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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Third Medical Department for Hematology and
Oncology and the Ludwig Boltzmann Institute for Leukemia Research and
Hematology, Hanusch Hospital, Vienna, Austria.
In 1999 a working group of the World Health Organization (WHO)
published a revised classification for myelodysplastic syndromes (MDS):
RA, RARS, refractory cytopenia with multilineage dysplasia (RC+Dys),
RAEB I and II, del (5q) syndrome, and MDS unclassifiable. Chronic
myelomonocytic leukemia (CMML) and RAEB-t were excluded. Standard
French-American-British (FAB) and new WHO classifications have been
compared in a series of patients (n = 431) from a single center,
analyzing morphologic, clinical, and cytogenetic data. According to the
WHO findings, dysgranulocytopoiesis or dysmegakaryocytopoiesis only
were found in 26% of patients with less than 5% medullary blasts.
These patients are thus unclassified and should remain in the
subgroups RA and RARS. Splitting of heterogeneous RAEB into 2 subgroups
according to blast count was supported by a trend to a statistically
significant difference in the single-center study population. Patients
with CMML whose white blood cell counts are above 13 000/µL may be
excluded from the MDS classification, as warranted by WHO, but a
redistribution of patients with dysplastic CMML according to medullary
blast count leads to more heterogeneity in other WHO subgroups.
Although the natural courses of RAEB-T and acute myeloid leukemia (AML)
with dysplasia are different, comparable median survival durations
after treatment in patients with RAEB-T and AML were in favor of the
proposed 20% medullary blast threshold for AML. The homogeneity of
subgroups was studied by evaluating prognostic scores. A significant
shift into lower IPSS risk groups was evident in the new
classification. These data cannot provide evidence for the new WHO
proposal, which should not be adopted for routine clinical use at
present. Some of its aspects can provide a starting point for further
studies involving refined cytogenetics and clinical results.
(Blood. 2001;98:2935-2941) Myelodysplastic syndromes (MDS) are clonal
hematologic stem cell disorders characterized clinically and
morphologically by ineffective hematopoiesis. The natural history of
these diseases ranges from a chronic course that may span years to a
rapid course toward leukemic progression. Unfortunately, the
nomenclature and classification systems used to describe these
conditions are cumbersome and contentious. These diseases were
initially described as preleukemias; then, in 1976, the
French-American-British (FAB) group renamed these disorders
dysmyelopoietic syndromes.
In 1982, this same study group proposed a classification based on
morphologic features in blood and bone marrow, namely medullary and
peripheral blast cell count, ringed sideroblasts, number of monocytes
in peripheral blood, and Auer rods.1 Five subgroups with
significantly different prognoses were established: refractory anemia
(RA), RA with ringed sideroblasts (RARS), RA with excess of blasts
(RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic
leukemia (CMML). For nearly 2 decades this classification served as the
standard for the evaluation of MDS, though further characteristics of
MDS subtypes In 1999, the World Health Organization (WHO) published a revised
classification of MDS.13 The definitions of RA and RARS became more consistent and included the presence of dysplastic features
in the erythroid lineage only. At the moment RAEB remains unchanged,
though some investigators suggest further discrimination into RAEB I
with 5% to 10% and into RAEB II with 11% to 20% blasts in the bone
marrow. Three new subgroups were incorporated: (1) refractory cytopenia
with multilineage dysplasia (RC+Dys), which is equivalent to RA or RARS
in the FAB classification with the presence of dysplastic features in 2 or 3 cell lineages; (2) del (5q) syndrome, characterized by
dysplastic features in the erythroid lineage only, thrombocytosis, and
hypolobulated micromegakaryocytic hyperplasia (an isolated interstitial
deletion of the long arm of chromosome 5 is now a distinct entity); and
(3) MDS unclassifiable (MDS unclass). Two other FAB subgroups have been
excluded from the new MDS classification: RAEB-T, because of
similarities in biologic function and treatment strategies with acute
myeloid leukemia (AML), and CMML, because of its close relation to
myeloproliferative diseases. CMML, together with atypical chronic
myeloid leukemia (aCML) and the juvenile form of CMML, JMML, is now
part of a new disease group called myelodysplastic/myeloproliferative
diseases, and RAEB-T ceases to exist because of the new threshold of
20% blasts in the bone marrow set for AML.
In this study we provide a comparison of the FAB and WHO
classifications by evaluating data from 431 well-documented patients with primary MDS whose disease was diagnosed at our institution between
1976 and 1999.
All patients with primary MDS (n = 431) that was diagnosed
between 1976 and 1999 at the Department of Hematology and Oncology of
the Hanusch Hospital in Vienna were subjected to a retrospective analysis. Patients with secondary MDS were excluded from this study.
Care was also taken to eliminate other borderline diseases such as
aCML, paroxysmal nocturnal hemoglobinuria, and reactive bone marrow
changes. Diagnosis was made by cytomorphologic and histologic methods
according to the proposals made by the FAB group in 1982.1
Dysplasia of the 3 cell compartments in the bone marrow was assessed
according to published criteria Patients were evaluated for clinical features and for blood and bone
marrow parameters at the time of diagnosis and were followed up for
survival and leukemic progression. In most patients, data for
cytogenetic bone marrow examinations was also available. Cytogenetic analysis was carried out according to standard procedures at our institution using the tri-staining method for simultaneous production of fluorescent R and C bands.14 Whenever possible, 20 or
more metaphases from each patient were analyzed to demonstrate the clonal nature of the aberrations. Analysis was performed according to
the international system for human genetic nomenclature.15
We calculated prognostic scores for both classification systems using
the following scoring systems: international score (IPSS) for all
patients with WBC counts below 12 000/µL and available cytogenetics16 and the prognostic index (PI) score based on cytogenetics only.17
Data were given as counts, percentages, medians, ranges, and the
Kendall Evaluation of patients according to FAB MDS
According to the IPSS definition, 222 patients were evaluable with 58%
in the lower risk groups (low, 23%; intermediate 1, 35%) and 42% in
the higher risk groups (intermediate 2, 23%; high, 19%). Details for
the different subgroups are shown in Table 1. Figure
1 shows the corresponding survival curves
for the 5 MDS entities according to the FAB classification. Two
different risk groups can easily be discriminated
Evaluation of patients according to WHO-MDS
Because of the low number of patients, the subgroups with RARS and del
(5q) syndrome were ineligible for statistical evaluation of survival
and preleukemic duration. Remarkably, the subgroup with refractory
cytopenia with multilineage dysplasia had a longer median survival
duration (86 months) than the assumed low-risk group with RA (66 months; P = .68). Although MDS unclassifiable had a median
survival time of 67 months, the unchanged subgroup with RAEB still had
a median survival duration of 15 months. Survival time differences
between RAEB I (18 months) and RAEB II (12 months) were not
statistically significant, but P = .08 indicated a certain trend toward significance. Concerning the transition to AML, striking features were the low rate of 11% for the RC+Dys group (compared to
26% for the RA group; P = .02) and the high rate of 44%
for the patients defined as MDS unclassifiable; of interest also was the significant difference between RAEB I and RAEB II (28% vs 52%;
P = .03) (Table 2). The IPSS, according to its
definition,16 could be used to evaluate 153 patients with
76% in the lower risk groups (low 31%; intermediate-1, 45%) and 24%
in the higher risk groups (intermediate-2, 19%; high, 5%). Details
for the different subgroups are shown in Table 2. Figure
2 shows the corresponding survival curves
for the 5 MDS entities according to the WHO proposal (P < .01; no survival curve for del (5q) syndrome was
calculated). Based on survival curves alone, the subgroups according to
the WHO classification, apart from RAEB (or RAEBI and RAEBII) were similar (P = .90).
Evaluation of patients with RAEB-T and CMML RAEB-T (n = 51).
Patients with RAEB-T were incorporated in the AML group because the
threshold for the blast cell count in the bone marrow was reduced from
30% to 20%. At our institution, 16 of 51 (31%) patients with RAEB-T
were treated with AML-style induction therapy and had a median survival
duration of 11 months. To evaluate this cohort retrospectively, we
compared these patients with 448 unselected AML patients (de novo, or
with prior MDS phase and therapy-related), 258 (58%) of whom underwent
induction chemotherapy. Median overall survival duration was 6 months
for all AML patients and 11 months for the treated subgroup (not
significantly different from the respective RAEB-T subgroups). Among
the patients with AML, 138 (31%) had a previous MDS phase. Median
survival duration of these patients was 6 months untreated (compared
with RAEB-T, P < .01) and 8 months in 52 (38%) patients
receiving AML treatment (compared with RAEB-T, P = .13).
These results are summarized in Table
3.
CMML (n = 99). In the first publication, the CMML subgroup was excluded from the WHO classification of MDS. Recently, WHO proposed a refined classification by which CMML with WBC counts lower than 13 000/µL would now be considered MDS and would be classified according to the medullary blast cell count and the number of dysplastic cell lineages in the bone marrow.20 In our CMML cohort of 99 patients, 64 had the dysplastic type of disease and 35 had the proliferative type. Fifty-two patients with dysplastic disease were reclassifiable as follows: 5 patients with RC+Dys, 46 patients with RAEB (of whom 6 had RAEB I and 40 had RAEB II), and 1 patient with MDS unclassifiable. As expected, the RA and RARS subgroups did not change. Concerning the median survival duration for each subgroup, no significant differences were observed. Analysis of a possible redistribution of unclassifiable MDS and CMML Taking into consideration patients with CMML whose WBC counts were below 13 000/µL and redistributing patients with unclassifiable MDS with less than 5% blast cells in the bone marrow and dysplastic features in only one cell lineage except the erythroid, one yielding 33 RA and 17 RARS patients, 333 patients were classifiable according to the modified WHO proposal: 76 patients with RA (median survival, 63 months), 21 patients with RARS (median survival, 77 months), 96 patients with RC+Dys (median survival, 86 months), 138 patients with RAEB (median survival, 18 months), of whom 56 with RAEB I and 82 with RAEB II (median survival, respectively, 27 and 15 months; P = .23), 1 patient with del (5q) syndrome and 1 patient with MDS unclassifiable. Finally, Table 4 shows the major features of this refined WHO classification and Figure 3 shows the corresponding survival curves, which, except for RAEB I and RAEB II, are still close to each other and lack statistical significance in this population (P = .42).
For nearly 2 decades, the FAB classification of myelodysplastic syndromes was the criterion standard and was essential for clinicians, morphologists, and pathologists working in and investigating the field of MDS. Nearly all studies performed on MDS biology, morphology, treatment, and prognosis were based on the FAB classification. Nevertheless, it was obvious that this classification had some disadvantages, which were addressed by the WHO proposals for a new classification. The comparison was performed by evaluating data of a single-center MDS cohort that had characteristics similar to those of other large MDS study populations, except for a slightly higher percentage of women. However, no significant differences in outcome existed between the male and female patients, even in subgroup analysis (data not shown). The FAB subgroups were heterogeneous. Several studies provided evidence
that the division of RA (and RARS) into RA (and RARS) with dysplastic
features in the erythroid cell lineage only and into refractory
cytopenia with dysplasia in 2 or 3 cell lineages was useful in terms of
prognosis.11,12,21 Details of the splitting, as warranted
by the WHO classification, are shown in Figure
4. Our data do not confirm these results.
There was no significant difference in median overall survival time
between RA and RC+Dys classified according to the WHO proposal. In
contrast to our expectations, the transition rate into AML was
considerably lower in RC+Dys than in RA (Table 2). Thus, our data
cannot support the proposed splitting of RA and RARS according to FAB
in the WHO classification.
A considerable number of patients in our study population had blast cell counts in the bone marrow that were lower than 5% and dysplastic features in only one cell lineage, other than the erythroid one. Using the subtype definitions according to the first WHO proposal, these patients did not fit into the RA, RARS, or RC+Dys subgroup and remained unclassifiable, though they are still closely related to these 3 entities. To reduce the number of patients with MDS unclassifiable, it would be practicable to include patients with only dysplasia of granulocytopoiesis or megakaryocytopoiesis in the subgroups RA and RARS according to the WHO classification, as shown in Figure 4. In the FAB classification, the RAEB entity was heterogeneous, with blast cell counts in the bone marrow ranging from 5% to 20%. Because this medullary feature is the most important single prognostic parameter and several analyses showed that a threshold of 10% is of prognostic importance, the splitting into RAEB I and RAEB II seems to be justified.16,22,23 Our results in this respect indicate a trend toward significance. Furthermore, the significant difference in transition rate into overt AML suggests that dividing RAEB into 2 subtypes according to the medullary blast cell count may be reasonable. CMML, a heterogeneous entity, shares features with myelodysplastic syndromes and myeloproliferative disorders. However, until the WHO proposals, no agreement could be reached whether it should be assigned to the group of myeloproliferative diseases or myelodysplastic syndromes. Several studies were performed to distinguish a dysplastic and a proliferative variant of CMML, with an arbitrary leukocyte threshold of 13 000/µL. Analysis of our study group provided significant differences between both entities in terms of overall survival and other features (eg, lactate dehydrogenase).4-6,24 We therefore agree that patients with CMML whose WBC counts are above 13 000/µL should be removed from the MDS group and assigned to the group of myeloproliferative disorders. However, in our opinion, redistribution of patients with dysplastic CMML among the other subgroups, as warranted by the WHO group, would lead to a much more heterogeneous classification.20 The dysplastic variant of CMML should remain a distinct entity among the myelodysplastic syndromes. RAEB-T was removed from the MDS classification according to WHO because of similarities with AML in biologic function and treatment strategies.25 As shown in the "Results" section, median survival times are identical in RAEB-T and AML and indicate similarity in disease prognoses. However, in subgroup analysis, patients with RAEB-T had significantly longer median survival times than AML patients with dysplasia (treated and untreated, Table 3), indicating a different stage of disease, as reflected in the original FAB classification. Comparing only treated patients, survival data are not different. The use of other prognostic instruments can be helpful for further decision making. Prognostic scoring systems are important for risk assessment at time of diagnosis, especially if classification systems remain insufficient in this respect, and they are necessary for risk stratification in clinical trials. The most recent and powerful instrument established for MDS classified according to the FAB proposal is the IPSS, primarily based on medullary blast cell count, number of cytopenias, and cytogenetics.16 It is apparent that comparing both classifications in this respect represents a significant shift to the lower risk groups according to the IPSS. Although in the FAB classification 57% of the patients were in the lower risk (low and intermediate-1) groups and 43% were in the higher risk (intermediate-2 and high) groups, in the WHO classification 76% of the patients belonged to the lower risk groups and only 24% to the higher risk groups. Taking into consideration the refined WHO proposal, the results were still in favor of the lower risk groups, with 69% versus 31%. This phenomenon can easily be explained: in the higher risk groups, RAEB-T and (partially) CMML are removed. Consequently, this would have implications for future clinical trials, especially in high-risk MDS, because of a significantly lower number of eligible patients. Furthermore, new prognostic models, including cytogenetic analysis, for the changed AML patient population are warranted. Thus, the role of the IPSS as the predominant prognostic instrument seems to be uncertain in the new WHO classification. As mentioned above, it was established by evaluating data of patients classified according to the FAB proposal. Given that inclusion criteria (especially the upper limit for the medullary blast cell percentage) have been changed in the WHO classification, the IPSS maintains its validity even if its use in the WHO remains unclear. Nevertheless the major prognostic importance of cytogenetics in
MDS is evident and could be confirmed by our study group by establishing the PI score.17,23,26,27 Based on
cytogenetics only, it is easily applicable in both classification
systems: Figure 5 illustrates the
corresponding survival curves, supporting once more the importance of
cytogenetics in MDS. In this respect, the WHO proposal took into
account the well-known del (5q) syndrome, characterized by refractory
anemia (FAB) with thrombocytosis, hypolobulated micromegakaryocytic
hyperplasia, and an isolated interstitial deletion of the long arm of
chromosome 5 as a distinct entity. According to this definition, the
del (5q) syndrome is a rare disease with good
prognosis.28,29 In contrast, a subgroup of all patients
with an isolated deletion of the long arm of chromosome 5, excluding
the above-mentioned criteria, would be too heterogeneous, indicating
against the formation of a distinct subgroup. Therefore, prospective
multicenter studies with detailed evaluation of cytogenetics, preferably metaphase and interphase analyses, are warranted to define
other low- or high-risk entities based on structural or numerical
aberrations, such as the 7q syndrome in childhood MDS.
Our data from a single-center experience cannot provide clear evidence that the new WHO proposal improves the standard FAB classification. The original goal of the WHO study group was to establish a classification, for the use of pathologists and clinicians, that included morphologic, biologic, and clinical features of MDS. The new WHO proposal has to be validated for all these aspects in unselected patient populations. Because of the heterogeneity of MDS, larger multicenter studies will be needed to finally resolve the issue of a new classification for these disorders. At present, with respect to our data, adopting the WHO proposal as a final classification seems not to be justified. Nevertheless, some aspects of this proposal could be a starting point for further investigations toward a classification for MDS.
Submitted February 27, 2001; accepted July 9, 2001.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Thomas Nösslinger, Third Medical Department for Hematology and Oncology, Hanusch Hospital, Heinrich Collinstrasse 30, A-1140 Vienna, Austria; e-mail: thomas.noesslinger{at}wgkk.sozvers.at.
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J. W. Vardiman, N. L. Harris, and R. D. Brunning The World Health Organization (WHO) classification of the myeloid neoplasms Blood, September 18, 2002; 100(7): 2292 - 2302. [Abstract] [Full Text] [PDF]
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S. M. Dunkley, A. Manoharan, Y. L. Kwan ;, T. Nosslinger, R. Reisner, H. Tuchler, E. Pittermann, and M. Pfeilstocker Myelodysplastic syndromes: prognostic significance of multilineage dysplasia in patients with refractory anemia or refractory anemia with ringed sideroblasts Blood, May 15, 2002; 99(10): 3870 - 3872. [Full Text] [PDF]
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J. M. Bennett, R. D. Brunning, and J. W. Vardiman Myelodysplastic syndromes: from French-American-British to World Health Organization: a commentary Blood, April 15, 2002; 99(8): 3074 - 3075. [Full Text] [PDF]
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 P. L. Greenberg, N. S. Young, and N. Gattermann Myelodysplastic Syndromes Hematology, January 1, 2002; 2002(1): 136 - 161. [Abstract] [Full Text]
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Top
Abstract
Introduction
for example, hypoplastic MDS,
rank correlation test b values. Distributional differences regarding nominal variables were tested for by the 
2 test in the case of 2 × 2 tables, including Yates
correction for continuity. Correlations of ordered categorical data
were tested by the Kendall 
