Risk-Adjusted Therapy of Acute Lymphoblastic Leukemia Can Decrease Treatment Burden and Improve Survival: Treatment Results of 2169 Unselected Pediatric and Adolescent Patients Enrolled in the Trial ALL-BFM 95.
Authors: Möricke Anja , Reiter Alfred , Zimmermann Martin , Gadner Helmut , Stanulla Martin , Ludwig Wolf-Dieter , Harbott Jochen , Mann Georg , Niggli Felix , Henze Günter , Welte Karl , Klingebiel Thomas , Niemeyer Charlotte , Zintl Felix , Riehm Hansjörg , Schrappe Martin 
Published: November 2019

Abstract
An unselected patient population of 2169 children with acute lymphoblastic leukemia (ALL) was enrolled in the multicenter trial ALL-BFM 95 of the Berlin-Frankfurt-Münster (BFM) study group. The study was designed to minimize acute and long-term toxicity through well-directed treatment reduction in a large patient subset with expectedly good prognosis. On the other hand extensive therapy intensification was implemented in a subgroup with very poor prognosis. The precondition was the clear definition of distinct risk groups enabled by a new risk stratification: patients (pts) with translocation t(9;22) and t(4;11), poor response to the cytoreductive prednisone prephase and/or to induction treatment were allocated to the high-risk (HR) group. Non-HR pts were stratified by age, white blood cell count (WBC) and immunophenotype to standard risk (SR, age 1–5 years, WBC <20 Gp/L, and no T-immunology) or medium risk (MR, all other pts). Compared to the previous trial ALL-BFM 90, the following treatment modifications were made in ALL-BFM 95: 1. reduction of the daunorubicin dose by 50% in induction in SR pts; 2. extension of maintenance by 12 months in SR boys; 3. in the MR group, randomized evaluation of intermediate-dose (ID) cytarabine in addition to high-dose methotrexate in the extracompartment/consolidation phase; 4. omission of preventive cranial radiotherapy (pCRT) in all MR pts with Non-T-ALL; 5. intensification of consolidation/reinduction in HR pts by dose increase in the block elements and reintroduction of protocol II as element providing a continuous drug exposure. Except for the randomized question, event-free survival was analyzed in comparison to the matching subsets of the historical control group treated in ALL-BFM 90. Estimated 6-year event-free survival (6y-pEFS) for the total group was 80±1% (median follow-up 7.3 years). The large SR group (35% of pts) achieved excellent 6y-pEFS of 89±1% despite significant reduction of the daunorubicin dose. The elongation of maintenance in boys yielded no significant relapse reduction. In MR (53% of pts), 6y-pEFS was 80±1%; no improvement was accomplished by the use of additional ID-cytarabine. Omission of pCRT in non-T-ALL MR pts was possible without reduction of EFS though the 6-year cumulative incidence of CNS relapses increased from 2.0±0.5% to 4.5±0.8%%. In the small HR group (12% of pts), treatment intensification led to considerable improvement over the previous ALL-BFM trials yielding a 6y-pEFS of 49±3%. Compared with the previous trial ALL-BFM 90, favorable results in SR and MR were firmly established despite significant treatment reduction in the majority of these patients.