Supported in part by the Deutsche Krebshilfe and DAL/GPO
1 Department of Hematology/Oncology, Klinikum Sleglitz, Free University of Berlin, Federal Republic 01 Germany
2 Department of Pediatrics, Hannover Medical School. Hannover, Federal Republic of Germany

A. Introduction

The application of immunological marker studies to acute lymphoblastic leukemias (ALL) has established a solid basis for precise diagnosis and classification [1] and, in combination with enzymatic, cytogenetic, and molecular analyses [2 4], has helped to unravel a great deal of the biological heterogeneity of childhood ALL. Up to now, investigations examining the impact of the immunophenolype on trcalment outcome have mostly rcported results based upon conventional marker studies and have indicated a worse prognosis for children with pre-B, B-, and T lineage ALL [58]. Due to the paucity of controlled prospective studies on clinical and prognostic implications of immunophcnotypes, however, doubts have arisen regarding the value of the immunophenotype as an independent prognostic parameter in ALL [9]. Furthermore, the improvement of intensive therapy has affected the prognostic importance of most clinical and biological features in childhood ALL [10]. There fore, the main objective of immunological marker studies in the therapy study ALL-BFM 83 was to determine prospectively the incidence, the clinical and hematological features, and the prognostic significance of immunophenotypic subgroups defined by monoclonal antibodies (MoAbs) in childhood ALL.

D. Discussion

In the light of the progress made in the immunophenotyping of ALL, several studies have attempted to identify immunological subtypes with differing prognoscs, thc long-term goal being to individualize therapy according to the leukemic immunophenotype [17]. Identification of immunophenotypic features with potential prognostic significance in the large common-ALL group is rather difficult due to the relatively low failure rate for these patients. Recently, however, the prognosis in precursor Bcell-lineage ALL has been correlated with cytoplasmic µ chain expression [5] and quantitativc Ievels of CD10 expression [18]. Since cytoplasmic Ig was not generally investigated in this study, we selected the CD20 antigen for further subclassification of the common-ALL group and observed that the duration of EFS was shorter to a statistically significant degree for patients with CD20+ common ALL than for those in the CD20- common-ALL subgroup. This difference could not be explained by unequal distribution of the two well-established clinical prognostic factors, age and initial leukocyte count, nor could it be ascribed to other significant differences of clinical characteristics among these subgroups, e. g., incidence of extramedullary involvement or initial CNS disease. Within the common-ALL group, Cox regression analysis revealed independent prognostic value for only three factors, i. e., WBC, hemoglobin level, and expression of the CD20 antigen. These data suggest that common-ALL subgroups of potential prognostic significance can be defined by monoclonal antibodies and that the prognosis in precursor B-cell-lineage ALL is related to the degree of maturity of the malignant cells. Reasons for the poorer treatment outcome of the CD20+ common-ALL patients are uncertain, and additional studies on the biological characteristics of this subgroup are necessary for clarification. T -cell neoplasms have been categorized according to stages of normal differentiation into pre- T, early, cortical or common, and mature thymocyte subtypes [19]. The potential clinical relevance of subset designation, however, has not yet been demonstrated among patients with T -cell-lineage ALL. In the ALL-BFM 83 study, children with preT/T immunophenotype did not differ significantly in their response to induction therapy from other immunophenotypical subgroups, but they had a significantly shorter duration of EFS than children with common ALL. The poorer treatment outcome of T -lineage ALL, however, was mainly related to the association with unfavorable clinical features, and the pre-TIT-ALL phenotype did not retain independent prognostic significance in the multivariate model. Immunopheno typic subgroups of T -lineage ALL (i. e., pre- T vs. early vs. cortical vs. mature T-ALL) did not differ significantly with regard to clinical features, response to induction therapy, and EFS. Interestingly, four of five children in the small mature- T -cell subgroup relapsed within 16 months after diagnosis. The prognostic impact of this subgroup, however, has to be evaluated in larger series of patients. Furthermore, it should be emphasized that eight patients with T -lineage ALL did not fit into the T -cell-differentiation stages, indicating that any phenotypic categorization of T -lineage ALL is likely to be an oversimplification and does not reflect the real extent of heterogeneity of T -cell ontogeny. In contrast to a recent report from the Pediatric Oncology Group [20], the expression of CD10 within T -lineage ALL was not prognostically important in the ALL-BFM 83 study, but slight differences with regard to clinical features (age, WBC, mediastinal mass) were observed among CD10+ and CD10 pre-TIT-ALL patients. In conclusion, our data confirm the reported incidence of immunophenotypic subgroups and the clinical usefulness of monoclonal-antibody phenotyping in childhood ALL. The expression of the CD20 antigen could be identified as an independent prognostic factor in patients with precursor B-cell-Lineage ALL and may be important for risk assignment in future treatment planning. The poorer treatment outcome of T -lineage ALL can be explained largely by the association with unfavorable clinical factors. In contrast to results in adult ALL [21], immunophenotypic subgroups in childhood T -lineage ALL (i. e., pre-T vs. T ALL) did not differ significantly with regard to clinicopathological features and clinical outcome. Further studies of immunological features in combination with characterization by lineage-associated molecular probes are needed to evaluate the clinical significance of subset designation within T -lineage ALL.

Acknowledgements.
The authors are grateful to Drs B. Dörken and W. Knapp for supplying their monoclonal antibodies. We also thank J. Weirowski for helpful suggestions in preparing this manuscript.

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