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© 2003 American Society for Clinical Oncology Morphologic Dysplasia in De Novo Acute Myeloid Leukemia (AML) Is Related to Unfavorable Cytogenetics but Has No Independent Prognostic Relevance Under the Conditions of Intensive Induction Therapy: Results of a Multiparameter Analysis From the German AML Cooperative Group Studies
From the Department of Medicine III, Ludwig-Maximilians-University, Grosshadern, Munich, Germany. Address reprint requests to Torsten Haferlach, MD, Department of Internal Medicine III, Laboratory for Leukemia Diagnostics, Ludwig-Maximilians-University, Marchioninistr 15, 81377 Munich; email: torsten.haferlach{at}med3.med.uni-muenchen.de.
Purpose: On the basis of cytomorphology according to the French-American-British (FAB) classification, we evaluated the prognostic impact of dysplastic features and other parameters in de novo acute myeloid leukemia (AML). We also assessed the clinical significance of the recently introduced World Health Organization (WHO) classification for AML, which proposed dysplasia as a new parameter for classification. Patients and Methods: We analyzed prospectively 614 patients with de novo AML, all of whom were diagnosed by central morphologic analysis and treated within the German AML Cooperative Group (AMLCG)-92 or the AMLCG-acute promyalocytic leukemia study. Results: Patients with AML M3, M3v, or M4eo demonstrated a better outcome compared with all other FAB subtypes (P < .001); no prognostic difference was observed among other FAB subtypes. The presence or absence of dysplasia failed to demonstrate prognostic relevance. Other prognostic markers, such as age, cytogenetics, presence of Auer rods, and lactate dehydrogenase (LDH) level at diagnosis, all showed significant impact on overall and event-free survival in univariate analyses (P < .001 for all parameters tested). However, in a multivariate analysis, only cytogenetics (unfavorable or favorable), age, and high LDH maintained their prognostic impact. Dysplasia was not found to be an independent prognostic parameter, but the detection of trilineage dysplasia correlated with unfavorable cytogenetics. Conclusion: Our results indicate that cytomorphology and classification according to FAB criteria are still necessary for the diagnosis of AML but have no relevance for prognosis in addition to cytogenetics. Our results suggest that the WHO classification should be further developed by using cytogenetics as the main determinant of biology. Dysplastic features, in particular, have no additional impact on predicting prognosis when cytogenetics are taken into account.
ACUTE MYELOID leukemia (AML) is a heterogeneous disease as reflected by differences in the morphology of leukemic blasts, by variations in the clinical picture and therapeutic outcome, and by differences in their preceding history arising de novo or from a preleukemic state of myelodysplasia, or after treatment for another malignant disease. To date, morphology has remained the cornerstone of diagnosis and provided the basis for the first widely accepted classification system that was developed by the joint efforts of French-American-British (FAB) hematologists in 1976.1 With the progress in diagnostic techniques, subsequent modifications of the FAB proposal have also included cytochemistry, and cytogenetic and immunophenotypic analyses in specific subtypes.2–6 In recent years, cytogenetic and molecular techniques have provided deeper insights into the biology of AML and have partly unraveled the molecular genetic events that underlie the different AML subtypes. Therefore, strong associations were found between the AML subtypes M3 and M3v and the translocation t(15;17) and with the subtype M4eo and inv(16) or t(16;16).7–9 A weaker relation was found between AML M2 and the translocation t(8;21),10,11 whereas 11q23 aberrations were more frequently found in AML with involvement of the monocytic lineage.12,13 Using cytogenetic analyses, the following three major groups of AML can be distinguished: AML with balanced chromosomal aberrations as the primary abnormality, AML with unbalanced chromosomal aberrations, and AML without detectable cytogenetic abnormalities. The majority of AML with balanced aberrations comprise chromosomal translocations, the fusion partners of which have been identified, cloned, and functionally characterized. Most of the genes involved code for transcription factors that regulate essential steps in normal hematopoiesis and frequently involve core binding factors.14 AML with unbalanced chromosomal aberrations comprise gain and loss of chromosomal material but are as yet poorly characterized on the molecular level. In an effort to adapt the classification of AML to this knowledge and to pave the way toward a more biology-oriented grouping, a new classification system of AML was recently introduced by the World Health Organization (WHO).15,16 This classification is based on the following three major determinants: cytogenetics, the presence of dysplastic features, and the preceding history. For cases that cannot be categorized by these criteria, the descriptions of the FAB classification are maintained. This mixture of biologic and morphologic discriminators indicates that the new WHO classification must be considered as an up-to-date reflection of the current, still incomplete understanding of AML biology rather than as a definite end point. Therefore, controlled clinical trials are needed to verify the clinical relevance of the different categories in this classification and to test its broad applicability. This study in de novo AML was undertaken to assess the relevance of dysplastic features for classification and prediction of prognosis. The evaluation was based on a standardized therapeutic approach of intensive double-induction therapy of the German AML Cooperative Group (AMLCG) study.17 In addition to morphologic features, cytogenetics and several other clinical and laboratory parameters were assessed in a multiparameter analysis. The results indicate that cytomorphology and classification according to FAB criteria are still necessary for diagnosis, but that cytomorphology has only minor relevance for prognosis and treatment outcome. Dysplastic features, in particular, have no additional impact on predicting prognosis when cytogenetics is taken into account.
Patients and Protocols This study included 614 consecutive patients with de novo AML from whom bone marrow and blood smears were sent at diagnosis for central morphologic review to our institution between December 1992 and June 1999 (T.H., H.L., and W.G.). All patients were treated according to the protocol AMLCG-92 of AMLCG.18 In the AMLCG-92 trial, all patients less than 60 years of age received cytarabine (ara-C), daunorubicin, and thioguanine (TAD) followed by ara-C and mitoxantrone (HAM) as double induction and TAD consolidation, and were randomly assigned to long-term monthly maintenance versus a second consolidation course by a sequentially modified version of HAM (S-HAM). Patients 60 years of age or older received a second course of HAM with a reduced dose of ara-C of 1.0 g/m2 only if there was an inadequate response to the first cycle of TAD. TAD consisted of 100 mg/m2 of ara-C by continuous intravenous infusion daily on days 1 and 2 and a 30-minute intravenous infusion every 12 hours on days 3 to 8; a 30-minute intravenous infusion of 60 mg/m2 of daunorubicin on days 3, 4, and 5; and 100 mg/m2 of thioguanine orally every 12 hours on days 3 to 9. HAM consisted of 3 g/m2 of ara-C by intravenous infusion for 3 hours every 12 hours on days 1 to 3 and 10 mg/m2 of mitoxantrone by intravenous infusion for 30 minutes on days 3, 4, and 5. Patients with AML M3 or AML M3v were treated within the acute promyelocytic leukemia (APL) study of the AMLCG,19 and received chemotherapy as outlined above and simultaneous administration of 45 mg/m2 of all-trans-retinoic acid (ATRA) daily until complete remission or for a maximum of 90 days. All patients in complete remission were assigned to monthly maintenance over a period of 3 years versus one course of S-HAM as randomly assigned at the start of therapy. Monthly maintenance consisted of courses of 100 mg/m2 of ara-C by subcutaneous injection every 12 hours for 5 days, with a second drug being administered in rotation, comprising 45 mg/m2 of daunorubicin on days 3 and 4 (course 1), 100 mg/m2 of thioguanine orally every 12 hours on days 1 through 5 (course 2), 1 g/m2 of cyclophosphamide intravenous injection on day 3 (course 3), or thioguanine again (course 4) and restarting with daunorubicin (course 5). One course of S-HAM consisted of ara-C (1 g/m2 in younger patients and 500 mg/m2 in older patients) every 12 hours on days 1, 2, 8, and 9 combined with 10 mg/m2 of mitoxantrone on days 3, 4, 10, and 11. Before randomization, all patients gave their informed consent after having been advised about the purpose and investigational nature of the study as well as of the potential risks. The study is in accordance with the modified Helsinki Declaration, and the protocols received approval from the ethics committees of the participating institutions.
Cytomorphology In parallel, in all cases a detailed examination of bone marrow features was performed, including the following: percentage of blasts (type I, II, or III),21, monocytes, basophils, eosinophils (in case of AML M4eo, in addition, percentage of abnormal eosinophils), erythropoiesis, and MPO or NSE positivity, and detection of Auer rods during the investigation of MGG and MPO stains. The categorization of dysplasia followed the definitions of Goasguen et al22 and the new WHO classification.16 Dysgranulopoiesis (DysG) was defined as more than 50% of at least 10 polymorphonuclear neutrophils (PMN) being agranular or hypogranular, or with hyposegmented nuclei (pseudo Pelger-Huet anomaly). At least 25 cells were evaluated, but usually 100 cells were counted. MPO deficiency in the PMN was defined as 50% or more MPO-negative cells in at least 10 PMN after strong positivity of eosinophils or other PMN was confirmed. Dyserythropoiesis (DysE) was defined as 50% or more of dysplastic features in at least 25 erythroid precursors: megaloblastoid aspects, karyorrhexis, nuclear particles, or multinuclearity. Dysmegakaryopoiesis (DysM) was diagnosed when at least three megakaryocytes or more than 50% in at least six cells showed dysplastic features such as microkaryocytes, multiple separated nuclei, or very large single nuclei. Trilineage dysplasia (TLD) was diagnosed when DysG, DysE, and DysM were detectable. According to the WHO proposal, the multilineage dysplasia category was added, comprising dysplastic features in two or three cell lineages.15,16
Cytogenetics
Immunophenotyping
Definition of Clinical Response
Statistics
Pretherapeutic Characteristics Between December 1992 and May 1999, 614 consecutive patients with de novo AML entered the trials AMLCG-92 or AMLCG-APL and were fully evaluated for pretherapeutic characteristics, remission duration, and survival. Of these patients, 314 (51.1%) were male, 300 (48.9%) were female, and the median age was 53 years (range, 16 to 82 years).
Cytomorphologic classification according to FAB criteria.
In all cases, bone marrow smears were analyzed, and in most cases, blood smears were also evaluated. The frequency of FAB subtypes is shown in Table 1
Dysplastic features. In 45.5% of patients, no dysplastic features were detectable. DysM was observed in 15.3% of patients as a single-cell lineage, and DysG alone was detected in 9.9% of patients. DysE alone or dysplasia in only two cell lineages was seen in only 2.3 to 5.2% of patients. Dysplastic features in all three cell lineages (TLD) were detected in 14.9% of patients.
The frequency of dysplasia found in our investigation correlated with data of other published studies (Table 2
According to the WHO proposal,15,16 we grouped patients with no dysplasia and with dysplastic features in one cell lineage and compared them to patients with so-called multilineage dysplasia (ie, two or three lineages involved). This led to the following distribution of patients: dysplasia in zero or one lineage, n = 462 (75.2%) versus dysplasia in two or three lineages, n = 152 (24.8%). Cytogenetics. Cytogenetic data were available for 453 (73.7%) of 614 patients. Three subgroups according to standard definitions given above were analyzed.36 Ninety-four patients (20.7%) were classified as favorable risk, 280 patients (61.8%) were classified as intermediate risk, and 79 patients (17.5%) were classified as unfavorable risk. The intermediate-risk group comprised 205 patients showing a normal karyotype and 75 patients with one or two karyotype aberrations. In the latter 75 cases, chromosome aberrations comprised trisomy 8 (n = 22), abnormalities (abn) of 12p (n = 5), abn 7 excluding 7q- and monosomy 7 (n = 5), abn 1 (n = 4), trisomy 21 (n = 4), trisomy 13 (n = 4), abn 3 (n = 3), abn 2 (n = 3), abn 18 (n = 2), abn 9 (n = 2), loss of one sex chromosome (n = 2), 13q- (n = 1), abn 17p (n = 1), abn 20 (n = 1), and abn 11 (n = 1). Other rare abnormalities were found in 38 cases. In 27 of 30 patients with AML M3, nine of 11 patients with M3v, and 24 of 38 patients with AML M4eo with morphologic features fulfilling the FAB criteria, cytogenetic and/or molecular genetic results were available in addition to morphology and proved the morphologic diagnosis. Thirty patients with AML and cytogenetically proven t(8;21) were classified as AML M2 (n = 26) and as AML M1 (n = 4) cytomorphologically. Blast count. According to FAB definitions, the proportion of blasts in the bone marrow was more than 30% in all cases.1 For statistical analysis, the percentage of blasts was grouped into three subcategories: 30% to 50% (50 [8.1%] of 614 patients); 51% to 80% (284 [46.3%] of 614 patients); and more than 80% (280 [45.6%] of 614 patients). In another grouping, the percentage of blasts was grouped into two subcategories comparing patients less than 75% (257 [41.8%] of 614 patients) versus more than 75% (357 [58.2%] of 614 patients). Auer rods. Auer rods were detectable in 279 (45.6%) of 612 patients and were absent in the other 333 (54.4%) assessable patients, using MGG staining and/or MPO reaction. Lactate dehydrogenase (LDH) levels. We demonstrated previously that LDH at diagnosis had a prognostic impact.17 In 566 of 614 patients, LDH measurements were available for this analysis. LDH was in the normal range (< 240 U/L) in 109 cases (19.3%) and was elevated more than 240 U/L in the other 457 patients (80.7%). The median LDH level was 420 U/L (range, 63 to 5,220 U/L). To define a poor prognostic group according to LDH, we selected patients with LDH greater than 700 U/L, representing the upper quartile of the population, with the cutoff point being approximately three times the upper limit of normal.17 We observed 408 (72%) of 566 patients below 700 U/L and 158 (28%) of 566 cases above this threshold.
Response to Induction Therapy and Survival
Cytomorphologic classification according to FAB criteria. The FAB subtype did not make an impact on response rates with the exception of cases with AML M3, M3v, and M4eo (Table 3  ). For these patients, this translates into a significantly better OS (P < .001; Fig 2A and 2B) and EFS in comparison with all other FAB subtypes (P < .001; figures not shown).
Dysplastic features. Patients without any dysplasia achieved a CR in 71.5% of cases, NR was seen in 13.7% patients, and 14.8% of patients suffered an ED. In patients with dysplasia in only one lineage, the CR rate was 61.1%, 22.7% had NR, and the ED rate was 16.2%. Patients having dysplasia in two lineages showed a CR rate of 67.9%, an NR rate of 19.6%, and an ED rate of 12.5%. In TLD patients, the CR rate was 66.7%, the NR rate was 24.4%, and the ED rate was 8.9% (Table 4 ).
The evaluation of OS and EFS was made for the four subcategories as defined by Goasguen et al22 (0 v 1 v 2 v 3 lineage) and for the two subgroups of zero plus one versus two plus three lineages according to the WHO proposal.15,16 The OS and EFS survival of patients grouped in the four subcategories both demonstrated no significant difference (Fig 3 for OS). Furthermore, no statistical differences for OS or EFS were seen with respect to the zero plus one versus two plus three lineages involved according to the WHO categories (P = .67 for OS and .86 for EFS, respectively; Fig 4).
With respect to age (< 60 v  60 years), the OS and EFS differed significantly in favor of younger patients (P = .0001). However, dysplasia had no further impact on the prognosis of the patients within the respective age groups. This was true both for calculations according to the number of lineages involved (0 v 1 v 2 v 3) and for calculations according to the WHO proposal. For patients 60 years old, the median OS was 10 months (zero plus one dysplasia) versus 8 months (multilineage dysplasia; P = .54). The median EFS was 5 months (zero plus one dysplasia) versus 3 months (multilineage dysplasia; P = .2). Cytogenetics. In patients with favorable risk according to cytogenetics, the CR rate was 83%, the NR rate was 6.4%, and the ED rate was 10.6%. For patients in the intermediate risk group, the CR rate was 69.5%, the NR rate was 17.4%, and the ED rate was 13.1%. In contrast, in patients with unfavorable cytogenetics, the CR rate was only 48.6%, the NR rate was 32.5%, and the ED rate was 18.7%.
The difference for OS and EFS survival was highly significant between favorable- and intermediate-risk patients and between intermediate- and unfavorable-risk patients (Fig 5
We also performed a subgroup analysis on the basis of the WHO criteria for dysplasia. There was no impact of dysplasia (zero plus one dysplasia v multilineage dysplasia) on OS and EFS among patients with favorable-risk cytogenetics (P = .36 and .92, respectively) or with unfavorable-risk cytogenetics (P = .16 and .09, respectively). Also, for the intermediate-risk group, including patients with normal karyotypes and other aberrations, no statistical differences were observed (OS, P = .02; EFS, P = .19; Table 5 ). In addition, the EFS was not influenced by dysplasia (zero plus one dysplasia v multilineage dysplasia) in patients with normal karyotype (P = .24), in patients with aberrant karyotype changes in the intermediate-risk group (P = .81), and in patients in whom no cytogenetic analysis or data were available (n = 156; P = .42).
For further calculations, we followed the WHO classification and first excluded all patients with t(8;21), t(15;17), inv(16), or 11q23 abnormalities. When comparing zero or one-lineage dysplasia (n = 356) versus two- or three-lineage dysplasia (n = 135), no statistical differences were found for OS and EFS (P = .24 and .34, respectively).
A correlation was found, however, between the presence or absence of dysplastic features and cytogenetic subgroups (P < .001, Table 6
Blast count. Using a threshold of 75% of blasts in the bone marrow, the CR was 68.9% in patients with blasts below 75% and 66.1% in patients with a blast count of 75% or higher; NR was achieved in 20.6% and 14.9%, respectively; and 10.5% and 19% of patients, respectively, suffered an ED (not significant). However, a better prognosis was demonstrated for patients with lower blast counts at diagnosis. The median OS was 24 months for patients with blasts below 75% and only 14 months for patients demonstrating more than 75% of blasts in the bone marrow. This translated into a significantly better OS (P = .009) but not a significantly better EFS or relapse-free survival (P = .08 and P = .17, respectively; figures not shown).
Auer rods.
When Auer rods were detected, 72.2% of patients reached a CR, 15.4% of patients had an NR, and 12.4% of patients suffered from ED. In comparison, for patients without Auer rods, only 63.4% of patients reached a CR, NR was documented in 21.3% of patients, and ED was seen in 15.3% of patients. Therefore, the detection of Auer rods was correlated with a better OS (P = .00031, Fig 6
Age. Patients younger than age 60 years (n = 410) had a CR rate of 72.6%, an NR rate of 13.4%, and an ED rate of 14%. For patients age 60 years and older (n = 204), the CR rate was 56.3%, the NR rate was 28.9%, and the ED rate was 14.8%. This translated into a significantly different OS (P < .0001) and EFS (P < .0001).
LDH.
With respect to the previously established threshold of LDH less than or more than 700 U/L, the CR rate was 71.0%, the NR rate was 12.7%, and the ED rate was 16.3% in patients with LDH less than 700 U/L. In contrast, for patients with LDH
Univariate and multivariate statistical analysis. For univariate and multivariate analyses, we selected those factors that had demonstrated a significant prognostic impact and combined them with factors that had shown their prognostic impact in preceding analyses of the AMLCG studies. Parameters tested were age, LDH at diagnosis, dysplasia, Auer rods, and karyotype. Results of univariate analysis based on  2 testing for OS and EFS are listed in Tables 7 and 8.
In a second step, we combined factors demonstrating significance in univariate analysis in an additional multivariate analysis. All parameters were available in 417 of 614 patients. Because dysplasia showed no influence on OS and EFS in the univariate analysis, it was discarded from further calculations. The results of the final model are listed in Tables 9 and 10.
The current study was performed to assess the clinical significance of the recently introduced WHO classification for AML15,16 and, particularly, to evaluate the impact of dysplastic features on response to induction therapy and long-term outcome. The data were obtained on 614 consecutive patients with de novo AML who were treated in two studies of the AMLCG. The obtained results clearly demonstrate that the morphologic detection of dysplasia has no prognostic importance for remission rate, disease-free survival, or OS. Dysplastic features were associated with other factors of poor prognosis and were more frequent in patients with an unfavorable karyotype. A multivariate analysis, however, revealed no independent prognostic significance for any subgroup analyzed. Therefore, dysplastic features were also detected in other cytogenetic subgroups. Still, even within the three major cytogenetic subgroups, no differences in response rates were observed among patients with or without morphologic signs of dysplasia. This conclusion also remained valid when the more refined criteria of dysplastic subgroups as proposed by Goasguen et al22 were applied. This finding contradicts, to some degree, preceding studies by other investigators who reported an inferior outcome for patients with dysplastic features with respect to remission rate or EFS.22,26,28,30,32,34,35 However, the criteria for dysplasia varied considerably in these investigations. Some investigators26,27,30,34 did not apply the criteria defined by Goasguen et al.22 In addition, some of them did not consider cytogenetics for statistical analysis.26,37 The most striking differences showing worst prognosis for TLD patients in comparison to non-TLD patients were published by Estienne et al28 and by Kuriyama et al.31,35 However, in all three series, patients with t(8;21) or t(15;17) accounted for 33.6%, 31.3%, or 33% of patients, respectively, in the non-TLD subgroup but were never detected in the TLD subgroup. This may explain the better outcome of non-TLD patients in these studies that could not be seen in our analysis, which demonstrated only 13.3% of patients with favorable cytogenetics in the non-TLD group. It should be emphasized that chemotherapy was less intensive in all preceding studies compared with the AMLCG approach of intensive double-induction and postremission therapy. Therefore, the statement that dysplasia has no prognostic implication can only be made under the conditions of the currently evaluated therapeutic concept and may be different for less-intensive treatment modalities. Still, the data clearly demonstrate that the category of dysplasia cannot be accepted as a general and independent criterion for the classification of AML or for the definition of prognostic subgroups. On the other hand, the prognostic significance of other categories of the WHO proposal was confirmed under the conditions of a multivariate analysis considering a broad spectrum of potential prognostic parameters. In particular, the presence of numeric karyotype aberrations or of balanced chromosomal changes was strongly related to treatment response and long-term outcome, and supports the WHO proposal to discriminate among these AML subtypes. In addition, patients older than 60 years of age and patients with high LDH in the serum at diagnosis demonstrated a shorter EFS and OS. Although a high LDH is not generally accepted as a prognostic determinant by other groups, cytogenetics and age are unequivocally considered as major predictors of therapeutic outcome. Despite this fact, the relation between cytogenetics and prognosis cannot be considered independent of therapy. In a preceding study from AMLCG, it could be demonstrated that the incorporation of high-dose ara-C into induction therapy significantly improves the remission rate of patients with unfavorable cytogenetics and abolishes the difference for OS in patients with favorable karyotypes.37 In contrast, for high-dose ara-C applied during consolidation therapy, patients with t(8;21) particularly benefited from this treatment, as indicated by Cancer and Leukemia Group B data.38 A striking example for the impact of therapy on the prognosis of cytogenetic subgroups is also given by the incorporation of ATRA into the treatment of acute promyelocytic leukemia.19,39 Although this AML subtype was characterized by a high ED rate and an overall intermediate prognosis before the ATRA era, it currently has a very low rate of induction failures and an excellent long-term prognosis. These examples illustrate that any prognostic determinant, including cytogenetics, can only be used in association with specific therapies and should not be considered as a treatment-independent variable. Such considerations are also relevant for using cytogenetics as a means for the classification of AML. In this context, cytogenetics should be considered predominantly as a reflection of biology rather than of treatment response and prognosis. This approach is realized by the WHO proposal, which discriminates in its first step of hierarchy between AML with recurrent balanced chromosomal aberrations [ie, t(8;21), t(15;17), inv(16), and 11q23- abnormalities] and all other AML subtypes. The mixture of cytogenetic and morphologic criteria that underlies this classification, however, indicates that the understanding of AML biology is still unsatisfactory and that more information is needed to design a biology-based classification system. This article supports these efforts because it suggests that the morphologic parameter of dysplasia can be discarded if other studies confirm the lack of biologic and clinical significance. It also suggests developing the WHO classification further by using cytogenetics as the main determinant of biology. Accordingly, AML can be grouped into the following three major categories: (1) AML with balanced chromosomal aberrations as the primary abnormality; (2) AML with unbalanced karyotype abnormalities; and (3) AML without detectable cytogenetic aberrations. Within each of these main groups, additional subgroups can be defined as the current knowledge increases. Currently, distinct subentities can already be defined, such as AML with t(8;21), t(15;17), or inv(16), within the category of AML with balanced chromosomal abnormalities, or of AML with trisomy 8 or 5q- in AML with unbalanced karyotype abnormalities.36,40 Even in AML without detectable cytogenetic aberrations, subgroups, such as AML with FLT3 mutations or MLL tandem duplications, can already be defined.41,42 Such a flexible classification system stimulates both clinicians and basic researchers to consider this system predominantly as a reflection of disease biology rather than as a primary guide for therapeutic decisions. It also provides the basis for an easy adaptation to new insights into the biology that will certainly arise in the near future using microarray technology, for example.43–45 Diagnosis of AML will still depend on morphology, immunophenotyping, and, in part, on metaphase cytogenetics. However, the classification and pathophysiologic understanding of AML is on the move away from morphology toward a biology-based system and, in consequence, also toward a new orientation of therapeutic strategies along this path.
Supported by grant no. M17/92/Bü1 from Deutsche Krebshilfe, Bonn, Germany.
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ABSTRACT
INTRODUCTION
