- Email: [email protected]
Classification and Prognostic Evaluation of Myelodysplastic Syndromes
Classification and Prognostic Evaluation of Myelodysplastic Syndromes Mario Cazzola, Matteo G. Della Porta, Erica Travaglino, and Luca Malcovati Myelodysplastic syndromes (MDS) are myeloid neoplasms characterized by dysplasia in one or more cell lines and increased risk of development of acute myeloid leukemia (AML). The current diagnostic approach to MDS includes peripheral blood and bone marrow morphology to evaluate abnormalities of peripheral blood cells and hematopoietic precursors; bone marrow biopsy to assess marrow cellularity, fibrosis, and topography; and cytogenetics to identify non-random chromosomal abnormalities. The 2008 World Health Organization (WHO) classification currently provides the best diagnostic approach to MDS and also has considerable prognostic relevance. The WHO classification-based prognostic scoring system (WPSS) is able to classify MDS patients into five risk groups showing different survivals and probabilities of leukemic evolution. The WPSS is able to predict survival and leukemia progression at any time during follow-up, and can therefore be used for implementing risk-adapted treatment strategies in patients with primary MDS. Since comorbidities have a significant impact on the outcome of patients with MDS, accounting for both disease status and comorbid conditions considerably improves risk stratification. Semin Oncol 38:627-634 © 2011 Elsevier Inc. All rights reserved.
M
yelodysplastic syndromes (MDS)1 are included in the World Health Organization (WHO) classification of the myeloid neoplasms2 together with myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN),3,4 and acute myeloid leukemia (AML). MDS typically occur in elderly people and represent one of the most common hematologic malignancies in Western countries, their annual incidence exceeding 20 per 100,000 persons over the age of 70 years.5 MDS are characterized by clonal proliferation of hematopoietic cells, which partly retain their capacity to differentiate and maturate, but do so in an inefficient manner, basically as a result of excessive apoptosis of hematopoietic precursors.1 The bone marrow is generally hypercellular while peripheral blood cells are variably reduced (cytopenia), and several morphological abnormalities are observed in these two compartments.6 In addition, clones of hematopoietic cells carrying non-random cytogenetic abnormalities are typically found in these patients.7 With time there is a progressive impairment in the capacity of Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo and University of Pavia Medical School, Pavia, Italy. Address correspondence to Mario Cazzola, MD, Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy. E-mail: [email protected] 0270-9295/ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2011.04.007
Seminars in Oncology, Vol 38, No 5, October 2011, pp 627-634
hematopoietic cells to differentiate and maturate: blast cells may appear in the bone marrow and peripheral blood, and there is an increasingly high risk of evolution to overt AML.
CLASSIFICATION OF MDS The current diagnostic approach to MDS includes peripheral blood and bone marrow morphology to evaluate abnormalities of peripheral blood cells and hematopoietic precursors; bone marrow biopsy to assess marrow cellularity, fibrosis, and topography; and cytogenetics to identify non-random chromosomal abnormalities. The combination of overt marrow dysplasia and clonal cytogenetic abnormality allows a conclusive diagnosis of MDS, but this is found in only a portion of patients.1 Standardization of flow cytometry might improve diagnosis of MDS in the future.8 –10 Although bone marrow biopsy may be considered too invasive for elderly patients, it provides extremely useful diagnostic and prognostic information regarding cellularity, fibrosis, and CD34⫹ cell topography.11 Hypoplastic MDS needs to be distinguished from both aplastic anemias and hypocellular AML.12 Bone marrow fibrosis identifies a distinct subgroup of MDS with multilineage dysplasia, high transfusion requirement, and poor prognosis, while the presence of CD34⫹ cell clusters is an independent risk factor for progression to acute leukemia.11 627
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Table 1. FAB Classification of Myelodysplastic Syndromes13
Peripheral Blood Category Refractory anemia (RA) RA with ring sideroblasts (RARS) RA with excess of blasts (RAEB) Chronic myelomonocytic leukemia (CMML) RAEB “in transformation” (RAEB-t)
Bone Marrow
Monocytes (109/L)
Blast (%)
Ringed Sideroblasts (%)
Blast (%)
Auer Rods
ⱕ1 ⱕ1
ⱕ1% ⱕ1%
ⱕ15% ⬎15%
⬍5% ⬍5%
— —
ⱕ1
⬍5%
5%–20%
—
⬎1
⬍5%
Ringed sideroblasts may be seen Ringed sideroblasts may be seen
0%–20%
—
ⱕ1
ⱖ5%
Ringed sideroblasts may be seen
21%–30%
⫹
MDS were defined and classified in 1982 by the French-American-British (FAB) group.13 The FAB classification included five categories and is described in Table 1. From a prognostic point of view, this classification was essentially able to identify two risk groups based on the absence or presence of blast excess14 (Figure 1). In 2001 the WHO classification was developed.15 This classification, updated in 2008 and illustrated in Table 2,16 carries relevant prognostic information as shown in Figure 2.14,17
PROGNOSTIC EVALUATION OF MDS Although the FAB classification has been relatively effective for categorizing MDS patients since 1982,
Figure 1. Kaplan-Meier survival curves of 943 patients diagnosed with MDS according to the 2008 WHO criteria and here grouped according to the FAB classification (patients with 5%–19% bone marrow blasts and Auer rods were classified as RAEB-t). Reproduced from Cazzola with permission.14
its limitations soon became evident. According to Greenberg et al18 these limitations include the wide range of marrow blast percentages for patients with refractory anemia with excess blasts (RAEB) and chronic myelomonocytic leukemia (CMML), lack of inclusion of critical biological determinants such as marrow cytogenetics, and the degree and number of morbidity-associated cytopenias. These limitations led to the development of additional risk-based stratification systems.18 The International MDS Risk Analysis Workshop (IMRAW) concluded that the percentage of marrow blasts, cytogenetic pattern, and number and degree of cytopenias were the most powerful prognostic indicators in MDS, and this resulted in the definition of the International Prognostic Scoring System (IPSS; Table 3).19 After introduction of the WHO classification, we found that WHO categories, cytogenetic pattern, and transfusion dependency were the most powerful prognostic indicators. We therefore developed a prognostic model that accounted for these parameters.20 This WHO classification-based prognostic scoring system (WPSS) could classify patients into five risk groups showing different survivals and probabilities of leukemic evolution. A refined version of the WPSS, based on a study on prognostic significance of the degree of anemia,21 is reported in Table 4. Kantarjian and coworkers22 performed a multivariable analysis of prognostic factors in 1,915 MDS patients. They identified the following adverse, independent factors: poor performance, older age, thrombocytopenia, anemia, increased bone marrow blasts, leukocytosis, chromosome 7 or complex (⬎2) abnormalities, and prior transfusions. Based on these parameters, a new MDS prognostic model divided
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Table 2. 2008 WHO Classification of Myelodysplastic Syndromes: Basic Criteria, Improvements, and Open Questions*
Condition
Blood Findings
Refractory cytopenia Unicytopenia (anemia, with unilineage neutropenia, or dysplasia (RCUD)† thrombocytopenia), no or rare blasts (⬍1%). Bicytopenia may occasionally be observed. Refractory anemia Anemia, no blasts. with ringed sideroblasts (RARS)
Refractory cytopenia Cytopenia(s) with multilineage (unicytopenia, dysplasia (RCMD) bicytopenia or pancytopenia), no or rare blasts (⬍1%), no Auer roads, ⬍1x109/L monocytes.
Refractory anemia Cytopenia(s), ⬍5% with excess blastsblasts, no Auer roads, 1 (RAEB-1) ⬍1x109/L monocytes (cases with Auer rods and ⬍5% blasts in the peripheral blood and ⬍10% blasts in the marrow should be classified as RAEB-2).
Refractory anemia Cytopenia(s), 5–19% with excess blastsblasts, occasional Auer 2 (RAEB-2) roads, ⬍1x109/L monocytes. Myelodysplastic Anemia, normal to syndrome increased platelet associated with count, no or rare isolated del(5q) blasts (⬍1%).
Bone Marrow Findings
Remarks
Unilineage dysplasia (ⱖ10% The diagnosis of this condition of the cells in one myeloid is definitely easier when a lineage) ⬍5% blasts, cytogenetic abnormality is ⬍15% ringed sideroblasts found. within erythroid precursors. Erythroid dysplasia only, ⬍5% Ringed sideroblasts represent a blasts, ⱖ15% ringed robust marker of abnormal sideroblasts within erythropoiesis. They must be erythroid precursors. distinguished from ferritin sideroblasts: consensus criteria have been published for the definition and enumeration of ringed sideroblasts.6 Dysplasia in ⱖ10% of cells Multilineage dysplasia was in 2 or more myeloid cell introduced in 2001 and was lineages (erythroid criticized as a feature that precursors and/or requires considerable expertise neutrophil precursors and/ and is poorly reproducible. or megakaryocytes), ⬍5% However, this is true for many blasts, no Auer roads (the other morphological features percentage of ringed of myeloid and lymphoid sideroblasts is irrelevant). neoplasms. More importantly, multilineage dysplasia has relevant negative prognostic implications (see Figure 2).17 Unilineage or multilineage Consensus criteria have been dysplasia, 5% to 9% published for the definition blasts, no Auer roads and enumeration of blasts.6 (cases with Auer rods and ⬍5% blasts in the peripheral blood and ⬍10% blasts in the marrow should be classified as RAEB-2). RAEB1 includes also cases with 2–4% blasts in the peripheral blood and ⬍5% in the bone marrow. Unilineage or multilineage Consensus criteria have been dysplasia, 10% to 19% published for the definition blasts, occasional Auer and enumeration of blasts.6 roads. Normal to increased Diagnosis of MDS with isolated megakaryocytes with del(5q) is generally easy due hypolobated nuclei, ⬍5% to its typical hematologic blasts, no Auer roads, picture, morphological isolated del(5q). abnormalities, and cytogenetic aberration.
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Table 2. Continued
Condition Myelodysplastic syndrome, unclassifiable (MDS-U)
Blood Findings
Bone Marrow Findings
Remarks
Cytopenia (various Dysplasia in less than 10% These patients need to be combinations), no or of cells in one or more followed closely in order to rare blasts (⬍1%). myeloid cell lines when better define their condition. accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS, ⬍5% blasts.
*Information on the WHO classification is from Brunning et al.16 †Refractory anemia (RA), refractory neutropenia (RN), or refractory thrombocytopenia (RT).
patients into four prognostic groups with significantly different outcomes (Table 5). The authors concluded that this new risk model (M.D. Anderson Prognostic Scoring System [MPSS]) refines the prognostic precision of the IPSS and is applicable to all patients with primary or secondary MDS and to those with CMML rather than only to patients with untreated primary MDS. In conclusion, there are 3 risk models at present; their advantages and disadvantages are summarized in Table 6.
PROGNOSTIC RELEVANCE OF COMORBIDITIES IN MDS PATIENTS Most patients with MDS are elderly and typically have comorbid diseases that have a significant impact on their clinical outcome.25,26 We recently performed a study aimed to develop a scoring model that accounted for comorbidities commonly found in MDS patients and to establish how these comorbid conditions affected survival.27 Comorbidity was present in 54% of patients and had a significant impact on both non-leukemic death and overall survival. Cardiac disease was the most frequent comorbidity and the main cause of non-leukemic death. Cardiac, liver, renal, and pulmonary
Table 3. International Prognostic Scoring Sys-
tem (IPSS) of Myelodysplastic Syndromes19 Points
Figure 2. Kaplan-Meier survival curves of 943 patients diagnosed with MDS according to the 2008 WHO criteria. Patients classified as RA or RARS according to the FAB classification in Figure 1 are split here into two subgroups with different survival based on the presence of unilineage [RCUD or RARS, including also MDS with del(5q)] or multilineage dysplasia (RCMD). Moreover, patients with RAEB in Figure 1 are also split here into two subgroups according to their blast percentage (5–9% in RAEB-1, 10 –19% in RAEB2). Reproduced from Cazzola.14
Variable
0
0.5
Marrow blasts (%) Karyotype* Cytopenias†
⬍5
5–10
Good 0 or 1
Intermediate 2 or 3
1
1.5
2
11–20 21–30 Poor
IPSS Risk Group
Score
Low Intermediate 1 Intermediate 2 High
0 0.5–1.0 1.5–2.0 2.5–3.5
*Good: normal, del(5q) only, del(20q) only, –Y only; Poor: very complex (⬎2) abnormalities, chromosome 7 anomalies; Intermediate: other abnormalities. †Cytopenias: hemoglobin ⬍10 g/dL, neutrophil count ⬍ 1.8 ⫻ 109/L, platelet count ⬍ 100 ⫻ 109/L.
Classification of myelodysplastic syndromes
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Table 4. Refined WHO Classification–Based Prognostic Scoring System (WPSS) of Myelodysplastic
Syndromes Points Variable
0
WHO category Karyotype* Severe anemia (Hb ⬍9 g/dL in males or ⬍8 g/dL in females)
1
RA, RARS, MDS with isolated deletion (5q) Good Absent
2
3
RCMD
RAEB-1
RAEB-2
Intermediate Present
Poor —
WPSS Risk Group
— — Score
Very low Low Intermediate High Very high
0 1 2 3–4 5–6
NOTE. The original criterion of transfusion requirement20 has now been replaced by severe anemia (hemoglobine [Hb] ⬍9 g/dL in males or ⬍8 g/dL in females). This latter definition is based on a recent study on prognostic significance of the degree of anemia.21 *Good: normal, del(5q) only, del(20q) only, –Y only; Poor: very complex (⬎2) abnormalities, chromosome 7 anomalies; Intermediate: other abnormalities.
disease and solid tumors were found to independently affect the risk of non-leukemic death. Using this information, a time-dependent MDS-Specific Comorbidity Index (MDS-CI) was developed for predicting the effect of comorbidity on outcome. This identified three groups of patients that showed significantly different probabilities of survival as shown in Figure 3. We concluded that accounting for both disease status by means of the WPSS and comorbidity through the
MDS-CI considerably improves risk stratification in MDS, particularly in the lower risk groups according to disease-related criteria. More recently, Naqvi et al28 reported on the effect of comorbidities on the survival of 600 consecutive patients with MDS followed at the M.D. Anderson Cancer Center. They used the Adult Comorbidity Evaluation-27 (ACE-27), an instrument specifically designed for patients with cancer,29 to measure the
Table 5. M.D. Anderson Prognostic Scoring System (MPSS) of Myelodysplastic Syndromes22
Points Variable Performance status Age, yr Platelet, x 109/L Hemoglobin, g/dL Bone marrow blasts, % WBC, x 109/L Karyotype Prior transfusion MPSS Risk Group Low Intermediate 1 Intermediate 2 High
1 60–64 50–199 5–10
2 ⱖ2 ⱖ65 30–49 ⬍12 11–29 ⬎20
3
⬍30
chromosome 7 abnormality or complex ⬎ 2 abnormalities Yes Score 0–4 5–6 7–8 ⱖ9
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M. Cazzola et al
Table 6. Advantages and Limitations of Currently Available Risk Models for Prognostication in MDS
Patients Arguments In Favor (pros)
Against (cons)
IPSS
Risk Model
The presence of three variables makes it easy to use in clinical practice. Largely utilized in the last 12 years for risk assessment both in clinical practice and clinical trials. Adopted by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for approval of novel drugs for treatment of MDS (azacitidine, decitabine and lenalidomide).
WPSS
The presence of three variables makes it easy to use in clinical practice. This scoring system is able to classify patients into five risk groups showing different survivals and probabilities of leukemic evolution. It predicts survival and leukemia progression at any time during follow-up. WPSS may therefore be used for implementing riskadapted treatment strategies and for stratifying patients enrolled in clinical trials. WPSS have a relevant prognostic value in post-transplantation outcome of MDS patients.24
MPSS
MPSS can be used both in untreated and treated MDS patients. MPSS can be used for risk assessment in CMML and in therapy-related MDS. However, this latter condition has almost always an unfavorable outcome.
IPSS was derived from a multivariate analysis of hematological characteristics of 816 patients at clinical onset and therefore untreated. It included also individuals with 20 –30% marrow blasts (now diagnosed as AML) and patients with chronic myelomonocytic leukemia (now categorized as MDS/ myeloproliferative neoplasms [MPN]). This scoring system does not consider the severity of anemia, in particular transfusion dependency, which represents one of the most important negative prognostic factors in MDS. Furthermore, it underestimates the negative impact of poor cytogenetics (especially relative to blast count). IPSS is inferior to both WPSS23 and MPSS22 in risk stratification of MDS patients. Finally, a major limitation is lack of applicability to MDS patients on investigational programs, because most of them would have had the disease for a significant time and would have received prior therapies. This scoring system was developed in patients with primary MDS, and therefore is not applicable to patients with secondary MDS. However, the 2008 WHO classification of myeloid neoplasms has introduced the unique category of therapy-related neoplasms,2 which includes therapy-related AML, therapy-related MDS and therapy-related MDS/MPN. These conditions are always associated with an unfavorable outcome, and do not require a specific risk assessment. Evaluation of multilineage dysplasia requires considerable expertise, but this is true for many other cytologic and histologic features regarding tumors of hematopoietic and lymphoid tissues. The current use of specific hemoglobin thresholds (⬍9 g/dL in males and ⬍8 g/dL in females) for defining severe anemia has improves the reproducibility of WPSS. The presence of 8 variables makes it uneasy to use in clinical practice. MPSS ignores the WHO classification, which provides the best diagnostic approach to MDS and has considerable prognostic relevance. The hemoglobin cut-off of 12 g/dL (weight 2 in Table 5) appears to be overestimated compared to the WPSS definition of severe anemia (see Table 4). The bone marrow blast range includes cases classified as AML according to WHO criteria.
severity of comorbidities, and found that 35% of MDS patients had moderate to severe comorbid conditions.28 In particular, 55% of MDS patients had a disease of the cardiovascular system, and this was associated with worse survival. Median survival ranged from 32 months in patients with no comorbidity to 10 months in those with severe comorbidities. Of note, these latter subjects had a 50% decrease in overall survival, which was independent of age and IPSS risk group. Finally, Naqvi et al28 built up a prognostic model based on age, IPSS score, and ACE-27 score. This model identified three risk groups, whose median survivals were 43 months
(low risk), 23 months (intermediate risk), and 9 months (high risk), respectively.
CONCLUSIONS AND PERSPECTIVES The 2008 WHO classification currently provides the best diagnostic approach to MDS and has considerable prognostic relevance. For the optimal management of MDS, its implementation into clinical practice is mandatory. As far as risk assessment is concerned, the WPSS can be used reliably in all patients with primary MDS, while
Classification of myelodysplastic syndromes
633
7.
8.
9.
Figure 3. Relationship between MDS-specific comorbidity index (MDS-CI) and overall survival in MDS patients. Reproduced from Della Porta et al with permission.27
10.
the MPSS allows risk assessment also in those with secondary MDS and in patients with CMML. Since comorbidities have a significant impact on the outcome of patients with MDS, accounting for both disease status and comorbid conditions considerably improves risk stratification. Both the MDS-CI27 and the ACE-2729 can be employed for assessing the severity of comorbidities in MDS patients. In perspective, the available evidence indicates that advances in our ability to improve diagnosis and prognostication of MDS likely will be made possible by a better understanding of the molecular basis of these myeloid neoplasms. A very recent work studied the clinical impact of point mutations in a cohort of 439 patients with MDS.30 Somatic mutations of TP53, EZH2, ETV6, RUNX1, and ASXL1 were found to be independent predictors of decreased survival and to improve the risk stratification provided by the IPSS. These observations suggest that incorporation of somatic mutations may add relevant information to the risk stratification systems currently used in clinical practice.
11.
12.
13.
14.
15.
16.
17.
REFERENCES 1. Cazzola M, Malcovati L. Myelodysplastic syndromes— coping with ineffective hematopoiesis. N Engl J Med. 2005;352:536 – 8. 2. Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008. 3. Malcovati L, Cazzola M. Myelodysplastic/myeloproliferative disorders. Haematologica. 2008;93:4 – 6. 4. Reiter A, Invernizzi R, Cross NC, Cazzola M. Molecular basis of myelodysplastic/myeloproliferative neoplasms. Haematologica. 2009;94:1634 – 8. 5. Tefferi A, Vardiman JW. Myelodysplastic syndromes. N Engl J Med. 2009;361:1872– 85. 6. Mufti GJ, Bennett JM, Goasguen J, et al. Diagnosis and classification of myelodysplastic syndrome: International
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Working Group on Morphology of myelodysplastic syndrome (IWGM-MDS) consensus proposals for the definition and enumeration of myeloblasts and ring sideroblasts. Haematologica. 2008;93:1712–7. Haase D, Germing U, Schanz J, et al. New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood. 2007;110:4385–95. Della Porta MG, Malcovati L, Invernizzi R, et al. Flow cytometry evaluation of erythroid dysplasia in patients with myelodysplastic syndrome. Leukemia. 2006;20: 549 –55. Ogata K, Della Porta MG, Malcovati L, et al. Diagnostic utility of flow cytometry in low-grade myelodysplastic syndromes: a prospective validation study. Haematologica. 2009;94:1066 –74. van de Loosdrecht AA, Alhan C, Bene MC, et al. Standardization of flow cytometry in myelodysplastic syndromes: report from the first European LeukemiaNet working conference on flow cytometry in myelodysplastic syndromes. Haematologica. 2009;94:1124 –34. 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;27:754 – 62. Bennett JM, Orazi A. Diagnostic criteria to distinguish hypocellular acute myeloid leukemia from hypocellular myelodysplastic syndromes and aplastic anemia: recommendations for a standardized approach. Haematologica. 2009;94:264 – 8. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol. 1982;51:189 –99. Cazzola M. Risk assessment in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms. Haematologica. 2011;96:349 –52. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2292–302. Brunning RD, Orazi A, Germing U, et al. Myelodysplastic syndromes/neoplasms, overview. In: Swerdlow SH, Campo E, Harris NL, et al eds. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: IARC; 2008:88 –93. Malcovati L, Della Porta M, 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;23:7594 – 603. Sanz GF, Sanz MA, Greenberg PL. Prognostic factors and scoring systems in myelodysplastic syndromes. Haematologica. 1998;83:358 – 68. Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079 – 88. 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;25:3503–10. Malcovati L, Della Porta MG, Strupp C, et al. Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification-based Prognostic Scoring System
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(WPSS). Haematologica. 2011 Jun 9. [Epub ahead of print]. 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;113:1351– 61. Cazzola M, Malcovati L. Prognostic classification and risk assessment in myelodysplastic syndromes. Hematol Oncol Clin North Am. 2010;24:459 – 68. Alessandrino EP, Della Porta MG, Bacigalupo A, et al. WHO classification and WPSS predict posttransplantation outcome in patients with myelodysplastic syndrome: a study from the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Blood. 2008;112:895–902. Zipperer E, Pelz D, Nachtkamp K, et al. The hematopoietic stem cell transplantation comorbidity index is of prognostic relevance for patients with myelodysplastic syndrome. Haematologica. 2009;94:729 –32.
26. Della Porta MG, Malcovati L. Clinical relevance of extrahematologic comorbidity in the management of patients with myelodysplastic syndrome. Haematologica. 2009; 94:602– 6. 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;96:441–9. 28. 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;29:2240 – 6. 29. Piccirillo JF, Tierney RM, Costas I, Grove L, Spitznagel EL, Jr. Prognostic importance of comorbidity in a hospitalbased cancer registry. JAMA. 2004;291:2441–7. 30. Bejar R, Stevenson K, Abdel-Wahab O, et al. Clinical effect of point mutations in myelodysplastic syndromes. N Engl J Med. 2011;364:2496 –506.
M
yelodysplastic syndromes (MDS)1 are included in the World Health Organization (WHO) classification of the myeloid neoplasms2 together with myeloproliferative neoplasms (MPN), myelodysplastic/myeloproliferative neoplasms (MDS/MPN),3,4 and acute myeloid leukemia (AML). MDS typically occur in elderly people and represent one of the most common hematologic malignancies in Western countries, their annual incidence exceeding 20 per 100,000 persons over the age of 70 years.5 MDS are characterized by clonal proliferation of hematopoietic cells, which partly retain their capacity to differentiate and maturate, but do so in an inefficient manner, basically as a result of excessive apoptosis of hematopoietic precursors.1 The bone marrow is generally hypercellular while peripheral blood cells are variably reduced (cytopenia), and several morphological abnormalities are observed in these two compartments.6 In addition, clones of hematopoietic cells carrying non-random cytogenetic abnormalities are typically found in these patients.7 With time there is a progressive impairment in the capacity of Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo and University of Pavia Medical School, Pavia, Italy. Address correspondence to Mario Cazzola, MD, Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Viale Golgi 19, 27100 Pavia, Italy. E-mail: [email protected] 0270-9295/ - see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2011.04.007
Seminars in Oncology, Vol 38, No 5, October 2011, pp 627-634
hematopoietic cells to differentiate and maturate: blast cells may appear in the bone marrow and peripheral blood, and there is an increasingly high risk of evolution to overt AML.
CLASSIFICATION OF MDS The current diagnostic approach to MDS includes peripheral blood and bone marrow morphology to evaluate abnormalities of peripheral blood cells and hematopoietic precursors; bone marrow biopsy to assess marrow cellularity, fibrosis, and topography; and cytogenetics to identify non-random chromosomal abnormalities. The combination of overt marrow dysplasia and clonal cytogenetic abnormality allows a conclusive diagnosis of MDS, but this is found in only a portion of patients.1 Standardization of flow cytometry might improve diagnosis of MDS in the future.8 –10 Although bone marrow biopsy may be considered too invasive for elderly patients, it provides extremely useful diagnostic and prognostic information regarding cellularity, fibrosis, and CD34⫹ cell topography.11 Hypoplastic MDS needs to be distinguished from both aplastic anemias and hypocellular AML.12 Bone marrow fibrosis identifies a distinct subgroup of MDS with multilineage dysplasia, high transfusion requirement, and poor prognosis, while the presence of CD34⫹ cell clusters is an independent risk factor for progression to acute leukemia.11 627
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Table 1. FAB Classification of Myelodysplastic Syndromes13
Peripheral Blood Category Refractory anemia (RA) RA with ring sideroblasts (RARS) RA with excess of blasts (RAEB) Chronic myelomonocytic leukemia (CMML) RAEB “in transformation” (RAEB-t)
Bone Marrow
Monocytes (109/L)
Blast (%)
Ringed Sideroblasts (%)
Blast (%)
Auer Rods
ⱕ1 ⱕ1
ⱕ1% ⱕ1%
ⱕ15% ⬎15%
⬍5% ⬍5%
— —
ⱕ1
⬍5%
5%–20%
—
⬎1
⬍5%
Ringed sideroblasts may be seen Ringed sideroblasts may be seen
0%–20%
—
ⱕ1
ⱖ5%
Ringed sideroblasts may be seen
21%–30%
⫹
MDS were defined and classified in 1982 by the French-American-British (FAB) group.13 The FAB classification included five categories and is described in Table 1. From a prognostic point of view, this classification was essentially able to identify two risk groups based on the absence or presence of blast excess14 (Figure 1). In 2001 the WHO classification was developed.15 This classification, updated in 2008 and illustrated in Table 2,16 carries relevant prognostic information as shown in Figure 2.14,17
PROGNOSTIC EVALUATION OF MDS Although the FAB classification has been relatively effective for categorizing MDS patients since 1982,
Figure 1. Kaplan-Meier survival curves of 943 patients diagnosed with MDS according to the 2008 WHO criteria and here grouped according to the FAB classification (patients with 5%–19% bone marrow blasts and Auer rods were classified as RAEB-t). Reproduced from Cazzola with permission.14
its limitations soon became evident. According to Greenberg et al18 these limitations include the wide range of marrow blast percentages for patients with refractory anemia with excess blasts (RAEB) and chronic myelomonocytic leukemia (CMML), lack of inclusion of critical biological determinants such as marrow cytogenetics, and the degree and number of morbidity-associated cytopenias. These limitations led to the development of additional risk-based stratification systems.18 The International MDS Risk Analysis Workshop (IMRAW) concluded that the percentage of marrow blasts, cytogenetic pattern, and number and degree of cytopenias were the most powerful prognostic indicators in MDS, and this resulted in the definition of the International Prognostic Scoring System (IPSS; Table 3).19 After introduction of the WHO classification, we found that WHO categories, cytogenetic pattern, and transfusion dependency were the most powerful prognostic indicators. We therefore developed a prognostic model that accounted for these parameters.20 This WHO classification-based prognostic scoring system (WPSS) could classify patients into five risk groups showing different survivals and probabilities of leukemic evolution. A refined version of the WPSS, based on a study on prognostic significance of the degree of anemia,21 is reported in Table 4. Kantarjian and coworkers22 performed a multivariable analysis of prognostic factors in 1,915 MDS patients. They identified the following adverse, independent factors: poor performance, older age, thrombocytopenia, anemia, increased bone marrow blasts, leukocytosis, chromosome 7 or complex (⬎2) abnormalities, and prior transfusions. Based on these parameters, a new MDS prognostic model divided
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Table 2. 2008 WHO Classification of Myelodysplastic Syndromes: Basic Criteria, Improvements, and Open Questions*
Condition
Blood Findings
Refractory cytopenia Unicytopenia (anemia, with unilineage neutropenia, or dysplasia (RCUD)† thrombocytopenia), no or rare blasts (⬍1%). Bicytopenia may occasionally be observed. Refractory anemia Anemia, no blasts. with ringed sideroblasts (RARS)
Refractory cytopenia Cytopenia(s) with multilineage (unicytopenia, dysplasia (RCMD) bicytopenia or pancytopenia), no or rare blasts (⬍1%), no Auer roads, ⬍1x109/L monocytes.
Refractory anemia Cytopenia(s), ⬍5% with excess blastsblasts, no Auer roads, 1 (RAEB-1) ⬍1x109/L monocytes (cases with Auer rods and ⬍5% blasts in the peripheral blood and ⬍10% blasts in the marrow should be classified as RAEB-2).
Refractory anemia Cytopenia(s), 5–19% with excess blastsblasts, occasional Auer 2 (RAEB-2) roads, ⬍1x109/L monocytes. Myelodysplastic Anemia, normal to syndrome increased platelet associated with count, no or rare isolated del(5q) blasts (⬍1%).
Bone Marrow Findings
Remarks
Unilineage dysplasia (ⱖ10% The diagnosis of this condition of the cells in one myeloid is definitely easier when a lineage) ⬍5% blasts, cytogenetic abnormality is ⬍15% ringed sideroblasts found. within erythroid precursors. Erythroid dysplasia only, ⬍5% Ringed sideroblasts represent a blasts, ⱖ15% ringed robust marker of abnormal sideroblasts within erythropoiesis. They must be erythroid precursors. distinguished from ferritin sideroblasts: consensus criteria have been published for the definition and enumeration of ringed sideroblasts.6 Dysplasia in ⱖ10% of cells Multilineage dysplasia was in 2 or more myeloid cell introduced in 2001 and was lineages (erythroid criticized as a feature that precursors and/or requires considerable expertise neutrophil precursors and/ and is poorly reproducible. or megakaryocytes), ⬍5% However, this is true for many blasts, no Auer roads (the other morphological features percentage of ringed of myeloid and lymphoid sideroblasts is irrelevant). neoplasms. More importantly, multilineage dysplasia has relevant negative prognostic implications (see Figure 2).17 Unilineage or multilineage Consensus criteria have been dysplasia, 5% to 9% published for the definition blasts, no Auer roads and enumeration of blasts.6 (cases with Auer rods and ⬍5% blasts in the peripheral blood and ⬍10% blasts in the marrow should be classified as RAEB-2). RAEB1 includes also cases with 2–4% blasts in the peripheral blood and ⬍5% in the bone marrow. Unilineage or multilineage Consensus criteria have been dysplasia, 10% to 19% published for the definition blasts, occasional Auer and enumeration of blasts.6 roads. Normal to increased Diagnosis of MDS with isolated megakaryocytes with del(5q) is generally easy due hypolobated nuclei, ⬍5% to its typical hematologic blasts, no Auer roads, picture, morphological isolated del(5q). abnormalities, and cytogenetic aberration.
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Table 2. Continued
Condition Myelodysplastic syndrome, unclassifiable (MDS-U)
Blood Findings
Bone Marrow Findings
Remarks
Cytopenia (various Dysplasia in less than 10% These patients need to be combinations), no or of cells in one or more followed closely in order to rare blasts (⬍1%). myeloid cell lines when better define their condition. accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS, ⬍5% blasts.
*Information on the WHO classification is from Brunning et al.16 †Refractory anemia (RA), refractory neutropenia (RN), or refractory thrombocytopenia (RT).
patients into four prognostic groups with significantly different outcomes (Table 5). The authors concluded that this new risk model (M.D. Anderson Prognostic Scoring System [MPSS]) refines the prognostic precision of the IPSS and is applicable to all patients with primary or secondary MDS and to those with CMML rather than only to patients with untreated primary MDS. In conclusion, there are 3 risk models at present; their advantages and disadvantages are summarized in Table 6.
PROGNOSTIC RELEVANCE OF COMORBIDITIES IN MDS PATIENTS Most patients with MDS are elderly and typically have comorbid diseases that have a significant impact on their clinical outcome.25,26 We recently performed a study aimed to develop a scoring model that accounted for comorbidities commonly found in MDS patients and to establish how these comorbid conditions affected survival.27 Comorbidity was present in 54% of patients and had a significant impact on both non-leukemic death and overall survival. Cardiac disease was the most frequent comorbidity and the main cause of non-leukemic death. Cardiac, liver, renal, and pulmonary
Table 3. International Prognostic Scoring Sys-
tem (IPSS) of Myelodysplastic Syndromes19 Points
Figure 2. Kaplan-Meier survival curves of 943 patients diagnosed with MDS according to the 2008 WHO criteria. Patients classified as RA or RARS according to the FAB classification in Figure 1 are split here into two subgroups with different survival based on the presence of unilineage [RCUD or RARS, including also MDS with del(5q)] or multilineage dysplasia (RCMD). Moreover, patients with RAEB in Figure 1 are also split here into two subgroups according to their blast percentage (5–9% in RAEB-1, 10 –19% in RAEB2). Reproduced from Cazzola.14
Variable
0
0.5
Marrow blasts (%) Karyotype* Cytopenias†
⬍5
5–10
Good 0 or 1
Intermediate 2 or 3
1
1.5
2
11–20 21–30 Poor
IPSS Risk Group
Score
Low Intermediate 1 Intermediate 2 High
0 0.5–1.0 1.5–2.0 2.5–3.5
*Good: normal, del(5q) only, del(20q) only, –Y only; Poor: very complex (⬎2) abnormalities, chromosome 7 anomalies; Intermediate: other abnormalities. †Cytopenias: hemoglobin ⬍10 g/dL, neutrophil count ⬍ 1.8 ⫻ 109/L, platelet count ⬍ 100 ⫻ 109/L.
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Table 4. Refined WHO Classification–Based Prognostic Scoring System (WPSS) of Myelodysplastic
Syndromes Points Variable
0
WHO category Karyotype* Severe anemia (Hb ⬍9 g/dL in males or ⬍8 g/dL in females)
1
RA, RARS, MDS with isolated deletion (5q) Good Absent
2
3
RCMD
RAEB-1
RAEB-2
Intermediate Present
Poor —
WPSS Risk Group
— — Score
Very low Low Intermediate High Very high
0 1 2 3–4 5–6
NOTE. The original criterion of transfusion requirement20 has now been replaced by severe anemia (hemoglobine [Hb] ⬍9 g/dL in males or ⬍8 g/dL in females). This latter definition is based on a recent study on prognostic significance of the degree of anemia.21 *Good: normal, del(5q) only, del(20q) only, –Y only; Poor: very complex (⬎2) abnormalities, chromosome 7 anomalies; Intermediate: other abnormalities.
disease and solid tumors were found to independently affect the risk of non-leukemic death. Using this information, a time-dependent MDS-Specific Comorbidity Index (MDS-CI) was developed for predicting the effect of comorbidity on outcome. This identified three groups of patients that showed significantly different probabilities of survival as shown in Figure 3. We concluded that accounting for both disease status by means of the WPSS and comorbidity through the
MDS-CI considerably improves risk stratification in MDS, particularly in the lower risk groups according to disease-related criteria. More recently, Naqvi et al28 reported on the effect of comorbidities on the survival of 600 consecutive patients with MDS followed at the M.D. Anderson Cancer Center. They used the Adult Comorbidity Evaluation-27 (ACE-27), an instrument specifically designed for patients with cancer,29 to measure the
Table 5. M.D. Anderson Prognostic Scoring System (MPSS) of Myelodysplastic Syndromes22
Points Variable Performance status Age, yr Platelet, x 109/L Hemoglobin, g/dL Bone marrow blasts, % WBC, x 109/L Karyotype Prior transfusion MPSS Risk Group Low Intermediate 1 Intermediate 2 High
1 60–64 50–199 5–10
2 ⱖ2 ⱖ65 30–49 ⬍12 11–29 ⬎20
3
⬍30
chromosome 7 abnormality or complex ⬎ 2 abnormalities Yes Score 0–4 5–6 7–8 ⱖ9
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Table 6. Advantages and Limitations of Currently Available Risk Models for Prognostication in MDS
Patients Arguments In Favor (pros)
Against (cons)
IPSS
Risk Model
The presence of three variables makes it easy to use in clinical practice. Largely utilized in the last 12 years for risk assessment both in clinical practice and clinical trials. Adopted by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for approval of novel drugs for treatment of MDS (azacitidine, decitabine and lenalidomide).
WPSS
The presence of three variables makes it easy to use in clinical practice. This scoring system is able to classify patients into five risk groups showing different survivals and probabilities of leukemic evolution. It predicts survival and leukemia progression at any time during follow-up. WPSS may therefore be used for implementing riskadapted treatment strategies and for stratifying patients enrolled in clinical trials. WPSS have a relevant prognostic value in post-transplantation outcome of MDS patients.24
MPSS
MPSS can be used both in untreated and treated MDS patients. MPSS can be used for risk assessment in CMML and in therapy-related MDS. However, this latter condition has almost always an unfavorable outcome.
IPSS was derived from a multivariate analysis of hematological characteristics of 816 patients at clinical onset and therefore untreated. It included also individuals with 20 –30% marrow blasts (now diagnosed as AML) and patients with chronic myelomonocytic leukemia (now categorized as MDS/ myeloproliferative neoplasms [MPN]). This scoring system does not consider the severity of anemia, in particular transfusion dependency, which represents one of the most important negative prognostic factors in MDS. Furthermore, it underestimates the negative impact of poor cytogenetics (especially relative to blast count). IPSS is inferior to both WPSS23 and MPSS22 in risk stratification of MDS patients. Finally, a major limitation is lack of applicability to MDS patients on investigational programs, because most of them would have had the disease for a significant time and would have received prior therapies. This scoring system was developed in patients with primary MDS, and therefore is not applicable to patients with secondary MDS. However, the 2008 WHO classification of myeloid neoplasms has introduced the unique category of therapy-related neoplasms,2 which includes therapy-related AML, therapy-related MDS and therapy-related MDS/MPN. These conditions are always associated with an unfavorable outcome, and do not require a specific risk assessment. Evaluation of multilineage dysplasia requires considerable expertise, but this is true for many other cytologic and histologic features regarding tumors of hematopoietic and lymphoid tissues. The current use of specific hemoglobin thresholds (⬍9 g/dL in males and ⬍8 g/dL in females) for defining severe anemia has improves the reproducibility of WPSS. The presence of 8 variables makes it uneasy to use in clinical practice. MPSS ignores the WHO classification, which provides the best diagnostic approach to MDS and has considerable prognostic relevance. The hemoglobin cut-off of 12 g/dL (weight 2 in Table 5) appears to be overestimated compared to the WPSS definition of severe anemia (see Table 4). The bone marrow blast range includes cases classified as AML according to WHO criteria.
severity of comorbidities, and found that 35% of MDS patients had moderate to severe comorbid conditions.28 In particular, 55% of MDS patients had a disease of the cardiovascular system, and this was associated with worse survival. Median survival ranged from 32 months in patients with no comorbidity to 10 months in those with severe comorbidities. Of note, these latter subjects had a 50% decrease in overall survival, which was independent of age and IPSS risk group. Finally, Naqvi et al28 built up a prognostic model based on age, IPSS score, and ACE-27 score. This model identified three risk groups, whose median survivals were 43 months
(low risk), 23 months (intermediate risk), and 9 months (high risk), respectively.
CONCLUSIONS AND PERSPECTIVES The 2008 WHO classification currently provides the best diagnostic approach to MDS and has considerable prognostic relevance. For the optimal management of MDS, its implementation into clinical practice is mandatory. As far as risk assessment is concerned, the WPSS can be used reliably in all patients with primary MDS, while
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7.
8.
9.
Figure 3. Relationship between MDS-specific comorbidity index (MDS-CI) and overall survival in MDS patients. Reproduced from Della Porta et al with permission.27
10.
the MPSS allows risk assessment also in those with secondary MDS and in patients with CMML. Since comorbidities have a significant impact on the outcome of patients with MDS, accounting for both disease status and comorbid conditions considerably improves risk stratification. Both the MDS-CI27 and the ACE-2729 can be employed for assessing the severity of comorbidities in MDS patients. In perspective, the available evidence indicates that advances in our ability to improve diagnosis and prognostication of MDS likely will be made possible by a better understanding of the molecular basis of these myeloid neoplasms. A very recent work studied the clinical impact of point mutations in a cohort of 439 patients with MDS.30 Somatic mutations of TP53, EZH2, ETV6, RUNX1, and ASXL1 were found to be independent predictors of decreased survival and to improve the risk stratification provided by the IPSS. These observations suggest that incorporation of somatic mutations may add relevant information to the risk stratification systems currently used in clinical practice.
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16.
17.
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