K. Wheatley

Mortality in relation to consumption of alcohol: 13 years' observations on male British doctors

Abstract Objective : To assess the risk of death associated20with various patterns of alcohol consumption. Design - Prospective study of mortality in relation to alcohol drinking habits in 1978, with causes of death sought over the next 13 years (to 1991). Subjects : 12 321 British male doctors born between 1900 and 1930 (mean 1916) who replied to a postal questionnaire in 1978. Those written to in 1978 were the survivors of a long running prospective study of the effects of smoking that had begun in 195120and was still continuing. Results - Men were divided on the basis of their response to the 1978 questionnaire into two groups according to whether or not they had ever had any type of vascular disease, diabetes, or “life threatening disease” and into seven groups according to the amount of alcohol they drank. By 1991 almost a third had died. All statistical analyses of mortality were standardised for age, calendar year, and smoking habit. There was a U shaped relation between all cause mortality and the average amount of alcohol reportedly drunk; those who reported drinking 8-14 units of alcohol a week (corresponding to an average of one to two units a day) had the lowest risks. The causes of death were grouped into three main categories: “alcohol augmented” causes (6% of all deaths: cirrhosis, liver cancer, upper aerodigestive (mouth, oesophagus, larynx, and pharynx) cancer, alcoholism, poisoning, or injury), ischaemic heart disease (33% of all deaths), and other causes. The few deaths from alcohol augmented causes showed, at least among regular drinkers, a progressive trend, with the risk increasing with dose. In contrast, the many deaths from ischaemic heart disease showed no significant trend among regular drinkers, but there were significantly lower rates in regular drinkers than in non-drinkers. The aggregate of all other causes showed a U shaped dose-response relation similar to that for all cause mortality. Similar differences persisted irrespective of a history of previous disease, age (under 75 or 75 and older), and period of follow up (first five and last eight years). Some, but apparently not much, of the excess mortality in non-drinkers could be attributed to the inclusion among them of a small proportion of former drinkers. Conclusion : The consumption of alcohol appeared to reduce the risk of ischaemic heart disease, largely irrespective of amount. Among regular drinkers mortality from all causes combined increased progressively with amount drunk above 21 units a week. Among British men in middle or older age the consumption of an average of one or two units of alcohol a day is associated with significantly lower all cause mortality than is the consumption of no alcohol, or the consumption of substantial amounts. Above about three units (two American20units) of alcohol a day, progressively greater levels of consumption are associated with progressively higher all cause mortality.

Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukaemia: results of the United Kingdom Medical Research Council's 10th AML trial

359 eligible children with acute myeloid leukaemia (AML) entered the MRC AML 10 trial between May 1988 and March 1995. Patients received four courses of intensive induction and consolidation chemotherapy, with or without subsequent autologous (A‐BMT) or allogeneic (allo‐BMT) bone marrow transplant. There were randomized comparisons of thioguanine versus etoposide in induction and of A‐BMT versus not. Allo‐BMT was recommended for patients with a HLA‐matched sibling and was evaluated by donor versus no donor comparison. The complete remission rate was 92%. In first remission there were 20 deaths during consolidation chemotherapy and 11 after BMT (8/61 allo‐BMTs, 1/60 A‐BMTs and 2/4 matched unrelated donor transplants). The relapse rate was low, decreasing from 26% in the first year to 2% in the fourth. Long‐term outcome was excellent with survival at 7 years from entry of 56% and event‐free survival of 48%. There were no significant differences between thioguanine and etoposide, whereas both A‐BMT and allo‐BMT reduced relapse risk but did not produce a significant survival benefit. It appears that over half the children entered into AML 10 are cured, a result which compares favourably with other reported series. We conclude that four courses of intensive chemotherapy are an effective approach to the treatment of paediatric AML, which avoids the acute toxicity and long‐term side‐effects of BMT and also avoids the need for prolonged maintenance therapy or cranial irradiation.

AML associated with previous cytotoxic therapy, MDS or myeloproliferative disorders: results from the MRC's 9th AML trial.

Summary. The outcome of treatment with standard first line therapy of 66 patients with acute myeloid leukaemia (AML) secondary to preceding chemotherapy (Group 1), a myelo‐dysplastic state (Group 2) or a myeloproliferative disorder (Group 3) was analysed in relation to the preceding disorder, the cytogenetic pattern where available, and the cytology and cytochemistry of blood and bone marrow.

Treatment-related deaths during induction and first remission of acute myeloid leukaemia in children treated on the Tenth Medical Research Council Acute Myeloid Leukaemia Trial (MRC AML10)

Between 1988 and 1995, 341 children with acute myeloid leukaemia (AML) were treated on the Medical Research Council Acute Myeloid Leukaemia Trial (MRC AML10). The 5‐year overall survival was 57%, much improved on previous trials. However, there were 47 deaths (13.8%), 11 of which were associated with bone marrow transplantation (BMT). The treatment‐related mortality was significant at 13.8%, but decreased in the latter half of the trial from 17.8% in 1998–91 to 9.6% in 1992–95 (P = 0.03%). The main causes of death were infection (65.9%), haemorrhage (19.1%) and cardiac failure (19.1%). Fungal infection was a significant problem, causing 23% of all infective deaths. Haemorrhage occurred early in treatment, in children with initial white cell counts >100 × 109/l (P = 0.001), and was more common in those with M4 and M5 morphology. Cardiac failure only occurred from the third course of chemotherapy onwards, with 78% (7/9) in conjunction with sepsis as a terminal event. Some deaths could be prevented by identifying those most at risk, and with prompt recognition and aggressive management of complications of treatment. Future options include the prophylactic use of antifungal agents, and the use of cardioprotectants or alternatives to conventional anthracyclines to decrease cardiac toxicity.

Guidelines on the management of acute myeloid leukaemia in adults

1 Bone marrow aspirate and trephine biopsy unless the peripheral blast count is high. 2 Immunophenotyping [CD3, CD7, CD13, CD14, CD33, CD34, CD64, CD117 and cytoplasmic myeloperoxidase (MPO)]. 3 Cytochemistry (MPO or Sudan Black, combined esterase). Can be omitted if four-colour flow cytometry is available. 4 Cytogenetics [with reverse-transcription polymerase chain reaction (RT-PCR) for AML 1-ETO and CBFBMYH11 in non-acute promyelocytic leukaemia (APL) and promyelocytic leukaemia (PML) and retinoic acid receptor-alpha (RARA) in suspected APL; fluorescent in situ hybridisation (FISH) in selected cases].

Dose intensification in acute myloid leukaemia: greater effectiveness at lower cost. Principal report of the Medical Research Council's ATML9 study

Between 1984 and 1990, 972 patients aged 1–79 years with acute myeloid leukaemia (AML), from 85 British hospitals, were entered into the MRCs 9th AML trial. Patients were randomized between DAT 1+5 (daunorubicin for 1 d, with cytarabine and 6‐thioguanine for 5 d) and DAT 3+10 (same dose drugs for 3 and 10 d respectively) as induction therapy. The 63% who achieved complete remission (CR) were randomized to receive two courses of DAT 2+7 alternating with two courses of either MAZE (m‐AMSA, 5‐azacytidine, etoposide) or COAP (cyclophosphamide, vincristine, cytarabine, prednisone). Finally, those still in CR were randomized to receive either 1 year of maintenance treatment with eight courses of cytarabine and thioguanine followed by four courses of COAP, or no further cytotoxic therapy.  Resistance to induction therapy was less common with the DAT 3+10 regimen than with DAT 1+5 (13% v 23%; P==0.0001) and hence, despite a 5% increase in the risk of induction death, the CR rate was higher (66% v 61%; P=0.15). Moreover, CR was achieved more rapidly with DAT 3+1 (median 34 v 46 d; P<0.0001) and thus patients required less time in hospital (mean 20 v 29 d) and less blood product support. 5‐year relapse‐free survival (28% v 23%; P=0.05) and survival (23% v 18%; P<0.05) were also better with DAT 3+10. Post‐remission intensification of therapy with MAZE resulted in fewer relapses (66% v 74% at 5 years; P=0.03) but patients allocated MAZE required considerably more supportive care and 14 (4.5%) died following 312 MAZE courses, whereas no deaths occurred following COAP. 5‐year survival was not significantly higher with MAZE (37% v 31%). Finally, although 1 year of out‐patient maintenance treatment appeared to delay, but not prevent, recurrence it did not improve 5‐year survival which was non‐significantly worse for those allocated maintenance treatment (41% v 44%).  We conclude that the more intensive induction regimen, DAT 3+10, is not only more effective than DAT 1+5, even for older patients, but is also less expensive; intensive post‐remission therapy with MAZE achieves better leukaemic control but at the cost of substantial toxicity; whereas low‐level maintenance therapy confers no apparent advantage in survival as well as being inconvenient and costly.

Outcome for children with relapsed acute myeloid leukaemia following initial therapy in the Medical Research Council (MRC) AML 10 trial. MRC Childhood Leukaemia Working Party.

Between May 1988 and March 1995, 359 children with acute myeloid leukaemia (AML) were treated in the MRC AML 10 trial. Three risk groups were identified based on cytogenetics and response to treatment. One hundred and twenty-five children relapsed – 103 in the bone marrow only, 12 in the bone marrow combined with other sites, and six had isolated extramedullary relapses (site was not known in four cases). Eighty-seven children received further combination chemotherapy, one all-trans retinoic acid for acute promyelocytic leukaemia, and one a matched unrelated donor allograft in relapse, and 61 achieved a second remission. One patient with no details on reinduction therapy also achieved second remission. Treatment in second remission varied – 44 children received a BMT (22 autografts, 12 matched unrelated donor allografts, 10 family donor allografts), and 17 were treated with chemotherapy alone. The overall survival rate for all children (treated and untreated) was 24% at 3 years, with a disease-free survival of 44% for those achieving a second remission. Length of first remission was the most important factor affecting response rates – children with a first remission of less than 1 year fared poorly (second remission rate 36%, 3 year survival 11%), whereas those with longer first remissions had a higher response rate (second remission rate 75%, 3 year survival 49%, P < 0.0001).

Incidence of AML1/ETO fusion transcripts in patients entered into the MRC AML trials

Acute myeloid leukaemia (AML) with the t(8;21)(q22;q22) is deemed to be a ‘good‐risk’ disease. 396 patients with AML at diagnosis were screened for the presence of t(8;21) and AML1/ETO fusion transcripts by cytogenetic and RT‐PCR techniques respectively. 32 cases of t(8;21) were detected, all of which were also PCR positive. A further 19 cases were detected at the molecular level, predominantly but not exclusively in M1 and M2 FAB types. Approximately 12% of all new cases of AML are estimated to have AML1/ETO fusion transcripts and it is suggested that molecular screening should be performed in all cases with the possible exception of the M3 FAB type.

Frequency of CBFβ/MYH11 fusion transcripts in patients entered into the U.K. MRC AML trials

It has been established that cytogenetic findings at diagnosis of acute myeloid leukaemia (AML) are a powerful prognostic indicator. Patients who have the inv(16)(p13q22), closely associated with the FAB subtype M4Eo, are deemed to have good‐risk disease. This subtle translocation may be difficult to detect in poor‐quality metaphase preparations and if missed could lead to the incorrect assignment of risk group and influence further treatment strategies.

Adverse impact of bone marrow transplantation on quality of life in acute myeloid leukaemia patients; analysis of the UK Medical Research Council AML 10 Trial.

The increasing success of intensive consolidation chemotherapy (CCT) as an alternative to bone marrow transplant (BMT) in acute myeloid leukaemia (AML) necessitates comparison of the impact on quality of life (QoL) of these two treatment modalities. Most QoL studies following BMT involve small patient numbers and provide ambivalent results. The present study examines QoL in a large number of patients 1 year from the end of treatment within the United Kingdom Medical Research Council (UK MRC) AML10 trial of BMT versus CCT. Allogeneic-BMT (Allo-BMT) was observed to have an adverse impact on most QoL dimensions compared with Autologous-BMT (A-BMT) and CCT. More patients receiving BMT had mouth dryness problems and worse sexual and social relationships, professional and leisure activities than CCT patients. QoL in A-BMT patients was less impacted than Allo-BMT. Intention-to-treat analysis showed similar results. These results indicate that a reconsideration of treatment strategies is warranted, and that further, good prospective studies are needed to evaluate more clearly the effects of these treatments in long-term survivors.