Risk Adapted Treatment in Childhood Acute Lymphoblastic Leukemia: Data from the Berlin-Frankfurt-Münster Group

Abstract

Experience with approximately 3700 patients in the last four multicenter trials for childhood acute lymphoblastic leukemia (ALL) performed over the last 13 years by the Berlin-Frankfurt-Münster (BFM) study group established and reconfirmed basic knowledge on the risk of relapse. A series of randomized and prospective questions, however, allowed new insights into additional biological and therapyrelated factors. In trials ALL-BFM 83, evidence was generated on the importance of delayed intensification, even for standard-risk ALL that was later confirmed in the following trial ALLBFM 86. Patients with standard-risk ALL treated without reinduction therapy had an even higher risk of relapse than patients stratified into the medium-risk group. From 1981 to 1986. the impact of adequate maintenance therapy with 6-mercaptopurine (6-MP) and methotrexate (MTR) on event-free surival was evaluated by randomization of 18 vs. 24 months total therapy duration, proving the impact of prolonged exposure on disease-free survival. Also in trial ALL-BFM 83, the blast cell reduction after the 1 week of treatment with prednisone and MTX i.th. was prospectively evaluated to find a reliable prognostic parameter for early prediction of increased risk of relapse. Thus, a new independent risk factor called the “prednisone poor response”(PRED-PR) was generated that identified approximately 10% of all patients with ALL. The prognosis for this group, however, has not yet improved from the time of discovery in trial ALL-BFM 83, despite various attempts at treatment intensification. Patients in this group are predominantly boys, have an high initial leukemic cell burden, present with T cell ALL in 40% of the cases, and have an increased risk of remission failure. The probability of event-free survival (pEFS) in the group is less than 50%. Among these patients with PRED-PR, a subgroup can be identified that is at even higher risk of relapse: with the coexpression of myeloid markers on their blast population, T-ALL, or a very high White blood cell count (WBC). Translocation t(9; 22), the equivalent BCR-ABL recombination, or t(4;11) are, together with nonresponse to primary treatment, additional high-risk features that qualify any patient for maximum therapy, including allogeneic bone marrow transplantation (BMT). Despite the difficulties for high-risk patients a pEFS of 75% for the total study population is encouraging. Yet improved from the time of discovery in trial ALL-BFM 83, despite various attempts at treatment intensification. Patients in this group are predominantly boys, have an high initial leukemic cell burden, present with T cell ALL in 40% of the cases, and have an increased risk of remission failure. The probability of event-free survival (pEFS) in the group is less than 50%. Among these patients with PRED-PR, a subgroup can be identified that is at even higher risk of relapse: with the coexpression of myeloid markers on their blast population, T-ALL, or a very high White blood cell count (WBC). Translocation t(9; 22), the equivalent BCR-ABL recombination, or t(4;11) are, together with nonresponse to primary treatment, additional high-risk features that qualify any patient for maximum therapy, including allogeneic bone marrow transplantation (BMT). Despite the difficulties for high-risk patients a pEFS of 75% for the total study population is encouraging.KeywordsAcute Lymphoblastic LeukemiaConsolidation TherapyChildhood Acute Lymphoblastic LeukemiaHigh White Blood Cell CountPred ResponseThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.