Excellent Prognosis of Late Relapses of ETV6/RUNX1 Childhood Acute Lymphoblastic Leukemia: Lessons From the FRALLE 93 Protocol
Authors: Gandemer Virginie , Chevret Sylvie , Petit Arnaud , Vermylen Christiane , Leblanc Thierry , Michel Gerard , Schmitt Claudine , Lejars Odile , Vannier Jean-Pierre , Demeocq Francois , Bader-Meunier Brigitte , Bernaudin Francoise , Perel Yves , Auclerc Marie-Francoise , Cayuela Jean Michel , Leverger Guy , Baruchel Andre 
Published: October 2019

Abstract
Abstract 1508

Background.
The long term prognosis of ETV6/RUNX1 -positive acute lymphoblastic leukemia (ALL) remains to be evaluated with regard to the frequency of late relapses and the possible existence of a preleukemic stem cell. We performed a retrospective study based on a long-term follow up of the FRALLE 93 ALL relapses to address the issue of the outcome of ETV6/RUNX1 -positive ones.

Methods.
1395 patients aged 0 to 20 years with untreated ALL (except L3) were included between 01-Jan-1993 and 31-Dec-1999. From 1995, children were systematically screened for four fusion transcripts (ETV6-RUNX1, BCR-ABL, E2A-PBX1, MLL-AF4). The FRALLE 93 study population was stratified into three groups (low-risk [LR], intermediate-risk [IR], and high-risk [HR]) based on the following prognostic factors: age, white-cell count at diagnosis, haemoglobin level, immunophenotype, karyotype, and response to steroids. Patients received an initial treatment comprised of a prednisone prophase and a triple-drug intrathecal injection. Induction treatment then included prednisone, vincristine, L-asparaginase, daunorubicin (except for the LR group), and one or two more triple-drug intrathecal injections (TIT). The main treatment features of the SR and IR protocol were induction, consolidation, delayed intensification, and maintenance (total treatment duration of 26 and 38 months for girls and boys respectively). Treatment of the HR patients consisted of induction, consolidation, two delayed intensifications, and maintenance with a total treatment time of 2 years. Depending on subgroups, CNS-directed therapy included intrathecal injections +/− high-dose methotrexate +/− cranial irradiation. Following factors influencing survival after first relapse were analyzed: age, leukocytosis, gender, duration of first remission (CR1), risk groups defined in the REZ-BFM 95/96 study, sites of relapse and post CR2 consolidation treatment (AlloSCT or not).
Results. ETV6/RUNX1 status was defined for 724 patients B lineage ALL. Overall, 162 of the 713 children who reached CR1 (45 % of boys) relapsed, including 43 with t(12;21). Cumulative incidence of relapses did not differ between ETV6/RUNX1 -positive and negative ALL (p=0.94), with a 5-year estimate at 19.4% and 19.9%, respectively nor according to gender and type of relapse. Nevertheless, 11 out of 26 relapses in the ETV6/RUNX1 -positive ALL males (43%) were testicular (4 testis isolated) versus 16 out of 70 (23%) in ETV6/RUNX1 -negative ALL cases (p= 0.04). Thirty three (77%) had been stratified as LR (n=6) or IR (n=27) group and 32 displayed good early response at initial diagnosis. Thirty five (81.4%) patients were classified as S1/S2 and 8 (18.6%) as S3/S4. All but three received second line salvage therapy (37/40 were included in the COOPRALL 97) and 16 underwent an AlloSCT (6 S3/S4). Based on univariate analyses, the overall survival of ETV6-RUNX1 -positive ALL after relapse was significantly affected by the duration of the first remission with a OS that was significantly improved when relapse occurred after 36 months (5-year OS: 80.6+/−7.9% versus 34.7+/− 12.3, p=0.002). Female gender was also associated with a poor survival (p= 0.015), whereas the site of relapse (p= 0.13), age at initial diagnosis (p= 0.81), leukocytosis (p=0.42), and consolidation strategy (p=0.18) had no affect on survival. In multivariate Cox-regression analysis, only the duration of first remission remained associated with the outcome (Figure 1).

Conclusions.
We found a high rate of testicular relapse without any increase of other extramedullary sites and an excellent outcome for ETV6/RUNX1 -positive leukemia relapses occurring over 36 months post-diagnosis. These findings highlight the interest of a primary treatment able to cross the testicular barrier. They also support the hypothesis that ETV6/RUNX1 “late relapses” are due to a novel leukemic clone, sensitive to a novel cycle of ALL chemotherapy.

Disclosures:
No relevant conflicts of interest to declare.