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Abstract
In this chapter, Drs. Keating and Willman review recent advances in our understanding of the pathophysiology of acute myeloid leukemia (AML) and allied conditions, including the advanced myelodysplastic syndromes (MDS), while Drs. Goldstone, Avivi, Giles, and Kantarjian focus on therapeutic data with an emphasis on current patient care and future research studies.
In Section I, Dr. Armand Keating reviews the role of the hematopoietic microenvironment in the initiation and progression of leukemia. He also discusses recent data on the stromal, or nonhematopoietic, marrow mesenchymal cell population and its possible role in AML.
In Section II, Drs. Anthony Goldstone and Irit Avivi review the current role of stem cell transplantation as therapy for AML and MDS. They focus on data generated on recent Medical Research Council studies and promising investigation approaches.
In Section III, Dr. Cheryl Willman reviews the current role of molecular genetics and gene expression analysis as tools to assist in AML disease classification systems, modeling of gene expression profiles associated with response or resistance to various interventions, and identifying novel therapeutic targets.
In Section IV, Drs. Hagop Kantarjian and Francis Giles review some promising agents and strategies under investigation in the therapy of AML and MDS with an emphasis on novel delivery systems for cytotoxic therapy and on targeted biologic agents.
Armand Keating, MD*
Over the past decade, rapid advances have been made in elucidating some of the key molecular lesions that lead to acute myeloid leukemia (AML).1 The therapeutic implications of a detailed knowledge of aberrant signal transduction in malignant cells are evident, as the success of imatinib mesylate in the treatment of chronic myeloid leukemia dramatically attests. It is perhaps not surprising, then, that considerably less attention has been directed toward examining the role of the hematopoietic microenvironment (HM) in the initiation and progression of leukemia. The definition of the HM as an entity that regulates hematopoiesis through interactions with progenitor cells, hematopoietic cytokines, and the biosynthetic products of stromal and other cells suggests, however, that much may be learned about the leukemic state by a better understanding of this area. The recent resurgence of interest in the stromal or nonhematopoietic marrow mesenchymal cell population may serve as a springboard for further studies of how stroma influences, or is influenced by, leukemia. A brief overview of the normal HM will serve as a prelude to a review of stromal cells in AML.
The Normal Hematopoietic Microenvironment
The HM in the bone marrow consists of a heterogeneous population of hematopoietic and nonhematopoietic stromal cells, their extracellular biosynthetic products, and hematopoietic cytokines (reviewed in Clark and Keating2). The cells include myofibroblasts, other fibroblastoid cells, endothelial cells, osteogenic precursors, adipocytes, and macrophages. These cells produce a complex array of extracellular matrix (ECM) molecules consisting of proteoglycans and their constituent sulfated glycosaminoglycans, chondroitin, heparan, and dermatan species as well as hyaluronic acid.2 In addition, they make a variety of interstitial (fibril-forming) and basal lamina collagens, including collagen types I, III, IV, V, and VI. Stromal cells also synthesize other matrix molecules, such as fibronectin, thrombospondin, hemonectin, sialoadhesin, laminin, and the tenascin glycoproteins (reviewed in Klein3 and Verfaillie et al4) (Table 1
). Cells comprising the HM also provide a source of many hematopoietic cytokines, either secreted or membrane bound, including GM-CSF, G-CSF, and stem cell factor (kit ligand) (Table 2).
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Evidence is emerging that, in addition to hematopoietic cytokines, adhesion molecules are involved in mediating signal transduction in hematopoietic precursors and hence play an important role in cell proliferation that extends beyond brokering hematopoietic cell contact and adhesion to stromal cells and ECM elements (reviewed in Levesque and Simmons5).
Interaction of Adhesion Molecules on Hematopoietic Precursors and Marrow Stroma
Hematopoietic progenitors express cell adhesion molecules (CAMs) that can be classified into six structurally distinct superfamilies: integrins; selectins; sialomucins, including CD34; immunoglobulins; CD44 cell surface proteoglycans; and cadherins.5,6
Integrins
The integrins are particularly important because they are involved in stromal cell–stem cell, as well as stem cell–ECM, adhesion. They are heterodimeric proteins consisting of noncovalently linked 
and ß chains that uniquely pair to form at least 20 different integrin receptors. The receptors are transmembrane structures in which the cytoplasmic domain initiates intracellular signaling involving the phosphorylation of cytoplasmic proteins and modulation of cell proliferation by activation of the ras and other pathways.5 The cytoplasmic portion of the integrin interacts with cytoskeletal elements (talin) that in turn influence the development of focal adhesion contacts between the cell and the ECM.
There are two main ß integrin families involved in hematopoiesis, the ß1 and ß2 integrins. Binding specificity of the integrins is largely conferred by the particular chain.
ß1 Integrins
The ß1 common chain (CD29) combines with different a chains to form a variety of VLA (very late antigen) molecules that mediate the adhesion of hematopoietic cells to ECM components and ligands on stromal and endothelial cells. CD34(+) cells express the integrin receptor VLA-4 (4ß1) (CD49d), whose ligand is VCAM-1 (vascular adhesion molecule-1) on marrow stromal cells and fibronectin in the ECM. VCAM-1 is variably expressed on marrow stromal and endothelial cells and can be upregulated by several cytokines, including interleukin-1 (IL-1). Because VLA-4 and its ligands are widely distributed, specificity is most likely conferred by the coexpression of other adhesion molecules and can be modulated by hematopoietic cytokines. The VLA-4/VCAM-1 interaction is a critical component of the complex process of stem cell homing.7 The chemokine and chemoattractant stromal-derived factor 1 (SDF-1), another important element in the homing of hematopoietic stem cells to the bone marrow, is secreted by stromal cells and strongly upregulates the VLA-4-mediated adhesion of CD34(+) cells to stroma and ECM fibronectin.8 Early precursors also express VLA-5 (5ß1) (CD49e), which can bind to ECM fibronectin.
ß2 Integrins
Of the three ß2 integrins (CD18), the best characterized is LFA-1 (lymphocyte function antigen-1) (CD11a), which is associated with the adhesion of more mature leukocytes to the ligand ICAM1 on endothelium but is also found on early hematopoietic precursors. Mac-1 (CD11b), another ß2 integrin, is found on mature monocytic and granulocytic cells but not on early hematopoietic precursors.
Selectins
The selectins, a family of three glycoproteins, are also involved in adhesion and signaling. L-selectin is expressed not only on mature leukocytes but also on early hematopoietic precursors. Its role in adhesion is best documented in leukocyte attachment to endothelium. In contrast, P- and E-selectin are found on endothelial cells, while their ligands are found on early hematopoietic cells.
Sialomucins
Other adhesion molecules include the sialomucins, glycoproteins carrying O-linked sugars: CD34, CD45RA, leukosialin (CD43), and the more recently identified CD164 molecule (reviewed in Simmons et al9). CD164 (MGC-24) is expressed on both marrow stromal and CD34(+) cells and mediates adhesion between the two cell populations. Recent studies show that in addition, this molecule is involved in modulating the proliferation of early precursors.10 Other sialomucins, including leukosialin, also appear to act as negative regulators of hematopoiesis.11
Immunoglobulin superfamily
These cell adhesion molecules (CAMs) share a degree of sequence homology with immunoglobulins and are involved in cell-cell interactions. There are three main CAMs of relevance to hematopoiesis: VCAM-1, the ICAMs, and NCAM. VCAM-1 is expressed on marrow stromal cells and endothelial cells and interacts with the ß1 integrin VLA-4 (4ß1) on early hematopoietic progenitors. Expression of VCAM-1 can be upregulated by a variety of cytokines, notably IL-1ß and tumor necrosis factor- (TNF-). Stromal cells also express ICAM1, which can interact with the ß2 integrins such as LFA-1 and Mac-1. NCAM-1 (CD56), which is a marker of natural killer (NK) cells and is found on neuronal tissue, is also expressed on marrow stromal cells and is involved in supporting lymphopoiesis.
CD44 proteoglycans
The CD44 family, highly expressed on stromal cells, binds the nonsulfated glycosaminoglycan hyaluronic acid, a major component of the ECM present in long-term marrow culture adherent layers. Although CD44 is also expressed on hematopoietic precursors, only a small proportion (presumably high-affinity receptors) binds hyaluronate.12 CD44 can also bind to other ECM components, including fibronectin.13 Because CD44 is widely expressed, specificity of interaction is conferred by numerous isoforms generated by alternative splicing. Anti-CD44 antibody-blocking studies suggest that CD44 interactions are important in maintaining hematopoiesis in long-term marrow cultures.14
Cadherins
The cadherins (E-, N-, and P-cadherin) are transmembrane glycoproteins that mediate calcium-dependent cell adhesion in embryonic development and in the maintenance of tissue architecture. Their role in hematopoiesis is unclear, although recent studies indicate that both E- and N-cadherin are expressed on stromal cells and a subset of CD34(+) cells and erythroid progenitors.15–17 Their role in affecting leukemic cell development is unknown, but E-cadherin expression can be downregulated in AML blasts by hypermethylation mechanisms.
The Hematopoietic Microenvironment in AML
Given the multitude of interactions possible between hematopoietic progenitor cells and the HM, the acquisition of a leukemic clone may have numerous effects on this relationship and influence the clinical characteristics of the leukemia. At least three possible consequences to changes in leukemia cell–HM interactions have been proposed,11 as shown in Table 3.
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2, 3, or 6 chains of the ß1 integrins in the blasts of yet other AML patients.20 Perhaps the most interesting observation is from Lyon, where a correlation was shown between the expression of VLA-4 on leukemic blasts and a high initial white count as well as extensive marrow involvement.21
Studies by the Westmead group in Sydney confirm that adhesion of AML blasts, at least in part, is mediated by the interaction of VLA-5 with ECM fibronectin as well as via both ß1 (VLA-4) and ß2 (LFA-1) integrin interactions with stromal cells.22–24 Bendall and colleagues have also shown that the adhesion of AML blasts to marrow fibroblasts can be modulated by a variety of mechanisms, including the upregulation of stromal VCAM-1 by TNF- and interferon 
.25
The adhesion of AML cells to ECM elements may explain the tenacity with which residual leukemic blasts may persist in the marrow. The blasts from all patients in a small cohort with AML expressed the sialylated Lewis x antigen, a ligand for E-selectin, on endothelial cells, suggesting a mechanism for migration across the vascular wall and into extravascular tissue.26
Further studies are required to determine whether differences in the expression of adhesion molecules on leukemic blasts influence cell trafficking and the clinical phenotype in AML, as appears to be the case for chronic myeloid leukemia.27
Stromal Interaction with Leukemic Cells
Leukemic cells, like their normal hematopoietic counterparts, are subject to the influence of the HM. Encounters between the HM and leukemic cells can affect the apoptosis, differentiation, and proliferation of AML blasts.
Cell-Cell Interactions
Direct contact of leukemic cells with stromal layers strongly inhibits the apoptosis of the leukemic cells.28 The reduction in apoptosis correlates with enhanced growth of clonogenic leukemic cells. The growth factors, stem cell factor (SCF), GM-CSF, and TNF- in serum-free medium could achieve the same degree of inhibition of apoptosis in only half the cases studied. The co-culture of primary untreated AML cells with a stromal cell line in the presence of chemotherapy agents inhibits drug-induced apoptosis and increases the viability of leukemic clonogenic cells.29 The interaction of acute lymphoblastic leukemia (ALL) cells with stromal cells in the presence of chemotherapy drugs reduces the level of caspase 3 in leukemic cells and may account for the reduced apoptosis.30 These studies indicate that direct contact between leukemic and stromal cells enhances the survival of clonogenic leukemic cells and may explain how the small numbers of malignant cells remaining after chemotherapy are protected in vivo.
These observations contrast with the demonstration of the relative inhospitability of long-term marrow cultures to CML and AML progenitors, which are preferentially lost, allowing normal precursors to be reexpressed,31,32 and formed the basis for the clinical purging of grafts for patients undergoing intensive therapy and autotransplant.33,34 It is possible that, over the extended period of culture, the system does not provide critical survival factors for neoplastic clones. Loss of malignant progenitors is much less likely in the cultures of patients with advanced disease,35 suggesting that such limitations to growth in vitro are overcome and that normal hematopoiesis remains severely suppressed, if it exists at all.
Cytokines
The growth-promoting effects on leukemic blasts of cytokines such as G-CSF, SCF, GM-CSF, macrophage colony-stimulating factor (M-CSF), and IL-6 secreted by stromal cells have been documented.11 There is evidence that the secretion of IL-1ß by leukemic cells can stimulate the release of G-CSF and GM-CSF from endothelial cells, which, in turn, may affect the proliferation of leukemic blasts.36 Hepatocyte growth factor (HGF) or scatter factor, a pleiotropic cytokine involved in hepatocyte morphogenesis, is secreted by marrow stromal cells and, in conjunction with other growth factors (GM-CSF, IL-3), can augment the growth of committed progenitors through interaction with its receptor, c-met, found on CD34(+) cells.37,38 Alone, HGF appears to selectively stimulate AML blast colony growth and promotes migration of leukemic cells.39
In addition to cytokines, stromal cells release other factors that may influence the behavior of leukemic cells. For example, SDF-1, a chemokine and chemoattractant involved in the homing of stem cells, may affect leukemic cell trafficking.40 SDF-1 appears to selectively attract FAB M4/5 AML blasts that express the chemokine receptor CXCR4, a mechanism that may, in part, explain the marrow and tissue infiltration in this AML subtype.41
Changes in Cellular Composition of the HM
Studies comparing bone marrow biopsies obtained from AML patients with those from normal donors reveal normal numbers of macrophages but increased numbers of alkaline phosphatase–positive stromal cells and endothelial cells.42 Increased microvessel density in untreated AML correlates with vascular endothelial growth factor (VEGF) and VEGF receptor levels on AML blasts. The frequency of endothelial cells normalizes when remission is achieved,43,44 suggesting that AML blasts may stimulate endothelial cell growth in a paracrine fashion and change the HM in AML. AML blasts also secrete platelet-derived growth factor (PDGF),45 a potent mitogen for marrow stromal cells,46 possibly accounting for the increased frequency of stromal cells in active AML. An alternative explanation is that marrow adipocytes transdifferentiate to fibroblastic cells in response to other signals.11,47
A more detailed understanding of the composition and characteristics of the AML stromal population has been provided by studying the long-term marrow culture adherent layer, arguably the best in vitro model of the HM, than has been possible by conducting investigations in vivo. Stromal layers generated from patients with AML frequently appear abnormal because the adherent population either is sparse or absent, or appears morphologically disorganized. Several studies show that fibroblast progenitors (CFU-F) are reduced in frequency in the majority of patients with AML48 but can be restored to normal levels during remission.49 The reduction in CFU-F levels is probably not due to dilution by high numbers of leukemic blasts. Macrophages and adipocytes can also be reduced in AML adherent layers.50 Although the elaboration of inhibitors of stromal progenitors by AML blasts has been proposed as an explanation,51 mechanisms are needed to reconcile the observation of increased stromal cells in biopsy specimens and the report that CFU-F levels can be increased during leukemia relapse.52 At least one consequence of reduced cellularity in the stromal population has been documented. Mayani and colleagues showed that for some patients with AML, the reduced frequency of CFU-F correlated with reduced M-CSF levels in the adherent layer conditioned medium.50 Of interest, AML layers with normal cellularity had normal levels of CFU-F and M-CSF.
A Functional Defect in AML Stromal Layers
The inability of AML stromal layers, including those with normal cellularity, to adequately support normal hematopoiesis is well documented.50 However, fibroblastic cells derived from AML cultures free of macrophages have a normal capacity to support committed progenitor growth.53 Suppression of hematopoiesis is attributed, in part, to the production of TNF- and possibly, prostaglandin E by macrophages.54 More recent work shows by cytogenetic analysis that the macrophages in AML long-term culture adherent layers are part of the leukemic clone in some cases but that defective support of normal hematopoiesis is also observed, with layers lacking leukemic adherent cells.55 There is defective differentiation of normal CD34(+)CD38(–) cells but not the more committed CD34(+)CD38(+) cells,56 suggesting selective inhibition of primitive hematopoietic precursors.
Functional defects in stromal layers may also be due to abnormalities in cytokine production, in addition to the reduced M-CSF and increased TNF- levels described previously. Constitutive expression of IL-1ß, IL-6, and G-CSF transcripts was observed in AML but not in normal adherent layers.57 Leukemia inhibitory factor (LIF) protein levels were significantly raised in AML stromal layer supernatants compared with normal controls.58 The significance of raised LIF levels in this context is unclear, but in conjunction with marrow stromal cells, the factor is known to enhance the proliferation of CD34(+)CD90(+) cells.59
It is evident that the interactions of hematopoietic and stromal growth factors and inhibitors on normal and leukemic hematopoiesis in in vitro cultures are highly complex. Results from different studies may be difficult to compare because culture conditions and cellular composition of the stromal layers can vary significantly, especially for levels of stromal macrophages. The relative proportions of cellular components of primary stromal layers are rarely reported but may have a profound effect on cytokine profiles, making comparisons of studies with cloned stromal lines even more problematic. Caution should also be exercised in evaluating studies that report cytokine messenger RNA versus protein levels because of the uncertain significance of subliminal levels of the former.
Interaction of Leukemic Cells with Stromal Extracellular Matrix
AML cells can adhere to a wide variety of ECM components.23 As discussed above, AML blasts adhere to ECM fibronectin and laminin through the ß1 (VLA-4, VLA-5, VLA-6) and ß2 (LFA-1) integrins found on the leukemic cells.22,24 Antibody-blocking studies show that this only partially accounts for the adhesion24 and that other mechanisms, including CD44 binding, have been invoked.23 Many more CD44 variants are expressed on leukemic than on normal hematopoietic cells, and they may affect the interaction of AML cells with stroma.60 A 67-kd receptor present on CD14(+)CD11a(+) AML cells with monocytic morphology but absent on normal bone marrow cells mediates specific adhesion to laminin and represents a novel mechanism for the interaction of leukemic cells with the HM.61
The reduced apoptosis of AML cells documented in several in vitro models is not restricted to stromal cell contact-mediated mechanisms. The adhesion of c-kit(+) AML blasts to fibronectin is enhanced by SCF, which augments the fibronectin/VLA-5-mediated inhibition of apoptosis and increases leukemic cell proliferation.62
Evidence for Malignant Stromal Cells
Although stromal macrophages have been shown to be of leukemic origin,55 definitive studies demonstrating that nonhematopoietic stromal cells are part of the neoplastic clone are lacking. Moreover, marrow stromal cells from patients with the best-characterized multipotent stem cell disorder, Ph(+) chronic myeloid leukemia, are Ph negative.63 However, in a study of patients with myeloproliferative disorders heterozygous for glucose-6-phosphate dehydrogenase, the nonhematopoietic stromal cells from adherent layers of long-term marrow cultures were derived from the same clonal progenitors involved in the multipotent stem cell disorder.64 In contrast, the stromal cells were nonclonal in a patient with a restricted-type AML (clonal granulopoiesis and nonclonal erythropoiesis). Further investigation is needed with better clonal markers and methodologies that completely eliminate contaminating stromal macrophages to test this intriguing possibility, especially in light of recent work demonstrating stem cell plasticity. Nonetheless, the paucity of positive data makes the possibility that there are malignant stromal cells less likely; or at least these cells are at best probably uncommon.
Conclusion
It is evident that leukemic cells interact with the HM at many levels and mimic the action of normal early precursors to a variable extent, as summarized in Figure 1 and Table 4. Like normal cells, AML blasts adhere to stromal cells and ECM components, but in contrast, they may receive additional protection from endogenous apoptotic mechanisms or apoptosis-mediated chemotherapy. In situ, leukemic cells may proliferate in response to any, or all, of the adhesive interactions with stromal cells, ECM components such as fibronectin and laminin, or local gradients of cytokines in the HM that are secreted by stromal cells, are generated by autocrine mechanisms, or are found in association with glycosaminoglycans (for example, heparan sulfate). Aberrant expression of CAMs on leukemic blasts may account for different patterns of trafficking and possibly the clinical presentation of AML subtypes. In these many steps there are opportunities for therapeutic intervention. One approach that merits further investigation is to develop ways to interfere with the suppression of the apoptosis of AML cells that is mediated in particular by ECM fibronectin.
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Anthony H. Goldstone, MD,* and Irit Avivi, MD
Despite the fact that 70-80% of patients with AML achieve complete remission (CR) most of them eventually relapse and die of the disease.1,2 Once remission has been achieved, further intensive therapy is needed to prevent relapse. Patients under the age of 60 have three main options after going into remission: intensive chemotherapy (IC), autologous stem cell transplantation (ASCT), or allogeneic stem cell transplantation (allo SCT) of some kind.3–8 Patients with standard-risk disease have traditionally been referred for a matched sibling allograft if a donor is available and the patient’s performance status is adequate. In recent years, chemotherapy postremission has improved patients’ outcome, with a 50% 5-year overall survival (OS) and 40% disease-free survival (DFS) similar to that achieved with allo SCT, narrowing the differences between chemotherapy and such transplants8 (MRC AML 12, Burnett et al, unpublished data, 2002) (Figure 2). The high mortality of allograft (20%-25%), even today, is therefore making it less attractive in comparison with chemotherapy, and selection of patients to be given allografts in first remission (CR1) should be done very carefully.
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).9,11 However, most patients do not belong to these two categories and are classified as having standard-risk disease (5-year OS = 43%).9,11
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Prevention of Relapse in Young Patients
A significant reduction in relapse rate (RR) has been observed since the introduction of intensified postremission therapy.1,3 The Cancer and Leukemia Group B (CALGB) randomly assigned 596 patients in CR1 to receive 4 courses of cytarabine at 1 of 3 doses.1 High-dose cytarabine (18 g/m2/course) was demonstrated to be superior to 2 g/m2/course, with a DFS of 44% versus 29% (P = 0.003) and an OS of 52% versus 40% (P = 0.02).1
A different consolidation regimen, containing no more than 1 g/m2 cytarabine rather than high dose, has been successfully used by the Medical Research Council (MRC) AML 10 trial (DFS and OS were 43% and 40%, respectively).2,3
The number of postremission chemotherapy courses required is unresolved. Recent data of the MRC AML 12 trial seem to show no advantage for 4 consolidations compared with 3.13
Main prospective trials
Several prospective trials of postremission therapies have been designed to evaluate the efficacy of the three treatment options: chemotherapy, HSCT, and allo SCT.3–8,13
EORTC/GIMEMA AML 8 trial (1986-1991)
The European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups5 carried out the first published prospective randomized study designed to review the best consolidation therapy for AML patients (Table 6).5
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and 8). It seems that these results reflect the relatively poor outcome observed with chemotherapy, rather than being a true "superior effect" of the transplant (alloSCT/ASCT) itself.
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Nearly half of the patients without a donor had ASCT. A donor versus no donor analysis revealed a reduced RR with increased DFS in the donor group (RR: 31.2% vs 52.9%, P = 0.0001; DFS = 51.4% vs 41.2%, P = 0.046). A survival advantage was most noticeable in poor-risk patients who had a donor (4-year DFS = 43.8% vs 19%; OS = 50.4% vs 27.7%).
GOELAM trial
In the Groupe Ouest Est Leucemies Aigues Myeloblastiques (GOELAM) trial, patients with de novo AML who entered CR were assigned to allograft if they had a matched related donor and were less than 40 years old.6 All other patients were consolidated with 1 chemotherapy course of high-dose cytarabine and anthracycline. At this stage, patients were randomized to receive ASCT, or a second course of IC, containing amsacrine and etoposide (Table 6
).
Despite the relatively low mortality rate (22%) reported in those assigned to allograft, there was no increase in OS compared with patients without a donor, partially because of the high RR (37%) observed in the donor group. There were no significant differences in DFS and OS between patients assigned to ASCT versus IC (Table 8). However, ASCT was associated with high myelotoxicity, especially prolonged thrombocytopenia (109.5 days with ASCT vs 18.5 days with IC).
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).3,8 Analysis of donor versus no donor groups revealed a significantly higher transplant-related mortality (TRM) rate in the donor group: 19% versus 9% (P < 0.001). Twenty-four percent (62/255) of the patients who received allo SCT died in remission, compared with 17 of 156 (11%) who had a donor available but did not receive an allograft.8 Relapse risk was significantly lower and DFS was significantly higher in the donor group compared with the "no available donor" group (RR: 36% versus 52%, P = 0.0001; DFS: 50% versus 42%, P = 0.001).8 Nevertheless, there was no survival advantage for allo SCT compared with other treatments (7-year OS = 56% for donor group vs 50% in no donor group, P = 0.1).8 However, it seems that patients with standard-risk cytogenetics who are younger than 35 do have a survival advantage with allo SCT.8 This favorable outcome observed with allo SCT might result from patient selection bias (selection of patients with a favorable biology of disease who succeed in remaining in CR during the chemotherapy courses preceding the transplant) rather than being due to the superiority of transplant.
Intent-to-treat analysis assessing the outcome of ASCT versus no further treatment showed a significant reduction in RR in patients assigned to autograft (37% vs 58%, P = 0.0007) (Table 8).3 Despite the increased DFS in patients assigned to ASCT (DFS = 54% vs 40% with no further treatment, P = 0.04, Figure 3), there was no increase in OS, reflecting the higher mortality rate (12%) observed with autologous transplantation (P = .008).3 The main cause of death was impaired hematopoietic reconstitution.
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Patients with de novo or secondary AML were randomized to receive MAE (mitoxantrone, cytarabine, etoposide) versus ADE (cytarabine, daunorubicin, etoposide) [replaced from 1998 by S-DAT (daunorubicin, cytarabine 100 mg/m2, thioguanine) versus H-DAT (daunorubicin, cytarabine 200 mg/m2, thioguanine) with or without all-trans retinoic acid (ATRA)] as first chemotherapy course (Table 2). Patients who remained in CR after the third course of chemotherapy underwent a second randomization into 4 versus 5 courses of treatment and transplant versus chemotherapy.13 Those who were randomized to transplant and had a matched related donor were assigned to allograft, whereas patients without a donor were assigned to peripheral blood stem cell transplantation (PBSCT) or bone marrow stem cell transplantation (BMSCT).
First results of AML 12 (still unpublished) show reduced relapse risk in patients having a donor. However, no significant survival advantage for having a donor has been observed in any of the 3 risk groups (Figure 2). There was no increase in OS in patients assigned to autograft, and 5 chemotherapy courses in total appeared to provide the same results as 4.13
The Intergroup (SWOG, CALGB, ECOG) trial
In the Intergroup (Southwestern Oncology Group [SWOG], CALGB, Eastern Cooperative Oncology Group [ECOG]) trial, high-dose consolidation therapy was compared with ASCT and allo SCT in CR1.4 Patients who achieved CR were treated with modest-dose cytarabine (500 mg/m2) followed by allo SCT if a matched related donor was available. Patients without a donor were randomized to receive a purged ASCT versus one high-dose cytarabine course (Table 6).
Allo SCT appeared to provide the best antileukemic effect, associated with a RR of 29%, compared with 48% in patients assigned to ASCT, and 61% for patients assigned to chemotherapy. However, the lower RR observed with allograft was reversed by a high mortality rate, approaching 25% (TRM = 25% with allo SCT vs 14% for ASCT and 3% for IC). Despite the high RR observed with chemotherapy, chemotherapy appeared to be superior to ASCT or allo SCT (Table 7). It seems that the low delivery rates of assigned treatments, a longer duration from CR to transplantation compared with IC and the relatively high TRM observed with high dose therapy (HDT) (especially higher than expected for patients assigned to autograft) might explain the unsatisfactory results observed with HDT rather than reflecting a real advantage of IC.
Main Problems Interpreting Results of Prospective Trials
There remain some problems with interpreting the results of major prospective AML trials.14 Patients who receive allo SCT are clearly selected, because a proportion of patients with a matched sibling donor do not receive a transplant. Patients may be excluded from transplant because of early relapse/death, previous complications with chemotherapy, or other medical problems. It is not possible to predict the direction of such biases14 and indeed they are at the core of problems with interpreting registry data.
). As a result, both beneficial and harmful effects might be underestimated.
Allo SCT in AML
With chemotherapy producing a less than 20% chance of survival before the early 1980s, durable survivals up to 50%, with a low relapse risk of 15-25%, were reported in patients receiving allografts in CR1.15,16 Today, the DFS and OS in nontransplanted patients begin to achieve this rate of durable survival and make such treatment comparable to that achieved with allograft3,8 (MRC AML 12, unpublished data).
Allo SCT in the main prospective trials
All trials confirmed allo SCT to be the best antileukemic treatment, associated with a relapse risk of 24%-36% compared with 46%-61% observed with ASCT/IC.3-8,17 However, almost all prospective studies failed to show an improved OS in patients assigned to allo SCT (see Table 7).
The MRC AML 10 trial observed a survival advantage for patients treated with allograft compared with patients treated with IC who had no available donor. 8 However, the survival of patients who had a donor but were eventually treated with only IC was inferior to the survival of not only allografted patients but also the "no donor" group. These data indicate that patients who eventually received the transplant were biologically selected to have a favorable prognosis, as patients with poorer prognosis did not get the transplant. However, the EORTC/GIMEMA AML 10 trial has recently reported a higher survival rate in poor-risk patients assigned to allograft (OS = 50.4% versus 27.7%).7
Summarizing the data regarding allograft in CR1 in AML patients remains difficult:
). This variability in the number of courses might affect transplant outcome in relation to both toxicity and time to treatment bias. ). This might underestimate both its efficacy and toxicity. ). ).
BMSC or PBSC for Allo SCT?
The main reason for the increasing use of PBSC relies on the rapid hematopoietic recovery observed with PBSC compared with BMSC.18,19 A few studies have also reported improved immune reconstitution using PBSC.18,20 However, PBSCT might be associated with increased incidence/severity of acute graft-versus-host disease (AGVHD) and chronic graft-versus-host disease (CGVHD).21 Champlin et al, on behalf of the European Group for Blood and Marrow Transplantation (EBMT) and the International Bone Marrow Transplant Registry (IBMTR) working committee, have retrospectively compared the outcome of patients treated with PBSCT (n = 288) and BMSCT (n = 536).21 Incidence of CGVHD, but not AGVHD, appeared to be higher in patients who received PBSCT. Patients with advanced disease at transplantation (AML patients in second remission [CR2] and chronic myelogenous leukemia patients in accelerated phase) seemed to have reduced TRM and increased leukemia-free survival (LFS) when receiving PBSC compared with BMSC.21 However, these advantages were not observed in AML patients receiving PBSCT in CR1.21 Conversely, Russell et al have reported an improved DFS in patients who received PBSCT in CR1.22
Randomized trials confirmed an improved engraftment with PBSCT compared with BMSCT.19 The Seattle Group randomized 172 patients with hematological malignancies (including 21% AML patients) to receive PBSCT versus BMSCT.19 Despite the improved DFS observed with PBSCT compared to that with BMSCT (2-year RR: 14% vs 25%, P = 0.04, DFS: 65% versus 45%, P = 0.03), there was no significant increase in OS (OS = 66% versus 54%, P = 0.06). TRM, though lower in patients treated with PBSC, was still high (21% versus 30%, hazard ratio 0.7; 95% confidence interval 0.38-1.28; P = 0.24). In contrast to the higher incidence of CGVHD reported in some retrospective studies,21 there was no significant difference in the incidence of AGVHD/CGVHD in this prospective trial. Further studies comparing PBSCT and BMSCT and allowing longer follow-up are needed before any one stem cell source can be deemed superior.
T-cell depletion
GVHD is a major cause of mortality and morbidity after allo SCT, and removing the T lymphocytes from the donor bone marrow can decrease the incidence of both. However, unselected T-cell depletion may theoretically increase RR (preventing the graft-versus-leukemia effect) and enhance treatment-related infections due to delayed immunological recovery.
Nevertheless, it seems that T-cell depletion may not necessarily increase relapse risk in AML allografted patients, though decreasing GVHD.23,24
However, it is still unclear whether T-cell depletion can provide any benefit beyond reducing GVHD and improving the quality of life.23,24
Low-intensity stem cell transplantion
Low-intensity stem cell transplantation (LI SCT) is being increasingly used, aiming to exploit the curative potential of allo SCT by inducing graft-versus-tumor effect without the morbidity and mortality associated with conventional transplantation. Low-intensity SCT is less toxic and therefore may be considered for some patients who are otherwise not eligible for conventional allogeneic transplant. However, its efficacy in AML patients has still not proven to be as good as that of high-intensity allo BMT. The EBMT reported on 69 patients (median age 51) treated with LI BMT for AML or myelodysplastic syndrome (MDS).25 More than half of the patients had refractory/relapsed disease at transplantation. Graft failure was more frequent than observed with conventional allo SCT, though 77% achieved > 95% donor chimerism. Patients’ outcome was highly dependent on disease status at transplantation: 1-year TRM, RR, and OS were 47%, 30%, and 41% for the whole group, compared with 17%, 21%, and 67% in patients transplanted in CR (CR1 or later). However, follow-up was still short at time of publication.25
Peggs et al have recently reported 44% progression-free survival (PFS) and 53% OS (median follow-up, 18 months) in 24 patients aged 18-60 years (median 47) treated with low-intensity matched related/unrelated SCT (total body irradiation, melphalan, fludarabine, Campath-1H) for MDS/AML (n = 17).26 DFS and OS were higher in AML patients transplanted in CR1 (n = 15), approaching 57% and 62%, respectively.26 Longer follow-up and prospective comparison with IC are needed in order to define the role of LI SCT in selected AML patients. The MRC AML 15 trial intends to allow the possibility of LI SCT in patients aged 35-45 years who have a matched related donor, while suggesting conventional transplant for the younger recipients.
Autologous Stem Cell Transplantation
ASCT in CR1
On the assumption that HDT has value in AML, several groups conducted nonrandomized trials using ASCT as consolidation therapy in CR1.27–29 Encouraging results, observing a reduced RR with improved DFS compared with chemotherapy, were reported.27–29 Patient selection, however, might have played a role.
Does stem cell purging improve patient’s outcome?
Despite the superior DFS observed with an ASCT compared with chemotherapy,27–29 RR remained higher than observed with allo SCT and the main cause of death was recurrence of disease. Some investigators have tried to purge stem cells pretransplantation, aiming to reduce RR and improve OS.28,30,31However, results were variable.4,30,31 Furthermore, pretransplant purging may carry a risk of loss of accessory and progenitor cells, resulting in delayed hematopoietic and immunological reconstitution.
ASCT in prospective randomized trials
One of the main unsolved questions is whether there is any place for ASCT in CR1 and which patients (if any) should be transplanted. All three prospective trials designed to compare IC with ASCT 4–7 observed a reduced RR in patients assigned for autograft, reflecting its superior antileukemic effect compared with chemotherapy (Table 8).4–7 The MRC AML 10 trial, comparing ASCT with no further treatment, reported a significantly increased DFS in patients assigned to ASCT (Figure 3).3 Failure to deliver assigned treatment, observed with all trials (Table 6), might underestimate the real efficacy of ASCT. All prospective trials failed to show a survival advantage in patients assigned to autograft compared with chemotherapy. The high mortality rate reported with ASCT (12%) offsets the antileukemic advantage provided with autograft. In addition, some patients who relapsed postchemotherapy were salvaged with HDT.3,5 However, the TRM associated with ASCT is no longer today significantly higher than that observed with IC. A reduced TRM might therefore be translated into increased OS.
ASCT for patients in second or later CR
ASCT might have a place in rescuing patients who have relapsed postchemotherapy, with up to 20-50% relapse-free survival in selected patients.3,5,32–34
Linker et al34 have recently reported a 5-year DFS of 54% in patients with advanced leukemia (patients with primary induction failure who remitted with salvage therapy/patients in CR2 or later CR) who were treated with high dose cytarabine/etoposide consolidation, followed by an ASCT.34
It is still unclear if patients in CR2 or later without a donor should be referred to matched unrelated donor (MUD) transplantation instead of ASCT. A prospective comparison of MUD versus ASCT in this situation is very difficult because time to treatment might be delayed and some MUD patients may not be in true remission while others, proposed autograft, might fail to obtain an adequate stem cell harvest.
BMSCT or PBSCT in ASCT?
Retrospective studies observed a faster hematopoietic recovery, associated with a lower morbidity and mortality (TRM = 5%) in patients treated with PBSCT compared with BMSCT.28,29
Most studies did not show any differences in RR or DFS between stem cell sources.35–37 The EORTC/GIMEMA AML 10 trial randomized patients with no available donor to BMT (n = 146) or PBSCT (n = 146).37 There were no significant differences in DFS and OS between the two groups (4-year DFS = 49.8% with BMSCT vs 42.6% with PBSCT, P = 0.33; OS = 55% vs 55.3%, respectively).37 It is still unclear whether PBSCT provides any other advantage compared with BMT, except of facilitating stem cell engraftment.
Outcome of Allo SCT in Different Risk Groups
Good-risk patients
All prospective studies3,5–8 except the Intergroup trial4,10 failed to show a survival advantage with allo SCT in CR1 in patients with favorable cytogenetics. It appears that the Intergroup result might reflect a random result rather than a genuine tendency, because of the small number of patients included.
Acute promyelocytic leukemia (APL) patients, but not patients with t(8:21) or inversion 16, were reported to have a significantly lower RR with allograft in CR1 (donor vs no donor analysis: 22% vs 43%, P = 0.02).8 However, it seems that since the introduction of ATRA, nontransplant therapy can provide the same good result. The only study that observed a survival advantage in good-risk patients treated with autograft was the Intergroup study.4,10 However, this "superior" outcome might actually reflect the poor results achieved with chemotherapy.4 It now seems that there is no place for allo SCT or ASCT in CR1 in patients with favorable-risk cytogenetics.
Standard-risk patients
Both the MRC AML 10 trial3,8 and the EORTC/GIMEMA AML 10 trial7 reported reduced RR and improved DFS in patients with standard-risk disease assigned to allo SCT. However, it is still unclear whether allo SCT can improve patients’ OS (MRC AML 12, unpublished data).7
There is still significant heterogeneity in this group of patients and RR is influenced (independent of cytogenetics) by response to first induction and the presence of the FLT3 mutation. It is possible that some of these standard-risk patients (e.g., those who express the FLT3 mutation or failed to remit with first course of induction) will do better with allo SCT, while others will gain no advantage from being transplanted.
Poor-risk patients
Researchers from the EORTC/GIMEMA AML 10 trial have recently reported their current results.7 When patients are divided into risk subgroups based on their cytogenetics, it seems that patients with unfavorable cytogenetics get the maximal benefit from having allo SCT compared with ASCT or IC.7 Of interest, the EORTC/GIMEMA AML 10 study considered all patients without a favorable/normal karyotype as having poor-risk disease (Table 5). However, the MRC AML 10,8 which failed to show an advantage for allograft in poor-risk patients but showed one for the standard-risk group, included approximately half of these patients with unfavorable cytogenetics in the standard-risk group rather than in the unfavorable-risk one.
Other Options for Transplantation for Patients Without a Matched Related Donor
Matched unrelated donor transplantation (MUD)
MUD in CR1. Despite the controversy about the advantage of matched related donor allograft in CR1 in poor-risk patients,7,8,10 the very grim prognosis observed with chemotherapy (less than 30% DFS) might justify using MUD in CR1 in this group of patients. However, there is currently little evidence that any kind of allo SCT can cure large numbers of these poor-risk patients.
MUD in CR2. Patients with unfavorable cytogenetics who achieve a second CR and have no matched related donor are often referred to MUD SCT. However, MUD in CR2 in patients with favorable-/standard-risk cytogenetics remains controversial and its superiority compared with ASCT is still questionable.38–40 Lazarus et al, on behalf of the IBMTR, have retrospectively compared the outcome of AML patients (CR1/CR2) treated with MUD versus ASCT between 1989-1996.39 Three-year LFS was 33% in MUD patients versus 40% with an autograft. However, long-term side effects were significantly higher in MUD patients and selection bias is unknown.
On the basis of these incomplete retrospective data, it may be reasonable to consider MUD in young patients with adverse cytogenetics and short CR1s who have a matched unrelated donor (at least 10 antigen matching).40 Conversely, patients older than 40 with a long CR1 may do better with ASCT, if their disease is in genuine remission and enough cells can be harvested.40
T-replete versus T-depleted MUD. The reduced GVHD-related mortality achieved with T-cell depletion is often balanced by increased RR and overwhelming infections.
In contrast to patients with some other malignancies, AML patients may achieve a survival advantage with T-depleted marrows compared with T-replete ones,40 justifying T cell depleted MUD in selected AML patients. Nevertheless, data justifying this are still scanty and further studies are needed to support this strategy.
Haploidentical BMT
Haploidentical BMT is an option for patients who do not have a matched related donor (approximately 70% of patients). The historical data concerning haploidentical BMT in AML patients were disappointing. These disappointing results might be attributed to patient selection for transplant (advanced disease) as well as to a high rate of transplant-related complications, mainly GVHD, which in turn was replaced by a high incidence of graft failure as T-cell depletion has been introduced to prevent GVHD. T-cell depletion by itself was associated with delayed immune recovery, resulting in high incidence of severe infections. However, it seems that recent modifications have succeeded in making some progress. Stem cell megadose (106 CD34 cells/kg) is essential to overcome the HLA barrier in full haplotype-mismatched transplants.41 Further reduction of T-cell dose infused reduces the frequency and the severity of GVHD significantly. Posttransplant granulocyte colony-stimulating factor (G-CSF) appears to interfere with natural killer (NK) cell recovery and has therefore been excluded.42 Donor’s NK cell alloreactivity, a unique phenomenon of mismatched transplants, appears to play an essential role in preventing relapse and supporting stem cell engraftment.43 A recent update from Perugia suggests that the current morbidity and mortality in AML patients having haploidentical BMT is not higher than reported with matched allogeneic BMT.44 Event-free survival in high-risk patients transplanted in CR1/CR2 approached 45%, with an RR of less than 15%.44 A donor versus recipient NK cell alloreactivity is essential for achieving graft-versus-tumor effect and may therefore become a major criterion for donor selection in mismatched SCT.
Acute Promyelocytic Leukemia
None of the large randomized trials showed a survival advantage with ASCT/allo SCT in CR1 compared with the outcome achieved with ATRA-containing regimens. However, for patients in second CR, there might be an advantage with both kinds of transplants.45 An achievement of molecular remission pre-autograft is essential and is associated with a high cure rate.45,46 Conversely, patients transplanted with evidence of minimal residual disease (MRD) (morphological remission without molecular remission) have high risk for relapse46,47 and should therefore be considered for an alternative therapy such as allo SCT or arsenic trioxide.45,47 Postautograft maintenance therapy with ATRA might further reduce RR, although this has to be confirmed.
Options for Treatment in Elderly Patients
The age-related differences in biology of disease partly explain the poor outcome observed in patients older than 60 than in younger patients. However, undertreatment might also contribute to these inferior results.
Postremission therapy with high-dose cytarabine failed to improve the outcome of patients older than 60 and has been associated with high toxicity.1
The advantage of ASCT in CR1 is not proven either, though some investigators have reported an improved survival with ASCT;48,49 however, a selection bias might be involved. Allo SCT, being associated with higher TRM in elderly patients (especially GVHD related), is even less feasible. Deeg et al50 have recently reported a nonrelapse mortality of 39% in 50 MDS patients (16 with transformation to leukemia) aged 55-66 years (median 58.8) treated with conventional allo SCT. However, encouraging results with low-intensity SCT in elderly AML patients have recently been reported.26
It appears that stem cell transplantation (ASCT or allo SCT), being often associated with high toxicity, will not be the routine treatment in elderly patients. Overcoming the drug resistance that frequently exists in elderly patients with AML has remained one of the main challenges to treating them.
Minimal Residual Disease
Detection of MRD posttherapy, aiming to identify patients who are at higher risk for relapse, remains a major challenge.51,52 Molecular methods (polymerase chain reaction [PCR]),51,52 as well as immunological methods (multi-parametric flow cytometry analysis)52,53 have been employed. Whereas immunophenotype analysis can be informative in 80%-85% of AML patients, molecular analysis can be useful in less than 30% of patients, as only the minority of AML patients express a traceble molecular marker (e.g., AML1/ETO, PML/RAR, and possibly the FLT-3 mutation).51,52 There are some patients whose leukemic cells present chromosomal abnormalities that can be monitored with fluorescence in situ hybridization (FISH).51 However, FISH is usually less sensitive than molecular monitoring, and the sensitivity of it may be inadequate.51,52 Furthermore, 30%-50% of AML patients have normal karyotype.
The significance of a positive MRD finding is not always clear and a different level of residual disease seems to be significant for different types of AML.54,55 Tobal et al reported a tenfold difference in MRD levels between patients in long-term remission from APL54 compared with patients with t(8;21).55 Molecular remission in APL patients seems to be associated with long-term DFS, whereas failure to achieve a molecular remission does not.45–47,56,57 In contrast, a positive molecular result in patients with t(8;21) who obtained clinical remission is not necessarily associated with impending relapse.51,58 APL patients who achieved a molecular remission have an excellent prognosis having IC only.45–47 However, data are still too scanty to apply this strategy to other AML subtypes, and further studies including quantitative monitoring should be investigated.
Conclusions and Future Directions
Despite the contributions of large prospective trials comparing the efficacy of allo SCT with that of IC or ASCT, it is still unclear what the best postremission therapy is for AML patients.
ASCT in CR1
It appears that patients in the favorable-risk group do not require HDT in CR1, as their outcome with chemotherapy is excellent.8 There is no clear evidence that standard-risk patients are doing better with allo SCT than with IC either (MRC AML 12 unpublished data, Figure 2). With the lack of major benefit for allo SCT, the poorer quality of life often observed post allograft should be considered.59 Patients will need to decide whether increasing their chance of survival by a few percentage points is worth the potential long-term morbidity. Also, issues of infertility will be perceived differently by the patients in different age groups and those with different family circumstances.60
The role of allo SCT in CR1 in poor-risk patients remains unclear,8 although some studies have showed some advantage compared with chemotherapy.4,7,10
However, all these large prospective studies have used BMSC, whereas recent studies have shown a possible reduced RR with PBSCT compared with BMSCT.18,19 Prospective studies comparing PBSCT with BMSCT are needed to clarify these issues.
Better understanding of prognostic factors (e.g., FLT3 status, MRD status) might help in selection of the patients who will benefit from allo SCT. The number of chemotherapy courses needed pretransplantation is unclear61 and might be influenced by patients’ risk group (including evaluation for MRD) and planned HDT.
New kinds of allo SCT based on reduced chemotherapy doses (LI SCT) or T-cell depletion allograft may succeed in reducing TRM observed with conventional allo SCT and allow transplantation to be considered in patients who are not eligible for conventional allograft, including elderly patients.
ASCT/IC in CR1
The role of ASCT in CR1 is not clear. All prospective trials showed reduced RR in autografted patients. However, survival was not higher than observed with chemotherapy, mainly because of the high TRM reported with ASCT. A current prospective study, including a large number of patients, comparing IC with PBSCT and BMSCT is needed. Improving the outcome achieved with chemotherapy remains one of the main challenges to be addressed by current studies. Attempts to overcome chemotherapy resistance, which is most noticeable in elderly patients, need to be ongoing.
Future studies
In the absence of any clear evidence for the role of both allo SCT and ASCT in CR1, the main trial groups have designed different directions for future research. ECOG is soon starting a new treatment protocol retaining the option for autotransplant compared with allo SCT and chemotherapy. Chemotherapy intensification will be further investigated, including an increased dose of daunorubicin and combining anti-CD33 with chemotherapy (Figure 4).
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). Patients 35-45 years old who have a matched related donor can receive a conventional allograft, or an LI BMT, depending on investigator or patient choice (but not randomized).
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III. Biologic and Genetic Risk Assessment of AML in the Genomic Era
Cheryl L. Willman, MD*
In the past two decades, important scientific advances have yielded new insights into the epidemiologic, genetic, and biologic features of the AMLs.1–6 Yet despite these scientific advances, the majority of patients affected by AML still die of their disease.6 With the exception of acute promyelocytic leukemia (APL), we have not yet succeeded in translating our scientific discoveries into more effective treatments for the majority of AML patients. While therapeutic intensification and improved supportive care have led to gradual improvements in outcome in children and younger adults with AML (particularly those with more favorable cytogenetic abnormalities), overall survival in this age group still approaches only 50%.6 In older individuals (> 55-60 years) and in secondary AML patients, in whom resistance to current therapies and an increase in unfavorable cytogenetics characterizes the disease, the outlook is even more dismal, with overall survivals of 10% to 15%.7–14 As the majority of individuals affected by AML are in this older age group,15 we thus lack effective therapeutic approaches for the majority of patients with this disease. New laboratory and clinical approaches that can be successfully translated into more effective diagnostic and therapeutic strategies are desperately needed for AML. We must define the most important questions to advance our knowledge and focus on the discovery of new therapeutic strategies for AML patients with high-risk as well as low-risk disease. Molecular genetics and gene expression profiling hold promise to improve AML disease classification systems, to model gene expression profiles associated with chemoresistance or response to various agents, and to identify novel therapeutic targets.16–23 This section will briefly review preliminary accomplishments and ongoing studies in this field of investigation.
AML Prognostic Factors 2002: Age, Antecedent Disease, Cytogenetics
From the past two decades to the present day, the most important prognostic factors in AML have remained: (1) patient age; (2) presenting white blood cell count; (3) whether the AML presents clinically as de novo disease or secondary to antecedent myelodysplasia (MDS) or leukemogenic therapies (therapy-related AML, t-AML); and (4) the presence of specific cytogenetic abnormalities, usually clustered as "favorable," "intermediate," or "unfavorable" (Table 9).1,3,6 While AML accounts for only 13% to 14% of leukemia cases in the first 10 years of age (the majority being acute lymphoblastic leukemia or ALL), AML constitutes nearly 36% of the leukemia cases in older children.15 In adults, AML rates begin to rise exponentially after 50 years of age; age-specific incidence rates are 3.5 per 100,000 in adults 50 years of age, increasing significantly to 15 at age 70 and 35 at age 90. The mean age of AML in the United States is 63 years. Currently accounting for 10% to 20% of all AML cases, the incidence of secondary AML appears to be increasing due to the use of DNA damaging agents in cancer therapy at higher dose intensities and an increased length of survival for many cancer patients.24
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). Although "favorable" cytogenetic abnormalities [such as t(8;21), inv(16), or t(15;17)] are more frequently seen in children and younger adults less than 55 years of age, it should be noted that these "good prognosis" cases still constitute a minority (< 35%) of the AML cases seen in this age group. In contrast to AML in younger patients, AML in older individuals is more frequently associated with unfavorable cytogenetic abnormalities (such as 7, 7q, 5, 5q, or complex karyotypes) and other poor prognosis biologic features (trilineage dysplasia suggestive of antecedent myelodysplasia or marrow injury and an increased frequency of intrinsic drug resistance).7–14,25 The significantly poorer outcome seen in older AML patients is, in part, explained by a higher frequency of these unfavorable cytogenetic abnormalities and biologic features.7–14 While younger and older AML patients define the extremes of response, the majority of patients affected by AML in all age groups fall into the "intermediate" cytogenetics category, in which risk classification and stratification are currently ill defined. While large clinical trials have demonstrated that AML-associated cytogenetic abnormalities confer important prognostic information, striking differences in therapeutic response and outcome may still be observed in leukemias with the same cytogenetic profile, implying that other more subtle genetic abnormalities and functional activation or inactivation of critical cellular pathways (signal transduction abnormalities, apoptosis, drug resistance, angiogenesis, cell cycle regulation, DNA repair) also impact disease biology and therapeutic response. Although all of these critical cellular pathways provide potentially important therapeutic targets for AML, w
