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Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997-2004)

Veerman, A. J., Kamps, W. A., van den Berg, H., van den Berg, E., Bokkerink, J. P. M., Bruin, M. C. A., van den Heuvel-Eibrink, M. M., Korbijn, C. M., Korthof, E. T., van der Pal, K., Stijnen, T., Sipman, M. H. V. W., Weerden, van, F., van Wering, E. R., van der Does-van den Berg, A. & Dutch Childhood Oncology Grp, Oct-2009, In : Lancet Oncology. 10, 10, p. 957-966 10 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Anjo J. Veerman
  • Willem A. Kamps
  • Henk van den Berg
  • Eva van den Berg
  • Jos P. M. Bokkerink
  • Marrie C. A. Bruin
  • Marry M. van den Heuvel-Eibrink
  • Carin M. Korbijn
  • Elisabeth T. Korthof
  • Karin van der Pal
  • Theo Stijnen
  • Margreet H. van Weel Sipman
  • Fransje Weerden, van
  • Elisabeth R. van Wering
  • Anna van der Does-van den Berg
  • Dutch Childhood Oncology Grp

Background A population-based cohort of children aged 1-18 years with acute lymphoblastic leukaemia (ALL) was treated with a dexamethasone-based protocol (Dutch Childhood Oncology Group [DCOG] ALL-9). We aimed to confirm the results of the most effective DCOG ALL protocol for non-high-risk (NHR) patients to date (ALL-6), compare results with ALL-7 and ALL-8, and study prognostic factors in a non-randomised setting.

Methods From Jan 1, 1997, until Nov 1, 2004, patients with ALL were treated according to the ALL-9 protocol in eight Dutch academic centres with their affiliated peripheral hospitals. Patients were stratified into NHR and high risk (HR) groups. HR criteria were white-blood-cell count of 50 000 cells per mu L or more, T-cell phenotype, mediastinal mass, CNS or testicular involvement, and Philadelphia chromosome or MLL rearrangement; patients who did not fulfil these criteria were deemed to be NHR. The NHR group was treated with a three-drug induction (dexamethasone, vincristine, and asparaginase) for 6 weeks, medium-dose methotrexate for 3 weeks, then maintenance therapy. HR patients received a four-drug induction (as for the NHR patients plus daunorubicin) for 6 weeks, high-dose methotrexate for 8 weeks, and two intensification courses before receiving maintenance therapy. Triple intrathecal medication was given 13 times in NHR patients, 15 times in HR patients (17 times for patients with initial CNS involvement). No patient received cranial irradiation. Maintenance therapy was given until 109 weeks for all patients and consisted of mercaptopurine and methotrexate for 5 weeks, alternated with dexamethasone and vincristine for 2 weeks. Kaplan-Meier analysis was done on an intention-to-treat basis with event-free survival as the primary endpoint. This trial is registered at trialregister.nl, number NTR460/SNWLK-ALL-9.

Findings 859 patients were recruited to the study. Complete remission was achieved in 592 (98.5%) of the 601 patients in the NHR group and 250 (96.9%) of the 258 in the HR group. Five patients in the NHR group and four in the HR group died during induction. Median follow-up for patients alive was 72.2 (range 4.8-132.7) months as of August, 2008. 5-year event-free survival was 81% (SE 1%) in all patients: 84% (2%) in NHR patients, and 72% (3%) in HR patients. Isolated CNS relapses occurred in 22 (2.6%) of 842 patients. In a multivariate analysis, DNA index was the strongest predictor of outcome (<1.16 vs >= 1.16; relative risk 0.42, 95% CI 0.22-0.78), followed by age (1-9 vs >= 10 years; 2.23, 1.60-3.11) and white-blood-cell count (<50000 vs >= 50000 cells per mu L; 1.60,1.13-2.26).

Interpretation The overall results of the dexamethasone-based DCOG ALL-9 protocol are better than those of our previous Berlin-Frankfurt-Munster-based protocols ALL-7 and ALL-8. The results for NHR patients were achieved with high cumulative doses of dexamethasone and vincristine, but without the use of anthracyclines, etoposide, cyclophosphamide, or cranial irradiation, therefore minimising the risk of side-effects.

Original languageEnglish
Pages (from-to)957-966
Number of pages10
JournalLancet Oncology
Volume10
Issue number10
Publication statusPublished - Oct-2009

    Keywords

  • STANDARD-RISK, CRANIAL RADIOTHERAPY, INTENSIVE TREATMENT, RANDOMIZED-TRIAL, CHILDREN, CHEMOTHERAPY, PREDNISOLONE, VINCRISTINE, IRRADIATION, INDUCTION

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