Search

An intensive 7-day combination chemotherapy protocol was designed to reinduce children with early bone marrow relapse of acute lymphoblastic leukemia (less than 6 months after the end of or during preceding treatment). This aggressive approach seemed to be justified for a group of patients who were at the highest risk for ultimate treatment failure. In all, 38 children were enrolled for study. The ratio of male (median age, 10 years) to female (median age, 13 years) subjects was 27:11. Thirty patients were treated for their first relapse and eight for their second or subsequent relapse. Isolated bone marrow involvement was present in 24 cases. All patients had received heavy pretreatment including anthracyclines with cumulative doses of between 120 and 240 mg/m2. 22 of these patients, achieved complete remission, ten did not respond to therapy, and six died from the toxicity of the protocol. Cardiac failure was the cause of death in one child (after additional radiotherapy for a mediastinal mass). No further clinical manifestation of cardiomyopathy could be observed. The other five patients died from hemorrhages or infectious complications. The main side effects were fever, gastrointestinal problems, stomatitis, and severe bone marrow aplasia lasting for about 2 weeks with nadirs of platelets and white blood count around days 10-14. The remission rate of 60% was acceptable, though not satisfactory. Only four children survived disease-free for 13+, 14+, 20+, and 22+ months after diagnosis of relapse.

149 children with acute lymphocytic leukemia (ALL) were admitted to a prospective therapeutic regime. Remission induction was achieved by vincristine, daunorubicine, L-asparaginase and prednisone. During consolidation the patients received three intermediate dose methotrexate (MTX) infusions over 24 hours combined with intrathecal MTX, followed by L-asparaginase. High-risk patients were treated in addition with high dose cyclophosphamide and ARA-C over 3 weeks. Standard risk patients received cranial irradiation with 18 Gy, high-risk patients with 24 Gy. Maintenance therapy was performed with 6-mercaptopurine and MTX orally. Immunologic phaenotyping revealed: c-ALL 73%, pre-T or T-ALL 15%, c/T-ALL 4% and undifferentiated leukemia (AUL) 8%. Only 1 patient was nonresponder, 7 patients died during induction therapy, 5 patients during continuous complete remission (CCR). 18 relapses occurred, 12 of which were systemic, 8 CNS and 2 testicular relapses. In the total group the 54 months probability of CCR is 0,68 +/- 0,05 (life-table-analysis), for the reduced group 0,75 +/- 0,05. In the reduced group the probability of CCR at 54 months for standard risk patients is 0,86 +/- 0,06; for high-risk patients 0,60 +/- 0,09; for patients with c-ALL 0,73 +/- 0,08; for patients with c/T-ALL 1,0 +/- 0,0; for patients with pre-T or T-ALL 0,58 +/- 0,2 and for patients with AUL 0,45 +/- 0,25. For the reduced group the CCR probability at 54 months in relation to the leukocytes (WBC) at diagnosis is in patients with WBC less than 25 X 10(3)/mm3: 0,80 +/- 0,06; for patients with WBC greater than 25 X 10(3)/mm3: 0,63 +/- 0,11.

During the last 6 years 73 previously untreated children and adolescents with acute lymphoblastic leukemia were enrolled on a non-randomized therapy protocol. In this longitudinal sutdy the specific accent was put on the intensified induction treatment of 8 weeks' duration which was thought to achieve a higher remission quality. In this phase 8 effective drugs were applied up to the patient's tolerance limits; in addition prophylactic irradiation to the central nervous system was given in two modifications. After 4 weeks all patients were in complete remission. During the first 4 months 6 children died due to complications for which therapy must be at least partially responsible. 17 out of 67 patients relapsed between 4 and 59 months after diagnosis, which corresponds to a remission rate according to the life table analysis of 62% (50 out of 67 patients in first remission). The majority of patients with relapse is characterized at diagnosis by a specific pattern of clinical findings. 2 therapy groups, differently treated in respect to central nervous system irradaiation and duration of continuation therapy, do not at present statistically differ from each other. According to statistics 8 more children may be expected to suffer from relapse. The improved results are due to a lower incidence of bone marrow relapses; it seems that there is a direct relation between intensity of treatment during the induction phase and the occurrence of bone marrow relapses. The specific problems of the presented study take place during the induction phase, which, due to toxicity, regularly results in a number of side effects and severe complications. In order to realize the induction therapy, the use of prophylactic and supportive procedures is of utmost importance. Profound knowledge of possible side effects and complications is most essential as well as the knowledge of how to cope with these problems. It is the authors' opinion that the induction phase can only be performed in specialized institutions, because only at these places enough information may be obtained from an adequate number of patients and only there pediatric oncologists may share in the decisions and responsibilities. Only by using every kind of medical service this method of therapy may be justified at present, according to the results of this study, for the benefit of children with leukemia.

Analyses of the cellular DNA content were carried out in 226 patients with acute lymphoblastic leukemia (ALL) and in 61 children with acute myeloid leukemia (AML) to assess the incidence and clinical significance of DNA aneuploidies. All children were treated within the BFM studies ALL 79/81 and 81/83 as well as AML 78 und 83. DNA aneuploidies were identified in ALL in 39,8% and in AML in 36,1% of cases. Within the ALL group a significantly higher rate of aneuploid DNA stemlines was observed for non-T/non-B ALL with 44,1% as compared to T-ALL with 14,3% (p less than 0,01). In AML the morphologic subgroups M 1/2 revealed a lower frequency of 21,7% DNA aneuploidies than M 4/5 leukemias with 44,4%. The rates of complete remissions were not different between patients with and without DNA aneuploidy neither in ALL nor in AML. In the study ALL 79/81, however, a tendency towards longer remissions for patients with DNA aneuploidy was found (p = 0.053) which could not be confirmed at present by the study ALL 81/83. In both ALL trials patients with the lowest pretherapeutic risk-score revealed the highest rate of aneuploid DNA stemlines.