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Poor Outcome of Pediatric Patients with Acute Lymphoblastic Leukemia Harboring Low P16 Deletion Ratio: A Post-Hoc
Kun-Yin Qiu1,2, Xiong-Yu Liao1,2, Hai-Lei Chen2,3
1Department of Hematology/Oncology, Children's Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
Insights
P16 deletion ratio in pediatric acute lymphoblastic leukemia (ALL) significantly impacts survival. A threshold of 0.8 indicates a critical turning point for risk stratification and personalized therapy, especially when combined with MRD status.
Area of Science:
- Hematology
- Oncology
- Genetics
Background:
- The prognostic value of P16 (CDKN2A) deletion (P16del) in pediatric acute lymphoblastic leukemia (ALL) is debated, possibly due to simplified classification methods.
- Accurate prognostic markers are crucial for tailoring treatment intensity in pediatric ALL.
Purpose of the Study:
- To investigate the prognostic significance of P16 deletion (P16del) ratio in pediatric ALL.
- To identify a critical P16del ratio threshold for risk stratification.
- To assess the interaction between P16del ratio and minimal residual disease (MRD) in predicting outcomes.
Main Methods:
- Prospective cohort study of 413 pediatric ALL patients (SCCLG-ALL-2016 protocol).
- Quantification of P16del status and ratio using standardized FISH.
- Multivariable statistical models and piecewise linear regression to identify prognostic thresholds and assess survival outcomes (RFS, OS).
Main Results:
- P16del was an independent adverse prognostic factor (RFS HR=2.2, OS HR=2.7).
- A critical P16del ratio threshold of 0.8 was identified: ratios <0.8 increased relapse/death risk, while ratios ≥0.8 decreased risk.
- Outcomes were significantly worse for low P16del ratios (<0.8) compared to high ratios (≥0.8). MRD's prognostic impact was dependent on P16del ratio, with low ratios and MRD+ predicting poor outcomes.
Conclusions:
- The P16del ratio threshold of 0.8 may enable precision risk-adapted therapy in pediatric ALL.
- This threshold could refine prognostic assessment, particularly in conjunction with MRD status.
- Further validation in larger, diverse cohorts is necessary before clinical implementation.
Object:
The prognostic significance of P16 (CDKN2A) deletion (P16del ) in pediatric acute lymphoblastic leukemia (ALL) remains controversial, potentially due to the historical reliance on binary classification.
Methods:
In this prospective cohort study (SCCLG-ALL-2016 protocol), we analyzed 413 pediatric ALL patients. P16del status and ratio were quantified using standardized FISH. Statistical models adjusting for key prognostic factors were performed. Piecewise linear regression identified prognostic thresholds for P16del ratio. Survival outcomes (relapse-free survival, RFS; overall survival, OS) and interactions with minimal residual disease (MRD) were assessed.
Results:
P16del prevalence was 18.2% (75/413). Multivariable analysis confirmed P16del as an independent adverse prognostic factor (RFS: HR=2.2, p=0.020; OS: HR=2.7, p=0.024). Crucially, a nonlinear dose-response relationship identified 0.8 as the critical P16del ratio threshold: Below 0.8, each unit ratio increase conferred a 93% higher relapse/death risk (adjusted LogHR=1.93, p=0.031); above 0.8, higher ratios reduced risk by 33% (adjusted LogHR=0.67, p=0.048). Patients with low ratios (<0.8, n=37) had significantly inferior 5-year outcomes (RFS: 57.7%, OS: 72.2%) compared to high ratios (≥0.8, n=38; RFS: 88.5%, OS: 94.7%) (p<0.001). The prognostic impact of MRD was critically dependent on P16del ratio: Low ratio with D33 MRD+ predicted catastrophic outcomes (5-year RFS=27.8%), while high ratio patients maintained excellent survival regardless of MRD status (D33 MRD+ RFS=100%). High-ratio patients exhibited enrichment for RAS mutations (p=0.046).
Conclusion:
The identified P16 deletion ratio threshold of 0.8 may guide precision risk-adapted therapy in pediatric ALL, but its clinical utility must be validated in larger, diverse cohorts before implementation.
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