogamicin Reduces Relapse Risk in FLT3/ITD Acute Myeloid Leukemia: A Report from the Children's Oncology Group.

Year of Publication

2015

Date Published

2015 Dec 7

ISSN Number

1078-0432

Abstract

<p><strong>PURPOSE: </strong>Gemtuzumab ozogamicin (GO), a calicheamicin-conjugated mAb against CD33, has been used in the treatment of acute myeloid leukemia (AML). We evaluated the impact of the addition of GO to standard chemotherapy and hematopoietic stem cell transplant (HCT) in patients with FLT3/ITD.</p>

<p><strong>EXPERIMENTAL DESIGN: </strong>We analyzed children with FLT3/ITD-positive AML (n = 183) treated on two consecutive Children's Oncology Group AML trials (NCT00070174 and NCT00372593). Outcomes were assessed for FLT3/ITD patients receiving standard chemotherapy with or without GO (GO vs. No-GO, respectively), and the impact of consolidation HCT for high-risk FLT3/ITD patients [high FLT3/ITD allelic ratio (ITD-AR)].</p>

<p><strong>RESULTS: </strong>For all FLT3/ITD patients, complete remission (CR) rates for the GO versus No-GO cohorts were identical (64% vs. 64%; P = 0.98). Relapse rate (RR) after initial CR was 37% for GO recipients versus 59% for No-GO recipients (P = 0.02), disease-free survival (DFS) was similar (47% vs. 41%; P = 0.45), with higher treatment-related mortality (TRM) in GO recipients (16% vs. 0%; P = 0.008). Among high-risk FLT3/ITD patients with high ITD-AR, those who received HCT in first CR with prior exposure to GO had a significant reduction in RR (15% vs. 53%; P = 0.007), with a corresponding DFS of 65% versus 40% (P = 0.08), and higher TRM (19% vs. 7%; P = 0.08).</p>

<p><strong>CONCLUSIONS: </strong>CD33 targeting with HCT consolidation may be an important therapeutic strategy in high-risk FLT3/ITD AML and its efficacy and associated toxicity warrant further investigation. Clin Cancer Res; 1-7. ©2015 AACR.</p>

DOI

10.1158/1078-0432.CCR-15-1349

Alternate Title

Clin. Cancer Res.

PMID

26644412

Title

CD33 Expression and Its Association With Gemtuzumab Ozogamicin Response: Results From the Randomized Phase III Children's Oncology Group Trial AAML0531.

Year of Publication

2016

Number of Pages

747-55

Date Published

2016 Mar 1

ISSN Number

1527-7755

Abstract

<p><strong>PURPOSE: </strong>CD33 is variably expressed on acute myeloid leukemia (AML) blasts and is targeted by gemtuzumab ozogamicin (GO). GO has shown benefit in both adult and pediatric AML trials, yet limited data exist about whether GO response correlates with CD33 expression level.</p>

<p><strong>PATIENTS AND METHODS: </strong>CD33 expression levels were prospectively quantified by multidimensional flow cytometry in 825 patients enrolled in Children's Oncology Group AAML0531 and correlated with response to GO.</p>

<p><strong>RESULTS: </strong>Patients with low CD33 expression (lowest quartile of expression [Q1]) had no benefit with the addition of GO to conventional chemotherapy (relapse risk [RR]: GO 36% v No-GO 34%, P = .731; event-free survival [EFS]: GO 53% v No-GO 58%, P = .456). However, patients with higher CD33 expression (Q2 to Q4) had significantly reduced RR (GO 32% v No-GO 49%, P &lt; .001) and improved EFS (GO 53% v No-GO 41%, P = .005). This differential effect was observed in all risk groups. Specifically, low-risk (LR), intermediate-risk (IR), and high-risk (HR) patients with low CD33 expression had similar outcomes regardless of GO exposure, whereas the addition of GO to conventional chemotherapy resulted in a significant decrease in RR and disease-free survival (DFS) for patients with higher CD33 expression (LR RR, GO 13% v No-GO 35%, P = .001; LR DFS, GO 79% v No-GO 59%, P = .007; IR RR, GO 44% v No-GO 57%, P = .044; IR DFS, GO 51% v No-GO 40%, P = .078; HR RR, GO 40% v No-GO 73%, P = .016; HR DFS, GO 47% v No-GO 28%, P = .135).</p>

<p><strong>CONCLUSION: </strong>We demonstrate that GO lacks clinical benefit in patients with low CD33 expression but significantly reduces RR and improves EFS in patients with high CD33 expression, which suggests a role for CD33-targeted therapeutics in subsets of pediatric AML.</p>

DOI

10.1200/JCO.2015.62.6846

Alternate Title

J. Clin. Oncol.

PMID

26786921

Title

Concordance of copy number alterations using a common analytic pipeline for genome-wide analysis of Illumina and Affymetrix genotyping data: a report from the Children's Oncology Group.

Year of Publication

2015

Number of Pages

408-13

Date Published

07/2015

ISSN Number

2210-7762

Abstract

<p>Copy number alterations (CNAs) are a hallmark of pediatric cancer genomes. An increasing number of research groups use multiple platforms and software packages to detect and analyze CNAs. However, different platforms have experimental and analysis-specific biases that may yield different results. We sought to estimate the concordance of CNAs in children with de novo acute myeloid leukemia between two experimental platforms: Affymetrix SNP 6.0 array and Illumina OmniQuad 2.5 BeadChip. Forty-five paired tumor-remission samples were genotyped on both platforms, and CNAs were estimated from total signal intensity and allelic contrast values using the allele-specific copy number analysis of tumors (ASCAT) algorithm. The two platforms were comparable in detection of CNAs, each missing only two segments from a total of 42 CNAs (4.6%).&nbsp;Overall, there was an interplatform agreement of 96% for allele-specific tumor profiles. However, poor quality samples with low signal/noise ratios showed a high rate of false-positive segments independent of the genotyping platform. These results demonstrate that a common analytic pipeline can be utilized for SNP array data from these two platforms. The customized programming template for the preprocessing, data integration, and analysis is publicly available at https://github.com/AplenCHOP/affyLumCNA.</p&gt;

DOI

10.1016/j.cancergen.2015.04.010

Alternate Title

Cancer Genet

PMID

26163103

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