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Current Issues in the Management of Children with Acute Lymphocytic Postgrad Med J: first published as 10.1136/pgmj.61.712.93 on 1 February 1985. Downloaded from Postgraduate Medical Journal (1985) 61, 93- 102 Current issues in the management ofchildren with acute lymphocytic leukaemia Donald Pinkel Department ofPediatrics, Temple Universiti School of Medicine, Philadelphia, PennslIvania and St Christopler s Hospitalfor Children, Philadelphia, PennsYlvania, USA. Introduction In the 12 years since curative therapy for acute curative treatment. How can this be accomplished? As lymphocytic leukaemia (ALL) became accepted, the physicians and scientists we can only suggest that lecterns and literature have reflected considerable political leaders place highest priority on child health, concern and activity toward establishing optimal including facilities for curative leukaemia therapy. methods. Many issues have been raised about clas- However, we have the power within our own ranks to sification and prognostic stratification, drug selection, insist that therapeutic research be directed toward drug combination and dosage, duration of therapy, simplification, reduced technology and less cost so prevention of meningeal and testicular relapse, infec- that ready availability and accessibility of curative tion control, psychosocial support and sequelae of therapy will be more feasible. treatment. In addition, the use of alternate methods such as immunotherapy and bone marrow transplan- tation have been explored. Classification and prognostic stratification by copyright. The purpose of this paper is to describe some of these issues and to present some thoughts about them. Biological species of ALL can be identified using a combination ofmorphological, cytochemical, immun- ological, genetic and clinical criteria. Not every strain The goal of management of ALL within a species will demonstrate all criteria. As with enteric bacteria, some strains do not clearly Although palliation was once the goal of leukaemia fall into one species or the other. However, for therapy, most haematologists and cancer therapists purposes of investigation and management, the deter- have come to accept cure as a reasonable expectation mination of biological species appears to be as impor- http://pmj.bmj.com/ for children with ALL. This means that the criterion tant to leukaemia therapy as to antibacterial therapy. for success is continuous leukaemia-free survival, off Children's ALL can be divided into that of B- all therapy, and at little or no risk of relapse. For the lymphocyte lineage and that of T-lymphocyte deriva- majority of children with ALL, this point appears tion (Table I). The most frequent B-lymphocyte approximately 7 years after diagnosis and 4 years after species is common ALL (Bowman et al., 1981 a; Pullen cessation oftreatment (George et al., 1979). Treatment et al., 1981; Greaves et al., 1981; Greaves et al.. 1983). regimens, therefore, need to be evaluated and com- pared in terms of 7 year cure rates. The custom of on September 23, 2021 by guest. Protected utilizing complete remission durations, persisting from the pre-curative era, can be discontinued. Table I Biological species of acute lymphocytic leukaemia The importance of curative therapy is directly in children proportional to its availability and accessibility for everyone who needs it. For children, who have no Species % ofpatients* control over their socioeconomic status and residence, B-lymphocyte series it is mandatory that there be no barriers to their Common 60 Pre-B 15 Null 10 B-lymphoblastic I Donald Pinkel, M.D. T-lymphocyte series 14 Correspondence: Department of Pediatrics, Temple Univer- sity School of Medicine, 2600 N. Lawrence Street, Philadel- * Approximate % (Greaves et al., 1981; Pullen et al., 1981; phia, PA 19133 USA. Bowman et al., 1981a). ) The Fellowship of Postgraduate Medicine, 1985 Postgrad Med J: first published as 10.1136/pgmj.61.712.93 on 1 February 1985. Downloaded from 94 D. PINKEL This occurs most often in white children between ages often present. An 11: 14 chromosomal translocation 2 and 6 years who dwell in the temperate zones. Boys has been described in 4 of 16 cases examined (Williams and girls are equally affected. The disease arises in et al., 1984). Mitoses are frequent and thymidine bone marrow and is typically marked by pan- labelling index and percent S phase cells average cytopenia, bleeding, fever, bone and joint pain. The 12-14% (Look et al., 1982; Murphy et al., 1977). The leukaemic lymphoblasts are generally monotonous in disease can progress rapidly with peripheral blood appearance. They display la and common antigens at leukaemia cell counts reaching the hundreds of their surfaces and often are hyperdiploid by cytogen- thousands and early development of frank meningeal etic analysis and flow cytometry (Look et al., 1982). leukaemia. Metabolic complications are common. Mitotic activity is low and thymidine labelling index It is popular to use various clinical and laboratory and percent S phase are usually less than 6% (Murphy features of patients with ALL to estimate prognosis et al., 1977; Look et al., 1982). The course of the and to select therapy according to this assessment. The disease tends to be relatively slow. Complete remis- validity of this approach is questionable. First, these sions are readily induced, remission durations are long prognostic criteria are usually based on complete and, with conventional combination chemotherapy, remission duration rather than cure rate. Since some the cure rate is in the 60% range. species of ALL tend to relapse late and other species Pre-B ALL is a more frequent species in black tend to relapse early, this gives undue weight to children with leukaemia than in white (Crist et al., biological and clinical features associated with the 1984). The cells display cytoplasmic immunoglobulin species in which relapses tend to occur early. For heavy chains as well as the surface antigens noted in example, thymic ALL tends to relapse within 18 common ALL. A 1: 19 chromosomal translocation months while non-T non-B ALL continues to relapse has been recently identified in 7 of23 pre-B ALL cases over 4 to 5 years (Sallan, 1981). Use of complete tested (Williams et al., 1984). Duration of remission remission duration as a criterion for prognosis can and cure rate with conventional therapy are less than exaggerate the importance of thymic species as an for common ALL. unfavourable sign. It also results in exaggeration ofthe Specific cell surface or cytoplasmic markers have importance of features more often associated with not been identified in null ALL (Greaves et al., 1981). thymic species, such as male sex, older age, mediastinal by copyright. Its B-lymphocyte lineage has been identified by gene mass, high initial white blood cell count and normal rearrangement studies (Waldmann & Korsmeyer, haemoglobin value in predicting a poor prognosis. 1983). This species of ALL is more often seen in Secondly, methods ofprognostic stratification often infants, adolescents and adults (Bowman et al., 1981 b; ignore the most important prognostic factor - Greaves et al., 1983). Remission duration and cure appropriate treatment. Combination chemotherapy rate are less than in common or pre-B (Pullen et al., results in higher cure rates than single drug treatment 1983; Greaves et al., 1981; Pullen et al., 1981; Bowman and full dosage of drugs is more effective than half et al., 198 la). dosage. Selection of drugs according to biological B-lymphoblastic ALL ('Burkitt-like' cell leuk- species of ALL can also alter outcome. For example, aemia) occurs more frequently in boys than girls and in one comparative study, the long-term leukaemia- http://pmj.bmj.com/ tends to rise from submucosal lymphoid tissue, lymph free survival rate for children with thymic ALL was the nodes and viscera (Preud'homme et al., 1981). The same as for those with non-thymic ALL provided the cells have a distinct morphology with deep basophilic children with thymic ALL received periodic infusions cytoplasm and cytoplasmic vacuoles and a distinctive ofcytosine arabinoside and cyclophosphamide (Lauer 8:14 chromosomal translocation. Immunoglobulin is et al., 1983). Thus the prognostic disadvantage ofmale secreted at the cell surfaces. Mitoses are frequent sex, older age, mediastinal mass and high initial white and percent S phase cells are in the 20-25% range blood cell count was overcome in children who on September 23, 2021 by guest. Protected (Look et al., 1982). The disease progresses rapidly with received chemotherapy more appropriate to their severe metabolic complications. Although remissions species of ALL. are produced by treatment, they are often incomplete It appears that present systems of prognostic and transient. Early mortality is high and survival is stratification of ALL are largely artefacts resulting poor. from our failure to identify biological species of ALL Thymic (T-cell) ALL usually arises in thymic tissue. and to treat each accordingly. Our impression, for Patients are more frequently boys, more often older example, that male sex, mediastinal mass and high than 6 years and initially tend to have higher peri- white blood cell count are bad prognostic signs and pheral blood values for haemoglobin, granulocytes these patients require 'more intensive' therapy is and platelets than patients with ALL of B-lymphocyte probably incorrect. It is simply that such patients have derivation (Greaves et al., 1981). The cells have thymic a distinct biological species of ALL that requires antigens at their surfaces and often form heat stable different therapy and that we need to use cure rate and rosettes with sheep red blood cells. Pseudodiploidy is not remission duration as our criterion of success. Postgrad Med J: first published as 10.1136/pgmj.61.712.93 on 1 February 1985. Downloaded from CURRENT ISSUES IN PAEDIATRIC ALL 95 Inducing remission These results suggest that children with typical thymic ALL can survive as frequently as children with There is more agreement about methods of initial non-T non-B ALL provided they are given repeated induction ofcomplete remission of ALL than perhaps courses of Ara-C and cyclo in addition to the usual any other features of management.
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