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

Medical Outcomes, Quality of Life, and Family Perceptions for Outpatient vs Inpatient Neutropenia Management After Chemotherapy for Pediatric Acute Myeloid Leukemia.

2021

e2128385

2021 Oct 01

2574-3805

<p><strong>Importance: </strong>Pediatric acute myeloid leukemia (AML) requires multiple courses of intensive chemotherapy that result in neutropenia, with significant risk for infectious complications. Supportive care guidelines recommend hospitalization until neutrophil recovery. However, there are little data to support inpatient over outpatient management.</p>

<p><strong>Objective: </strong>To evaluate outpatient vs inpatient neutropenia management for pediatric AML.</p>

<p><strong>Design, Setting, and Participants: </strong>This cohort study used qualitative and quantitative methods to compare medical outcomes, patient health-related quality of life (HRQOL), and patient and family perceptions between outpatient and inpatient neutropenia management. The study included patients from 17 US pediatric hospitals with frontline chemotherapy start dates ranging from January 2011 to July 2019, although the specific date ranges differed for the individual analyses by design and relative timing. Data were analyzed from August 2019 to February 2020.</p>

<p><strong>Exposures: </strong>Discharge to outpatient vs inpatient neutropenia management.</p>

<p><strong>Main Outcomes and Measures: </strong>The primary outcomes of interest were course-specific bacteremia incidence, times to next course, and patient HRQOL. Course-specific mortality was a secondary medical outcome.</p>

<p><strong>Results: </strong>Primary quantitative analyses included 554 patients (272 [49.1%] girls and 282 [50.9%] boys; mean [SD] age, 8.2 [6.1] years). Bacteremia incidence was not significantly different during outpatient vs inpatient management (67 courses [23.8%] vs 265 courses [29.0%]; adjusted rate ratio, 0.73; 95% CI, 0.56 to 1.06; P = .08). Outpatient management was not associated with delays to the next course compared with inpatient management (mean [SD] 30.7 [12.2] days vs 32.8 [9.7] days; adjusted mean difference, -2.2; 95% CI, -4.1 to -0.2, P = .03). Mortality during intensification II was higher for patients who received outpatient management compared with those who received inpatient management (3 patients [5.4%] vs 1 patient [0.5%]; P = .03), but comparable with inpatient management at other courses (eg, 0 patients vs 5 patients [1.3%] during induction I; P = .59). Among 97 patients evaluated for HRQOL, outcomes did not differ between outpatient and inpatient management (mean [SD] Pediatric Quality of Life Inventory total score, 70.1 [18.9] vs 68.7 [19.4]; adjusted mean difference, -2.8; 95% CI, -11.2 to 5.6). A total of 86 respondents (20 [23.3%] in outpatient management, 66 [76.7%] in inpatient management) completed qualitative interviews. Independent of management strategy received, 74 respondents (86.0%) expressed satisfaction with their experience. Concerns for hospital-associated infections among caregivers (6 of 7 caregiver respondents [85.7%] who were dissatisfied with inpatient management) and family separation (2 of 2 patient respondents [100%] who were dissatisfied with inpatient management) drove dissatisfaction with inpatient management. Stress of caring for a neutropenic child at home (3 of 3 respondents [100%] who were dissatisfied with outpatient management) drove dissatisfaction with outpatient management.</p>

<p><strong>Conclusions and Relevance: </strong>This cohort study found that outpatient neutropenia management was not associated with higher bacteremia incidence, treatment delays, or worse HRQOL compared with inpatient neutropenia management among pediatric patients with AML. While outpatient management may be safe for many patients, course-specific mortality differences suggest that outpatient management in intensification II should be approached with caution. Patient and family experiences varied, suggesting that outpatient management may be preferred by some but may not be feasible for all families. Further studies to refine and standardize safe outpatient management practices are warranted.</p>

10.1001/jamanetworkopen.2021.28385

JAMA Netw Open

34709389