Integration of genomic and transcriptomic markers improves the prognosis prediction of acute promyelocytic leukemia

Purpose: The current stratification system for acute promyelocytic leukemia (APL) is based on the white blood cell (WBC) and the platelet counts (i.e., Sanz score) over the past two decades. However, the borderlines among different risk groups are sometimes ambiguous, and for some patients, early death and relapse remained challenges. Besides, with the evolving of the treatment strategy from ATRA-chemotherapy to ATRA-ATO-based synergistic targeted therapy, the precise risk stratification with molecular markers is needed. Patients and Methods: This study performed a systematic analysis of APL genomics and transcriptomics to identify genetic abnormalities in 348 patients mainly from the APL2012 trial (NCT01987297) to illustrate the potential molecular background of Sanz score and further optimize it. The least absolute shrinkage and selection operator (LASSO) algorithm was used to analyze the gene expression in 323 cases to establish a scoring system (i.e., APL9 score). Results: Through combining NRAS mutations, APL9 score with WBC, 321 cases can be stratified into two groups with significantly different outcomes. The estimated 5-year overall (P = 0.00031), event-free (P < 0.0001), and disease-free (P = 0.001) survival rates in the revised standard-risk group (95.6%, 93.8%, and 98.1%, respectively) were significantly better than those in the revised high-risk group (82.9%, 77.4%, and 88.4%, respectively), which could be validated using The Cancer Genome Atlas dataset. Conclusions: We have proposed a two-category system improving prognosis in APL patients. Molecular markers identified in this study may also provide genomic insights into the disease mechanism for improved therapy. A total of 348 APL patients (age 18-65 years; 54.3% males, 45.6% females) were included in an IRB-approved study, including a majority part of the patients (n = 304) coming from the APL2012 clinical trial (NCT01987297) from December 6, 2012 to December 31, 2017, and a small group of the patients (n = 44) from the historical cases between June 1, 2012 to November 31, 2012, who received the similar treatment. These above candidates were eligible to enter our study with available bone marrow (BM) samples containing blasts over 80%. Among the 348 cases, WES was applied to 202 cases and WGS to 2 cases for the detection of genomic abnormalities; 189 out of these 204 cases had their own matched control samples (complete remission BM samples). On the other hand, 323 cases were subject to RNA-seq for transcriptome analysis.