Burnett, Alan K.
The therapeutic approach to acute myeloid leukemia (AML) recognizes that there are three broad patient groups. In younger patients in whom there is limited medical comorbidity and a higher proportion of responsive disease, potential therapeutic levels of intensity can be applied, including myeloablative stem cell transplantation. In older patients, the proportion of chemosensitive disease is diminished and the frequency of comorbidities increased leading to an initial consideration of the suitability of conventional intensity chemotherapy. In general, these two groups have been segregated by the age of around 60 years. Although it may be inappropriate for such an arbitrary division, most clinical trial data reflect this division. The third group, which has gained prominence in recent years, is the older patient for whom a conventional intensive chemotherapy approach is considered unsuitable. The definition of this group remains a matter for debate. More usually, it is taken to mean that the risks of precipitating early death by giving intensive therapy are considered to be too high. Some refinement to this definition might be that they are not considered likely to benefit (even where they might be considered fit) from intensive treatment, for example, because of an adverse risk karyotype. This group has come to prominence because there is a recognition with an increasing older population that more AML patients will emerge. It appears that the therapeutic aspirations also increase and this population are an attractive group for new drug development.
The standard of care for conventional induction therapy is induction with the combination of an anthracycline and cytarabine (Ara-C), the so-called 3 + 7. Studies continue to emerge attempting to improve on this, most recently by dose escalation or the addition of antibody-directed therapy, or with alternatives to Ara-C for induction and the increasing use of reduced intensity transplantation for older patients for whom myeloablative transplantation is not advantageous.
The standard 3 + 7 frequently uses daunorubicin at a dose of 45 or 50 mg/m2 on days 1, 3 and 5. Less frequently, it has been used at 60 mg/m2. This choice developed as a result of experience over several years [1–3]. Meta-analysis with alternatives suggested that idarubicin may be modestly more advantageous in younger patients . Cardiotoxicity has always been a deterrent to daunorubicin dose escalation ; however, recent studies have examined the option of daunorubicin dose intensification, which can be defined as dose escalation: increased frequency of standard dose or increase in total dose. Three recent studies have re-opened the daunorubicin dose issue by testing the first option of increasing the dose to 90 mg/m2, given at the usual day 1, 3 and 5 intervals or in one study by continuous infusion over 3 days. In younger patients, the ECOG 1900 trial [6▪] randomized 657 patients, of whom 582 were evaluable for response. Remission rate was higher in the 90 mg arm, 70 vs. 56% (P < 0.001). Overall survival was also superior, 23.7 vs. 15.7 months (P = 0.003), with a median follow-up of 25 months. Remission was obtained in one course more frequently in the 90 mg arm (83 vs. 72%) after which patients went on to consolidation with high-dose Ara-C with or without autologous transplantation, thus they were exposed to a total dose of daunorubicin of 270 mg/m2. Twenty-nine patients in the high-dose arm were not in complete remission after course 1 and were given a second daunorubicin course (45 mg/m2 for three days) and so received a total exposure of 405 mg/m2.
The same question was examined in a study from Korea [7▪▪], in which 383 patients, under the age of 60 years, were randomized to 90 vs. 45 mg/m2 on three consecutive days, with the daunorubicin given by continuous infusion. Patients not in complete remission received a second course in which the daunorubicin dose was 45 mg/m2 again given by continuous infusion for 2 days. The remission rate (82 vs. 72%, P = 0.014) and overall survival (47 vs. 35%, P = 0.03) were both superior in the 90 mg arm. A total of 71% of patients on the 90 mg arm vs. 56% on the 45 mg arm achieved complete remission with one course. In both of these studies, the overall survival benefit was largely because of a benefit in intermediate-risk patients, rather than in favourable or unfavourable groups.
A third study from the HOVON-SAKK group [8▪] compared a 90-mg/m2 dose vs. 45 mg/m2 given for 3 days in the 7 + 3 schedule in older patients. The overall remission rate was superior in the 90 mg arm (64 vs. 54%, P = 0.002) with more patients on the high dose achieving complete remission with one course, but there was no overall survival benefit except in the patient subgroup aged 60–65 (38 vs. 23%) at 2 years. Although the patient numbers were small, there was also a benefit in the favourable cytogenetic group.
There has been discussion for a long time about dose equivalence between daunorubicin and alternatives such as idarubicin. A study from the French ALFA group  compared daunorubicin 80 mg/m2 on days 1 to 3 vs. idarubicin 12 mg/m2 for either three or four consecutive days in patients aged 50–70 years. In 468 randomized patients, idarubicin for 3 or 4 days produced more remissions than daunorubicin (83 vs. 78 vs. 70%, P = 0.04); however, this did not result in any difference in survival. A recent Japanese trial [10▪▪] in 1057 younger patients tested intensification, not by dose escalation, but by administration of 50 mg/m2 daily for 5 days compared with the traditional 3 days, that is at total course 1 exposure of 250 vs. 150 mg, against idarubicin for 3 days. The remission rates were similar (77.5 vs. 78.2%) and survival was not different.
The question arises as to whether this evidence is sufficient to establish daunorubicin 90 mg as a new standard of care. The overall survival achieved in the ECOG and HOVON-SAKK trials is reminiscent of that in several trials with conventional daunorubicin induction. This is confirmed in a comparison of patients in the MRC 12 and 15 trials who were 15–60 years in which the induction dose of daunorubicin was 50 mg/m2 for three days (Fig. 1). Similarly, when a similar comparison was done with the HOVON-SAKK trial in patients over 60 years or in the 60–65 year subset (Fig. 2), equivalent survival was seen. Of interest in the MRC/NCRI trials, all patients were routinely given two induction daunorubicin-containing courses irrespective of whether they achieved complete remission with course 1, so the total dose given over the two courses was 300 mg/m2. It is clear from these studies that so far at least cardiac toxicity has not been problematic.
Some investigators have adopted a 60-mg/m2 dose as standard. It is conceivable that although equivalent overall survivals are seen with a conventional daunorubicin dose, as illustrated in the figures, inclusion of a 90-mg option could further improve these results. Surprisingly, a 60 vs. 90 mg comparison has never been undertaken, but this question has now been incorporated into the NCRI AML17 trial in younger patients (ISCRTN 55675535).
THE ADDITION OF GEMTUZUMAB OZOGAMICIN
Antibody-directed chemotherapy is an attractive option to enable dose intensification to the target cell population without collateral toxicity. Gemtuzumab ozogamicin (Mylotarg) has been available for over a decade, but to date there are few published randomized studies [11,12]. The HOVON-SAKK group tested it in as maintenance [8▪], and the ECOG 1900 trial tested it as extra consolidation before autologous transplantation [6▪]. Although neither study was adequately powered, there seemed to be no difference between the randomized arms. At least four large trials have now been reported, either in abstract or in full publication, of its use as an intensification of induction. The MRC conducted a feasibility study with the intention of adding gemtuzumab ozogamicin, or not, to each of four courses of chemotherapy in younger patients. The conclusion was that 3 mg/m2 could safely be added to courses 1 and 3, but higher doses or its use in consecutive courses resulted in both haematological and liver toxicity . In the subsequent randomized trial (AML15), 1113 patients generally under 60 years were randomized to receive gemtuzumab ozogamicin on day 1 of the first induction and or in course 3 in a 2 × 2 trial design . There was no difference in overall remission rate, induction toxicity or overall survival; however, there was a striking survival benefit in the core binding factor subgroup and a trend for survival benefit for intermediate-risk patients. Using an internally validated multiparameter risk score, it was shown that 70% of all patients had a 10% survival benefit at 5 years. The 3 mg dose did not increase toxicity. A similar study by the SWOG group (SWOG 106)  compared induction chemotherapy (3 + 7 with daunorubicin at a 60 mg/m2 dose level) vs. 3 + 7 with daunorubicin at 45 mg/m2 with gemtuzumab ozogamicin (6 mg/m2) given on day 4 to avoid co-administration with the anthracycline. This trial was also negative, but there was also a trend for benefit in the favourable subgroup and the reduced daunorubicin dose raises the possibility that a beneficial effect was masked. Importantly, there was an increased rate of early death in the gemtuzumab ozogamicin arm (5.4 vs. 1.8%), which contributed to a Data Monitoring Committee decision to close the trial early and as this was the postapproval trial it was in due course voluntarily withdrawn from the US market, in spite of other trials in which no detriment was shown and a recognition that an induction death rate of 5.4% is unexceptional with standard chemotherapy. Two large studies in older patients have recently been reported, both of which show a significant improval in survival. The French ALFA Group randomized 278 patients aged 50–70 years (median 62.2 years) to induction chemotherapy (3 + 7) which comprised daunorubicin (60 mg/m2) and cytarabine with or without gemtuzumab ozogamicin. The gemtuzumab ozogamicin was given in a fractioned schedule of 3 mg/m2 or a maximum of 5 mg, given on days 1, 4 and 7 . This did not improve the remission rate or cause major excess toxicity, although there were a small number of patients with liver toxicity in the gemtuzumab ozogamicin arm. The median follow-up of survivors was 25 months at the time of the report. The event-free (18.7 vs. 39.6%, P = 0.0002) and overall survival (43.5 vs. 53.1%, P = 0.047) at 2 years was superior in the gemtuzumab ozogamicin arm. This was achieved even though significantly fewer patients in the gemtuzumab ozogamicin arm received the planned consolidation chemotherapy.
The second recent study from the UK  mimicked the MRC AML15 trial by evaluating the addition of gemtuzumab ozogamicin (3 mg/m2) on day 1 of induction chemotherapy which was either daunorubicin (50 mg/m2)/cytarabine or daunorubicin/clofarabine. Eleven hundred and fifteen patients generally over 60 years with a median age of 67 years with de novo, secondary AML or high-risk myelodysplastic syndrome were present. The overall remission rate was 69% (60% complete remission: 9% CRp) which was not improved by the addition of gemtuzumab ozogamicin. At a median follow-up of 30 months, the cumulative incidence of relapse at 4 years was significantly reduced in the gemtuzumab ozogamicin arm (73 vs. 78%, P = 0.007), and overall survival was improved (20 vs. 15%, P = 0.05). This was achieved with little extra toxicity. When the total experience of the UK trials across all aged groups was examined together in 2228 randomized patients, there was a significant reduction in the risk of relapse and overall survival when the gemtuzumab ozogamicin 3 mg/m2 was added to induction.
ALTERNATIVE INDUCTION SCHEDULES
There is increasing concern that it has not been possible to substantially improve on the standard 3 + 7 induction, which has been particularly unsatisfactory in patients with poor risk cytogenetics. Escalation of cytarabine dose has been unconvincing, but there has been recent investigation into alternative nucleoside analogues such as cladrabine and fludarabine. The Polish Adult Leukaemia Group (PALG) have compared cladrabine to cytarabine in two randomized trials [18,19▪▪]. In the first trial, the inclusion of cladrabine significantly increased the proportion of patients who achieved complete remission with one course, but an improved survival was not confirmed possibly because there were insufficient patients. In a recent study, the addition of cladrabine or fludarabine to cytarabine plus daunorubicin was compared to cytarabine/daunorubicin alone in a three-arm study which recruited 652 patients under 60 years. The inclusion of cladrabine improved the remission rate compared with daunorubicin; however, the addition of fludarabine did not. This was also reflected in a survival benefit (44 vs. 33%, P = 0.02) at 2 years for cladrabine, but not for the addition of fludarabine (35 vs. 33%). In a subgroup analysis, the addition of either nucleoside appeared to be beneficial in patients with an adverse karyotype.
One of the questions in the UK MRC AML15 trial  was to compare FLAG-Ida (fludarabine/cytarabine/G-CSF/idarubicin) against daunorubicin/cytarabine in younger patients. This did not improve the complete remission rate or the overall survival. It did significantly reduce the risk of relapse (42 vs. 55%, P = 0.0001), but was more myelosuppressive, and as a consequence, fewer patients had the planned consolidation delivered. However, in a retrospective analysis comparing the patients who had received only the two induction FLAG-Ida courses with those who had received both daunorubicin induction courses plus the two consolidation courses, there was no difference in survival. When the patients who did receive all the four planned courses were compared with the daunorubicin patients who received all planned courses, there was a clear benefit for the recipients of the FLAG-Ida induction (67 vs. 53%, P = 0.00001). Although these retrospective analyses have limitations, they do suggest that alternative nucleosides may have an advantage and should receive further study. There are on-going trials incorporating clofarabine – which was engineered to combine the beneficial features of both cladrabine and fludarabine – into induction.
The conventional morphologically based definition of remission has limitations. Its ‘depth’ will vary between patients as indicated by molecular or immunological or even cytogenetic techniques to measure residual disease, with consequent prognostic implications. Similarly, the speed of blast clearance is also prognostically important. Which approach to postinduction treatment is taken will be influenced by some or several independent prognostic factors which are not discussed here.
The classic approach was established by the CALGB  and comprises four courses of high-dose cytarabine (3 g/m2 on days 1, 3 and 5) (HidAC) followed by four maintenance courses, which still remains the standard albeit without the maintenance component. There are alternatives based on combinations of amsacrine/etoposide/motoxantrone/cytarabine which produce similar survival outcomes. The UK MRC15 trial compared this to a curtailed CALGB high-dose cytarabine schedule and found it to be equivalent in terms of survival but more myelosuppressive . Patients were, in addition, randomized to a comparison of the traditional HidAC dose of 3 vs. 1.5 g. The outcome was the same for both dose levels. When these questions were assessed within the cytogenetically based risk groups, there was evidence that the ‘MRC’ combination was superior to HidAC for poor risk patients. The next issue is how many postinduction courses are required? The problem with prescribing several courses is that compliance will be imperfect, particularly if induction has been intensified. In the UK MRC AML15 trial, a total of five courses (which included induction) was compared to four courses and no difference was seen overall, or in any subgroup with the possible exception of high-risk patients who appeared to benefit from a fifth course if it could be delivered. The AML17 trial is currently comparing a total of 4 vs. 3 courses for favourable and intermediate-risk patients. What is optimum for older patients is less clear. The increasing toxicity of HidAC with age requires dose attenuation, and it is not unusual for older patients to be given only one postinduction course. The question of how many courses was examined in the NCRI AML14 trial , which concluded that there was no benefit in a fourth course, and the current NCRI AML16 trial is testing 3 vs. 2 courses for patients who had a complete remission or partial remission to the first induction course.
Reduced intensity allografts from siblings or volunteer-matched donors are feasible and studies are in progress to clarify if, and in which subgroups, they should be the preferred choice.
Molecular, cytogenetic and other information may influence the choice of postinduction therapy, particularly in younger patients in whom the preferred option could be myeloablative allogeneic transplantation (SCT). The unsuitability of HidAc for those with adverse cytogenetics has been mentioned, so there is general agreement that transplantation whether from a sibling or a matched unrelated donor is the preferred choice. However, survival after SCT is 30–40%, and with more recent recognition of the particularly unfavourable effect of a monosomal karyotype, it is clear that not all adverse groups derive benefit.
OLDER LESS FIT PATIENTS
This is a numerically important subgroup who in former days were provided only with supportive care to avoid inflicting toxicity. However, low-dose Ara-C (LDAC) has been established as offering some benefit without increasing toxicity and represents a treatment to be challenged by new options. Although some new agents are effective [23,24], randomized comparison has not yet established a new standard. Demethylation therapy can prolong survival without disease eradication, and comparative trials will be reported shortly.
There is an increasing body of evidence to indicate that intensification of daunorubicin may have a beneficial effect without any extra toxicity. However, it is not clear that this results in a better overall survival than can be achieved with other treatments involving conventional doses or that a 90-mg dose is superior to 60 mg. Gemtuzumab ozogamicin has had a chequered history, but the two recent studies in older patients suggest that this agent can have a positive role to play and should be re-evaluated. Alternative nucleoside analogues such as fludarabine and cladrabine may be more effective than Ara-C in induction, particularly in high-risk patients, and on-going studies that incorporate clofarabine, which is manufactured to incorporate the advantages of both drugs, are awaited.
Although the standard of care in consolidation remains high-dose Ara-C, the precise dose and number of courses required appears to be less than in the classic CALGB schedule and alternatives are needed for high-risk patients.
Conflicts of interest
The author has served on Advisory Boards for Wyeth/Pfizer and Genzyme.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 125–126).
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