AML is a clonal proliferation of hematopoietic stem cells characterized by blocked or severely impaired differentiation of the hematopoietic stem cell, resulting in an accumulation of cells at various stages of incomplete maturation with an associated reduced production of normal hematopoietic elements. As a consequence, various levels of cytopenia usually occur and the clinical manifestations include symptoms of anemia (such as fatigue and dyspnea), neutropenia (infections) and thrombocytopenia (hemorrhage), which are usually present at the time of diagnosis and dominate the clinical picture as treatment is administered. The mechanisms by which the expanding leukemic clone suppresses the growth and differentiation of normal polyclonal residual hematopoiesis are poorly understood, but it appears that this suppression is at least partially protective against the cytotoxic effects of chemotherapy in that regeneration of normal blood counts occurs reliably when the leukemia clone is reduced. In absence of treatment, AML leads to death in a variable period of time, ranging from a few days to some months. AML can arise as a “de novo” disease, or after a previously diagnosed blood disorder, in most cases a myelodysplastic syndrome (MDS) or, less frequently, a myeloproliferative disorder (MPD), such as idiopathic myelofibrosis, policythemia vera and essential thrombocythemia (Ferrara F, Schiffer CA, 2013PubMed).

 

Epidemiology

AML is the most common type of leukemia in adults and accounts for 3% of all cancers and 25% of all leukemias. Worldwide, the incidence of AML is highest in the U.S., Australia, and Western Europe (Siegel R et al, 2012PubMed). The age-adjusted incidence rate of AML in the U.S. is approximately 3.4 per 100,000 persons (2.5 per 100,000 persons when age-adjusted to the world standard population). AML occurs in people of all ages with a major increase in people greater than 65 years of age (Figure I). Patients newly diagnosed with AML have a median age of 65 years and the disease is rarely diagnosed before the age of 40; thereafter, the incidence increases progressively with age (Thein MS et al, 2013PubMed).

 

Ferrara_ACUTE MYELOID LEUKEMIA_Figure_1

Figure I. Increase of AML incidence with age

 

 

Etiology and pathogenesis

The development of AML has been related to a number of risk factors (Table I), in particular exposure to ionizing radiation and chemical agents which damage DNA; however, a clear history of contact with known carcinogens is unusual in AML patients (Deschler B, Lubbert M, 2006PubMed).

 

Ferrara_ACUTE MYELOID LEUKEMIA_Table_

Table I. Main Risk Factors Associated With Acute Myeloid Leukemia

 

Conversely, two general patterns of leukemia development have been described following exposure to chemotherapy. Patients exposed to agents which affect topoisomerase II, such as the anthracyclines and epidophyllotoxins, can develop a usually rapidly proliferative AML often with a monocytic histology and cytogenetic abnormalities at the MLL gene locus at chromosome 11q23, within months to 1-2 years following treatment with these agents (Deschler B, Lubbert M, 2006PubMed). Perhaps more common is the so-called “alkylator agent” induced type of AML occurring at a peak of 5-6 years after exposure and characterized by a myelodysplastic prodrome with complex karyotypes and deletions of all or part of chromosomes 5 and 7 (Godley LA, Larson RA, 2008PubMed). Of note is that these same changes and the same clinical course occur much more often in older patients, probably implicating as yet unquantifiable, repeated exposure to environmental carcinogens as contributors to AML in older individuals. Among children, genetic disorders and constitutional genetic defects are important risk factors associated with AML (Table I). Children with Down syndrome have a 10 to 20-fold increased likelihood of developing acute leukemia. Other inherited diseases associated with AML include Klinefelter syndrome, Li- Fraumeni syndrome, Fanconi anemia, and neurofibromatosis (Deschler B, Lubbert M, 2006PubMed).

The mechanisms by which distinctive types of AML and other cancers develop are poorly understood and the contribution of inherited polymorphisms in the ability to metabolize different toxins and to repair DNA damage are under investigation (D’andrea AD, 2010PubMed). Using a variety of in vitro and preclinical models, it has been shown that a multistep series of mutations are needed to produce AML (Figure II), with evidence suggesting that at a minimum, activating mutations in class I genes that activate signal transduction pathways and induce cellular proliferation in cooperation with mutations in class II genes that affect transcription factors and compromise normal differentiation are necessary for leukemogenesis (Link DC, 2012PubMed; Marcucci G et al, 2011PubMed).

 

Ferrara_ACUTE MYELOID LEUKEMIA_Figure_2

Figure II. Model of leukemogenesis with two cooperating classes of mutations

 

Mutations leading to activation of the receptor tyrosine kinase FLT3, c-kit (KIT) and Ras signalling pathway belong to class I mutations, while RUNX1/ETO, CBFβ/MYH11 and PML/RARα, which are fusion transcripts generated by well known recurring chromosomal abnormalities such as t(8; 21), inv(16) and t(15; 17), respectively, represent examples of class II mutations (Gilliland DG et al, 2004PubMed). Mutations of the transcription factors RUNX1, C/EBPα and MLL also fall into this group. A third class of genes encoding epigenetic modifiers, including DNMT3A, IDH1, IDH2, TET2, ASXL1, and EZH2, also appear to play a major role in AML pathogenesis although the mechanisms by which these aberrations contribute to the leukemia phenotype are poorly understood. Of note, most of these abnormalities are associated with a worse patient outcome and are more frequent in older patients (Shen Y et al, 2011PubMed). While many mutations that contribute to the pathogenesis of AML are undefined and the relationships between patterns of mutations and epigenetic phenotypes are not yet clear, it has been recently demonstrated that at least one potential driver mutation exists in nearly all AML samples and that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories (Cancer Genome Atlas Research Network, 2013PubMed).

It has long been appreciated that AML is clinically and biologically a very heterogeneous disease with distinct clinical presentations found in different morphologic and cytogenetic subtypes. Recent molecular analyses have expanded our understanding of this heterogeneity and have the potential to point to new directions for therapy. Interestingly, although most leukemic blasts from a patient have a similar morphologic appearance, only the ~ 0.5% of these cells with an immature CD34+, CD38- immunophenotype are clonogenic with the potential for repetitive colony formation in vitro and the ability to establish leukemia when transplanted into immunodeficient mice. These cells share many features with hematopoietic stem cells, including the presence of enhanced mechanisms of resistance to a variety of cytotoxic therapies (Hoang VT et al, 2012PubMed; Pandolfi A et al, 2013PubMed). More recently, on the basis of sophisticated molecular characterization, it has been demonstrated that multiple subclones with different patterns of molecular abnormalities are present at diagnosis with the eventual expansion of different subclones under the selective pressure of serial chemotherapy treatments (Walter MJ et al, 2012PubMed; Ding L et al, 2012PubMed). The heterogeneity of leukemia cells within a single patient has implications for the use and development of therapies that specifically “target” the products of these gene mutations. In addition, this heterogeneity in what some term leukemia “stem cells”, may also complicate attacking these progenitors with specific antibodies or pharmacologic agents.

 

Diagnosis and classification of AML

Light microscopy still remains the first method for the diagnosis of AML and its further sub-classification. Examination of blood and bone marrow specimens stained with Wright-Giemsa or May-Grunwald-Giemsa provides a rapid initial and frequently conclusive diagnosis. By assessing morphologic features, a majority of cases of AML and acute lymphoblastic leukemia (ALL) can be accurately diagnosed. In some cases of poorly differentiated acute leukemia, however, the morphologic features may be equivocal, requiring additional studies. Cytochemical stains can be useful in distinguishing poorly differentiated AML from ALL and in identifying subsets of AML. The myeloperoxidase and Sudan black B stains are the most commonly used and the most valuable in distinguishing AML from ALL. In the majority of cases of AML, a variable proportion of the leukemic cells (blasts) are reactive for myeloperoxidase and Sudan black B, whereas the stains are uniformly negative in ALL. With the addition of cytochemistry to the morphologic assessment, most cases of acute leukemia can be appropriately designated as either AML or ALL. However, there remains a significant minority of cases that cannot be definitively diagnosed by these methods. In the older French-American-British (FAB) criteria, the classification of AML was solely based upon morphology as determined by the degree of differentiation along different cell lines and the extent of cell maturation (Bennett JM et al, 1985bPubMed). More recently, the World Health Organization (WHO) classification of AML (Table II) incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers in an attempt to construct a classification that is universally applicable and prognostically valid (Vardiman JW et al, 2009PubMed). Under the WHO classification, the category “acute myeloid leukemia not otherwise categorized” is morphology-based and reflects the FAB classification with a few significant modifications. The most significant difference between the WHO and FAB classifications is the WHO recommendation that the requisite blast percentage for the diagnosis of AML be at least 20% blasts in the blood or bone marrow. The FAB scheme required the blast percentage in the blood or bone marrow to be at least 30%. This threshold value for blast percentage eliminated the category “refractory anemia with excess blasts in transformation” (RAEB-t) found in the FAB classification of MDS, where RAEB-t is defined by a marrow blast percentage between 20% and 29%. In the WHO classification, RAEB-t is no longer considered a distinct clinical entity and is instead included within the broader category “AML with multilineage dysplasia” as “AML with multilineage dysplasia following a myelodysplastic syndrome”. Although this lowering of the blast threshold has been met with some criticism, several studies indicate that survival patterns for cases with 20% to 29% blasts are similar to survival patterns for cases with 30% or more blasts in the bone marrow. Nonetheless, the diagnosis of AML in itself does not represent a therapeutic mandate in that, in addition to the blast percentage, the decision to treat should be based on a variety of factors including patient age, previous history of MDS, clinical findings, disease progression, and most importantly, patient preference.

 

Ferrara_ACUTE MYELOID LEUKEMIA_Table_2

Table II. WHO classification of AML

 

The lineage of most cases of morphologically and cytochemically poorly differentiated acute leukemia can be accurately characterized by immunophenotyping. Multiparametric flow cytometry is the preferred method for immunophenotyping acute leukemias (Kern W et al, 2010PubMed). There is an abundance of monoclonal and polyclonal antibodies available to assess myeloid and lymphoid lineage-associated antigens by cytometry, and blood and bone marrow aspirate specimens lend themselves particularly well to flow cytometric analysis because the cells are naturally in a fluid suspension. Multicolor flow cytometry allows for the characterization of different antigens on a single cell, resulting in precise immunophenotypic characterization of leukemic cells even when they are present in low numbers. Immunohistochemical staining can be used to immunophenotype leukemias when a specimen is not submitted for flow cytometry or only bone marrow trephine biopsies are available for examination. An array of antibodies to myeloid- and lymphoid-associated antigens is also available for immunohistochemical stains. The antigenic diagnostic pattern can be variably wide, however investigation of at least CD19, CD7, CD13, CD33, CD14, CD117, CD15 and CD34 should be considered. Of note, immunophenotyping should be never used in substitution of morphological examination; in addition, the count of CD34+ cells should not replace the morphological evaluation of blast count, in that about 25% of all AML cases are CD34-. On the contrary, immunophenotypic analysis can be extremely useful for the investigation of minimal residual disease, in that an abnormal immunophenotypic pattern occurs in about 90 percent of AML cases (Paietta E, 2012Pubmed).

Cytogenetic analysis of metaphase cells is a key component to the evaluation of all patients with newly diagnosed or suspected AML, in that the malignant cells in 55-60% of subjects with AML have non-random, acquired clonal chromosomal abnormalities (Morrissette JJ, Bagg A, 2011PubMed). In some cases (Table III), specific cytogenetic abnormalities are closely, and sometimes uniquely, associated with morphologically and clinically distinct subsets of the disease. In addition to establishing the type of AML according to the WHO classification, specific cytogenetic abnormalities have diagnostic, prognostic, and therapeutic importance (Fang M et al, 2011PubMed; Byrd JC et al, 2002PubMed; Grimwade D et al, 2010bPubMed; Slovak ML et al, 2000PubMed).  Approximately 40% of AML patients present with normal karyotype (NK-AML) with no identifiable cytogenetic abnormality by using modern cytogenetic and fluorescence in-situ hybridization (FISH) methods; these patients have been classified as an intermediate risk group with overall survival rates between 24% to 42% (Mawad R, Estey EH, 2012PubMed). Recently, several retrospective studies demonstrated that some molecular markers could identify good and poor risk NK-AML patients and suggested that these patients should be treated accordingly (Martelli MP et al, 2013PubMed). Furthermore, some of the molecular abnormalities have also been found to be useful for minimum residual disease monitoring and as potential therapeutic targets (Garcés-Eisele J, 2012PubMed). In daily practice, at least mutations of NPM1, FLT3, and CEPBα should be investigated. Finally we recommend the storage of samples of bone marrow and peripheral blood from any patient with AML, in order to collect biological material, potentially useful for future studies. An integrated approach to diagnosis of AML is shown in figure III.

 

Ferrara_ACUTE MYELOID LEUKEMIA_Table_3

Table III. Cytogenetic Findings in AML

 

Ferrara_ACUTE MYELOID LEUKEMIA_Figure_3

Figure III. Integrated diagnosis of AML. Morphology, immunophenotyping, cytogenetics and selected molecular markers (NPM1 and FLT3) are mandatory.

 

 

Clinical presentation

Early signs and symptoms of AML may mimic those of the flu or other common diseases. Within a few days, symptoms caused by replacement of normal bone marrow with leukemic cells, which causes a drop in erythrocytes, platelets, and normal leukocytes, become predominant. Generally, patients present with fatigue, shortness of breath, easy bruising and bleeding, and fever in absence, in the majority of cases, of documented infections. Less frequently, bone pain, swollen lymph nodes, swollen gums, chest pain and abdominal discomfort due to a swollen spleen or liver can be present. Occasionally, AML is diagnosed following blood examination performed in the suspect of other diseases or routinely. Hyperleukocytosis (WBC > 100 x 109/l) is infrequent (10% of all cases) and can be associated with clinical signs of leukostasis and/or the presence of tumor lysis syndrome (TLS). Clinical symptoms of leukostasis include neurological symptoms (headache, seizures, blurred vision, coma, CNS hemorrhage), papilloedema, thrombosis, pulmonary leukostasis (dyspnea, cyanosis, hypoxia acidosis, pulmonary hemorrhage) and severe gastro-intestinal tract bleeding. TLS is a life-threatening complication during induction chemotherapy in patients with AML and is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia and acute renal failure. These abnormalities may occur spontaneously before the initiation of chemotherapy due to increased catabolism and the turnover of leukemic cells, but more frequently TLS is induced or exacerbated by intensive induction chemotherapy (Montesinos P et al, 2008Pubmed). Rarely, AML can occur as extramedullary tissue mass (Figure IV), defined as granulocytic sarcoma (GS). The more frequent sites of involvement are the skin, lymph nodes, gastrointestinal tract, bone, soft tissue, and testis (Klco JM et al, 2011PubMed). Occasionally, multiple anatomic sites are involved (< 10% of cases). The tumor mass is composed of granulocytic precursors with varying degrees of differentiation. In some cases, there is a predominance of myeloblasts; in other cases, there is a spectrum of granulocytic differentiation. Myeloid sarcoma may occur de novo, may precede or coincide with AML, or may represent a blastic transformation of a preceding MDS or MPD (Ohanian M, et al, 2013PubMed).

 

Ferrara_ACUTE MYELOID LEUKEMIA_Figure_4

Figure IV. Granulocytic sarcoma of the skin, breast and central nervous system

 

 

Prognostic Factors

 

Age

Age still represents the most relevant adverse prognostic factor in AML, in that the prognosis of the disease steadily worsens with increasing age. While chemoresistance of the disease itself is part of the explanation, with a high frequency of adverse biology occurring at older age, therapeutic results in older patients are poorer in any cytogenetic and molecular subgroup, due to the reduced capacity of aged individuals to withstand the side effects of chemotherapy and stem cell transplantation procedures (Ferrara F et al, 2008PubMed; Klepin HD et al, 2013PubMed; Ferrara F et al, 2013PubMed). The presence of medical co-morbidities, often summed up as “performance status”, can also preclude the feasibility of less intensive chemotherapy (34). Age is a continuous variable and the age limit to define “old” an AML patient is arbitrary; however, most clinical trials set an eligibility cut-off at 60-65 years. Recently, a number of co-morbidity indices have been developed that have the potential to more reliably quantify the presence and impact of other medical and psycho-social factors, helping to guide treatment decisions and comparisons across clinical trials purporting to focus on “higher risk”, older patients (Walter RB et al, 2011PubMed; Krug U et al, 2010Pubmed).

 

Drug Resistance

With the decrease in treatment related mortality, drug resistance remains the major cause of treatment failure. A host of resistance mechanisms have been investigated, with a focus on clinical and laboratory studies of cytarabine (ARA-C) metabolism and the ABC cell surface membrane drug efflux pumps. Over-expression of p-glycoprotein (Pgp) produces resistance to anthracyclines by rapidly pumping these drugs out of the cell before their cytotoxic effects occur, and is associated with poorer outcome due to drug resistance, particularly in older patients (Leith CP et al, 1997PubMed). A number of clinical studies were completed using inhibitors of Pgp administered with chemotherapy (38,39). Unfortunately, randomized trials did not show a benefit, with some demonstrating increased toxicity in patients receiving inhibitors such as cyclosporine, zosuquidar trihydrochloride (40) and valspodar (41), in part because the inhibitors also affect the disposition of anthracyclines and epidophyllotoxins, resulting in slower metabolism and increased drug exposure (42). These drug resistance mechanisms are also exaggerated in leukemia stem cells, presumably mimicking the over-expression in normal stem cells, which teleologically is designed to protect against the “normal” background of environmental toxins to which these cells are exposed.

 

Cytogenetics and Molecular Genetics

Many intrinsic “biologic” characteristics of the leukemia cells themselves can predict sensitivity to chemotherapy. The important influence of cytogenetic findings on both the initial response and long term cure rate was identified in the 1980’s and reconfirmed by large cooperative groups more recently (Grimwade D, Mrózek K, 2011PubMed; Fang M et al, 2011PubMed; Byrd JC et al, 2002PubMed; Grimwade D et al, 2010bPubMed; Slovak ML et al, 2000PubMed). For example, patients with core binding factor AML (t(8;21) and abn16q22) have cure rates of 60+ % using high dose ARA-C based chemotherapy alone, such that allogeneic transplantation is generally not recommended in first CR (43,44), while other balanced translocations such as t(6;9), abnormalities involving chromosome 3q26 and complex karyotypes, have dismal outcomes following chemotherapy (Slovak ML et al, 2006PubMed; Lugthart S et al, 2008PubMed ). Of note, major alterations in chromosome number, recently termed “monosomal karyotype”, are another distinctly unfavorable marker even in patients who receive allogeneic transplantation (Fang M et al, 2011PubMed). Notably, despite knowing about these findings for more than three decades, the mechanism(s) by which they produce drug resistance or sensitivity remain poorly, if at all, understood. Many cooperative groups have suggested risk classifications according to karyotype, with a recent iteration provided by the European Leukemia Net (Dohner H et al, 2010PubMed).

There is however, considerable variability in outcome within well-defined cytogenetic groups, raising the question of whether additional abnormalities predictive of outcome could be identified. The remarkable advancements in molecular genetics initially focused on the characterization of the heterogeneous group of patients with normal karyotypes (NK), who actually constitute the majority of patients with AML. In brief, large numbers of mutations present alone or in combination, have been identified by a variety of molecular biologic techniques in patients with NK and mutations in the nucleophosmin-1 (NPM1)37, and fms tyrosine kinase (FLT3) genes are now routinely tested for because treatment recommendations are often based on these results (Falini B et al, 2005PubMed; Gale RE et al, 2008PubMed; Schnittger S et al, 2002PubMed; Thiede C et al, 2002PubMed; Whitman SP et al, 2001PubMed).

Patients with NPM1 mutations have an improved outcome using chemotherapy alone while mutations in FLT3, which lead to autonomous receptor activation, dysregulation of FLT3 signal transduction pathways and stimulate cell proliferation, confer an inferior prognosis, with a more marked “negative” effect if the mutations are homozygous. When occurring in combination (e.g. NPM1 and FLT3 mutated), the “bad” trumps the “better” and the outcome is poorer than when NPM1 is mutated and FLT3 is germline (Dohner K et al, 2005PubMed; Burnett AK et al, 2010bPubMed). Based on these findings, most clinicians do not recommend allogeneic transplantation in first CR for NPM1 mutated/ FLT3 germline patients while considering transplantation for those with FLT3 ITD mutations (Schlenk RF et al, 2008PubMed.

A large number of other mutations have also been identified and are listed in table IV. The prognostic impact of many of these findings is still uncertain with sometimes discrepant results reported by different groups. Further analyses and pooling of data are needed to clarify these issues. Of interest is that, while some mutations can be detected as partners with two or three other mutations, thereby increasing the molecular heterogeneity, others appear to be mutually exclusive, suggesting that in some patients these may be critical “drivers” that may be targets for therapy (Patel JP et al, 2012PubMed; Ley TJ et al, 2008PubMed). It is likely that other mutations or abnormal, recurrent patterns of gene expression will be detected with whole genome sequencing of leukemia cells, and in particular, studies of the less differentiated “stem cell” subpopulation (Roboz GJ, Guzman M, 2009PubMed). The challenge, as was originally presented by the discovery of recurrent chromosomal abnormalities, will be to elucidate the mechanisms by which these changes affect the response to treatment and to accordingly develop more rational, perhaps individualized, therapies. Easier said than done, however, even without consideration of changes in patterns of microRNA expression (Marcucci G et al, 2011bPubMed) and epigenetic modification of gene expression, which also contribute to the AML phenotype (Oki Y, Issa JP, 2010PubMed; Melnick AM, 2010PubMed ; Hackanson B et al, 2008PubMed).

 

Ferrara_ACUTE MYELOID LEUKEMIA_Table_4

Table IV. Molecular Markers in AML

 

At this time, FLT3 is the only mutation that can be address pharmacologically and a number of inhibitors are being evaluated clinically. Inhibitors such as midostaurin (PKC412) and lestaurtinib (CEP701) can be combined with chemotherapy, and trials in new diagnosed patients evaluating standard chemotherapy with or without these inhibitors are in progress (Knapper S, 2011PubMed). One randomized trial using lestaurtinib in patients in first relapse failed to show a benefit, perhaps because the target was not completely inhibited due to pharmacokinetic problems (Levis M et al, 2011PubMed). Other FLT3 inhibitors are currently under investigation (Kindler T et al, 2010PubMed).

 

Early blast clearance

An important factor of potential utility into clinical practice is the early assessment of marrow blasts after administration of induction chemotherapy. A threshold value of 10% at day 14-15 from the beginning of chemotherapy has major prognostic impact (Kern W et al, 2003PubMed). The degree to which the blasts are cleared from the marrow in response to the first course of chemotherapy represents a clear indication for chemosensitivity or chemoresistance and patients who fail to adequately clear their blast count will do badly even if CR is subsequently achieved (Arellano M et al, 2012PubMed). Data deriving from morphologic analysis and based on the reported blast percentage in the bone marrow from individual investigators has been recently confirmed by cytometric quantification of early blast count (Gianfaldoni G et al, 2006PubMed). In addition, there is a clear relationship between the morphological blast status after course 1 and the cytogenetic and/or molecular risk group (Schneider F et al, 2009Pubmed). The combination of cytogenetics and day 15-16 morphologic and/or cytometric evaluation of bone marrow may be particularly useful in patients with prognostically intermediate karyotypes in whom prognostication is currently difficult to achieve, especially when and where subtle molecular evaluation of FLT3 and NPM1 are not routinely available.

 

Treatment of AML

There have been major advances in supportive care of AML including widespread availability of high quality platelet transfusions, improved and less toxic broad spectrum antibiotics and anti-viral agents, virtual elimination of post-transfusion hepatitis, as well as newer anti-fungal agents which have largely replaced amphotericin B such that patients no longer experience the sometimes debilitating fevers and renal dysfunction that accompanied treatment with that drug. Perhaps less appreciated are the salutary effects of improved anti-emetics, so that patients no longer develop erosive esophagitis and inanition from poor nutrition. The thirty-day mortality of older patients entered on clinical trials with intensive chemotherapy is now < 10%, largely related to improved supportive care, although it must be acknowledged that patients entered on clinical trials are a highly selected population. A practical approach to the management of AML is summarized in figure V.

 

Ferrara_ACUTE MYELOID LEUKEMIA_Figure_5

Figure V. Practical approach to the management of AML

 

 

Induction and consolidation therapy

The conventional treatment of AML consists of two phases: induction and consolidation, which includes stem cell transplantation. Induction therapy aims to achieve complete remission (CR), consolidation to eliminate residual leukemia cells that persist after induction. CR is defined as bone marrow blasts less than 5% in a normocellular bone marrow, absence of extramedullary leukemia, neutrophil count > 1,000/uL and platelet count more than 100,000/uL (Cheson BD et al, 2003PubMed). In addition, the patient should be transfusion independent. These criteria of morphological CR still represent the current standard definition of response to induction therapy in routine practice. However, more sensitive technologies using flow cytometry and polymerase chain reaction can quantify much lower amounts of leukemic burden beyond the sensitivity of the light microscope and definitions of CR will continue to evolve and if shown to correlate with clinical outcome, will most likely be used in the context of clinical trials in the future (Buccisano F et al, 2012PubMed; Rubnitz JE et al, 2010bPubMed).

After induction, occasional patients can achieve reduction of marrow blasts to < 5%, but their neutrophil and/or platelet count may not reach 1,000/uL and 100,000/uL, respectively. In these cases, response is defined as CRi (CR with incomplete hematologic recovery) and the outcome is generally poorer than in patients achieving CR (Walter RB et al, 2010PubMed). More than 30 years since its introduction (Yates JW et al, 1973PubMed) the combination of an anthracycline, usually daunorubicin, given for 3 days, with continuous infusion of ARA-C for 7 days (3+7) still represents the standard for induction therapy for AML and results in a CR rate of ~70% in patients aged less than 60 years. A number of trials have been conducted to improve the rate and quality of CR including the use of anthracyclines other than daunorubicin (idarubicin and mitoxantrone), the addition of a third drug (most often etoposide), adoption of high-dose instead of conventional dose ARA-C, the use of hematopoietic growth factors such as G-CSF and GM-CSF and the combination of anthracyclines with fludarabine or cladribine and intermediate dose ARA-C (Yates JW et al, 1973PubMed; Arlin Z et al, 1990PubMed; Berman E et al, 1991PubMed; Wiernik PH et al, 1992PubMed; Bishop JF et al, 1996PubMed; Lyman GH et al, 2010PubMed; Estey EH et al, 2001PubMed; Appelbaum FR, 2012PubMed). Overall, results have been disappointing, in that they have failed to show important and consistent improvements in outcome, although a recent trial from the Polish Adult Leukemia Group showed somewhat higher CR rates and possibly improved overall survival with the addition of cladrabine to daunorubicin (60 mg/ m2) and ARA-C in adults < 60 years of age; there was no benefit from adding fludarabine to 3 +7 (Holowiecki J et al, 2012PubMed). The greatest difference was seen in patients above 50 years and in those with unfavorable karyotypes and it is important to see if these findings can be reproduced, perhaps in older patients. It is conceivable, although largely unproved, that the benefit of these manipulations could be limited to genetically distinct AML subgroups, which could not be evaluated in the older clinical trials. As an example, a recent trial from the United Kingdom MRC AML group demonstrated that the addition to chemotherapy of gemtuzumab-ozogamycin (GO), an anti-CD33 monoclonal antibody conjugated with calicheamicin (a cytotoxic antineoplastic antibiotic), produces major clinical benefit in patients with CBF-AML, with a possible advantage for those with intermediate cytogenetics (Burnett AK et al, 2011bPubMed). More recently, two further studies in older patients with AML demonstrated a survival advantage for GO in subjects with intermediate but not adverse karyotypes (Castaigne S et al, 2012PubMed; Burnett AK et al, 2012bPubMed). A major challenge in stratifying patients by their biologic characteristics when evaluating new agents in induction is that the diagnosis of AML is generally considered to be a medical emergency requiring immediate treatment. However, apart from patients presenting with hyperleukocytosis, in whom leukapheresis and/or hydroxyurea could be considered, many groups have shown that it is feasible to select specific induction treatment for patients according to molecular subtyping, which may become the standard for clinical trials in the future. More contemporary trials have also addressed the optimal dose of daunorubicin in induction. A recent trial from the U.S. in younger patients, suggested an advantage of 90 mg/m2 compared to 45mg/m2, particularly in the heterogeneous group with intermediate risk cytogenetics (Fernandez HF et al, 2009PubMed). The study has been criticized because the control arm had an unusually low CR rate (54%), but, because the toxicity was similar in the two arms, many institutions have adopted the 90 mg/m2 dose, although others feel that outside of a clinical trial, a daunorubicin dose of 60 mg/m2 for three days would be reasonable. A trial of similar design has shown that 90 mg/m2 is also well tolerated and perhaps slightly more effective in older patients as well (Lowenberg B et al, 2009PubMed). These studies somewhat complicate the interpretation of older trials that utilized the older “standard” of 45 mg/m2 as the comparator in the control arm.

Lastly, some groups utilize so-called “double induction”, which administers a second course of induction therapy on day 14 of therapy, irrespective of marrow status (Buchner T et al, 2006PubMed; Ferrara F et al 2010PubMed). This approach relies on the judgment of the attending physician as to the eligibility of patients for the second induction, in that virtually all patients are severely pancytopenic and fever or infections can be present. However, it has been shown that ~ 80% of younger patients can tolerate this and a reasonable study might be to evaluate double induction specifically in patients with significant amounts of persistent leukemia (more than 10% BM blast) after morphologic and/or flow cytometric bone marrow examination.

Following achievement of CR, all patients will ultimately relapse without further therapy (Rowe JM, 2010PubMed). Accordingly, the administration of consolidation therapy is mandatory, provided that patients have adequate organ function, with the ultimate goal being cure of the AML. In 1994, the CALGB cooperative group randomized 596 patients to receive four cycles of high-dose cytarabine (HDARA–C 3 g/m2 every 12 hours over 3 days) or four courses of intermediate-dose (400 mg/m2) or standard-dose (100 mg/m2) cytarabine (Mayer RJ et al, 1994PubMed). A survival advantage was demonstrated for patients up to the age of sixty years who received HD ARA-C with long term relapse free survival of ~ 45%. Subsequent analysis showed that the greatest clinical benefit was seen in patients with favorable cytogenetics, without significant improvement in patients with high-risk cytogenetic subtypes  (Bloomfield CD et al, 1998PubMed). Similar OS rates are reported from multiple cooperative groups using a variety of HD ARA-C based regimens, sometimes with the addition of other drugs (Moore JO et al, 2005PubMed). The optimal dosage and number of cycles have not been definitively established, although recent data demonstrate that three cycles using lower doses of ARA-C at 1.5 g/ m2 reduce toxicity without worsening treatment outcome, suggesting that is reasonable for routine practice (94,95).

Clinical trials and registry data have provided convincing evidence of much lower relapse rates after allogeneic stem-cell transplantation (allo-SCT) than with either autologous SCT (ASCT) or chemotherapy, because of the graft-versus-leukemia effect. However, allo-SCT has a treatment-related mortality of 10–25% because of graft vs. host disease and substantial adverse effects on quality of life, such that randomized trials have not shown a survival benefit from allo-SCT in the overall population of AML patients (Cassileth PA et al, 1998PubMed; Zittoun RA et al, 1995PubMed; Burnett AK et al, 2002PubMed). However, most of these trials were based on matched sibling donor vs. no donor analysis, a methodology that is not free of problems, particularly given the increasing use of transplants using matched unrelated donors, partially mismatched donors and umbilical cord blood. In addition, both morbidity and mortality following allo-SCT are declining in any allogeneic setting (Gooley TA et al, 2010PubMed).

Currently, clinical research is focusing on identification of subgroups of patients who do poorly with chemotherapy alone and might benefit maximally from allo-SCT, using matched sibling or alternative donors. Currently, it is appropriate to consider allo-SCT in patients with intermediate karyotype, with the exception of those with NPM1 mutation in the absence of FLT3 mutation, those with FLT3 ITD mutations and all those with unfavorable cytogenetics (Burnett AK, Hills RK, 2011PubMed). On the contrary, subjects with CBF AML should receive HDARA-C, apart from those harboring c-KIT mutations, who could be considered for SCT, although there is some controversy about whether the additional KIT mutation has a negative impact, at least in children and younger adults (Paschka P et al, 2006PubMed; Pollard JA et al, 2010PubMed). There is however no data from randomized or prospective trials supporting these recommendations and it should be noted that the relapse rate post allo-SCT is approximately twice as high in FLT3 mutated patients compared to FLT3 negative patients (Brunet S et al, 2012PubMed) and is also higher in patients with adverse karyotypes and those transplanted with minimal residual disease (Middeke JM et al, 2012PubMed; Walter RB et al, 2011bPubMed).

Over the past 20 years, a number of reduced intensity conditioning regimens (RIC) have been developed, aimed at induction of GVL, while limiting non haematological toxicity. Overall, RIC has expanded the number of patients eligible to undergo allo-SCT including those previously excluded because of age or comorbidities. Encouraging results have been reported in terms of reduction of mortality, although some data suggest a higher relapse rate compared to standard conditioning regimens ((Shimoni A, Nagler A, 2011PubMed; Hamadani M et al, 2011PubMed). No definite criteria are available for the selection of patients to assign to RIC although older patient age and the presence of toxicities accumulated during induction and/or consolidation therapy are considerations.

The role of high dose therapy with ASCT support is less clear and the procedure is more popular in Europe than in the U.S. Randomized trials have shown similar outcomes using ASCT compared to repeated courses of HD-ARA-C, perhaps because of the presence of minimal residual disease contaminating the graft. Trials in patients without MRD would be of interest, and ASCT represents an arena for the investigation of new conditioning regimens as well as for experimental post-transplant maintenance treatment. Finally, there are now attempts reported to find subgroups of patients that might profit from an autologous approach more than others, potentially leading to a more individualized approach to consolidation treatment (Ferrara F, 2012bPubMed).
Attualmente, la percentuale di RC nei giovani adulti è del 75-80%, con percentuali di guarigione pari al 40-45% (Ferrara F, Schiffer CA, 2013PubMed).
Currently, the CR rate for young adult patients is 75-80% and the cure rate 40-45% (1). Most relevant issues in the treatment of AML are summarized in table V.

 

Ferrara_ACUTE MYELOID LEUKEMIA_Table_5

Table V. Relevant issues in the treatment of AML in young adults

 

 

AML in older patients

More than half of patients with AML are 65 years of age and older with about one-third > 75 years. In the great majority of cases, AML in older patients has a dismal prognosis; conventional induction therapy results in CR rates in the range of 45–55%, and fewer than 10% of intensively treated patients survive for 5 years; there have been no improvements in these results for decades (Burnett AK, 2013PubMed). Of note, these results derive from multicenter trials based on aggressive treatment aimed at CR achievement and do not take into account the considerable proportion of elderly AML patients who are only given best supportive care (BSC) with periodic treatment with hydroxyurea (HU) to control the peripheral white blood count (Ferrara F, 2011PubMed). The poor outcome is related to concomitant comorbidities, which render chemotherapy and transplantation more toxic or impossible to administer, as well as the higher incidence of adverse biologic features such as unfavorable cytogenetics and/or AML arising after a previously diagnosed (or sometimes unrecognized) blood disorder, particularly myelodysplasia.

As a consequence, a common dilemma in daily practice is the identification of older patients who can tolerate aggressive therapy and potentially derive benefit should CR be achieved. Predictive scores, based on clinical and biologic factors are being developed which could help physicians inform patients about the risks and benefits of treatment options (Ferrara F et al, 2013PubMed; Walter RB et al, 2011PubMed; Krug U et al, 2010Pubmed). Nonetheless, such discussions remain extremely difficult, sometimes because patients’ and relatives’ expectations are overly optimistic, but also because many are inappropriately nihilistic after learning of the need for hospitalization and the side effects of treatment. Current therapeutic options for AML in older individual are summarized in table VI.

 

Ferrara_ACUTE MYELOID LEUKEMIA_Table_6

Table VI. Therapeutic options for older patients with AML

 

In general, the current approach is to offer induction with “7 + 3” or its variants to most older patients whom we deem to be medically suitable, acknowledging that some chromosomal abnormalities (complex and monosomal karyotypes) are associated with CR rates lower than 30%. In general, CR rates are lower than in younger adults and usually do not exceed 50-55%, but patients who achieve CR derive clinical benefit in terms of the potential for many months of normal or “safe” blood counts with a return to their baseline performance status. A recent large study in AML patients > 60 years of age demonstrated better outcomes using an escalated daunorubicin dose of 90 mg/m2 with major improvement noted in patients aged 60-65 years as well as in the very small number of older patients with CBF-AML (Lowenberg B et al, 2009PubMed). More recently, two randomized trials evaluated the addition of GO in older patients. A French study added fractionated doses of GO (3 mg/m2/d on day 1, 4, and 7) to standard chemotherapy and noted significantly improved event free survival and to a lesser degree overall survival in patients aged 50-70 years (Castaigne S et al, 2012PubMed).  The UK AML 16 study administered GO 3mg/m2 on day one of induction chemotherapy and showed that the addition of GO produced a small but statistically significant overall survival benefit without unacceptable increases in toxicity (Burnett AK et al, 2012bPubMed). Of note, in both studies there was no benefit of GO in patients with unfavorable cytogenetics. GO is no longer available, but should it be “resurrected”, further studies of dose and schedule as well as its effects in different patient subgroups would be relevant.

The role of consolidation in older patients is less clear and CALGB trials showed that with the possible exception of the small fraction of older patients with CBF AML, high dose ARA-C did not increase overall survival and was more toxic than lower doses of ARA-C  (Mayer RJ et al, 1994PubMed; Stone RM et al, 2001PubMed). While a standard consolidation regimen for elderly patients with AML has not been established, one to two cycles of intermediate-dose ARA-C or other combination chemotherapy may be considered. Of interest, a randomized phase 3 study conducted by the ALFA French group testing the benefit of a high dose chemotherapy consolidation course versus small dose ambulatory chemotherapy courses, suggested that multiple lower intensity cycles may be equivalent, or even superior, to fewer intensive cycles (Gardin C et al, 2007PubMed).

Reduced-intensity conditioning (RIC) regimens allow a proportion of older patients to undergo allogeneic stem cell transplantation (allo-SCT) and some studies have shown outcomes and complication rates comparable to myeloablative SCT in younger patients. However, because it is likely that only the “best “ older patients were considered for RIC-HSCT, these results may not be applicable to the vast majority of older patients in CR1. To address this issue prospectively, two studies explored the feasibility of allo-SCT in large consecutive cohorts of older patients with AML. In both studies, allo-SCT was actually given to only 5% of patients (Lowenberg B et al, 2009PubMed; Estey E et al, 2007PubMed). Failure to achieve CR, toxicity after induction/consolidation chemotherapy, problems in identifying donors because of older sibling age and early relapse were some of the difficulties encountered. ASCT using peripheral blood stem cells is feasible in older individuals, although it is used infrequently and it is sometimes difficult to mobilize adequate numbers of stem cells (Ferrara F et al, 2006PubMed).

 

Older, “Unfit” Patients

From a general point of view, the term unfit refers to older cancer patients not amenable to standard treatment and therefore needing a modified or attenuated treatment or also not deserving any therapeutic approach aimed at altering the natural history of disease  (Ferrara F, 2011PubMed). With specific reference to AML, such a definition implies the existence of two ill-defined categories of patients, i.e. those in whom an attenuated approach that is nonetheless aimed at CR achievement and/or disease control can be proposed and attempted, and those in whom no more other than BSC and HU can be administered. The latter category includes the vast majority of patients aged over 80 years, independently from performance status (PS) and comorbid conditions; the former is almost exclusively limited to the age range of 70-80 years, in which there is a greater element of uncertainty and the physician’s attitude plays a major role.

Low-dose cytarabine (LDARA-C) has been for many years the prototype of attenuated chemotherapy that is nonethelesss aimed at CR achievement. Previous data demonstrated that LD-ARAC is able to induce CR in about 20% of older AML patients (Ferrara F, 2011PubMed); notwithstanding, hematologic toxicity of this approach is substantial and many patients experience prolonged cytopenia. The only LDARA-C randomized study present in the literature specifically designed for AML patients considered as unsuitable for intensive chemotherapy was conducted by Burnett and coworkers (Burnett AK et al, 2007PubMed). Overall, LD Ara-C treatment was superior to BSC in that 13 out of 71 patients (18%) achieved CR, whereas only one on the HU arm achieved CR; in addition, survival was significantly longer in the LDAra-C arm. Of note, no survival advantage was recorded for patients with adverse karyotype and there was evidence that patients with a poor PS did not benefit from the treatment. Following this study, the UK MRC cooperative group devised a ‘Pick a Winner’ trial design, whereby several candidate treatments would be compared simultaneously by randomization with LDARA-C. Based on an interim analysis by the independent data monitoring committee, only those treatments that were likely to double the response rate and thereby improve survival would be pursued (Hills RK, Burnett AK, 2011PubMed). Accordingly, 166 older patients with AML, considered as unfit for conventional chemotherapy, were randomized to receive LDARA-C or the same LDARA-C schedule with arsenic trioxide (ATO) at 0.25 mg/kg on days 1-5, 9 and 11, for at least four courses every 4 to 6 weeks (Burnett AK et al, 2011cPubMed). The trial was terminated, as the projected benefit was not observed, given that no differences in response rate or survival between the arms was recorded, while grade 3/4 cardiac and liver toxicity, and supportive care requirements were greater in the ATO arm. In a further trial, the same group investigated the combination of the farnesyltransferase inhibitor, tipifarnib, and LDARA-C compared to LDARA-C, with initial evaluation after 100 patients (Burnett AK et al, 2012cPubMed). Tipifarnib is a selective, nonpeptidomimetic, orally active inhibitor of the enzyme farnesyltransferase, which has been tested in a wide array of solid tumors and hematologic malignancies, with antitumor activity seen in several tumor types, including MDS and AML (Tsimberidou AM et al, 2010PubMed). After reviewing the first 45 patients, the Data Monitoring Committee concluded that the addition of tipifarnib had no effect on response, toxicity or survival and the trial was discontinued. LDARA-C was also compared to LDARA-C in combination with GO, at a dose of 5 mg on day 1 of each course of LDAC, with the intention of improving the remission rate and consequently survival (Burnett AK et al, 2013bPubMed). The addition of GO significantly improved the remission rate (30% vs 17%), but not the 12-month survival (25% vs 27%). The reason for the induction benefit failing to improve OS was two-fold: both survival of patients in the LDAC arm who did not enter CR and survival after relapse were superior in the LDAC arm. Finally, as part of “pick a winner” trial programme, clofarabine (CLO), a new purine analogue, 20m was compared to LDARA-C, each for up to 4 courses, with patients deriving benefit allowed to continue on treatment. CLO was shown to double the CR rate compared with LDAC (38% vs 20 %), but did not result in an improvement in survival in any demographic or risk subgroup (Burnett AK et al, 2013cPubMed).

In a phase 3, multicenter, open-label study the efficacy and safety of tipifarnib was evaluated in comparison to BSC and or HU, as first-line therapy in elderly patients (>or=70 years) with newly diagnosed, de novo, or secondary AML (Harousseau JL et al, 2009PubMed) Survival was comparable, even though CR rate for tipifarnib was higher. The median CR duration was 8 months. The most frequent grade 3 or 4 adverse events were cytopenias in both arms, slightly more infections (39% vs 33%), and febrile neutropenia (16% vs 10%) seen in the tipifarnib arm. Table 3 summarizes therapeutic results, achieved in recent randomized trials in unfit older patients with AML.

 

Hypomethylating agents

In leukemias, alterations in DNA methylation are characterized by the hypermethylation of different genes. Hypermethylation represses transcription of the promoter regions of tumor suppressor genes leading to gene silencing. This change is reversible, making it a potential therapeutic target (Kwa FA et al, 2011PubMed; Boultwood J, Wainscoat JS, 2007PubMed). Drugs such as methyltranferase inhibitors including (azacitidine) AZA and decitabine (DAC) have been demonstrated to be clinically active in patients with MDS and AML and are extensively used in daily practice (Thomas X, 2012PubMed). Of interest, either AZA or DAC induce gene hypomethylation, but this has not been consistently correlated with re-expression of methylated, silenced tumor suppressor genes, in that treatment is associated with DNA damage and may work as a low-level cytotoxic agent. Noticeably, while the two drugs share mechanisms of action on DNA-mediated markers of activity, different effects on cell viability, protein synthesis, cell cycle and gene expression have been demonstrated (Hollenbach PW et al, 2010Pubmed). As opposed to conventional cytotoxic chemotherapy, the use of HMA offers the possibility of disease control, without necessarily achieving CR in patients population otherwise candidate to receive BSC only (Ferrara F, 2013PubMed). In a phase 2 multicenter studies, 55 patients (mean age, 74 years) were treated with a median of three cycles (range, one to 25 cycles) of DAC (Cashen AF et al, 2010PubMed). The overall response rate was 25% (CR: 24%) and was consistent across subgroups, including patients with poor-risk cytogenetics and those with a history of MDS. The median OS was 7.7 months, and the 30-day mortality rate was 7%. Promising results were also reported by adopting an alternative schedule of decitabine (20 mg/m2 i.v. over 1 h on days 1 to 10) in a series of 53 subjects with AML and median age of 74 years  (Blum W et al, 2010PubMed). A remarkable CR rate of 47% was achieved after a median of three cycles of therapy. Of interest, in this study higher levels of miR-29b were associated with clinical response (P = 0.02). More recently, Kantarjan and coworkers (Kantarjian HM et al, 2012PubMed) explored the potential therapeutic advantage of DAC over the so-called “treatment choice” (TC) in older patients with AML. In this study, TC included LDARA-C and BSC. Overall, results from this trial demonstrated a superior activity of DAC vs. TC (CR 17.8 % for DAC as opposed to 7.8 % for TC) with a possible survival advantage, without major differences in safety. Finally, in a further phase 2 study (Lübbert M et al, 2012PubMed), DAC was given to 227 older patients with AML (median age, 72 years) at an initial total dose of 135 mg/m2, infused intravenously over 72 hours every 6 weeks. Only 52 patients, who completed four cycles of treatment, subsequently received a median of five maintenance courses with a lower dose of 20 mg/m2. The overall response rate (CR + PR) was 26%, and responses were also recorded in patients with adverse cytogenetics, including those with monosomal karyotypes. However, the median OS from the start was 5.5 months (range, 0-57.5+) and the 1-year survival rate was 28%. Toxicities were predominantly hematologic. The AZA study by Fenaux and coworkers was designed for patients initially classified as high-risk MDS and not as AML (Fenaux P et al, 2010Pubmed). In a subsequent analysis, in one third of the patients (n:113) who were reclassified as having AML under current WHO criteria (bone marrow blast percentage 20-30%), the effects of AZA were compared versus conventional care regimen (CCR), having as primary end-point overall survival. Of note, CCR encompassed three completely different therapeutic strategies for AML, including BSC, LDARA-C and intensive chemotherapy. At a median follow-up of 20.1 months, median OS for AZA-treated patients was 24.5 months compared with 16.0 months for CCR treated patients, and 2-year OS rates were 50% and 16%, respectively. Two-year OS rates were higher with AZA versus CCR in patients considered unfit for intensive chemotherapy. In addition, AZA was associated with fewer total days in hospital than CCR. The most common toxicities were myelosuppression, febrile neutropenia, and fatigue. Overall, response rate (namely CR rate) seems to be superior with DAC as opposed to AZA in AML of the older patients (Quintás-Cardama A et al, 2012PubMed); notwithstanding, data on survival is poorer in all DAC studies as compared to Fenaux’s trial based on AZA, in which selection of patients with hypoproliferative disease, aged less than 70 years and few with high-risk karyotype clearly accounts for unusually favourable results. In this regard, it should emphasized that AZA data from compassionate programs as well as retrospective nationwide surveys produced significantly poorer results (Ramos F et al, 2012; Maurillo L et al, 2012PubMed; Ozbalak M et al, 2012PubMed). A head-to-head comparison of AZA vs. DAC is therefore warranted. Data demonstrating survival advantage in absence of CR is exciting and suggests an alternative mechanism of disease control, but still needs a careful and definitive confirmation in larger and well-conducted new trials. Furthermore, a true superiority with respect to intensive chemotherapy remains to be definitively demonstrated. Notwithstanding, epigenetic therapy is expected to become more sophisticated and in coming years it will probably work through specific, on-target actions (Pollyea DA et al, 2012PubMed). A methylation prognostic model, based on a combination of 10 genes and validated in independent samples of patients from two consecutive studies, has been reported as potentially able to predict both overall and progression-free survival in patients with MDS. Of interest, methylation at baseline does not predict response to decitabine, but decreased methylation after therapy is associated with clinical response (Shen L et al, 2010PubMed). Finally, the oral formulation of AZA, which is bioavailable and demonstrated biologic and clinical activity in patients with MDS and AML, will probably result in an easier and, therefore, more frequent adoption of epigenetic therapy in AML of the elderly (Garcia-Manero G et al, 2011PubMed). Table VII summarizes therapeutic results from most relevant studies with hypomethylating agents in AML of the elderly.

 

Ferrara_ACUTE MYELOID LEUKEMIA_Table_7

Table VII. Most relevant studies with hypomethylating agents for the treatment of older patients with AML

 

Relapsed AML

Recurrence of AML still represents a major obstacle to overcome when cure is the objective of the treatment. Different patterns of relapse can be distinguished including haematologic (most frequent), extramedullary and molecular relapse (Ferrara F et al, 2004cPubMed). The latter needs treatment in acute promyelocytic leukemia subtype in that, if untreated, it invariably results in haematologic relapse (Sanz MA, Lo-Coco F, 2011PubMed). As at diagnosis, a number of prognostic factors have been reported as able to predict the final outcome of relapsed patients. In particular, advanced age, unfavorable cytogenetic at presentation, duration of first CR less than 12-18 months and previous stem cell transplantation are major determinants for low second CR rate and survival (Breems DA et al, 2005PubMed). Nonetheless, prognosis is generally poor and, whatever the donor cells source, allo-SCT should be offered once second or CR has been achieved. Selected patients with limited bone marrow blast count would be considered for allo-SCT without receiving salvage chemotherapy (Feldman EJ, Gergis U, 2012PubMed). Most therapeutic results for relapsed AML derive from retrospective studies, therefore it is no possible to establish a standard salvage therapy. High or intermediate dose ARA-C based regimens still represent the most frequently adopted therapy. However, older patients with unfavorable cytogenetics and/or CR1 lasting for less than 12 months as well as young adults in early relpase after allo-SCT or in advanced relapse would be selected for investigational therapy, in order to avoid toxicity not balanced by actual survival advantage.

 

Conclusions

While current therapeutic results in AML remain unsatisfactory, the treatment of these patients can represent an ideal field of clinical investigation in the near future and different new agents are under investigation Ferrara F, 2012PubMed). Future strategies would include the development of well-designed, randomized phase II trials based on multiple outcomes and including novel target-based agents. These studies may also be designed to account for novel prognostic information deriving from global gene expression analysis and other intrinsic genomic properties of leukemic progenitors in the elderly. Accordingly, several new therapies could be evaluated, providing new and exciting advances. In the design of such studies, however, the great clinical heterogeneity, the typical multiple comorbidity of elderly subjects, the psychological attitudes of patients and their relatives and the practical feasibility of a given treatment in daily practice also need to be seriously considered to properly evaluate the global clinical impact of novel strategies.

 

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