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58 children were admitted to a prospective randomized leukemia induction and CNS-prophylaxis three different protocols were followed for maintenance. A (n = 20): 6-MP (50 mg/m2) p.o. daily + MTX (20-30 mg/m2) p.o. weekly; B (n = 20): 6-MP (50 mg/m2) p.o. daily + MTX (75-150 mg/m2) i.v. every two weeks; C (n = 18): 6-MP (50 mg/m2) p.o. daily + alternating 8-week-courses of four biweekly i.v. injections of MTX (75-150 mg/m2) and four biweekly i.v. injections of Cyclo (600 mg/m2). After all patients have been followed for at least 48 months, the rates of continuous complete remission are 42% in protocol A, 63% in protocol B, and 29% in protocol C. No encephalopathies have been observed with regimen B.

495 children and adolescents with acute lymphoblastic leukemia entered a non-randomized therapy study between January 1st, 1971, and December 31st, 1974. They were treated at 40 pediatric clinics in the Federal Republic of Germany according to the protocol of the Deutsche Arbeitsgemeinschaft für Leukämieforschung und -Behandlung im Kindesalter, which was closely adapted to the Memphis protocol VII. These patients were analyzed retrospectively, data of evaluation was July 31st, 1978. 7 patients (1.4%) did not achieve remission, 14 patients (2.8%) died during the induction period, and another 37 patients (7.5%) died in continuous complete remission (CCR). For purposes of comparison only the remaining 437 patients were evaluated (remission group). The 7 1/2 years' probability of CCR is 0.33 +/- 0.02 for the total group (495 patients) and 0.37 +/- 0.03 for the remission group. The probability of survival for these groups is 0.40 +/- 0.03 and 0.45 +/- 0.03, respectively. After relapse the 5 years' probability of survival is 0.03 +/- 0.02. Patients with testicular relapse have a markedly better prognosis compared to those with bone-marrow or central nervous system relapses. The most important prognostic factor was found to be the white blood count at diagnosis. There is a negative correlation between the initial white blood count and the probability of CCR. Girls fared significantly better than boys (0.46 +/- 0.04 vs 0.31 +/- 0.03 in CCR, p less than 0.01). There is convincing evidence that the impaired prognosis in boys is at least partly due to the incidence of testicular relapses (36 of 268 relapses were found to be testicular, isolated in 20 patients and combined with bone-marrow relapse in 16 patients). Patients with thymic involvement and/or positive reaction of the acid phosphatase in their blast cell did significantly worse (0.12 +/- 0.05 in CCR). Irradiation of the skull was performed in two different doses (1800 and 2400 rads). Concerning the incidence of relapses primarily located in the central nervous system patients with low-dose irradiation had no worse prognosis than those with high-dose irradiation but the incidence of bone-marrow relapses was found to be higher in the 2400 rad group (50.5% vs. 41.7% in the 1800 rad group), possibly due to the higher initial white blood count (median 8900/mul vs. 6500/mul). The addition of vincristine/prednisone reinduction courses during the first year of continuation therapy showed no significant advantage.

In two consecutive therapy studies, the BFM multicenter study group treated 55 children with B-NHL from 1975 until 1981 and another 55 children with B-NHL and 22 with B-ALL since 1981. In the 1975/81 study, a therapeutic regimen which produced excellent results in non-B-NHL and -ALL, emerged to be much less effective in disseminated B-NHL. With this regimen the probability of continuous complete remission (CCR) in advanced disease was 34% only after 7 years. Since 1981, a new therapeutic regimen of higher specificity for B-neoplasias improved the probability of CCR at the present time to 100% in localised B-NHL, to 63% in disseminated B-NHL and even in B-ALL to 49%.

Lymphomatous cell samples from 86 patients with B-cell neoplasia (34 chronic lymphocytic leukaemia, 8 hairy-cell leukaemia, 5 prolymphocytic leukaemia, 20 immunocytic lymphoma, 9 centrocytic lymphoma, 3 centroblastic/centrocytic lymphoma, 3 lymphoblastic lymphoma, 1 plasma cell leukaemia and 3 plasmacytoma) were studied using the monoclonal antibody Leu 1, detecting a p69,71 antigen complex present on nearly all thymocytes, most (greater than 85%) peripheral T-lymphocytes as well as some malignant B-cells. Furthermore, we compared the reactivity of Leu 1-positive B-cells with those exhibiting conventional surface markers such as mouse-erythrocyte-receptor, FcIgG-receptor, C3b- or C3d-receptor and surface immunoglobulins of the various heavy- and light-chain types. Our results demonstrate a correlation between the expression of p69,71 antigen complex and distinct phenotypes revealed by conventional markers and underline the value of Leu 1 monoclonal antibody in the differential diagnosis of human B-cell neoplasia.

The principle of giving intensive polychemotherapy in the time between operation and irradiation was applied in a cooperative phase-2-study in children with medulloblastoma of the posterior fossa. A first evaluation of 33 of 47 registered patients was attempted after the study existing now for 1 year and 10 months. In the majority of patients the chemotherapy protocol could be fully realized without any deductions. Side effects including two therapy related fatalities were analysed. In all patients irradiation was not delayed and could be started about 11 weeks after operation and could be carried through without any major draw-backs. Analysis of survival can only be preliminary due to the short duration of the study, but patients' survival is compatible with other reported studies. The therapeutic principle presented here shall be compared in a randomized and extended fashion with a conventional therapeutic approach.

From 1970 to 1977, two nonrandomized groups of children with acute lymphoblastic leukemia (ALL) were treated with two different induction regimens. A total of 168 patients (group DAL) received induction therapy closely adapted to St. Jude protocol VII. A total of 119 patients (group BFM) were treated with the West Berlin induction protocol. Evaluable for analysis were 138 patients of group DAL and 113 patients of group BFM. Thirty children had thymic involvement (Thy+), 15 in each group. In children without thymic involvement (Thy+), the median initial white blood count (WBC) was 8400/mm3 in group DAL and 8000/mm3 in group BFM. In contrast, the initial WBC was 42,000/mm3 and 79,200/mm3 in the corresponding group with thymic involvement (Thy+). The probability of continuous complete remission (CCR) at 9 years is 0.41 +/- 0.05 for patients without thymic involvement and 0.09 +/- 0.09 for patients with thymic involvement in group DAL, and 0.65 +/- 0.05 for those without thymic involvement and 0.52 +/- 0.13 for those who had thymic involvement in group BFM. After adjustment for initial WBC (regression analysis) the presence of thymic involvement was still a predictor of poor outcome in group DAL (p less than 0.001), whereas it was not a predictor of poor response in group BFM. In view of comparable patient composition in both treatment groups, the favorable prognosis in BFM patients has to be related to the mode of induction therapy.

A retrospective statistical analysis of the acute lymphoblastic leukemia study BFM 70/76 revealed the prognosis being strongly dependent on the initial leukemia cell count/mm3 in the peripheral blood, and the enlargement of liver and spleen below the costal margin. Based on postmortem examinations reported in the literature a method was developed to estimate the tumor mass in these three compartments in an order of magnitude. The estimated blast cell mass related to the patient's body weight proved to be highly significant (p much less than 0.001). Simplification of the method led to the definition of a "risk factor" allowing the separation of patients into 3 groups with a distinctly different risk for relapse. In the current study BFM 81 the risk factor is used to stratify patients with respect to the individually needed therapeutic intensity.

From 1970 to 1979, two subsequent BFM studies were performed with different modalities of systemic chemotherapy and preventive central nervous system (CNS) therapy. Eighteen out of 275 children experienced isolated CNS relapses within 2 years after diagnosis. The present analysis should clarify the following questions: 1. Could the risk for CNS relapse be assessed by initial diagnostic findings? 2. Is the CNS relapse rate influenced by more intensive systemic chemotherapy? 3. Is the CNS relapse rate altered by different doses of radiation therapy? The risk for relapse was assessed using a risk index (RI) based on findings at diagnosis. All patients were treated with an 8 weeks induction and consolidation chemotherapy protocol. In part, children with increased risk for relapse (RI greater than = 3) received an additional 6 weeks reinduction protocol within the first six months after diagnosis. Preventive treatment to the CNS consisted of radiotherapy at doses of less than = 18 Gy or 24 Gy and intrathecal methotrexate given during the consolidation phase. The results are as follows: 1. The RI proved to be predictive also for the risk of CNS relapse. However, CNS relapse rates were not substantially higher in children with RI greater than = 3 when they had been exposed to radiation doses of 24 Gy instead of less than = 18 Gy. 2. Intensive systemic reinduction therapy did not influence the CNS relapse rate in children with RI greater than = 3. 3. Three percent of children with RI less than = 2 experienced CNS relapses, irrespectively of lower or higher radiation doses. In patients with RI greater than = 3, however, irradiation at doses of less than = 18 Gy instead of 24 Gy led to a 3-4 fold higher incidence of CNS relapses, irrespectively of chemotherapy. We conclude that radiation doses of less than = 18 Gy are capable of preventing CNS relapses effectively in children with RI less than = 2. The exposure of patients with RI greater tha = 3 to doses of 24 Gy is justified.

Between December, 1978, and October, 1982, 151 children with acute myelogenous leukemia from 30 pediatric clinics entered the cooperative study. The treatment consisted of a 10-week intensive induction therapy and a subsequent maintenance therapy, which is terminated for children in complete continuous remission after 2 years. The induction treatment during the first 4 weeks consisted of a combination of prednisone, 6-thioguanine (TG), vincristine, adriamycin (ADR) and cytosine-arabinoside (ARA-C). In the following 4 weeks i.v. cyclophosphamide, i.th. methotrexate and prophylactic cranial irradiation were administered in addition to TG, ARA-C and ADR. 119 of the 151 patients (79%) achieved complete remission. 13 children (9%) died of early hemorrhages, 2 of them before onset of therapy. 5 patients died initially of other complications, another 6 after remission has been achieved. 13 children did not respond or responded poorly to the induction therapy. So far, 40 relapses occurred, mainly in the bone marrow. In 6 relapses the central nervous system was involved. The probability for a continuous complete remission for the total group is 0.41 +/- 0.05 (life table analysis) and for the total group 0.56 +/- 0.06 after 45 months. The corresponding probability for survival after 46 months are 0.43 +/- 0.06 for the remission group. The risk for occurrence of early fatal hemorrhages was higher in children with acute monocytic leukemia than in the other morphological subtypes. An initial leukocyte count of more than 100,000/microliters was found significantly more often in patients who did not achieve remission (early deaths and nonresponders) than in children of the remission group. So far, no factors could be identified which influence the risk for relapse. The present results of the study allow the conclusion, that with the applied treatment strategy it is possible to achieve not only in a high portion of children with AML remission but also to improve the chances for long-time remission and perhaps cure.