Research Council Acute Myeloid Leukemia Research Articles

Results of a randomized trial in children with Acute Myeloid Leukaemia: Medical Research Council AML12 trial

The Medical Research Council Acute Myeloid Leukaemia 12 (MRC AML12) trial (children) addressed the optimal anthracenedione/anthracycline in induction and the optimal number of courses of consolidation chemotherapy. 504 children (<16 years) with AML were randomized between mitoxantrone/cytarabine/etoposide or daunorubicin/cytarabine/etoposide as induction chemotherapy and 270 entered a second randomization between a total of four or five courses of treatment. Ten-year event-free (EFS) and overall survival (OS) was 54% and 63% respectively; the relapse rate was 35%. There was no difference in complete remission rate between the induction regimens, but there was a benefit for mitoxantrone with regard to relapse rate [32% vs. 39%; Hazard ratio (HR) 0·73; 95% confidence interval (CI) 0·54, 1·00] and disease-free survival (DFS; 63% vs. 55%; HR 0·72; 95% CI 0·54, 0·96). However, this did not translate into a better EFS or OS (HR 0·84; 95% CI 0·63, 1·12). Results of the second randomization did not show a survival benefit for a fifth course of treatment (HR 1·01; 95% CI 0·63, 1·62), suggesting a ceiling of benefit for conventional chemotherapy and demonstrating the need for new agents. EFS was superior compared to the preceding trial AML10, partly due to fewer deaths in remission, highlighting the importance of supportive care.

Fludarabine and cytosine are less effective than standard ADE chemotherapy in high-risk acute myeloid leukemia, and addition of G-CSF and ATRA are not beneficial: results of the MRC AML-HR randomized trial

AbstractThe optimum chemotherapy schedule for reinduction of patients with high-risk acute myeloid leukemia (relapsed, resistant/refractory, or adverse genetic disease) is uncertain. The MRC AML (Medical Research Council Acute Myeloid Leukemia) Working Group designed a trial comparing fludarabine and high-dose cytosine (FLA) with standard chemotherapy comprising cytosine arabinoside, daunorubicin, and etoposide (ADE). Patients were also randomly assigned to receive filgrastim (G-CSF) from day 0 until neutrophil count was greater than 0.5 × 109/L (or for a maximum of 28 days) and all-trans retinoic acid (ATRA) for 90 days. Between 1998 and 2003, 405 patients were entered: 250 were randomly assigned between FLA and ADE; 356 to G-CSF versus no G-CSF; 362 to ATRA versus no ATRA. The complete remission rate was 61% with 4-year disease-free survival of 29%. There were no significant differences in the CR rate, deaths in CR, relapse rate, or DFS between ADE and FLA, although survival at 4 years was worse with FLA (16% versus 27%, P = .05). Neither the addition of ATRA nor G-CSF demonstrated any differences in the CR rate, relapse rate, DFS, or overall survival between the groups. In conclusion these findings indicate that FLA may be inferior to standard chemotherapy in high-risk AML and that the outcome is not improved with the addition of either G-CSF or ATRA.

Autografting as a risk factor for persisting iron overload in long-term survivors of acute myeloid leukaemia

We studied the iron status of 32 evaluable adult acute myeloid leukaemia (AML) survivors who were entered into the UK Medical Research Council acute myeloid leukaemia (AML) 10 and 12 trials at our institution between 1988 and 1998. Patients were required to have been independent of all blood products for at least 3 years. As a group, the median first serum ferritin level was 1323 mug/l (NR 19-300 mug/l) at a median of 1321 days from the last transfusion confirming the presence of significant iron overload persisting for some years after completion of all therapy and blood products. There was a general trend for the serum ferritin level to fall with time, but the fall was less pronounced in men and carriers of the C282Y mutation. Recipients of autologous stem cell transplantation (SCT) had a higher median first serum ferritin level (3245 mug/l) than patients who received chemotherapy alone (1148 mug/l) or allogeneic SCT (1334 mug/l) because of increased use of transfused blood. Nine of the 10 recipients of autologous SCT underwent venesection. No evidence of end organ damage was seen in any patient. Serial monitoring of serum ferritin and assessment of the C282Y status may be useful in all long-term AML survivors, especially autograft recipients.

Be skeptical about unexpected large apparent treatment effects:: the case of an MRC AML12 randomization

The preliminary results of the twelfth Medical Research Council acute myeloid leukemia trial show no evidence of a survival advantage for five courses of therapy compared to four courses in a randomized comparison involving 1078 patients (hazard ratio 1.09, 95% confidence interval [CI] 0.87–1.37, p=0.4). However, the data presented to the independent data monitoring and ethics committee (DMEC) at both its reviews in 1998 suggested large benefits for the additional course with hazard ratios of 0.47 and 0.55 (95% CIs 0.29–0.77 and 0.38–0.80, p=0.003 and p=0.002, respectively). Despite these highly significant findings, the DMEC did not recommend closure of the randomization, a decision vindicated by the subsequent reversion to a null result. The main reason for not closing the randomization was that the treatment effects observed in 1998 (53% and 45% reductions in the odds of death) were considered too large to be clinically plausible, despite the p-values associated with them. Investigations have not identified any clinical explanations, such as different types of patients in the early and later parts of the trial, to explain the loss of benefit as the trial progressed. Thus, the most likely current explanation for the large benefit observed early on is the play of chance. Lessons to be learned from this example are that: fixed stopping rules based on some predetermined p-value should not be used and the decision to close a randomization or not should take account of other factors such as the medical plausibility of the magnitude of the treatment effect; chance effects do occur and happen more frequently than many clinicians realize; it is important that DMEC members are experienced in the interpretation of clinical trial evidence and aware of the dangers of early stopping without wholly convincing evidence.

Relationships between age at diagnosis, clinical features, and outcome of therapy in children treated in the Medical Research Council AML 10 and 12 trials for acute myeloid leukemia

AbstractBetween May 1988 and June 2000, 698 children were treated in the Medical Research Council acute myeloid leukemia 10 and 12 trials. The presenting features and outcomes of therapy in these children were compared by age. Although there was no single cutoff in age, younger children were more likely to have intermediate risk and less likely to have favorable cytogenetics (P < .001), and they had a higher incidence of translocations involving chromosome 11q23 (P < .001). The distribution of French-American-British (FAB) types also varied with age; FAB types M5 (P < .001) and M7 (P < .001) were more common in early childhood, whereas older children were more likely to have FAB types M0 (P = .03), M1 (P = .04), M2 (P = .005), and M3 (P < .001). Involvement of the central nervous system at diagnosis was also more common in the youngest children (P = .01). Younger children had more severe diarrhea (P = .002), whereas older children had worse nausea and vomiting (P = .01) after chemotherapy. When adjusted for other important factors, complete remission rates were similar (P = .5) and although there was less resistant disease in younger children (P = .003), this was partially balanced by a slight increase in deaths during induction therapy in younger patients (P = .06). On multivariate analysis overall survival (P = .02), event-free survival (P = .02), and disease-free survival were better (P = .06) in younger children due to a lower relapse rate (P = .02) especially in the bone marrow (P = .02).

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 &gt;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.