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First Published Online October 15, 2008
The Oncologist, Vol. 13, No. 10, 1097-1108, October 2008; doi:10.1634/theoncologist.2008-0100
© 2008 AlphaMed Press

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Geriatric Oncology

Current and Emerging Strategies for the Management of Acute Myeloid Leukemia in the Elderly

Jacob Laubach, Arati V. Rao

Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina, USA

Key Words. Acute myeloid leukemia • Elderly • Chemotherapy • Gemtuzumab ozogamicin • Bone marrow transplantation

Correspondence: Arati V. Rao, M.D., 111G, 508 Fulton Street, Durham, North Carolina 27705, USA. Telephone: 919-286-6944; Fax: 919-286-6896; e-mail: rao00012{at}mc.duke.edu

Received April 21, 2008; accepted for publication August 18, 2008; first published online in THE ONCOLOGIST Express on October 15, 2008.

Disclosure: The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.


   Learning Objectives
Top
 Learning Objectives
Abstract
 Introduction
 Host Factors and Biological...
 Role of Cytogenetics and...
 Current Treatment Modalities for...
 Emerging Therapeutic Modalities...
 Summary
 Author Contributions
 References
 
After completing this course, the reader should be able to:

  1. Describe the epidemiology of AML in the U.S.
  2. Identify the biological characteristics of AML in elderly patients that confer resistance to therapy.
  3. Discuss the targets of emerging therapies for AML in elderly patients.

This article is available for continuing medical education credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Host Factors and Biological...
 Role of Cytogenetics and...
 Current Treatment Modalities for...
 Emerging Therapeutic Modalities...
 Summary
 Author Contributions
 References
 
Acute myeloid leukemia (AML) accounts for approximately 80% of acute leukemias diagnosed in adults. The elderly are disproportionately affected by AML, as 35% of newly diagnosed patients are aged ≥75 and the median age at diagnosis is 67. Elderly individuals also respond less well to standard chemotherapy than do younger individuals, as reflected by lower complete remission and relapse-free survival rates in major clinical trials. A higher prevalence of comorbid conditions as well as the unique biological features of elderly AML patients account for the relatively poor response to therapy observed in this population. Compared with AML in younger individuals, for example, AML in the elderly more often emerges from a preceding myelodysplastic syndrome and is more frequently associated with poor-prognosis karyotypes such as 5q– or 7q–. The introduction of novel therapies over the past decade has already altered the treatment paradigm of elderly individuals with AML. The first of these to emerge was gemtuzumab ozogamicin. Other agents are currently under evaluation in clinical trials, including inhibitors of multidrug resistance, farnesyltransferase inhibitors, novel nucleoside analogues, and inhibitors of the FMS-like tyrosine kinase-3. This review describes the biological features of AML in the elderly and summarizes both the current and emerging strategies for the treatment of this disease in older individuals.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Host Factors and Biological...
 Role of Cytogenetics and...
 Current Treatment Modalities for...
 Emerging Therapeutic Modalities...
 Summary
 Author Contributions
 References
 
Worldwide, acute leukemia affects approximately four in 100,000 individuals per year [1]. It is estimated that AML accounts for 70% of newly diagnosed acute leukemias. In the U.S., approximately 13,000 individuals were diagnosed with AML in 2007 and nearly 9,000 died of the disease [2]. Approximately 35% of patients with newly diagnosed AML are ≥75 years of age and the median age at diagnosis is 67 [2]. The incidence of AML will likely increase over time, as the number of individuals aged ≥65 years in the U.S.—estimated to be 37.3 million in 2006—is expected to double by the year 2030 and represent 20% of the population [3, 4]. Elderly patients, defined in the AML literature as aged ≥60 years, historically have lower complete remission (CR) and relapse-free survival (RFS) rates than their younger counterparts [5]. The Medical Research Council (MRC) AML8 trial, in which younger and older patients with AML received the same therapy, demonstrated a CR rate of 70% among individuals aged <50, a CR rate of 52% for patients 60–69 years of age, and a dismal CR rate of 26% for individuals aged >70 [6]. Similar age-related differences were seen in the Cancer and Leukemia Group B (CALGB) 8525 trial [7], in which individuals aged <60 had a CR rate of 73% and 4-year disease-free survival (DFS) rate of 31%, while patients who were aged ≥60 had a CR rate of 47% and 4-year DFS rate of 14%. This review highlights important host and disease characteristics of elderly AML patients and summarizes the current and emerging classes of drugs for the treatment of this disease. A literature search using PubMed was performed using the keywords "acute myeloid leukemia," "elderly," and "aged."


   HOST FACTORS AND BIOLOGICAL FEATURES OF AML IN THE ELDERLY
Top
 Learning Objectives
 Abstract
 Introduction
 Host Factors and Biological...
Role of Cytogenetics and...
 Current Treatment Modalities for...
 Emerging Therapeutic Modalities...
 Summary
 Author Contributions
 References
 
Differences in both host and disease biology distinguish AML in the elderly from that in younger individuals. These have been the focus of excellent reviews [5, 8, 9] and are briefly summarized here. With regard to the host, comorbid conditions common among the elderly, such as heart disease, renal insufficiency, vascular disease, and coexisting hematologic conditions, impact the metabolism of chemotherapeutic agents and the ability to withstand intensive therapy. Elderly patients are also more likely than younger patients to develop severe, life-threatening infections during the course of treatment [10]. Also, as might be expected, some older individuals with AML tend to have a poor performance status at diagnosis in comparison with younger individuals. Multiple studies have demonstrated a correlation between poor performance status and unfavorable response to therapy [9, 11, 12]. The biology of AML in elderly patients is different from that of AML in younger patients (Table 1). Compared with younger AML patients, elderly individuals with the disease have a higher incidence of poor-prognosis karyotypes (5q–, 7q–), a higher frequency of a preceding myelodysplastic syndrome (MDS), and greater expression of proteins involved in intrinsic resistance to chemotherapeutic agents [9, 13, 14]. It has been shown that leukemic blasts derived from elderly AML patients are less likely to undergo apoptosis following treatment with cytarabine and daunorubicin [15]. Other studies have shown that the multidrug resistance gene (MDR1) is more often expressed in blasts derived from older AML patients than in those from younger individuals [16, 17]. Elegant work has demonstrated that individuals with MDR1+ AML have lower CR and DFS rates than those with MDR1– AML [16, 18]. Thus, the relatively high level of resistance to therapy observed in elderly patients with AML can be explained by various cellular processes, along with host factors associated with the normal aging process such as poor performance status, comorbidities, and organ function impairment.


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  		Table 1. Characteristics of AML biology in elderly versus younger individuals

 

   ROLE OF CYTOGENETICS AND GENETIC MARKERS IN ELDERLY AML PATIENTS
Top
 Learning Objectives
 Abstract
 Introduction
 Host Factors and Biological...
 Role of Cytogenetics and...
Current Treatment Modalities for...
 Emerging Therapeutic Modalities...
 Summary
 Author Contributions
 References
 
Cytogenetic aberrations detected at the time of diagnosis are an important predictor of clinical outcome in AML patients [19–21]. Acquired, clonal chromosome abnormalities are detected in the pretreatment bone marrow of 50%–60% of adults with de novo AML. Ten percent to twenty percent of patients with AML harbor a complex karyotype with at least three chromosome aberrations. Patients with t(15;17)(q22;212–21) have an excellent prognosis while those with inv(16)(p13q22)/t(16;16)(p13;q22) or t(8,21) (q22;q22) have a relatively favorable prognosis in most studies [21].

As in younger patients with AML, cytogenetic abnormalities predict response to induction therapy in the elderly. This was confirmed by the assessment of the cytogenetic findings and clinical outcome of 1,065 elderly individuals who had enrolled in the MRC AML11 trial [22]. More recently, a study of 635 elderly AML patients (excluding French–American–British subtype M3) led to the conclusion that pretreatment cytogenetics along with WBC, marrow blast percentage, sex, and age have prognostic significance in elderly AML patients (Table 2) [23]. Patients with five or more chromosomal aberrations appear to benefit minimally from current treatment and are better suited for investigational therapy or supportive care.


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  		Table 2. Prognostic cytogenetic groups in elderly AML patients based on a study of 635 individuals ≥75 years of age

 
A number of genetic alterations also affect clinical outcome in AML (Table 3). The prevalence and potential biological role of these mutations in the elderly have been investigated in several studies. In one study of 140 elderly AML patients, for example, FMS-like tyrosine kinase-3 (FLT3), RAS, and tumor protein 53 (TP53) mutations were found in 34%, 19%, and 9% of patients, respectively [24]. Also seen are nucleophosmin (NPM1) gene mutations that occur frequently in younger patients and are typically associated with a normal karyotype. However, one study evaluated the correlation between mutations in the NPM1 and FLT3 (internal tandem duplication [ITD]) genes and outcome in 99 elderly patients (median age, 71 years; range, 60–85 years) with newly diagnosed AML [25]. In that study, the primary treatment approach was curative in 54 patients, palliative in 38 patients, and supportive only in the remaining seven patients. In patients who were FLT3 ITD negative, the presence of the NPM1 mutation was associated with a higher CR rate (40.5% in NPM1– versus 80.0% in NPM1+; p = .03) but not with a significant difference in DFS or overall survival (OS). Meanwhile, the presence of the FLT3 ITD mutation was associated with a shorter OS regardless of the NPM1 status (210 days in FLT3+ versus 634 days in FLT3–; p = .03).


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  		Table 3. Submicroscopic genetic alterations and their impact on clinical outcome in AML

 

   CURRENT TREATMENT MODALITIES FOR AML IN THE ELDERLY
Top
 Learning Objectives
 Abstract
 Introduction
 Host Factors and Biological...
 Role of Cytogenetics and...
 Current Treatment Modalities for...
Emerging Therapeutic Modalities...
 Summary
 Author Contributions
 References
 
Standard Chemotherapy
Since the 1970s, intensive chemotherapy with cytarabine (for 7 days) and an anthracycline such as daunorubicin or idarubicin, or the anthracenedione mitoxantrone (for 3 days), has been standard therapy for AML. The benefit of intensive chemotherapy in the management of elderly AML patients was demonstrated in a phase III trial comparing chemotherapy with supportive care in patients aged >65 [26]. Those in the chemotherapy group received daunorubicin, vincristine, and cytarabine as both induction and consolidation, while those in the other study arm received supportive care. The CR rate in patients treated with chemotherapy was 58% and the 2-year DFS rate was 17%. The median survival time was longer for those who received chemotherapy than for those who did not (21 weeks versus 11 weeks), and days of hospitalization were similar in the two groups. The MRC AML9 study subsequently demonstrated greater treatment efficacy with more intensive chemotherapy (daunorubicin for 3 days, with cytarabine and 6-thioguanine for 10 days) than with less intensive therapy (daunorubicin for 1 day, with cytarabine and 6-thioguanine for 5 days), even among elderly individuals [27].

The use of consolidative high-dose cytarabine (HiDAC) in the postremission setting for elderly AML patients is controversial. In the CALGB 82525 trial, HiDAC was superior to lower doses of cytarabine, with a 4-year DFS rate of 44% and 4-year OS rate of 46% in AML patients aged <60 years [7]. However, in patients aged ≥60 years, among whom only 29% were able to complete all four cycles of HiDAC, the 4-year DFS rate was ≤16% and the 4-year OS rate was only 9%. Cerebellar toxicity occurred in >30% of patients aged ≥60 who received HiDAC. Poor tolerance of HiDAC thus presumably accounted for the inferior outcome observed in elderly patients treated with HiDAC as compared with younger patients who received such therapy.

Gemtuzumab Ozogamicin
Gemtuzumab ozogamicin (GO, Mylotarg®; Wyeth Pharmaceuticals, Inc., Madison, NJ) is a humanized anti-CD33 monoclonal antibody conjugated to a derivative of the cytotoxic antibiotic calicheamicin [28]. The agent selectively targets the CD33 antigen expressed on 90% of myeloid blast cells. Binding of the antibody to CD33 results in internalization and release of calicheamicin, leading to cell death. Table 4 summarizes important studies conducted using GO as monotherapy or in combination with other agents.


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  		Table 4. Clinical trials of gemtuzumab as monotherapy or combination therapy in elderly AML patients

 


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  		Table 5. Novel agents evaluated for the treatment of AML in the elderly

 
GO received U.S. Food and Drug Administration approval in May of 2000 for monotherapy in patients aged ≥60 years with relapsed, CD33+ AML who are not considered candidates for cytotoxic chemotherapy. In 2005, the Mylotarg® Study Group reported updated results from three multicenter, open-label, single-arm, phase II studies in 277 patients with CD33+ AML at first recurrence, in which patients received two i.v. doses of GO of 9 mg/m2 [29]. Among individuals aged ≥60, the overall response rate (ORR) was 24%, the CR rate was 12%, and the complete remission with incomplete platelet recovery (CRp) rate was 12%. Patients in whom a CR after initial therapy persisted for >12 months prior to relapse experienced the best response to GO, with an ORR of 35%. Infusion-related events included chills, fever, nausea, hypotension, and hypertension, all of which occurred in ≤8% of cases. Grade 3 or 4 neutropenia and thrombocytopenia developed in 98%–99% of patients. Other important, though less frequent, therapy-related toxicities included hyperbilirubinemia, elevations in liver transaminases, and hepatic veno-occlusive disease (VOD). A higher incidence of VOD after stem cell transplantation (SCT) was seen in patients who received GO within 6 months of the procedure [30].

GO has also been studied as part of first-line therapy in older patients with AML. In a phase II trial involving 12 individuals aged ≥65 with newly diagnosed AML, patients were scheduled to receive GO at a dose of 9 mg/m2 on days 1 and 14 [31]. Those who recovered bone marrow function received consolidation therapy with 6 mg/m2 GO 45–60 days after induction, followed by maintenance with 3 mg/m2 GO every 4 weeks. CR was attained in 25% of the patients, and only one patient was taken off study because of unsatisfactory bone marrow recovery. Our institution has conducted a phase I study of intensive, dose-dense therapy with HiDAC and GO as the sole induction and consolidation therapy in nine newly diagnosed AML patients aged ≥60 years. In this small study, the ORR was 88% with a 66% CR rate, and two patients continue to be alive (DFS duration, 40 and 49 months). All patients had significant hematologic toxicity with grade 4 pancytopenia, and two patients developed dose-limiting neurotoxicity [32].

SCT
Elderly patients with hematologic malignancies such as AML are often poor candidates for SCT because of comorbid medical conditions. The development of reduced-intensity conditioning (RIC) regimens, however, has challenged convention regarding patient age and SCT. There is increasing evidence derived from clinical trials that appropriately selected individuals may benefit from allogeneic SCT following RIC [33, 34]. In one phase II trial, for instance, 19 older patients (median age, 64 years) with AML or high-risk MDS who received a RIC regimen consisting of fludarabine, melphalan, and carmustine followed by allogeneic SCT achieved an 89% CR rate and a 1-year survival rate of 68% [33].

The feasibility and efficacy of autologous SCT has also been studied. In a phase II study involving 160 elderly patients with AML (median age, 69 years), patients were treated with intensive induction chemotherapy and, if CR was achieved, one cycle of consolidation therapy followed by autologous SCT for selected patients <70 years of age [35]. While autologous SCT was feasible in this population it did not prevent early relapse and thus did not translate into longer DFS or OS.


   EMERGING THERAPEUTIC MODALITIES FOR AML IN THE ELDERLY
Top
 Learning Objectives
 Abstract
 Introduction
 Host Factors and Biological...
 Role of Cytogenetics and...
 Current Treatment Modalities for...
 Emerging Therapeutic Modalities...
Summary
 Author Contributions
 References
 
Multidrug Resistance Modulators
Overexpression of the MDR1 gene product P-glycoprotein (P-gp), a 170-kDa protein that belongs to the ABC superfamily of proteins, is the most extensively studied mechanism of resistance in AML. Among individuals with de novo AML, P-gp protein and mRNA expression have been reported in the malignant cells of 20%–75% of patients [36]. Apart from its role as a drug-efflux pump, P-gp has been implicated as an inhibitor of apoptosis in leukemic cells [37]. Other genes involved in drug resistance include MRP1 and its various homologues. Lung resistance protein (LRP), breast cancer resistance protein (BRCP), and glutathione S-transferases have also been implicated in drug resistance mechanisms in AML.

Recently, multidrug resistance status has been incorporated into prognostic models for AML [38, 39] and efforts to modulate multidrug resistance with pharmacologic agents are ongoing. Several trials have used the first-generation P-gp inhibitors quinine and cyclosporine A in combination with chemotherapy for the treatment of relapsed AML [40–42]. While two of these studies found no difference in the CR rate, DFS time, or OS time between patients who received a P-gp inhibitor as part of their induction therapy and those who did not, one trial that included cyclosporine as part of the induction therapy did demonstrate superior RFS and OS [42]. The addition of cyclosporine did not increase the toxicity associated with induction therapy, and the survival benefit conferred by the addition of cyclosporine to the induction therapy occurred in patients with higher levels of P-gp expression.

Two phase III trials have incorporated the P-gp inhibitor PSC-833 into induction regimens for the treatment of AML in patients aged ≥60. In one trial, patients were randomized to either cytarabine, daunorubicin, and etoposide or the same regimen with PSC-833 given at 2.8 mg/kg per day over 2 hours then 10 mg/kg per day by a 3-day infusion [43]. The study was discontinued early because of excess early mortality in the group of patients who received the PSC-833, and an interim analysis revealed that the DFS and OS rates were similar in the two arms. The incidences of hyperbilirubinemia, stomatitis, esophagitis, and diarrhea were greater in patients who received PSC-833 as part of their induction therapy. In another trial, patients were randomized to two cycles of cytarabine and daunorubicin induction with or without PSC-833 followed by one cycle of consolidation with cytarabine, mitoxantrone, and etoposide [44], again with no differences between the two groups with regard to the outcome.

To conclude, there has been only one positive trial involving an inhibitor of multidrug resistance. However, interest in this class of agents persists because of the important role multidrug resistance proteins play in AML biology. The recent discovery that MRP1 expression is controlled by the phosphoinositide 3 kinase–Akt pathway may offer another therapeutic target for modulation of multidrug resistance proteins [45].

Farnesyltransferase Inhibitors
This class of agents targets farnesyltransferase, an enzyme that catalyzes the transfer of a farnesyl moiety to the C-terminus cysteine residue of Ras and other proteins [46]. Such post-translational modification directs proteins to the plasma membrane, where they carry out their specific cellular, or in the case of mutated RAS, oncogenic function. Disruption of these events theoretically interrupts the oncogenic activity of mutated RAS.

In one phase II trial, the oral farnesyltransferase inhibitor tipifarnib was evaluated in poor-risk elderly patients with previously untreated AML [47]. Patients were treated with tipifarnib at a dose of 600 mg orally twice daily for 21 days followed by a 42-day rest period. Up to four cycles of therapy were given to patients who experienced a clinical response. There was an ORR of 23% with a 14% CR rate, 2% partial remission (PR) rate, and 7% hematologic improvement rate (PR without full neutrophil or platelet recovery). Among individuals who experienced CR, the median duration of survival was 18 months. Serious drug-related toxicity occurred in 47% of patients. Eleven patients (7%) died within 30 days of the final dose of tipifarnib from causes other than progressive disease. A majority of patients (60%) required hospitalization during treatment with tipifarnib for a median duration of 14 days. Tipifarnib was evaluated in a second trial involving individuals with relapsed or refractory AML [48]. Patients received tipifarnib at a dose of 600 mg orally twice daily for 21 days of each 4-week cycle until disease progression. While the drug was well tolerated, a CR or CRp was achieved in only 4% of patients.

Finally, tipifarnib was compared with best supportive care in the management of elderly patients in a study that enrolled 457 AML patients aged >70 who did not wish to undergo combination chemotherapy [49]. Those individuals randomized to tipifarnib received the drug at 600 mg orally twice daily for 21 consecutive days of each 28-day cycle. At the time of the interim analysis, there was no survival difference between patients who received tipifarnib and those who received best supportive care, and final results from this interesting study are pending.

Cloretazine (VNP40101M)
Cloretazine is a member of the novel sulfonylhydrazine class of alkylating agents that causes DNA damage by releasing the DNA-chloroethylating agent 90CE after entering the blood. In preclinical models, the drug was found to have activity against a broad range of tumors, including lung carcinoma, colon cancer, glioblastoma, and leukemia [50]. In preclinical work, the compound was active even in leukemia cell lines resistant to cyclophosphamide, melphalan, and BCNU.

In a multicenter phase II study, 104 older patients with previously untreated AML or high-risk MDS received cloretazine at a dose of 600 mg/m2 as a single i.v. infusion [51]. Patients enrolled in that trial included those with an Eastern Cooperative Oncology Group performance status score of 2 (30%), pre-existing cardiac disease (45%), and pre-existing hepatic disease (24%). Despite this, an ORR of 32% with a 28% CR rate and 4% CRp rate was achieved, and the ORR in patients with de novo AML was 50%. Grade 3 or 4 myelosuppression was seen in 100% of patients, while severe infection with febrile neutropenia occurred in 21% of patients. The median OS duration was 94 days, with a 1-year survival rate of 14%. The results of a confirmatory phase II trial of single-agent cloretazine administered as a 600-mg/m2 infusion to 85 elderly patients (median age, 73 years) with poor-risk de novo AML were recently reported [52]. An ORR of 35% was achieved, with a 28% CR rate and an 8% CRp rate. The response rate was 34% in patients aged >70.

Cloretazine has also been combined with cytarabine in the treatment of AML. Results from a double-blind, placebo-controlled, randomized phase III study using high-dose continuous infusion cytarabine (1.5 g/m2 on days 1–3) with or without cloretazine (600 mg/m2 on day 1) for the treatment of AML patients in first relapse were recently reported [53]. Although the ORR in the combination arm was nearly twice that in the cytarabine alone arm (37% versus 19%), the death rate was significantly higher in the combination arm (39% versus 8.6%). The majority of deaths in patients who received combination therapy occurred as a result of infection, sepsis, or pneumonia. The study has now been placed on hold, pending further investigation of the excess mortality observed when the two agents were used in combination.

Newer Nucleoside Analogues
Ongoing work has sought to refine the use of nucleoside analogues in a disease for which cytarabine already represents a cornerstone of therapy. In recent years, these efforts have focused primarily on two new agents: clofarabine and troxacitabine. Clofarabine is a next-generation nucleoside analogue designed to combine the most favorable pharmacokinetic properties of fludarabine and cladribine and at the same time avoid the dose-limiting neurotoxicity of other deoxynucleoside analogues. Initial phase I and II trials of clofarabine monotherapy in the setting of relapsed or refractory AML yielded encouraging results, with significant response rates and a favorable toxicity profile featuring minimal neurotoxicity [54, 55].

More recently, preliminary results were reported from a single-arm phase II trial involving previously untreated elderly patients (median age, 71 years) with one or more adverse prognostic factors who received clofarabine monotherapy [56]. Clofarabine was administered as a 30-mg/m2 (induction) or 20-mg/m2 (reinduction/consolidation) infusion on days 1–5 of each cycle to a maximum of six cycles. Treatment-related toxicity, primarily hematologic, was manageable. The ORR was 43%, with a 40% CR rate and a 3% CRp rate.

Other studies have combined clofarabine with cytarabine based on the ability of clofarabine to inhibit ribonucleotide reductase and thus theoretically augment the activity of cytarabine [57]. A phase II study in 32 relapsed and refractory AML patients (median age, 59 years) using clofarabine (40 mg/m2 i.v. for 5 days) along with cytarabine (1,000 mg/m2 i.v. for 5 days) led to an ORR of 38%, with a 22% CR rate and a 16% CRp rate [58]. This approach was extended to the treatment of 60 newly diagnosed AML patients aged ≥50 years with doses of clofarabine and cytarabine similar to those used in upfront induction therapy [59] and produced a higher ORR of 60% (CR rate, 52%; CRp rate, 8%). Myelosuppression was common, and four patients (7%) died during induction. Adverse events (grade ≤2) included diarrhea, nausea, vomiting, mucositis, skin reactions, liver test abnormalities, and infusion-related facial flushing and headaches. The authors concluded that while the combination of clofarabine and cytarabine does lead to good response rates, it does not appear to result in longer survival times than with other regimens. Modifications of this combination in the therapy of older AML patients warrant further evaluation.

Troxacitabine is an L-nucleoside analogue (most nucleoside analogues are in the D-configuration) that has been studied in phase I/II studies as monotherapy in patients with relapsed or refractory AML [60, 61]. The drug was subsequently assessed in previously untreated patients aged ≥50 with an adverse karyotype in a prospective, randomized trial comparing idarubicin plus cytarabine with troxacitabine plus cytarabine and with troxacitabine plus idarubicin [62]. Neither troxacitabine-containing regimen was superior in terms of response rate to the standard combination of idarubicin and cytarabine. Survival was equivalent in the three treatment groups. More recently, the safety and efficacy of continuous-infusion troxacitabine (10.1 mg/m2 over 48 hours) were studied in a phase I/II trial involving 48 patients with refractory AML [63]. The dose-limiting toxicities were mucositis and hand–foot syndrome. There was a 15% CR or CRp rate and the median survival time among responders was 12 months. Given the acceptable toxicity profile and response rate observed in previously refractory patients treated with troxacitabine, additional study of this agent alone or in combination with other agents seems warranted.

FLT3 Inhibitors
A member of the class III receptor tyrosine kinase family, the FLT3 receptor plays an important regulatory role in normal hematopoiesis. Mutations of FLT3 in AML were first described >10 years ago and are now known to occur in a substantial percentage of patients with the disease [64]. An ITD involving the juxtamembrane of FLT3 occurs in 15%–35% of patients with AML, while a mutation in the tyrosine kinase domain (TKD) occurs in 5%–10% [65, 66]. The presence of the FLT3 ITD confers an inferior clinical outcome [65, 67]. Among elderly patients with AML, the FLT3 TKD mutation is uncommon, while the FLT3 ITD is seen in approximately 35% of individuals [24]. In this patient population, the mutation is associated with leukocytosis and a higher peripheral blast percentage, but does not appear to correlate with an inferior clinical outcome [24].

Several phase I and phase II trials have assessed the activity of FLT3 inhibitors in patients with relapsed/refractory AML or in older patients with disease not amenable to therapy with conventional chemotherapy [68–71]. Recently, a phase II trial employed the oral FLT3 inhibitor lestaurtinib (CEP701) as first-line therapy in previously untreated older patients with AML who were not candidates for intensive chemotherapy [72]. Patients were treated regardless of their FLT mutation status, and received lestaurtinib at a dose of 60 mg orally twice daily initially with dose escalation to 80 mg twice daily as tolerated. There were no CRs or PRs, though a bone marrow response occurred in 19% of patients, with an 11% hematologic response rate. The most common therapy-related high-grade toxicities of nausea and diarrhea occurred in <10% of patients. Further clinical trials are necessary to define the role of FLT3 inhibition in the treatment of AML, but the mutated receptor remains an attractive target given its prevalence and biological function within hematopoietic cells.

Other Therapeutic Agents with a Potential Role in Elderly Patients with AML
In addition to those discussed, various other classes of drugs are being investigated for their role in the treatment of AML. They may play a specific role in the management of elderly patients, who stand to benefit most from less toxic therapies. Histone deacetylase (HDAC) inhibitors, for example, have shown promising anticancer activity in preclinical and early-phase investigation [73, 74]. In targeting HDAC, this class of agents has been shown to have a variety of effects on tumor cells, including HDAC-associated apoptosis, cell-cycle arrest, and antiangiogenic activity [75]. A phase I study of the HDAC inhibitor MS-275 in patients with relapsed, refractory, or newly diagnosed poor-risk AML confirmed the agent's biologic activity as reflected by increases in H3/H4 acetylation and p21 expression, but failed to show clinical responsiveness based on standard response criteria [76].

Bcl-2, a potent inhibitor of apoptosis, is overexpressed in various hematologic malignancies, including AML, and has been explored as a therapeutic target [77]. Phase I and II studies of the Bcl-2 antisense oligonucleotide G3139 as part of induction therapy in AML patients with relapsed, refractory, as well as previously untreated disease demonstrated biological activity with a decrease in Bcl-2 expression following therapy, significant clinical responses, and minimal toxicity [78–80]. However, a randomized phase III trial involving untreated older individuals with AML who received cytarabine and daunorubicin with or without Bcl-2 antisense oligonucleotide showed no difference in the CR rate or OS duration between the two treatment groups [81].

Anti–vascular endothelial growth factor (VEGF) therapy now figures prominently in the management of various solid tumors. The potential role of such therapy in the treatment of AML is being assessed. VEGF and its receptor VEGFR-2 are overexpressed in the bone marrow of patients with AML [82]. Furthermore, in vitro studies suggest that VEGF inhibits apoptosis and promotes survival in AML by inducing expression of Bcl-2 [83]. A single-arm phase II trial of bevacizumab in combination with cytarabine and mitoxantrone yielded an ORR of 48% and a CR rate of 33%, with a favorable toxicity profile [84]. The drug thus warrants further evaluation of its role in the treatment of AML.

Recent work has also explored the safety and efficacy of the DNA-hypomethylating agent 5-azacytidine in combination with other agents for the treatment of older individuals with AML [85, 86]. Finally, preclinical data have provided evidence that the Akt–mammalian target of rapamycin pathway and proteasome complex may serve as therapeutic targets for drug development in AML [87, 88]. A phase I study that incorporated the proteasome inhibitor bortezomib within induction therapy for individuals with previously untreated or relapsed AML confirmed the safety of this agent as a component of AML induction therapy [89].


   SUMMARY
Top
 Learning Objectives
 Abstract
 Introduction
 Host Factors and Biological...
 Role of Cytogenetics and...
 Current Treatment Modalities for...
 Emerging Therapeutic Modalities...
 Summary
Author Contributions
 References
 
Research in the field of AML has yielded important insights regarding the biology of the disease and the distinctive characteristics of elderly AML patients. The novel agents described in this review have emerged as a result of these insights and rigorous assessment in the context of clinical trials. It should be noted that elderly patients with AML continue to be under-represented in clinical trials. One study reported that, over a 12-year period, only approximately 33% of 6,334 patients enrolled in various multicenter AML studies were aged ≥60 years, despite the fact that the median age at diagnosis of the disease is 67 [8]. In order to ensure further progress in the care of elderly AML patients, it is critical that willing individuals be offered the opportunity to participate in clinical trials whose aim is to ultimately provide more effective, less toxic therapy.


   AUTHOR CONTRIBUTIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Host Factors and Biological...
 Role of Cytogenetics and...
 Current Treatment Modalities for...
 Emerging Therapeutic Modalities...
 Summary
 Author Contributions
References
 
Conception/design: Jacob Laubach, Arati Rao

Manuscript writing: Jacob Laubach, Arati Rao

Final approval of manuscript: Jacob Laubach, Arati Rao


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Host Factors and Biological...
 Role of Cytogenetics and...
 Current Treatment Modalities for...
 Emerging Therapeutic Modalities...
 Summary
 Author Contributions
 References
 

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