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

2021

e29281

2021 Oct 01

1545-5017

<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>

10.1002/pbc.29281

Pediatr Blood Cancer

34596937

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

2021

2021 May 05

1528-0020

<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>

10.1182/blood.2020009652

Blood

33951732

Occurrence of Treatment-Related Cardiotoxicity and Its Impact on Outcomes Among Children Treated in the AAML0531 Clinical Trial: A Report From the Children's Oncology Group.

2018

JCO1800313

2018 Oct 31

1527-7755

<p><strong>PURPOSE: </strong>Late cardiotoxicity after pediatric acute myeloid leukemia therapy causes substantial morbidity and mortality. The impact of early-onset cardiotoxicity on treatment outcomes is less well understood. Thus, we evaluated the risk factors for incident early cardiotoxicity and the impacts of cardiotoxicity on event-free survival (EFS) and overall survival (OS).</p>

<p><strong>METHODS: </strong>Cardiotoxicity was ascertained through adverse event monitoring over the course of follow-up among 1,022 pediatric patients with acute myeloid leukemia treated in the Children's Oncology Group trial AAML0531. It was defined as grade 2 or higher left ventricular systolic dysfunction on the basis of Common Terminology Criteria for Adverse Events (version 3) definitions.</p>

<p><strong>RESULTS: </strong>Approximately 12% of patients experienced cardiotoxicity over a 5-year follow-up, with more than 70% of incident events occurring during on-protocol therapy. Documented cardiotoxicity during on-protocol therapy was significantly associated with subsequent off-protocol toxicity. Overall, the incidence was higher among noninfants and black patients, and in the setting of a bloodstream infection. Both EFS (hazard ratio [HR], 1.6; 95% CI, 1.2 to 2.1; P = .004) and OS (HR, 1.6; 95% CI, 1.2 to 2.2, P = .005) were significantly worse in patients with documented cardiotoxicity. Impacts on EFS were equivalent whether the incident cardiotoxicity event occurred in the absence (HR, 1.6; 95% CI, 1.1 to 2.2; P = .017) or presence of infection (HR, 1.6; 95% CI, 1.0 to 2.7; P = .069) compared with patients without documented cardiotoxicity. However, the reduction in OS was more pronounced for cardiotoxicity not associated with infection (HR, 1.7; 95% CI, 1.2 to 2.5; P = .004) than for infection-associated cardiotoxicity (HR, 1.3; 95% CI, 0.7 to 2.4; P = .387).</p>

<p><strong>CONCLUSION: </strong>Early treatment-related cardiotoxicity may be associated with decreased EFS and OS. Cardioprotective strategies are urgently needed to improve relapse risk and both short- and long-term mortality outcomes.</p>

10.1200/JCO.18.00313

J. Clin. Oncol.

30379624

Central nervous system disease in pediatric acute myeloid leukemia: A report from the Children's Oncology Group.

2017

2017 Apr 28

1545-5017

<p><strong>BACKGROUND: </strong>The prognostic impact of central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) has varied in past trials, and controversy exists over the degree of involvement requiring intensified CNS therapy. Two recent Children's Oncology Group protocols, AAML03P1 and AAML0531, directed additional intrathecal (IT) therapy to patients with CNS2 (≤5 white blood cell [WBC] with blasts) or CNS3 (&gt;5 WBC with blasts or CNS symptoms) disease at diagnosis.</p>

<p><strong>METHODS: </strong>We examined disease characteristics and outcomes of the 1,344 patients on these protocols, 949 with CNS1 (no blasts), 217 with CNS2, and 178 with CNS3, with the latter two receiving additional IT therapy.</p>

<p><strong>RESULTS: </strong>Young age (P = 0.003), hyperleukocytosis (P&nbsp;&lt; 0.001), and the presence of inversion 16 (P&nbsp;&lt; 0.001) were the only factors more prevalent in patients with CNS2 or CNS3 disease. Complete remission at the end of induction (EOI) 2 was achieved less often in patients with CNS involvement (P&nbsp;&lt; 0.001). From diagnosis, event-free survival (EFS) for patients with CNS involvement was significantly worse (P&nbsp;&lt; 0.001), whereas overall survival (OS) was not (P = 0.16). From the EOI1, there was a higher relapse rate (RR) and worse disease-free survival (DFS), but less impact on OS (CNS1:DFS 58.9%, RR 34.1%, OS 69.3%; CNS2:DFS 53.2%, RR 40.9%, OS 74.7%; CNS3:DFS 45.2%, RR 48.8%, OS 60.8%; P = 0.006, P&nbsp;&lt; 0.001, P = 0.045, respectively). Multivariable analysis showed that independently CNS2 and CNS3 status adversely affected RR and DFS. Traumatic diagnostic lumbar puncture was not associated with worse outcome.</p>

<p><strong>CONCLUSIONS: </strong>CNS leukemia confers greater relapse risk despite more aggressive locally directed therapy. Novel approaches need to be investigated in this group of patients.</p>

10.1002/pbc.26612

Pediatr Blood Cancer

28453910