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Aims: Children in a United Kingdom national trial for relapsed non-B lymphoblastic leukaemia (ALL) had their diagnostic and relapse marrow cytomorphology compared to see what changes occur during the evolution of the disease., Methods: Each relapse slide was assessed blindly for French American British (FAB) type and other morphological features by a panel of three independent microscopists without reference to each other or any diagnostic material. Diagnostic slides had been assessed by the same panel on an earlier occasion., Results: A total of 134 consecutive children was studied. Six (5%) were classified as FAB type L2 at diagnosis, compared with 18 (13%) at relapse (a difference of 9%). Twenty two (16%) changed their FAB type, 17 (13%) from L1 to L2 and five (4%) from L2 to L1. The FAB score fell at relapse in 34 children and rose in 14, a difference of 14%. Cell size was the commonest feature to change (increasing in 22 and diminishing in nine) followed by prominent nucleoli (appearing in 21 and disappearing in six). Forty four (33%) children had vacuolated blasts at diagnosis, compared with 48 (36%) at relapse. Twenty five changed their vacuole score substantially, 14 gaining > 10% and 11 falling < 10%., Conclusions: These findings reflect the variability of lymphoblast cytomorphology, but also show a trend for cells to have more prominent nucleoli and greater size at relapse. Factors controlling these features of the FAB type are unknown, but they may simply be related to the growth fraction of a particular disease and not to any lineage specific biological feature.

To define further the clinical importance of cytogenetic analysis in acute lymphoblastic leukaemia (ALL) a prospective study was performed on 139 unselected children. Analyses were considered adequate in 104, of whom 35 were normal and 69 had clonal abnormalities. Abnormalities were categorised according to banded chromosome analysis as well as chromosome count. Karyotypes were correlated with clinical and laboratory features at diagnosis and with survival. Of the successful analyses, thirty five (34%) children had no abnormalities; this group contained an excess of T cell disease. Twenty five (24%) had a "characteristic" hyperdiploid karyotype and as a group had lower presenting white counts, a tendency to CD10, and periodic acid schiff positivity of the blast cells and smaller spleens. None was an infant and only one was over 10 years old. Seven (7%) children with t(9; 22), t(8; 14), or t(4; 11) translocations were grouped together as "specific" translocations. Collectively they had a significantly worse prognosis than the remainder. Nine children developed central nervous system relapse, six of whom had either t(4; 11) or abnormalities of 9p or 19p. A descriptive classification taking into account chromosome bonding pattern is cytogenetically more appropriate and may be more clinically useful than grouping children simply by chromosome number. As knowledge and techniques improve, the classification of cytogenetic abnormalities in ALL will need to be kept under frequent review.

Pretreatment marrow blast cells were studied in 38 boys and 27 girls (aged 1-14) with acute lymphoblastic leukaemia by flow cytometry after staining with propidium iodide.The percentage of blast cells in the S phase of the cell cycle ranged from 1% to 40% (median 6%). A correlation was found between the percentage of cells in S and the morphological classification of the French American British Cooperative Group (FAB), presence of T or B cell markers, haemoglobin concentration, blast size, bone pain, platelet count, and an inverse correlation with coarse granule and block staining with Periodic-acid-Schiff (PAS).63 of the 65 children attained complete remission. During the first 24 months of follow up there were fewer relapses (P = 0·054), and deaths (P = 0·004) in those children with 6% or fewer blasts in S phase. The difference was most marked in the first 12 months with 4 relapses out of 33 in the group with 6% or fewer cells in S compared with 13/30 in the group with > 6% cells in S.In order to investigate the prognostic significance of the pretreatment proliferative studies in greater detail, remission duration was correlated with 17 presenting features. Each feature was correlated individually and then the simultaneous effect of all the features was assessed by stepwise multiple regression.Only 3 features of the disease at diagnosis were individually correlated with duration of remission. These were% cells in S (P < 0·001), log white cell blood count (WBC) (P < 0·01) and the presence of T- or B-cell surface markers (P < 0·05). However, the multiple regression analysis showed that cell markers were not an independent prognostic feature, whereas the percentage cells in S and log WBC were independently and significantly correlated with duration of first remission (P < 0·001 in each case).

Bone marrow smears taken at diagnosis and subsequent haematological relapse from 41 patients with lymphoblastic leukaemia (ALL) were compared to assess the proportion of blast cells showing a positive periodic acid-Schiff (PAS) reaction at different stages of the same disease. 20 patients never displayed more than 10% PAS positive blasts at any stage, and of these 8 never had any PAS positivity at all. 7 patients maintained a proportion of PAS positive cells over 10% of the total but with no loss or gain in the numbers of such cells. 14 patients showed a significant change in the PAS reaction during the course of their disease, 7 showing a marked reduction in PAS positive cells, and 7 showing an equally marked increase. From these results it seems that the PAS reaction does not identify a sub-type of ALL or mark the degree of differentiation of a given case. It could be indicative of a specific stage of the lymphoblast mitotic cycle.

Blast cell morphology was assessed at diagnosis and subsequent bone marrow relapse in 33 unselected patients with lymphoblastic leukemia (ALL). Each marrow was classified 'blind' according to the French-American-British (FAB) criteria, and it was found that 19 of 24 (79%) patients initially typed as FAB L1 changed to FAB L2 during the course of their disease, but no patient made the reverse morphological change (p is less than 0.001). Five patients retained FAB L1 appearances; these included three of the four who had T-cell markers. One patient typed as FAB L3 did so consistently. This study indicates that FAB L2 ALL frequently emerges as a treatment-resistant offshoot of FAB L1 and provides further evidence that this marks a more aggressive form of the disease.

Diagnostic bone marrow smears from 132 patients with acute lymphoblastic leukaemia, (ALL) were stained simultaneously by the periodic acid-Schiff (PAS) reaction, and the blast cell positivity was assessed quantitatively. The patients fell naturally into two unequal groups: those with more than 20% PAS-positive blast cells (44 patients) and those with less (88 patients). There was no relation between the degree of positivity and age, sex, or presenting leucocyte count. Actuarial survival studies showed that the group with more than 20% PAS-positive blast cells survived longer, but that this difference assumed statistical significance only after the exclusion of patients over 14 years old and those with high white cell counts at the time of diagnosis. It appears that the PAS reaction can identify long survivors among patients with ALL, but not in the absence of features strongly associated with a poor prognosis.

Children from the UKALL V trial were studied to assess the clinical importance of myelosuppression during uninterrupted 'maintenance' treatment of 'standard risk' lymphoblastic leukaemia. Those receiving daily 6-mercaptopurine and weekly methotrexate who were in first remission 20 months from diagnosis were divided into two groups on the basis of whether or not they had ever had an absolute neutrophil count of less than 0.5 x 10(9)/l recorded during maintenance treatment up to that time. Of 105 evaluable children, 45 (43%) became neutropenic at least once, and 60 (57%) did not. Seven (16%) of the neutropenic group subsequently relapsed compared with 27 (45%) of the remainder. This difference was still significant if the analysis was stratified by total treatment time (two or three years), age, sex, or diagnostic white cell count. Seven (16%) neutropenic children died in remission, compared with one (2%) of the non-neutropenic children. Therapeutic myelosuppression during standard maintenance treatment of 'standard risk' lymphoblastic leukaemia is associated with increased toxicity but a reduced risk of relapse. The unexplained improvement in long term survival in the United Kingdom in recent years may in large part be due to this.

As part of a central review of cell morphology in childhood lymphoblastic leukaemia (ALL), marrow smears from entrants to the Medical Research Council trial UKALL VIII, other than those from children with B-ALL, were studied prospectively for the presence or absence of blast cell vacuoles and for any clinical or biological relevance this feature might have. Adequate slides were available from 733 patients (88% of the trial entrants) after five with B ALL were excluded. Vacuolated blast cells (greater than 10%) were present in 204 (28%). The presence of vacuoles was associated with PAS positivity (chi 2 = 27.8; P less than 0.0001), a diagnostic white cell count (WBC) less than 50 x 10(9)/l (chi 2 = 13.1; P less than 0.0001), and the immunophenotype of 'common' ALL (CD10 positive) (chi 2 = 9.1; P less than 0.01). There was no clear association with French-American-British (FAB) type L1 or L2. The 204 patients with vacuoles had a significantly superior disease free survival compared to the remainder (2P = 0.01), a difference which remained significant when the analysis was stratified by FAB type (2P = 0.01), age (2P = 0.02) or sex (2P = 0.02), but which was lost when stratified by WBC (2P = 0.06). These findings provide further evidence that, outside the context of B-ALL, vacuoles are indicative of a relatively benign disease which responds well to therapy. The French-American-British (FAB) classification should be modified to take this into account.