Polygenic Ara-C Response Score Identifies Pediatric Patients With Acute Myeloid Leukemia in Need of Chemotherapy Augmentation.

2022

JCO2101422

2022 Jan 06

1527-7755

<p><strong>PURPOSE: </strong>To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment.</p>

<p><strong>MATERIALS AND METHODS: </strong>Single nucleotide polymorphisms (SNPs) in the ara-C-pathway genes were analyzed with outcome in patients from the multicenter-AML02 trial (N = 166). Multi-SNP predictor modeling was used to develop 10-SNP Ara-C_SNP score (ACS10) using top SNPs predictive of minimal residual disease and event-free survival (EFS) from the AML02-cohort and four SNPs previously associated with ara-C triphosphate levels in the AML97 trial. ACS10 was evaluated for association with outcomes in each clinical trial arms: the standard low-dose ara-C (LDAC, n = 91) and augmented high-dose ara-C (HDAC, n = 75) arms of AML02 and the standard Ara-C, daunorubicin and etoposide (ADE) (n = 465) and the augmented ADE + gemtuzumab ozogamicin (GO; n = 466) arms of AAML0531 trial.</p>

<p><strong>RESULTS: </strong>In the standard LDAC-arm of AML02 cohort, the low-ACS10 score group (≤ 0) had significantly worse EFS (ACS10 low high hazard ratio [HR] = 2.81; 95% CI, 1.45 to 5.43; = .002) and overall survival (OS; HR = 2.98; 95% CI, 1.32 to 6.75; = .009) compared with the high-ACS10 group (score &gt; 0). These results were validated in the standard-ADE arm of AAML0531, with poor outcome in the low-ASC10 group compared with the high-ACS10 group (EFS: HR = 1.35, 95% CI, 1.04 to 1.75, = .026; OS: HR = 1.64, 95% CI, 1.2 to 2.22, = .002). Within the augmented arms (AML02-HDAC and AAML0531-ADE + GO), EFS and OS did not differ between low- and high-ACS10 score groups. In both cohorts, patients with low-ACS10 consistently showed a 10-percentage point improvement in 5-year EFS with augmented therapy (AML02-HDAC or AAML0531-ADE + GO arms) than with standard therapy (AML02-LDAC or AAML0531-ADE arms).</p>

<p><strong>CONCLUSION: </strong>Patients with low-ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose ara-C or GO addition improved outcome in low-ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.</p>

10.1200/JCO.21.01422

J Clin Oncol

34990262

Cytarabine dose reduction in patients with low-risk acute myeloid leukemia: A report from the Children's Oncology Group.

2021

e29313

2021 Sep 02

1545-5017

<p><strong>BACKGROUND: </strong>The optimal number of chemotherapy courses for low-risk (LR) pediatric acute myeloid leukemia (AML) is not known.</p>

<p><strong>OBJECTIVE: </strong>To compare outcomes for four (21.6&nbsp;g/m cytarabine) versus five (45.6&nbsp;g/m cytarabine) chemotherapy courses for LR-AML using data from Children's Oncology Group (COG) AAML0531 and AAML1031.</p>

<p><strong>METHODS: </strong>We compared relapse risk (RR), disease-free survival (DFS), and overall survival (OS), and the differential impact in LR subgroups for patients receiving four versus five chemotherapy courses. Cox (OS and DFS) and risk (RR) regressions were used to estimate hazard ratios (HR) to compare outcomes.</p>

<p><strong>RESULTS: </strong>A total of 923 LR-AML patients were included; 21% received five courses. Overall, LR-AML patients who received four courses had higher RR (40.9% vs. 31.4%; HR&nbsp;=&nbsp;1.40, 95% confidence interval [CI]: 1.06-1.85), and worse DFS (56.0% vs. 67.0%; HR&nbsp;=&nbsp;1.45, 95% CI: 1.10-1.91). There was a similar decrement in OS though it was not statistically significant (77.0% vs. 83.5%; HR&nbsp;=&nbsp;1.45, 95% CI: 0.97-2.17). Stratified analyses revealed the detrimental effects of cytarabine dose de-escalation to be most pronounced in the LR-AML subgroup with uninformative cytogenetic/molecular features who were minimal residual disease (MRD) negative after the first induction course (EOI1). The absolute decrease in DFS with four courses for patients with favorable cytogenetic/molecular features and positive MRD was similar to that observed for patients with uninformative cytogenetic/molecular features and negative MRD at EOI1, though not statistically significant.</p>

<p><strong>CONCLUSIONS: </strong>Our results support de-escalation of cytarabine exposure through the elimination of a fifth chemotherapy course only for LR-AML patients who have both favorable cytogenetic/molecular features and negative MRD after the first induction cycle.</p>

10.1002/pbc.29313

Pediatr Blood Cancer

34472213

Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group.

2020

2020 Feb 06

1592-8721

<p>New therapeutic strategies are needed for pediatric acute myeloid leukemia to reduce disease recurrence and treatment-related morbidity. The Children's Oncology Group Phase III AAML1031 trial tested whether the addition of bortezomib to standard chemotherapy improves survival in pediatric patients with newly diagnosed acute myeloid leukemia. AAML1031 randomized patients younger than 30 years of age with de novo acute myeloid leukemia to standard treatment with or without bortezomib. All patients received the identical chemotherapy backbone with either four intensive chemotherapy courses or three courses followed by allogeneic hematopoietic stem cell transplantation for high-risk patients. For those randomized to the intervention arm, bortezomib 1.3 mg/m2 was given on days 1, 4 and 8 of each chemotherapy course. For those randomized to the control arm, bortezomib was not administered. In total, 1097 patients were randomized to standard chemotherapy (n=542) or standard chemotherapy with bortezomib (n=555). Remission induction rate did not differ between bortezomib and control treatment arms (89% vs 91%, p=0.531). Bortezomib failed to improve three-year event-free survival (44.8+/-4.5% vs 47.0+/-4.5%, p=0.236) or overall survival (63.6+/-4.5 vs 67.2+/-4.3, p=0.356) compared with the control arm. However, bortezomib was associated with significantly more peripheral neuropathy (p=0.006), and intensive care unit admissions (p=0.025) during the first course. The addition of bortezomib to standard chemotherapy increased toxicity but did not improve survival. These data do not support the addition of bortezomib to standard chemotherapy in children with de novo acute myeloid leukemia. (NCT01371981; https://www.cancer.gov/clinicaltrials/NCT01371981).</p>

10.3324/haematol.2019.220962

Haematologica

32029509

Functional Properties of KIT Mutations are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia.

2019

2019 Jun 10

1078-0432

<p><strong>PURPOSE: </strong> mutations (+) are common in core binding factor (CBF) AML and have been associated with varying prognostic significance. We sought to define the functional and clinical significance of distinct mutations in CBF pediatric AML.</p>

<p><strong>EXPERIMENTAL DESIGN: </strong>Following transfection of exon 17 (E17) and exon 8 (E8) mutations into HEK293 and Ba/F3 cells, KIT phosphorylation, cytokine independent growth, and response to tyrosine kinase inhibitors (TKI) were evaluated. Clinical outcomes of patients treated on COG AAML0531 (NCT01407757), a phase III study of gemtuzumab ozogamicin (GO), were analyzed according to mutation status (+ vs wild type (-)) and mutation location (E8 vs. E17).</p>

<p><strong>RESULTS: </strong> mutations were detected in 63/205(31%) patients; 22 (35%) involved only E8, 32(51%) only E17, 6(10%) both exons, and 3(5%) alternative exons. Functional studies demonstrated that E17, but not E8, mutations result in aberrant KIT phosphorylation and growth. TKI exposure significantly impacted growth of E17, but not E8, transfected cells. + CBF AML patients had comparable overall survival (OS) to that of - (78%, vs. 81%, p=0.905) but higher relapse rates (RR 43% vs. 21%, p=0.005). E17 + outcomes were inferior to patients [disease free survival (DFS) 51% vs. 73%, p=0.027; RR 21% vs. 46%, p=0.007)] although GO abrogated this negative prognostic impact. E8 mutations lacked significant prognostic impact and GO failed to significantly improve outcome.</p>

<p><strong>CONCLUSIONS: </strong>E17 mutations impact prognosis in CBF AML, as well as response to GO and TKIs, thus clinical trials utilizing both agents should be considered for + patients.</p>

10.1158/1078-0432.CCR-18-1897

Clin. Cancer Res.

31182436

ABCB1 SNP predicts outcome in patients with acute myeloid leukemia treated with Gemtuzumab ozogamicin: a report from Children's Oncology Group AAML0531 Trial.

2019

51

2019 May 21

2044-5385

<p>Gemtuzumab-ozogamicin (GO), a humanized-anti-CD33 antibody linked with the toxin-calicheamicin-γ is a reemerging and promising drug for AML. Calicheamicin a key element of GO, induces DNA-damage and cell-death once the linked CD33-antibody facilitates its uptake. Calicheamicin efflux by the drug-transporter PgP-1 have been implicated in GO response thus in this study, we evaluated impact of ABCB1-SNPs on GO response. Genomic-DNA samples from 942 patients randomized to receive standard therapy with or without addition of GO (COG-AAML0531) were genotyped for ABCB1-SNPs. Our most interesting results show that for rs1045642, patients with minor-T-allele (CT/TT) had better outcome as compared to patients with CC genotype in GO-arm (Event-free survival-EFS: p = 0.022; and risk of relapse-RR, p = 0.007). In contrast, no difference between genotypes was observed for any of the clinical endpoints within No-GO arm (all p &gt; 0.05). Consistent results were obtained when genotype groups were compared by GO and No-GO arms. The in vitro evaluation using HL60-cells further demonstrated consistent impact of rs1045642-T-allele on calicheamicin induced DNA-damage and cell-viability. Our results show the significance of ABCB1 SNPs on GO response in AML and warrants the need to investigate this in other cohorts. Once validated, ABCB1-SNPs in conjunction with CD33-SNPs can open up opportunities to personalize GO-therapy.</p>

10.1038/s41408-019-0211-y

Blood Cancer J

31113932

Genomic architecture and treatment outcome in pediatric acute myeloid leukemia: a Children's Oncology Group report.

2017

3051-8

2017 Jun

1528-0020

<p>Childhood acute myeloid leukemia (AML) is frequently characterized by chromosomal instability. Approximately 50% of patients have disease relapse, and novel prognostic markers are needed to improve risk stratification. We performed genome-wide genotyping in 446 pediatric patients with de novo AML enrolled on Children's Oncology Group (COG) studies, AAML0531 (NCT01407757), AAML03P1 (NCT00070174), and CCG2961 (NCT00003790). Affymetrix and Illumina Omni 2.5 platforms were used to evaluate copy number alterations (CNAs) and determine their associations with treatment outcome. Data from Affymetrix and Illumina studies were jointly analyzed with ASCAT and GISTIC software. An average of 1.14 somatically acquired CNAs per patient were observed. Novel reoccurring altered genomic regions were identified, and the presence of CNAs was found to be associated with decreased 3-year overall survival (OS), event-free survival (EFS), and relapse risk from the end of induction I (HR 1.7, 95%CI 1.2-2.4, HR 1.4, 95%CI 1.0-1.8, and HR 1.4, 95%CI 1.0-2.0, respectively). Analyses by risk group demonstrated decreased OS and EFS in the standard risk group only (HR 1.9, 95%CI 1.1-3.3, and HR 1.7, 95%CI 1.1-2.6, respectively). Further studies are required to test the prognostic significant of CNA presence in disease relapse in AML patients.</p>

10.1182/blood-2017-03-772384

Blood

28411282

Disease Characteristics and Prognostic Implications of Cell Surface FLT3 Receptor (CD135) Expression in Pediatric Acute Myeloid Leukemia: A Report from the Children's Oncology Group.

2017

2017 Jan 20

1078-0432

<p><strong>PURPOSE: </strong>The FLT3 cell-surface receptor tyrosine kinase (CD135) is expressed in a majority of both acute lymphoid leukemia (ALL) and myeloid leukemia (AML). However, the prognostic significance of CD135 expression in AML remains unclear. We therefore evaluated the association between FLT3 surface expression and disease characteristics and outcomes in pediatric patients with AML.</p>

<p><strong>EXPERIMENTAL DESIGN: </strong>We analyzed FLT3 receptor expression on AML blasts by multi-dimensional flow cytometry and its association with disease characteristics, clinical outcomes, and FLT3 transcript level in 367 children with AML treated on the Children's Oncology Group trial AAML0531.</p>

<p><strong>RESULTS: </strong>There was high variability in blast CD135 cell-surface expression across specimens. CD135 expression measure by flow cytometry was not correlated with FLT3 transcript expression determined by quantitative RT-PCR. Overall, CD135 expression was not significantly different for patients with FLT3/WT and those with FLT3/ITD and FLT3/ALM (p=0.25). High cell-surface CD135 expression was associated with FAB M5 subtype (p&lt;0.001), KMT2A rearrangements (p=0.009) and inversely associated with inv(16)/t(16;16) (p&lt; 0.001). Complete remission rate, overall survival, disease-free survival, and relapse rates were not significantly different between patients with low and high CD135 expression.</p>

<p><strong>CONCLUSIONS: </strong>FLT3 cell-surface expression did not vary by FLT3 mutational status, but high FLT3 expression was strongly associated with KMT2A rearrangements. Our study found that there was no prognostic significance of FLT3 expression in pediatric AML.</p>

10.1158/1078-0432.CCR-16-2353

Clin. Cancer Res.

28108543