Hematologic, clinical, and cytogenetic analysis in 109 patients with primary myelodysplastic syndrome

Hematologic, Clinical, and Cytogenetic Analysis in 109 Patients with Primary Myelodysplastic Syndrome Prognostic Significance of Morphology and Chromosome Findings V. Parlier, G. van Melle, Ph. Beris, P.M. Schmidt, A. Tobler, E. Hailer, and M. Jotterand Bellomo

ABSTRACT: One hundred and nine patients with primary myelodysplastic syndrome (MDS) were classified according to the French-American-British (FAB) criteria: 27 refractory anemia (RA, 25%), 26 RA with ringed sideroblasts (RARS, 24%), 16 RA with excess of blasts (RAEB, 15%), 10 RAEB in transformation (RAEB-t, 9%), 25 chronic myelomonocytic leukemia (CMMoL, 23%), and five unclassifiable MDS (4%). Forty-three were women and 66 were men (sex ratio 2:3). Age ranged from 30-92 years (mean 69 years) with nine patients aged less than 50 years (8%). A cytogenetic result was obtained in all cases. At initial study, a chromosome defect was observed in 56% of patients. Rates of abnormality depended on FAB subtype: 52% in RA, 100% in RA 5q-, 50% in RARS, 56% in RAEB, 70% in RAEB-t and 44% in CMMoL. The most frequent single defects were del(5q), -7/del(7q), del(2Oq), Y loss, and +8. Except for the 5qsyndrome entity, specific chromosome defects were not associated with particular FAB subtypes. Bone marrow (BM) insufficiency (22%) and leukemic transformation (21%) were the most important causes of death. The rate of leukemic transformation increased with the number of dysplastic BM cell lineages and was also associated with karyotype complexity and the proportion of abnormal/normal metaphases. The longest median survivals were observed in RARS (142 months) and RA/RA5q- (91 months) types. Median survivals decreased with increasing Bournemouth score values. Patients with three abnormal cell lijneages had a median survival shorter than those with one or two abnormal lineages. Similarly, patients with complex defects had shorter survival than those with single or double defects or a normal karyotype. There was no statistically significant difference between survival of NN (normal), A N (abnormal/normal), and A A patients or between survival of patients with del(Sq), -7/del(7q), + 8 or del(2Oq).

INTRODUCTION Myelodysplastic syndrome (MDS) is a group of hematopoietic disorders characterized by hematologic abnormalities reflecting an uncoupling of proliferation and differentiation or maturation in clonal hematopoietic progenitors. Ineffective hematopoiesis is predominant and, in most cases, is characterized by bone marrow (BM) hypercellularity, increased intramedullary cell death, and peripheral cytopenias [1]. An increasing number of recurring chromosome abnormalities has been recognized in primary MDS (p-MDS). The incidence of clonal chromosome defects ranges from 32

From Divisions de G~n~tique M~dicale (V.P., M.J.B.) et d~I~matologie (E M. S.), Centre Hospitalier Universitaire Vaudois, Lausanne, Institut de M~decine Sociale et Preventive, Universit~ (G. V. M., E. H.), Lausanne, Division d'H~matologie, H6pital Cantonal Universitaire (Ph. B.), Gen~ve, and H~matologisches Zentrallabor, Inselspital (A. T.), Bern, Switzerland. Address reprint requests to: M. Jotterand Bellomo, Ph.D., Division de G~n~tique M~dicale, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland. Received February 3, 1994; accepted May 2, 1994.

to 73% [2-44]. In p-MDS, the most frequently observed abnormalities are del(5q), +8, -7/del(7q), and del(20q). Approximately 20-40% of MDS patients die of complications secondary to BM insufficiency and progression to acute leukemia (AL) occurs in 10-40% of patients [45]. In view of marked variations in survival, not only between French-American-British (FAB) classification types but also within a single subtype, assessment of prognostic factors at initial presentation and during the disease course is particularly important in terms of therapeutic decisions and trials. As suggested by numerous studies, the patient's chromosome status at referral and subsequent examination is a major prognostic indicator of survival, leukemic transformation and response to treatment [2-27, 46-48]. Most of these studies indicate that patients with a normal karyotype survive longer and experience leukemic transformation less frequently than those with an abnormal karyotype, but in several studies survival and rates of leukemic transformation were not significantly different in the two groups of patients [14, 19, 29, 30, 33-38, 42, 49]. Several studies have shown that patients with an admixture of normal and abnormal metaphases (AN) are less likely 219

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Cancer Genet Cytogenet 78:219-231 (1994) 0165-4608/94/$07.00

220 to develop acute nonlymphocytic leukemia (ANLL) and have longer survival than patients who have all abnormal mitoses (AA) [16, 21, 26, 35]. Other studies did not confirm such findings [2, 12, 36]. Patients with complex chromosome defects have been reported to be at greater risk of short survival and leukemic transformation than those with single defects or a normal karyotype. Furthermore, specific single chromosome abnormalities have been shown to influence prognosis. Several prognostically significant cytogenetic categories were recognized [12, 13]. A normal karyotype or del(5q) alone represents a rather favorable prognosis as opposed to -7/del(7q), + 8, and complex defects. Subsequent studies provided further evidence of the existence of good- and poorrisk chromosome features [17, 19-21, 23, 27, 28, 36]. We report in detail the clinical, hematologic, and cytogenetic data of 109 patients with p-MDS. The aims of the study were to 1) evaluate whether the FAB classification, the Bournemouth prognostic score, and the number of abnormal BM cell lineages are related to disease course and the risk of leukemic transformation; 2) determine whether specific chromosome findings are associated with FAB types; and 3) determine if survival and leukemic progression are related to NN/AN/AA and complexity cytogenetic classifications and to specific chromosome defects.

PATIENTS AND METHODS Patients One hundred and nine patients with the diagnosis of p-MDS were included in the study. Forty-three were reported in part previously [41, 50, 51]; in these cases, hematologic, clinical and cytogenetic data have been reviewed in detail. Patients were diagnosed in the divisions of hematology of the university hospitals of Lausanne (27 patients), Geneva, (67), and Bern (six) and in the district hospitals of Martigny, Neuch~tel, and Vevey (nine). Informed consent was obtained from each patient. Morphologic and Cytochemical Studies Diagnosis and classification of MDS according to the criteria of the FAB cooperative group [52] were made on examination of peripheral blood (PB) smears, BM aspirates and, in some patients, biopsies obtained before therapy and during disease evolution. Blood and BM films were stained by Wright, Giemsa, and hematoxylin-eosin standard techniques. Identification of blast cells was obtained by standard cytochemical stainings (peroxidase, Sudan black B, periodic acidSchiff, leukocyte esterase) and a panel of monoclonal antibodies. Sideroblasts were disclosed by Prussian blue stain. In addition, BM specimens of 99 of the patients were assessed for evidence of dyserythropoiesis, dysgranulopoiesis, dysmegakaryopoiesis (qualitative defects) and of cell lineage hypo- or hyperplasia (quantitative defects). Qualitative and quantitative abnormalities were defined according to the criteria described by Bennett et al. [52]. Cytogenetic Studies Chromosome analysis was performed on mononuclear BM cells obtained after separation on Ficoll-Paque density gra-

V. Parlier et al. dient (1.O77g/L). Cytogenetic preparations were made according to protocols described previously [41, 51]. The first analysis was made at presentation in 59 patients, during the year after diagnosis in 20, and more than 1 year after diagnosis in 30. For 23 patients, follow-up examinations were made (data not shown). Two cytogenetic classifications were used, one based on complexity and the other on clonal status. The complexity classification consisted of four categories as follows: N, no abnormality found; S, single defect; D, double defect; and C, complex defects. A double defect was defined as two chromosome abnormalities in the same cell. The presence of two cytogenetic clones, each with a single defect, was considered S. Complex defects (C) indicated more than two clonal defects in the same cell. Clonal status was defined by the NN/AN/AA classification as follows: NN, no clonal abnormality detected; AN, mixture of normal cells and cells with a clonal defect; and AA, all cells belonged to one or more abnormal clone(s). Chromosome defects were defined according to the International System for Human Cytogenetic Nomenclature [53]. The criteria adopted at the First International Workshop on Chromosomes in Leukemia [54] were used for identification of abnormal clones: at least two cells with the same trisomy or structural rearrangement or at least three cells with the same monosomy. Accordingly, patient 13275, who had del(5q) in one of 36 metaphases, and patient 20108, with + 8 in one of 25, were considered NN. For almost nearly completely abnormal cases, no general rule allows decision regarding time when they should be classified AN. For the purpose of statistical analysis, the minimal normal cell percentage was fixed at 3%. Consequently, cases 16297 and 15767 with one of 257 (0.4%) and one of 48 (2%) normal cells, respectively, were considered AA.

Clinical Data Infections, bleeding, and progression to AL were classified as MDS-related causes of death. Death owing to BM transplant failure, diseases other than MDS, or accidents were considered unrelated to MDS. ANLL subtypes were identified according to FAB criteria (MO-M7) [55]. Disease not readily subclassified was considered ANLL unspecified. In two patients, MDS progressed to biphenotypic AL (Bi-AL). Clinical status was obtained for all patients between January and March 1992. The Bournemouth score was established according to the original criteria of Mufti et al., [56], i.e., one point each to hemoglobin less than 10 g/dl, neutrophil count less than 2.5 × 109/L, platelet count less than 100 x 109/L, and BM blasts exceeding 5%. In chronic myelomonocytic leukemia (CMMoL), the scoring system proposed by Worsley et al. [57], a modification of the original Bournemouth score in which one point is assigned to neutrophil count less than 2.5 × 109/L or more than 16 × 109/L, was used. Statistical Methods Comparisons of frequency distributions were made by chisquare test. Rates of leukemic transformation within the various groups were compared by Fisher's exact test. Survival curves were established by the Kaplan-Meier method [58] and compared by log-rank test.

Prognostic Factors in MDS

RESULTS

Patient Characteristics and Clinical Features Study patients were 43 women (39%) and 66 men (61%); sex ratio was 2:3. Mean age was 69 years for men (range 31-90 years} and 71 years for women (range 30-92 years}. Patients aged less than 50 years represented 8% of the total (nine patients); those aged more than 80 years constituted 20% (22}. Age distribution did not differ significantly between the sexes (p = 0.35}. At time of diagnosis, 27 patients had refractory anemia (RA} (25%}, 26 had RA with ringed sideroblasts (RARS) (24%), 16 had RA with excess of blasts (RAEB) (15%), 10 had RAEB in transformation (RAEB-t) (9%), and 25 had CMMoL (23%). Five patients had MDS that could not be classified at presentation according to FAB criteria (4%). Two of them presented with isolated thrombocytopenia (patients 20643 and 16784). Clinical evolution and cytogenetic analysis performed only later during the disease course (presence of complex defects in one case, del{2Oq) in the other) allowed retrospective diagnosis of MDS with the unusual presentation of refractory thrombocytopenia type [59]. In one patient (13303) with peripheral pancytopenia, BM cells could not be aspirated at presentation owing to fibrosis, but increased cellularity was prominent in the trephine biopsy specimen. Six months later, a BM aspirate could be performed and cytogenetic examination showed complex defects in all metaphases analysed. Patient 22738 had severe anemia (6.1 g/dl). The poor quality of BM smears did not allow precise diagnosis, but decreased cellularity and presence of blasts and maturation defects were noted and a chromosome defect was present in all mitoses. In the fifth patient (15064), hemoglobin was normal, but discrete thrombocytopenia with morphologically abnormal red blood cells was evident. Dyserythropoietic features were noted in BM. Karyotype was normal. Twenty-four patients (22%) died of infections and/or bleeding, 23 of leukemic transformation (21%} and 23 (21%} of causes not related to MDS. Disease related death rates varied according to FAB prognostic groups. In high-risk categories, 75-90% of patients die of these causes (12 of 16 RAEB, nine of 10 RAEB-t), as compared with only 23-30% in lowrisk types (six of 26 RARS, eight of 27 KA). Eight of 25 (32%) patients with CMML died of related causes. Sixty-nine patients {63%} had stable disease, 14 (13%} experienced a change in FAB subtype and one patient had RARS {15564} that evolved to myelofibrosis with myeloid metaplasia. Twenty-five patients (23%} had transformation to AL in a median time of 5 months (range 1-89 months} after diagnosis {Table 1}. The highest rate of leukemic progression was noted in RAEB-t (five of 10, 50%), followed by RAEB (five of 16, 31%), RARS (five of 26, 19%), CMML (four of 25, 16%), and RA (three of 2Z 11%). Most patients received supportive treatment consisting of transfusions and/or polyvitamin therapy. Eleven patients received differentiating or aggressive chemotherapy. Two had allogeneic BM transplant: One was alive 4 months after transplantation (18187); the other (21541} died after graft failure. Survival curves according to FAB subgroups were significantly different (p = 0.0001}. Overall median survival was

221 53 months from initial diagnosis. Median survivals in patients with RARS (142 months} and RA/RASq- (91 months} were significantly longer than those in patients with RAEB (19 months) and RAEB-t (5 months). Median survival for CMML was 47 months. The survival of unclassifiable MDS cases was not interpretable owing to the small number of patients in this group. The Bournemouth score could be established for 97 patients. The difference between survival rates in patients with a score of 0-1 (37 patients), 2-3 (40) or 4 (20) was statistically significant (p = 0.0001). Median survivals were 17 and 3 months in groups 2-3 and 4, respectively. In group 0-1, median survival could not be assessed (it is longer than 60 months} because only six of 37 patients had died and other survivals were censored (death not related to MDS or withdrawn from study alive}.

Abnormal Hematopoietic Cell Lineages Survival in patients with one (nine patients), two (21), or three (67) abnormal lineages was significantly different (p = 0.0003} (Fig. la). Patients were then separated into two groups. Group A patients (44) had qualitative (QL) and quantitative (QT) defects in one, two, or three lineage(s} as assessed by morphology; group B patients {55}were characterized by either a QL or a QT defect but not both in one, two, or three lineage{s}. Differences between survival in groups A and B were not significant when one or two lineages were dysplastic but were highly significant when three lineages were abnormal (p = 0.0004} (Fig. lb}. Median survival was 4 months in group A and was not reached in group B, in which, after 23 months, 11 of 35 patients had died and the remaining survival times were censored. Leukemic transformation was observed in 8% (one of 12), 11% (three of 27} and 30% {18 of 60} of patients with one, two, and three abnormal cell lineages, respectively (p = 0.02} (Fig. 2a). With three dysplastic lineages, the rate of transformation was 48% (11 of 23) in group A and 19% (seven of 37) in group B {p = 0.002} (Fig. 2b).

Cytogenetic Findings A cytogenetic result was obtained in all 109 cases. The number of metaphases fully analyzed varied between 4 and 257. Chromosome resolution ranged from 350 to 650 bands. At the first chromosome examination, a clonal karyotypic abnormality was detected in 61 patients (56%}, of whom 35 were AN (57%) and 26 were AA (43%). Data are shown in detail in Tables 1 and 2. No constitutional abnormality has been observed. Survival was calculated from the time of first chromosome study (102 patients). In 55 patients, chromosome analysis was performed at referral; in 47 it was performed later during the course of the disease. The study did not include seven patients for whom hematologic, clinical, and cytogenetic data were not simultaneously available. The leukemic transformation rates were estimated for all 109 patients. Survival times of patients with N, S, D, and C karyotypes were significantly different (p = 0.0001). Median survival was 35 months in S patients (37), 15 months in D patients (eight}, and 3 months in C patients (16}; it was not reached

V. Parlier et al

222 Table 1

Cytogenetic findings and clinical outcome in 109 patients with p-MDS Metaphases

Diagnosis Evolution Patient/sex/age (yr) (FAB) (FAB)

Survival (mo)

Cause of death

analyzed A N

Karyotype

%

Normal

lO142a/F/71 12278a/M~63 13832a/F/41 19196/M/77 20089/F/86 20431/M/78 20623/M/60 22038/F/80 22090/M/66

22678/F/46 13378a/M/80 13408a/F/92 14741a/M/64 15326a/F/77 16948/M/68 17489/F/90 17784/M/69

18387/M/68 18516/F/78 18600/M/88 18742/F/89 20108/F/52 20360/M/57 10541a/M/64 12719a/M/66 13042a/M/58 18187/M/31 20078/M/77

20653/F/77 22083/F/75 19074/M/67 20829/M/57 20923/F/90 13275a/M/78 13971a/M/54 15106a/F/83 15228a/F/62 19446/M/77 20162/M/84

20227/M/71 20535/M/90 20553/M/53 21269/M/84 22883/M/74 23066/M/71 18063/F/81 20079/M/64 15064a/M/64 Single defects del(5q)

17909/F/75 13092a/F/69 16229a/F/77 17000/F/66

17827/F/87 19149/F/61

22985/F/83 19379/F/76 14237a/M/76

RA RA RA RA RA RA RA RA RA

93

1 RAEB RAEB Bi-AL REM

RA RARS RARS RARS RARS RARS RARS RARS RARS RARS RARS RARS RARS RARS RAEB RAEB RAEB RAEB RAEB RAEB RAEB RAEB-t RAEB-t RAEB-t CMML CMML CMML CMML CMML CMML CMML CMML CMML CMML CMML CMML CMML-t CMML-t MDS

RA 5q 5q 5q 5q 5q 5q RARS RAEB-t

ANLL

M4

CMML RAEB-t Bi-AL REM M5 RAEB-t ANLL M2

CMML-t

M2 ANLL

RARS

RA ANLL

79 + 43 18 11 27 + 29 46 + 10 + 45 14 83 93 + 28 34 + 36 + 142 10 29 + 44 + 23 + 141 + 43 29 11 34 + 10 27 11 + 1 12 2 19 113 + 63 + 68 47 10 67 1 26 + 18 + 16 + 8+ 12 24 + 34

85 102 + 24 40 + 3 49 + 6÷ 4 4

NR

0

15

R

0

7

NR NR R R

NR NR NR R

R R

NR R R R R R R R NR

R R NR NR NR

R R

R R NR

NR R

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Ib 0 0 0 0 0 0 0 0 0 0 0 Ib 0 0 0 0 0 0 0 0 0 0 0 0 0 0

105 8 3 22 73 36 8 15 10

10 26 25 25 10 17 13 11 7 8 15 15 9 25 9 27 26 26 25 24 23 9 12 4 50 25 10 15 25 30 25 35 30 11 22 26 25 24 10 28 16 20 20 99 25 10

4 0 10 0 24 7 1 10 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 4 0 0 0 0 0 0 0 0 0 0 0 2.8 0 0 0 0 0 0 0 0 0 0 0 0 0 0

96 100 23 100

75 84 89 60 100

46,XX 46,XY 46,XX 46,XY 46,XX 46,XY 46,XY 46,XX 46,XY 46,XX 46,XY 46,XX 46,XY 46,XX 46,XY 46,XX 46,XY 46,XY 46,XX 46,XY 46,XX 46,XX 46,XY 46,XY 46,XY 46,XY 46,XY 46,XY 46,XX 46,XX 46,XY 46,XY 46,XX 46,XY 46,XY 46,XX 46,XX 46,XY 46,XY 46,XY 46,XY 46,XY 46,XY 46,XY 46,XY 46,XX 46,XY 46,XY

46,XX,del(5) (q15q33)/46,XX 46,XX,del(5)(q?) 46,XX,del(5)(q15q33)/46,XX 46,XX,del(5)(q13q33)

46,XX,del(5)(q13q33)[73%]/47,XX, + 812%]/46,XX 46,XX,del(5)(q15q33)/46,XX 46,XX,del(5)(q?)/46,XX 46,XX,del(5)(qlsq33 or q13q31)/46,XX 46,XY,del(5)(q13q33)

223

Prognostic Factors in MDS Table 1

Continued

Patient/sex/age (yr) - 7/del(7q) 13028a/M/71 16440/M/72

14358a/M/59 20541/M/85 16839a/M/65 +8 13970a/M/38

15564a/F/66 22486/M/66 92189/F/74 del(20q)

19225/M/79 22848/M/77 21451/M/49 21811/M/84 16784a/F/77 Y loss 22188/M/69

14704a/M/82 15321a/M/76 15767a/M/88 92253/M/80 Miscellaneous 13419a/M/82 15508°/M/64 22832/M/63 16297a/M/73 18902/M/84 18743/M/77 22370/F/66 14886/F/64 22738/F/71 T w o defects 10395a/M/51 23261/F/30

Diagnosis Evolution Survival Cause (FAB) (FAB) (mo) of death

RA RA RARS RAEB CMML RARS RARS CMML CMML

RAEB RAEB CMML-t

MMM

47 9 24 19 35

14 7+ 5 2 38 +

RARS CMML CMML CMML CMML

10 + 57 32 3 0+

CMML RAEB RAEB

M7

NR NR R R

56+ 47+ 9+ 0+

RA RA RAEB RAEB MDS

RA RA RA RARS RARS RARS RAEB RAEB-t MDS

R

3 93 45 + 149 41 + 30 + 53 13 3

NR NR R

NR R R

NR R NR

R R R

NR

Metaphases analyzed Karyotype

A

N

%

19 10 10 4 26

11 11 0 12 0

63 48 100 25 100

7 8 5 9

19 4 15 1

27 67 25 90

5 28 13 20 4

52 2 12 0 6

9 93 52 100 40

46,XY,del(20)(q11.21q13.31 or q13.32)/46,XY 46,XY,del(20)(q11.2q13.3)/46,XY 46,XY,del(20)(qllq13)/46,XY 46,XY,del(20)(q11.2q13.3) 46,XX,del(20)(qllq13.2)/46,XX

4 10 9 47 10

16 0 3 1 0

20 100 75 98 100

45,X,-Y/46,XY 45,X,-Y 45,X, - Y / 4 6 , X Y 45,X,-Y 45,X,-Y

6 19 13 256 20 2 4 15 10

4 2 2 1 0 23 8 0 0

60 90 87 99.6 100 8 33 100 100

47,XY, + 14/46,XY 46,XY,del(1)(p22.1p32.3)/46,XY 46,XY,t(7;21)(q32 ;q22)/46,XY 47,XY, + m a r 46,XY,t(9; 22)(q34;q11) 46,XY,deI(9)(q?)/46,XY 46,XX,der(20)/46,XX 46,XX,t(6;9)(p23;q34) 47,XX, + der(1)t(1;19)(q10;p10)

12 12

0 5

100 71

18 17 10

0 22 0

100 44 100

46,XY,t(2;11)(p21;q23),del[5)(qlSq33) 46,XX,add[8){q24)[53 %]/46,idem,t(6;13)(q23;q14) [18%]/46,XX 47,XY, + 8183%]/46,X, - Y, + 8117%] 46,XX,del(7)(q31.3q34},del(20)(q11.2q13,31)/46,XX 47,XY, + 8150%]/47,idem,del(5)(q11 or q12q34)

45,XY,t(1;7)[qlO;p10), - 7/46,XY 45,X, - Y[29%]/46,XY,del(7)(q22q32)[19%]/46,XY 45,XY, - 7 45,XY, - 7/46,XY 45,XY, - 7 47,XY, 47,XX, 47,XY, 47,XX,

+ 8/46,XY + 8/46,XX + 8/46,XY + 8/46,XX

RA RA

29 7+

RARS RARS RAEB

ANLL

63 + 42 + 4

RAEB-t RAEB-t CMML-t

M2 M1 M5

15 10 10 +

R R

12 7 3

0 19 46

100 27 6

46,XX,t(3;3)(q21;q26),del(7)(q22q36) 45,XX,inv(3)(q21q26), - 7/46,XX 48,XX, + 1, + 8/46,XX

RA

ANLL

91

R

10

0

100

15462C/M/51

RARS

ANLL

18

R

12

0

100

18512/F/68 22937/F/64

RARS RARS

ANLL M6

45 7

R R

8

4

23

0

67 100

45,t(X;14}(p22.2 or p22.3;?q22},Y, - 12, + der(12} t(12;20)(q10;p13), - 20 42,XY,der(3)t(3;17)(p11;q11, q12 or q21.1), del(5)(q22q33),der(6)t(6;15)(p12;q11), + der(7) t(7;21)(p11;q11), - 15, - 17, - 18, - 21169%]/40,idem, - 15, - 2218%]/39,idem, - 9, - 12, - 14123%] 45,XX, - 5, - 16,add(19~(q13~, + max/46,XX 43,XX,der(1)t(1;?;15)(p?36;?;q10 or q11.2), del(5)(q11.2q33),der(7)t(7;14)(p15;q11.2), - 14, - 15, - 18,[13%]/43,XX,der(1),del(5), der(7),add(13)(q34), - 14, - 15, - 1814.3%]/ 43,XX, - 1, + der(1),del(5),der(7), - 14, - 15, - 17,add(18)(q23)[26 %]/44,XX,der(1),del(5),

13136a/M/69 19867/F/47 16058a/M/73

R

[5o%] 13629a/F/63 18274Q/F/33 24085/F/67 Complex defects 22147/M/66

continued

V. Parlier et al.

224 Table 1

Continued Metaphases

P a t i e n t / s e x / a g e (yr)

Diagnosis

Evolution

Survival

Cause

(FAB)

(FAB)

(mo)

of death

analyzed A

N

%

Karyotype d e r ( 7 ) , - 14, - 1 5 , - 1 7 , a d d ( 1 8 ) , + m a r [ 2 6 % ] / 4 3 , X X , d e r ( 1 ) , d e l ( 5 ) , d e r ( 7 ) , - 13, - 14, 1 5 , d e l ( 1 8 ) ( p 1 1 ) [ 8 . 7 % ] / 4 3 , X X , - 1, + d e r ( 1 ) , d e l ( 5 ) , t ( 5 ; 8 ) ( p 1 5 ; q 2 2 ) , d e r ( 7 ) , - 14, - 15, - 18, del(20)(qllq13)[8.7%]/44,XX,der(1),del(5),t(5;8), d e r ( 7 ) , - 14, - 15, - 1 8 , d e 1 ( 2 0 ) , + d e 1 ( 2 0 ) [ 4 . 3 % ] / 41,XX,der(1),del(5),der(7),der(8)t?(8;17)? ( q t e r ; p t e r ) , - 14, - 15, - 17, - 17, - 1 8 , a d d ( 1 9 ) ( p 1 3 ) , d e l ( 2 0 ) [ 4 . 3 % ] / 4 7 , X X , - 1, - 1, + 3, + 4 , d e l ( 5 ) , + 6 , + 6, + 8 , - 9 , - 9 , - 10, + 11, + 12, + 13, - 15, - 18, - 1 9 1 4 . 3 % ] 4 3 , X Y , - 1 , t ( 3 ; 9 ) ( q 2 6 - 2 7 ; q 1 3 ) , - 4, + d e r ( 4 ) t ( 1 ; 4 ) ( q 2 1 ; q 3 1 ) , - 5, - 6, - 7, - 16, - 1 7 , a d d ( 1 9 ) ( q 1 3 ) , + marl, + mar2, + mar3/46,XY 46,XX,del(20)(qllq13.3)[5%]/46,XX, - 14, + 19, del(20)[5%]/48,XX, + 19,de1(20), + de1(20)[80%]/ 4 9 , X X , + 13, + 1 9 , d e 1 ( 2 0 ) , + d e 1 ( 2 0 ) [ 1 0 % ] 47,XY, + 8,del(20)(q11)[17%]/47,idem,t(3;6) (p14;p11)[76%]/46,XY 46,XX,t(6;12)(q13;q14 or q15)[11%]/46,idem,del(5) (q15q33)[61%]/46,idem,del(5),del(13) (q12.3q21)[28% ] 4 4 , X X , d e l ( 3 ) ( p ? ) , - 5 , a d d ( 7 ) ( p ? ) , + 8, - 1 0 , a d d ( 1 7 ) (p?), - 1 8 / 4 6 , X X 44,X, -Y, - 5,del(8)(p?),?inv(12),del(16)(q?),del(17) (p?)/46,XY 4 5 , X Y , d e l ( 5 ) ( q 1 5 q 3 1 ) , a d d ( 7 ) ( q ? ) , a d d ( 1 0 ) ( q ? ) , - 13, - 21, + m a r 4 3 , X Y , a d d ( 3 ) ( p ? ) , - 4, + d e r ( 4 ) t ( 4 ; 8 ) ( p 1 1 ; q 1 1 ) , - 5, 8 , a d d ( 1 1 ) ( p ? ) , - 12, - 17, + m a r 4 3 , X , - Y, - 2, + d e r ( 2 ) t ( 2 ; 1 3 ) [ p 2 3 - 2 5 ; q 1 2 - 1 4 ) , - 3, 5,del(7)(q22q33 or q34), add(12)(p11.2-12), 13,del(16)(q12-13q24), + r[23%]/42,idem, - r [ 6 % ] / 4 4 , i d e m , + 1 3 1 6 % ] / 4 3 , i d e m o r + Y, - r [24%]/46,XY 46,XX,del(5)(q13 or q14q34 or q35),?t(9;13)(q11, q 1 2 o r q 1 3 ; p 1 1 ) , - 17, + d e r ( 1 7 ) t ( 1 7 ; ? 2 0 ; 1 o r 12) (qter;?pter;p31 or q21.2), - 20,add(21)(q22), + mar1140%]/44,XX,del(5),? - der(9)t(9;13), ? + 1 1 , ? t ( 1 1 ; 1 7 ) ( q 1 3 ; q 2 5 ) , - 13, + d e r ( 1 3 ) t ( 9 ; 1 3 ) , - 1 6 , a d d ( 1 6 ) ( p ? 1 3 ) , - 17, - 18, - 2 0 , a d d ( 2 1 ) , + marl, + mar2[60%] 48,XX,?add(3)(p21),del(5)(q15q33),add(6)(q23), a d d ( 1 1 ) ( p ? ) , ? d e l ( 1 6 ) ( q ? ) , a d d ( 1 7 ) ( p ? ) , - 20, + 22, + marl, + mar2 46,XY,del(5)(q22q31.3 or q31.3q33),del(11) (q13q23.3)[23 %]/46,idem,add(1)(p?36),add(17) (q11.2,q12 or q21)[2%] -

3

R

12

1

92

ANLL

4

R

20

0

100

M4

5

R

27

2

93

63

R

18

0

100

RAEB-t

4

R

19

3

86

09450C/M/72

RAEB-t

5

R

13

1

93

14515C/M/61

RAEB-t

1

NR

10

0

100

12757C/M/62

CMML

2

R

12

0

100

18488/M/80

CMML

1

NR

27

19

59

09540C/M/68

RAEB

15872a/F/77

RAEB

17908/M/79

RAEB

19013/F/82

RAEB

09324C/F/67

M4

-

-

-

18629/F/80

CMML

13303C/F/84

MDS

20643/M/50

MDS

M4

RAEB

2

R

15

0

100

8

R

8

0

100

48

R

10

30

25

Abbreviations: RA, refractory anemia; RARS, RA with r i n g e d sideroblasts; RAEB(-t), RA w i t h excess of blasts (in transformation); CMML, chronic m y elomonocytic leukemia; ANLL, acute n o n l y m p h o c y t i c leukemia; MDS, myelodysplastic syndrome; FAB, French-American-British classification; Bi-AL b i p h e n o t y p i c acute leukemia; REM, remission; Survival + , still alive after x - m o n t h survival; R, related; NR, not related; N, normal; A, abnormal; %, percen tage of a b n o r m a l metaphases; mar, marker c h r o m o s o m e (numbered if different markers are present in the same clone). a Patients described in Jotterand Bellomo et al. [41, 50, 51]. b Patient 20108 w i t h + 8 in one of 25 metaphases a n d patient 13275 with del(5q) in one of 36 m e t a p h a s e s have been considered NN. c In seven cases (a above), karyotypes have been corrected (misprinted) or reviewed.

Prognostic Factors in MDS

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(a) Kaplan-Meier survival curves according to degree of lineage involvement {one, two, or three abnormal lineages) (p = 0.0003). (b) Survival in patients with three abnormal bone marrow cell lineages according to type of defect. A; qualitative and quantitative defect; B, qualitative or quantitative defect (p = 0.0004).

Figure I

226

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(a)

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Figure 2 (a) Rates of leukemic transformation according to degree of lineage involvement (one, two, or three abnormal lineages). (b) Rates of leukemic transformation in patients with three abnormal cell lineages according to type of defect. A3, qualitative and quantitative defect; B3, qualitative or quantitative defect. in N patients after 60 months (41). The rate of leukemic transformation was significantly higher in D (four of eight, 50%) and C (nine of 16, 56%) patients than in S patients (two of 37, 5%) and N patients (10 of 48, 21%) (p < 0.001). The difference between S and N was not significant (p = 0.06) (Fig. 3). The difference between survival in AA/AN/NN patients did not reach statistical significance (p = 0.19). Median survival was 7 months in AA (26 patients), 24 months in AN (35), and could not be assessed in NN (41). Leukemic progression rate was significantly higher in AA (11 of 26, 42 %) than in AN (four of 35, 11%) (p < 0.01) or in NN (10 of 48, 21%) (p < 0.05); however, the difference between AN and NN (p = 0.2) was not statistically significant, nor was that between NN versus AN and AA together (p = 0.6) (Fig. 4). No inference can be drawn for the joint effect of the two cytogenetic classifications due to the smaller number of patients. For specific chromosome defects, survival was calculated from time of first chromosome study for all 109 patients. Survival of del(5q), - 7/del(7q), del(2Oq), + 8, other single defects (S), and D or C defects were not all identical (p = 0.007) (Fig. 5). Survival in D and C patients was considerably reduced (median 4 months). Median survival was 35 months in -7/del(7q) patients and 28 months in del(5q). It could not be estimated in del(20q) and + 8 patients and was 23 months in other S patients. DISCUSSION Our results, in agreement with the results of Foucar et al. [60], show that the main causes of death are disease-related

in RAEB and RAEB-t types, whereas most RA and RARS patients die of unrelated causes. Two thirds of CMML patients died of MDS-related disorders. The differences in survival observed between the various FAB types are in accordance with previously published results, although overall survival of our sample is somewhat longer than that in comparable studies [45, 61], probably owing to the high proportion of RA and RARS included in our series (49%) and to the relatively long survival observed in these two types (median of 91 and 142 months, respectively). According to Bournemouth scoring system, the three risk groups proposed by Mufti et al. [56] showed significantly different survival; the difference was slightly more pronounced in our series because patients in the higher risk groups with scores equal to 2-3 and 4 points had relatively shorter median survival (17 and 3 versus 22 and 8.5 months, respectively). Additional prognostic information in MDS is provided by degree of BM lineage involvement. In this series, the risk of developing AL was significantly higher in patients with severe dyspoiesis of three cell lineages than in those with one- or two-lineage dysplasia; the differences in survival times between patients with one, two, or three dysplastic lineages were statistically significant. These findings are in agreement with those of Varela et al. [62] and Jacobs et al. [14]. In a survey of 128 cases of RA and RARS [21], however, survival times appeared to decrease with a greater degree of lineage involvement, without reaching statistical significance and, in a recent study of 27 cases of RA [38], the presence of three-lineage dysplasia had no significant influence on

Prognostic Factors i n MDS

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AN

AA

F i g u r e 4 Rates of leukemic transformation according to the NN/AN/AA classification.

F i g u r e 5 Kaplan-Meier survival curves in 109 patients according to karyotype: normal (N); del(5q), - 7/del(2l), del(20q), + 8; other single chromosome defects (S); and double or complex defects (D. C) (p = 0.007). Survival was measured from time of first chromosome study. 1 O0 +8

(~=4)

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12

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I

I

i

I

i

24

30

56

42

48

54

Time (months)

60

228

V. Parlier et al. Table 2

Recurrent chromosome subgroups according to FAB classification

Normal Single defects del(Sq) - 7/del(7q) del(2Oq) Y loss +8 Miscellaneous Two defects Complex defects Total Abnormality (%)

RA

5q-

10 1 2 2 3 2 1 21 52

RARS

RAEB

RAEB-t

CMML

MDS

0

13

7

3

14

1

6

1 1

6 100

1 2 3 2 3 26 50

1 1 2

1 1 4 2

1 1 4 16 56

1 2 3 10 70

1 1 3 25 44

2 5 80

Total (%) 48(44) 9 5 5 5 4 9

37(34)

8(7) 16(15) 109

Abbreviations as in Table 1. survival. Our data also indicate that in the presence of three abnormal lineages the risk of leukemic transformation as well as survival vary significantly with type of defect (both quantitative and qualitative anomalies versus either one of qualitative or quantitative abnormality}. At diagnosis, 56 % of patients exhibited a clonal chromosome defect. Single abnormalities (34%} were observed more frequently than double (7%) or complex (15%) defects. Our rates of chromosome defects for RARS {50%} and CMML {44%} are higher than those in other reports, those for RA (52%} and RAEB (56%} are comparable, and that for RAEB-t {70%} is lower. The discrepancies occurring between studies may be accounted for by several factors, such as accuracy of diagnosis and classification criteria, difficulty of diagnosis in the early stages of the disease, presence or absence of secondary MDS, time of chromosome study (on presentation or during evolution}, cytogenetic protocols, banding pattern resolution, and number of metaphases analyzed [23, 41, 51, 63]. As in other studies, the most frequent single abnormalities were de](5q), - 7/del(7q), de](20q), Y loss, and + 8. Among nine patients with del(5q), six were elderly women (age range 66-87 years) with the 5q- syndrome described previously [64]. Apart from this clinicocytogenetic entity, we observed no specific association between recurring chromosome abnormalities and FAB types. One patient had -7, + der t(1;7)(q10;p10), which has been described in secondary MDS and ANLL after cytotoxic therapy as well as in de novo disorders; the history of our patient showed no exposure to mutagenic agents. The significance of Y loss is not clear. Although it appears to be an age-related chromosome defect, several observations suggest that it could be of biologic significance in malignant hemopathies [65]. In our study, it was observed in five patients aged 69-88 years, four with CMML and one with RARS. Abnormalities in 3q21 and 3q26 were observed in two patients with RAEB-t, who both had clinical, hematologic, and cytogenetic features characteristic of the 3q21q26 syndrome [51]. Of 9 patients with miscellaneous defects, one showed a marker chromosome that could not be identified despite its relatively large size and good-quality banding pattern resolution [41]. Because it was the sole defect, it has been con-

sidered a single abnormality, but such marker chromosomes generally result from complex rearrangements most often involving several different chromosomes. This indicates a weakness of the classification method particularly relevant in prognostic studies. In several reports, AN patients had better survival than AA patients. Our results, like those of Nowell and Billstr6m, disagree with such findings. Several factors may account for the lack of significant differences in survival between our NN, AN, and AA patient groups. Clonal chromosome defects have been demonstrated to have little prognostic effect in the RA and RARS groups [23] and, in our study, 49% (30 of 61) of patients with abnormal karyotype belonged to these two subgroups. Recorded survival is likely to be biased by the fact that chromosome analysis was performed at differing times in the disease course. Obviously, if such analysis is performed in the early stages of the disease, the observed survival time will be longer than if it is performed later; e.g., in patient 19146 with CMML and NN karyotype, survival is 47 months after initial diagnosis and only I month after chromosome analysis. Therefore, to be comparable, survival studies should include only patients who have undergone cytogenetic analysis at initial diagnosis. Another possible reason relates to the number of metaphases analyzed: In our series, four cases were classified as NN, but the low number of metaphases examined (< 10 due to technical reasons) does not exclude the presence of an AN karyotype. We observed a higher rate of leukemic transformation in AA patients than in AN and NN patients, as previously reported [10, 23, 35] and, as in the study of Taniwaki et al. [35], leukemic transformation rates were not significantly different between AN and NN. At present, no definite evidence suggests that the size of the abnormal clone in MDS is of no prognostic value. Fluorescence in situ hybridization techniques provide a powerful tool to investigate and understand further the biologic and clinical relevance of clonality. In our series, survival was significantly shorter for patients with double or complex defects than for those with normal karyotype or single defects. That patients with complex abnormalities have shorter survival than patients with normal karyotype is well documented [3, Z 11-13, 16, 19, 20, 22, 23,

Prognostic Factors in MDS 25-27, 36, 42, 49]. Although in numerous studies, survival was shown to be significantly longer for patients with single defects than for patients with complex defects [11, 12, 14, 20-22, 25, 26], other workers observed little or no difference in survival between the two groups of patients [23, 27, 42]. Similarly, researchers disagree about comparison of patients with single defects and patients with a normal karyotype. In several studies, normal patients survived longer than those with single defects [12, 13, 21-23, 25, 27], whereas in other reports the difference was not statistically significant [3, 11, 20, 36]. In the present study, leukemic transformation occurred significantly more frequently in patients with double or complex defects than in those with single defects or a normal karyotype, but no significant difference was observed between the latter two. Some investigators report a higher frequency of leukemic transformation in the presence of complex defects [2, 7, 11, 14, 15, 19, 49]; for others, it was not statistically significant between patients with complex and single abnormalities [3, 12, 16, 20]. The existence of specific defects may influence both survival and frequency of leukemic transformation [12, 14, 20, 23, 28, 36]. Our observations must be interpreted with caution owing to the few patients in each group. As supported by our data, del(5q) as a sole abnormality associated with the characteristic features of the 5 q - syndrome has a good prognosis and a low risk of leukemic transformation [66]. Trisomy 8, as a single defect, is generally considered an intermediate- or high-grade chromosome abnormality because of the findings of Yunis et al. [12, 13] (nine patients, median survival 18 months), Nowell et al., [28] (seven patients, survival 5-36 months), and Geddes et al. [23] (five patients, median survival about 8 months). However, in other studies, patients with trisomy 8 had survival longer than 36 months [5, 7, 36, 67]. In our series, two of the four patients had 47- and 56-month survival, respectively. The latter, a patient with RARS complicating the course of paroxysmal nocturnal hemoglobinuria, has now survived more than 70 months [68]. These observations suggest the presence of distinct types of clinical evolution among the trisomy 8 entity. Three of our 5 patients with - 7/del(7q) died of MDS-related causes at 19, 35, and 47 months, respectively. In patients with -7/del(7q) as sole abnormality, Yunis et al. [12, 13] observed a median survival of 12 months (11 patients), Nowell et al. [28] reported survivals ranging from 4 to 35 months (six patients), and Geddes et al. [23] reported median survival of about 6 months (6 patients). In other series, some patients survived for more than 30 months [14, 38, 69, 70]. As in trisomy 8, there may be different patterns of disease evolution for MDS patients with -7/del(7q). We report several features of MDS constituting major prognostic indicators for survival and leukemic transformation. They include FAB classification, the Bournemouth scoring system, degree of BM lineage dysplasia, and the complexity and NN/AN/AA cytogenetic classifications. However, no single parameter yields a satisfactory prediction of clinical course and outcome in MDS. Multivariate analyses have shown that the combination of hematologic and clinical features may improve that prediction [45]. Using all data from

229 the present study, we constructed a multivariate regression model [71] from which a simplified scoring system can be proposed based on the combination of chromosome findings and the Bournemouth score. This work was supported by grants from the Ligue Suisse contre le Cancer, the Ligue Zougoise contre le Cancer, the Ligue Vaudoise contre le Cancer, Muschamp Foundation, Lausanne, SIPCA Foundation, Lausanne, and Sandoz Foundation, Sandoz A.G., Basel to M.J.B. The authors thank Danielle Berrut and the technicians of the cytogenetics laboratory of the Division Autonome de G6n6tique M6dicale (Professor G. Pescia), CHUV, Lausanne, Drs. J. Petite, J.C. Piguet, and P. Cornu for referral of some of the patients, R. Dimo for technical assistance, and Jacqueline Doily for typing the manuscript. REFERENCES

1. List AF, Jacobs A (1992): Biology and pathogenesis of the myelodysplastic syndromes. Semin Oncol 19:14-24. 2. Nowell P, Finan J (1978): Chromosome studies in preleukemic states. IV. Myeloproliferative versus cytopenic disorders. Cancer 42:2254-2261. 3. Nowell PC, Besa EC, Stelmach T, Finan JB (1986): Chromosome studies in preleukemic states. V. Prognostic significance of single versus multiple abnormalities. Cancer 58:2571-2575. 4. Nowell PC (1982): Cytogenetics of preleukemia. Cancer Genet Cytogenet 5:265-278. 5. Geraedts JPM, Weber RFA, Kerkhofs H, Leeksma CHW (1980): The preleukemic syndrome. II. Cytogenetic findings. A~a Med Scand 207:447-454. 6. Second International Workshop on Chromosomes in Leukemia 1979 (1980):Chromosomes in preleukemia. Cancer Genet Cytogenet 2:108-113. 7. Anderson RL, Bagby GC (1982): The prognostic value of chromosome studies in patients with the preleukemic syndrome (hemopoietic dysplasia). Leuk Res 6:175-181. 8. Ayraud N, Donzeau M, Raynaud S, Lambert JC (1983): Cytogenetic study of 88 cases of refractory anemia. Cancer Genet Cytogenet 8:243-248. 9. Coiffier B, Adeleine P, Viala JJ, Bryon PA, Fi6re D, Gentilhomme O, Vuvan H (1983): Dysmyelopoietic syndromes. A search for prognostic factors in 193 patients. Cancer 52:83-90. 10. Gold EJ, Conjalka M, Pelus LM, Jhanwar SC, Broxmeyer H, Middleton AB, Clarkson BD, Moore MAS (1983): Marrow cytogenetic and cell-culture analyses of the myelodysplastic syndromes: Insights to pathophysiology and prognosis. J Clin Oncol 1:627-634. 11. Fitchett M, Griffiths MJ, Mufti GJ, Hamblin TJ, Oscier DG, Seabright M (1985): Cytogenetic analysis of 113 patients with myelodysplastic syndrome [Abstract]. Br J Haematol 61:571. 12. Yunis JJ, Rydell RE, Oken MM, Arnesen MA, Mayer MG, Lobell M (1986): Refined chromosome analysis as an independent prognostic indicator in de novo myelodysplastic syndromes. Blood 67:1721-1730. 13. Yunis JJ, Lobell M, Arnesen MA, Oken MM, Mayer MG, Rydell RE, Brunning RD (1988): Refined chromosome study helps define prognostic subgroups in most patients with primary myelodysplastic syndrome and acute myelogenous leukaemia. Br J Haematol 68:189-194. 14. Jacobs RH, Cornbleet MA, Vardiman JW, Larson RA, Le Beau MM, Rowley JD (1986): Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes. Blood 67:1765-1772.

230

15. Pedersen B, Kerndrup G (1986): Specific minor chromosome deletions consistently occurring in myelodysplastic syndromes. Cancer Genet Cytogenet 23:61-75. 16. Kerkhofs H, Hermans J, Haak HI, Leeksma CHW (1987): Utility of the FAB classification for myelodysplastic syndromes: Investigation of prognostic factors in 237 cases. Br J Haemato165:73-81. 17. Groupe Fran~ais de Cytog6n6tique H6matologique (1986): Cytogenetics of chronic myelomonocytic leukemia. Cancer Genet Cytogenet 21:11-30. 18. Groupe Fran~ais de Cytog6n6tique H6matologique (1991): Chronic myelomonocytic leukemia: Single entity or heterogeneous disorder? A prospective multicenter study of 100 patients. Cancer Genet Cytogenet 55:57-65. 19. Horiike S, Taniwaki M, Misawa S, Abe T (1988): Chromosome abnormalities and karyotypic evolution in 83 patients with myelodysplastic syndrome and predictive value for prognosis. Cancer 62:1129-1138. 20. Musilova J, Michalova K (1988): Chromosome study of 85 patients with myelodysplastic syndrome. Cancer Genet Cytogenet 33:39-50. 21. Pierre RV, Catovsky D, Mufti GJ, Swansbury GJ, Mecucci C, Dowald GW, Ruutu T, Van Den Berghe H, Rowley JD, Mitelman F, Reeves BR, Alimena G, Garson OM, Lawler SD, de la Chapelle A (1989): Clinical-cytogenetic correlations in myelodysplasia (preleukemia). Cancer Genet Cytogenet 40:149-161. 22. Suciu S, Kuse R, Weh HJ, Hossfeld DK (1990): Results of chromosome studies and their relation to morphology, course, and prognosis in 120 patients with de novo myelodysplastic syndrome. Cancer Genet Cytogenet 44:15-26. 23. Geddes AD, Bowen DT, Jacobs A (1990): Clonal karyotype abnormalities and clinical progress in the myelodysplastic syndrome. Br J Haematol 76:194-202. 24. Vila L, Charrin C, Archimbaud E, Treille-Ritouet D, Fraisse J, Felman P, Fibre D, Germain D (1990): Correlations between cytogenetics and morphology in myelodysplastic syndromes. Blut 60:223-227. 25. Benitez J, Perez Rous G, Sanchez Fayos J (1991): Prognostic value of complex karyotypes in patients with simple refractory anemia. Cancer Genet Cytogenet 53:279-280. 26. Gonzalez Manso AI, Garcia Marcilla A, Barreiro E, Gilsanz F (1992): Cytohematologic and cytogenetic prognostic factors at diagnosis and in the evolution in 46 primary myelodysplastic syndromes. Cancer Genet Cytogenet 61:174-182. 27. White AD, Culligan DJ, Hoy TG, Jacobs A (1992): Extended cytogenetic follow-up of patients with myelodysplastic syndrome (MDS). Br J Haematol 81:499-502. 28. Nowell PC, Besa EC (1989): Prognostic significance of single chromosome abnormalities in preleukemic states. Cancer Genet Cytogenet 42:1-7. 29. Tricot G, De Wolf-Peeters C, Vlietinck R, Verwilghen RL (1984): Bone marrow histology in myelodysplastic syndromes. II. Prognostic value of abnormal localization of immature precursors in MDS. Br J Haematol 58:217-225. 30. Tricot G, Vlietinck R, Boogaerts MA, Hendrickx B, De WolfPeeters C, Van Den Berghe H, Verwilghen RL (1985): Prognostic factors in the myelodysplastic syndromes: Importance of initial data on peripheral blood counts, bone marrow cytology, trephine biopsy and chromosomal analysis. Br J Haematol 60:19-32. 31. Knapp RH, Dowald GW, Pierre RV (1985): Cytogenetic studies in 174 consecutive patients with preleukemic or myelodysplastic syndromes. Mayo Clin Proc 60:507-516. 32. Benitez J, Carbonell F, Sanchez Fayos J, Heimpel H (1985): Karyotypic evolution in patients with myelodysplastic syndromes. Cancer Genet Cytogenet 16:157-167. 33. Bynoe AG, Stark AN, Bhati B, Williams J, Scott CS, Roberts BE (1986): Correlation between chromosomal abnormalities and a

V. Parlier et al.

34.

35.

36.

37.

38.

39.

40. 41.

42.

43.

44.

45.

46. 47.

46.

49. 50.

51.

scoring system of dysmyelopoiesis in the myelodysplastic syndrome (MDS) [Abstract]. Br J Haematol 64:814. Web HJ, Calavrezos A, Seeger D, Kuse R, Hossfeld DK (1987): Cytogenetic studies in 69 patients with myelodysplastic syndromes (MDS). Eur J Haematol 38:166-172. Taniwaki M, Horiike S, Inazawa J, Nishida K, Misawa S, Takino T, Abe T (1987): Cytogenetic studies in 32 patients with myelodysplastic syndrome: Insights to specific chromosomal abnormalities and prognosis. Jpn J Clin Oncol 17:141-150. Billstr6m R, Thiede T, Hansen S, Heim S, Kristoffersson U, Mandahl N, Mitelman F (1968): Bone marrow karyotype and prognosis in primary myelodysplastic syndromes. Eur J Haematol 41: 341-346. Gyger M, Infante-Rivard C, ErAngelo G, Forest L, Lussier P (1988): Prognostic value of clonal chromosomal abnormalities in patients with primary myelodysplastic syndromes. Am J Hematol 28:13-20. Gyger M, D'Angelo G, B~langer R, Forest L, Lussier P, Busque L, Perreault C, Boileau J, Bonny Y, Lavall~e R, Lacombe M, Roy DC (1992): Cytogenetic characterization of primary refractory anemia. Am J Hematol 41:241-246. Lessard M, Brizard A, Guilhot F, Tanzer J (1988): Chromosomal results in 50 patients with myelodysplastic syndromes (MDS) [Abstract]. Blut 56:C9. Arthur DC (1989): Cytogenetics. Leukemia 3:833-834. Jotterand Bellomo M, Parlier V, Schmidt PM, Beris Ph (1990): Cytogenetic analysis of 54 cases of myelodysplastic syndrome. Cancer Genet Cytogenet 46:157-172. Verhoef G, De Wolf-Peeters C, Kerim S, Van De Broeck J, Mecucci C, Van Den Berghe H, Boogaerts M (1991): Update on the prognostic implication of morphology, histology, and karyotype in primary myelodysplastic syndromes. Hematol Pathol 5:163-175. Sol~ F, Prieto F, Badia L, Woessner S, Florensa L, Caballin MR, Coil MD, Besses C, Sans-Sabmfen J (1992): Cytogenetic studies in 112 cases of untreated myelodysplastic syndromes. Cancer Genet Cytogenet 64:12-20. Wu HK, Kitamura K, Xi YR, Wang YT, Liu SL, Zhou DB (1992): Cytogenetic analysis of bone marrow from patients with primary myelodysplastic syndrome. J Int Med Res 20:254-266. Mufti GJ (1992/: A guide to risk assessment in the primary myelodysplastic syndrome. Hematol Oncol Clin North Am 6:587-606. Todd WM, Pierre RV (1986): Preleukaemia: A long-term prospective study of 326 patients. Scand J Haemato145 (suppl 1:114-120. Fenaux P, Morel P, Rose C, LaYJL, Jouet JP, Bauters F (1991): Prognostic factors in adult de novo myelodysplastic syndromes treated by intensive chemotherapy. Br J Haematol 77:497-501. Hellstr6m-Lindberg E, Robert KH, Gahrton G, Lindberg, G, Forsblom AM, Kock Y, Ost A [1992): A predictive model for the clinical response to low dose ara-C: A study of 102 patients with myelodysplastic syndromes or acute lenkaemia. Br J Haematol 81:503-511. Borgstr6m GH (1966): Cytogenetics of the myelodysplastic syndromes. Scand J Haematol 45(suppl):74-77. Jotterand Bellomo M, Parlier V, Petite J, Beris Ph (1990): A now case of myelodysplastic syndrome with 6p rearrangement. Cancer Genet Cytogenet 44:271-274. Jotterand Bellomo M, Parlier V, Mfihlematter D, Grob JP, Beris Ph (1992): Three now cases of chromosome 3 rearrangement in bands q21 and q26 with abnormal thrombopoiesis bring further evidence to the existence of a 3q21q26 syndrome. Cancer Genet Cytogenet 59:138-160.

52. Bennett JM, Catovsky D, Daniel MT, FlandrinG, Galton DAG, Gralnick HR, Sultan C [1982): Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51:169-199. 53. ISCN 1991 (1992): Guidelines for Cancer Cytogenetics. Sup-

Prognostic Factors in MDS

54.

55.

56.

57.

58. 59.

60.

61.

62.

plemeut to An International System for Human Cytogenetic Nomenclature. S. Karger, Publishers, Inc. First International Workshop on Chromosomes in Leukaemia 1977 (1978): Chromosomes in acute non-lymphocytic leukaemia. Br J Haematol 39:311-316. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C (1985): Proposed revised criteria for the classification of acute myeloid leukemia. Ann Intern Med 103:620-625. Mufti GJ, Stevens JR, Oscier DG, Hamblin TJ, Machin D (1985): Myelodysplastic syndromes: A scoring system with prognostic significance. Br J Haematol 59:425-433. Worsley A, Oscier DG, Stevens J, Darlow S, Figes A, Mufti GJ, Hamblin TJ (1988): Prognostic features of chronic myelomonocytic leukaemia: A modified Bournemouth score gives the best prediction of survival. Br J Haematol 68:17-21. Kaplan EL, Meier P (1958): Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481. Beris Ph, Soulier-Lanper M, Parlier V, Jotterand Bellomo M (1991): Pr6sentation initiale inhabituelle d'un cas d'an~mie r6fractaire avec exc~s de blastes. Schweiz Med Wochenschr 121:1499-1502. Foucar K, Langdon RM, Armitage JO, Olson DB, Carroll TJ (1985): Myelodysplastic syndromes. A clinical and pathologic analysis of 109 cases. Cancer 56:553-561. Third MIC Cooperative Study Group 1987 (1988): Morphologic, immunologic, and cytogenetic (MIC)working classification of the primary myelodysplastic syndromes and therapy-related myelodysplasias and leukemias. Cancer Genet Cytogenet 32:1-10. Varela BL, Chuang C, Woll JE, Bennett JM (1985): Modifications in the classification of primary myelodysplastic syndromes: The addition of a scoring system. Haematol Oncol 3:55-63.

231

63. Parlier V (1992): Cytog6n~tique des syndromes myelodysplasiques. Th~se de doctorat, Universit6, Lausanne, Switzerland. 64. Van Den Berghe H, Vermaelen K, Meccuci C, Barbieri D, Tricot G (1985):The 5q- anomaly. Cancer Genet Cytogenet 17:189-225. 65. Kuffel DG, Schulz CG, Ash RC, Dewald GW (1991): Normal cytogenetic values for bone marrow based on studies of bone marrow transplant donors. Cancer Genet Cytogenet 53:39-48. 66. Mecucci C, Van Den Berghe H (1992): Cytogenetics. Hematol Oncol Clin North Am 6:523-541. 67. Iwabuchi A, Ohyashiki K, Ohyashiki JH, Sasao I, Murakami T, Kodama A, Toyama K (1992): Trisomy of chromosome 8 in myelodysplastic syndrome. Significance of the fluctuating trisomy 8 population. Cancer Genet Cytogenet 62:70-74. 68. Parlier V, Tiainen M, Beris Ph, Miescher PA, Knuutila S, Jotterand Bellomo M (1992): Trisomy 8 detection in granulomonocytic, erythrocytic and megakaryocyticlineages by chromosomal in situ suppression hybridization in a case of refractory anaemia with ringed sideroblasts complicating the course of paroxysmal nocturnal haemoglobinuria. Br J Haematol 81:296-304. 69. Pasquali F, Bernasconi P, Casalone R, Fraccaro M, Bernasconi C, Lazzarino M, Morra E, Alessandrino EP, Marchi MA, Sanger R (1982): Pathogenetic significance of "pure" monosomy 7 in myeloproliferative disorders. Analysis of 14 cases. Hum Genet 62:40-51. 70. Michiels JJ, Mallios-ZorbalaH, Prins MEF,Hiihlen K, Hagemeijer A (1986): Simple monosomy 7 and myelodysplastic syndrome in thirteen patients without previous cytostatic treatment. Br J Haematol 64:425-433. 71. Parlier V, Van Melle G, Beris Ph, Schmidt PM, Tobler A, Hailer E, Jotterand Bellomo M (1994): Prediction of 18 months survival in patients with primary myelodysplastic syndrome: A regression model and scoring systembased on the combinationof chromosome findings and the Bournemouth score. Cancer Genet Cytogenet (In press).