Low CNS Relapse Incidence without Radiotherapy and Improvement of Outcome: Results of Subsequent EORTC-CLG 58881 and 58951 Trials in Pediatric T-Cell Acute Lymphoblastic Leukemia (ALL)
Authors: De Moerloose Barbara , Suciu Stefan , Ferster Alina , Mazingue Françoise , Sirvent Nicolas , Costa Vitor , Yakouben Karima , Lutz Patrick , Uyttebroeck Anne , Plantaz Dominique , Plat Geneviève , Millot Frédéric , Rohrlich Pierre , Poiree Maryline , Van der Werff Ten Bosch Jutte , Hoyoux Claire , Boutard Patrick , Cavé Hélène , Girard Sandrine , Sirvent Francisco Bautista , Benoit Yves , Bertrand Yves 
Published: October 2019

Abstract
Abstract 133

Background:
T-cell acute lymphoblastic leukemia (ALL) accounts for 15% of ALL cases in children and has been associated with a higher risk for central nervous system (CNS) relapse and a worse prognosis. In EORTC trials 58831 and 2, standard risk (SR) patients (pts) were not irradiated but received intermediate dose methotrexate (MTX) courses; for medium and high risk pts, high dose (HD) MTX was added to the treatment regimen and the administration of cranial radiotherapy (RT) was randomised. The omission of RT didn't result in an increase of CNS or systemic relapse and consequently, CNS-directed chemotherapy was substituted for RT in all following trials. The long-term outcome of T-ALL pts in the subsequent phase III trials (58881 and 58951) are presented here.

Methods:
The BFM backbone for ALL treatment was applied to all EORTC-CLG trials since 1983. As CNS treatment in study 58881, SR pts received 4 HD MTX courses (5 g/m2) in interval therapy and 10 IT MTX injections during the intensive treatment phases. Pts with CNS-3 status at diagnosis received 2 additional IT injections during induction, 2 during consolidation and 6 HD MTX courses + IT during maintenance. T-ALL pts with poor prephase response (PPR) at day 8 or who didn't achieve complete remission (CR) after induction were included in the very high risk (VHR) group. VHR CNS-directed chemotherapy included 10 IT MTX injections, 6 IT triple and 10 HD MTX courses during intensive treatment phases, followed by 4 IT MTX injections during maintenance (the latter for CNS-3 pts only). In the 58951 trial, all T-ALL pts had an intensified induction. The CNS-directed therapy of all average risk T-ALL pts was intensified to 11 HD MTX courses, 1 IT with MTX and 15 triple IT. MRD ≥ 1% at the end of induction was added as VHR criterium. All non-transplanted VHR pts received 1 IT MTX injection, 19 IT triple and 9 HD MTX courses. Several randomized questions were addressed in both trials of which most relevant for T-ALL pts: in study 58881 the comparison E.coli asparaginase (ASP) Medac versus (vs) “other ASP” (= Erwinia ASP or E.coli ASP Bayer); in trial 58951 1) the comparison dexamethasone (DEX 6 mg/m2/d) vs prednisolone (PRED 60 mg/m2/d) in induction and 2) conventional vs prolonged E.coli ASP for non-VHR pts.

Results:
303 and 296 T-ALL pts were included in trials 58881 and 58951 resp, representing 14.5% and 15.2% of all pts. Outcome results and type of events for the entire 58881 and 58951 cohorts and according to several subgroups are presented in the table. The 8-year isolated and overall CNS relapse incidences were 6.8% and 10.9% in study 58881, 5.3% and 8.5% in study 58951. The 8-year EFS, DFS and OS improved remarkably in study 58951. In the latter trial, outcome improvement was particularly seen in pts with initial WBC<100x10E9/L and in the good prephase responders (GPR) which had a significant better outcome than those with PPR. 58881 pts assigned to the “other ASP” arm had an inferior outcome. Concerning the DEX/PRED comparison in the 58951 T-ALL cohort, no advantage was seen for EFS (hazard ratio (HR) (99%CI): 1.26 (0.70;2.27)) or OS. There even was a trend towards worse EFS for pts with initial WBC>100x10E9/L and for pts with PPR treated in the DEX arm (HR (99%CI): 1.52 (0.63;3.64) and 1.47 (0.64;3.35)). Prolonged ASP treatment did not improve outcome of the whole T-ALL 58951 cohort.

Conclusion:
Prophylactic and therapeutic RT can safely be omitted from frontline treatment of children with T-ALL. Adequate ASP therapy, intensified induction treatment and CNS directed therapy can result in a significant improvement of the outcome of at least 2/3rd of T-ALL pts, particularly those with initial WBC<100x10E9/L and GPR.

Disclosures:
No relevant conflicts of interest to declare.