BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991–1996)

Abstract

Modern treatment strategies, consisting of intensive chemotherapy and cranial irradiation, have remarkably improved the prognosis for children with acute lymphoblastic leukemia. However, patients with a potential for cure are at risk of severe acute and late adverse effects of treatment. Furthermore, in 25-30% of patients treatment still fails. The objectives of the DCLSG study ALL 8 were to decrease the toxicity and to increase the effectivity of BFM-oriented treatment. Decrease of toxicity was aimed at by confirmation of the results of the previous DCLSG study ALL-7, showing that the majority (94%) of children with ALL can succesfully be treated with BFM-oriented therapy without cranial irradiation, and by reduction of treatment for standard risk (SRG) patients. To increase the cure rate in medium risk (MRG) patients the efficacy of high doses of intravenous 6-mercaptopurine (HD-6MP) during protocol M and in SRG patients the efficacy of high doses of L-asparaginase (HD-L-ASP) during maintenance treatment was studied in randomized studies. Patient stratification and treatment were identical to protocol ALL-BFM90, with the following differences: no prophylactic cranial irradiation, SRG patients received only phase 1 of protocol I. Four hundred and sixtyseven patients entered the protocol: 170 SRG, 241 MRG and 56 HRG patients. The 5 years event-free survival rate for all patients was 73% (s.e. 2%); for SRG, MRG and HRG patients 85% (s.e. 3%), 73% (s.e. 3%) and 39% (s.e. 7%), respectively. In patients Ͼ1 year of age at diagnosis unfavorable prognostic factors were male sex, Ͼ25% blasts in the bone marrow at day 15 and initial white blood cell count (WBC) Ͼ50 × 10 9 /l. The cumulative risk of CNS relapse rate was 5% (s.e. 1%) at 5 years. These results confirm that the omission of cranial irradiation in BFM-oriented treatment does not jeopardize the overall good treatment results, nor does early reduction of chemotherapy in SRG patients. No benefit was observed from treatment intensification with HD-L-ASP in SRG patients, nor from HD-6MP in MRG patients.

Visuomotor control in survivors of childhood acute lymphoblastic leukemia treated with chemotherapy only

“…The children with ALL had been treated according to the consecutive Dutch Childhood Leukemia Study Group (DCLSG) ALL treatment protocols 6 to 9 (Kamps et al, , 2002Veerman et al, 1996), and were diagnosed between 1985 and 1999. Patients were stratified into risk groups based on leukemia cell load, cell phenotype and spread of the disease.…”

“…The criteria for risk group classification varied across the different protocols. In our study, 15 children had been treated according to the ALL standard treatment protocols and 19 according to intensified protocols, these numbers corresponding with the distribution of risk groups nationwide (Kamps et al, , 2002Veerman et al, 1996). CNSdirected treatment consisted of intrathecal chemotherapy and of systemically administered methotrexate and corticosteroids.…”

“…CNS-directed treatment is a standard component of therapy for ALL. Evidence of a detrimental effect of prophylactic cranial irradiation on neurocognitive function in children with ALL (Cousens et al, 1988;Jankovic et al, 1994;Meadows et al, 1981) has resulted in reduction of the use of cranial irradiation and the development of chemotherapy-only protocols with the same or better rate of treatment success (Kamps et al, 2002;Tubergen et al, 1993).…”

Long-term results of Dutch Childhood Oncology Group studies for children with acute lymphoblastic leukemia from 1984 to 2004

“…5,8,9,10 These are briefly described below and summarized in Figures 1a and b. Protocol ALL-6 opened to children with newly diagnosed ALL in the Netherlands diagnosed from December 1984 to July 1988.…”

“…Another major difference was the reinduction protocol II and maintenance therapy with methotrexate and 6-mercaptopurine (MP) but without vincristine and prednisone pulses. 8,9 When in the early 1990 s of the last century, the favorable EFS and overall survival (OS) data of the DCLSG-ALL-6 study emerged, the DCLSG felt that the 'Total Therapy' concept and stratification criteria of DCLSG-ALL-6 should be reintroduced for all patients with ALL in the Netherlands. This DCLSG-ALL-9 study started in 1997, using the DCLSG-ALL-6 treatment strategy for NHR patients.…”