Die Corticosteroid-abhängige Dezimierung der Leukämiezellzahl im Blut als Prognosefaktor bei der akuten lymphoblastischen Leukämie im Kindesalter (Therapiestudie ALL-BFM 83)

Abstract

In therapy study ALL-BFM 83 a total of 630 patients with acute lymphoblastic leukemia (ALL) have prospectively been evaluated for initial response on therapy with corticosteroids. It was the aim to qualify the in vivo cytoreduction as a new predictor for therapy failure. All patients were exposed for 7 days to prednisone before combination chemotherapy at day 8 has been started. At day 0 one additional dose of Methotrexate was given intrathecally. Therapy for all patients with non-B-ALL has been stratified according to initial tumor burden (risk factor) providing four therapy branches: standard risk low (SR-L), standard risk high (SR-H), medium risk (MR), high risk (HR). After a median duration of study of 21 months, event-free survival (EFS) is for all 630 patients 73%, 81% for SR-L, 76% for SR-H, 69% for MR, and 35% for HR patients (date of evaluation Jan. 1, 1987). In this prospective study, a small subgroup of patients (n = 48; 7.6% of total group) is characterized by greater than 1000 leukemic blasts/mm3 peripheral blood at day 8 after exposure to prednisone. In this subgroup the EFS is only 43% in contrast to 76% in the complementary group of 582 patients with less than 1000 leukemic blasts/mm3 peripheral blood at day 8. Patients of that risk group are derived from therapy branches SR-H, M and HR, the latter contributing relatively most patients. In this negatively selected group all patients with an initial high white blood count, CNS disease at diagnosis, immune subtypes as prae-T-ALL (n = 6), T-ALL (n = 18), null-ALL (n = 5), and males clearly dominate. Of 48 patients with greater than 1000 blasts/mm3 at day 8 4 subsequently failed to enter remission and 8 were qualified as lateresponders. 18 patients relapsed, most of them earlier compared to those of the complementary group. The initial in vivo response on corticosteroid therapy is considered a supplementary prognostic predictor for early failure. It will be utilized in trial ALL/NHL-BFM 86 to qualify patients at the highest risk for relapse. This group of patients is supplemented in addition by non- and lateresponders and children with acute undifferentiated leukemia (AUL). The in vivo corticosteroid test is simple, generates early and reliable results and can be obtained almost always. Thus it may be recommended for use in a multicenter trial.

Genetic Variations in the Glucocorticoid Receptor Gene Are Not Related to Glucocorticoid Resistance in Childhood Acute Lymphoblastic Leukemia

“…The in vivo prednisone response as used in the BFM studies has been found to be one of the strongest prognostic factors for therapy outcome in childhood ALL (1,29,33). The in vitro prednisolone sensitivity of untreated leukemic cells, as determined by the MTT assay, is a strong risk factor for outcome as well and can predict the occurrence of a relapse even within the group of patients with a good in vivo prednisone response (2,4,5,31).…”

“…These protocols start with a 7-day monotherapy of prednisone and one intrathecal dose of methotrexate. The prednisone response was determined on day 8: prednisone good response is defined as <1,000 leukemic blasts/AL peripheral blood and prednisone poor response as z1,000 blasts/AL (29). Patient material was taken before initial therapy.…”

Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000

“…Details regarding dosage and exact timing are provided in the key references published earlier [13][14][15]17,21 and are provided in Supplementary Tables 1-5. The major study questions addressed in each trial are summarized under section Introduction.…”

“…The number of leukemic blasts in PB was centrally evaluated. 14 Extensive data analysis revealed that in approximately 10% of the patients a leukemic blast cell count in PB of 1000 per ml or more on day 8 ('Prednisone poor response', PPR) could be found. This is highly predictive of a particularly high relapse risk.…”

Clinicopathological Features and Prognostic Implications of Immunophenotypic Subgroups in Childhood ALL: Experience of the BFM-ALL Study 83

“…From October 1983 to September 1986, 709 previously untreated children with ALL were stratified for risk-adapted multidrug chemotherapy in the ALL-BFM 83 multicenter trial [11]. Complete immunophenotypic determinations were performed in 607 (85.6%) of these patients.…”