Refining Risk Stratification in Relapsed Childhood B-Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common malignancy diagnosed in children. The survival rates of ALL have greatly improved throughout the past several decades thanks to research by cooperative working groups, with overall five-year survivals now approaching 90 percent — a true success story in medicine. Yet despite this increase in survival, conventional cytotoxic chemotherapy is relatively ineffective against certain high-risk (HR) ALL subtypes, including patients who suffer early bone marrow relapse. Additionally, even standard-risk (SR) patients still relapse. Recently, two large clinical trials of pediatric B-cell precursor ALL were studied systemically by the same group of investigators who demonstrated that integration of genetic and clinical risk factors enables improved patient stratification and outcome.

In their article, Dr. Anthony Moorman and colleagues integrated copy-number alteration (CNA) data from the eight most commonly deleted genes (IKZF1, CDKN2A/B, PAX5, EBF1, ETV6, BTG1, RB1, and PAR1) subordinately with established chromosomal abnormalities at initial diagnosis of B-ALL to develop a two-tier genetic classification by evaluating 809 ALL97/99 study patients and validated using 742 United Kingdom (UK) ALL2003 trial patients. Good-risk genetic features included ETV6-RUNX1, high hyperdiploidy, normal copy-number status for all eight genes, isolated deletions affecting ETV6/PAX5/BTG1, and ETV6 deletions with a single additional deletion of BTG1/PAX5/CDKN2A/B. All other genetic features were classified as poor risk. They found that 75 percent of UKALL2003 patients had a good-risk genetic profile and a significantly improved event-free survival (EFS; 94%) compared with patients with a poor-risk genetic profile (EFS of 79%), and they further identified a large subset of children suitable for treatment de-intensification.

Current risk stratification in B-ALL is primarily based on CR1 duration. In the article by Dr. Julie A.E. Irving and colleagues, the authors comprehensively evaluated the spectrum and frequency of chromosomal abnormalities, CNAs, and sequence mutations including key exons of the TP53, NRAS, KRAS, PTPN11, FLT3, and CBL genes, by analyzing cytogenetic data from 427 children with relapsed B-ALL treated on the international trial, ALLR3, and screened 238 patients with a marrow relapse for selected CNAs and mutations. Patients were assigned to three clinical risk groups (SR, intermediate-risk [IR], or HR) at relapse according to immunophenotype, site of relapse, and time to relapse, with shorter CR1, T-ALL, and marrow involvement linked to poor outcome after relapse. SR and IR were combined as “SR.” Cytogenetic testing at diagnosis and/or relapse was used to classify patients into three previously defined mutually exclusive cytogenetic risk groups: 1) good risk (CYTO-GR) — high hyperdiploidy (HeH) and ETV6-RUNX1; 2) IR (CYTO-IR) — TCF3-PBX1, IGH translocations, and B-other (none of these established abnormalities); and 3) HR (CYTO-HR) — BCR-ABL1, KMT2A (MLL) translocations, near haploidy, low hypodiploidy, iAMP21, TCF3-HLF. All of the 245 patients tested had concordant cytogenetic results at both diagnosis and at the time of marrow relapse.

This study demonstrated that cytogenetic risk groups were predictive of outcome postrelapse; survival rates at five years for patients with good risk, IR, and HR cytogenetics were 68 percent, 47 percent, and 26 percent, respectively (p<.001). The cytogenetic, CNA, and mutational profile of clinical SR and HR patients was distinctive (Figure). SR patients were enriched for ETV6-RUNX1, HeH, ETV6 and RB1 deletions, and PTPN11 mutations. In contrast, TCF3-PBX1, KMT2A translocations, haploidy, low hypodiploidy, TCF3-HLF, TP53 alterations, and NR3C1 deletions were more frequent among HR patients. CDKN2A/B, IKZF1, PAX5, and KRAS alterations were equally prevalent among SR and HR patients. The outcome of HR patients was universally poor, and none of the genetic alterations were associated with a superior outcome.

Among clinical SR patients, those with CYTO-GR and CYTO-HR had superior or inferior risks of progression/death compared with CYTO-IR patients, respectively. The most prevalent secondary abnormalities among SR patients were deletions or alterations of CDKN2A/B, IKZF1, and PAX5, which were not associated with response or outcome. TP53 mutations and 17p13 deletions occurred at an increased frequency in the CYTO-HR groups at initial diagnosis, and they were associated with a poor outcome at relapse. SR patients with a TP53 alteration also had an inferior outcome and an increased risk of death. NR3C1/BTG1 deletions were more common among cytogenetic and clinical HR patients and associated with an inferior outcome in both SR and HR groups, with the strongest effect in the HR group correlating with a high rate of induction failure and death. The good outcome of ETV6-RUNX1 and HeH was not adversely affected by ETV6 deletions and PTPN11 mutations. However, the presence of NRAS mutations was associated with a threefold increased risk of progression/death among SR HeH patients.

CYTO-HR patients had a uniformly poor outcome, with high rates of induction, failure/death, and second relapse, and they may benefit from alternative therapeutic strategies. The five-year progression-free and overall survival rates for SR patients with CYTO-HR were 25 percent (95% CI, 8%-46%) and 29 percent (95% CI, 9%-52%), respectively, which are almost identical to those of HR patients overall, and not different from those of CYTO-HR patients classified as HR. This is the first study examining the prognostic effect of CYTO-HR abnormalities by clinical risk group in relapsed ALL, and it indicates that all CYTO-HR patients should be treated on future HR protocols regardless of clinical risk stratification.