First name
Todd
Middle name
M
Last name
Cooper

Title

Blood Count Recovery Following Induction Therapy for Acute Myeloid Leukemia in Children Does Not Predict Survival.

Year of Publication

2022

Number of Pages

Date Published

2022 Jan 26

ISSN Number

2072-6694

Abstract

<p>International Working Group (IWG) and European LeukemiaNet (ELN) response definitions are utilized to evaluate the efficacy of new agents for childhood acute myeloid leukemia (AML) for regulatory purposes. However, these criteria are not consistent with definitions used in pediatric AML trials or with standard pediatric practice to proceed with subsequent therapy cycles prior to IWG/ELN-defined count recovery. We retrospectively analyzed data from the two most recent Phase 3 pediatric AML clinical trials conducted by the Children's Oncology Group (COG) to assess the incidence, timing, and prognostic significance of count recovery following induction chemotherapy. Of the patients with fewer than 5% bone marrow blasts at the end of first induction, 21.5% of patients proceeded to a second induction cycle prior to achieving ANC ≥ 500 cells/μL and platelets ≥ 50,000 cells/μL, both well below the IWG/ELN thresholds of ANC &gt; 1000 cells/μL and platelets &gt; 100,000 cells/μL. In these two sequential childhood AML Phase 3 trials, neither ANC nor platelet recovery predicted survival. Intensification of treatment through the initiation of subsequent therapy cycles prior to attainment of IWG/ELN-defined CR is common practice in clinical trials for children with AML, suggesting that updated response definitions are needed for pediatric AML.</p>

DOI

10.3390/cancers14030616

Alternate Title

Cancers (Basel)

PMID

35158884
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Title

CD123 Expression Is Associated With High-Risk Disease Characteristics in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group.

Year of Publication

2021

Number of Pages

JCO2101595

Date Published

2021 Dec 02

ISSN Number

1527-7755

Abstract

<p><strong>PURPOSE: </strong>Increased CD123 surface expression has been associated with high-risk disease characteristics in adult acute myeloid leukemia (AML), but has not been well-characterized in childhood AML. In this study, we defined CD123 expression and associated clinical characteristics in a uniformly treated cohort of pediatric patients with newly diagnosed AML enrolled on the Children's Oncology Group AAML1031 phase III trial (NCT01371981).</p>

<p><strong>MATERIALS AND METHODS: </strong>AML blasts within diagnostic bone marrow specimens (n = 1,040) were prospectively analyzed for CD123 protein expression by multidimensional flow cytometry immunophenotyping at a central clinical laboratory. Patients were stratified as low-risk or high-risk on the basis of (1) leukemia-associated cytogenetic and molecular alterations and (2) end-of-induction measurable residual disease levels.</p>

<p><strong>RESULTS: </strong>The study population was divided into CD123 expression-based quartiles (n = 260 each) for analysis. Those with highest CD123 expression (quartile 4 [Q4]) had higher prevalence of high-risk rearrangements and -ITD mutations ( &lt; .001 for both) and lower prevalence of low-risk t(8;21), inv(16), and mutations ( &lt; .001 for all). Patients in lower CD123 expression quartiles (Q1-3) had similar relapse risk, event-free survival, and overall survival. Conversely, Q4 patients had a significantly higher relapse risk (53% 39%, &lt; .001), lower event-free survival (49% 69%, &lt; .001), and lower overall survival (32% 50%, &lt; .001) in comparison with Q1-3 patients. CD123 maintained independent significance for outcomes when all known contemporary high-risk cytogenetic and molecular markers were incorporated into multivariable Cox regression analysis.</p>

<p><strong>CONCLUSION: </strong>CD123 is strongly associated with disease-relevant cytogenetic and molecular alterations in childhood AML. CD123 is a critical biomarker and promising immunotherapeutic target for children with relapsed or refractory AML, given its prevalent expression and enrichment in patients with high-risk genetic alterations and inferior clinical outcomes with conventional therapy.</p>

DOI

10.1200/JCO.21.01595

Alternate Title

J Clin Oncol

PMID

34855461
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Title

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

Year of Publication

2021

Number of Pages

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
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Title

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

Year of Publication

2021

Number of Pages

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
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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

Number of Pages

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
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Title

Phase I/II Study of CPX-351 Followed by Fludarabine, Cytarabine, and Granulocyte-Colony Stimulating Factor for Children With Relapsed Acute Myeloid Leukemia: A Report From the Children's Oncology Group.

Year of Publication

2020

Number of Pages

JCO1903306

Date Published

2020 May 13

ISSN Number

1527-7755

Abstract

<p><strong>PURPOSE: </strong>Effective regimens are needed for children with relapsed acute myeloid leukemia (AML). AAML1421 is a phase I/II study of CPX-351, a liposomal preparation of daunorubicin and cytarabine. AAML1421 sought to determine the recommended phase II dose (RP2D) of CPX-351 and the response rate after up to 2 cycles of therapy.</p>

<p><strong>PATIENTS AND METHODS: </strong>Children &gt; 1 and ≤ 21 years of age with relapsed/refractory AML were eligible for dose finding; those in first relapse were eligible for the efficacy phase. Dose-limiting toxicity (DLT) assessment occurred during cycle 1. Two cycles of therapy were offered (cycle 1: CPX-351; cycle 2: FLAG [fludarabine 30 mg/m/dose on days 1-5; cytarabine 2,000 mg/m/dose on days 1-5; and granulocyte-colony stimulating factor 5 µg/kg/dose, days 1-5 and day 15 through absolute neutrophil count &gt; 500/µL]). Response was assessed after each cycle.</p>

<p><strong>RESULTS: </strong>Thirty-eight patients enrolled: 6 in the dose-finding phase and 32 in the efficacy phase. During dose finding, 1/6 patients experienced a DLT (grade 3 decrease in ejection fraction). The RP2D was 135 units/m on days 1, 3, and 5. Toxicities of grade ≥ 3 during cycle 1 included fever/neutropenia (45%), infection (47%), and rash (40%). There was no toxic mortality. Best responses included 20 complete response (CR; 54%), 5 CR with partial recovery of platelet count (CRp; 14%), and 5 CR with incomplete blood count recovery (14%). Twenty-one of 25 with CR/CRp had no detectable residual disease (RD; 84%) by flow cytometry. Hematopoietic stem cell transplantation (HSCT) was used as consolidation in 29/30 responders (96.7%); 20/25 (80%) had no RD before HSCT.</p>

<p><strong>CONCLUSION: </strong>The RP2D of CPX-351 is 135 units/m/dose on days 1, 3, and 5. Toxicity was manageable, and protocol therapy was effective. Response rates are superior to prior published North American cooperative group clinical trials for children with AML in first relapse.</p>

DOI

10.1200/JCO.19.03306

Alternate Title

J. Clin. Oncol.

PMID

32401633
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Title

Effect of Dexrazoxane on Left Ventricular Systolic Function and Treatment Outcomes in Patients With Acute Myeloid Leukemia: A Report From the Children's Oncology Group.

Year of Publication

2020

Number of Pages

JCO1902856

Date Published

2020 Apr 28

ISSN Number

1527-7755

Abstract

<p><strong>PURPOSE: </strong>To determine whether dexrazoxane provides effective cardioprotection during frontline treatment of pediatric acute myeloid leukemia (AML) without increasing relapse risk or noncardiac toxicities of the chemotherapy regimens.</p>

<p><strong>PATIENTS AND METHODS: </strong>This was a multicenter study of all pediatric patients with AML without high allelic ratio FLT3/ITD treated in the Children's Oncology Group trial AAML1031 between 2011 and 2016. Median follow-up was 3.5 years. Dexrazoxane was administered at the discretion of treating physicians and documented at each course. Ejection fraction (EF) and shortening fraction (SF) were recorded after each course and at regular intervals in follow-up. Per protocol, anthracyclines were to be withheld if there was evidence of left ventricular systolic dysfunction (LVSD) defined as SF &lt; 28% or EF &lt; 55%. Occurrence of LVSD, trends in EF and SF, 5-year event-free survival (EFS) and overall survival (OS), and treatment-related mortality (TRM) were compared by dexrazoxane exposure.</p>

<p><strong>RESULTS: </strong>A total of 1,014 patients were included in the analyses; 96 were exposed to dexrazoxane at every anthracycline course, and 918 were never exposed. Distributions of sex, age, race, presenting WBC count, risk group, treatment arm, and compliance with cardiac monitoring were similar for dexrazoxane-exposed and -unexposed patients. Dexrazoxane-exposed patients had significantly smaller EF and SF declines than unexposed patients across courses and a lower risk for LVSD (26.5% 42.2%; hazard ratio, 0.55; 95% CI, 0.36 to 0.86; = .009). Dexrazoxane-exposed patients had similar 5-year EFS (49.0% 45.1%; = .534) and OS (65.0% 61.9%; = .613) to those unexposed; however, there was a suggestion of lower TRM with dexrazoxane (5.7% 12.7%; = .068).</p>

<p><strong>CONCLUSION: </strong>Dexrazoxane preserved cardiac function without compromising EFS and OS or increasing noncardiac toxicities. Dexrazoxane should be considered for cardioprotection during frontline treatment of pediatric AML.</p>

DOI

10.1200/JCO.19.02856

Alternate Title

J. Clin. Oncol.

PMID

32343641
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