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).

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 successfully 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 sixty-seven 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 >1 year of age at diagnosis unfavorable prognostic factors were male sex, >25% blasts in the bone marrow at day 15 and initial white blood cell count (WBC) >50 x 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.

Precursor-B-ALL with D(H)-J(H) gene rearrangements have an immature immunogenotype with a high frequency of oligoclonality and hyperdiploidy of chromosome 14.

The IGH gene configuration was investigated in 97 childhood precursor-B-ALL patients at initial diagnosis. Rearrangements were found by Southern blotting in all but three patients (97%) and in 30 cases (31%) we observed oligoclonal IGH gene rearrangements. Heteroduplex PCR analysis revealed at least one clonal PCR product in all Southern blot-positive cases. In 89 patients (92%) complete V(D)J rearrangements were found, while incomplete D(H)-J(H) rearrangements occurred in only 21 patients (22%). In 5% of cases the D(H)-J(H) rearrangements were the sole IGH gene rearrangements. Sequence analysis of the 31 identified incomplete rearrangements revealed preferential usage of segments from the D(H)2, D(H)3 and D(H)7 families (78%). While D(H)2 and D(H)3 gene rearrangements occur frequently in normal B cells and B cell precursors, the relatively frequent usage of D(H)7-27 (19%) in precursor-B-ALL patients is suggestive of leukemic transformation during prenatal lymphopoiesis. Among J(H) gene segments in the incomplete D(H)-J(H) rearrangements, the J(H)6 segment was significantly overrepresented (61%). This observation together with the predominant usage of the most upstream D(H) genes indicates that many of the identified clonal D(H)-J(H) gene rearrangements in precursor-B-ALL probably represent secondary recombinations, having deleted pre-existing D(H)-J(H) joinings. The patients with incomplete D(H)-J(H) gene rearrangements were frequently characterized by hyperdiploid karyotype with additional copies of chromosome 14 and/or by IGH oligoclonality. The presence of incomplete D(H)-J(H) joinings was also significantly associated with a less mature immunogenotype: overrepresentation of V(H)6-1 gene segment usage, absence of biallelic TCRD deletions, and low frequency of TCRG gene rearrangements. This immature immunogenotype of precursor-B-ALL with incomplete IGH gene rearrangements was not associated with more aggressive disease.

Extramedullary infiltrates at diagnosis have no prognostic significance in children with acute myeloid leukaemia.

This retrospective study was designed to review the relative frequency and prognostic significance of extramedullary infiltrates in children with acute myeloid leukaemia (AML). The registration data and initial discharge summaries were reviewed for all children diagnosed with AML, and registered by the Dutch Childhood Leukaemia Study Group (DCLSG). Between 1972 and 1998, 477 children were diagnosed with AML. Of these patients, 120 (25.1%) had extramedullary leukaemia (EML) at diagnosis. Four categories of EML were found: skin, soft tissue or bone, gingival infiltration and central nervous system (CNS) involvement. Patients who presented with gingival infiltrates, were older than those without EML or those in the other EML subgroups, had a high initial WBC count and a high proportion of M4/M5 morphological variants. This type of presentation could indicate a special biological entity. Univariate analysis of prognostic factors in patients treated after 1985 with intensive protocols showed that initial WBC count and the presence of favourable cytogenetic findings were significant. The presence of EML at diagnosis had no significant effect on event-free survival. In a stepwise multiple regression analysis only favourable cytogenetic findings remained significant.

Long-term follow-up of Dutch Childhood Leukemia Study Group (DCLSG) protocols for children with acute lymphoblastic leukemia, 1984-1991.

Here we report the long-term results of the DCLSG protocols ALL-6 and -7 with special emphasis on the incidence of CNS relapse after treatment without cranial irradiation. In DCLSG protocol ALL-6 (1984-1988), designed for patients with ALL non-high risk (ALL-NHR) (WBC <50 x 10(9)/l, no mediastinal mass, no B cell phenotype and no CNS involvement at diagnosis, comprising 71% of all ALL patients), CNS prophylaxis consisted of a combination of three methods of chemotherapeutic CNS prophylaxis (the use of dexamethasone during induction and maintenance therapy, i.v. medium dose methotrexate and prolonged administration of intrathecal triple therapy). Total duration of treatment: 116 weeks. 190 patients were enrolled in the study. At 10 years, the EFS rate for all patients is 81.5 +/- 2.8%, the survival rate 84.8 +/- 2.7%, and the cumulative incidence of isolated CNS relapse 1.1 +/- 0.8%. The 10-year survival rate for the 139/190 (73.1%) patients with standard risk non-T lineage ALL according to the NCI risk criteria is 80.5 +/- 3.4%. DCLSG protocol-7 was identical to the intensive ALL-BFM-86 protocol, but cranial irradiation was restricted to patients with initial CNS involvement. Patients were stratified into three risk groups (SRG, RG and EG). Treatment duration was 18 months. 218 patients were enrolled in the study. At 10 years, the EFS rate for all patients is 63.4 +/- 3.3%, the survival rate 76.4 +/- 3.0%, the 5-year cumulative incidence of isolated CNS relapse 5.7 +/- 1.8%. The EFS rate at 10 years of the 127/218 (58.3%) patients with standard risk non-T-lineage ALL according to the NCI risk criteria was 67.9 +/- 4.3%, which is not significantly different from the results achieved in this category of patients with the moderately intensive treatment according to protocol ALL-6 (logrank P = 0.17). These DCLSG studies indicate that omission of cranial irradiation does not jeopardize the overall good results.

Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: results of Dutch Childhood Leukemia Study Group Protocol ALL-7 (1988-1991).

In The Netherlands from July 1988 to October 1991, children (0 to 16 years of age) with de novo acute lymphoblastic leukemia (ALL) were treated according to protocol ALL-7 of the Dutch Childhood Leukemia Study Group (DCLSG). In this protocol, chemotherapy and treatment stratification were identical to the ALL-BFM-86 protocol (Reiter et al, Blood 84:3122, 1994), but cranial irradiation was restricted to patients with initial central nervous system (CNS) involvement. Patients were stratified into 3 risk groups, based on leukemia cell mass and response to initial treatment: standard-risk group (SRG), risk group (RG), and experimental group (EG). As in ALL-BFM-86, a randomized study on late intensification (protocol S) was performed in RG patients, and during the study (since October 1990), early reinduction treatment (protocol II) was introduced for SRG patients. Treatment duration for all patients was 18 months. Two hundred eighteen children entered the study: 74 SRG, 127 RG, and 17 EG patients. The overall complete remission (CR) rate was 98%. The 5-year event-free survival (EFS) for all DCLSG ALL-7 patients was 65. 3% (standard error [SE] 3.2%), which was significantly different from the 73% (SE 1%) 5-year EFS achieved in the ALL-BFM-86 study (P =.02, Z-test). However, restricting the analysis to SRG patients receiving protocol II with a total duration of treatment of 18 months, the 5-year EFS rates were 64.6% (SE 4.0%) and 67% (SE 4%), respectively, and no significant difference could be established (P =.67, Z-test). The 5-year EFS rates for SRG, RG, and EG patients were 63.5% (SE 5.6%), 66.6% (SE 4.2%), and 63.3% (SE 12.0%), respectively. SRG patients receiving protocol II fared better than patients not receiving protocol II (5-year EFS 76.7% [SE 7.7] and 54. 5% [SE 7.5], respectively). No difference in 5-year EFS was observed in RG patients randomized to receive or not to receive late intensification with protocol S. The overall CNS relapse rate at 5 years was 5.5%. The incidence rate at 5 years was 11.4% in SRG patients not receiving protocol II, whereas no CNS relapses occurred in SRG patients receiving protocol II. Six children died in first complete remission and 2 children developed a second malignancy (thyroid carcinoma and acute nonlymphoblastic leukemia). Systemic high-dose methotrexate (MTX) and intrathecal chemotherapy is a safe and effective method of CNS prophylaxis in the context of BFM-oriented treatment for all children with ALL, regardless of the risk group (with the possible exception of T-ALL patients with high white blood cell counts). The results of the DCLSG ALL-7 study confirm those of the ALL-BFM-86 study showing that early reinduction with protocol II is essential in the treatment of SRG patients and that late intensification with protocol S does not improve the prognosis for RG patients.

Late effects among long-term survivors of childhood acute leukemia in The Netherlands: a Dutch Childhood Leukemia Study Group Report.

Late events and side effects are reported in 392 children cured of leukemia. They originated from 1193 consecutively newly diagnosed children between 1972 and 1982, in first continuous complete remission for at least 6 y after diagnosis, and were treated according to Dutch Childhood Leukemia Study Group protocols (70%) or institutional protocols (30%), all including cranial irradiation for CNS prophylaxis. Data on late events (relapses, death in complete remission, and second malignancies) were collected prospectively after treatment; late side effects were retrospectively collected by a questionnaire, completed by the responsible pediatrician. The event-free survival of the 6-y survivors at 15 y after diagnosis was 92% (+/- 2%). Eight late relapses and nine second malignancies were diagnosed, two children died in first complete remission of late toxicity of treatment, and one child died in a car accident. The most important long-term side effects reported were learning disabilities (50%), short stature, obesity, and delayed pubertal development. No increase in the incidence of cardiovascular, pulmonary, urogenital, or gastrointestinal tract diseases or an increased vulnerability of the musculoskeletal system was found. However, prolonged follow-up is necessary to study the full-scale late effects of cytostatic treatment and radiotherapy administered during childhood.