- Acute Leukemias VI - Prognostic Factors and Treatment Strategies | Thomas Büchner | Springer
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- Prognostic Factors and Treatment Strategies
This association of toxicity with GST genotype is likely associated with the specific drug combinations used in different AML therapy platforms. Response to therapy has been an important predictor of clinical outcome in leukemias. Historically, response to therapy has been measured by the morphologic presence of disease at defined periods after the start of induction therapy. In addition, the presence of disease below the level of morphologic detection has been evaluated.
We review induction failure as well as the presence of minimal residual disease MRD as a means of identifying high-risk patients. Studies evaluating the morphologic presence of disease have shown that such patients have a dismal outcome even if they are reinduced into remission [ 2 , 10 ]. Because morphologic disease response has been shown to be such a powerful prognostic factor, the role of disease persistence below detection at the morphologic level MRD has been evaluated as a prognostic factor in AML. However, nearly half of these patients are destined for relapse and poor outcome.
Identification of occult disease in patients in morphologic remission may identify patients at high risk for impending relapse. Appropriate intervention in this group of patients could potentially prevent morphologic relapse and be more effective. Despite its potential in risk management in AML, the clinical utility of MRD, which represents an in vivo measure of response to therapy, is related to several factors.
First, MRD should have general applicability and be able to identify a significant proportion of patients at risk for relapse. Second, there should be adequate time from the detection of MRD to morphologic relapse to allow for intervention. And, most importantly, therapy of MRD must lead to a better outcome, otherwise the detection of MRD is clinically meaningless.
The majority of the data on the detection of MRD in AML has been generated using polymerase chain reaction PCR -based methods in which detection of unique fusion genes has been correlated with morphologic relapse [ 12 — 15 ]. In these studies reverse transcription RT -PCR was used to detect MRD in patients with specific cytogenetic abnormalities [acute myeloid leukemia with t 8;21 , inv 16 , or t 15;17 ] and correlate the presence of occult disease with morphologic relapse.
In APML, detection of persistent t 15;17 fusion product is significantly associated with a high risk for relapse, and early therapeutic intervention, prior to morphologic relapse, has been shown to improve outcome [ 16 , 17 ]. In contrast, the t 8;21 translocation-generated fusion product may not only be present in the general population [ 18 ], but may remain positive by PCR for many years in patients with AML in morphologic remission [ 19 ].
Thus, the mere detection of an abnormal transcript may not be clinically meaningful. More recent studies, using real-time quantitative PCR have proven to be more important in the identification of clinically relevant MRD. Schnittger et al. In addition, patients with increasing transcript levels are at extremely high risk for relapse.
The question of whether therapeutic intervention in the context of molecular MRD in core binding factor CBF leukemias improves clinical outcome needs be addressed. Leukemic blasts usually express aberrant surface antigen patterns that differ from the pattern observed in normal progenitors. This difference has been exploited to develop flow cytometric—based MRD assays with which the presence of one cell with a leukemic immunophenotype can be detected in 1,—10, normal nucleated cells [ 21 ]. Recent studies have evaluated the utility of multidimensional flow cytometry to detect disease presence in patients in morphologic remission and correlated the presence of MRD with clinical outcome.
They demonstrated that patients with occult disease detected by flow cytometry had a significantly greater risk for relapse than patients without occult leukemia. In a multivariate analysis, flow cytometric detection of MRD showed the strongest correlation with relapse-free survival. That study thus demonstrated that flow cytometry can be used to screen for occult disease in pediatric AML, and that patients with MRD are at high risk for relapse.
More importantly, in that study, the median time to relapse for the MRD-positive population was days, more than adequate for intervention. In contrast, results from a Berlin-Frankfurt-Muenster BFM report have shown that MRD detection did not provide prognostic information additional to that of the more traditional risk factors [ 24 ].
The question of how to optimally manage such MRD-positive patients, however, has not been resolved. There are currently no data to suggest whether intervention in MRD-positive patients would alter their overall clinical outcome. The utility of flow-based MRD is being prospectively evaluated as part of clinical trials being conducted through a St. Historically, characteristics believed to be inherent to leukemia have included factors such as diagnostic WBC, morphologic classification French American British [FAB] subtype , and biological characteristics such as cytogenetics.
Acute Leukemias VI - Prognostic Factors and Treatment Strategies | Thomas Büchner | Springer
More recently, with the advances in molecular diagnostics and genomic and proteomic profiling, disease classification has expanded significantly. Diagnostic WBC has been shown to be a continuous variable for outcome, as an increase in the WBC is associated with an incremental decline in outcome. Such a continuous variable has thus far been difficult to incorporate into risk stratification strategies in AML, as many molecular events that mediate myeloid leukemogenesis lead to leukocytosis i.
Thus, identification of the underlying biological mechanisms responsible for leukemic proliferation and survival characteristics leading to leukocytosis should provide a more definitive means of assessing the risk for treatment failure. Because of the subjective nature of such a classification and lack of uniformity or correlation with underlying biology, the World Health Organization WHO recently developed a system for comprehensive AML classification based on cytogenetics, disease biology, and clinical history Table 1.
Scrutiny of the FAB subtypes e. The WHO classification schema relies mainly on recurrent cytogenetic alterations and clinical history for AML classification [ 27 ]. Diagnostic cytogenetics is widely recognized as one of the most significant prognostic factors in AML. The prognostic significance of karyotypic abnormalities has been evaluated retrospectively in several trials, and specific favorable and unfavorable subgroups of AML have been identified.
We discuss specific favorable and unfavorable cytogenetic markers and their clinical impact across several pediatric trials. The presence of t 8;21 or inv 16 has also been associated with longer survival in pediatric patients [ 34 ]; however, available data suggest that there may be a difference in outcome between patients with t 8;21 and inv 16 in different clinical trials.
Patients with t 8;21 and inv 16 had significantly better remission induction and overall survival than patients with the normal karyotype. The clinical significance of cytogenetic abnormalities in children with pediatric AML was evaluated in the POG study [ 28 ]. Patients with t 8;21 and inv 16 had a significantly better remission induction rate than patients with the normal karyotype. However, the postremission outcome was different between patients with inv 16 and those with t 8; In contrast, patients with t 8;21 had a higher relapse rate, which was not different from that of patients with the normal karyotype.
However, the salvage rate for patients with t 8;21 was significantly higher than for those with the normal karyotype, leading to longer overall survival. This maturation arrest can be overcome with pharmacologic doses of ATRA. Mixed lineage leukemia MLL rearrangements have been implicated in myeloid leukemogenesis, and their clinical significance has been evaluated in numerous trials [ 29 , 41 , 42 ]. Although in earlier studies the presence of 11q23 abnormalities was associated with an unfavorable outcome, more contemporary studies have not shown such a prognostic significance [ 29 , 35 ].
Evaluation of 42 patients with 11q23 treated in St. Jude Children's Research Hospital trials in — showed no overall difference in the outcome of patients with or without 11q However, within the 11q23 population, patients with t 9;11 had a significantly better overall and event-free survival rate than patients with the normal karyotype or other 11q23 abnormalities [ 30 , 43 ]. Further evaluation is needed regarding this cytogenetic subtype.
Karyotypes associated with poor outcome have been identified in a small proportion of pediatric patients with AML. Abnormalities of chromosome 5 and 7 have been associated with poor outcome in pediatric AML [ 2 , 28 , 35 ]. The MRC 10 study, which evaluated adult and pediatric patients for risk groups, initially identified chromosome 3 abnormalities as a high-risk karyotype [ 35 ].
These patients have a lower rate of remission induction and a worse overall outcome. Other uncommon, recurrent cytogenetic abnormalities, such as t 6;9 , have been associated with poor outcome. However, because of its low prevalence and significant association with other molecular abnormalities i. The presence of complex cytogenetics has been associated with worse outcome in AML. Some classification systems define complex karyotype as the presence of five or more abnormalities [ 35 , 45 ], whereas others use three or more abnormalities [ 46 — 48 ].
A majority of the data on the prognostic significance of complex cytogenetics has been derived from adult studies, with scant published data on pediatric patients. Available data suggest that complex cytogenetics are highly associated with specific high-risk karyotypes, where a significant proportion of those with defined complex cytogenetics have chromosome 5 or 7 abnormalities [ 49 ].
In the Farag et al. Other studies have demonstrated that the favorable outcome of those with CBF AML is not diminished in the presence of complex cytogenetics [ 50 ], supporting the notion that the presence of specific translocations, and not the number of translocations, may define clinical outcome.
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This is a particularly important distinction to make in pediatric patients, because the prevalence of complex karyotypes is lower and the prevalence of favorable cytogenetics is higher than in adult patients. Recent evaluation of CCG data failed to demonstrate prognostic significance for the presence of at least five karyotypic abnormalities in those with standard risk AML T. Alonzo, unpublished data. Larger numbers of patients with subtypes of AML characterized by specific chromosomal alterations and treated with uniform approaches may be required to prove smaller but still relevant outcome differences.
Therapeutic resistance is a major obstacle in the treatment of AML. It is expected that expression levels of genes that mediate drug resistance may correlate with response to chemotherapy and clinical outcome. Numerous studies have evaluated the prognostic significance of expression of MDR genes with varying conclusions [ 51 — 54 ].
Early studies demonstrated significant prognostic significance to the expression of MDR genes [ 55 — 57 ], wherein those whose leukemic blasts had a high expression level of MDR genes were more resistant to chemotherapy and had a worse survival. However, more comprehensive evaluation of the prognostic significance of MDR expression in the context of contemporary, intensive chemotherapy protocols failed to demonstrate independent prognostic significance to MDR expression when evaluated in the context of other adverse prognostic factors such as cytogenetics [ 53 ].
These studies have demonstrated that MDR genes are highly expressed in older patients and those with high-risk cytogenetics, thus, not providing additional, clinically useful prognostic information. Evaluation of MDR genes in pediatric patients also failed to demonstrate prognostic significance [ 52 ]. Sievers et al. However, the clinical outcomes of those with and without PgP expression were not different. Additional pediatric studies have demonstrated that MDR-1 expression is not higher overall in patients with relapsed AML [ 58 ]. Although MDR expression may not be an independent prognostic factor, it may be a useful therapeutic target in the management of AML.
Several agents have been shown to impair the function of proteins encoded by MDR genes, which may potentially sensitize the cells to the therapeutic effects of the specific chemotherapy agents [ 59 — 61 ]. In combination with conventional chemotherapy, such agents may augment response to chemotherapy and improve survival.
Mutations in the FLT3 receptor gene have been demonstrated to be the most common genetic alteration in AML thus far identified. Furthermore, these mutations have been implicated in rapid disease progression and resistance to conventional therapy [ 72 , 75 — 77 ]. FLT3 receptor structure. Several studies have now shown that the proportion of the ITD to wild-type PCR product varies significantly from patient to patient, and this difference may have clinical implications.
Thiede et al. Recent identification of an additional activating mutation of the FLT3 gene has further increased the interest in FLT3 as a prognostic marker. It is unclear why these two types of activating mutation involving the same receptor are associated with different AML phenotypes and patient outcome.
Activating mutations in the c- KIT receptor gene involve mutations in the juxtamembrane or the kinase domains of the receptor gene and lead to constitutive activation of the c- KIT receptor. Although initial studies did not demonstrate a prognostic significance for c- KIT mutations, separate evaluation of D mutations suggested that, in patients with CBF leukemia, those with D mutations have a significantly higher relapse risk than those without mutations [ 91 — 93 ].
The prevalence of KIT mutations and their prognostic significance in pediatric AML remain to be established, although a report from Shimada et al.
Small molecule inhibitors targeting RTK receptors have shown significant efficacy in vitro and in animal models; however, their use as single-agent therapy in relapsed AML has not resulted in significant responses [ 95 — 98 ]. Trials evaluating the utility of FLT3 inhibitors in combination with conventional chemotherapy in both relapsed AML as well as de novo AML are ongoing [ 95 , 99 — ]. Early data are promising, and it appears that FLT3 inhibitors may augment response to chemotherapy in those with FLT3 mutations.
Investigations have been conducted to identify novel and more predictive markers of high-risk disease in AML in order to help in risk-based therapy. Such efforts have led to the identification of potential prognostic markers as well as the refinement and reassessment of a number of historic markers.
ipdwew0030atl2.public.registeredsite.com/116867-mobile-snooping.php New technologies and molecular tools have enabled investigators to evaluate biologically relevant markers for their role in disease response. Mutations in genes regulating critical pathways in hematopoiesis have been identified and their prognostic significance is under study. Mutations in the NPM gene have been reported in AML that lead to the abnormal cytoplasmic localization of the affected protein [ ].
However, evaluation of the prevalence and prognostic significance of NPM mutations in children with AML treated in the CCG trial failed to demonstrate any prognostic significance for this mutation in pediatric AML [ ]. In addition to such function-altering mutations, regulation of the expression level of various transcription factors may have biologic and prognostic significance.
Although the WT1 expression level at the time of diagnosis has been correlated with clinical outcome [ ], such findings have not been uniformly observed [ ]. However, more recently, it was demonstrated that patients with a high WT1 expression level at the end of induction had a worse clinical outcome, suggesting its utility as an MRD marker at the time of clinical remission [ ].
Telomerase activity has been implicated in leukemogenesis, and there are data to suggest that telomerase activity may have prognostic significance in pediatric AML [ ]. BAALC brain and acute leukemia, cytoplasmic is a gene whose elevated expression level has recently been associated with adverse outcome in adults with AML [ ]. AF1q , an MLL fusion partner whose expression regulates hematopoietic differentiation, is differentially expressed in AML, and a high expression level of this gene has been shown to be associated with an undifferentiated phenotype and worse outcome [ , ].
Substantiation of all novel prognostic markers should be done in large, multicenter trials, and preferably analyzed prospectively, prior to their use in therapeutic planning and stratification. In addition, there is a growing need for evaluation of all putative prognostic markers in the same patient population in order to delineate overlap and possible interaction with prognostic factors, as well as with the type of treatment used.
New technologies allowing the determination of gene- and protein-expression profiles have opened up an important era in refining the diagnostic subtyping of AML, identification of new prognostic factors, and drug development. DNA microarray analysis has allowed disease classification based on gene-expression profiling [ ]. This technology has recently been successfully applied to predict outcome in adult malignancies [ — ]. Genomic classification of relapse risk is being applied to pediatric AML and early data are encouraging [ ].
Lacayo et al. They identified an expression profile that identified patients with FLT3 mutations and were further able to determine high-risk and low-risk subpopulations among the patients with FLT3 mutations. Furthermore, they were able to validate their microarray findings using quantitative RT-PCR, wherein they assigned relapse risk using the expression level of two genes previously identified by microarray profiling. Yagi et al. They identified 35 genes whose expression pattern correlated with clinical outcome.
More recent studies in adult AML used microarrays to identify specific expression profiles that correlated with disease response and clinical outcome [ , ]. Such studies have demonstrated that the clustering was primarily driven by the presence of chromosomal alterations. This finding highlights the significant impact of the underlying cytogenetic characteristics of the leukemia and their profound prognostic significance.
Larger studies using gene-expression profiling for prognostic determination from pediatric cooperative group studies are required to establish the role of genomic profiling in risk identification in pediatric AML. Future application of this technology may not only allow for prognostic determination in AML, but may identify specific therapeutic targets. With the elucidation of the human genome sequence and emerging data on epigenetic changes, the field of molecular medicine is also moving toward exploring the utility of the proteome.
Proteomics allows for the identification of a protein-expression pattern just as genomics uses a gene-expression pattern. Although this field is in its early stages and data on clinical application are scarce, it remains a promising frontier in diagnostics and prognostics in AML. Despite significant efforts toward improving the clinical outcome of pediatric AML patients, much progress is still needed. A contributing factor to the relatively slow progress may be that, despite significant heterogeneity in AML, we have historically treated AML uniformly. The idea of identifying subpopulations within AML for treatment stratification is likely to play an increasingly important role in future therapeutic strategies.
APML has been proven to be a unique subgroup of AML with very specific therapy requirements in both children and adults. Other data are also emerging that particular morphologic or cytogenetic subgroups may respond differently to specific therapies [ 43 , , ]. The St. Jude Children's Research Hospital AML consortium is putting this hypothesis to test in an ongoing multicenter AML trial in which patients with specific FAB, molecular, or cytogenetic subtypes are treated differently, although such approaches may be compromised in their ability to reach firm conclusions without prospective randomization.
In addition, many risk factors have not been generally acted upon because of limited therapeutic options, lack of prospectively acquired data, and significant nonrelapse mortality, which has obscured appropriate statistical analysis of potential risk factors. At least three areas are emerging that have great potential to help identify high-risk patients. Cytogenetic markers associated with poor outcome appear to maintain significance across nearly all trials tested. Unfortunately, nearly half of these patients fail to achieve a CR, thus limiting possible postremission interventions.
Options to intervene in such high-risk patients must be carefully evaluated. Targeted therapies are being developed for patients with FLT3 mutations, but their clinical applications for newly diagnosed patients will require evaluation in clinical trials, and patients with MRD or poor cytogenetic markers may not have readily available alternatives.
At this time, the standard of care for patients who relapse is intensive chemotherapy remission reinduction prior to allogeneic SCT. If a patient group that is determined to be at an extremely high risk for relapse can be identified, it can be argued that such patients need to be considered for hematopoietic stem cell transplantation HSCT prior to relapse. Unfortunately, despite the routine utility of SCT in relapsed AML, its role in the treatment of high-risk patients has not been clearly established. The question of treatment options for high-risk patients needs to be addressed within the context of multi-institutional trials; and whether such high-risk patients are to be quickly transplanted or randomized to HSCT versus intensive chemotherapy with or without targeted agents needs be addressed.
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Given the nature of AML therapy, HSCT may be the only available short-term option for therapy intensification in high-risk patients, and because most patients do not have matched family donors for transplantation, the use of matched URD transplantation needs to be considered in patients without family donors. Given that HSCT, especially from a URD, carries significant short- and long-term toxicities, its utility in high-risk patients must therefore be carefully examined.
However, if patients at high risk for relapse do not receive an HSCT during CR1, there is a high chance that they will relapse and will need a transplant as therapy after relapse if they achieve a second CR. Thus, the option for these patients may not be whether they should receive an HSCT, but whether they should be transplanted in first or second CR if a second CR is achievable.
Similarly, for patients with prognostic features placing them in a good risk category, the use of HSCT from matched family donors remains controversial [ — ]. Several cooperative groups, including the MRC and BFM, have concluded that patients with good-risk AML can be effectively treated with only chemotherapy and that allogeneic HSCT should be reserved for patients who relapse [ , ].
This type of approach depends on the ability to reinduce a remission as well as the effectiveness of HSCT in this group of patients. North American studies have demonstrated that the best relapse-free and overall survival for pediatric patients with AML is achieved in those receiving family donor HSCT in CR1, except for patients with inv 16 [ , ]. Because HSCT may not have the same effectiveness in all groups of newly diagnosed or relapsed patients, as well as uncertainties regarding the long-term outcomes for relapsed patients following different initial therapies, questions regarding the application of HSCT should best be determined through prospective clinical trials.
As clinicians caring for children with AML, our most important objective is to improve the outcome with the least toxicity. Managing patients who are at extremely high risk for relapse is difficult, but the reality is that one may have to choose extremely intensive therapy to overcome disease resistance in at least the near future. Prognostic markers for relapse should also be prospectively studied and validated in large multi-institutional trials. Once such markers are validated, they must be acted upon, and a relapse threshold and survival after relapse must be established; patients identified with a particular marker s that would put them below an accepted threshold would be promptly referred for HSCT with the hope that this would improve outcome.
Future work should be directed not only toward identifying prognostic factors, but also toward therapeutically exploiting those factors. The development of specifically targeted therapies that will both cytoreduce the leukemic burden and also eliminate or control the leukemic stem cell population is likely to be critical for achieving improved outcomes for patients with AML. As these more effective therapies are developed to target one or more of the critical genetic changes observed in specific subtypes of AML, the role of SCT will hopefully decrease.
This hope should be applicable for children and adults with both high-risk as well as good-risk AML. User Name Password Sign In. Arceci, M. Accepted January 17, Previous Section Next Section. Overview Prognostic factors include host factors, response to therapy, as well as disease characteristics.
Host Factors Host factors, such as gender, age, race, and constitutional abnormalities, have been associated with outcome in pediatric patients with AML. Response to Therapy Response to therapy has been an important predictor of clinical outcome in leukemias. Primary Induction Failure Studies evaluating the morphologic presence of disease have shown that such patients have a dismal outcome even if they are reinduced into remission [ 2 , 10 ]. MRD Because morphologic disease response has been shown to be such a powerful prognostic factor, the role of disease persistence below detection at the morphologic level MRD has been evaluated as a prognostic factor in AML.
Molecular MRD The majority of the data on the detection of MRD in AML has been generated using polymerase chain reaction PCR -based methods in which detection of unique fusion genes has been correlated with morphologic relapse [ 12 — 15 ]. Immunophenotypic MRD Leukemic blasts usually express aberrant surface antigen patterns that differ from the pattern observed in normal progenitors.
Disease Characteristics Historically, characteristics believed to be inherent to leukemia have included factors such as diagnostic WBC, morphologic classification French American British [FAB] subtype , and biological characteristics such as cytogenetics. View this table: In this window In a new window. Table 1. WHO classification of acute myeloid leukemia. Cytogenetics Diagnostic cytogenetics is widely recognized as one of the most significant prognostic factors in AML.
Favorable, Cytogenetics. Table 2. Potential risk factors for pediatric acute myeloid leukemia. Unfavorable Cytogenetics Karyotypes associated with poor outcome have been identified in a small proportion of pediatric patients with AML. FLT3 Mutations. Figure 1. Figure 2. Novel Molecular Markers Investigations have been conducted to identify novel and more predictive markers of high-risk disease in AML in order to help in risk-based therapy.
Genomics and Proteomics in Risk Assessment New technologies allowing the determination of gene- and protein-expression profiles have opened up an important era in refining the diagnostic subtyping of AML, identification of new prognostic factors, and drug development. Previous Section. Leukemia ; 13 : 25 - CrossRef Medline Google Scholar.
A simple, robust, validated and highly predictive index for the determination of risk-directed therapy in acute myeloid leukaemia derived from the MRC AML 10 trial. Br J Haematol ; : 69 - Ethnicity and survival in childhood acute myeloid leukemia: A report from the Children's Oncology Group. Blood ; : 74 - Gamis AS.
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