Recent developments in management of older patients with acute myeloid leukemia

Abstract

Introduction

Patients with acute myeloid leukemia (AML) are currently primarily classified as ‘younger’ or ‘older’. The latter are typically regarded as those who are 60 or above. Inherent in the above approach is the view that age is the principal predictor of outcome in AML. The two principal determinants of outcome are whether the patient incurs treatment-related mortality (TRM) or whether, absent TRM, the patient’s AML is resistant to treatment, with resistance manifested as failure to enter complete remission (CR) or relapse from CR.

A problem with this single-minded focus on age less or above 60 is that it is intuitively obvious that a 71-year-old patient, for example, can be fitter than a patient 15 years younger. Indeed data indicate that the effect of age in AML is numerical (continuous) [Thall and Estey, 2001]. Thus, other things being equal, there is more difference in outcome between a patient age 68 and a patient age 61 (both ‘older’) than between the latter patient and a patient age 59 (‘younger’).

Even more important the effect of age is modified by the effect of other factors. Walter and colleagues studied TRM and resistance in 1127 patients (median age 57) treated on Southwest Oncology (SWOG) trials from 1986 to 2009 and 1604 patients (median age 61) treated on M.D. Anderson Cancer Center protocols during the period 2000–2008 [Walter et al. 2010b]. They first found that the weekly risk of death declined sharply once 3–5 weeks had elapsed from the start of remission induction therapy. This was true in various age groups and prompted the authors to define TRM as death occurring within the first 30 days of such therapy, with patients having this outcome comprising a qualitatively distinct group. The authors then used the area under the receiver operator characteristic curve (AUC) to quantify the effects of covariates for prediction of TRM and resistance (no TRM but patient does not enter CR or relapses within 1 year of CR), where an AUC of 1 indicates that a covariate is perfect at prediction while an AUC of 0.5 indicates no prediction (i.e. it is no better than flipping a coin). Age alone had an AUC of 0.67 for prediction of TRM while performance status alone had an AUC of 0.72. The inclusion of various additional covariates resulted in an AUC of 0.86. Elimination of age from this model lowered the AUC only to 0.85, suggesting that age is primarily a surrogate for these other covariates. Prediction of resistance was more difficult than prediction of TRM (AUC with our best model, which included de novo or secondary AML, leukemia cell cytogenetics and FLT3 internal tandem duplication [ITD] status, was only 0.70). Here again, however, age alone was inadequate (AUC 0.64), and elimination of age from the best model lowered the AUC only to 0.67. These data suggest that using age as the sole criterion to assign patients to treatment, as is commonly done, is analogous to using hair color (gray or not) to decide a person’s age.

Treatment-related mortality versus resistance

A common misconception is that TRM is the main problem in the management of older patients. However Appelbaum and colleagues illustrated that even in patients age 75 or over resistance was a more likely cause of failure to enter CR than TRM (defined as death by day 30 of ‘3 + 7’ remission induction therapy) [Appelbaum et al. 2006]. Specifically the CR rate in 80 such patients was 33%, the TRM rate was 31% and the resistance rate was 36%. When account is made for the threefold to fourfold greater frequency of relapse than of death in CR even in patients age 70 or above, the relative magnitude of resistance rather than TRM becomes even more apparent. Thus, henceforth we focus on therapies claimed to reduce the risk of resistance, recalling that, while resistance is primarily associated with older age (e.g. >60 years), such therapies might also find application in younger patients.

Before beginning, we review the principal covariates associated with resistance in AML, regardless of patient age [Dohner et al. 2010]. It must be stressed that these covariates have primarily been identified in patients given standard 3 + 7 therapy. The chief factor is cytogenetics. A monosomal karyotype (MK) is now recognized as the least favorable cytogenetic pattern [Breems et al. 2008; Medeiros et al. 2010]. The criteria for an MK are at least one autosomal monosomy, or one autosomal monosomy and one structural abnormality, such as a translocation or a deletion, but not a trisomy. The prognostic significance of a complex karyotype (CK; at least three or in some definitions five distinct abnormalities) is due to its association with an MK; in particular, patients with a CK who do not have an MK have better outcomes than patients with an MK but not a CK. An MK is found in 25% of patients age 60 or above and 10% of patients age <60, with the increased frequency in older patients responsible for some of the poorer outcome of such patients. SWOG data indicate that in patients age 60 or above an MK is associated with a CR rate of 13% and a median survival of 2 months (versus a CR rate of 24% and a median survival of approximately 6 months in younger patients with MK) [Medeiros et al. 2010]. Although patients with other unfavorable cytogenetics (such as CK, a single monosomy involving chromosomes 5 or 7, a deletion of the long arm of these chromosomes or of chromosome 11) fare better than those with an MK, the difference is more quantitative than qualitative. Thus, patients age 60 or above with unfavorable non-MK cytogenetics have a CR rate of 27% and a median survival of 9-12 months, with a 4-year survival probability of 13% [Medeiros et al. 2010].

Although not associated with as poor an outcome as unfavorable cytogenetics (with or without an MK), lack of a mutation in the nucleophosmin (NPM1) gene, or presence of an ITD in the FLT3 gene, also convey poor prognoses. NPM mutations and FLT3 ITDs are typically found in patients with normal karyotypes. Reporting for the CALGB, Becker and colleagues noted that approximately 50% of patients age 60 or above, and 45% of those aged 70 or above, with de novo AML and a normal karyotype and 45% of had an NPM1 mutation [Becker et al. 2010]. The median survival of such patients was about 3 years, in contrast to a median survival of approximately 1 year in older patients without an NPM1 mutation. This study can be criticized because the outcome of all patients (NPM1 positive and negative) is much better than might be expected in patients age 60 or above. Furthermore, the CALGB data do not make clear the extent to which an FLT3 ITD modulates the effect of an NPM1 mutation, but other studies suggest that the effect of an FLT3 ITD is quite unfavorable, converting the probability of relapse (although not the CR rate) of a patient with a normal (or other ‘intermediate prognosis’ karyotype) into almost that of a patient with an unfavorable, but not MK, karyotype. In turn the effect of an FLT3 ITD depends to a considerable extent on the ‘allelic ratio’, the proportion of ITD-derived protein relative to that of normal ITD protein [Gale et al. 2008]. The difference in the cumulative incidence of relapse between patients with an allelic ratio >50% and patients with an allelic ratio of 1–50% is as great as the difference between the latter and patients with no FLT3 ITD. These data make clear the need to assess the NPM1 and FLT3 ITD status of all older patients. For example, there would be considerably more reluctance to give an older patient therapy other than 3 + 7 in the presence of an NPM1 mutation.

Numerous other molecular markers have been described as being of prognostic significance: IDH1, IDH2, TET2, DNMT3a, ASXL1, etc. While I think it is premature to use these in therapeutic decision making, some will undoubtedly be shown to be useful for this purpose. Thus, there will be an even greater number of distinct prognostic subsets, and, as more is learned about these, it is likely that each will be treated with different drugs. Under these circumstances it seems that there will be too few patients in any one subgroup to support the false-positive and false-negative rates of 5% and 20% that have become enshrined in clinical trial design. Thus while it is difficult to forecast which of these molecular markers will be of clinical use, it relatively simple to predict that they will compel re-examination of these false-positive and false-negative rates, which will become very difficult to attain.

Another factor predicting for resistance in patients age 60 or above is secondary AML, defined as AML resulting after chemotherapy for another disorder or following a >3-month duration of abnormal blood counts (‘antecedent hematologic disorder’). The effect of secondary AML is independent of that of cytogenetics or of abnormalities in NPM1 or FLT3. In contrast, there is no independent prognostic significance of a morphologic finding of ‘multilineage dysplasia’ in AML [Haferlach et al. 2010].

Standard versus investigational treatment

The fundamental decision for any physician seeing a patient with newly diagnosed AML is whether to treat the patient and, if so, whether the therapy offered should be ‘standard’ (such as 3 + 7) or investigational. Since the outcome of investigational therapy is inherently unknown, the latter decision can only be based on the outcome of standard treatment. Several ‘scoring systems’ are available that account for cytogenetics, secondary AML, age, performance status and other covariates to arrive at a prognosis for patients age 60 or above after administration of such therapy [Dombret et al. 2008; Kantarjian et al. 2006; Krug et al. 2010; Wheatley et al. 2009]. In my opinion, patients age 60 or above with unfavorable cytogenetics do not benefit from standard therapy since the CR rate is itself < 30%, as noted above, without accounting for the probable transient nature of a remission even following an allogeneic hematopoietic-cell transplant (HCT). As discussed below, current data lead me to include azacitidine and decitabine in ‘standard induction therapy’. If a clinical trial is unavailable, and given the inconvenience of such standard therapy, patients with unfavorable cytogenetics should be offered supportive care. In older patients with normal cytogenetics use of standard induction therapy is much more plausible. However, it is important to note that remission induction therapy can influence not only achievement of CR, but also duration of CR, even after HCT. In particular, Pagel and colleagues have noted that the presence of minimal residual disease (MRD) by multiparameter flow cytometry prior to myeloablative HCT in first CR greatly increases the relapse rate (thereby decreasing survival) after HCT [Pagel et al. 2008]. The presence of such MRD of course reflects the ineffectiveness of induction chemotherapy even though such therapy resulted in CR. This in turn makes a case for the possible use of investigational therapy even in patients who are likely to enter CR, such as those with a normal karyotype. Of course it is quite conceivable that investigational therapy might result in a lower CR rate; this possibility is more consequential for patients with a normal karyotype than for patients with an unfavorable karyotype. Hence, given the same information about prognosis after standard therapy, some patients with a normal karyotype might prefer standard therapy, while others might prefer investigational therapy; the former choice would appear less likely in patients with unfavorable karyotypes.

The word ‘acute’ in AML often leads physicians and patients to believe that treatment cannot be delayed for 1–2 weeks before information about cytogenetics, NPM1 and FLT3 become available. However, Sekeres and colleagues have noted that such delays are unlikely to be harmful in patients who present with a white blood cell count (WBC) <50,000 [Sekeres et al. 2009]. Certainly the risk of such a delay appears lower than the risk entailed in giving standard therapy to a patient who is not only unlikely to respond but also not unlikely to experience morbidity (if not TRM) and inconvenience.

‘New’ therapies

If the decision is made to give investigational therapy to an older patient what investigational therapies might be offered?

Single agents

Higher-dose daunorubicin

Daunorubicin has typically been given at 45 or 60 mg/m² daily × 3 days together with ara-C (cytarabine) 100 mg/m² daily × 7 days by continuous infusion. However, Breems and colleagues randomized patients age 60 or over with untreated AML to 3 + 7 using daunorubicin at either 45 mg/m² or 90 mg/m² [Breems et al. 2009]. The 30-day TRM rates were 11% with the higher and 12% with the lower dose, CR rate was higher (64% versus 54%) with 90 mg/m² and survival was also longer at this dose in patients aged 60–65, with 2-year survival probabilities of 38% versus 23%. While these data seem to establish 3 + 7 at 90 mg/m² as the new standard for patients age 60–65 with a performance status (PS) of <2 (88% of patients in the trial had PS <2), it is unlikely that this can be generalized to all subgroups of such patients. In particular among 102 patients with an MK the risk of death was 1.34-fold higher with the 90 mg/m² dose. This failure of higher-dose daunorubicin to improve outcome in patients at high risk of resistance is reminiscent of Bloomfield and colleagues’ observation that ara-C at 3 g/m² on days 1, 3, and 5 was not superior to 100 mg/m² daily × 5 by continuous infusion as consolidation therapy in patients with abnormal karyotypes other than inv 16 or t(8;21) [Bloomfield et al. 1998].

Azacitidine or decitabine

The general dissatisfaction with standard 3 + 7 has prompted interest in these two drugs, found to have activity in myelodysplastic syndrome (MDS), in AML. Fenaux and colleagues randomized patients with high-risk MDS to receive azacitidine 75 mg/m² daily × 7 days or, depending on physicians’ choice, either supportive care only, low-dose ara-C (LDAC), or 3 + 7; these three options were considered ‘conventional care regimens’ (CCRs) [Fenaux et al. 2010]. A total of the 113 of the randomized patients (approximately one third of those randomized) patients had ‘AML’ by WHO criteria (20–30% marrow blasts). Their median age was 70. Survival was longer in the azacitidine AML group than in the CCR group (p = 0.005, with medians of 24.5 versus 16 months) [Fenaux et al. 2010]. A total of 81% of patients randomized to CCR received supportive care only, LDAC and azacitidine was superior to either; too few received 3 + 7 to be confident of its relative merits versus azacitidine.

For many patients an 8–9-month improvement in likely (i.e. median) survival time is sufficient to warrant choice of azacitidine. For others this is not the case and these patients would be candidates for clinical trials. An example is the combination of azacitidine and 3 + 7.

There is less randomized AML data with decitabine than with azacitidine. In a single-arm trial, Cashen and colleagues gave 20 mg/m² daily × 5 to 55 patients age 60 or above [Cashen et al. 2010]. The CR rate was 24% and the median survival 8 months. A total of 86% of the patients who discontinued decitabine did so because of ‘progressive disease’, death, an ‘adverse event’ or patient decision. Given these results, the author would have difficulty in recommending single-agent decitabine to older patients with AML.

With conventional chemotherapy (containing ara-C ± other drugs), Walter and colleagues have reported a direct relation between achievement of CR and longer survival, after accounting for time needed to achieve CR [Walter et al. 2010a]. CRp (as in CR but with platelet count 20,000–100,000) also conveyed a survival advantage compared with patients who achieved neither CR nor CRp, although, after accounting for various other prognostic factors, this was less than that associated with CR and although the vast majority of patients who lived >3 or 5 years had CR rather than CRp or lesser responses [Walter et al. 2010a]. However, the same may not be true with azacitidine (or other regimens not containing drugs such as anthracyclines or ara-C). Thus, the French Group for Study of Myelodysplasia (GFM) reported that the majority of patients alive 2 years after receiving azacitidine for AML had achieved ‘hematologic improvement’ or had only stable disease [Itzykson et al. 2010].

Another important question is whether response to ‘hypomethylating agents’ such as azacitdine or decitabine parallels hypomethylation. A positive answer would lend support to the hypothesis that combining azacitidine or decitabine with drugs that may similarly induce re-expression of silent (e.g. tumor suppressor) genes would be beneficial. Numerous such trials are in progress, although none have yet proven superior to single agent azacitidine or decitabine.

Lenalidomide

Like the hypomethylating agents, lenalidomide’s use in AML followed experience with the drug in patients with MDS. Using the 10 mg daily dose typically employed in deletion 5q (del 5q) MDS, Ades and colleagues reported a CR rate of 5% (1/18) in patients with AML and del 5q [Ades et al. 2009]. Administering a 50 mg daily dose, Fehniger and colleagues observed six CR and four responses <CR in 30 patients age 60 or above with newly diagnosed AML, none of whom had a del 5q [Fehniger et al. 2011]. Unlike the case with conventional 3 + 7, there was no evidence that cytogenetics influenced response; nor was marrow hypocellularity (<10%) a precondition for response. Rather response was most heavily correlated with blast count. Although patients who had a CRi appeared to have similar survival as patients with CR, median survival was only 4 months. Similarly, administering 50 mg daily, Sekeres and colleagues found only an 11% CR + CRi rate in 37 patients age 60 or above with newly diagnosed AML, whose median survival was 2 months [Sekeres et al. 2010]. All of these 37 had del 5q, and thus, based on MDS data, might be expected to be more likely to respond than the patients treated by Fehniger and colleagues. The reasons for this seeming discrepancy may have to do with the multicenter cooperative group nature of the Sekeres and colleagues study and the single-center nature of the Fehniger and colleagues trial. For example, there may have been more commitment to continuing lenalidomide in the latter study. At any rate, while the median survivals in both the Fehniger and colleagues and the Sekeres and colleagues studies argue against the use of single-agent lenalidomide in AML, the future of this drug, as with azacitidine or decitabine, may lie in combinations; reports of the ‘feasibility’ of 3 + 7 + lenalidomide have appeared [Ades et al. 2010].

Clofarabine

Burnett and colleagues have found that, after adjusting for other prognostic factors, CR and survival rates in 106 patients (median age 71) considered unfit for 3 + 7 and thus given the adenosine analog clofarabine were higher than when similarly unfit patients received LDAC [Burnett et al. 2010] and comparable to those observed when fitter older patients received 3 + 7 like therapy. Of note, CR rates with clofarabine were similar in patients with unfavorable and intermediate cytogenetics (44% versus 52%). In 70 relatively fit patients (median age 71) randomized to clofarabine or clofarabine + LDAC, the combination produced superior CR (63% versus 31%), event-free survival, and survival rates, but survival remained short (median 11 months) even with the combination [Faderl et al. 2008].

CPX 351

This is a liposomal combination of daunorubicin and ara-C in a molar ratio that maximizes synergy between the two drugs. Lancet and colleagues randomized 125 newly diagnosed patients in a 2:1 ratio between CPX 351 and 3+7 (daunorubicin dose 60 mg/m² daily × 3 days) [Lancet et al. 2010]. While CR rates were essentially identical (40% versus 39%), CR with incomplete recovery (CRp) rates were much higher with CPX 351 (26% versus 13%). The same held true in patients with unfavorable cytogenetics (CR 35% versus 31%, CRp 39% versus 8%). Because toxicity (but not 60-day mortality 5% versus 15%) was greater with CPX 3451, it is possible that the better results with CPX351 simply reflected administration of ‘more’ drug, although this would be inconsistent with the relation between dose intensification and outcome in patients with unfavorable cytogenetics noted above. As is often the case, the contribution of CRp to survival is also not clear, as median survival was only 2 months longer with CPX351.

Other agents

The rapid entry into trials of many new drugs makes virtually any list of ‘new drugs in trial’ incomplete and outdated. Examples of such drugs include those that: (a) interfere with the protective effect of marrow stroma on AML blasts (plerixafor, MDX-1338); (b) affect apoptotic pathways (flavopridol, AG35156); and (c) target AML stem cells (diphtheria toxin-linked to IL3). The number of these agents and their potential to be used in combination call into question the role of conventional phase III trials, which often require years to investigate a single new therapy, while assuming an unrealistic homogeneity among patients. Indeed one of the themes of treatment of AML in coming years will likely be more individualization of treatment. A good example is use of ATRA in patients with AML other than acute promyelocytic leukemia. An M.D. Anderson trial randomizing patients among fludarabine + ara-C + idarubicin with or without ATRA found that addition of ATRA conferred no survival advantage [Estey et al. 1999]. However, after performing a similar trial (without fludarabine) in patients age 60 or above, Schlenk and colleagues reported superior survival (p = 0.04) with ATRA but only in the subset of patients who were NPM1 positive and FLT3 ITD negative [Schlenk et al. 2009].

Combination therapies

Experience suggests that, without data from a clinical trial, it is very difficult to know which therapies will be successful. Fludarabine in CLL, cladaribine in hairy cell leukemia, thalidomide in myeloma, and ATRA and arsenic trioxide in APL are examples of drugs whose entry into routine clinical practice owes as much to empirical observation as to a ‘bench-to-bedside’ route. Likewise, many drugs that appear to have an unimpeachable preclinical rationale are unsuccessful clinically. Under these circumstances it seems reasonable to study a wide range of different combinations, each of which (for example, azacitidine + lenalidomide) might be explored using different schedules. One approach is to randomize a relatively small number of patients among several investigational combinations. Although this method has been criticized as ‘underpowered’ it might avoid the worst false negative in which a combination is not studied at all. This principle underlies the use of play-the-winner designs by, among others, the Medical Research Council in the United Kingdom.

Toxicity versus efficacy

Experience similarly suggests that most new drugs are ultimately unsuccessful because of a lack of efficacy rather than excess toxicity. This suggests that: (1) the starting dose of many drugs is too low; and (2) there is a need to adaptively monitor response as well as toxicity in phase I studies; these thus would formally be phase I–II studies. The argument against point (2) is that lack of response at previous doses is irrelevant to response at the dose to be used in phase II. The author is not sure however whether this is true; an analysis of past phase I followed by phase II trials for various drugs might be informative. It is at times noted that phase II trials should be conducted at the optimal biologic dose (OBD) rather than at the more toxic maximal tolerated dose (MTD). This hypothesis is also testable, for example by randomizing patients in phase II between the OBD and the MTD.

Reduced intensity allogeneic hematopoietic-cell transplant (RI-HCT)

It is now well established that the T cells infused as part of an allogeneic transplant have a significant anti-AML effect (graft versus leukemia [GVL]). This has permitted a reduction in the intensity of transplant conditioning regimens, whose principal role becomes provision of adequate immunosuppression to allow engraftment. This reduction has made it possible for patients in their 70s to receive a transplant, most commonly in first CR. To avoid bias, several studies have compared patients with and without sibling donors, rather than patients who did or did not receive reduced intensity allogeneic hematopoietic- cell transplant (RI-HCT). In general, if the donor group does better so would patients who actually receive HCT. These studies have generally found an advantage for the donor group [Mohty et al. 2005]. Although there is often reluctance to submit older patients to RI-HCT, comorbidities, rather than age, are the principal predictors of toxicity and/or death after the procedure [Sorror et al. 2007]. Thus, in patients with no or few comorbidities the probability of death within the first 100 days after RI-HCT is only 10–15% and sharply declines thereafter. Although this risk is undoubtedly higher than that observed after chemotherapy in first CR, this increase is more than offset by the decreased risk of relapse. Furthermore, in the absence of randomized studies, it is widely accepted that outcome after RI-HCT is similar if a matched unrelated donor is used rather than a matched sibling [Mielcarek et al. 2007]. All this being said there are methodologic problems with donor–no donor analyses [Wheatley and Gray, 2004]. These tend to favor HCT, and questions of feasibility and selection bias have arisen [Estey et al. 2007].

Nonetheless and despite the lack of studies randomizing patients with donors to HCT or not, the author believes that all older patients with unfavorable cytogenetics or even a normal karyotype, particularly if accompanied by an FLT3 ITD, are candidates for RI-HCT in CR1 using either sibling or unrelated donors. The similarly deleterious influence of unfavorable cytogenetics, FLT3 ITDs, and MRD on outcome after HCT and after consolidation chemotherapy without HCT suggests that these approaches are not as different as they might appear. More specifically, relapse rates remain high in high-risk patients even after RI- HCT [Gyurkocza et al. 2010]. Hence, the author recommends that such patients consider participation in trials investigating different HCT preparative regimens (e.g. ¹³¹I linked to antiCD45) [Pagel et al. 2009] or administration after HCT of drugs such as azacitidine [de Lima et al. 2010] or AC220 [Cortes et al. 2009] that might reduce risk of relapse. As less-toxic therapies are developed, the latter type trials may become increasingly common.

Footnotes

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

The authors declare no conflicts of interest in preparing this article.

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