First name
Alan
Middle name
S
Last name
Gamis

Title

Bortezomib is significantly beneficial for de novo pediatric AML patients with low phosphorylation of the NF-κB subunit RelA.

Year of Publication

2021

Number of Pages

e2100072

Date Published

2021 Nov 01

ISSN Number

1862-8354

Abstract

The addition of the proteasome inhibitor (PI) bortezomib to standard chemotherapy (ADE: cytarabine [Ara-C], daunorubicin and etoposide,) did not improve overall outcome in the Children's Oncology Group AAML1031 phase 3 randomized clinical trial (AAML1031). Bortezomib prevents protein degradation, including RelA via the intracellular NF-kB pathway. In this study, we hypothesized that subgroups of pediatric AML patients benefitting from standard therapy plus bortezomib (ADEB) could be identified based on pre-treatment RelA expression and phosphorylation status. RelA-total and phosphorylation at serine 536 (RelA-pSer ) levels were measured in 483 patient samples using reverse phase protein array technology. In ADEB-treated patients, low-RelA-pSer was favorably prognostic when compared to high-RelA-pSer (3-yr overall survival (OS): 81% vs. 68%, p = 0.032; relapse risk (RR): 30% vs. 49%, p = 0.004). RR in low-RelA-pSer patients significantly decreased in ADEB compared to ADE (RR: 30% vs. 44%, p = 0.035). Correlation between RelA-pSer and 295 other assayed proteins identified a strong correlation with HSF1-pSer , another protein previously identified as modifying ADEB response. The combination of low-RelA-pSer and low-HSF1-pSer was a significant predictor of ADEB response (3-yr OS: 86% vs. 67%, p = 0.013). Thus, bortezomib may improve clinical outcome in a subgroup of AML patients identified by low-RelA-pSer and low-HSF1-pSer . This article is protected by copyright. All rights reserved.

DOI

10.1002/prca.202100072

Alternate Title

Proteomics Clin Appl

PMID

34719869

Title

Morphologic remission status is limited compared to ΔN flow cytometry: a Children's Oncology Group AAML0531 report.

Year of Publication

2020

Number of Pages

5050-5061

Date Published

2020 Oct 27

ISSN Number

2473-9537

Abstract

Risk stratification for acute myeloid leukemia (AML) uses molecular and cytogenetic abnormalities identified at diagnosis. Response to therapy informs risk, and morphology continues to be used more frequently than flow cytometry. Herein, the largest cohort of pediatric patients prospectively assessed for measurable residual disease (MRD) by flow cytometry (N = 784) is reported. The "difference from normal" (ΔN) technique was applied: 31% of all patients tested positive (AML range, 0.02% to 91%) after the first course of treatment on Children's Oncology Group study AAML0531. Detection of MRD following initial chemotherapy proved the strongest predicator of overall survival (OS) in univariable and multivariable analyses, and was predictive of relapse risk, disease-free survival, and treatment-related mortality. Clearance of MRD after a second round of chemotherapy did not improve survival. The morphologic definition of persistent disease (>15% AML) failed 27% of the time; those identified as MRD- had superior outcomes. Similarly, for patients not achieving morphologic remission (>5% blasts), 36% of patients were MRD- and had favorable outcomes compared with those who were MRD+ (P < .001); hence an increase in myeloid progenitor cells can be favorable when ΔN classifies them as phenotypically normal. Furthermore, ΔN reclassified 20% of patients in morphologic remission as having detectable MRD with comparable poor outcomes. Retrospective analysis using the relapse phenotype as a template demonstrated that 96% of MRD- patients had <0.02% of the relapse immunophenotype in their end of induction 1 marrow. Thus, the detection of abnormal myeloid progenitor cells by ΔN is both specific and sensitive, with a high predictive signal identifiable early in treatment. This trial was registered at www.clinicaltrials.gov as #NCT00372593.

DOI

10.1182/bloodadvances.2020002070

Alternate Title

Blood Adv

PMID

33080007

Title

Clinical relevance of proteomic profiling in de novo pediatric acute myeloid leukemia: a Children's Oncology Group study.

Year of Publication

2022

Date Published

2022 Jan 13

ISSN Number

1592-8721

Abstract

<p>Pediatric acute myeloid leukemia (AML) remains a fatal disease for at least 30% of patients, stressing the need for improved therapies and better risk stratification. As proteins are the unifying feature of (epi)genetic and environmental alterations, and are often targeted by novel chemotherapeutic agents, we studied the proteomic landscape of pediatric AML. Protein expression and activation levels were measured in 500 bulk leukemic patient samples and 30 control CD34+ samples, using the reverse phase protein arrays with 296 strictly validated antibodies. The multi-step "MetaGalaxy" analysis methodology was applied and identified nine protein expression signatures (PrSIG), based on strong recurrent protein expression patterns. PrSIGs were associated with cytogenetics and mutational state, and with both favorable or unfavorable prognosis. Analysis based on treatment (i.e., ADE vs. ADE plus bortezomib (ADEB)) identified three PrSIGs that did better with ADEB vs. ADE. When PrSIGs were studied in the context of genetic subgroups, PrSIGs were independently prognostic after multivariate analysis, suggesting a potential value for proteomics in combination with current classification systems. Proteins with universally increased (n=7) or decreased (n=17) expression were observed across PrSIGs. Expression of certain proteins significantly differentially expressed from normal could be identified, forming a hypothetical platform for personalized medicine.</p>

DOI

10.3324/haematol.2021.279672

Alternate Title

Haematologica

PMID

35021602

Title

Adolescent and young adult (AYA) versus pediatric patients with acute leukemia have a significantly increased risk of acute GVHD following unrelated donor (URD) stem cell transplantation (SCT): the Children's Oncology Group experience.

Year of Publication

2022

Date Published

2022 Jan 06

ISSN Number

1476-5365

Abstract

<p>Adolescent and young adult (AYA) patients with acute leukemia (AL) have inferior outcomes in comparison to younger patients, and are more likely to develop acute and chronic GVHD than younger children following HLA matched sibling donor stem cell transplant (SCT). We compared the incidence of grade II-IV acute GVHD, chronic GVHD, and survival in AYA (age 13-21 years) to younger children (age 2-12 years) who received an unrelated donor SCT for acute leukemia on Children's Oncology Group trials between 2004-2017. One hundred and eighty-eight children and young adults ages 2-21 years underwent URD SCT. Sixty-three percent were aged 2-12 and 37% were age 13-21. Older age was a risk factor for grade II-IV acute GVHD in multivariate analysis with a hazard ratio (HR) of 1.95 [95% confidence interval (CI) 1.23-3.10], but not for chronic GVHD, HR 1.25 [95% CI 0.57-2.71]. Younger patients relapsed more often (34.5 ± 4.4% vs. 22.8 ± 4.0%, p = 0.032), but their Event-Free Survival (42.6 ± 4.7% vs. 51.8 ± 6.1%, p = 0.18) and Overall Survival at 5 years (48.5 ± 4.9% vs. 51.5 ± 6.4%, p = 0.56) were not different than AYA patients. AYA patients who receive an URD SCT for acute leukemia are significantly more likely to develop grade II-IV acute GVHD, though survival is similar.</p>

DOI

10.1038/s41409-021-01558-6

Alternate Title

Bone Marrow Transplant

PMID

34992254

Title

CBFB-MYH11 Fusion Transcripts Distinguish Acute Myeloid Leukemias with Distinct Molecular Landscapes and Outcomes.

Year of Publication

2021

Date Published

2021 Sep 21

ISSN Number

2473-9537

Abstract

<p>Patients with inv(16)/CBFB-MYH11 AML are considered favorable risk, however, nearly one-third relapse despite intensive therapy. Despite efforts to define risk groups within this favorable risk cohort, CBFB-MYH11 AML patients continue to be treated as a uniform cohort. Through transcriptome sequencing of 186 patients with inv(16) AML, we demonstrate that fusion junction breakpoints (exon 5-exon 33 versus other) are highly associated with outcome. The presence of exon 17 KIT mutations provides additional prognostic significance. Additionally, we provide insights into the transcriptional landscapes that differentiate these distinct CBFB-MYH11 AML subtypes. Children's Oncology Group trials include CCG-2961 (registered at www.clinicaltrials.gov as NCT00002798), AAML03P1 (NCT00070174), AAML0531 (NCT00372593), and AAML1031 (NCT01371981).</p>

DOI

10.1182/bloodadvances.2021004965

Alternate Title

Blood Adv

PMID

34547772

Title

Outcomes of intensification of induction chemotherapy for children with high-risk acute myeloid leukemia: A report from the Children's Oncology Group.

Year of Publication

2021

Number of Pages

e29281

Date Published

2021 Oct 01

ISSN Number

1545-5017

Abstract

<p><strong>BACKGROUND: </strong>High-risk pediatric acute myeloid leukemia confers a poor prognosis, and alternative strategies are needed to improve outcomes. We hypothesized that intensifying induction on the AAML1031 clinical trial would improve outcomes compared to the predecessor trial AAML0531.</p>

<p><strong>METHODS: </strong>Patients on AAML0531 received cytarabine (1600&nbsp;mg/m )/daunorubicin (150&nbsp;mg/m )/etoposide (ADE) for induction II and patients on AAML1031 received mitoxantrone (48&nbsp;mg/m )/cytarabine (8000&nbsp;mg/m ) (MA). Stem cell transplant (SCT) conditioning included busulfan/cyclophosphamide on AAML0531, whereas AAML1031 used busulfan/fludarabine and liberalized donor eligibility. Patients were included in this analysis if they met high-risk criteria common to the two trials by cytogenics or poor disease response after induction I ADE.</p>

<p><strong>RESULTS: </strong>MA provided no benefit over ADE at: induction II response (complete response [CR]: 64% vs. 62%, p&nbsp;=&nbsp;.87; measurable residual disease [MRD]+: 57% vs. 46%, p&nbsp;=&nbsp;.34); or intensification I response (CR: 79% vs. 94%, p&nbsp;=&nbsp;.27; MRD+: 27% vs. 20%, p&nbsp;=&nbsp;1.0). When considered with altered SCT approach, MA did not improve 5-year disease-free survival (24% ± 9% vs. 18% ± 15%, p&nbsp;=&nbsp;.63) or 5-year overall survival (35% ± 10% vs. 38% ± 18%, p&nbsp;=&nbsp;.66). MA was associated with slower neutrophil recovery (median 34 vs. 27&nbsp;days, p&nbsp;=&nbsp;.007) and platelet recovery (median 29 vs. 24.5&nbsp;days, p&nbsp;=&nbsp;.04) and longer hospital stay (32 vs. 28&nbsp;days, p&nbsp;=&nbsp;.01) during induction II.</p>

<p><strong>CONCLUSION: </strong>Intensification of induction II did not improve treatment response or survival, but did increase toxicity and resource utilization. Alternative strategies are urgently needed to improve outcomes for pediatric patients with high-risk acute myeloid leukemia (trials registered at clinicaltrials.gov NCT01371981, NCT00372593).</p>

DOI

10.1002/pbc.29281

Alternate Title

Pediatr Blood Cancer

PMID

34596937

Title

Survival Following Relapse in Children with Acute Myeloid Leukemia: A Report from AML-BFM and COG.

Year of Publication

2021

Date Published

2021 May 12

ISSN Number

2072-6694

Abstract

<p>Post-relapse therapy remains critical for survival in children with acute myeloid leukemia (AML). We evaluated survival, response and prognostic variables following relapse in independent cooperative group studies conducted by COG and the population-based AML-BFM study group. BFM included 197 patients who relapsed after closure of the last I-BFM relapse trial until 2017, while COG included 852 patients who relapsed on the last Phase 3 trials (AAML0531, AAML1031). Overall survival at 5 years (OS) was 42 ± 4% (BFM) and 35 ± 2% (COG). Initial high-risk features (BFM 32 ± 6%, COG 26 ± 4%) and short time to relapse (BFM 29 ± 4%, COG 25 ± 2%) predicted diminished survival. In the BFM dataset, there was no difference in OS for patients who had a complete remission with full hematopoietic recovery (CR) following post-relapse re-induction compared to those with partial neutrophil and platelet recovery (CRp and CRi) only (52 ± 7% vs. 63 ± 10%, = 0.39). Among 90 patients alive at last follow-up, 87 had received a post-relapse hematopoietic stem cell transplant (HSCT). OS for patients with post-relapse HSCT was 54 ± 4%. In conclusion, initial high-risk features and early relapse remain prognostic. Response assessment with full hematopoietic recovery following initial relapse therapy does not predict survival. These data indicate the need for post-relapse risk stratification in future studies of relapse therapies.</p>

DOI

10.3390/cancers13102336

Alternate Title

Cancers (Basel)

PMID

34066095

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

CEBPA bZip Mutations are Associated with Favorable Prognosis in de novo AML: A Report from the Children's Oncology Group.

Year of Publication

2021

Date Published

2021 May 05

ISSN Number

1528-0020

Abstract

<p>Bi-allelic CEBPA mutations are associated with favorable outcomes in AML. We evaluated the clinical and biologic implications of CEBPA-bZip mutations in childhood/young adult newly diagnosed AML. CEBPA-bZip mutation status was determined in 2,958 AML patients enrolled on COG trials (NCT00003790, NCT0007174, NCT00372593, NCT01379181). Next generation sequencing (NGS) was performed in 1,863 patients, 107 with CEBPA mutations, to characterize the co-occurring mutations. CEBPA mutational status was correlated with disease characteristics and clinical outcomes. CEBPA-bZip mutations were identified in 160/2958 (5.4%) patients, with 132 (82.5%) harboring a second CEBPA mutation (CEBPA-dm) and 28 (17.5%) with a single CEBPA-bZip only. The clinical and laboratory features of the two CEBPA cohorts were very similar. CEBPA-dm and CEBPA-bZip patients experienced identical event-free survival (EFS) of 64% and similar overall survival (OS) of 81% and 89%, respectively (p=0.259); this compared favorably to EFS and OS in CEBPA wild type (CEBPA-WT) of 46% and 61%, respectively (both p&lt;0.001). Transcriptome analysis demonstrated similar expression profiles for CEBPA-bZip and CEBPA-dm cases. Comprehensive NGS of CEBPA-mutant cases identified co-occurring CSF3R and GATA2 mutations in 13.1% and 21.5% of patients, respectively. Patients with dual CEBPA/CSF3R mutations had an EFS of 17% vs. 63% for CEBPA-mutant/CSF3R-WT (p&lt;0.001) with a corresponding relapse rate (RR) of 83% vs. 22%, respectively (p&lt;0.001); GATA2 co-occurrence did not impact outcome. CEBPA bZip domain mutations are associated with favorable clinical outcomes, regardless of mono or bi-allelic status. Co-occurring CSF3R and CEBPA mutations are associated with a high RR and nullifies the favorable prognostic impact of CEBPA mutations.</p>

DOI

10.1182/blood.2020009652

Alternate Title

Blood

PMID

33951732

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

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