Treatment of acute myeloid leukemia: are we makingprogress?

Alan K. Burnett1

1School of Medicine, Cardiff University, Cardiff, United Kingdom

With a few subgroups as exceptions, such as younger patients with more favorable genetic disease, improvement inthe treatment of acute myeloid leukemia has been slow. There is a possibility that improving the quality of remissioncan reduce the risk of relapse. Escalation of daunorubicin dose, addition of Ab-directed chemotherapy, and alternativenucleoside analogs in induction may displace the longstanding standard of “3 � 7” daunorubicin � cytarabine (Ara-C)as induction, and several prognostic factors are emerging that enable a more personalized approach to postinductiontreatment, in particular, which patients should be offered allogeneic transplantation in first remission. In addition toproviding prognostic information, molecular characterization provides potential therapeutic targets and, in some cases,an opportunity to more precisely monitor residual disease. With few exceptions, the predictive value of prognosticfactors (ie, what therapy to adopt) has yet to be established. A major challenge is the treatment of older patients withacute myeloid leukemia (AML), who represent the majority of patients with this disease. Only about half of older AMLpatients will enter complete remission (CR) with conventional chemotherapy and, of these, most will relapse within2 years. Little impact has been made on these dismal outcomes over the past 3 decades, and new treatments andapproaches to trial design are required. Another population of concern is older AML patients who are not considered tobe fit for an intensive approach based on concerns about their ability to withstand the consequences of treatment. Thisgroup is not easy to define objectively, but age represents a useful surrogate because it is associated with morechemoresistant disease and medical comorbidity. Older patients represent a therapeutic challenge, but several newtreatments may offer some potential to improve their situation.

IntroductionBeing predominantly a disease of older people, the therapeuticstrategy offered for AML is determined by assessment of thepatient’s age and general fitness level. For those thought to besuitable for, or who might benefit from (not necessarily the samepatients), the standard of care for over 3 decades has been thecombination of daunorubicin given for 3 days combined withcytarabine (Ara-C) given over 7 days, the so-called “3 � 7”schedule. The majority of younger patients who achieve a CR willdo so with one course; however, a second course will converthalf of the remainder so that, overall, 70%-75% will enter CR.1

Based on the landmark Cancer and Leukemia Group-B (CALGB)study,2 the standard of care for consolidation was 4 courses ofhigh-dose IV Ara-C 3 g/m2 given every 12 hours on days 1, 3,and 5, which was demonstrated to be more effective than either adose of 100 or 400 mg/m2 by continuous infusion for 5 daysfollowed by 4 courses of monthly maintenance. If a suitabledonor is available (formerly limited to a matched sibling, butnow a matched unrelated donor as well), an allogeneic transplan-tation will be considered as alternative consolidation.3,4 Deliver-ing this approach to younger patients will provide a 40%-45%chance of cure. This represents a steady improvement over the past40 years (Figure 1), although much of this can be attributed toimprovements in supportive care, much of which has been learnedfrom the transplantation experience. There are, however, severalunresolved issues around this “conventional” approach, such asalternative anthracyclines or nucleoside analogs in induction, dose,and number of courses of consolidation, and which patients shouldreceive an allograft in first remission.

Unlike what is seen in younger patients, for older patients, mostcollaborative group and large center experience has shown littleevidence for an increase in the cure rate, even though these patientshave been thought suitable for conventional chemotherapy (Figure2). In addition, there are a substantial number of patients who are notconsidered suitable for intensive chemotherapy, for whom a pallia-tive approach is usually offered. Comparisons of published series isless reliable in this population because of different eligibility criteriain different trials, but approximately 50% of older patients, definedarbitrarily as over 60 years, will enter remission. Unfortunately,85% of those entering remission will subsequently relapse, and theoutcome from relapse in older patients is poor, with relatively fewsurviving.

Options for improvementSeveral alternatives to 3 � 7 have been assessed in multiple studies,with little convincing evidence that they will change the standard ofcare. In particular, there is no consistent evidence to support theaddition of a conventional therapeutic as a third drug or escalationof the dose of Ara-C.5-7 However, there is recent interest indaunorubicin dose escalation or intensification and the role ofAb-directed chemotherapy as a way of delivering more treatmentwithout significant extra toxicity. It may well be possible to improvethe quality of remission, which would be reflected in a reduction ofrelapse risk, rather than just the remission rate. A substantial numberof prognostic factors (Table 1) have been identified, each of whichin many cases can be shown to independently indicate a favorable orunfavorable average outcome and thus offer the potential to directtherapy appropriately. Not all of these factors are molecular or

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genetic, and traditional factors such as initial response, presentingWBC count, and secondary disease, still have value.8 However, it ishoped that the substantial molecular heterogeneity of AML cur-rently being revealed will bear therapeutic fruit by providing“druggable” targets, rather than simply adding to the alreadyextensive list of prognostic factors.

Challengers to standard of careAnthracycline doseWhether daunorubicin should remain as standard of care has beenquestioned in randomized comparisons with idarubicin or mitoxan-trone in several randomized trials, without convincing evidence forsubstantial differences in survival. Four recent studies evaluateddifferent ways of intensifying daunorubicin administration. TheE1900 trial,9 which was undertaken by the Eastern CooperativeOncology Group (ECOG) in 657 younger patients, compared adaunorubicin dose of 90 mg/m2 versus 45 mg/m2 in a 3 � 7 schedulefor the first induction course. The higher does achieved a signifi-cantly higher overall remission rate, with more patients in CR afterthe first course and a better overall survival (23.7 vs 15.7 months). Asimilar approach was taken by the Dutch-Belgian Hemato-Oncology Cooperative Group and the Swiss Group for ClinicalCancer Research (HOVON-SAKK)10 in older patients. In that

study, the overall remission rate was similarly improved, but overallsurvival was not, except in the case of patients in the 60- to 65-yearsubgroup (38% vs 23%). These data received further support from aKorean trial11 in younger patients showing that the higher dose ofdaunorubicin (90 mg/m2 vs 45 mg/m2 by continuous infusion over3 days) also resulted in a superior remission rate and overallsurvival.

There has been discussion for a long time about dose equivalencebetween daunorubicin and alternatives such as idarubicin. A studyfrom the Acute Leukemia French Association (ALFA) groupshowed that daunorubicin 80 mg/m2 on days 1-3 versus idarubicin12 mg/m2 for either 3 or 4 consecutive days in patients 50-70 yearsof age produced an equivalent overall survival.12 A recent Japanesetrial13 in 1057 younger patients tested intensification, not by doseescalation, but by administration of 50 mg/d for 5 days comparedwith the traditional 3 days (ie, a total first-course exposure of 250 vs150 mg against idarubicin for 3 days). The remission rates andsurvival were similar. Whether these studies justify a higherdaunorubicin dose as the standard of care is not clear. All studiesconfirm, at least with the follow-up available, that cardiotoxicity isnot a concern in adults. The benefits appear to differ in thecytogenetic risk subgroups, being less clear in the favorable and

Figure 1. Survival for younger patients, 1970-2009.

Figure 2. Survival for older patients, 1970-2009.

2 American Society of Hematology

unfavorable subgroups, but recent multigene mutation characteriza-tion may be useful in identifying those who benefit from theescalated dose.14

Ab-directed chemotherapyAugmentation of standard chemotherapy in relapsed or refractorypatients with naked CD33-directed Ab therapy failed.15 Howeverwhen the Ab was conjugated to the powerful intercalating agentcalicheamicin, an effective agent, gemtuzumab ozogamicin (GO;Mylotarg), was created that gained regulatory approval for thetreatment of older patients in relapse who were considered unsuit-able for intensive therapy.16 Several trials have been reportedrecently; however, failure to show benefit and some concern aboutan excess of induction death in the SWOG-106 trial, whichaugmented daunorubicin � Ara-C with a single dose of GO (6 mg/m2)17 and which was presented for regulatory approval, led towithdrawal of the drug from the US market. Three other Europeantrials involving nearly 3000 randomized patients have shown asurvival benefit when combined, at lower daily dose levels, withinduction chemotherapy. In the United Kingdom Medical ResearchCouncil/National Cancer Research Institute (9MRC/NCRI) trials inyounger and older patients, 3 mg/m2 was safe and effective,18,19

whereas the French ALFA trial used 3 mg/m2 in a fractionatedschedule.20 All showed an improved survival in favorable andintermediate-risk, but not in poor-risk patients. The Italian Groupfor Haematological Diseases in Adults (GIMEMA) AML17 trialcompared pretreatment with GO at a dose of 6 mg/m2 � 2 beforeinitiating chemotherapy. However, when used in this way, there wasno overall benefit.21 In addition, GO is a very effective agent in acutepromyelocytic leukemia and provided a useful option for relapseddisease,22 so perhaps it will reemerge as a therapeutic option.23

Alternative nucleoside analogs in inductionEscalation of the Ara-C dose has been unconvincing, but there hasbeen recent investigation into alternative nucleoside analogs such ascladribine,24 fludarabine,25 and clofarabine.26,27 The Polish AdultLeukaemia Group (PALG) compared cladribine with cytarabine in2 randomized trials. In the first trial,24 the inclusion of cladribineincreased the proportion of patients who achieved CR with onecourse significantly, but an improvement in survival was notdemonstrated, possibly because there was an insufficient number ofpatients. In a second, more recent study,28 the addition of cladribineor fludarabine to 3 � 7 cytarabine was compared with 3 � 7 alonein a 3-arm study (daunorubicin/Ara-C [DA]/cladribine vs DA/fludarabine vs DA alone) in patients less than 60 years of age. Theinclusion of cladribine, but not fludarabine, improved the remission

rate and overall survival. In a subgroup analysis, the addition ofeither nucleoside appeared to be beneficial in patients with anadverse karyotype. The MRC AML15 trial compared FLAG-Ida(fludarabine/Ara-C/G-CSF/idarubicin) with DA or DAE (DA � etopo-side) in induction in younger patients. There was no difference inremission rate or overall survival, but FLAG-Ida reduced the risk ofrelapse significantly.25 However, this reduction in risk was offset bythe consequences of increased myelosuppression, which also lim-ited compliance with postinduction therapy. The overall survival ofthe selected patients who did receive the planned consolidation was67%. The United Kingdom NCRI AML16 trial compared clofara-bine at a lower dose level of 20 mg/m2 against Ara-C, both incombination with standard-dose daunorubicin in older patients. Thiswas based on encouraging data when clofarabine was used asmonotherapy, particularly in patients with adverse cytogenetics.However, there was no difference in response or overall survival inany risk subgroup.

Postinduction therapyThe prognosis for patients who have completed induction courseone, even though they have not achieved CR, can be estimated byseveral molecular and genetic factors (discussed below) which areincreasingly being considered when deciding postremission strat-egy. Important information can be derived at this point in relation totreatment response to the first course. If the patient has achieved atleast a partial remission (ie, BM blast reduction to � 15%),29 orblast eradication on a day 15 BM or is in a CR with full countrecovery, he or she has more chemosensitive disease and a lowerrisk of subsequent relapse from remission. There remains uncer-tainty about the value of complete BM response with incompletecount recovery, the so-called “CRp/Cri,” which was a responsecriterion brought to life in the assessment of the Mylotarg responses.Although there may be caveats about when in relation to the BMsampling the recovery definition was made and the level of theplatelet count and transfusion dependence, it is generally concludedthat CRp/CRi is associated with an inferior survival compared withconfirmed CR.30,31 The ability to move forward from a morphologi-cal definition to one based on cytogenetic or molecular or immuno-phenotypic assessment of minimal residual disease may prove to bemore useful.

Whereas high-dose Ara-C at a dose of 3 g/m2 is the standard of carecompared with an intermediate 400 mg/m2 dose, no further refine-ment of dose or the optimal number of courses has been described.The MRC15 trial compared a 1.5 g/m2 dose against the 3 g/m2 doseand found no difference in major outcome end points. In addition,

Table 1. Prognostic factors in AML

Pretreatment characteristics

Major AlsoCytogenetics WT1 mutation Resistance proteinsAge EVI1 P53 mutationWBC MLL-PTD Autonomous growthSecondary disease RUNX1 mutation Stem cell phenotypeFLT3-ITD BAALC ERGNPM1 mutation MiR profile MN1CEBPA mutation Gene-expression profileIDH1/2 DMT3A ASXL1

Posttreatment predictorsInitial response (blast count postinduction)Minimal residual disease

WBC indicates white blood cell.

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there was no benefit in giving more than 2 courses in the context ofhaving given 2 induction courses. However, compared with anamsacrine/etoposide/mitoxantrone–based consolidation approach,both high-dose Ara-C dose levels were inferior in patients withpoor-risk cytogenetics.25 There is continuous debate about the roleof stem cell transplantation in first remission. Large studies fromcollaborative groups show no significant overall survival benefitof myeloablative transplantation if the recipient’s age exceeds35-40 years,3,4 based on a donor versus no donor method of analysis.In meta-analyses based on a heterogeneous collection of studieswith risk defined in a nonuniform way (but usually cytogeneticallybased), the availability of a donor was associated with an improvedrelapse-free survival and, in some cases, overall survival for bothintermediate- and poor-risk patients. There is an increasing aware-ness that a donor versus no donor analysis as a surrogate for arandomized comparison must be viewed with care. For example, insome studies, it is assumed that if a sibling donor is identified, atransplantation has actually been undertaken and that it has beenundertaken in first remission, but these assumptions may beincorrect. For example, patients who do not have a sibling donor,but do have an unrelated donor, will be in the “no donor” group and,in the analysis, the transplantation may or may not have been donein first remission. An alternative is the Mantel-Byar method,32 inwhich all patients start on the “chemo” arm and when the transplanta-tion is delivered, they populate the “transplantation” arm. Tocompensate for the selection of patients who survive long enoughand are in good condition, a time adjustment on the “chemo” curvecan be made. While not an ideal alternative, having a tendency tofavor transplantation, this sort of analysis can allow the inclusion ofnonsibling donors, only counts those in whom the transplantationwas given, and can be applied to assess the impact of transplantationin CR1 only. An additional issue is the appropriate end point. Ifevent-free or relapse-free survival is the chosen end point, in moststudies showing a benefit from transplantation, patients on chemo-therapy who are salvaged after relapse are excluded. For example, ina recent analysis of 1271 patients in the United Kingdom databasewho relapsed without being transplanted in CR1, 32%, 17%, and7% of favorable-, intermediate-, and poor-risk patients, respec-tively, survived.33 Therefore, a Mantel-Byar analysis with overallsurvival as the end point appears to be the appropriate methodology.This makes the benefit for intermediate risk based on cytogeneticsless clear. However, by more precisely defining risk using age,cytogenetics, response to induction course 1, presenting WBCcount, and de novo or secondary disease, approximately 20%-25%of intermediate-risk patients have a higher than average risk and,based on a Mantel-Byar analysis, will benefit from a myeloablativetransplantation in CR1.34 Nonmyeloablative conditioning (re-duced intensity conditioning) enables older patients to accessstem cell transplantation and the associated GVL effect. This isclearly feasible, but there are few comparative studies clarifying theoverall benefit or describing which patient subgroups benefit.

Prognostic factors and clinical applicationCytogenetics has traditionally been used in younger patients toinfluence the choice of postinduction therapy because it effectivelypredicts the average relapse risk. The usual therapeutic option underconsideration is who should, or should not, be put forward forallotransplantation. Patients in the core binding factor (CBF)subgroup have a favorable outlook and are not considered to need afirst CR transplantation; these patients may have their risk reduced ifthey receive GO in induction. There is an increased risk of relapsefor the 20%-30% of patients who have a cKIT mutation, and themolecular targets are capable of predicting impending relapse by

quantitative RT-PCR with approximately 3 months’ notice based onBM transcript load in the postinduction remission BM. Experiencewith cKIT inhibitors is accumulating. Bi-allelic CEBP� and NPM1mutations without an associated FLT3 mutation have a similarprognosis to the CBF leukemias, so they do not require a transplan-tation approach. Conversely, patients with adverse cytogenetics(including chromosome 5 and 7 abnormalities, inv3, and complexand monosomal karyotypes) will relapse rapidly. Morphologicalresponse to induction course 1 (blast reduction in BM to � 15%) isan independent adverse feature even if remission is achievedsubsequently. Because there is no satisfactory conventional chemo-therapy approach for such patients, allograft is recommended, butwill only cure 30%-40% of patients, and some will relapse beforethe transplantation can be delivered. A large volume of moleculardata have emerged showing a better or poorer prognosis with themain aim being to determine the intermediate-risk group.35 Of theNPM1 mutants, which occur in 50% of normal karyotypes, approxi-mately 40% are associated with a FLT3 mutation that balances outthe favorable effect of NPM1, although the allelic ratio of the FLT3mutation may influence this. The impact of FLT3 mutations iscomplex and is influenced by the association with NPM1 whether itoccurs alone and by the allelic ratio. It is likely that the prognosticimpact of each mutation will be modified by its association withother mutations.

It is important to be aware that “prognostic” does not mean“predictive,” in that the latter means that a validated therapeuticoption has been identified. In most cases, there is a lack of robustdata pointing to a particular validated therapeutic option. Allogeneictransplantation is frequently considered for FLT3 mutations, al-though the results may be disappointing and the evidence base forbenefit is not settled,36,37 particularly when the allelic ratio andassociation (or not) with NPM1 is considered. The association of acKIT mutation with the CBF group, TET2, DMNT3a, IDH1/2, andASXL-1 have all emerged recently, and a consistent prognosticpicture has yet to emerge. The picture becomes even morecomplicated by the prognostic implication of mutations occurringalone or in combination.14 It will require large, extensively charac-terized clinical databases to clarify this information

The importance of the molecular heterogeneity could be in identify-ing targets for therapeutics or for minimal residual disease monitor-ing. Most attention has so far focused on FLT3 as a target, but thereare no randomized data to show a benefit of FLT3 inhibition,although such information is imminent. An important component ofthis approach is to have associated pharmacodynamic markers.There is preliminary information that it is only when the target isinhibited that the risk of relapse is reduced.38 All-trans-retinoic acidhas a well-established role in acute promyelocytic leukemia, and hasbeen evaluated in nonacute promyelocytic leukemia patients basedon the concept that is can reduce the half-life on BCL2, but theresults are contradictory. Whether the NPM1-mutated subset inparticular benefit, as has been claimed, is open to question.

The challenge of the older patientCollaborative group studies have an undistinguished record inimproving the outcome of older patients. Although age is anindependent adverse prognostic factor, it also serves as a surrogatefor other negative factors such as comorbidities and biologicallymore resistant disease. An illustration of the problem is the serialoutcome for patients treated with conventional chemotherapy inUnited Kingdom trials over the past 40 years (Figure 2). Up to 60%of patients enter remission depending on the inclusion criteria, but

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most will relapse. There has been little success in altering this withconsolidation and, at best, maintenance has a modest effect. Recentevidence suggests that, at least for some patients, there may be adaunorubicin dose effect,10 and 2 of 3 European randomized trialssuggest a benefit for augmenting induction with GO.19,20 A smallminority of selected patients may benefit from a reduced intensityallograft. Cytogenetics is also a powerful prognostic factor in thispatient group, with a smaller proportion of favorable-risk and ahigher proportion of poor-risk subtypes. There is less molecularinformation and, because of the overall poorer prognosis, the impactis less clear. For example, FLT3 mutations still confer a negativeimpact, whereas NPM1 mutations are less predictive of an improvedoutcome. In addition, there are a substantial proportion of olderpatients who do not receive conventional chemotherapy. Thesepatients are sometimes referred to “the older unfit” patients and havetraditionally been offered supportive care. How these patients aredefined, and whether they would be better off with conventionalchemotherapy, is one of the present dilemmas. Population-basedinformation from Sweden showed that the outcome was superior ingeographic regions where intensive treatment was given comparedwith regions where it was not.39 However, there could be othervariables governing the choice of treatment approach. In aneffort to clarify this issue, a United Kingdom trial (AML14)intended to randomize patients for whom there was uncertainty to anintensive or nonintensive approach. However, in a recruitment of� 1600 patients, only 8 were randomized.31 Multifactorial riskscores that can more accurately characterize risk have been devel-oped40,41 in older patients treated either intensively or noninten-sively, but this does not clarify which approach is better for whichpatient. There is also a category of patients who may be fit, but arethought not likely to benefit from an intensive approach, such asolder patients with secondary disease or adverse cytogenetics, whoare candidates for experimental treatments.

Several new drugs have been tested in this patient group in recentyears, and although capable of improving response, none hasachieved regulatory approval, but this continues to be an active areaof study. One of the challenges is how to improve matters in a timelymanner. To that end, the traditional large randomized trial may notbe appropriate, so new designs are emerging, one of which is a “picka winner” concept42 in which several novel treatments are comparedwith standard of care (low-dose Ara-C in the United Kingdom). Theaim is to screen for options that could make a clinically importantdifference defined on a preliminary assessment against responserate, and to only continue within the trial the assessment of thosethat show promise; for example, double the remission rate as anearly surrogate for survival. New treatments can be introduced asthe trial progresses, but contemporaneous randomization remains anessential requirement. Whereas carrying some risk of progressing atreatment that will not improve survival, there is reasonable reliabilityin eliminating treatments that fail in the randomized setting.

Prospects for the futureIt could be argued that there is limited further mileage in conven-tional chemotherapeutic agents. The burgeoning molecular informa-tion could be valuable in several ways apart from shedding light onleukemic mechanisms and biology. Like others, AML doctorsalways hope for the “AML Glivec,” but with such heterogeneity,this is unlikely except possibly in well-defined subsets. The abilityto “personalize” treatment based on more accurate estimate of anindividual patient’s risk has a numbers of hurdles to jump. First,new prognostic subsets must be based on statistically robust datathat are applicable to contemporary treatment. They have to be

validated on a different dataset. Some may be unstable as newtreatments emerge. For example, it is not clear how prognostic acKIT mutation is in the CBF subset that has received GO ininduction. Minimal residual disease assessment, by molecular orimmunophenotypic methods, is now capable of reliably predictingfor each individual an accurate risk assessment. However, theimplication is that therapeutic intervention at the time of minimalresidual disease detection is a superior intervention at morphologi-cal relapse and this has yet to be established.

DisclosureConflict-of-interest disclosure: The author declares no competingfinancial interests. Off-label drug use: GO for the treatment of AML.

CorrespondenceAlan K. Burnett, School of Medicine, Cardiff University, HeathPark, Cardiff CF14 4YU, United Kingdom; Phone: 44-2920-742375; Fax: 44-2920-744655; e-mail: BurnettAK@Cardiff.ac.uk.

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