Pediatric acute lymphoblastic leukemia: the missing pieces in risk and survival

Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer in pediatric oncology. About 80–85% of cases of ALL comprise B-cell lymphoblastic leukemia (B-cell ALL) or B-precursor ALL, and approximately 15% of cases are T-cell lymphoblastic leukemia [1]. Because of extensive laboratory and clinical research efforts, the cure rate for B-cell ALL has significantly improved over the last several decades to about 80–85%. Several known factors play key roles in risk stratification. Favorable prognostic factors include the age at presentation (greater than 1 year and less than 10 years of age), leukemia immunophenotype (precursor B-cell ALL), initial white blood cell (WBC) count (less than 50  109/L), no cerebral spinal fluid infiltrate at diagnosis (central nervous system [CNS] 1 disease), minimal residual disease status (MRD) post-induction therapy (less than 0.01% detectable blasts) and favorable genetic markers [trisomy 4, 10 and 17, ETV6-CBFA2/t(12;21)] [2–4]. To date, it is known that iAMP21, MLL gene rearrangements (11q23), hypodiploidy (fewer than 44 chromosomes), CNS 3 disease and Philadelphia chromosome t(9;22) are unfavorable prognostic factors [2]. However, predicting subtypes of patients who are at increased risk for relapse still remains a challenge. In this issue of Leukemia and Lymphoma, JuarezVelazquez et al. [5] report an increased rate of relapse in patients with a high WBC count, T-cell immunophenotype and a low gene expression of CASP8AP2. Patients with both lower CASP8AP2 and H2AFZ gene expression had the lowest relapse-free survival (RFS) and event-free survival (EFS). However, a low gene expression of CASP8AP2 and low WBC count was not sufficient to have a significant risk for relapse. A low H2AFZ was not statistically significant although it yielded low RFS [5]. Although the authors make a compelling argument, the study includes a small patient population and did not show an association with MRD status or CNS grade. Only a few patients had genetic alterations that play a significant role in prognosis, but results were not statistically significant [5]. The importance of CASP8AP2 and H2AFZ has been previously reported in several studies. For example, Flotho et al. found an association between low levels of CASP8AP2 with positive MRD on days 19 and 46, resulting in increased risk for relapse [6,7]. Jiao and colleagues showed similar results, with higher rates of bone marrow relapse and lower RFS with low levels of CASP8AP2, but no significant difference in overall survival (OS) [8]. The study by Juarez-Velazquez et al. further validates CASP8AP2 as a predictive marker of high-risk disease and suggests that H2AFZ, along with a high WBC count, is a poor prognostic factor [5]. As future studies continue to discover new gene expression patterns that impact relapse in pediatric ALL, such as deletions of IKZF1 and inherited GATA3 variants [9,10], the pieces to this puzzle will continue to unfold. With early detection by gene expression profiling, we will be able to detect genomic aberrations that can further stratify patients with ALL. These genetic alterations may help to guide future targeted therapies in order to improve the OS, EFS and RFS in high-risk groups.