Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR-and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms 'complete MRD response', 'MRD persistence' and 'MRD reappearance'. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols.

Fifty-two percent of CESS 86 patients survived after risk-adapted therapy. High-risk patients seem to have benefited from intensified treatment that incorporated ifosfamide.

Co-operative study group for childhood acute lymphoblastic leukemia (COALL): longterm follow-up of trials 82, 85, 89 and 92DO Harms, GE Janka-Schaub on behalf of the COALL Study Group Children's University Hospital, Department of Hematology and Oncology, Hamburg, GermanyThe German Co-operative Study Group COALL for treatment of acute lymphoblastic leukemia (ALL) in childhood started the first trial in 1980. This report gives an overview of the long-term results of the four consecutive studies COALL-82, COALL-85, COALL-89 and COALL-92. Besides improvement in long-term survival major objectives were reduction of treatment-related toxicity by transferring asparaginase (ASP) from induction therapy to intensive phase and omitting CNS irradiation by stepwise increase of the initial white blood count (WBC) up to 50 × 10 9 /l (exception T-ALL) as criterion for irradiation. In study COALL-85 in high risk patients slow vs rapid rotational treatment was randomized. In study COALL-92 initial response to daunorubicin (DNR) as a 1-h vs 24-h infusion and its prognostic value was investigated. Furthermore, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) were randomized in maintenance treatment. In total, 1191 eligible patients were enrolled. Induction treatment without ASP has been shown to be as effective and less hazardous than the former four-drug induction. CNS control could be obtained in most without cranial irradiation (CNS relapse-free survival Ͼ95%). The leukemic cell kill with a 24-h DNR infusion was equivalent to that of a 1-h infusion. DNR response was of less prognostic significance than prednisone response. The rapid rotation regimen failed to improve outcome as well as 6-TG in maintenance treatment. However, intensification of systemic treatment resulted in an increase in overall event-free survival (EFS) to approximately 80% which is comparable to other groups. Leukemia (2000) 14, 2234-2239.

In this study, the long-term outcome of 1818 patients treated in five consecutive clinical trials (the cooperative study group for childhood acute lymphoblastic leukaemia (COALL) 82, 85, 89, 92 and 97) from 24 cooperating centres in Germany is reported. The probability of event-free survival (pEFS) improved significantly from the first two trials conducted in the 1980s (COALL 82 and COALL 85) to the three trials conducted in the 1990s (COALL 89, 92 and 97) (P ¼ 0.001). Through all COALL studies, age X10 years and initial white blood cell count (WBC) X50 Â 10 9 /l and pro-B immunophenotype were of significant prognostic relevance. A refinement of risk assessment has been achieved by in vitro drug sensitivity testing in COALL 92 and 97. In patients with very sensitive leukaemic cells, therapy could be reduced without loss of efficacy. In COALL 97, a further improvement in risk stratification was gained by the molecular assessment of minimal residual disease (MRD) under treatment, which proved to have a superior prognostic effect when compared with in vitro drug sensitivity testing. Importantly, the gradual reduction in central nervous system (CNS) irradiation led to a decreased incidence of brain tumours as a second malignancy. In general, the prevention of treatmentrelated late effects will be one of the major issues in future studies. It remains to be shown whether prolonged infusions of anthracyclines, which have been implemented into the COALL studies after equal efficacy compared with short-time infusions was confirmed, will be associated with fewer cardiac late effects. Another way to prevent late effects may be a more refined risk assessment allowing for a reduction in cumulative treatment burden. A great challenge in the future will be to improve the overall treatment results, which very likely can only be achieved by the identification of molecularly defined subgroups to which novel, rational therapeutic strategies can be applied.