Myelodysplastic syndromes in patients under 50 years old: a single institution experience

Leukemia Research 29 (2005) 749–754

Myelodysplastic syndromes in patients under 50 years old: a single institution experience Massimo Breccia a, ∗ , Andrea Mengarelli b , Marco Mancini a , Francesca Biondo a , Fabiana Gentilini a , Roberto Latagliata a , Franco Mandelli a , Giuliana Alimena a a

Department of Cellular Biotechnology and Hematology, University La Sapienza, Rome, Italy b Department of Haematology, Regina Elena Cancer Institute, Rome, Italy Received 23 December 2004; accepted 3 January 2005 Available online 24 February 2005

Abstract We report on our experience relating to 62 patients with myelodysplastic syndrome (MDS) aged less than 50 years, seen at our Institution and conservatively treated from July 1983 to December 2000. Patients demographics and clinical features at diagnosis were analysed for their prognostic value on survival and on risk of transformation to acute leukaemia. The median age at diagnosis was 43 years (range 21–50). According to FAB criteria there were 30 patients with refractory anaemia (RA), 3 with refractory anaemia with ringed sideroblasts (RARS), 18 with refractory anaemia with excess of blasts (RAEB), 6 with refractory anaemia with excess of blasts in transformation (RAEB-t) and 5 with chronic myelomonocytic leukaemia (CMML). Fifty patients had evaluable cytogenetic analysis: the most frequent karyotypic change was trisomy of chromosome 8 (10%), followed by monosomy 7 (6%); partial chromosome deletions and translocations were also common abnormalities, occurring on the whole in 16% of patients. At a median follow-up of 15 months 19 patients (31%) progressed to acute myeloid leukaemia (AML). From univariate analysis we identified some features, which appeared to be predictive of outcome and risk of transformation to AML. Age above 40 years (p = 0.002) and high risk according to IPSS score (p = 0.002) were found to be predictive for a shorter survival; FAB grouping (p = 0.0001), percentage >5% of blasts in the bone marrow (p = 0.001) and high risk by IPSS score (p = 0.0003) were found to be predictive for a higher risk of transformation to AML. Presenting features in young MDS patients may identify subjects at higher risk of unfavourable outcome. © 2005 Elsevier Ltd. All rights reserved. Keywords: Myelodysplastic syndromes; Young patients; Prognostic factors; IPSS

1. Introduction The myelodysplastic syndromes (MDS) are a heterogeneous group of blood disorders characterized by ineffective hematopoiesis and a peculiar propensity to evolve into acute leukaemia [1]. They can occur as a consequence of marrow injury by chemotherapy or radiotherapy for a prior malignancy or, more commonly, as a primary disor∗ Corresponding author. Present address: Department of Human Biotechnology and Hematology, Via Benevento 6, 00161 Rome, Italy. Tel.: +39 06 85 79 51; fax: +39 06 44 24 19 84. E-mail address: [email protected] (M. Breccia).

0145-2126/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2005.01.003

der in which no certain causes are identified [2]. These diseases are mostly observed in patients older than 65 years and in paediatric patients, in whom they present as specific syndromes [3]. Patients less than 50 years are only rarely described in literature, and the few reports refer to patients observed from different Institutions or high risk patients included in bone marrow transplantation registers [4–6]. In the present paper we report on a consecutive series of 62 MDS patients under 50 years old observed at our Institution, in whom we identified some clinical-biological features at diagnosis, that appeared predictive for shorter survival and higher risk of transformation to acute leukaemia.

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M. Breccia et al. / Leukemia Research 29 (2005) 749–754

2. Patients and methods

Table 1 Clinical and biological features at diagnosis of the 62 young MDS patients

Between July 1983 and December 2000, 689 cases of adult primary myelodysplastic syndromes were diagnosed at our Institution. Cases secondary to chemotherapy or to prior neoplasia were excluded. From this series, 62 patients were under 50 years (9%), and are the subject of the present study. Diagnosis was categorized according to FAB criteria [7]. Clinical parameters included in the analysis were: age at presentation, sex, presenting hemoglobin, white blood cell count, platelet count, neutrophil count, percentage of peripheral blood (PB) and bone marrow (BM) blasts, cell-lineage involvement in the BM, transfusional requirement, infectious episodes, disease status at last follow-up and cause of death. PB and BM smears were stained by May–Grunwald–Giemsa and for iron staining. A cytogenetic study was successfully performed at diagnosis on BM cells in 50 patients, by using standard G-banding with trypsin-Giemsa staining; a minimum of 20 metaphases was examined in each patient. The Bournemouth score [8] based on blood parameters and percentage of BM blast cells was determined in all patients; the Spanish score [9], which includes age at diagnosis, and the IPSS score [10], which includes cytogenetic data (available in 50 patients), were also determined. Patients demographics and clinical features at diagnosis were analysed for their prognostic value on survival and on risk of transformation to acute leukaemia, by using the log rank test.

Feature

3. Results 3.1. Clinical and biological findings Table 1 shows main clinical features of patients at diagnosis. Median age was 43 years (range 21–50); 30 patients were <40 years and 32 patients were over 40 years. There were 26 males and 36 females (ratio 0.7). No history of familiar myelodysplasia or other hematological disorders were present in any patient. A history of occupational exposure to potential carcinogens was recorded in 13/62 patients (21%): 5 patients had been exposed to benzene and its derivates, 5 patients to fertilizers and 3 patients to glues. According to FAB classification 30 patients (48%) had refractory anaemia (RA), 3 patients (4.8%) had refractory anaemia with ringed sideroblasts (RARS), 18 patients (29%) had refractory anaemia with excess of blasts (RAEB), 6 patients (9.6%) had refractory anaemia with excess of blasts in transformation (RAEB-t) and 5 patients (8%) had chronic myelomonocytic leukaemia (CMML). Bone marrow was normo or hypercellular in 58 patients and hypocellular in 4 patients; in these latter the diagnosis of MDS was performed on BM biopsy.

Age Sex Male Female FAB RA RARS RAEB RAEB-t CMML WBC (× 109 /l) Hb (g/dl) Plts (× 109 /l)

Median

n (%)

43

Range 21–50

26 (42) 36 (58) 30 (48.3) 3 (4.8) 18 (29) 6 (9.6) 5 (8) 4.3 9.8 109

1.3–51 3.4–15.1 11–401

Karyotype Normal +8 −7 Other aberrations Complex Not valuable Transformation to AML

34 (68) 5 (10) 3 (6) 8 (16) 1 (2) 12 (19.3) 19 (30.6)

Status Alive Dead

47 (75.8) 15 (24)

Reclassification according to WHO distinguished the 30 patients with RA in 15 patients with RA and 15 patients with RCMD, and the 18 patients with RAEB in 12 patients with RAEB-I and 6 patients with RAEB-II. Physical examination at diagnosis revealed the presence of splenomegaly in 3 patients (5%), hepatomegaly in four (6%), lymphadenopathy in two (3%). Median time from initial symptoms to diagnosis was 3 months. The most common presenting complaints were weakness in 45 patients (72.5%), headaches in 5 patients (8%), hemorrhagic symptoms in 10 patients (6.2%) and recurrent infections in 2 patients (3%). Median hemoglobin level was 9.8 gr/dl (range 3.8–14), median WBC count was 4.3 × 109 /l (range 1.3–16) and median platelet count was 109 × 109 /l (range 11–527). Cytogenetic analyses showed a normal karyotype in 34 out of the 50 patients investigated (68%), a trisomy 8 in 5 patients (10%), a monosomy 7 in 3 patients (6%) and other structural aberrations in 8 patients (16%). Considering the 13 patients with a history of exposure to carcinogens (Table 2), there was a prevalence of high risk disease (5 RCMD, 2 RAEB, 1 RAEB-t, 1 CMML versus 4 RA), a preponderance of older age (10 of 13 patients aged 40–50 years), a high rate of leukemic transformation (8/13 patients or 61.5%), presence of monosomy 7 in (3 cases) and del 5 in (2 cases). Comparison of the clinical and biological features of the 13 previously exposed patients with those of nonexposed patients, revealed significant differences in sex, age distribution, cytogenetics and evolution to AML (Table 2).

M. Breccia et al. / Leukemia Research 29 (2005) 749–754 Table 2 Comparison between young patients with (yes) and without (no) exposure to potential mutagens (only patients with available cytogenetics included) No (no. 49)

Yes (no.13)

p

Sex Male Female

8 29

9 4

0.03

Age < 40 years >40 years

14 23

3 10

0.03

16/5 3 16 5 4

4/5 – 2 1 1

0.73

26 – – 11

8 3 2 –

0.05

23 7 6 1 11/49

7 3 2 1 8/13

FAB/WHO RA/RCMD RARS RAEB RAEB-t CMML Karyotype Normal −7 Del (5) Others IPSS Low Int-1 Int-2 High Transformation to AML

0.781

0.02

3.2. Prognostic scoring systems and prognostic factors Prognostic factors for survival and time to transformation to AML are presented in Tables 3 and 4, respectively. The FAB stratification assigned on the basis of morphological criteria, was not able to show significant differences in survival between subgroups (p = 0.08, Table 3), but was able to distinguish the categories of patients at higher risk of transformation to AML (p = 0.0001, Table 4). Of the three different scoring systems applied, the Bournemouth and the Spanish scores were able to allocate patients into the distinct prognostic subgroups, but in univariate analysis they both were not predictive for survival (p = 0.32 and 0.07, respectively, Table 3). On the contrary, both systems were able to be predictive for transformation to AML (p = 0.02 and 0.0001, respectively, Table 4). IPSS was applied to 50 patients with available cytogenetic data. This system had the strength to predict both survival (p = 0.002, Table 3) and risk of transformation to AML (p = 0.0003, Table 4) in univariate analysis. By Cox regression model, in univariate analysis of prognostic factors for survival, we also found significant the stratification by age, a longer median survival being observed in patients less than 30 years old (45 months) as compared to patients between 40 and 50 years (11 months, p = 0.02). Also significant was the presence of PB blast cells, which appeared to be more important with respect to BM blastosis, and which was associated with a lower median survival (p = 0.04). Univariate analysis for transformation to AML (Table 4), identified other prog-

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Table 3 Univariate analysis of prognostic factors for survival in young MDS patients No. of patients

Survival (months)

p

Age ≤30 years ≤40 years ≤50 years

17 13 32

45 33 11

0.02

Sex Male Female

26 36

FAB RA RARS RAEB RAEB-t CMML

30 3 18 6 5

53 55 42 16 43

0.08

WBC >10 × 109 /l <10 × 109 /l

8 54

9 22

0.12

PB blast Yes No

4 58

1.4 22

0.04

Plts >100 × 109 /l <100 × 109 /l

36 26

16 10

0.61

BM blast >5% <5%

23 39

11 16

0.06

Trilineage dysplasia Yes No

36 26

10 15

0.13

Spanish score Low Intermediate High

46 15 1

48 26 0.5

0.07

IPSS Low Intermediate-1 Intermediate-2 High

12 24 10 4

48 30 20 0.8

0.002

Bournemouth score Low Intermediate High

26 36 0

69 40 –

0.32

0.179

nostic factors, such as FAB classification, presence of PB blast cells (p = 0.0001), percentage of blast cells in the BM >5% (p = 0.0001). Re-classification according to WHO showed that patients with RCMD, as compared to patients who remained in the RA category, had a higher incidence of transformation to AML and a shorter survival (40% versus 10% p = 0.001, and 32 months versus 45, respectively). Also RAEB patients, when re-classified according to WHO criteria had significant differences in median survival (30 months for RAEB-I versus 13 months for RAEB-II (p = 0.002) and rate of AML transformation (3/13 RAEB-I patients versus 4/5 RAEB-II patients, p = 0.001).

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M. Breccia et al. / Leukemia Research 29 (2005) 749–754

Table 4 Univariate analysis of prognostic factors for transformation to AML in young MDS No. of patients

Median survival (months)

p

Age ≤30 years ≤40 years ≤50 years

17 13 32

50 45 30

0.11

Sex Male Female

26 36

52 51

0.99

FAB RA RARS RAEB RAEB-t CMML

30 3 18 6 5

53 55 38 10 35

0.0001

WBC >10 × 109 /l <10 × 109 /l PB blast Yes No

8 54

53 52

0.14

4 58

15 52

0.0001

Plts >100 × 109 /l <100 × 109 /l

36 26

53 51

0.39

BM blast >5% <5%

23 39

16 52

0.001

Trilineage dysplasia Yes 36 No 26

48 52

0.21

Spanish score Low Intermediate High

46 15 1

45 23 0.5

0.0001

IPSS Low Intermediate-1 Intermediate-2 High

12 24 10 4

42 28 18 1

0.0003

Bournemouth score Low 26 intermediate 36 High –

58 38 –

0.02

3.3. Transformation to AML, treatments and outcome At a median follow-up time of 20 months (range 13–140), 19 patients (31%) evolved to acute myeloid leukaemia (AML). Eight of the 13 patients (61%) with previous exposure to potential carcinogens evolved to AML. At the time of this writing 47 patients (76%) are alive in stable disease and 15 patients (24%) are dead for progression of disease to AML. The causes of death were hemorrhages in 10 patients and life-threatening infections in 5 patients. Median time to transformation was 4 months.

Table 5 Comparison between MDS patients <50 and >50 years <50 years

>50 years

No. of patients Median survival (months) Sex ratio (m/f)

62 49 0.7

627 24.6 1.56

FAB classification (%) RA RARS RAEB RAEB-t CMML Progression to AML (%)

48 5 29 10 8 30.6

30 6 37 13.5 13.5 29.6

p 0.001 0.002 0.02

NS

One spontaneous hematologic and cytogenetic remission was observed in a RA patient with +8 at karyotype analysis. After diagnosis, in all patients a 6 months watch-and-wait strategy was followed for disease re-evaluation. Thereafter, 15 patients were treated with growth factors, including erythropoietin, G-CSF and tymophentin; 25 patients received only transfusions and vitamins. Prednisone was given in case of low platelet count. All 19 patients evolved to AML and three additional patients with RAEB-t diagnosis were given intensive chemotherapy consisting of 3 + 7 schedule (15 patients) or ICE schedule (7 patients). Of these 22 intensively treated patients, 10 (45%) achieved CR, 7 (32%) had a resistant disease and 5 (23%) died during induction. Five patients received allogenic BMT preceded by chemotherapy: all of them are alive, free from disease. Median actuarial survival is 49 months. 3.4. Comparison with series of patients aged >51 years Comparison of disease outcome of patients with less than 50 years of the present study and that of older patients observed in the same period of time at our Institution is shown in Table 5. A significant difference in the sex ratio was observed, with a prevalence of females in the young series as compared to the older MDS population (p = 0.002). A statistically significant difference in the FAB classification between the two series of younger versus older patients was also evident: in fact, we found a higher incidence of RA and RARS, and a lower incidence of RAEB and RAEB-t in younger patients as compared to older patients (p = 0.02). Also the incidence of CMML was lower in younger than in older patients (8% versus 13.5%, p = 0.02). Median survival, calculated for the whole series of older patients was 24.6 months as compared to 49 months of younger patients (p = 0.001); these data likely reflect the higher incidence of MDS with low percentage of blast cells observed in the young series of patients. 4. Discussion The present casistics of young MDS patients accounts for 9.5% of the whole MDS patient population seen at our Institu-

M. Breccia et al. / Leukemia Research 29 (2005) 749–754

tion in a period of 17 years. This figure, which falls within the range of 1.7–20% reported in the literature, has the relevance of being representative of a consecutive and unicentric series of patients, with respect to previous observations mostly describing young patients selected from BMT registries [4–6]. This consideration may explain the low incidence in our series of patients with more advanced, high-risk disease (RAEB-T and CMML), as compared to other reports. Exposure to potential carcinogens was detected in 13 patients who presented peculiar features such as high risk MDS category, karyotypic changes such as monosomy 7 and del 5 (q), age >40 years and high rate of transformation to AML. These findings are in line with those reported in literature [11], in which patients with a history of occupational exposure to potential carcinogens are mostly aged >40 years and present high rate of abnormal karyotypes. We did not find correlations between diagnosis of MDS and impaired immunity or autoimmune diseases or increased incidence of non-hematopoietic malignancies, which was conversely reported in large series of older MDS patients [12,13]. In our series, we documented three cases of RARS; this subtype was not described in the study of young MDS by Fenaux et al. [4], but was found in a similar percentage in the study of Chang et al. [5]. Thirty-two percent of our patients showed cytogenetic abnormalities, a value which is in line with that of 30–50% reported in de novo MDS [10,14,15], but very low if compared to the other two reports on young MDS patients [4,5]. This difference may be explained by the fact that our series was represented by consecutive and unselected patients, with a low incidence of high risk MDS subgroups as compared to other studies [4,5]. It is in fact well known that chromosome changes are more frequent in more advanced disease categories [10,16,17]. By contrast, with respect to other series [18,19], we found a very low number of patients with monosomy 7, which is generally detected in 50% of childhood MDS or secondary MDS and is associated to a very poor prognosis. It is noteworthy that all the three cases were among the patients with previous history of mutagenic exposure. Furthermore, we identified some clinical factors, which were of prognostic value for survival: the stratification by age displayed an advantage for very young patients, the presence of PB blast cells was a negative factor and the stratification by IPSS showed a longer median survival for the low/intermediate-1 group of patients. Our results are in accordance with those reported in large series of the whole MDS population [10]. Differently, the rate of AML transformation in our series was lower than that observed in other studies of young MDS patients (30.6% in our series as compared to 37% in the study of Fenaux et al. and 47% in the study of Chang et al.) [4,5]; this finding too might be the consequence of the lower incidence of high risk categories and the lower percentage of abnormal karyotypes in our cases.

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As regards the prognostic value of scoring systems in this subset of young MDS, the IPSS was found to be significantly predictive for both AML transformation and survival, as previously observed in the other two reports [4,5], while the Bournemouth and the Spanish scores were of statistical significance in univariate analysis only for predicting AML transformation. Finally, comparison of young patients with older patients consecutively seen at our Institution over the same time, showed some differences as regards sex distribution, median survival and FAB classification. In fact, a prevalence of females in the young series as compared to the older population (p = 0.002) was noticed and we also found a higher incidence of low risk MDS among younger patients as compared to older patients (p = 0.02). Unfortunately, we were unable to compare karyotypic findings in these two groups of patients, owing to the lack of available data in a consistent number of elderly patients. Another consideration relates to the value of IPSS, which showed to be an improved method for evaluating prognosis also in young MDS patients [10]. The percentage of high risk patients (28%) in our series was similar to that found in the series of patients in the IPSS study [10], but was significantly lower as compared to the fraction of high risk patients (61%) of the study by Chang et al. [5]. Our findings indicate the role of IPSS, when applied to a consecutive series of MDS patients. Also the WHO classification showed to add prognostic information concerning survival and to have a significant value for predicting transformation to AML (data not shown). In conclusion, some clinical and prognostic features of primary MDS in young patients appear to be significative for a disease differing from that of older patients; our analysis showed the usefulness of the IPSS and WHO reclassification, which should be tested in larger series of young patients to confirm its predictive value. Molecular investigations could be of interest, especially in poor outcome patients, for possible stratification and innovative therapeutic strategies to be adopted.

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