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The AML16 trial evaluated the combination of the farnesyltransferase inhibitor, tipifarnib, and low dose cytarabine (LDAC) in older acute myeloid leukaemia (AML) patients in a 'Pick a Winner' design. The aim was to double remission rates compared to LDAC, with initial evaluation after 100 patients. Failure to improve remission would result in discontinuation. A total of 65 patients, median age 74 years (range 62-86), were randomized. After reviewing the first 45 patients, the Data Monitoring Committee concluded that the overall aspirations would not be met and recommended closure. The addition of tipifarnib had no effect on response, toxicity or survival.

The role of granulocyte colony stimulating factor (G-CSF) as supportive therapy following intensive induction chemotherapy for acute myeloid leukaemia (AML) in adults was investigated in a randomized trial. G-CSF (Lenograstim, 263 lg/d) or placebo was administered from day 8 after the end of chemotherapy until neutrophil recovery to 0AE5 · 109/l (or for up to 10 d). Eight hundred and three patients were entered. Neutrophil recovery was quicker with G-CSF (P < 0AE0001), but this did not lead to differences in the number, severity or duration of infections. There were no substantial supportive care savings, although G-CSF patients spent 2 d less in hospital (P = 0AE01). Complete remission (CR) rates were similar between arms (73% G-CSF, 75% placebo, P = 0AE5), as were reasons for failure (induction death: P = 0AE7; resistant disease: P = 0AE5) and, for remitters, 5-year disease-free survival (34% vs. 38%, P = 0AE3). Overall survival at 5 years was 29% with G-CSF vs. 36% with placebo (P = 0AE10). Both CR rate (P = 0AE006) and overall survival (P = 0AE006) were worse with G-CSF in patients aged

This analysis, of 2483 patients with acute myeloid leukaemia (AML) aged 60+ years entered into two UK trials, was performed to determine the baseline parameters related to survival and to develop a risk index. The Medical Research Council (MRC) AML11 trial (n = 1071) was used to develop the index; this was validated using data from the Leukaemia Research fund (LRF) AML14 trial on 1137 intensively (AML14I) and 275 nonintensively (AML14NI) treated patients. In AML11, cytogenetic group, age, white blood count, performance status and type of AML (de novo, secondary) were all highly significantly related to prognosis in multivariate analysis. The regression coefficients were used to define good, standard and poor risk groups, with 1-year survival of 53%, 43% and 16% respectively (P < 0AE0001). The risk index showed very good discrimination in both AML14I and AML14NI (both P < 0AE0001), thereby providing validation, although survival in all groups was very poor in AML14NI. The risk factors for survival in older AML patients were similar to those in younger ones and discrimination of patient groups with relatively good to very poor prognosis was possible. These risk groups apply to both intensively and non-intensively treated patients. Randomized trials of intensive versus non-intensive therapy are needed to determine which types of patient should be given which type of treatment.

The acute myeloid leukaemia (AML)14 trial addressed four therapeutic questions in patients predominantly aged over 60 years with AML and High Risk Myelodysplastic Syndrome: (i) Daunorubicin 50 mg/m2 vs. 35 mg/m2; (ii) Cytarabine 200 mg/m2 vs. 400 mg/m2 in two courses of DA induction; (iii) for part of the trial, patients allocated Daunorubicin 35 mg/m2 were also randomized to receive, or not, the multidrug resistance modulator PSC-833 in a 1:1:1 randomization; and (iv) a total of three versus four courses of treatment. A total of 1273 patients were recruited. The response rate was 62% (complete remission 54%, complete remission without platelet/neutrophil recovery 8%); 5-year survival was 12%. No benefits were observed in either dose escalation randomization, or from a fourth course of treatment. There was a trend for inferior response in the PSC-833 arm due to deaths in induction. Multivariable analysis identified cytogenetics, presenting white blood count, age and secondary disease as the main predictors of outcome. Although patients with high Pgp expression and function had worse response and survival, this was not an independent prognostic factor, and was not modified by PSC-833. In conclusion, these four interventions have not improved outcomes in older patients. New agents need to be explored and novel trial designs are required to maximise prospects of achieving timely progress.

The monoclonal gammopathies are a group of disorders associated with monoclonal proliferation of plasma cells. The characterization of specific entities is an area of difficulty in clinical practice. The International Myeloma Working Group has reviewed the criteria for diagnosis and classification with the aim of producing simple, easily used definitions based on routinely available investigations. In monoclonal gammopathy of undetermined significance (MGUS) or monoclonal gammopathy, unattributed/unassociated (MG[u]), the monoclonal protein is < 30 g/l and the bone marrow clonal cells < 10% with no evidence of multiple myeloma, other B-cell proliferative disorders or amyloidosis. In asymptomatic (smouldering) myeloma the M-protein is greater than or equal to 30 g/l and/or bone marrow clonal cells greater than or equal to 10% but no related organ or tissue impairment (ROTI)(end-organ damage), which is typically manifested by increased calcium, renal insufficiency, anaemia, or bone lesions (CRAB) attributed to the plasma cell proliferative process. Symptomatic myeloma requires evidence of ROTI. Non-secretory myeloma is characterized by the absence of an M-protein in the serum and urine, bone marrow plasmacytosis and ROTI. Solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas (+/- recurrent) are also defined as distinct entities. The use of these criteria will facilitate comparison of therapeutic trial data. Evaluation of currently available prognostic factors may allow better definition of prognosis in multiple myeloma.

Patients under 55 years in the United Kingdom Medical Research Council Acute Myeloid Leukaemia 10 trial who entered complete remission were tissue typed (n = 1063). Four hundred and nineteen had a matched sibling donor and 644 had no match. When compared on a donor versus no donor basis the relapse risk was reduced in the donor arm (36%vs 52%; P = 0·001) and the disease-free survival (DFS) improved (50%vs 42%; P = 0·01), but overall survival (OS) was not different (55%vs 50%; P = 0·1). Sixty-one per cent of patients with a donor underwent transplantation. When patients were subdivided into risk groups based on cytogenetics alone or with the addition of blast response to course 1, a reduction in relapse risk was seen in all risk groups and in three age cohorts (0–14, 15–34 and 35+ years). Significant benefit in DFS was only seen in the intermediate-risk cytogenetic group (50%vs 39%; P = 0·004). The OS benefit was only seen in intermediate-risk patients (55%vs 44%; P = 0·02). The reduction in relapse risk in good-risk patients was attributable to patients with t(15;17) and not to patients with t(8;21) or inv(16). Allogeneic transplantation given after intensive chemotherapy was able to reduce relapse in all risk and age groups. However, due to the competing effects of procedural mortality and an inferior response to chemotherapy if relapse does occur, there was a survival advantage only in patients of intermediate risk. This trial found no survival advantage in children, patients over 35 years or good-risk disease.

This aim of the acute myeloid leukaemia (AML)-R trial was to compare sequential (Seq) ADE (cytarabine, daunorubicin, etoposide) with standard (Std) ADE as remission re-induction treatment and to assess any benefit of cyclosporine (CSA) as a multidrug resistance modulator in refractory/relapsed AML patients. Seq ADE, based on the concept of Timed Sequential Therapy, comprised the same drugs as Std ADE but given at higher doses and in a different sequence. Between 1992 and 1997, 235 patients with relapsed (175) and refractory (60) AML were entered: 170 were randomized between Std versus Seq ADE and 213 between CSA versus no CSA. CSA was initially given at a dose of 5 mg/kg/d and increased to 10 mg/kg/d in the latter part of the trial. Overall, the complete remission (CR) rate was 43%, with Std ADE being significantly better than Seq ADE (54% versus 34%, P = 0·01). CR rates did not differ between the CSA and no CSA arms (41% versus 45%, P = 0·6). Overall, 3 year disease-free survival (DFS) of remitters was 16%, with a relapse risk of 70%. DFS was not significantly different between the chemotherapy or the CSA arms. Overall, 3 year survival was 8%. Survival with Std ADE was significantly better than with Seq ADE (12% versus 6%, P = 0·03). CSA did not affect overall survival, except in patients ≥ 60 years, who fared worse on CSA (P = 0·0003). No difference in haematological toxicity between the chemotherapy or CSA arms was seen. Survival was better with longer first CR duration (P

Approaches to the management of adolescents and young adults with acute leukaemia were investigated by sending a questionnaire to hospitals identified as having diagnosed or treated patients aged 15-29 years. The responses demonstrated the types of hospital treating these patients, the haematologists' perceived practice for entry of patients to Medical Research Council (MRC) leukaemia trials and reasons for non-entry. Data were linked to MRC trials data to determine the proportion of patients aged 15-29 years at diagnosis in responding hospitals actually treated in MRC leukaemia trials in the 5 years preceding the questionnaire. Eighty-two per cent of haematologists stated that they entered patients 'always' or 'whenever possible' for acute myeloid leukaemia (AML) and 76% for acute lymphoblastic leukaemia (ALL), but actual entry rates from the study hospitals were 46% of 239 AML patients and 36% of 182 ALL patients. The reasons most commonly reported for not entering eligible patients to national leukaemia trials were clinician preference for one arm of an MRC trial, a regional study or non-trial protocol, and concern about workload and ethical approval.

Data on 1711 patients, aged up to 55 years, in the MRC AML 10 trial were used to create a prognostic index for use in risk-directed therapy decision making for younger patients with acute myeloid leukaemia (AML). Two parameters, response after course 1 and cytogenetics, were strongly predictive of outcome. For patients with complete remission, partial remission and resistant disease, 5-year survival from the start of course 2 was 53%, 44% and 22% and relapse rates were 46%, 48% and 69% respectively, and for patients with favourable, intermediate and adverse karyotypic abnormalities, survival was 72%, 43% and 17% and relapse rates were 34%, 51% and 75% respectively (all P < 0.0001). Patients with FAB type M3 but no cytogenetic t(15;17) also had a low relapse rate (29%). These three factors were combined to give three risk groups: good (favourable karyotype or M3, irrespective of response status or presence of additional abnormalities), standard (neither good nor poor), poor (adverse karyotype or resistant disease, and no good-risk features). Survival for these three groups was 70%, 48% and 15% respectively and relapse rates were 33%. 50% and 78% (both P < 0.0001). The index is simple (based on just three parameters), robust (derived from 1711 patients), highly discriminatory (55% survival difference between good and poor risk) and validated, so can be applied in the clinical setting to assist with therapeutic decisions as in the current AML 12 trial.

We have used a combination of flow cytometric assays to define multidrug resistance (MDR) positive and negative blasts in cryopreserved samples from 47 MRC trial patients with acute myeloblastic leukaemia (AML). Our primary test is a standardized assay for daunorubicin accumulation. Confirmatory assays for MDR comprised the cyclosporin modulation assay for rhodamine-123 uptake as a measure of functional P-glycoprotein and the measurement of lung resistance protein and multidrug resistance associated protein (with LRP-56 and MRPr1 respectively). 57% of samples had both low accumulation and at least one positive confirmatory test. 32% were MDR negative in all four assays. 15% of patients had primary chemo-resistant disease. Resistant disease rates were 22% for confirmed MDR-positive patients and 0% for confirmed MDR-negative patients (P = 0.07). Complete remission was achieved in 74% of patients, with rates of 63% in confirmed MDR-positive patients and 93% in confirmed MDR-negative patients (P = 0.06). The use of a standardized method for daunorubicin uptake, combined with the use of confirmatory tests, should reduce the uncertainty that is currently characteristic of MDR evaluation in leukaemia. In comparison with daunorubicin uptake, p-gp expression, measured using MRK-16 antibody, was more closely associated with remission rates (P = 0.01). This suggests an additional role for p-glycoprotein in mediating drug resistance beyond that of a drug efflux pump.

A collaborative overview, using individual patient data, has been performed to compare idarubicin versus daunorubicin or other anthracyclines, when used with cytosine arabinoside as induction chemotherapy for newly diagnosed acute myeloid leukaemia. There were 1052 patients in five trials versus daunorubicin, 100 in one trial versus doxorubicin, and 745 in one trial versus zorubicin. In the trials of idarubicin versus daunorubicin, early induction failures were similar with the two treatments (20% idarubicin v 18% daunorubicin; P = 0.4), but after day 40 the later induction failures were fewer with idarubicin (17% v 29%; P

Detection of the t(15;17) or its molecular consequence, the PML-RAR alpha rearrangement, is critical for meaningful analysis of clinical trials involving patients with suspected acute promyelocytic leukaemia (APL). Its presence remains the best predictor of a favourable response to retinoids, such as ATRA, which in combination with chemotherapy confer significant improvements in disease-free survival. We have evaluated the relative efficacy of RT-PCR, cytogenetics and PML immunofluorescence staining to identify the existence of the translocation in 100 patients entered into the Medical Research Council (M.R.C.) ATRA trial. RT-PCR successfully identified PML-RAR alpha rearrangements in 93/100 patients, including 65 where only peripheral blood or post-induction marrow samples were available for analysis and in 12 patients in whom cytogenetic assessment failed to demonstrate t(15;17) due to poor-quality metaphases (10/12) or as a reflection of cryptic PML-RAR alpha rearrangements (2/12). Parallel employment of the RAR alpha-PML assay confirmed expression of del(17q)-derived transcripts in 81% and permitted determination of the PML breakpoint (a potential independent prognostic variable) in all 93 cases. Sequencing of RT-PCR products derived from 50 patients with 3' PML breakpoints revealed five bcr 2 cases, including a novel exon 5 breakpoint. 35/81 (43%) patients with cytogenetic evidence of t(15;17) possessed additional karyotypic abnormalities. In four patients with available buffy coat smears, lack of cytogenetic or molecular evidence of the t(15;17) was confirmed by a wild-type PML immunofluorescence nuclear staining pattern, in contrast to the characteristic microparticulate distribution detected in 14 patients with RT-PCR evidence of the rearrangement. However, although PML immunofluorescence staining is suitable for rapid determination of patients likely to benefit from ATRA, this approach does not obviate the need for cytogenetic and RT-PCR analysis of all patients entered into APL clinical trials, because both techniques provide additional information which may prove to be of independent prognostic significance.

This short report presents the results of a comparison of complete remission rates and reasons for failure, between two series of patients aged 60 years or over with acute myeloid leukaemia (AML), and discusses their interpretation.

Patients under 55 years in the United Kingdom Medical Research Council Acute Myeloid Leukaemia 10 trial who entered complete remission were tissue typed (n = 1063). Four hundred and nineteen had a matched sibling donor and 644 had no match. When compared on a donor versus no donor basis the relapse risk was reduced in the donor arm (36%vs 52%; P = 0.001) and the disease-free survival (DFS) improved (50%vs 42%; P = 0.01), but overall survival (OS) was not different (55%vs 50%; P = 0.1). Sixty-one per cent of patients with a donor underwent transplantation. When patients were subdivided into risk groups based on cytogenetics alone or with the addition of blast response to course 1, a reduction in relapse risk was seen in all risk groups and in three age cohorts (0-14, 15-34 and 35+ years). Significant benefit in DFS was only seen in the intermediate-risk cytogenetic group (50%vs 39%; P = 0.004). The OS benefit was only seen in intermediate-risk patients (55%vs 44%; P = 0.02). The reduction in relapse risk in good-risk patients was attributable to patients with t(15;17) and not to patients with t(8;21) or inv(16). Allogeneic transplantation given after intensive chemotherapy was able to reduce relapse in all risk and age groups. However, due to the competing effects of procedural mortality and an inferior response to chemotherapy if relapse does occur, there was a survival advantage only in patients of intermediate risk. This trial found no survival advantage in children, patients over 35 years or good-risk disease.

Between 1990 and 1999, 36 children with refractory anaemia with excess blasts (RAEB) and RAEB in transformation (RAEBt), not associated with Down's syndrome, were diagnosed in Britain. A total of 31 children received intensive chemotherapy, six of whom proceeded to a bone marrow allograft in first remission, whereas two received an autograft. Of the 23 given chemotherapy only, four died of toxicity, 10 relapsed and nine are alive in first remission. Out of the 10 who relapsed, four are alive and disease-free following an allograft. Out of the 6 children given an allograft in first remission, two died of disease and four are alive in first remission. Both children given an autograft died of disease. Two children received an allograft without prior chemotherapy but died of toxicity. Three children received supportive care only, and one child survived. The overall survival was 51% at 5 years, and was superior in children with RAEBt (63%) compared with RAEB (28%, P = 0.03). Cytogenetics were available in 35 cases. Monosomy 7 was the most common abnormality (33% of cases). Survival in children with monosomy 7 was 22% at 5 years compared with 66% for the other patients (P = 0.05). Allowing for cytogenetics, outcomes of therapy appear similar to those for de novo acute myeloid leukaemia (AML), and it is appropriate for children with RAEB/RAEBt to be registered in AML trials.

Summary. This short report presents the results of a comparison of complete remission rates and reasons for failure, between two series of patients aged 60 years or over with acute myeloid leukaemia (AML), and discusses their interpretation.