Experimental Hematology
Volume 37, Issue 6 , Pages 649-658, June 2009

Acute myelogenous leukemia

  • Joshua L. Shipley
    • ,
  • James N. Butera

      Affiliations

    • Corresponding Author InformationOffprint requests to: James N. Butera, M.D., Department of Hematology/Oncology, Brown University, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903

Department of Hematology/Oncology, Brown University, Providence, RI., USA

Received 2 June 2008; received in revised form 9 April 2009; accepted 13 April 2009. published online 20 April 2009.

Article Outline

Acute myeloid leukemia (AML) is a heterogenous disease with outcomes dependent upon several factors, including patient age, karyotype, mutational status, and comorbid conditions. For younger patients, approximately 60% to 80% achieve complete remission with standard therapy involving cytarabine and an anthracycline. However, only 20% to 30% have long-term disease-free survival. For adults older than 60 years of age, only 40% to 55% achieve a complete remission, with dismal long-term survival rates. Unfortunately, the median age at diagnosis for AML is 70 years. Significant advances in our understanding of the molecular biology of AML have led to newer therapies that specifically target molecular abnormalities. Examples of such therapies include the immunoconjugate gemtuzumab ozogamicin, FMS-like tyrosine kinase 3 inhibitors, farnesyl transferase inhibitors, histone deacetylase inhibitors, DNA hypomethylating agents, multidrug-resistance inhibitors, BCL-2 inhibitors, antiangiogenesis agents, and various nucleoside analogs. This review summarizes the standard treatments for AML and discusses the role of novel therapies.

 

Acute myeloid leukemia (AML) is a hematopoietic stem cell disorder characterized by a block in differentiation of hematopoiesis, resulting in growth of a clonal population of neoplastic cells or blasts. This malignant alteration in hematopoietic stem cells leads to a loss of normal hematopoietic function, which, if left untreated, typically leads to death within weeks to months of its clinical presentation.

This review will be a thorough summary of the treatment, prognosis, and future therapies of patients with AML. It will not include acute promyelocytic leukemia because of the unique treatment strategies and differing prognosis of this subtype of AML.

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Prognosis and genetics of AML 

Remission rates with standard induction chemotherapy in patients with AML range from 50% to 85% [1]. However, the majority of patients will relapse and die of their disease within 2 years of achieving a remission. Remission rates and overall survival depend on a number of features, including age of the patient, cytogenetics, other molecular changes within the malignant leukemic clone, previous bone marrow disorders (e.g., myelodysplasia [MDS] or a myeloproliferative disorder), and comorbid illnesses as well as others.

Prognosis and genetics of AML are tightly linked. Risk stratification based on cytogenetics divides patients into three main groups, those with favorable, intermediate, and unfavorable cytogenetics. Although the specific chromosomal aberrations within each group are not entirely consistent among all studies, a general consensus exists (Table 1) [2].

Table 1. Cytogenetic-based risk stratification
Favorable riskIntermediate riskUnfavorable risk
Chromosomalt(15;17)(q22;q12-21)Normal karyotypeComplex karyotype
aberrationt(8:21)(q22;q22)t(9;11)(p22;q23)inv(3)(q21q26)/t(3;3)(q21;q26)
inv(16)(p13q22)/del(7q)t(6;9)(p23;q34)
t(16;16)(p13;q22)del(9q)t(6;11)(q27;q23)
del(11q)t(11;19)(q23;p13.1)
del(20q)del(5q)
−Y−5
+8−7
+11
+13
+21

Data from reference 2.

Age and cytogenetics have a close relationship. Adverse cytogenetic abnormalities increase with increasing age and, within each cytogenetic risk group, prognosis with standard treatment worsens with increasing age. One study found that the percentage of favorable cytogenetics dropped from 17% in patients aged younger than 56 years to 4% in those aged older than 75 years. Furthermore, the percentage of patients with unfavorable cytogenetics increased from 35% in those younger than 56 years to 51% in patients older than 75 years 1, 3.

Core-binding factor (CBF) AML is a frequent subtype of AML with a relatively favorable prognosis. CBFs are a group of heterodimeric transcriptional regulators containing a common β (CBFβ-PEPBP2β) and one of three α (AML1-RUNX1, PEBP2αB, CBFα2) components. CBF AML results from translocations involving either AML1 or CBFβ. In t(8;21) AML, ETO on chromosome 8 is fused with RUNX1 on chromosome 21 and is associated with the French-American-British M2 morphology. In inv(16) AML, CBFβ on chromosome 16 is fused to the MYH11 gene on chromosome 16 and is associated with French-American-British M4Eo morphology 4, 5. Each of these fusion products is thought to lead to leukemia through dominant negative inhibition of normal myeloid differentiation. Despite a similar and favorable response rate among these two cytogenetic subsets of AML, it has recently been recognized that they differ with respect to their pattern of secondary chromosomal aberrations, their gene-expression signatures, and how various KIT mutations affect prognosis 6, 7, 8.

Approximately 40% to 50% of patients with AML have a normal karyotype and represent the largest subset of AML [6]. Not all patients in this subset have the same response to treatment. This is likely a result of the large variability in gene mutations and gene expression in this population. Mutations in the nucleophosmin, member 1 gene and the CCAAT/enhancer-binding protein-α gene seem to confer a better prognosis, whereas internal tandem duplications of the FMS-like tyrosine kinase 3 (FLT3), partial tandem duplication of the myeloid/lymphoid or mixed lineage leukemia gene, overexpression of the brain and acute leukemia gene, and overexpression of the ETS-related gene are associated with a poorer prognosis [9]. Although further research is needed, eventually gene-expression profiling may be used to help prognosticate patients with cytogenetically normal AML. It may also aid in guiding treatment, as each of these genetic alterations can ultimately become targets of therapeutic interventions.

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Standard treatment 

Induction chemotherapy with 7 days of continuous intravenous infusion of cytarabine 100mg/m2 and 3 days of daunorubicin 45 to 60mg/m2 (“7 and 3”) followed by 5 days of continuous intravenous infusion of cytarabine and 2 days of daunorubicin, if disease persists based on a day-14 bone marrow biopsy, has been the standard initial treatment for AML for the past 3 decades [10].

Other induction regimens, including altering the doses of cytarabine, substituting different anthracyclines, and the addition of other agents to enhance the efficacy of this standard treatment, have been studied. Despite theoretical benefits, none have convincingly shown a survival advantage over “7 and 3” (Table 2). Whether to use a daunorubicin dose of 60mg/m2 or 45mg/m2 in this standard regimen has recently been a subject of much debate. While some have advocated use of the higher dose, no randomized trial has evaluated outcomes between the two dose levels.

Table 2. Trials of alternative induction regimens
Induction regimenComplete responseOverall survivalOther
HDAC vs standard Ara-C 11, 12No improvementNo improvementIncreased toxicity
Ara-C (200 vs 100mg/m2) [13]No improvementNo improvement
Addition of etoposide to standard therapy [14] No improvement (possibly improved in age <55 years)Improved remission duration
GCSF+priming [15]No improvementNo improvementMay improve event-free survival
Idarubicin vs daunorubicin 15, 16, 17, 18Improved in two trialsImproved in two trials No improvement in 2 trialsConflicting results in four trials
Mitoxantrone vs daunorubicin [19]ImprovedNo improvement
Substitution of fludarabine for anthracycline [20]DecreasedDecreased
Adding fludarabine to Ara-C and anthracycline [21]InconclusiveNo improvement
Addition of MDR-1 modulator 22, 23No improvementNo improvement
Addition of gemtuzumab ozogamicin (3mg/m2) [24] No improvementImproved disease-free survival

Ara-C = cytarabine; GCSF = granulocyte colony-stimulating factor; HDAC = high-dose cytarabine; MDR-1 = multidrug resistance 1.

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Postremission therapy 

Several studies have evaluated the role of postremission therapy in AML. These studies have demonstrated a clear benefit in survival and cure rates for patients who receive some form of accepted consolidation treatment 25, 26, 27, 28.

Postremission therapy traditionally has included three standard acceptable modalities, i.e., more chemotherapy, autologous stem cell transplantation, or allogeneic bone marrow transplantation (BMT). Intensity of the postremission therapy is typically dependent on the age of patient, comorbidities, chance for recurrence based on cytogenetics, and whether or not the patient has a suitable bone marrow donor.

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Consolidation chemotherapy 

Standard consolidation chemotherapy for patients younger than 60 years old, provided the patient has good organ function, is high-dose Ara-C (cytarabine) [29]. Standard treatment doses are 3g/m2 twice a day on days 1, 3, and 5, for a total of six doses. Typically, three to four cycles of high-dose Ara-C are given. Patients who fall in the favorable or intermediate-risk groups appear to have the most benefit from this intensive consolidation regimen. From the available studies, it is clear that those patients who have favorable cytogenetics do equally well or better with intensive postremission chemotherapy as initial treatment. Patients who fall in the unfavorable risk group may not benefit from this intensive consolidation chemotherapy and are typically considered candidates for allogenic transplantation 29, 30, 31.

Patients older than 60 years of age do not benefit from the 3g/m2 dose of HiDAC regimen over other less intense forms of consolidation. Incidence of toxicity, including cerebellar toxicity, is higher in this age group, therefore, making it an unacceptable option 29, 30, 31.

A variety of consolidation regimens have been used for patients older than 60 years. One has not been shown to be clearly better than another. A reasonable approach is for two cycles of less-intense chemotherapy, such as 5 days of cytarabine 100 mg/m2 continuous intravenous infusion for 24hours and 2 days of daunorubicin 45mg/m2.

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Autologous BMT as postremission therapy 

Several trials have evaluated autologous stem cell transplantation in first remission. Typically, patients who have been studied are those who do not have a human leukocyte antigen (HLA)−matched donor. Large trials that have randomized patients to consolidation chemotherapy vs autologous stem cell transplantation during first remission have consistently shown an improvement in disease-free survival, however, no overall survival advantage has been demonstrated 29, 30, 31, 32, 33, 34. A large meta-analysis published by Nathan et al. [32] of six randomized trials with 1044 patients comparing autologous BMT to nonmyeloablative chemotherapy also showed similar findings. This lack of survival advantage, despite improved disease-free survival, has been attributed in part to the ability to effectively salvage patients with autologous or allogeneic BMT after relapse from chemotherapy. Mortality for autologous BMT is <6%. The higher mortality of autologous BMT compared with consolidation chemotherapy as well as the improved efficacy in consolidation chemotherapy with HiDAC has also diminished the ability for autologous BMT to show a survival advantage when compared to standard consolidation chemotherapy [32].

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Allogeneic BMT as postremission therapy 

Patients with unfavorable cytogenetics have traditionally been candidates for allogeneic BMT, given the poor results with standard consolidation chemotherapy. However, the results of randomized trials have been conflicting for its benefit. There have been five cooperative group trials in which the role of allogeneic BMT has been assessed in patients with AML in first remission 29, 30, 31, 33, 35, 36, 37. No prospective trials have been specifically designed to address an unfavorable risk group, allowing for interpretation to come only from the subset analyses of these larger trials. Conclusions from the subset analyses have been hampered in these studies because of lack of compliance of patients with the assigned treatment option, small amounts of patients, and the changing definition of an unfavorable risk group. Nonetheless, three trials do not suggest a survival benefit for allo-BMT for patients in first remission with unfavorable risk cytogenetics (i.e., European Organisation for Research and Treatment of Cancer/Gruppo Italiano Malattie Ematologiche dell'Adulto, AML 8/GOELAM [Groupe Ouest-Est Leuremies Aigues Myeloblastique], and Medical Research Council AML 10), while two trials do show a statistically significant benefit in overall survival with this modality (e.g., European Organisation for Research and Treatment of Cancer/Gruppo Italiano Malattie Ematologiche dell'Adulto AML 10, US Intergroup). However, because of the usual dismal results with standard chemotherapy in high-risk groups of patients with AML and the fact that two of the five trials have shown a survival benefit of allo-BMT in first remission in subset analysis for high-risk AML patients, and given that the lack of survival benefit may be due in part to the small numbers of patients, allogeneic BMT is the standard offered to high-risk patients in first remission.

Data is less clear for allo-BMT in patients with intermediate risk cytogenetics who are in first remission. The UK Medical Research Council AML trial did show an overall survival benefit for patients with intermediate-risk cytogenetics when allo-BMT was used in first remission, but this was a subset analysis and other studies have been contradictory [38].

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Relapsed disease 

Relapsed AML after initial chemotherapy in patients who cannot tolerate an autologous or allogeneic BMT is almost always fatal. However, patients who have a matched HLA-identical sibling donor, a matched unrelated donor, or those who do not but who can tolerate an autologous BMT, can still be salvaged. The standard approach is for patients to undergo reinduction chemotherapy in an attempt to obtain a second remission prior to proceeding to BMT. The single best predictor of success for obtaining a second remission is the length of initial remission duration. If the initial complete remission (CR) was <12 months, the chance for obtaining a second CR is 10% to 20%. If the initial CR was >12 months, success for obtaining a second CR increases to 40% to 50% 39, 40, 41. Reinduction with “7+3” is very reasonable if a durable remission was obtained upon this initial induction regimen. Alternative reinduction regimens have been used with similar success rates, with no one regimen proving superior to the others 42, 43, 44, 45.

Autologous BMT has been extensively evaluated for patients in second remission who cannot tolerate an allogeneic BMT or do not have a suitable donor. A recent review of follow-up data in the British Society of Blood and Marrow Transplantation registry database to establish long-term outcomes of autologous transplantation in patients with intermediate and good risk AML in second CR reported 10-year survival rate of 32% [46].

Allogenic BMT with an HLA-matched sibling after the first remission is lost has consistently shown 5-year survival rates of 20% to 35%. Patients do better if the duration of first remission is >6 months and if they are in a second remission prior to allo-BMT [47].

Matched unrelated allo-BMT is also an option for patients who can tolerate it, but mortality (approaching 30%) and severe graft-vs-host disease incidence are both high with this form of transplantation [48]. Although Caucasians have a 50% chance of obtaining a match, it is only a 10% chance for minorities, and frequently there is a delay to obtain donor cells, which can allow for relapse prior to the patients getting the allograft [49].

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Nonmyeloablative and reduced-intensity allogenicBMT 

The goal of both reduced-intensity conditioning regimens and nonmyeloablative regimens is to reduce the nonrelapse mortality of the allogeneic BMT, thereby allowing this treatment option to be offered to patients who otherwise could not tolerate a conventional myeloablative transplant, either due to age or comorbid illnesses. Both of these strategies are employed routinely for older individuals and appear effective, particularly in patients who are in a complete remission prior to either strategy [50].

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Gemtuzumab ozogamicin 

Gemtuzamab ozogamicin (GO) is an anti-CD33 immunoconjugate that binds to the surface of myeloid blasts and, after internalization, releases calicheamicin, a cytotoxic drug [51]. GO is approved by the US Food and Drug Administration for use in patients 60 years or older with CD33+ AML in first relapse who are not candidates for cytotoxic chemotherapy. Although this novel drug theoretically has advantages of being a “targeted” treatment, its CR rate as a single agent was only 13%. Another 13% of patients had a CR with incomplete platelet recovery with median recurrence-free survivals of 6.4 months for patients who received a CR and only 4.5 months for patients who received a CR with incomplete platelet recovery. Infusion-related toxicity, such as fever, chills, shortness of breath, and hypotension, is appreciable and grade 3 to 4 neutropenia and thrombocytopenia occurred in all patients. Grade 3 to 4 elevations in bilirubin were seen in 29%, and 0.9% of patients who did not undergo prior or subsequent hematopoietic transplantation developed hepatic veno-occlusive disease, therefore, GO should be avoided in patients with preexisting liver pathology [52].

Higher survival rates have been seen when patients are able to subsequently go on to an allogeneic or autologous BMT, however, these patients have a much higher incidence of hepatic veno-occlusive disease, particularly when the BMT is done within 4 months of GO administration [52].

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AML in the elderly 

There is no agreed upon age in which induction chemotherapy cannot be offered to patients with AML. However, once a patient is deemed too frail because of age or comorbidities for induction chemotherapy, treatment is focused mainly on supportive measures, such as transfusions when needed and antibiotics for treatable infections. Low doses of oral chemotherapy, such as hydroxyurea or melphalan, have been used palliatively to reduce the leukemia burden in patients. Low doses of cytarabine given either intravenously or subcutaneously have also been used palliatively with moderate success 53, 54, 55.

However, ultimately, these patients will die of their disease, typically within a matter of weeks to months. This population of patients may stand to benefit the most from novel agents that can be less toxic and more effective than current agents.

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Novel agents 

In recent years, we have begun to understand the molecular biology of AML. The identification of specific gene mutations and their protein products, as well as alterations in gene transcription that result in aberrant regulation of the cell cycle, have led the way for development of targeted therapies for AML. The remainder of this review will discuss the results of clinical trials with many of these novel agents in AML.

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FLT3 tyrosine kinase inhibitors 

FLT3 is a receptor tyrosine kinase that is normally expressed by hematopoietic stem/progenitor cells. It plays a role in cell survival, proliferation, and differentiation. FLT3 mutations occur in approximately 30% of AML in adults and confer a poor prognosis. The two major types of mutations that occur are internal tandem duplication mutations of the juxtamembrane region and point mutations, which frequently involve aspartic acid 835 of the kinase domain. Both mutations result in constitutive activation of the receptor's tyrosine kinase activity in the absence of ligand [56].

There are currently four FLT3 inhibitors undergoing clinical investigation: PKC-412 (Novartis, Summit, New Jersey), CEP-701 (Cephalon, Frazer, PA), MLN518 (Millenium, Cambridge, MA), and SU11248 (SuGen, San Francisco, CA). A number of phase I and II studies have been completed using these agents as monotherapy in relapsed/refractory AML. From these studies, we have learned that FLT3 inhibitors have demonstrated a clinical response in relapsed AML with activating mutations of FLT3 57, 58, 59, 60, 61, 62, 63, 64, 65, 66. There also appears to be a response in some patients without activating mutations, which may be explained by mutations at alternative sites that activate FLT3. Most studies have demonstrated only a transient reduction in peripheral blood and bone marrow blasts. However, preclinical studies have shown synergistic killing of leukemic cells in vitro when FLT3 inhibitors are combined with conventional chemotherapy [67]. A number of clinical trials are now underway evaluating FLT3 inhibitor therapy with chemotherapy. A phase III study of CEP-701 with MEC (mitaxantrone, etoposice, cytarabine) or HiDAC in relapsed FLT3 mutant AML is being conducted [68], as well as a study of PKC-412 with Ara-C and daunorubicin induction, and consolidation with HiDAC in newly diagnosed AML [69]. A phase I/II study of MLN518 plus standard induction with Ara-C and daunorubicin in newly diagnosed AML is also being investigated [70].

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Farnesyl transferase inhibitors 

The 21-kD proteins encoded by the K-Ras, N-Ras, and H-Ras proto-oncogenes regulate the growth and differentiation of many cell types. Ras proteins that have been recruited to the plasma membrane act by transducing extracellular signals to the nucleus via multiple potential metabolic pathways. Point mutations of Ras genes at codons 12, 13, and 61 result in constitutively active Ras pathways. The incidence of Ras mutations in myelodysplastic syndromes and AML has been reported between 3% and 40%, with N-Ras mutations being the most common, followed by H-Ras, which is rarely seen. Farnesyl transferase inhibitors work by inhibiting farnesylation of Ras, a step that is required for the transfer of Ras to the plasma membrane [71]. Preclinical data indicated that R115777 (Zarnestra) inhibited proliferation and induced apoptosis in leukemic blast cells in vitro 72, 73. A phase II study of tipifarnib in 158 poor-risk elderly patients with untreated AML showed an overall response rate of 23%, with 14% of patients achieving a complete response [74]. There is currently a Southwest Oncology Group phase II study evaluating tipifarnib in previously untreated AML patients age 70 or older, as well as an Eastern Cooperative Oncology Group study evaluating tipifarnib as maintenance therapy after consolidation in AML patients in second or higher CR. A recent trial evaluated tipifarnib in combination with idarubicin and cytarabine in 74 newly diagnosed AML or high-risk MDS patients. Overall response was 77% with 65% achieving a complete response [75].

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Transcription modulators (DNA demethylating agents and histone deacetylase inhibitors) 

Genetic changes refer to changes in the DNA sequence, whereas epigenetic changes refer to changes in gene transcription. Two well-known epigenetic modifications include DNA methylation and various histone modifications, which alter gene expression via the architectural remodeling of chromatin. It is believed that these mechanisms play a role in carcinogenesis through the silencing of tumor-suppressor genes. DNA demethylating agents and histone deacetylase inhibitors (HDAC) induce reexpression of tumor suppressor and proapoptotic genes [76].

5-Azacytidine and 5-aza-2′-deoxycytidine (Decitabine) are the most studied DNA demethylating agents in AML. Phase I trials of these agents used as monotherapy in relapsed/refractory AML or in patients not eligible for intensive chemotherapy have shown complete and partial responses. One study showed complete responses in 2 of 17 (12%) patients and complete or partial remissions in 11 of 17 (65%) patients 77, 78. Decitabine is currently being evaluated in a phase II Cancer and Leukemia Group B study as maintenance therapy following standard induction and consolidation therapy.

HDAC inhibitors that have been evaluated in clinical trials of AML and MDS include MS-275, MG-0103, sodium phenylbutyrate, Vorinostat (suberoyanilide hydroxamic acid), valproic acid, and depsipeptide (FK-228). Vorinostat used as monotherapy in a phase I trial of relapsed/refractory AML or MDS demonstrated complete and partial responses in 21% of patients [79]. Valproic acid has modest activity as monotherapy in low-risk MDS, and in AML in combination with all-trans retinoic acid 80, 81. Depsipeptide (FK-228) was shown to inhibit HDAC in vivo in a phase I trial in chronic lymphocytic leukemia and AML, but its administration was limited by progressive constitutional symptoms [82].

Several phase I/II studies have evaluated the combination of DNA demethylating agents with HDAC inhibitors. Results have indicated that the combination of these agents is safe and can effectively induce complete and partial remissions 83, 84, 85. Based on these promising results, a large intergroup study was initiated evaluating azacytidine with or without the HDAC inhibitor MS-275 for MDS, chronic myeloid leukemia, and AML with multilineage dysplasia.

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Multidrug resistance-1 modulators 

Multidrug resistance-1 gene encodes a 170-kDa P-glycoprotein (P-gp) that functions as an adenosine triphosphate-dependent export pump. This pump transports numerous antineoplastic agents out of the cell. P-gp expression in AML cells increases with advancing age and represents an independent poor prognostic variable. Numerous antineoplastic agents are substrates of P-gp, including anthracyclines, vinca alkaloids, taxanes, camptothecins, and epipodophyllotoxins. Most multidrug resistance-1 modulators function as competitive inhibitors by binding to P-gp within its substrate channel, interfering with the binding of antineoplastics [86].

The first-generation modulators included quinine and cyclosporine. Studies with these agents did not show a significant benefit, however, a Southwest Oncology Group trial of cyclosporine with cytarabine and daunorubicin demonstrated increased relapse-free and overall survival [87]. This led to trials with second-generation modulators, of which PSC-833 (Valspodar; Novartis) was the only one to complete phase III trials. Results of these studies were disappointing, showing no improvement in the rate of CR and excessive toxicity [88].

A number of third-generation modulators are currently under investigation. These agents include Tariquidar (XR9576; Xenova, Cambridge, MA), Zosuquidar (LY335979; Eli Lilly, Indianapolis, IN), Laniquidar (R101933), and ONT-093. These agents are more specific for P-gp, have less CYP-3A4 interaction, and have less pharmacokinetic interactions with chemotherapy than second-generation agents [86]. After a phase II study of Zosuquidar with cytarabine and daunorubicin that showed promising results [89], the Eastern Cooperative Oncology Group initiated a phase III, double-blind, randomized trial evaluating Zosuquidar with standard induction and consolidation chemotherapy.

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BCL-2 antisense oligonucleotide (Genasense) 

Bcl-2 is an apoptosis-regulating oncogene that is frequently overexpressed in lymphoid and myeloid malignancies. Normally, apoptotic signals are transmitted from the cell membrane to the mitochondria, resulting in release of cytochrome C, which induces caspase-mediated apoptosis. The bcl-2 protein stabilizes the inner mitochondrial membrane, preventing release of cytochrome C, which inhibits apoptosis [90]. Overexpression of the bcl-2 protein leads to resistance of tumor cells to apoptosis, and is associated with a poor prognosis in AML [91]. Oblimersen (Genasense; bcl-2 antisense oligonucleotide) binds to bcl-2 messenger RNA in the cytoplasm, which results in messenger RNA degradation and decreased level of the bcl-2 protein.

In a phase I study of Oblimersen with fludarabine, cytarabine, and granulocyte colony-stimulating factor in relapsed or refractory AML and acute lymphocytic leukemia, 9/20 (45%) of patients responded with 6 (5 AML, 1 acute lymphocytic leukemia) achieving a complete response [92]. In a subsequent phase I trial, Oblimersen was evaluated with standard cytarabine and daunorubicin induction therapy, and high-dose Ara-C consolidation therapy in previously untreated AML patients older than 60 years of age. In this study, 14 of 29 (48%) patients achieved a CR [93]. Based on these promising results, a randomized phase III study was initiated by the Cancer and Leukemia Group B evaluating oblimersen with cytarabine and daunorubicin induction, and with high-dose Ara-C consolidation in previously untreated patients older than 60 years with AML.

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Antiangiogenesis agents 

The role for antiangiogenesis therapy in AML was prompted by recognition that bone marrow biopsies from patients with AML demonstrated increased microvessel density and that increased levels of vascular endothelial growth factor correlate with a poor prognosis [94]. Clinical trials involving a variety of antiangiogenesis agents alone or in combination with chemotherapy have largely been disappointing. These trials have included the agents PTK787/ZK222584, AG-013736, SU11248, SU5416, bevacizumab, and thalidomide 95, 96, 97, 98, 99, 100, 101, 102. However, a trial of bevacizumab, given after chemotherapy with high-dose cytarabine and mitoxantrone in patients with relapsed and refractory AML, demonstrated an overall response rate of 48% (23 of 48 patients) and a complete response rate of 33% (16 of 48 patients) [99].

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Clofarabine 

Clofarabine is a second-generation nucleoside analog. It is a potent inhibitor of ribonucleotide reductase and is resistant to deamination by adenosine deaminase 91, 103. Clinical trials have demonstrated promising results when clofarabine is used alone or in combination with cytarabine in patients with AML or high-risk MDS. In a phase II trial of clofarabine monotherapy in patients with relapsed or refractory acute leukemia, 17 of 31 patients (55%) with AML had complete or partial responses [104]. In a subsequent phase I/II study of clofarabine plus cytarabine in relapsed/refractory acute leukemia, 12 of 29 (41%) patients with AML/high-risk MDS responded, with 24% achieving a CR [103]. In a recent phase II study of clofarabine plus cytarabine in previously untreated AML patients aged 50 years and older, an overall response rate of 60% (52% CR, 8% CRp) was achieved [105]. Based on these promising results, a randomized phase III trial of single-agent clofarabine compared to standard chemotherapy with daunorubicin and cytarabine in previously untreated elderly patients has been initiated.

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Acknowledgment 

No financial interest/relationships with financial interest relating to the topic of this article have been declared.

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References 

  1. Farag SS, Ruppert AS, Mrozek K, et al. Outcome of induction and postremission therapy in younger adults with acute myeloid leukemia with normal karyotype: a Cancer and Leukemia Group B study. J Clin Oncol. 2005;23:482
  2. Grimwade D, Walker H, Oliver F, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. Blood. 1998;92:2322-2233
  3. Farag SS, Archer KJ, Mrozek K, et al. Pretreatment cytogenetcs add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461. Blood. 2006;108:63–73
  4. Appelbaum FR, Kopecky KJ, Tallman MS, et al. The clinical spectrum of adult acute myeloid leukemia associated with core binding factor translocations. Br J Haematol. 2006;135:165–173
  5. Kuchenbauer F, Schnittger S, Look T, et al. Identification of additional cytogenetic and molecular genetic abnormalities in acute myeloid leukemia with t(8;21)/AML1-ETO. Br J Haematol. 2006;134:616–619
  6. Mrozek K, Bloomfield CD. Chromosome aberrations, gene mutations and expression changes, and prognosis in adult acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2006;169–177
  7. Ichikawa H, Tanabe K, Mizushima H, et al. Common gene expression signatures in t(8;21)- and inv(16)-acute myeloid leukemia. Br J Haematol. 2006;135:336–347
  8. Paschka P, Marcucci G, Ruppert AS, et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study. J Clin Oncol. 2006;24:3904–3911
  9. Mrozek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification?. Blood. 2007;109:431–448
  10. Dillman RO, Davis RB, Green MR, et al. A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood. 1991;78:2520–2526
  11. Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized investigation of high-dose versus standard –dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia; A Southwest Oncology Group Study. Blood. 1996;88:2841–2851
  12. Bishop JF, Matthews JP, Young GA, et al. A randomized study of high-dose cytarabine in induction acute myeloid leukemia. Blood. 1996;87:1710–1717
  13. Dillman RO, Davis RB, Green MR, et al. A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood. 1991;78:2520–2526
  14. Bishop JF, Lowenthal RM, Joshua D, et al. Etoposide in acute nonlymphocytic leukemia. Blood. 1990;75:27–32
  15. Rowe JM, Neuberg D, Friedenberg W, et al. A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group. Blood. 2004;103:479–485
  16. Vogler WR, Velez-Garcia E, Weiner RS, et al. A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group study. J Clin Oncol. 1992;10:1103–1111
  17. Wiernik PH, Banks PLC, Case DC, et al. Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood. 1992;79:313–319
  18. Berman E, Heller G, Santorsa J, et al. Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood. 1991;77:1666–1674
  19. Arlin Z, Case DC, Moore J, et al. Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia. Lederle Cooperative Group. Leukemia. 1990;4:177–183
  20. Estey EH, Thall PF, Cortes JE, et al. Comparison of idarubicin + ara-c-, fludarabine + ara-C-, and topotecan + ara-C-based regimens in treatment of newly diagnosed acute myeloid leukemia, refractory anemia with excess blasts in transformation, or refractory anemia with excess blasts. Blood. 2001;98:3575–3583
  21. Russo D, Malagola M, DeVivo A, et al. Multicenter phase III trial of fludarabine, cytarabine (Ara-C), and idarubicin versus idarubicin, Ara-C, and etoposide for induction treatment of younger, newly diagnosed acute myeloid leukemia patients. Br J Haematol. 2005;131:172–179
  22. Van Der Holt B, Sonneveld P, Burnett AK, et al. Daunorubicin and cytarabine compared with daunorubicin, cytarabine and the MDR1 reversal agent PSC-833 in elderly patients with acute myelogenous leukemia. Blood (ASH Annual Meeting Abstracts). 2004;104:Abstract 863
  23. Cripe LD, Li X, Litzow M, Rowe EJM, Luger S, Tallman M. A randomized, placebo controlled, double blind trial of the MDR modulator Zosuquidar, during conventional induction and post-remission therapy for patients >60 years of age with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome: ECOG 3999. Blood (ASH Annual Meeting Abstracts). 2006;108:Abstract 423
  24. Burnett AK, Kell WJ, Milligan AD, et al. The addition of gemtuzumab ozogamicin to induction chemotherapy for AML improves disease free survival without extra toxicity: preliminary analysis of 1115 patients in the MRC AML15 Trial. Blood (ASH Annual Meeting Abstracts). 2006;108:Abstract 13
  25. Stone RM, Mayer RJ. Treatment of the newly diagnosed adult with de novo acute myeloid leukemia. Hematol Oncol Clin North Am. 1993;7:47–64
  26. Champlin R, Gajewski J, Nimer S. Postremission chemotherapy for adults with acute myelogenous leukemia: improvement survival with high-dose cytarabine and daunorubicin consolidation treatment. J Clin Oncol. 1990;8:1199–1206
  27. Cassileth PA, Lynch E, Hines JD, et al. Varying intensity postremission therapy in acute myeloid leukemia. Blood. 1992;79:1924–1930
  28. Schlenk RF, Frohling S, Hartmann F, et al. Intensive consolidation verses oral maintenance therapy in patients 61 years or older with in acute myelogenous leukemia in first remission: results of second randomization of AML HD98-B treatment trial. Leukemia. 2006;20:748–750
  29. Cassileth PA, Harrington DP, Appelbaum FR, et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med. 1998;339:1649
  30. Zittoun RA, Mandelli F, Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared Cawith intensive chemotherapy in acute myelogenous leukemia. N Engl J Med. 1995;332:217
  31. Burnett AK, Goldstone AH, Stevens RMF, et al. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet. 1998;351:700
  32. Nathan PC, Sung L, Crump M, Beyene J. Consolidation therapy with autologous bone marrow transplantation in adults with acute myeloid leukemia: a meta-analysis. J Natl Cancer Inst. 2004;96:38
  33. Harousseau J, Cahn J, Pignon B, et al. Comparison of autologous bone marrow transplantation and intensive chemotherapy as postremission therapy in adult acute myeloid leukemia. Blood. 1997;90:2978–2986
  34. Tsimberidou AM, Stavroyianni N, Viniou N, et al. Comparison of allogeneic stem cell transplantation, high-dose cytarabine, and autologous peripheral stem cell transplantation as postremission treatment in patients with de nova acute myelogenous leukemia. Cancer. 2003;97:1721
  35. Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075–4083
  36. Keating S, de Whitte T, Suciu S, et al. The influence of HLA-matched sibling donor availability on treatment outcome for patients with AML: an analysis of the AML 8A study of the EORTC Leukaemia Cooperative Group and GIMEMA. European Organization for Research and Treatment of Cancer. Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto. Br J Haematol. 1998;102:1344–1353
  37. Suciu S, Mandelli F, de Witte , et al. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1):an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial. Blood. 2003;102:1232–1240
  38. Burnett A, Wheatley K, Goldstone A, et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC. AML trial. Br J of Haematol. 2002;118:385–400
  39. Estey EH. Treatment of relapsed and refractory acute myelogenous leukemia. Leukemia. 2000;14:276
  40. Craddock C, Tauro S, Moss P, et al. Biology and management of relapsed acute myeloid leukemia. Br J Haematol. 2005;129:18
  41. Breems DA, Van Putten WL, Huijgens PC, et al. Prognosic index for adult patients with acute myeloid leukemia in first relapse. J Clin Oncol. 2005;23:1969
  42. Brown RA, Herzig RH, Wolff SN, et al. High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy. Blood. 1990;76:473–479
  43. Ho AD, Lipp T, Ehninger , et al. Combination of mitoxantrone and etoposide in refractory acute myelogenous leukemia−an active and well-tolerated regimen. J Clin Oncol. 1988;6:213–217
  44. Jackson G, Taylor P, Smith GM, et al. A multicentre, open, noncomparative phase II study of a combination of fludarabine phosphate, cytarabine, and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess blasts in transformation. Br J Haematol. 2001;112:127–137
  45. Vignetti M, Orsini E, Petti MC, et al. Probability of long-term disease-free survival for acute myeloid leukemia patients after first relapse: a single-centre experience. Ann Oncol. 1996;7:933–938
  46. Chantry AD, Snowden JA, Craddock C, et al. Long-term outcomes of myeloablation and autologous transplantation of relapsed acute myeloid leukemia in second remission: a British Society of Blood and Marrow Transplantation registry study. Biol Blood Marrow Transplant. 2006;12:1310–1317
  47. Grigg AP, Szer J, Beresford J, et al. Factors affecting the outcome of allogeneic bone marrow transplantation for adult patients with refractory or relapsed acute leukaemia. Br J Haematol. 1999;107:409–418
  48. Boiron JM, Lerner D, Pigneux A, et al. Allogeneic transplantation for patients with advanced acute leukemia: a single center retrospective study of 92 patients. Leuk Lymphoma. 2001;41(3-4):285–296
  49. Mori M, Beatty PG, Graves M, et al. HLA gene and haplotype frequencies in the North American population: the National Marrow Donor Program Donor Registry. Transplantation. 1997;64:1017–1027
  50. Bertz H, Potthoff K, Finke J. Allogeneic stem-cell transplantation from related and unrelated donors in older patients with myeloid leukemia. J Clin Oncol. 2003;21:1480–1484
  51. VanDer Velden VH, te Marvelde JG, Hoogeveen PG, et al. Targeting of the CD33-calicheamicin immunoconjugate Mylotarg (CMA-676) in acute myeloid leukemia: in vivo and in vitro saturation and internalization by leukemic and normal myeloid cells. Blood. 2001;97:3197–3204
  52. Tsimberidou AM, Giles FJ, Estey E, et al. The role of gemtuzumab ozogamicin in acute leukaemia therapy. Br J Haematol. 2005;132:398
  53. Tilly H, Castaigne S, Bordessoule D, et al. Low-dose cytarabine versus intensive chemotherapy in the treatment of acute nonlymphocytic leukemia in the elderly. J Clin Oncol. 1990;8:272–279
  54. Aul C, Schneider W. The role of low-dose cytosine arabinoside and aggressive chemotherapy in advanced myelodysplastic syndromes. Cancer. 1989;64:1812–1818
  55. Robak T, Szmigielska-Kaplon A, Urbanska-Rys H, et al. Efficacy and toxicity of low-dose melphalan in myelodysplastic syndromes and acute myeloid leukemia with multilineage dysplasia. Neoplasma. 2003;50:172–175
  56. Small D. FLT3 mutations: biology and treatment. Hematology. 2006;178–184
  57. O'Farrell AM, Foran JM, Fiedler W, et al. An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res. 2003;15:5465–5476
  58. Fiedler W, Serve H, Dohner H, et al. A phase I study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for disease. Blood. 2005;105:986–993
  59. O'Farrell AM, Yuen HA, Smolich B, et al. Effects of SU5416, a small molecule tyrosine kinase receptor inhibitor, on FLT3 expression and phosphorylation in patients with refractory acute myeloid leukemia. Leuk Res. 2004;28:679–689
  60. Fiedler W, Mester R, Tinnefeld H, et al. A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood. 2003;102:2763–2767
  61. Giles FJ, Stopeck AT, Silverman LR, et al. SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients refractory acute myeloid leukemia or myelodysplastic syndromes. Blood. 2003;102:795–801
  62. Smith BD, Levis M, Beran M, et al. Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004;103:3669–3676
  63. Knapper S, Burnett AK, Littlewood T, et al. A phase 2 trial of the FLT3 inhibitor lestaurtinib (CEP701) as first-line treatment for older patients with acute myeloid leukemia not considered fit for intensive chemotherapy. Blood. 2006;108:3262–3270
  64. Stone RM, DeAngelo DJ, Klimek V, et al. Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2005;105:54–60
  65. Stone RM, Klimek V, DeAngelo DJ, et al. Oral PKC412 has activity in patients with mutant FLT3 acute myeloid leukemia: a phase II trial. Proc Am Soc Clin Oncol. 2003;22;Abstract. 2265
  66. DeAngelo DJ, Stone RM, Heaney ML, et al. Phase 1 clinical results with tandutinib (MLN518), a novel FLT3 antagonist, in patients with acute myeloid leukemia or high-risk myelodysplastic syndrome: safety, pharmacokinetics, and pharmacodynamics. Blood. 2006;108:3674–3681
  67. Levis M, Pham R, Smith BD, et al. In vitro studies of a FLT3 inhibitor combined with chemotherapy: sequence of administration is important to achieve synergistic toxic effects. Blood. 2004;104:1145–1150
  68. Levis M, Smith BD, Beran M, et al. A randomized, open-label study of Lestaurtinib (CEP-701), an oral FLT3 inhibitor, administered in sequence with chemotherapy in patients with relapsed AML harboring FLT3 activating mutations: clinical response correlates with successful FLT3 inhibition. Blood (ASH Annual Meeting Abstracts). 2005;106:Abstract 403
  69. Stone RM, Fischer T, Paquette R, et al. Phase IB study of PKC-412, an oral FLT3 kinase inhibitor, in sequential and simultaneous combinations with daunorubicin and cytarabine induction and high-dose cytarabine consolidation in newly diagnosed adult patients with acute myeloid leukemia under age 61. Blood (ASH Annual Meeting Abstracts). 2006;108:Abstract 157
  70. DeAngelo DJ, Amrein PC, Kovacsovics TJ, et al. Phase 1/2 study of Tandutinib (MLN518) plus standard induction chemotherapy in newly diagnosed acute myelogenous leukemia. Blood (ASH Annual Meeting Abstracts). 2006;108:Abstract 158
  71. Le DT, Shannon KM. Ras processing as a therapeutic target in hematologic malignancies. Curr Opin Hematol. 2002;9:308–315
  72. Korycka A, Smolewski P, Robak T. The influence of farnesyl protein transferase inhibitor R115777 (Zarnestra) alone and in combination with purine nucleoside analogs on acute myeloid leukemia progenitors in vitro. Eur J Haematol. 2004;73:418–426
  73. Liesveld JL, Lancet JE, Rosell KE, et al. Effects of farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis. Leukemia. 2003;17:1806–1812
  74. Lancet JE, Gojo I, Gotlib J, et al. A phase 2 study of the farnesyl transferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia. Blood. 2007;109:1387–1394
  75. Alvarez RH, Kantarjian H, Garcia-Manero G, et al. Farnesyl transferase inhibitor (Tipifarnib, Zarnestra) in combination with standard chemotherapy with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia or high risk myelodysplastic syndrome. Blood (ASH Annual Meeting Abstracts). 2006;108:Abstract 1999
  76. Fandy TE, Carraway H, Gore S. DNA demethylating agents and histone deacetylase inhibitors in hematologic malignancies. Cancer J. 2007;13:40–48
  77. Issa JP, Garcia-Manero G, Giles FJ, et al. Phase 1 study of low-dose prolonged exposure schedules of the hypomethylating agent 5-aza-2'-deoxycytidine (decitabine) in hematopoietic malignancies. Blood. 2004;103:1635–1640
  78. Al-Ali HK, Schwind S, Becker C, Mueller C, Niederwieser D. 5-Azacytidine induces hematologic responses in a high proportion of patients with acute myeloid leukemia refractory to or not eligible for intensive chemotherapy. Blood (ASH Annual Meeting Abstracts). 2006;108:Abstract 1953
  79. Garcia-Manero G, Yang H, Sanchez-Gonzalez B, et al. Final results of a phase 1 study of the histone deacetylase inhibitor Vorinostat (suberoyanilide hydroxamic acid SAHA), in patients with leukemia and myelodysplastic syndrome. Blood (ASH Annual Meeting Abstracts). 2005;106:Abstract 2801
  80. Kuendgen A, Schmid M, Schlenk R, et al. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer. 2006;106:112–119
  81. Kuendgen A, Knipp S, Fox F, et al. Results of a phase 2 study of valproic acid alone or in combination with all-trans retinoic acid in 75 patients with myelodysplastic syndrome and relapsed or refractory acute myeloid leukemia. Ann Hematol. 2005;84(Suppl 13):61–66
  82. Byrd JC, Marcucci G, Parthun MR, et al. A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia. Blood. 2005;105:959–967
  83. Maslak P, Chanel S, Camacho LH, et al. Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome. Leukemia. 2006;20:212–217
  84. Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al. Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. Blood. 2006;108:3271–3279
  85. Garcia-Manero G, Yang AS, Giles F, et al. Phase 1/2 study of the oral isotype selective histone deacetylase (HDAC) inhibitor MGCD0103 in combination with azacitidine in patients with high-risk myelodysplastic syndrome or acute myelogenous leukemia. Blood (ASH Annual Meeting Abstracts). 2006;108:Abstract 1954
  86. Mahadevan D, List AF. Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies. Blood. 2004;104:1940–1951
  87. List AF, Kopecky KJ, William CL, et al. Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study. Blood. 2001;98:3212–3220
  88. Greenberg PL, Lee SJ, Advani R, et al. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol. 2004;22:1078–1086
  89. Cripe L, Tallman M, Karanes C. A phase II trial of zosuquidar (LY335979), a modulator of P-glycoprotein (P-gp) activity, plus daunorubicin and high-dose cytarabine in patients with newly diagnosed secondary acute leukemia (AML), refractory anemia with excess blasts in transformation (RAEB-t) or relapsed/refractory AML [abstract]. Blood. 2001;98:595
  90. Chanan-Khan A. Bcl-2 antisense therapy in hematologic malignancies. Curr Opin Oncol. 2004;16:581–585
  91. Tallman MS. New strategies for the treatment of acute myeloid leukemia including antibodies and other novel agents. Hematology Am Soc Hematol Educ Program. 2005;143–150
  92. Marcucci G, Byrd JC, Dai G, et al. Phase 1 and pharmacodynamic studies of G3139, a bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. Blood. 2003;101:425–432
  93. Marcucci G, Stock W, Dai G, et al. Phase 1 study of oblimersen sodium, an antisense to bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity. J Clin Oncol. 2005;23:3404–3411
  94. Tallman MS, Gilliland DG, Rowe JM. Drug therapy for acute myeloid leukemia. Blood. 2005;106:1154–1163
  95. Roboz GJ, Giles FJ, List AF, et al. Phase 1 study of PTK787/ZK222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. Leukemia. 2006;20:952–957
  96. Giles FJ, Bellamy WT, Estrov Z, et al. The anti-angiogenesis agent, AG-013736, has minimal activity in elderly patients with poor prognosis acute myeloid leukemia or myelodysplastic syndrome. Leuk Res. 2006;30:801–811
  97. Fiedler W, Serve H, Dohner H, et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia or not amenable to conventional therapy for the disease. Blood. 2005;105:986–993
  98. Fiedler W, Mesters R, Tinnefeld H, et al. A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. Blood. 2003;102:2763–2767
  99. Karp JE, Gojo I, Pili R, et al. Targeting vascular endothelial growth factor for relapsed and refractory adult acute myeloid leukemias: therapy with sequential 1 beta-d-arabinofuranosylcytosine, mitoxantrone, and bevacizumab. Clin Cancer Res. 2004;10:3577–3585
  100. Zahiragic L, Schliemann C, Bieker R, Berdel WE, Mesters RM. Bevacizumab reduces VEGF expression in patients with relapsed and/or refractory acute myeloid leukemia without clinical antileukemic activity. Blood (ASH Annual Meeting Abstracts). 2006;108:Abstract 4543
  101. Thomas DA, Estey E, Giles FJ, et al. Single agent thalidomide in patients with relapsed or refractory acute myeloid leukemia. Br J Haematol. 2003;123:436–441
  102. Cortes J, Kantarjian H, Albitar M, et al. A randomized trial of liposomal daunorubicin and cytarabine versus liposomal daunorubicin and topotecan with or without thalidomide as initial therapy for patients with poor prognosis acute myelogenous leukemia or myelodysplastic syndrome. Cancer. 2003;97:1234–1241
  103. Faderl S, Gandhi V, O'Brien S, et al. Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-c) in relapsed and refractory acute leukemias. Blood. 2005;105:940–947
  104. Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003;102:2379–2386
  105. Faderl S, Verstovsek S, Cortes J, et al. Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia in patients 50 years of age or older. Blood. 2006;108:45–51

PII: S0301-472X(09)00130-1

doi:10.1016/j.exphem.2009.04.002

Experimental Hematology
Volume 37, Issue 6 , Pages 649-658, June 2009

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