title: Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90.
abstract: OBJECTIVE
  The multicenter trial ALL-REZ BFM (ie, Acute Lymphoblastic Leukemia Relapse Berlin-Frankfurt-Münster) 90 was designed to improve prognosis for children with relapsed acute lymphoblastic leukemia (ALL) by time-to-relapse- and site-of-relapse-adapted stratification and by introduction of novel chemotherapy elements and to evaluate new prognostic parameters in a large, population-based cohort.
  
  
  METHODS
  Five hundred twenty-five patients stratified into risk groups A (early bone marrow [BM] relapses), B (late BM relapses), and C (isolated extramedullary relapses) received alternating short-course intensive polychemotherapy (in blocks R1, R2, or R3) and cranial/craniospinal irradiation followed by maintenance therapy. Block R3 (high-dose cytarabine and etoposide) was introduced to improve the outcome compared with historical controls. Patients with early BM or T-ALL relapse (poor prognosis group [PPG]) were eligible for experimental regimens. One hundred seventeen patients received stem-cell transplantation (SCT).
  
  
  RESULTS
  The probabilities (and standard deviations) of event-free survival (pEFS) and overall survival (pOS) at 10 years were 0.30 +/- .02 and 0.36 +/- .02, respectively. Significant differences existed between strategic groups (pEFS(A) = .17 +/- .03; pEFS(B) = .43 +/- .04; pEFS(C) = .54 +/- .06; pEFS(PPG) = .15 +/- .03; log-rank P < .001). Patients of high-risk groups A plus PPG did better with SCT than with chemotherapy (pEFS = .33 +/- .05 v 0.20 +/- .05; P = .005). The pEFS was similar to trials ALL-REZ BFM 85/87 (.36 +/- .03. v 0.37 +/- .03; P = .419; PPG excluded). Time point, site of relapse, immunophenotype, and SCT were significant predictors of pEFS in multivariate analyses.
  
  
  CONCLUSIONS
  More than one third of patients in this large, population-based trial were cured. Neither R3 nor adaptation of chemotherapy intensity was capable of improving pEFS or of overcoming prognostic factors. In high-risk patients, remission induction regimens must be improved, and allogeneic SCT should be recommended in patients achieving second complete remission.
authors.affiliation: Departments of Pediatric and Arend von Stackelberg Oncology/Hematology and of General Pediatrics, Charit-Universitätsmedizin Berlin, Germany.
authors.forename: Gesche
authors.initials: G
authors.lastname: Tallen
authors.forename: Richard
authors.initials: R
authors.lastname: Ratei
authors.forename: Georg
authors.initials: G
authors.lastname: Mann
authors.forename: Gertjan
authors.initials: G
authors.lastname: Kaspers
authors.forename: Felix
authors.initials: F
authors.lastname: Niggli
authors.forename: Alexandr
authors.initials: A
authors.lastname: Karachunsky
authors.forename: Wolfram
authors.initials: W
authors.lastname: Ebell
authors.forename: Gabriele
authors.initials: G
authors.lastname: Escherich
authors.forename: Martin
authors.initials: M
authors.lastname: Schrappe
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
authors.forename: Ruediger
authors.initials: R
authors.lastname: Fengler
authors.forename: Günter
authors.initials: G
authors.lastname: Henze
authors.forename: Arend
authors.initials: A
authors.lastname: von Stackelberg
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D016371:Cranial Irradiation; D003561:Cytarabine / Q000008:administration & dosage; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016016:Proportional Hazards Models; D018714:Radiotherapy, Adjuvant; D012008:Recurrence; D018570:Risk Assessment; D012307:Risk Factors; D033581:Stem Cell Transplantation; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D003561:Cytarabine; D005047:Etoposide