Age

Age is a major prognostic factor in most of the hematological malignancies, including AML. Older patients have a poorer performance status and more comorbidities. Their leukemia is more frequently secondary to an antecedent hematological disorder or is therapy-related and the malignant cells commonly have unfavorable cytogenetics and express the multidrug resistance glycoprotein 1 (MDR1). The Swedish National Acute Leukemia Registry is the largest population-based unselected series that demonstrated that, regardless of management, age is a continuum and also has a strong poor prognostic impact within the group of older patients. Despite the importance of age as a prognostic factor, age alone should not be a barrier to treating patients. Performance status and comorbidities are of paramount consideration.

Performance status

Performance status was historically considered an important prognostic factor in AML. In a recent retrospective analysis from the Medical Research Council (MRC) in Great Britain of more than 1000 patients aged more than 60 years, performance status was found, by multivariate analysis, to be 1 of 5 independent factors that significantly influence prognosis. This finding was subsequently validated by data from another large MRC trial.

Comorbidities

One of the most common explanations for the poor prognosis of older patients is their comorbidities. A retrospective study from the MD Anderson Cancer Center examined the validity of the hematopoietic cell transplantation comorbidity index (HCTCI) in patients with AML aged more than 60 years. This scoring system includes pulmonary, cardiac, hepatic, and renal impairments, as well as psychiatric disturbances, infectious disease, obesity, and a history of a solid tumor. They found that the HCTCI was predictive of an early death rate and overall survival (OS).

Socioeconomic status

A Swedish study, using a cohort of more than 9000 patients with AML in Sweden between 1973 and 2005, observed that white-collar workers had a lower mortality than other socioeconomic status groups ( P = .005). Possible explanations for this observation are biologic differences in tumor characteristics, differences in the health care provider’s attitude toward management, and different frequencies among patients undergoing an allogeneic transplant. In addition, lifestyle factors, such as nutritional status, physical activity, obesity, among others, that are influenced by socioeconomic status may also have an impact on patients’ tolerance.

Race and gender

A retrospective analysis by the Cancer and Leukemia Group B (CALGB) of 2300 whites and 270 African American patients with de novo AML found a lower CR rate ( P = .001) and worse OS ( P = .004) among African American men compared with whites and African American women. A superior prognosis for women was also observed in white populations. The large Swedish study demonstrated a lower relative risk of death ( P = .02) in women compared with men.

White blood cell count

A high white blood cell (WBC) count at diagnosis expresses a high blast count and high tumor burden. Not surprisingly, this variable was historically considered an important poor prognostic factor. It is unknown whether the prognostic effect of a high WBC count is a result of a high tumor burden or is a surrogate for leukemias that have distinct entities with different pathophysiology and clinical characteristics. For example, a high leukocyte count may be associated with a molecular change, like the FLT3-ITD mutation, and the molecular aberration is likely to be responsible for the poor prognosis and not the WBC itself. Furthermore, a precise cutoff defining a high WBC has not been established. Different investigators have preferred different cutoffs of WBC: 20,000/μL, 30,000/μL, 50,000/μL, or 100,000/μL. When the WBC exceeds 100,000/μL, the term hyperleukocytosis is usually used and patients are at an increased risk of developing clinical symptoms of leukostasis. Dutcher and colleagues showed that among patients with AML, those with hyperleukocytosis have a lower CR rate, disease-free survival (DFS), and OS and a high rate of early mortality as opposed to Greenwood and colleagues, who demonstrated that only early mortality was affected by hypoleukocytosis without influence on the other prognostic parameters. In contrast to the importance of a high WBC count at diagnosis, leukopenia at diagnosis does not seem to have any prognostic significance in AML.

Immunophenotyping

Many studies have attempted to find an association between immunophenotyping and prognosis. Some reported on single antigen expression that correlate with poor prognosis and others identified clusters of antigens to be associated to the prognosis. Examples of antigens with a poor prognosis, demonstrated in more than one study include the following: CD7, CD11b, CD14, CD34 and HLA-DR. Li and colleagues demonstrated, in a cohort of more than 800 patients with AML, that the poor-risk antigens correlate not only with poor prognosis but also with unfavorable-risk cytogenetics. This finding confirms that antigens on the leukemic cells may not independently influence the prognosis. They are associated markers for the more important genetic changes.

Other factors, such as thrombocytopenia, organomegaly, and an elevated lactate dehydrogenase, have been proposed in some publications as poor prognostic factors, but these findings are clearly not consistently observed.

Cytogenetics

Cytogenics came into the forefront in AML in the 1970s, when some of the seminal early predictions of the impact on prognosis in AML were reported. Since that time, several refinements have been made because of improved karyotypic resolution. As a result, karyotypic analysis has become indispensable in the management of patients with AML and are now an inherent part of the analysis of data in any large clinical trial in AML. Several classifications have been reported, all following a similar broader outline that, nevertheless, includes important differences. Currently, cytogenetics are considered the single most important factor in the management of patients with AML. An abnormal karyotype is found in about 60% of patients with AML. Several studies in recent years have attempted to divide patients with AML into prognostic groups according to their karyotype. Most of the data from the different studies are consistent and the variations are summarized in Table 1 .

Only 3 types of karyotypes are considered as having a favorable outcome after intensive chemotherapy. These karyotypes are the following: t(15;17) in APL, inv(16)/t(16;16), and t(8:21), which are genomic aberrations that are characterized at the molecular stage by the interruption of genes encoding subunits of the core-binding factor (CBF). On the other hand, some types of karyotypes represent adverse prognostic outcomes that are associated with greater resistance to any form of aggressive chemotherapy. These karyotypes include abnormalities of (3q), monosomy 5 or 7, del (5q) or (7q), t(9;22), and a complex karyotype. There are other, less-frequent karyotypes lacking information because of the small number of patients in any group. Patients with a normal karyotype or with aberrations that are not included in the previous groups are considered an intermediate prognostic group. Recently, Grimwade and colleagues summarized the largest cytogenetic cohort of patients with AML containing cytogenetic and clinical information of 5876 younger adults (aged 16–59 years) who were treated in several MRC trials between 1988 and 2009. This study adds information about rare recurring cytogenetic abnormalities and several combinations of aberrations ( Table 2 ). In a multivariate analysis, the poorer outcome observed in this study was in patients with the following: abn(3q) excluding t(3;5)(q25;q34); inv(3)(q21q26)/t(3;3)(q21;q26); add(5q)/del(5q); -5,-7,add(7q)/del(7q); t(6;11)(q27;q23); t(10;11)(p11˜13;q23); other t(11q23), excluding t(9;11)(p21˜22;q23) and t(11;19)(q23;p13); t(9;22)(q34;q11); -17; and abn(17p). Another uncertainty that this study tried to resolve was the definition of a complex karyotype, which, among published studies, ranged between 3 and 5 aberrations. In this study, patients with 4 or more cytogenetic abnormalities, which are not included in the standard (favorable) and poor prognostic ones, were considered as having a complex karyotype with a poor prognosis. It is likely that the unfavorable prognostic group needs to be further subdivided into smaller groups. An important report from the Dutch Hovon group was the first to report on the unfavorable prognosis of patients with the monosomal karyotype, which was defined as 2 or more monosomies or a single monosomy in the presence of structural abnormalities, having an extremely poor prognosis. These data were subsequently confirmed by other groups evaluating a large cohort of patients with AML and correlating with cytogenetic abnormalities.

Another type of combination with conflicting reports is the favorable karyotype, such as inv(16), together with additional abnormalities. The data here are limited because of the small numbers of patients in the different studies. The huge cohort of the MRC suggested that additional cytogenetic aberrations do not adversely impact the favorable prognosis of patients with t(15;17), inv(16)/t(16;16), and t(8:21) treated on current intensive protocols. Furthermore, in patients with inv(16), the presence of additional chromosomal changes, such +22, have been reported to predict a better outcome.

The standard or favorable karyotype group accounts for about 20% of young patients with AML (aged <55 years) and about 7% of older patients, although the absolute incidence of patients with the favorable karyotype is not decreased with older age. The CR rate of these patients is high (about 90%), the 5-year OS is about 45% to 65%, and the relapse rate is low. On the other hand, the unfavorable cytogenetic group consists of about 15% to 20% of patients with AML, depending on the age and the different study definitions. The CR rate is less than 50% and the 5-year OS is less than 20%.

The practical implication of assigning patients to prognostic groups relates to the decision regarding which patients should be referred for allogeneic transplant in the first CR. In terms of DFS, the MRC study demonstrated a benefit for transplant mainly in the intermediate group, but the European Organization for Research and Treatment of Cancer – Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (EORTC-GIMEMA) found benefit only in the unfavorable group. A meta-analysis, which took into consideration these 2 studies together with the Dutch-Belgian Hemato-Oncology Cooperative Group – Swiss Group for Clinical Cancer Research (HOVON-SAKK) and Bordeaux Grenoble Marseille Toulouse Cooperative Group (BGMT) studies, showed a benefit for allogeneic transplant with both intermediate and high-risk groups. The benefit was not only in DFS but also in OS. Despite these conclusions of the meta-analysis, the intermediate risk group, especially the huge subgroup of normal karyotype, still comprises a large heterogeneous group of patients. The need for the refinement of prognostic subgroups has led to the use of molecular markers, which allows for better discrimination of the prognostic impact ( Fig. 1 ).

Distribution of cytogenetically and molecularly defined risk group in AML.

( Reproduced from American Society of Hematology (ASH), Smith ML, Hills RK, Grimwade D. Independent prognostic variables in acute myeloid leukaemia. Blood Rev 2011;25(1):39–51; with permission.)

KIT mutations

The KIT gene encodes a 145-kD transmembrane glycoprotein, which is a member of the type III receptor tyrosine kinase family. Following ligand binding, the receptor activates downstream signaling pathways involved in proliferation and differentiation. Gain-of-function mutations can cause ligand-independent activation of KIT. In CBF AML, KIT mutations cluster most frequently within exon 17, which encodes the KIT activation loop in the kinase domain, and in exon 8, which encodes a region in the extracellular portion of the KIT receptor that is thought to play a role in receptor dimerization. The incidence of KIT mutation is between 20% to 40% in both t(8;21) and inv(16) in different studies. Some studies examined the prognostic implication of KIT mutation but with different conclusions. In patients with t(8;21), the cumulative incidence of relapse is higher in patients with KIT mutation compared with wild type (WT). Most studies, but not all of them, also showed decreased OS in patients with a mutation. In patients with inv(16), some have reported that OS had an adverse impact among the mutated patients, whereas other studies failed to demonstrate any prognostic impact.

Mutations

Nucleophosmin mutations

Nucleophosmin (NPM1) is a nucleolar protein that shuttles between the nucleus and the cytoplasm. It has several functions, including regulation of the transport and import of different particles through the nuclear membrane and interaction with p53 in controlling cell proliferation and apoptosis. NPM1 mutations seem to be founder genetic alterations. These mutations are responsible for the aberrant expression of the nucleolar nucleophosmin in the cytoplasm of the leukemic cells. For this reason, these aberrations can be recognized not only by molecular assays but also by immunohistochemical staining and flow cytometry. The mutations can be found in about one-third of adult AML and about 50% of AMLs with normal karyotype. Several studies demonstrated the favorable effect of NPM1 mutations on prognosis. Some demonstrated this in patients with both FLT3-ITD mutations and FLT3-WT, creating 3 different prognostic groups: NPM1+/FLT3-WT (favorable), NPM1-/FLT3-WT or NPM1+/FLT3-ITD (intermediate), and NPM1-/FLT3-ITD (unfavorable) ( Fig. 2 ). Others confirmed its favorable effect only in patients with FLT3-WT and not in patients with FLT3-ITD. The NPM1 mutations, as founder aberrations, are stable throughout the course of the disease and can be used as markers for MRD assessment and for the detection of early relapse.

Kaplan-Meier survival curves for overall survival in AML with and without the CEBPα mutation. All 4 genotypes have improved overall survival with even a single CEBPα mutation ( left graph ).

( Reproduced from American Society of Hematology, Taskesen E, Bullinger L, Corbacioglu A. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA double mutant AML as a distinctive disease entity. Blood 2011;117:2469–75; with permission.)

Overexpression

Overexpression of some genes has been demonstrated to have significant prognostic impact in patients with normal karyotype AML. Important examples are the Brain and Acute Leukemia Cytoplasmic gene (BAALC), Meningioma1 gene, and Ectopic Virus Integration 1 gene. The interpretation of such quantitative tests is complex and it holds within it questions of standardization and establishment of reference values.

Early response

A different approach for the prediction of an individual outcome is by evaluation of early response parameters. The amount of residual leukemic blasts in bone marrow on the sixteenth day from the beginning of the induction therapy was demonstrated, in the German AMLCG, to predict for a long-term outcome, even in patients who achieved CR. Others showed that the number of blasts (less or more than 5%) on day 14 can predict CR but not long-term outcomes. There is also evidence for an association between the high number of plasma cells in day 14 marrow and residual leukemia. An Italian group attempted to substitute early bone marrow examination by following the clearance of the leukemic blasts from the peripheral blood using daily flow cytometry. They found correlation between the clearance rate and the day 14 marrow.

Cytogenetic CR

Achievement of CR is a requirement, although not sufficient, for cure. The CALGB demonstrated that patients with abnormal karyotype at diagnosis, in whom the bone marrow was converted to normal karyotype at first CR, have significantly better outcomes.

MRD

MRD is a developing and promising risk-assessment system. The model of MRD in AML came from APL, in which real-time quantitative polymerase chain reaction (RQ-PCR) for PML-RARA transcript level, after consolidation, became the follow-up standard of care. Basically, there are 2 main methods of MRD assessment based on PCR amplification of molecular abnormalities and flow cytometric detection of abnormal immunophenotypes. RQ-PCR is now considered the preferred PCR method because it is less prone to contamination, allows the kinetics of disease response and relapse to be defined, and enables poor quality samples that could have given rise to false negative results according to older PCR assays to be identified based on the level of endogenous control gene transcripts (eg, ABL ). The PCR method is based on amplification of fusion transcripts as AML1-ETO, CBFbeta/MYH11 and MLL-AF9 with the limitation that only about one-third of patients with AML have these transcripts. Patients with persistent high levels of fusion transcripts at the end of consolidation or reappearance of transcripts after molecular remission are prone to early relapse. Other options are based on the detection of overexpressed genes, like WT1, or mutated genes, like FLT3-ITD and NPM1. The European Leukemia study demonstrated that greater WT1 transcript reduction after induction can predict the relapse risk, although the background of normal bone marrow cells may limit the reliability of this assay. NPM1 MRD level was shown, by multivariate analysis, to be an important prognostic factor but FLT3-ITD is more controversial as an MRD marker because of the observation that this marker may not be stable during the course of disease. The other method of MRD detection uses flow cytometry for identifying the aberrant expression pattern of cellular markers on the leukemic cells. In about 75% of patients with AML there is abnormal immunophenotype. Because the immunophenotype can distinguish the leukemic cells from the normal bone marrow cells, the sensitivity of the test improves, in the range of between 1 leukemic cell among 1000 to 10,000 normal cells. An Italian study demonstrated that a bone marrow with more than 3.5 X 10 ⁻⁴ residual leukemic cells after consolidation is considered MRD positive and carries a poor prognosis. The limitations of this method are the option of immunophenotypic changes that may occur during the course of the disease and that the results depend on the investigator interpretation.

KIT mutations

The KIT gene encodes a 145-kD transmembrane glycoprotein, which is a member of the type III receptor tyrosine kinase family. Following ligand binding, the receptor activates downstream signaling pathways involved in proliferation and differentiation. Gain-of-function mutations can cause ligand-independent activation of KIT. In CBF AML, KIT mutations cluster most frequently within exon 17, which encodes the KIT activation loop in the kinase domain, and in exon 8, which encodes a region in the extracellular portion of the KIT receptor that is thought to play a role in receptor dimerization. The incidence of KIT mutation is between 20% to 40% in both t(8;21) and inv(16) in different studies. Some studies examined the prognostic implication of KIT mutation but with different conclusions. In patients with t(8;21), the cumulative incidence of relapse is higher in patients with KIT mutation compared with wild type (WT). Most studies, but not all of them, also showed decreased OS in patients with a mutation. In patients with inv(16), some have reported that OS had an adverse impact among the mutated patients, whereas other studies failed to demonstrate any prognostic impact.

Mutations

Nucleophosmin mutations

Nucleophosmin (NPM1) is a nucleolar protein that shuttles between the nucleus and the cytoplasm. It has several functions, including regulation of the transport and import of different particles through the nuclear membrane and interaction with p53 in controlling cell proliferation and apoptosis. NPM1 mutations seem to be founder genetic alterations. These mutations are responsible for the aberrant expression of the nucleolar nucleophosmin in the cytoplasm of the leukemic cells. For this reason, these aberrations can be recognized not only by molecular assays but also by immunohistochemical staining and flow cytometry. The mutations can be found in about one-third of adult AML and about 50% of AMLs with normal karyotype. Several studies demonstrated the favorable effect of NPM1 mutations on prognosis. Some demonstrated this in patients with both FLT3-ITD mutations and FLT3-WT, creating 3 different prognostic groups: NPM1+/FLT3-WT (favorable), NPM1-/FLT3-WT or NPM1+/FLT3-ITD (intermediate), and NPM1-/FLT3-ITD (unfavorable) ( Fig. 2 ). Others confirmed its favorable effect only in patients with FLT3-WT and not in patients with FLT3-ITD. The NPM1 mutations, as founder aberrations, are stable throughout the course of the disease and can be used as markers for MRD assessment and for the detection of early relapse.

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