Abstract

Risk stratification and prognostication are crucial for the appropriate management of patients with myelodysplastic syndromes (MDSs) or myelodysplastic neoplasms, for whom the expected survival can vary from a few months to >10 years. For the past 5 decades, patients with MDS have been classified into higher-risk vs lower-risk disease phenotypes using sequentially developed clinical prognostic scoring systems. Factors such as morphologic dysplasia, clinical hematologic parameters, cytogenetics, and, more recently, mutational information have been captured in prognostic scoring systems that refine risk stratification and guide therapeutic management in patients with MDS. This review describes the progressive evolution and improvement of these systems which has led to the current Molecular International Prognostic Scoring System.

1.
Cazzola
M
.
Myelodysplastic syndromes
.
N Engl J Med
.
2020
;
383
(
14
):
1358
-
1374
.
2.
Malcovati
L
,
Ambaglio
I
,
Elena
C
.
The genomic landscape of myeloid neoplasms with myelodysplasia and its clinical implications
.
Curr Opin Oncol
.
2015
;
27
(
6
):
551
-
559
.
3.
Block
M
,
Jacobson
LO
,
Bethard
WF
.
Preleukemic acute human leukemia
.
J Am Med Assoc
.
1953
;
152
(
11
):
1018
-
1028
.
4.
Meacham
GC
,
Weisberger
AS
.
Early atypical manifestations of leukemia
.
Ann Intern Med
.
1954
;
41
(
4
):
780
-
797
.
5.
Fisher
WB
,
Armentrout
SA
,
Weisman
R
,
Graham
RC
.
“Preleukemia.” A myelodysplastic syndrome often terminating in acute leukemia
.
Arch Intern Med
.
1973
;
132
(
2
):
226
-
232
.
6.
Blair
TR
,
Bayrd
ED
,
Pease
GI
.
Atypical leukemia
.
JAMA
.
1966
;
198
(
1
):
139
-
142
.
7.
Saarni
MI
,
Linman
JW
.
Preleukemia. The hematologic syndrome preceding acute leukemia
.
Am J Med
.
1973
;
55
(
1
):
38
-
48
.
8.
Linman
JW
,
Bagby
GC
.
The preleukemic syndrome (hemopoietic dysplasia)
.
Cancer
.
1978
;
42
(
suppl 2
):
854
-
864
.
9.
Bennett
JM
,
Catovsky
D
,
Daniel
MT
, et al
.
Proposals for the classification of the myelodysplastic syndromes
.
Br J Haematol
.
1982
;
51
(
2
):
189
-
199
.
10.
Greenberg
PL
,
Nichols
WC
,
Schrier
SL
.
Granulopoiesis in acute myeloid leukemia and preleukemia
.
N Engl J Med
.
1971
;
284
(
22
):
1225
-
1232
.
11.
Senn
JS
,
Pinkerton
PH
.
Defective in vitro colony formation by human bone marrow preceding overt leukaemia
.
Br J Haematol
.
1972
;
23
(
3
):
277
-
281
.
12.
Greenberg
PL
,
Mara
B
.
The preleukemic syndrome: correlation of in vitro parameters of granulopoiesis with clinical features
.
Am J Med
.
1979
;
66
(
6
):
951
-
958
.
13.
Sanz
GF
,
Sanz
MA
,
Vallespi
T
, et al
.
Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients
.
Blood
.
1989
;
74
(
1
):
395
-
408
.
14.
Mufti
GJ
,
Stevens
JR
,
Oscier
DG
,
Hamblin
TJ
,
Machin
D
.
Myelodysplastic syndromes: a scoring system with prognostic significance
.
Br J Haematol
.
1985
;
59
(
3
):
425
-
433
.
15.
Aul
C
,
Gattermann
N
,
Heyll
A
,
Germing
U
,
Derigs
G
,
Schneider
W
.
Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring system
.
Leukemia
.
1992
;
6
(
1
):
52
-
59
.
16.
Morel
P
,
Hebbar
M
,
Lai
JL
, et al
.
Cytogenetic analysis has strong independent prognostic value in de novo myelodysplastic syndromes and can be incorporated in a new scoring system: a report on 408 cases
.
Leukemia
.
1993
;
7
(
9
):
1315
-
1323
.
17.
Toyama
K
,
Ohyashiki
K
,
Yoshida
Y
, et al
.
Clinical implications of chromosomal abnormalities in 401 patients with myelodysplastic syndromes: a multicentric study in Japan
.
Leukemia
.
1993
;
7
(
4
):
499
-
508
.
18.
Oscier
DG
.
Myelodysplastic syndromes
.
Baillieres Clin Haematol
.
1987
;
1
(
2
):
389
-
426
.
19.
Tricot
G
,
Boogaerts
MA
,
De Wolf-Peeters
C
,
Van den Berghe
H
,
Verwilghen
RL
.
The myelodysplastic syndromes: different evolution patterns based on sequential morphological and cytogenetic investigations
.
Br J Haematol
.
1985
;
59
(
4
):
659
-
670
.
20.
Jacobs
RH
,
Cornbleet
MA
,
Vardiman
JW
,
Larson
RA
,
Le Beau
MM
,
Rowley
JD
.
Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes
.
Blood
.
1986
;
67
(
6
):
1765
-
1772
.
21.
Yunis
JJ
,
Lobell
M
,
Arnesen
MA
, et al
.
Refined chromosome study helps define prognostic subgroups in most patients with primary myelodysplastic syndrome and acute myelogenous leukaemia
.
Br J Haematol
.
1988
;
68
(
2
):
189
-
194
.
22.
Pierre
RV
,
Catovsky
D
,
Mufti
GJ
, et al
.
Clinical-cytogenetic correlations in myelodysplasia (preleukemia)
.
Cancer Genet Cytogenet
.
1989
;
40
(
2
):
149
-
161
.
23.
Greenberg
P
,
Cox
C
,
LeBeau
MM
, et al
.
International scoring system for evaluating prognosis in myelodysplastic syndromes
.
Blood
.
1997
;
89
(
6
):
2079
-
2088
.
24.
Malcovati
L
,
Porta
MG
,
Pascutto
C
, et al
.
Prognostic factors and life expectancy in myelodysplastic syndromes classified according to WHO criteria: a basis for clinical decision making
.
J Clin Oncol
.
2005
;
23
(
30
):
7594
-
7603
.
25.
Malcovati
L
,
Germing
U
,
Kuendgen
A
, et al
.
Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes
.
J Clin Oncol
.
2007
;
25
(
23
):
3503
-
3510
.
26.
Kantarjian
H
,
O'Brien
S
,
Ravandi
F
, et al
.
Proposal for a new risk model in myelodysplastic syndrome that accounts for events not considered in the original International Prognostic Scoring System
.
Cancer
.
2008
;
113
(
6
):
1351
-
1361
.
27.
Della Porta
MG
,
Malcovati
L
,
Strupp
C
, et al
.
Risk stratification based on both disease status and extra-hematologic comorbidities in patients with myelodysplastic syndrome
.
Haematologica
.
2011
;
96
(
3
):
441
-
449
.
28.
Vardiman
JW
,
Thiele
J
,
Arber
DA
, et al
.
The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes
.
Blood
.
2009
;
114
(
5
):
937
-
951
.
29.
Della Porta
MG
,
Tuechler
H
,
Malcovati
L
, et al
.
Validation of WHO classification-based Prognostic Scoring System (WPSS) for myelodysplastic syndromes and comparison with the revised International Prognostic Scoring System (IPSS-R). A study of the International Working Group for Prognosis in Myelodysplasia (IWG-PM)
.
Leukemia
.
2015
;
29
(
7
):
1502
-
1513
.
30.
Fenaux
P
,
Rose
C
.
Impact of iron overload in myelodysplastic syndromes
.
Blood Rev
.
2009
;
23
(
suppl 1
):
S15
-
19
.
31.
Garcia-Manero
G
,
Shan
J
,
Faderl
S
, et al
.
A prognostic score for patients with lower risk myelodysplastic syndrome
.
Leukemia
.
2008
;
22
(
3
):
538
-
543
.
32.
Itzykson
R
,
Thepot
S
,
Quesnel
B
, et al
.
Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine
.
Blood
.
2011
;
117
(
2
):
403
-
411
.
33.
Fenaux
P
,
Mufti
GJ
,
Hellstrom-Lindberg
E
, et al
.
Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study
.
Lancet Oncol
.
2009
;
10
(
3
):
223
-
232
.
34.
Wimazal
F
,
Sperr
WR
,
Kundi
M
, et al
.
Prognostic value of lactate dehydrogenase activity in myelodysplastic syndromes
.
Leuk Res
.
2001
;
25
(
4
):
287
-
294
.
35.
Germing
U
,
Hildebrandt
B
,
Pfeilstocker
M
, et al
.
Refinement of the international prognostic scoring system (IPSS) by including LDH as an additional prognostic variable to improve risk assessment in patients with primary myelodysplastic syndromes (MDS)
.
Leukemia
.
2005
;
19
(
12
):
2223
-
2231
.
36.
Sanz
G
,
Nomdedeu
B
,
Such
E
, et al
.
Independent impact of iron overload and transfusion dependency on survival and leukemic evolution in patients with myelodysplastic syndrome
.
Blood
.
2008
;
112
(
11
):
640
.
37.
Gatto
S
,
Ball
G
,
Onida
F
,
Kantarjian
HM
,
Estey
EH
,
Beran
M
.
Contribution of beta-2 microglobulin levels to the prognostic stratification of survival in patients with myelodysplastic syndrome (MDS)
.
Blood
.
2003
;
102
(
5
):
1622
-
1625
.
38.
Neumann
F
,
Gattermann
N
,
Barthelmes
HU
,
Haas
R
,
Germing
U
.
Levels of beta 2 microglobulin have a prognostic relevance for patients with myelodysplastic syndrome with regard to survival and the risk of transformation into acute myelogenous leukemia
.
Leuk Res
.
2009
;
33
(
2
):
232
-
236
.
39.
Verburgh
E
,
Achten
R
,
Maes
B
, et al
.
Additional prognostic value of bone marrow histology in patients subclassified according to the International Prognostic Scoring System for myelodysplastic syndromes
.
J Clin Oncol
.
2003
;
21
(
2
):
273
-
282
.
40.
Della Porta
MG
,
Malcovati
L
,
Boveri
E
, et al
.
Clinical relevance of bone marrow fibrosis and CD34-positive cell clusters in primary myelodysplastic syndromes
.
J Clin Oncol
.
2009
;
27
(
5
):
754
-
762
.
41.
Buesche
G
,
Teoman
H
,
Wilczak
W
, et al
.
Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes
.
Leukemia
.
2008
;
22
(
2
):
313
-
322
.
42.
Wang
R
,
Gross
CP
,
Halene
S
,
Ma
X
.
Comorbidities and survival in a large cohort of patients with newly diagnosed myelodysplastic syndromes
.
Leuk Res
.
2009
;
33
(
12
):
1594
-
1598
.
43.
Naqvi
K
,
Garcia-Manero
G
,
Sardesai
S
, et al
.
Association of comorbidities with overall survival in myelodysplastic syndrome: development of a prognostic model
.
J Clin Oncol
.
2011
;
29
(
16
):
2240
-
2246
.
44.
Schanz
J
,
Tuchler
H
,
Sole
F
, et al
.
New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge
.
J Clin Oncol
.
2012
;
30
(
8
):
820
-
829
.
45.
Greenberg
PL
,
Tuechler
H
,
Schanz
J
, et al
.
Revised international prognostic scoring system for myelodysplastic syndromes
.
Blood
.
2012
;
120
(
12
):
2454
-
2465
.
46.
Pfeilstocker
M
,
Tuchler
H
,
Schonmetzler
A
,
Nosslinger
T
,
Pittermann
E
.
Time changes in predictive power of established and recently proposed clinical, cytogenetical and comorbidity scores for myelodysplastic syndromes
.
Leuk Res
.
2012
;
36
(
2
):
132
-
139
.
47.
Voso
MT
,
Fenu
S
,
Latagliata
R
, et al
.
Revised International Prognostic Scoring System (IPSS) predicts survival and leukemic evolution of myelodysplastic syndromes significantly better than IPSS and WHO Prognostic Scoring System: validation by the Gruppo Romano Mielodisplasie Italian Regional Database
.
J Clin Oncol
.
2013
;
31
(
21
):
2671
-
2677
.
48.
Neukirchen
J
,
Lauseker
M
,
Blum
S
, et al
.
Validation of the revised international prognostic scoring system (IPSS-R) in patients with myelodysplastic syndrome: a multicenter study
.
Leuk Res
.
2014
;
38
(
1
):
57
-
64
.
49.
de Swart
L
,
Smith
A
,
Johnston
TW
, et al
.
Validation of the revised international prognostic scoring system (IPSS-R) in patients with lower-risk myelodysplastic syndromes: a report from the prospective European LeukaemiaNet MDS (EUMDS) registry
.
Br J Haematol
.
2015
;
170
(
3
):
372
-
383
.
50.
Ok
CY
,
Hasserjian
RP
,
Fox
PS
, et al
.
Application of the international prognostic scoring system-revised in therapy-related myelodysplastic syndromes and oligoblastic acute myeloid leukemia
.
Leukemia
.
2014
;
28
(
1
):
185
-
189
.
51.
Kuendgen
A
,
Nomdedeu
M
,
Tuechler
H
, et al
.
Therapy-related myelodysplastic syndromes deserve specific diagnostic sub-classification and risk-stratification – an approach to classification of patients with t-MDS
.
Leukemia
.
2021
;
35
(
3
):
835
-
849
.
52.
Patel
SS
,
Sekeres
MA
,
Nazha
A
.
Prognostic models in predicting outcomes in myelodysplastic syndromes after hypomethylating agent failure
.
Leuk Lymphoma
.
2017 11
;
58
(
11
):
2532
-
2539
.
53.
Sakatoku
K
,
Takeoka
Y
,
Miura
A
, et al
.
Combination of frailty status and comorbidity score improves the stratification of survival in patients with myelodysplastic syndrome owing to good predictive capability for infection-related mortality
.
Clin Lymphoma Myeloma Leuk
.
2019
;
19
(
12
):
799
-
805
.
54.
Starkman
R
,
Alibhai
S
,
Wells
RA
, et al
.
An MDS-specific frailty index based on cumulative deficits adds independent prognostic information to clinical prognostic scoring
.
Leukemia
.
2020
;
34
(
5
):
1394
-
1406
.
55.
Stauder
R
,
Yu
G
,
Koinig
KA
, et al
.
Health-related quality of life in lower-risk MDS patients compared with age- and sex-matched reference populations: a European LeukemiaNet study
.
Leukemia
.
2018
;
32
(
6
):
1380
-
1392
.
56.
Stauder
R
,
Nosslinger
T
,
Pfeilstocker
M
, et al
.
Impact of age and comorbidity in myelodysplastic syndromes
.
J Natl Compr Canc Netw
.
2008
;
6
(
9
):
927
-
934
.
57.
Wouters
H
,
Conrads-Frank
A
,
Koinig
KA
, et al
.
The anemia-independent impact of myelodysplastic syndromes on health-related quality of life
.
Ann Hematol
.
2021
;
100
(
12
):
2921
-
2932
.
58.
Abel
GA
,
Efficace
F
,
Buckstein
RJ
, et al
.
Prospective international validation of the Quality of Life in Myelodysplasia Scale (QUALMS)
.
Haematologica
.
2016
;
101
(
6
):
781
-
788
.
59.
Abel
GA
,
Hebert
D
,
Lee
C
, et al
.
Health-related quality of life and vulnerability among people with myelodysplastic syndromes: a US National Study
.
Blood Adv
.
2023
;
7
(
14
):
3506
-
3515
.
60.
Bejar
R
,
Stevenson
K
,
Abdel-Wahab
O
, et al
.
Clinical effect of point mutations in myelodysplastic syndromes
.
N Engl J Med
.
2011
;
364
(
26
):
2496
-
2506
.
61.
Papaemmanuil
E
,
Gerstung
M
,
Malcovati
L
, et al
.
Clinical and biological implications of driver mutations in myelodysplastic syndromes [quiz]
.
Blood
.
2013
;
122
(
22
):
3616
-
3627
.
62.
Haferlach
T
,
Nagata
Y
,
Grossmann
V
, et al
.
Landscape of genetic lesions in 944 patients with myelodysplastic syndromes
.
Leukemia
.
2014
;
28
(
2
):
241
-
247
.
63.
Nazha
A
,
Al-Issa
K
,
Hamilton
BK
, et al
.
Adding molecular data to prognostic models can improve predictive power in treated patients with myelodysplastic syndromes
.
Leukemia
.
2017
;
31
(
12
):
2848
-
2850
.
64.
Bersanelli
M
,
Travaglino
E
,
Meggendorfer
M
, et al
.
Classification and personalized prognostic assessment on the basis of clinical and genomic features in myelodysplastic syndromes
.
J Clin Oncol
.
2021
;
39
(
11
):
1223
-
1233
.
65.
Nazha
A
,
Komrokji
R
,
Meggendorfer
M
, et al
.
Personalized prediction model to risk stratify patients with myelodysplastic syndromes
.
J Clin Oncol
.
2021
;
39
(
33
):
3737
-
3746
.
66.
Radakovich
N
,
Sallman
DA
,
Buckstein
R
, et al
.
A machine learning model of response to hypomethylating agents in myelodysplastic syndromes
.
iScience
.
2022
;
25
(
10
):
104931
.
67.
GenoMed4All consortium
.
A sex-informed approach to improve the personalised decision making process in myelodysplastic syndromes: a multicentre, observational cohort study
.
Lancet Haematol
.
2023
;
10
(
2
):
e117
-
e128
.
68.
Bernard
E
,
Tuechler
H
,
Greenberg
PL
, et al
.
Molecular international prognostic scoring system for myelodysplastic syndromes
.
NEJM Evid
.
2022
;
1
(
7
). Evidoa2200008.
69.
Baer
C
,
Huber
S
,
Hutter
S
, et al
.
Risk prediction in MDS: independent validation of the IPSS-M-ready for routine?
.
Leukemia
.
2023
;
37
(
4
):
938
-
941
.
70.
Sauta
E
,
Robin
M
,
Bersanelli
M
, et al
.
Real-world validation of molecular international prognostic scoring system for myelodysplastic syndromes
.
J Clin Oncol
.
2023
;
41
(
15
):
2827
-
2842
.
71.
Khoury
JD
,
Solary
E
,
Abla
O
, et al
.
The 5th edition of the World Health Organization classification of haematolymphoid tumours: myeloid and histiocytic/dendritic neoplasms
.
Leukemia
.
2022
;
36
(
7
):
1703
-
1719
.
72.
Arber
DA
,
Orazi
A
,
Hasserjian
RP
, et al
.
International consensus classification of myeloid neoplasms and acute leukemia: integrating morphological, clinical, and genomic data
.
Blood
.
2022
;
140
(
11
):
1200
-
1228
.
73.
Zhang
Y
,
Wu
J
,
Xu
Z
, et al
.
Impact of the International Consensus Classification of myelodysplastic syndromes
.
Br J Haematol
.
2023
;
201
(
3
):
443
-
448
.
74.
Paterlini
M
.
There shall be order. The legacy of Linnaeus in the age of molecular biology
.
EMBO Rep
.
2007
;
8
(
9
):
814
-
816
.
75.
Bernard
E
,
Hasserjian
R
,
Greenberg
PL
, et al
.
Genomic classification of myelodysplastic syndromes
.
Leuk Res
.
2023
:
128S
.
76.
Gerstung
M
,
Pellagatti
A
,
Malcovati
L
, et al
.
Combining gene mutation with gene expression data improves outcome prediction in myelodysplastic syndromes
.
Nat Commun
.
2015
;
6
:
5901
.
77.
Shiozawa
Y
,
Malcovati
L
,
Galli
A
, et al
.
Gene expression and risk of leukemic transformation in myelodysplasia
.
Blood
.
2017
;
130
(
24
):
2642
-
2653
.
78.
Im
H
,
Rao
V
,
Sridhar
K
, et al
.
Distinct transcriptomic and exomic abnormalities within myelodysplastic syndrome marrow cells
.
Leuk Lymphoma
.
2018
;
59
(
12
):
2952
-
2962
.
79.
Kwok
B
,
Hall
JM
,
Witte
JS
, et al
.
MDS-associated somatic mutations and clonal hematopoiesis are common in idiopathic cytopenias of undetermined significance
.
Blood
.
2015
;
126
(
21
):
2355
-
2361
.
80.
Galli
A
,
Todisco
G
,
Catamo
E
, et al
.
Relationship between clone metrics and clinical outcome in clonal cytopenia
.
Blood
.
2021
;
138
(
11
):
965
-
976
.
81.
Malcovati
L
,
Galli
A
,
Travaglino
E
, et al
.
Clinical significance of somatic mutation in unexplained blood cytopenia
.
Blood
.
2017
;
129
(
25
):
3371
-
3378
.
82.
Weeks
LD
,
Niroula
A
,
Neuberg
D
, et al
.
Prediction of risk for myeloid malignancy in clonal hematopoiesis
.
NEJM Evid
.
2023
;
2
(
5
).
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