International Journal of Hematology

, Volume 96, Issue 2, pp 186–193 | Cite as

Acute myeloid leukemia in older adults

Progress in Hematology How to improve the outcome of adult acute myeloid leukemia?

Abstract

Acute myeloid leukemia (AML) is predominantly a disease of older adults, with a median age at diagnosis of over 65 years. AML in older adults differs biologically and clinically from that in younger ones, and is characterized by stronger intrinsic resistance and lower tolerance to chemotherapy. The effects of age on both patient- and disease-related factors result in a higher incidence of early death during chemotherapy, a lower rate of complete remission, and a reduced chance of long-term survival. Treatment options for older adults with AML include intensive chemotherapy, less-intensive chemotherapy, best supportive care, or enrolment in clinical trials. Given the heterogeneous nature of AML in older adults, therapeutic decisions need to be individualized after systematic assessment of disease biology and patient characteristics. Regardless of treatment, however, outcomes for older AML patients remain in general unsatisfactory. In contrast with the progress made for younger adults, the treatment of AML in older adults has not improved significantly in recent decades. Development of less toxic and more targeted agents may well provide treatment alternatives for a majority of these patients. The overall dismal outcome with currently available treatment approaches has encouraged older AML patients to participate in prospective clinical trials.

Keywords

Acute myeloid leukemia Older adults Elderly AML Chemotherapy Targeted therapy 

Introduction

Acute myeloid leukemia (AML) is a disease that primarily affects older adults, and the median age at diagnosis is over 65 years [1, 2, 3]. The cut-off age for differentiating younger from older AML is arbitrary; age 65 or older has traditionally been used as the eligibility criterion for previous studies of elderly AML by the Japan Adult Leukemia Study Group, whereas other study groups have chosen, among others, 60 or older, 70 or older, or 50–70 years. For practical purposes, however, age 60 or over is generally used to define elderly AML [4, 5]. Elderly AML is a biologically and clinically distinct disease with a diminished response to chemotherapy. Previous clinical trials of intensive chemotherapy showed rates of complete remission (CR) around 50 % and of long-term survival at less than 10 %, which are much worse than for younger patients [1, 2, 3]. Furthermore, such data likely overestimate the true outcome for elderly AML, as patients entered into clinical trials are screened using criteria such that they often do not represent the general patient population. In contrast with the progress made for younger adults, the outcome of treatment of elderly AML has improved little, if at all, in recent decades [6, 7]. The adverse prognostic impact of older age is attributable to differences both in disease-related factors (i.e., cytogenetics, secondary AML, and expression of the multidrug resistance phenotype) and patient-related factors (i.e., general condition, organ dysfunctions, and comorbidities). In addition to these therapeutic drawbacks, the net incidence of elderly AML is expected to increase as the population continues to age, making the management of elderly AML an even more critical issue.

Characteristics of AML in older adults

The unfavorable biologic characteristics of AML amplified in older adults, such as a higher proportion of unfavorable cytogenetics, higher frequency of antecedent hematologic disorders or previous treatment for one or more other malignancies, and more frequent expression of the multidrug resistance phenotype. Cytogenetic findings at diagnosis have important prognostic implications for both younger and older patients [8, 9, 10]. Favorable cytogenetic characteristics, e.g., core binding factor (CBF) abnormalities as defined by t(8;21) or inv(16)/t(16;16), are relatively uncommon in older adults, and are seen in less than 5 % of patients aged over 60 years [8, 9, 10]. In contrast, unfavorable cytogenetics represented by complex karyotype is predominant in older patients. Secondary AML arising from myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN), or AML related to prior chemotherapy for previous malignancies, both of which are known as subtypes with increased resistance to chemotherapy, is also common in this age group [1, 2, 3]. Response to chemotherapy is affected by the expression of genes that confer drug resistance, such as the multidrug resistance 1 (MDR1) gene that encodes the chemotherapy efflux pump P-glycoprotein. Overexpression of P-glycoprotein reportedly occurs in 71 % of older patients, compared to only 35 % of younger patients [11].

Patient-related factors, such as poor general condition, significant comorbidities, and diminished functional reserves, also contribute to the poorer outcomes for older patients. Moreover, because of their reduced performance status (PS) and increased prevalence of significant comorbidities, older patients are less tolerant of complications associated with chemotherapy. These conditions often make physicians reluctant to administer intensive chemotherapy to older patients. Indeed, according to a survey conducted in the United States, chemotherapy was administered to only 30 % of patients over the age of 65 years [12]. Although selected patients can tolerate and benefit from intensive chemotherapy, older adults as a whole are more likely to experience treatment-related mortality (TRM) and less likely to benefit from standard induction and post-remission therapies.

Taken together, these findings indicate that the effects of age in terms of both patient- and disease-related factors result in a higher incidence of early death during induction therapy, a lower rate of CR, and a reduced chance of long-term survival.

Prognosis and prognostic factors

The prognosis of AML worsens with age. When treated with intensive chemotherapy, CR rates for older adults range between 40 and 60 % [1, 2, 3], which is much lower than those for younger adults. Even if CR is achieved, older adults are more likely to experience relapse, leading to an extremely low expectation for long-term survival. Such a poor chance of treatment success is combined with a high risk of TRM, which ranges from 10 to 40 % even for selected older adults [1, 2, 3].

Because of intrinsic resistance to chemotherapy and excessive toxicity, the benefits associated with standard chemotherapy for older adults remain debatable. Since these patients represent a heterogeneous population, it is clinically important to identify those who are and are not likely to benefit from standard chemotherapy. This medical requirement has prompted the generation of several prognostic models incorporating multiple covariates (Table 1) [13, 14, 15, 16, 17]. These systems may help determine whether a patient should receive standard chemotherapy or alternative treatment. Among the most important prognostic factors are age, cytogenetics, and PS. In addition, some recent studies have shown genetic mutations involving the fms-like tyrosine kinase 3 (FLT3) gene, the nucleophosmin 1 (NPM1) gene, and others are as prognostically relevant for older as they are for younger patients [18, 19, 20, 21], while other studies have shown that gene expression profiles can identify prognostically distinct subgroups [22, 23]. These recent findings nonetheless need to be validated before they can be adopted for therapeutic decision-making.
Table 1

Covariates constituting predictive models for overall survival in older adults with AML

Study

Covariates

Kantarjian et al. [13]

Age (65–74 or ≥75 years), cytogenetics, PS, AHD, LDH, creatinine, laminar airflow room

Frohling et al. [14]

Age (61–69 or ≥70 years), cytogenetics

Malfuson et al. [15]

Age (65–74 or ≥75 years), cytogenetics, PS, WBC

Wheatley et al. [16]

Age (60–64, 65–69, 70–74 or ≥75 years), cytogenetics, PS, WBC, secondary leukemia

Rollig et al. [17]a

Age (61–65 or ≥66 years), WBC count, LDH, CD34 expression, NPM1 mutation

PS performance status, AHD antecedent hematologic disorder, LDH lactate dehydrogenase, WBC white blood cell, NPM1 nucleophosmin 1

aOnly patients with cytogenetically intermediate risk were analyzed

The PS classification is commonly used for assessing whether or not a patient is fit for intensive chemotherapy [4, 5]. However, this classification may be suboptimal, as it does not differentiate between functional impairments resulting from leukemia and those resulting from unrelated comorbidities. This distinction is important, as the former can be reversible with treatment, while the latter are not. In this respect, comorbidity scoring rather than PS assessment may be a potentially more accurate basis for therapeutic decisions [24].

Treatment

Induction therapy

Since a randomized study reported by Lowenberg et al. [25] in 1989 demonstrated that intensive chemotherapy could change the natural history of AML in elderly patients, induction therapy has been considered a viable option in the management of elderly AML. A recent population-based study in Sweden indicates that this may also be the case with unselected patients [26]. Another retrospective study using a propensity score matching analysis suggests that intensive chemotherapy has a beneficial effect on OS even for patients aged 70 years or older [27].

The standard induction therapy consists of an anthracycline combined with cytarabine (AraC), known as “3 + 7”, a regimen that has been the mainstay for more than three decades. For selected patients, standard induction therapy yields CR rates of around 50 % [1, 2, 3]. As shown in Table 2, a multitude of attempts have been made in the hope of improving the outcome, such as escalating doses, replacing or adding drugs, and using growth factors [25, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47], but most if not all failed to demonstrate survival benefit. However, a number of studies have reported positive results. Schlenk et al. [34] evaluated the effect of all-trans retinoic acid (ATRA) administered in combination with induction and consolidation therapy to 242 patients more than 60 years old. They showed that addition of ATRA significantly improved CR rate, event-free survival (EFS) and overall survival (OS). Lowenberg et al. [41] compared the effect of a doubled dose of daunorubicin (DNR) of 90 mg/m2 with that of a conventional dose of 45 mg/m2 in the context of the “3 + 7 regimen” administered to 813 patients aged 60 or older. Although no overall difference in outcome was observed, patients who were between 60 and 65 years old significantly benefited from the doubled dose of DNR. Very recently, Castaigne et al. [46] reported results from a phase 3 study that examined the effect of adding gemtuzumab ozogamicin (GO). In their study, a total of 280 patients aged 50–70 were randomly assigned to receive GO or a placebo in combination with chemotherapy during induction and consolidation courses. While CR rates for the two arms were not different, GO significantly improved relapse-free survival (RFS), EFS, and OS. Since none of these positive results have as yet been reproduced elsewhere, definitive conclusions regarding the effectiveness of these treatments await the results of further validation studies.
Table 2

Selected randomized studies using induction therapy for AML in older adults

Study

Age (years)

N

Treatments

Results

Lowenberg et al. [25]

>65

31

DNR, AraC, VCR

Compared to supportive care, intensive chemotherapy prolonged OS without increasing hospitalization time

29

Supportive care

Tilly et al. [28]

>65

46

RBX, AraC

Intensive chemotherapy increased both CR and early death rates, resulting in OS similar to that for low-dose AraC

41

Low-dose AraC

Lowenberg et al. [29]

>60

161

DNR, AraC

GM-CSF during and after induction therapy did not improve CR rate DFS or OS

157

DNR, AraC, GM-CSF

Lowenberg et al. [30]

>60

242

DNR, AraC

CR rate tended to be higher with MIT, but DFS and OS did not differ for the two arms

247

MIT, AraC

Goldstone et al. [31]

>55

328

DNR, AraC, 6TG

Neither addition of ETP nor replacement of DNR with MIT contributed to improvement in CR rate or OS

327

DNR, AraC, ETP

656

MIT, AraC

Anderson et al. [32]

>55

161

DNR, AraC

Results in terms of CR rate, RFS or OS for induction therapy with MIT and ETP were not superior to those for DNR and AraC

167

MIT, ETP

Baer et al.[33]

≥60

61

DNR, AraC, ETP

Addition of the P-glycoprotein modulator PSC-833 did not increase CR rate, DFS or OS, but was associated with excessive early mortality

59

DNR, AraC, ETP, PSC-833

Schlenk et al. [34]

>60

120

IDR, AraC, ETP

Addition of ATRA to induction and consolidation chemotherapy improved CR rate, EFS and OS

122

IDR, AraC, ETP, ATRA

van der Holt et al. [35]

≥60

211

DNR, AraC

Addition of the P-glycoprotein modulator PSC-833 did not improve CR rate, DFS, EFS or OS

208

DNR, AraC, PSC-833

Gardin et al. [36]

≥65

209

DNR, AraC

CR rate and OS were similar for the DNR (45 mg/m2 × 4 days) and IDR (9 mg/m2 × 4 days) arms

207

IDR, AraC

Burnett et al. [37]

>60

103

Low-dose AraC

Low-dose AraC resulted in higher CR rate and better OS than did hydroxyurea for patients considered unfit for intensive chemotherapy

99

Hydroxyurea

Pigneux et al. [38]

≥60

186

IDR, AraC

Adding the alkylating agent CCNU to induction therapy did not improve CR rate, DFS or OS

178

IDR, AraC, CCNU

Latagliata et al. [39]

>60

153

DNR, AraC

Liposomal DNR did not increase CR rate, but was associated with higher rate of early death and lower rate of relapse

148

DNX, AraC

Burnett et al. [40]

>60

450

DNR (35 mg/m2), AraC (200 or 400 mg/m2), ±PSC-833

The doses of DNR or AraC did not correlate with CR rate or OS. Addition of the P-glycoprotein modulator PSC-833 was associated with lower CR rate and shorter OS, due to excessive induction deaths

446

DNR (50 mg/m2), AraC (200 or 400 mg/m2)

Lowenberg et al. [41]

≥60

411

DNR (45 mg/m2), AraC

Higher dose of DNR increased CR rate. Improvement in EFS and OS was shown in the subset of patients aged 60–65 years

402

DNR (90 mg/m2), AraC

Harousseau et al. [42]

≥70

228

Tipifarnib

The farnesyl transferase inhibitor, tipifarnib, did not result in superior OS compared to that obtained with best supportive care

229

Best supportive care

Pautas et al. [43]

50–70

156

DNR (80 mg/m2 × 3 days), AraC

CR rate was lower for the DNR arm than for both IDR arms, without any differences in relapse, EFS or OS, among the three arms

155

IDR (12 mg/m2 × 3 days), AraC

157

IDR (12 mg/m2 × 4 days), AraC

Cripe et al. [44]

>60

221

DNR, AraC

Addition of the P-glycoprotein modulator zosuquidar did not improve CR rate or OS

212

DNR, AraC, zosuquidar

Burnett et al. [45]

≥60

82

Low-dose AraC

Addition of ATO to low-dose AraC provided no benefit in terms of CR rate or OS for patients considered unfit for intensive chemotherapy

84

Low-dose AraC, ATO

Castaigne et al. [46]

50–70

139

DNR, AraC

Addition of GO to conventional chemotherapy did not increase CR rate but improved EFS, RFS and OS

139

DNR, AraC, GO

Wakita et al. [47]

65–80

121

Set therapy

Extra doses of DNR and BHAC according to the bone marrow status at end of induction therapy did not result in improved CR rate, RFS or OS

121

Individually adjusted therapy

DNR daunorubicin, AraC cytarabine, VCR vincristine, OS overall survival, RBX rubidazone, CR complete remission, GM-CSF granulocyte–macrophage colony-stimulating factor, DFS disease-free survival, MIT mitoxantrone, 6TG 6-thioguanine, ETP etoposide, RFS relapse-free survival, PSC-833 valspodar, IDR idarubicin, ATRA all-trans retinoic acid, EFS event-free survival, CCNU lomustine, DNX liposomal daunorubicin, ATO arsenic trioxide, GO gemtuzumab ozogamicin, RFS relapse-free survival, BHAC behenoyl cytarabine

For patients unfit for intensive chemotherapy, treatment options include less-intensive chemotherapy, best supportive care, or enrolment in clinical trials. For less-intensive chemotherapy, low-dose AraC has been utilized since the 1960s. Burnett et al. [37] recently demonstrated in a phase 3 study that low-dose AraC significantly prolonged OS when compared to best supportive care for older patients who were considered unfit for intensive chemotherapy. Stratification by cytogenetic risk made it clear that low-dose AraC was beneficial for patients with favorable and intermediate cytogenetic risks. Despite the significant superiority of low-dose AraC over best supportive care, outcome with low-dose AraC remained far from satisfactory, as the probabilities of CR and 1-year OS were only 18 and 25 %, respectively [37].

Post-remission therapy

Once CR has been reached after induction therapy, however, there is no standard post-remission strategy for elderly AML. Table 3 summarizes selected randomized studies using post-remission therapy [30, 31, 36, 38, 40, 43, 47, 48, 49, 50, 51]. None of these studies have shown improved survival resulting from treatment intensification: increasing the dose of AraC did not result in better outcome when compared to the standard dose [48], and results for four cycles of consolidation therapy were not superior to those for three cycles [40], or even for a single cycle [31]. However, prolonged therapy with lower doses of chemotherapy may be beneficial for elderly patients. Gardin et al. [36] compared consolidation therapy consisting of six less-intensive courses administered monthly on an outpatient basis with one course of intensive chemotherapy. After achieving CR, 164 patients aged 65 years or older were randomized to either the outpatient or intensive arm, with the former showing significantly superior DFS and OS. In addition to this finding, several studies showed the beneficial effect of prolonged maintenance therapy for the prevention of relapse, although they did not show significant survival advantage [30, 49]. On the other hand, Schlenk et al. [50] reported that one course of intensive consolidation chemotherapy was superior to one year of oral maintenance therapy in terms of relapse prevention and OS. The reason for this discrepancy is unclear, but may be partly explained by differences in treatment regimens used in these studies. Older adults are highly likely to be unable to complete or even start planned post-remission therapy because of comorbidities or residual toxicities from previous chemotherapy. Hence, special consideration needs to be given to the feasibility of treatment when considering post-remission therapy for older adults.
Table 3

Selected randomized studies using post-remission therapy for AML in older adults

Study

Age (years)

N

Treatments

Results

Lowenberg et al. [30]

>60

74

Low-dose AraC

Eight cycles of low-dose AraC prolonged DFS, but this effect did not translate into improved OS

73

No further therapy

Stone et al. [48]

≥60

82

AraC (100 mg/m2)

There was no difference in DFS or OS between four courses of standard-dose AraC and two courses of intermediate-dose AraC

87

MIT, AraC (500 mg/m2)

Goldstone et al. [31]

>55

185

1 course

After two courses of induction therapy, one course and four courses of post-remission therapy yielded similar DFS and OS

186

4 courses

Buchner et al. [49]

≥60

140

Intensive consolidation

Remission duration lasted longer with monthly maintenance therapy than with a single course including intermediate-dose AraC

157

Monthly maintenance

Schlenk et al. [50]

>60

47

Intensive consolidation

Intensive consolidation resulted in lower relapse rate and superior OS than did one-year oral maintenance therapy

49

Oral maintenance

Gardin et al. [36]

≥65

82

Intensive treatment

Six monthly courses of outpatient therapy yielded better DFS and OS than did a single course of intensive chemotherapy

82

Outpatient treatment

Pigneux et al. [38]

≥60

50

1 course

One course and two courses of consolidation therapy yielded similar OS

51

2 courses

Burnett et al. [40]

>60

124

1 course

After two induction courses and one consolidation course, an additional consolidation course had no effect on relapse or OS

126

2 courses

Pautas et al. [43]

50–70

77

rIL-2

Maintenance therapy with rIL-2 for a total duration of 12 months did not result in improved EFS or OS

84

No maintenance

Lowenberg et al. [51]

≥60

113

GO

Post-remission therapy with up to three cycles of GO had no effect on relapse, NRM, DFS or OS

119

No post-remission therapy

Wakita et al. [47]

65–80

63

With ubenimex

Ubenimex, a dipeptide immunostimulator, administered during consolidation therapy tended to prolong RFS but not OS

56

Without ubenimex

AraC cytarabine, DFS disease-free survival, OS overall survival, MIT mitoxantrone, rIL-2 recombinant interleukin-2, EFS event-free survival, GO gemtuzumab ozogamicin, NRM non-relapse mortality, RFS relapse-free survival

Hematopoietic cell transplantation

While allogeneic hematopoietic cell transplantation (HCT) offers the best chance of long-term survival for patients with poor-risk hematologic malignancies such as seen in elderly AML, it does so at the cost of higher TRM. Due to this high risk, allogeneic HCT has traditionally been limited to younger patients. However, advances in supportive care and the use of reduced-intensity conditioning (RIC) have extended the application of this procedure to older adults who would previously not have been candidates for myeloablative allogeneic HCT. Indeed, recent studies have demonstrated the feasibility of allogeneic HCT for selected older patients, with reported post-transplant survival rates of around 50 % [2, 3]. A retrospective analysis of a large number of registry data showed that older age was not associated with inferior post-transplant OS [52]. In the absence of prospective studies, the efficacy of RIC-HCT for older patients remains to be verified, although accumulated evidence suggests that RIC-HCT during CR represents a reasonable therapeutic option for selected older patients. The most critical factor that interferes with the administration of allogeneic HCT could be the low CR rate attained with induction chemotherapy. Availability of a suitable donor is another obstacle for successful HCT for older patients, because their siblings are usually also elderly. The major issues for further incorporation of allogeneic HCT into treatment strategies for elderly AML that need to be addressed are improvement of the CR rate for chemotherapy, identification of a suitable donor in a timely manner, and development of transplant procedures that lead to reduced risk of post-transplant relapse and complications.

Novel therapies

Given the limitations of the intensive chemotherapy approach for AML in older adults, current clinical trials have focused on less-intensive therapies with the potential to be efficacious without impairing patients’ quality of life. A growing understanding of the underlying molecular mechanisms of AML has led to development of novel agents, most of which selectively target leukemic cells, such as monoclonal antibodies, tyrosine kinase inhibitors, farnesyl transferase inhibitors, hypomethylating agents, histone deacetylase inhibitors, and others. Details about individual agents are reviewed extensively elsewhere in this issue of the journal. Development of less toxic and more targeted agents may provide treatment alternatives for a majority of older adults with AML. Given the dismal prognosis with currently available therapies and the limited tolerance for toxicity, such patients are promising candidates for such targeted therapies. The National Comprehensive Cancer Network (NCCN) panel has therefore recommended the use of investigational therapy in clinical trials for all patients over 60 years [5].

Conclusions

AML in older adults poses a significant therapeutic challenge because of the refractoriness of the disease and the frailty of the patients. These patients are biologically and clinically heterogeneous, which means that intensive chemotherapy may be beneficial for some, whereas it may be harmful for others. There is thus an urgent need to accurately identify patients likely to benefit from intensive chemotherapy. Such decisions should be individualized after systemic assessment of disease biology and patient characteristics. Currently, a number of novel agents are under investigation, most of which are selective for certain molecular targets and these involve less toxicity than do existing chemotherapeutic agents. The overall dismal prognosis for the treatment of elderly AML patients with currently available treatments constitutes a strong motivation for their participation in prospective clinical trials that aim to develop more effective and less toxic therapies.

Notes

Conflict of interest

The authors declare no conflict of interest.

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Copyright information

© The Japanese Society of Hematology 2012

Authors and Affiliations

  1. 1.Department of HematologyFujita Health University School of MedicineToyoakeJapan
  2. 2.Department of Hematology and OncologyNagoya University Graduate School of MedicineNagoyaJapan

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