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E-rosetting of leukaemic blast cells is one of the markers of T-cell acute lymphoblastic leukaemia (ALL). In children, E+ ALL has a bad prognosis. In adults, data are scarce. This report provides information on 25 E+ ALL adult patients who have a minimum follow-up time of 36 months. Twenty-two of 25 patients (88%) achieved complete remission (CR) (median duration 16 months), and six of them were alive, relapse-free, and off therapy after 36-81 months, with a 26% projected 6-year relapse-free survival. In 97 patients with E-SmIg- ALL, who were treated at the same Institutions, over the same period of time, and by the same modalities, the outcome of therapy was almost identical: CR 80%, median duration of first CR 15 months, projected 6-year relapse-free survival 15%. The white blood cell (WBC) count at presentation influenced significantly and to the same degree first CR length in both E+ and E- cases. In this adult series, WBC count was not as high as in children. Moreover, a high Hb concentration, a very high WBC count, lymphadenomegaly, and mediastinal involvement, were found more frequently in adolescents and young adults than in adults. Based on these data, it is suggested that in adults E-rosetting as such is not a marker of a poorer prognosis, that some of the typical features of children E+ ALL weaken with age, and that in adults the disease can have a less aggressive character.

Between 1972 and 1982, 112 consecutive previously untreated adults (aged 15-69 years, median 26) commenced therapy for acute lymphoblastic leukaemia (ALL) at St Bartholomew's Hospital. The first 63 patients entered into the study received initial treatment which comprised four cycles of adriamycin and vincristine, prednisolone and L-asparaginase with the first cycle (OPAL). In 1978, six cycles were given, with escalating doses of adriamycin and cyclophosphamide from cycle 3 (HEAV'D). Central nervous system (CNS) prophylaxis incorporated intrathecal methotrexate and cytosine arabinoside with cranial irradiation. Maintenance chemotherapy consisted of 6-mercaptopurine, cyclophosphamide and methotrexate for 3 years. Results obtained with the OPAL and HEAV'D regimens were not significantly different. The overall complete remission (CR) rate was 66% (73/111), factors correlating unfavourably with achievement of CR being advanced age (P less than 0.001) and L3 morphology/B-ALL immunophenotype (P less than 0.01). Fifty-three patients have relapsed, the bone marrow being the primary site in 43. Extramedullary relapse alone occurred in 10 (seven CNS, two testicular and one skin). Only three of the 64 patients who had complete CNS prophylaxis subsequently relapsed in the CNS as an isolated site. One patient died in CR, 19 remain in continuous CR between 2.5 and 10.5 years. The median duration of remission of the 73 patients who achieved CR was 18.5 months, factors correlating favourably with duration of CR being low blast cell count at presentation (P less than 0.002) and common ALL immunophenotype (P less than 0.04). Twenty-four patients remain alive, with a median survival of all patients of 18 months. Long-term survival is possible for approximately 20% of adults with ALL treated relatively intensively.

In vitro incorporation of tritiated thymidine was measured in blast cells from 33 unselected and untreated patients with lymphoblastic leukaemia (ALL) both when autologous plasma was present and also when it was substituted by pooled normal plasma. A similar procedure was carried out on 19 patients with acute non-lymphoblastic leukaemia (AnonLL). Plasma from the patients with ALL was variably found to reduce the uptake of the radiolabelled DNA-precursor by their own blasts, with the most marked effect apparent in those with shorter survival times (P < 0.02). This phenomenon was not observed in AnonLL. The amount of plasma-mediated inhibition shown by the ALL patients also correlated overall with their WBC, a known feature of a poor outlook, but even in the 21 patients with WBC below 20.0 x 10(9)/l there was still a significant association between plasma effect and survival (P < 0.01). The demonstration of such inhibitory plasma may be a useful prognostic marker in otherwise 'standard risk' ALL, and also may indicate a large tumour mass where this is not reflected by the height of the circulating WBC.

A chromosomal classification of 93 children with acute lymphoblastic leukaemia (ALL) is presented. The chromosomal categories were normal, hyperdiploid, pseudodiploid and hypodiploid: the chromosomally abnormal cases were classified according to the presence of an abnormal clone. The longest follow-up was 9 years. Infants and older children were over-represented in the pseudodiploid category: this association was statistically significant. Patients in the hyperdiploid and hypodiploid categories had the longest first remissions and overall survival and those in the pseudodiploid category the shortest. These effects were statistically significant even when the effect of age and leucocyte count were taken into account. Thus chromosomal findings at diagnosis in ALL can be used as an independent prognostic factor.

Twelve patients with B-cell prolymphocytic leukaemia (PLL) were treated with splenic irradiation at a weekly dose of 100 cGy to a maximum total dose of 1000 cGy. There was no morbidity associated with this treatment. SEven patients responded. Three achieved a good response and four a partial response. Two of the patients who had a partial response have subsequently died of unrelated causes. Four of the five patients who failed to respond have died as a result of their disease. When more than 25% of the prolymphocytes formed rosettes with mouse red blood cells (MRBC) the patients appeared to respond better to splenic irradiation. There was no correlation between response and the initial white cell count or the size of the spleen.

Blood lymphocytes from 50 patients with chronic B-lymphocytic leukaemia (B-CLL) were cultured in vitro with and without the polyclonal B-cell activators (PBA) dextran sulphate (DxS), lipopolysaccharide from E. coli (LPS), and Epstein Barr virus (EBV). Patients with blood lymphocytes that showed a high spontaneous or PBA-induced 3H-thymidine uptake in 4 d cultures had a significantly shorter therapy-free survival than patients whose lymphocytes showed a low thymidine uptake. The DxS-induced cellular thymidine uptake was the most powerful predictor of prognosis. Eighteen patients with leukaemic cells responding to DxS stimulation had a median therapy-free survival of 17 months and a probability of 5 year therapy-free survival of less than 0.1, whereas for 30 patients with DxS unresponsive cells the corresponding figures were greater than 120 months and greater than 0.7, respectively (log rank, P less than 0.0001). A multivariate Cox's regression analysis revealed that the DxS-induced leukaemic cell response was of greater prognostic importance than clinical features such as blood counts and staging according to Rai and Binet. Therefore PBA-induced leukaemic cell thymidine uptake seems valuable in the prediction of prognosis in B-CLL.

In 100 untreated patients with chronic lymphocytic leukaemia (CLL) lymphocyte doubling time (LDT) has been investigated in relationship with clinical stages, bone marrow histological patterns, treatment-free period and survival. Although partially correlated with clinical stages and bone marrow patterns, LDT has a clear prognostic significance by itself: whereas a LDT of 12 or less months identifies a population of patients with poor prognosis, a LDT higher than 12 months is indicative of good prognosis as substantiated by a long treatment-free period and survival. This simple parameter can be useful in the clinical management of CLL patients.

HLA-A and -B antigens were determined for 94 children with acute lymphocytic leukaemia (ALL) and for 376 normal controls. Sixty-four of these 94 patients were typed for lymphocyte surface markers and 59 were defined as 'null cell' ALL. There was no difference in the distribution of the HLA-A or -B locus antigens between the control group and the entire group of patients with ALL or the 'null cell' subgroup. Patients with HLA-A9 determinants had a significant increase in early, first remission duration compared to patients without HLA-A9. This was particularly evident in the 'null cell' ALL subgroup. In addition, HLA-A9 appeared to be an independent factor affecting the length of first remission since there was no correlation between known prognostic factors such as patient age, sex or WBC and the presence or absence of the HLA-A9 antigen. Survival for the first 12-18 months was also greater in the HLA-A9 group than in the non-HLA-A9 population. Thus, the presence of HLA-A9 appears to be associated with some protective effect among patients with ALL.

The initial diagnostic bone marrow specimens from 90 consecutive, untreated patients with chronic lymphocytic leukaemia were examined for the pattern of lymphocytic infiltration in relation to clinical stage (International Workshop System) and survival. Three non-diffuse (interstitial, nodular, mixed nodular-interstitial) and one diffuse pattern were recognized. Generally, the bone marrow patterns correlated well with clinical stage: a non-diffuse pattern prevailed in early, and a diffuse pattern in later stages. However, with a Cox analysis of the covariate effect of clinical stage and bone marrow pattern on survival, the bone marrow pattern was shown to have independent prognostic significance in the early stage A in which a diffuse pattern carried a fourfold increase in death rate as compared to a non-diffuse pattern. These high risk patients could not be identified by the Rai substages of the International Workshop System.

Between 1979 and 1982, 192 patients with acute lymphoblastic leukaemia were given allogenic bone marrow transplants from HLA-identical siblings. Data on 57 patients transplanted in first remission were compared with the results in 96 patients transplanted in second remission, and 39 in third or subsequent remission. The majority of these patients were of the non-B non-T-ALL and T-ALL subtypes. The 2-year actuarial survival for non-B non-T-ALL was 58% for patients transplanted in first remission, 34% for second remission patients and 33% for patients transplanted in third or subsequent remission (P = 0.60). For patients with T-ALL, the survivals at 2 years for first and second remission transplant patients were 61% and 10%, respectively (P = 0.04). Multifactorial analysis demonstrated a significantly higher probability of survival for patients grafted in first remission (compared with more advanced remission states) and with bone marrow from young (age less than or equal to 20 years) donors. The 2-year actuarial risk of relapse for patients with non-B non-T-ALL transplanted in first remission was 0%, 32% and 69% for second and third or subsequent remission patients, respectively (P = 0.04). For T-ALL the actuarial risk of relapse at 2 years is 10% for first remission grafts and 48% for second remission grafts (P = 0.07). Only patients (with both non-B non-T/and T-ALL) transplanted in first remission have a high and stable probability of remaining in remission.

The value of the Rai clinical staging system and lymphocyte morphology in predicting survival in chronic lymphocytic leukaemia was examined in 83 patients who had been followed for at least 5 years. Patients with less clinical evidence of disease (Stages 0 and I) had significantly longer survivals than patients with more evidence of disease (Stages II, III and IV). Patients in whom greater than 35% of the lymphocytes resembled benign atypical lymphocytes had longer survivals than those in whom most of the lymphocytes had narrow rims of cytoplasm and coarsely clumped chromatin. The survival differences in the morphologic groups were less striking than those in the clinical stages, and when the morphological groups were corrected for clinical stage, no significant differences in survival among the morphologic groups remained.

Bone-marrow biopsy has been performed in 63 cases of chronic lymphocytic leukaemia (CLL). Four different histological patterns were observed: (a) interstitial (lymphoid infiltration without displacement of fat cells) in 12 cases; (b) nodular (abnormal lymphoid nodules without interstitial infiltration) in 10 cases; (c) mixed (combination of the first two patterns) in 21 cases; and (d) diffuse (replacement of both haemopoietic and fat cells by lymphoid infiltration) in 20 cases. Statistical analysis of actuarial curves showed a significant difference of survival probability according to the bone marrow infiltration patterns. Thus, in patients with interstitial or nodular patterns the life expectancy is significantly longer than in those with mixed or diffuse patterns. furthermore, a significant degree of correlation between bone marrow infiltration patterns and different methods of clinical staging in CLL was apparent. The different bone marrow infiltration patterns in CLL probably reflects variations in the amount of lymphoid accumulation during the natural course of this disease. Because of its prognostic significance, bone marrow biopsy should have a place in CLL evaluation and staging.

The prognostic value of biological, clinical and laboratory features was analysed in a series of 265 patients with chronic lymphocytic leukaemia (CLL) and prolymphocytic leukaemia (PLL). On univariate analysis seven features were shown to influence significantly the survival of the whole group of patients: absolute prolymphocyte count (ABS PROL), percentage of prolymphocytes (%PROL), WBC, spleen size, age, intensity of surface-membrane immunoglobulin (SmIg) and mouse (M) rosettes. Multivariate regression analysis of these features showed that only ABS PROL and spleen size had independent prognostic significance. The survival in PLL (38 cases) was significantly shorter than in CLL (227 cases) (median survival = 3 and 8 years, respectively). Patients with CLL with an increased %PROL (11-55%), defined as CLL/PL, could be divided into two groups: those with ABS PROL less than or equal to 15 X 10(9)/l (26 cases) fell within the 'standard-prognostic risk' for typical CLL (i.e. less than or equal to 10% PROL), whereas the survival outlook for the cases with ABS PROL greater than 15 X 10(9)/l (40 cases) was as bad as for PLL. A scoring system was generated with the four features that showed high prognostic significance: ABS PROL, spleen size, SmIg and M-rosettes. The score proved to be superior to any single feature as a predictor of survival, being especially useful in the analysis of the CLL/PL group: cases with high scores (greater than 2) had a median survival of 2.5 years, while the median has not been reached for those with low scores (less than or equal to 2). We suggest that this scoring system may help to identify the cases of CLL/PL that behave as PLL, and as such may benefit from different treatment.

Results of bone marrow transplantation (BMT) in 63 adults and children with ALL transplanted in the 5-year period 1979-83 were analysed. Twenty-one patients (33%) relapsed, 25% of the group died in relapse and 19% died from complications of BMT. The actuarial disease-free survival at 6 years was 38%. Relapse after BMT could be predicted by standard prognostic diagnostic features such as age, sex, cell type and presenting blast cell count. Patients transplanted in first remission selected for their poor prognosis had a lower relapse risk than a similar group of poor prognosis patients transplanted in second or subsequent remission (P less than 0.05). Relapse following second and subsequent remission BMT was predicted by a score based on standard prognostic features or by the pace of the disease: patients with an interval of less than 2 years between diagnosis and first relapse having a 15% actuarial disease-free survival, compared with 81% for patients with an interval greater than 2 years (P less than 0.001). These results emphasize that ALL is a heterogeneous disease and establishes the importance of determining relapse risk when selecting BMT and other treatment schedules for ALL patients.

Lymphocytes from 33 out of 63 patients with B-cell chronic lymphocytic leukaemia (B-CLL) were successfully stimulated for cytogenetic analysis by means of two B-cell mitogens: pokeweed mitogen and lipopolysaccharide-B, used after pretreatment of the cells with neuraminidase and galactose oxidase. All patients had abnormal clones in 30-100% of the cells analysed. Chromosomes more frequently involved were Nos. 1, 3, 6, 11, 12, 13 and 14. The most common abnormality was a marker 14q+ (breakpoint 14q32) seen in 17 cases; trisomy 12 was observed in seven cases. A clinical scoring system was used to investigate the correlation of chromosome abnormalities with prognosis. The group with 14q+ was often associated with features of progressive disease, namely; prolymphocytoid or Richter transformation, refractoriness to therapy, high WBC and advanced staging. A significant difference in survival was observed between patients with 14q+ and the rest: median survival from diagnosis being 45 months and over 64 months, respectively (P less than 0.05); when survival was calculated from the time of chromosome analysis the values were 8 months and more than 41 months, respectively (P less than 0.01). It is suggested that 14q+ is acquired during the evolution of CLL and that this development may be a key event in the clinical progression of B-CLL. Other abnormalities, including trisomy 12, were not found to be associated with a worse prognosis.

200 patients with B-cell chronic lymphocytic leukaemia (B-CLL) presenting to a single centre over 13 years have been studied. In 72.2% the diagnosis was made on an incidental blood count, and 70.1% were stage A at presentation. Those patients whose cells expressed surface IgM kappa were significantly more likely to be stage A at presentation and significantly less likely to have a lymphocyte count greater than 50 X 10(9)/l, to have progressive disease or to require treatment than those with other classes of surface Ig. Patients whose cells express surface IgM kappa have a significantly longer actuarial survival than others and this is also so when only patients in Binet stage A or when only patients presenting below the age of 75 are studied. By studying all of the cases presenting in a single catchment area we have attempted to avoid the bias against trivial disease likely to be seen in specialist referral centres.

From February 1975 to February 1977, 880 patients with acute lymphoblastic leukaemia were enrolled on Children's Cancer Study Group protocol 141 designed to evaluate prognostic factors and more intensive therapy for patients with poor prognosis. 765 diagnostic bone marrow aspirates from 23 institutions were available for classification using the French-American-British system. 60 of 615 patients with L1 morphology had vacuolated lymphoblasts. Patients with vacuolated lymphoblasts had a better disease-free survival (P = 0.14) and a significantly better survival (P = 0.03) but the presence of vacuoles was associated with a low initial WBC and an age range associated with improved prognosis for disease-free and over-all survival.

The first and second Medical Research Council UKALL trials have shown that alteration in the timing of methotrexate and 6-mercaptopurine maintenance therapy for the treatment of acute lymphoblastic leukaemia can markedly change drug induced toxicity. Maintenance chemotherapy in both trials used a similar total dosage of these drugs but the timing of their administration was different in the two schedules.

The records of 121 children presenting with acute lymphoblastic leukaemia between 1969 and 1982 were reviewed. The overall relapse free survival rate was 50%. However, girls presenting with a total white blood cell count of 20 X 10(9)/l or less (35% of all patients) had a particularly favourable prognosis with an 80% relapse-free survival rate at 12 years. The difference in prognosis between the sexes is confirmed but this difference is confined to the low initial white cell count group. We suggest that girls in this group should be excluded from the more intensive arms of new treatment protocols.

The use of T and B lymphocyte markers and of different antisera raised against malignant B cells and fetal thymocytes allowed the classification of 100 patients with acute lymphoblastic leukemia (ALL) into three groups. (I) Patients with non-T non-B ALL whose cells were devoid of conventional B and T markers but characterized by a leukaemia associated antigen (69 cases). (2) Patients with T-derived ALL (28 cases). (3) Patients with ALL of B cell origin (three cases). The search for haematological and clinical correlations showed that those patients with T-derived ALL tended to have a higher leucocyte count (P=0.05) and acid phosphatase positivity of blast cells (P= 0.01), a higher incidence of tumour presentation (P=0.05) and a thymic mass. Survival curves for the two main groups of patients are similar at 36 months but meningeal relapses were more frequent in patients with T-derived ALL (P=0.02).

Advances in both allogeneic marrow transplantation and conventional therapy for acute leukaemia have complicated the choice between bone marrow transplantation (BMT) and other remission treatment options. Because older patients may be more susceptible to BMT-related complications, this study analysed the effect of age on clinical outcome for 149 patients with acute leukaemia in remission receiving allogeneic BMT. Overall projected relapse-free survival at 3 years post-transplant is equivalent for 48 adults (18 years or older) and 101 children (less than 18) at 45.4% (31.1-59.6; 95% confidence interval) and 39.9% (30.1-49.7; 95% C.I.), respectively. Among 73 patients with acute lymphocytic leukaemia (ALL) 35.3% of adults and 30.1% of children survive relapse-free at 3 years. Cox multiple regression analysis demonstrated that higher diagnostic white count, but not pre-transplant extramedullary leukaemia, remission number, or age, was important as an independent adverse clinical prognostic factor for patients with ALL. Overall outcome was better for 76 patients with acute myeloid leukaemia (AML) with 51.6% of adults and 52.9% of children surviving relapse-free at 3 years post-transplant. Cox multivariate regression analysis identified first remission status and lower white cell count, but not patient age, as independent predictors of improved relapse-free survival for AML patients. Adults had greater transplant morbidity, predominantly related to a higher incidence of acute graft-versus-host disease (GVHD), resulting in longer hospital stay. Survival at 100 d, long-term survival and clinical performance status were similar in both age groups. These data suggest that results of allogeneic BMT for adults with acute leukaemia compare favourably with those found in children and are superior to most reports of conventional chemotherapy. Allogeneic BMT remains a reasonable option for remission acute leukaemia patients up to the age of 45.

The results of conventional chemotherapy in adult acute lymphoblastic leukaemia (ALL) have not improved substantially in recent years. The present study is based on a flexible policy of marrow transplantation (allograft and autograft without marrow purging) in first remission compared with a group treated with standard maintenance therapy after a common induction sequence. The actuarial disease free survival (DFS) and actuarial overall survival (OS) at 3 years for autologous marrow grafted patients was 30% and 65% respectively. The allogeneic transplant group had DFS of 30% and OS at 3 years of 38% compared with DFS (12%) and OS (12%) for patients on 6-mercaptopurine and methotrexate maintenance. The actuarial disease free survival calculations include patients on protocol not entering remission, therefore, giving the worst possible result. We conclude that high dose chemo/radiotherapy with autologous marrow rescue in first remission followed by no maintenance provides better results in terms of overall survival and quality of life than standard ALL maintenance in adult patients. Results for allogeneic transplant in ALL are less good in terms of duration and quality of survival and the majority of deaths are related to causes other than leukaemic relapse.

Isolated CNS relapse occurred as a first event in 23 (6%) of 354 children with acute lymphoblastic leukaemia (ALL) who shortly after achieving remission had been treated with craniospinal irradiation or cranial irradiation and intrathecal methotrexate. CNS relapse occurred at a median time of 79 weeks from diagnosis and in three cases was asymptomatic, being diagnosed on routine lumbar puncture at completion of maintenance therapy. CNS remission was achieved with weekly intrathecal methotrexate in all but two cases who died in relapse. A second course of radiotherapy was given in 12 cases; at the time of relapse in three and delayed from 14-170 weeks later in nine. Intensified systemic chemotherapy was used in 13 patients and all but three continued on regular maintenance intrathecal methotrexate. Disease free remission following CNS relapse ranged from 9 to 366 weeks (median 76 weeks) with subsequent relapses occurring in the testis, CNS and in particular the bone marrow. Survival after relapse ranged from 11 to 476 weeks (median 92); seven patients are alive; four in continued remission, two with recurrent but controlled CNS disease, and one in remission following bone marrow transplant after subsequent marrow relapse. Recurrent CNS disease was significantly less frequent in patients who were reirradiated. It appears that long-term survival is possible after isolated CNS relapse but that further intensification of systemic chemotherapy and possibly chemo-radiotherapy and bone marrow transplant will be required to reduce the high risk of subsequent bone marrow relapse.

Flow cytometry with propidium iodide and fluorescein isothiocyanate was used to study 46 cases of adult acute lymphoid leukaemia (ALL) before any form of chemotherapy. Cell proliferation was related to the other clinical and biological characteristics and its prognostic significance was evaluated. The following cell-cycle variables were determined: S, G2 + M, and the Low Protein Content fraction of G1 (LPC fraction). The L3 group, corresponding to B-ALL, had significantly higher proliferation than L1 and L2 (P less than 0.01). The proliferation rate was not significantly higher for T-ALL than for the other phenotypes. Complete remission was successfully induced significantly more often in cases with the LPC fraction under 50% (P less than 0.05). Failure was mainly related to resistance to chemotherapy. Of the four patients who died during aplasia, three had an LPC fraction below 25%. Duration of complete remission and survival were significantly shorter for L3 which is the most proliferative ALL (P less than 0.01). Survival was also found to be longer (P less than 0.05) when G2 + M was between 3.8% and 5.1%. This finding and the negative correlation between S and G2 + M (P less than 0.01) are discussed.