Excellent Outcome for ETV6/RUNX1-Positive Childhood Acute Lymphoblastic Leukemia (ALL) with Contemporary Therapy
Authors: Bhojwani Deepa , Pei Deqing , Sandlund John , Jeha Sima , Ribeiro Raul C. , Rubnitz Jeffrey E. , Raimondi Susana C. , Shurtleff Sheila , Onciu Mihaela , Cheng Cheng , Coustan-Smith Elaine , Bowman W. Paul , Howard Scott C. , Metzger Monika L. , Inaba Hiroto , Leung Wing H. , Evans William E. , Campana Dario , Relling Mary V. , Pui Ching-Hon 
Published: October 2019

Abstract
Abstract 495
The t(12;21)(p13;q22) translocation causes the fusion of the ETV6 and RUNX1 genes and occurs in approximately 25% of cases of childhood B-precursor ALL. The presence of ETV6/RUNX1 has been associated with a lower rate of relapse in multiple studies. However, it is not clear whether the ETV6/RUNX1 fusion retains independent prognostic significance in the context of current risk-adapted therapy and whether the outcome of these children can be further improved.
We studied clinical features, treatment response and adverse events of 168 children with newly diagnosed ETV6/RUNX1-positive B-precursor ALL enrolled in St Jude Total Therapy studies XIIIA (1991-1994; N=36), XIIIB (1994-1998; N=38) and XV (2000-2007; N=94). Results were compared to those of 495 ETV6/RUNX1-negative patients with B-precursor ALL. Total XV study used levels of minimal residual disease (MRD) during treatment for risk assignment.
Presence of ETV6/RUNX1 was significantly related with age 1–9 years old (p<0.001), lower prevalence of central nervous system (CNS) disease at diagnosis (p<0.001) and classification as low-risk ALL (p<0.001). ETV6/RUNX1 patients had significantly lower rates of MRD positivity on day 19 (p<0.001) and day 46 of remission induction therapy (p=0.01) than non ETV6/RUNX1 patients. Event-free survival (EFS) did not differ between patients with or without ETV6/RUNX1 in Total XIIIA (p=0.14; 5-year EFS 86.1 ± 5.7% versus 75.6 ± 4.8%) or XIIIB (p=0.76; 5-year EFS 84.1 ± 6.8% versus 81.2 ± 3.8%). Likewise, overall survival (OS) did not differ among patients treated in either Total XIIIA (p=0.41; 5-year OS 88.9 ± 5.2% versus 83.3 ± 4.2%) or Total XIIIB (p=0.67; 86.5 ± 5.6% versus 85.0 ± 3.5). By contrast, patients with ETV6/RUNX1 ALL had significantly better EFS (p=0.008) and marginally better OS (p=0.057) than those without ETV6/RUNX1 in Total XV; 5-year EFS estimate was 97.6± 2.8% versus 86.0 ± 3.3% for patients without the fusion and 5-year OS was 98.9 ± 1.8% versus 93.3 ± 2.4%. Overall, among 168 patients with ETV6/RUNX1 ALL, there were 17 treatment failures, including 2 deaths in complete remission, 6 secondary malignancies (4 in Total XIIIA and 2 in Total XIIIB) and 9 relapses (6 hematologic, 1 combined hematologic and CNS and 2 isolated CNS relapses). Three relapses occurred during or within 6 months of completion of therapy while 6 occurred later. The median time to relapse was 38 months (range 6–139 months) as compared to 36.5 months (range 3–119 months) in ETV6/RUNX1-negative patients (p=0.28). In the most recent Total XV study, the only causes of treatment failure were 2 hematologic relapses. Within the ETV6/RUNX1 group, age, gender, race, presenting leukocyte count, CNS status, risk group and even MRD at day 19 and day 46 were not associated with 5-year EFS or OS. Only treatment protocol, i.e. Total XV (versus Total XIIIA or XIIIB) was significantly associated with improved EFS (p=0.03) and OS (p=0.04) (Figure 1). With the Total XV treatment strategy, conventional risk factors such as age and leukocyte count did not have prognostic significance among patients with ETV6/RUNX1-positive ALL. In this protocol, there were 5 ETV6/RUNX1 patients who were ≥10 years old and 17 who were 1–9 years old and had a leukocyte count ≥50 × 109/L at presentation with a good MRD decline (<1% on Day 19 and <0.01% on day 46). These patients received lower-risk therapy and none of them have relapsed to date. The Total XV regimen intensified asparaginase, dexamethasone (post-remission) and vincristine; drugs which are known to be especially cytotoxic to ETV6/RUNX1 lymphoblasts in vitro. Patients on Total XV might have also benefited from the higher doses of methotrexate administered during the consolidation phase, as ETV6/RUNX1 lymphoblasts accumulate lower amounts of methotrexate polyglutamates. In addition, measures such as avoiding cranial radiotherapy and limiting the use of epipodophyllotoxins and alkylating agents led to decreased adverse events like secondary malignancies for all patients.
In conclusion, stringent risk-directed therapy featuring intensive asparaginase, dexamethasone and high-dose methotrexate resulted in excellent outcome for children with ETV6/RUNX1 ALL.

Kaplan-Meier Estimates of EFS and OS in ETV6/RUNX1-positive Patients by Study.

Disclosure:
Bhojwani: MedImmune: Research Funding. Sandlund:Seattle Genetics: Research Funding. Jeha:Genzyme: Honoraria, Research Funding. Relling:St. Jude Children's Research Hospital: Employment, Patents & Royalties; Enzon Pharmaceuticals: Research Funding. Pui:EUSA Pharma: Honoraria; Enzon: Honoraria; Sanofi-Aventis: Honoraria.