Clinical, morphological, cytogenetic, and prognostic features ... - Nature

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Clinical, morphological, cytogenetic, and prognostic features of patients with myelodysplastic syndromes and del(5q) including band q31 AAN Giagounidis1, U Germing2, S Haase1, B Hildebrandt3, B Schlegelberger4, C Schoch5, L Wilkens4, M Heinsch1, H Willems1, M Aivado2 and C Aul1 1 St Johannes Hospital, Medizinische Klinik II, Duisburg, Germany; 2Heinrich-Heine-Universita¨t Du¨sseldorf, Klinik fu¨r Ha¨matologie, Onkologie und klinische Immunologie, Du¨sseldorf, Germany; 3Institut fu¨r Humangenetik, Heinrich-HeineUniversita¨t Du¨sseldorf, Du¨sseldorf, Germany; 4Medizinische Hochschule Hannover, Institut fu¨r Zell- und Molekularpathologie, Hannover, Germany; and 5Labor fu¨r spezielle Leuka¨mie-Diagnostik, Ludwig-Maximilians-Universita¨t Mu¨nchen, Mu¨nchen, Germany

We analyzed data of 76 consecutive patients with myelodysplastic syndrome (MDS) and isolated del(5q) (n ¼ 66) or del(5q) plus one additional chromosomal abnormality (n ¼ 10) included in our MDS database over the last 26 years. The median age of our patient population was 66.8 years. The male to female ratio was 1:1.7. In all, 14 patients (18%) had advanced MDS with an increased medullary blast count. A total of 17 patients (22%) had significant dysplasia in the nonmegakaryocytic cell lines. Nearly half of the study population showed erythroid hypoplasia in the bone marrow. The projected median survival of patients with isolated del(5q) is 146 months for a median followup of 67 months. Patients with an increased medullary blast count and those with an additional chromosomal abnormality have a significantly shorter overall survival (24 and 45 months, respectively) than patients with isolated del(5q). We did not find survival differences for different cytogenetic breakpoints, nor did the amount of dysplasia have an impact on survival in our population. In total, 29 patients have died. Deaths occurred primarily due to transformation into acute leukemia, infection, or cardiac failure. Our data support the current definition of a separate entity of MDS with del(5q) that has been suggested by the World Health Organization. Leukemia (2004) 18, 113–119. doi:10.1038/sj.leu.2403189 Published online 30 October 2003 Keywords: 5q-syndrome; morphology; cytogenetics; prognosis

Introduction Myelodysplastic syndromes (MDSs) are acquired clonal bone marrow disorders characterized by varying degrees of pancytopenia, morphological and functional abnormalities of hematopoiesis and an increased risk of transformation into acute myeloid leukemia (AML).1 The most frequent karyotypic abnormality so far identified within this disease group is an interstitial deletion of the long arm of chromosome 5 (del(5q)) occurring in 10–15% of patients.2 This chromosomal abnormality together with macrocytic anemia, normal to elevated platelet counts, normal to moderately lowered leukocyte counts, and a significant number of hypolobulated megakaryocytes in the bone marrow is highly predictive of the 5q-syndrome.3 This specific MDS-syndrome is associated with a much better prognosis than other MDS subtypes.4 There is now accumulating evidence that one or more tumor suppressor genes located between the distal border of band 5q31 and band 5q33 are deleted in this syndrome,5 and that this deleted interval differs from those in acute myeloid leukemia associated with del(5q).5 It remains to be shown whether the proximal breakpoint on Correspondence: Dr AAN Giagounidis, Medizinische Klinik II, St Johannes Hospital, An der Abtei 7-11, Duisburg 47166, Germany; Fax: þ 49 0203 546 2479; E-mail: [email protected] Received 26 May 2003; accepted 19 September 2003; Published online 30 October 2003

chromosome 5q has got a prognostic impact. Although some basic morphological information has been provided and the disease has been recognized as a separate entity by the WHO committee for classification of neoplastic diseases,6 there is lack of detailed morphological analysis of this patient subset.7 Since 1977, we have been registering patients with MDSs in our blood and bone marrow registry, and recorded their clinical, laboratory, morphological, and cytogenetic data. In order to evaluate the WHO classification proposal by means of a large independent patient sample, we analyzed the morphological, laboratory, cytogenetic, and prognostic characteristics of 76 patients with MDS and interstitial deletion of the long arm of chromosome 5 including band q31, 66 of whom had del(5q) as the sole anomaly, and the remaining 10 patients having one additional chromosomal aberration.

Materials and methods

Patients Patients with an identical interstitial deletion of the long arm of chromosome 5 in at least two metaphases and evaluable bone marrow morphology were included in the study. All patients were classified according to FAB criteria.8 To evaluate the prognostic effect of one additional chromosomal abnormality and of the more advanced stages of MDSs, patients displaying these features were explicitly included into the study. Patients with AML at first diagnosis were excluded, owing to the fact that these patients apparently have different breakpoints from the 5q-syndrome.7 To compare del(5q) patients to other patient populations, we used the Du¨sseldorf bone marrow register that contains patient data of more than 1600 patients. Patients were followed up until their death, or December, 2002. Clinical follow-up was obtained by telephone calls to their local physicians, if treatment was performed at centers other than Duisburg or Du¨sseldorf, Germany. Unless otherwise stated, none of the parameters listed below showed a significant difference between the patients with isolated deletion of 5q and those with one additional chromosomal aberration. Therefore, unless explicitly reported, we present the pooled data of these patient groups.

Morphology Morphological evaluation was performed according to a standard evaluation protocol for peripheral blood and bone marrow by the reference morphologist for MDSs of the German MDS Study Group (CA, Duisburg). All patients had the

The 5q-syndrome AAN Giagounidis et al

114 peripheral blood and bone marrow smears of the time of diagnosis evaluated. Follow-up bone marrows were examined if available. Morphological abnormalities were indicated semiquantitatively by assigning 0 for not present and þ for rarely, or þ þ for frequently observed. According to the recent WHO definitions regarding dysplasia in MDS,6 dysplasia was recorded only if the dysplastic features within one cell line made up more than 10% of the cell line examined. The number of mononuclear megakaryocytes was given in percent of all megakaryocytes. Micromegakaryocytes were defined as having a diameter of no more than twice the size of a promyelocyte. Ring sideroblasts were defined according to the recent WHO proposals.6 Peripheral blood smears were stained with May– Gruenwald–Giemsa (MGG), bone marrow smears with MGG, Perls’ blue (Fe), Periodic-acid Schiff (PAS), Myeloperoxidase (POX), and a-naphthyl-butyrate esterase (a-NE).

When excluding cases of advanced MDS (refractory anemia with excess of blast (RAEB) and refractory anemia with excess of blasts in transformation (RAEB-t)), the male to female ratio remained nearly unchanged and was 1:1.58. The male to female ratio of the 14 patients with RAEB or RAEB-t was 1:2.5. Three patients had secondary MDS. Two of them had previously been treated with azathioprine for rheumatoid disease, and one patient had received chemotherapy for breast cancer 4 years before the diagnosis of 5q-syndrome. The median age of the patient population was 66.8 years, with a range from 32 to 83 years. There was no significant difference for the age at diagnosis between men and women (P ¼ 0.13). Only 7% of patients were younger than 50 years. In all, 4% of patients had lymph node enlargement. In total, 5% of the patients presented in WHO performance status X3.

Laboratory values Cytogenetics Cytogenetic studies were performed on short-term bone marrow cultures using conventional G- or R-banding fluorescence. The findings were described according to ISCN. In eight patients diagnosed before 1982, the exact breakpoints at chromosome 5q were not reported. Fluorescence in situ hybridization (FISH) was carried out on 31 patients using EGR1/D5S523 probes (Abbott, Wiesbaden, Germany), as has been reported previously. The cutoff limit for the detection of a deletion was set individually in each laboratory according to control studies defining the cutoff level for a deletion at mean þ 3 s.d. FISH studies were performed at Duisburg and at least at one of two German reference cytogenetic centers (BS and LW, Hannover, Germany; CS, Munich, Germany).

Table 1 gives an overview of laboratory results in 5q-syndrome patients. In all, 13 patients (17%) had thrombocyte counts below normal (150 000/ml), seven of whom (54%) had advanced stage MDS. Thrombocytosis 4350 000/ml was seen in 24 patients (32%), most of whom (20/24, 84%) had refractory anemia (RA) or refractory anemia with ring sideroblasts (RARS) subtype. All patients included in this series required transfusions at some time of their disease. One patient who initially did not require erythrocyte replacement became transfusion dependent 2 years later, and achieved a 4-year lasting freedom from transfusion after 3 years without medical treatment. One patient had severe autoimmune hemolytic anemia additional to the 5q-syndrome.

Morphological evaluation Laboratory data We reviewed the laboratory files of all patients entered into the study. Some patients have had their diagnosis of 5q-syndrome made considerable time after their first presentation at their primary care physician. The laboratory data refer to the time of diagnosis either by bone marrow morphology or by cytogenetics. Laboratory values sought for are represented in Table 1.

Results

Clinical presentation There were 76 patients evaluable, 28 male and 48 female. The male to female ratio for the entire group was therefore 1:1.7.

Table 1

Peripheral blood We could examine the peripheral blood from 53 out of 76 patients. Anisocytosis and poikilocytosis occurred in 97 and 71% of patients, respectively. Only 10% of patients were hypochromic and microcytic. Hyperchromasia and macrocytosis were common with 38 and 45% of cases. Tear drop cells (25%), polychromasia (10%), basophilic stippling (6%),

Laboratory values of 5q-syndrome patients at the time of diagnosis

Laboratory value Hemoglobin MCV Leukocytes Granulocytes Thrombocytes Reticulocyte count Erythropoietin Ferritin LDH

Leukemia

All patients were classified according to the FAB criteria.8 In all, 51 patients (67%) had RA, 11 had RARS (14%), 13 had refractory anemia with excess of blasts (RAEB) (17%), and one had RAEB-t (1%). No patient presented with chronic myelomonocytic leukemia.

Number of cases analyzed 76 53 76 66 76 38 20 56 71

Median value 8.4 92 4200 2240 252 000 0.5 1000 540 180

Range

Normal range

3.4–12.2 78–140 1700–13 200 600–10 500 23 000–1 540 000 0.1–1.6 122–2880 37–4830 97–433

14–18 g/dl 83–94 fl 4000–9000/ml 1920–6170/ml 150 000–300 000/ml 0.7–1.5% 6–25 U/l 15–350 ng/ml 120–240 U/l


and erythroid precursors in the peripheral blood (10%) were uncommon. In all, 25% of patients had a left shift in the granulocytic lineage. Three patients had blasts in the peripheral blood smear, one with RA, one with RAEB, and one with RAEBt. The Pseudo-Pelger-Huet anomaly was detected in 10% of patients in the peripheral blood in a significant amount of cells (ie X10% of granulocytes). Marked anisometry of thrombocytes with occasional occurrence of giant platelets was seen in 50% of cases.

Bone marrow Cellularity: In all, 20% of bone marrows were hypocellular, 40% were normocellular, and 40% hypercellular. Erythroid precursors: A total of 13% of cases showed erythroid hyperplasia (440% of erythrocyte precursors in the bone marrow). In total, 46% of the patients had erythroid hypoplasia (o20% of erythroid precursors), and another 40% had 20–40% erythroid precursors of all nucleated bone marrow cells. Erythroid dysplasia was defined as follows: megaloblastoid chromatin pattern changes, multinuclearity, nuclear fragmentation, internuclear bridging, irregular nuclear outline, atypical mitosis, and nuclear-cytoplasmic asynchrony. A total of 10 patients (13%) showed erythroid dysplasia in more than 10% of erythroid precursors. Interestingly, four of those patients had varying breakpoints between q12/13 and q32/33 without additional chromosomal anomalies. Six patients had del(5)(q22q33) (out of a total of 11 patients with these cytogenetic breakpoints). Four patients (5%) had positivity of erythroid precursors in the PAS stain.

Leukocytes: In all, 38% of patients had a predominance of early granulocytic precursors in the bone marrow. The blast percentage ranged from 0 to 28%. A total of 81% of patients (n ¼ 62) had less than 5% bone marrow blasts. Seven patients (9%) had more than 5% but less than 10%, six patients (8%) above 10% but below 20% and one patient 28%. Auer rods were not observed. Dysplastic features in X10% of the granulocytic series (Pseudo-Pelger-Huet anomaly, hypogranulation, hypersegmentation, atypical nuclear segmentation) were seen in 12% of patients. This was neither related to a specific breakpoint of chromosome 5 nor to any subtype of disease. In total, 5% of patients had myeloperoxidase deficiency in the granulocytic lineage. The monocytes were increased in one patient (10% monocytes of all nucleated cells). Megakaryocytes: With the exception of one patient, all patients had mononuclear megakaryocytes ranging between 30 and 80% (mean 55%). Micromegakaryocytes have been detected in up to 35% of cases. In nine patients, single hypersegmented megakaryocytes were noted. Other cells: In 30% of patients, lymphocytes contributed to more than 15% of nucleated bone marrow cells. Plasma cells were not increased in any case. Basophilia was a common finding. A total of 28% of patients had 2–5% basophils in the bone marrow.

Dysplastic features: Significant dysplasia in more than 10% of granulocytic or erythroid precursors was seen in 17 out of 76 patients (22%). All but one of these patients had an isolated 5q-anomaly.

115

Cytogenetics In all 76 patients, an interstitial deletion of 5q had been detected by classic chromosome analysis and karyotyping. The different breakpoints identified are listed in Table 2. We performed FISH on peripheral blood granulocytic cells of 31 patients to assess the number of interphases affected by the 5q deletion. We found that 30–88% of cells bear the 5q31 deletion identified by the Abbottt probe. Our FISH studies confirmed the breakpoint analysis performed by conventional cytogenetics in all 31 patients tested. All patients had the breakpoint 5q31 involved. FISH results of the central laboratory in Duisburg correlated strongly with the FISH data of the two German reference centers.

Prognostic features The median prospective survival time of patients with isolated del(5q) is 145 months for a median follow-up time of 67 months. Patients with one additional chromosomal abnormality have a median survival time of 45 months (Figure 1, P ¼ 0.0085). Interestingly, among patients with one additional chromosomal anomaly (n ¼ 10), only one patient had advanced MDS (RAEB). The remaining 13 patients with increased medullary blast count have an isolated del(5q). There is no significant difference in the overall survival between men and women (P ¼ 0.09). Patients with a blast count of X5% have a significantly shorter median overall survival time (24 months) than those with a blast count of less than 5% (P ¼ 0.0011, Figure 2). However, this holds true only if patients who were treated with aggressive chemotherapy or bone marrow transplantation are included in the study. If these patients were excluded, the numbers of patients with advanced MDS would become too small for statistical analysis. Cumulative development of AML in patients with less than 5% bone marrow blast cells and with an isolated del(5q) does not exceed 9%. This probability soars as high as 80% for patients

Table 2

Breakpoints identified by conventional cytogenetics

Cytogenetic aberration

n

del(5)(q13q31) del(5)(q13q33) del(5)(q13q34) del(5)(q15q31) del(5)(q22q33) del(5)(q12q32) del(5)(q12q33) del(5)(q14q31) del(5)(q14q32) del(5)(q14q33) del(5)(q15q35) del(5)(q?q?)

9 29 1 1 9 3 2 1 1 1 1 8

Karyotypes of patients with additional chromosomal abnormalities observed in patients with 5q-deletions 46,XX, der(3;20)(q10;q10),del(5)(q13q33) 46,XY, t(4;12)(q21;p11),del(5)(q13q33) 46,XY, t(1;3)(p36;p21),del(5)(q13q33) 47,XX,del(5)(q12q33),+21 47,XX,del(5)(q12q33),+21 46,XX,del(5)(q22q33),del(9)(p11) 47,XY,del(5)(q22q33),12 46,XY,del(5)(q23–1q34–5),inv(11)(p12q14) 46,XX,del(5)(q11q31–2),t(17;17)(p11;q21) 46,XY,del(5q); 45,XY,5

Leukemia


116 1.0

1.0 p = 0.0085

0.8

0.8 AML transformation

cumulative survival

p = 0.0095

blasts ≥ 5%, n=14

0.6 del (5q), n=66

0.4

del (5q) + add., n=10

0.2

0.6

0.4

0.2 blasts < 5%, n=62

0.0

0.0 0

60

120

180

240

300

0

360

60

120

months

Figure 1 Overall survival of patients with isolated del(5q) and with del(5q) and one additional chromosomal aberration (del(5q) þ add). All patients who were not treated with aggressive chemotherapy are included.

180 months

360

1.0 p = 0.5935

p = 0.0011

0.8 cumulative survival


300

Figure 3 Cumulative AML development for patients with o5% medullary blast count and X5% medullary blasts.

1.0

0.6

0.4

blasts < 5%, n=62 blasts ≥ 5%, n=14

0.6 del(5q), n=66

0.4

IPSS low-risk, n=60

0.2

0.2

0.0

0.0 0

60

120

180 months

240

300

360

Figure 2 Overall survival of patients according to their medullary blast count (o5 vs X5%). All patients included, regardless of type of administered therapy or additional chromosomal abnormality.

with X5% blasts in the bone marrow (Figure 3). We compared the prognosis of the patients with isolated del(5q) to another low-risk category of patients, namely those with a normal medullary blast count, normal cytogenetics, and only unilineage cytopenia, that is, an International Prognostic Scoring System (IPSS) value of 0. At a median follow-up of 38 months for the IPSS ¼ 0population (n ¼ 60), the projected median survival reaches 108 months. This is not significantly different from the del(5q) population that reaches 145 months (Figure 4). In order to further evaluate the prognostic homogeneity of the patient population with del(5q), we applied both the IPSS and the Du¨sseldorf score (Table 3)9 to our patient sample. While the IPSS does not properly distinguish prognostically relevant patient subgroups within the entire group of patients with del(5q) (Figure 5), the Du¨sseldorf score gives a good approach to patient survival using the lactate dehydrogenase levels as important criteria (Figure 6). However, it should be noted that the result for the IPSS might have become significant using a Leukemia

240

0

60

120

180 months

240

300

360

Figure 4 Comparison of overall survival of patients with isolated del(5q) and those with an IPSS ¼ 0 and a normal karyotype. No significant difference is found between the two patient populations. Patients with 45% marrow blasts are included in the del(5q) group, as omission of these patients does not change the median survival of the population.

bigger number of patients in the different risk groups. In univariate analysis, elevated LDH, blast count X5%, and thrombocytopenia (o100 000) are predictive of shortened survival. In multivariate analysis, however, the blast count remains the only prognostically relevant marker. Whether cytogenetic breakpoints are prognostically relevant is a matter of debate. Our investigation does not show significant differences between different cytogenetic breakpoints. The causes of death of 18 of the 29 deceased patients are given in Table 4. It is unknown for the remaining 11 patients. Infections and cardiac failure account for 28% of all deaths, each. Totally, 44% of all deaths are due to AML development (patients suffering from fatal infections were not bone marrow punctured at the time of their last hospital stay. Therefore, the exact percentage of AML development cannot be calculated with certainty). Comparing


117

The Du¨sseldorf score9

Table 3

1.0 p = 0.0207

Feature

Points 0 1

LDH Within normal range Elevated

0 1

Hemoglobin X9 g/dl o9 g/dl

0 1

Platelet count X100 000/ml o100 000/ml

0 1

Score A: point count: 0: low risk. Score B: point count: 1–2: intermediate risk. Score C: point count: 3–4: high risk.

cumulative survival

0.8

Blast count o5% X5%

0.6 DUS A, n=20

DUS C, n=5

0.4

DUS B, n=41

0.2

0.0 0

60

120

180 months

240

360

300

Figure 6 Du¨sseldorf score of the same patient population as in Figure 4. Risk groups are identifiable by including LDH levels in the risk stratification. DUS A: low-risk group; DUS B: intermediate-risk group; DUS C: high-risk group.

1.0 p = 0.7152

Table 4

Causes of death of 29 deceased patients with 5q-syndrome

cumulative survival

0.8

Cause of death 0.6

Acute leukemia

Infection

Cardiac failure

Unknown

4/4

3/2

3/2

8/3

Female/male (n)

0.4

IPSS low, n=37

IPSS Int-2 + high, n=5

0.2

IPSS Int-1, n=24

1.0 p = 0.7572

0.0 60

120

180 months

240

300

360

Figure 5 IPSS of patients with isolated del(5q) and del(5q) with one additional chromosomal abnormality. No significant difference is noted between the subgroups. Low: low-risk group; Int-1: intermediate 1; Int-2: Intermediate 2; High: high-risk group.

patients with significant dysplasia in the nonmegakaryocytic lineages to those without dysplasia, we were not able to find any significant difference in outcome between these groups (Figure 7). Six of 11 patients with del(5)(q22q33) had severe dysplastic features in their blood and bone marrow morphology.


0

0.6

0.4

dysplasia, n=17

0.2

0.0 0

Discussion The definition by the WHO morphology panel of a separate category for the 5q-syndrome within the MDS6 has raised several questions: although it has been shown by previous publications that the addition of several cytogenetic aberrations to a del(5q) has got a negative impact for the individual 5q patient,7 it remains unclear as to whether it is justified to exclude patients with one single additional chromosomal abnormality and typical bone marrow morphology from the ‘good-risk’ group of patients with isolated 5q deletion. Several larger series with 5q patients contain only a very small number of patients

no dysplasia, n=59

60

120

180 months

240

300

360

Figure 7 Comparison of overall survival between patients with isolated del(5q) and unilineage dysplasia and patients with isolated del(5q) and multilineage dysplasia. No significant survival difference is noted.

with one additional aberration.10,11 Six patients were reported by Dewald et al,12 but the authors failed to detail their prognosis. As our study shows, patients with one additional chromosomal abnormality in fact have a significantly worse overall survival than patients with an isolated del(5q), being intermediate between refractory anemia (WHO definition) and Leukemia


118

Leukemia

refractory cytopenia with multilineage dysplasia.13 This analysis is limited to some extent by the number of patients with one additional chromosomal abnormality analyzed in our series (n ¼ 10). Another question relates to patients with an increased blast count but otherwise typical 5q-syndrome, the significance of which is unclear to date.6 Our study shows the prognostically relevant difference in survival between patients with del(5q) and o5% medullary blasts and X5% blasts, and supports the exclusion of the latter from the WHO classification of MDS with 5q-anomaly. The survival difference is not explained by a selection of more adverse cytogenetics (ie additional anomalies) in the group with an increased medullary blast count, but is directly related to the medullary blast percentage. The medullary blast count became the strongest independent variable in multivariate analysis affecting the survival of our patient population. The calculation of median survival for patients with del(5q) varies greatly in different studies with the initial observation of van den Berghe et al3 reporting only 28 months, Mathew et al14 reporting 63 months, and Cermak et al15 recently reporting 44.6 months. In our study, the projected median survival of the patient population with isolated del(5q) at a median age of 67 years is 146 months, with a median follow-up time of 67 months. The statistical median survival for the same age group of the general German population is 244 months (women) and 188 months (men),16 which shows a significant mortality induced by the 5q deletion. The differences in median survival between the studies are striking. One reason for this might be that the report from van den Berghe et al predates the FAB classification, and the patients therefore might not be entirely comparable. The overall survival reported in Cermak’s study is low compared to Mathew’s and our series. These authors reported on 12 patients with a single 5q deletion. The median age of these patients was only 55 years, and the male to female ratio was 1, the AML frequency being 8%. The difference in the median age and male to female ratio suggests that some of the difference may merely be due to the low number of patients studied, while the low AML evolution is in keeping with the finding in our patient sample. Moreover, some of the survival differences in the different studies might be due to short median follow-up for the patients. Cermak et al do not mention the median follow-up time, but from the Kaplan–Meier plots published it seems to be rather short. Mathew et al. report a median follow-up of 31 months, which is less than half of that in our study. Their patient sample is more comparable to the one in this report with a higher number of patients reported on (n ¼ 43), a nearly identical median age of 68 years and a distinct female preponderance. The median projected overall survival was reported with 62 months, the longest follow-up of one single patient having been about 95 months. Finally, FISH confirmation studies for the del(5q) critical region to confirm the patients’ belonging to the target population have only been carried out in the present study and that of Cermak et al. A further question relates to the definition of the 5q-syndrome. The official text of the WHO classification describes the 5q-syndrome as being an MDS associated with an isolated del(5q) cytogenetic abnormality.6 However, without confirmation of the loss of the segment on band 5q31, this definition is incomplete, and therefore needs to be revised. Our data confirm previous observations that show a female predominance in the 5q-syndrome. However, in contrast to the observation published by Pedersen et al,17 our data neither show a prolonged survival of women nor a higher median age of female patients at diagnosis. Our data therefore do not allow the conclusion that the female preponderance in the 5q-syndrome is merely an effect of those phenomena. Moreover, the exclusion

of advanced MDS does not shift the sex ratio towards the female population, and there is no evidence that male patients generally belong to the higher risk groups of the 5q-syndrome. Causes of death of 29 patients are stated in Table 4. Although most of our patients are treated with iron chelators, there is still a significant rate of cardiac failure (24% of deaths of known cause). The fact that we could not discover a difference between various gross cytogenetic breakpoints supports the generally accepted view that the syndrome is caused by a critically deleted segment located at the distal border of 5q31–5q33. Therefore, the exact length of the cytogenetic deletion may only play a marginal role with respect to overall survival. Patients with del(5)(q22q33) seem to have a higher amount of dysplasia in the nonmegakaryocytic lineages, although this does not adversely affect survival. There has been no previous detailed morphological analysis of del(5q) patients in the medical literature. Mathew et al14 state that only 25% of their study population showed erythroid hypocellularity. On the contrary, our observation shows that this feature is one of the most prominent morphological abnormalities in these patients, as nearly one in two of the affected individuals show erythroid hypoplasia. This is in contrast to other early forms of MDS (RA with or without ring sideroblasts or refractory cytopenia with multilineage dysplasia). While increased intramedullary apoptosis has been identified as an important mechanism of peripheral cytopenia in other early-stage MDS,1 this pathomechanism remains to be investigated in patients with del(5q). The megakaryocytic morphology is very predictive of the 5qsyndrome. All but one patient display hypolobulated megakaryocytes, and about one-third display micromegakaryocytes. The difference in nomenclature should be respected, as there is a danger of over-reporting micromegakaryocyte presence in del(5q) patients. Implementation of the WHO classification in hematology will bring about the need for a new prognostic scoring system in MDS, as the IPSS4 cannot be calculated if the RAEBt group is omitted. Therefore, it is important to provide data for different risk subgroups, and we tried and compared the low-risk del(5q) patients (IPSS up to 0.5) with another low-risk population, namely those patients with only one peripheral cytopenia, a low medullary blast count, and a normal karyotype (IPSS ¼ 0) (Figure 4). We show that an interstitial deletion of the long arm of chromosome 5 is not a prerequisite for excellent prognosis in MDS patients, as these patients have an overall survival that is not different in a statistically significant manner. As far as del(5q) as a single aberration and the normal karyotype in low-risk patient populations are concerned, the IPSS seems to group good-risk patients in a very efficient way. Future scoring systems should therefore adopt the low-risk definition of the IPSS. Therapy of the 5q-syndrome has largely been disappointing. A few patients have successfully been treated with low-dose cytarabine and achieved transfusion independence of up to 36 months.18 An ongoing trial of the German MDS study group evaluates the safety and efficacy of all-trans-retinoic acid in these patients, as there are anecdotal reports of responding patients to this compound.19 Encouraging results regarding the thalidomide analog CC5013 have been presented at the 2002 meeting of the American Society of Hematology and warrant further investigations (List et al. Blood 2002; 100: 96, abstract). However, standard treatments for this patient group remain red blood cell transfusions and iron chelators. Patients should be enrolled into study protocols to acquire further knowledge about the pathobiology, cytogenetics, and treatment possibilities of this puzzling disease. As a conclusion, our report fully supports the new WHO classification of the 5q-syndrome as a separate entity within the


119 MDS. Exclusion of patients with an increased medullary blast count or additional cytogenetic aberrations from this good-risk group is substantiated by our data showing a deleterious effect of these parameters on overall survival.

Acknowledgements This work was supported by a grant of the German Bundesministerium fu¨r Bildung und Forschung, Kompetenznetz ‘Akute und chronische Leuka¨mien’. We thank Mr Peter Petersen for his assistance in preparing the manuscript.

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