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Prognostic work-up

Risk asessment

Myelodysplastic syndromes (MDS) constitute an extremely heterogeneous group of bone marrow malignancies, and a risk-adapted treatment strategy is mandatory. Prognostic factors may be subdivided into those related to the patient's characteristics and general health condition, and those related to the characteristics of their disease and the MDS clone.

This section aims to describe baseline prognostic factors and assessment models; predictive models specific to a particular treatment are described within each of their respective treatment sections. This section also includes risk assessment for HSCT

Disease-related factors

Risk, related to the characteristics of MDS, is based on the use of prognostic scoring systems combining multiple clinical and hematologic variables. In 1997, the International Prognostic Scoring System (IPSS) was developed: calculated risk is based on bone marrow blasts, cytogenetic abnormalities, and number of cytopenias. 

*Good: normal, -Y, del(5q), del(20q); Poor: complex, chromosome 7 anomalies; Intermediate: other abnormalities.
°Hemoglobin < 10 g/dL, absolute neutrophil count < 1,800/µL, platelet count < 100,000/µL.
Scores for risk groups are as follows: Low, 0; INT-1, 0.5-1.0; INT-2, 1.5-2.0; and High, >=2.5
Score +0 +0.5 +1 +1.5 +2
BM blasts % <5 5 - 10 - 11 - 20 21 - 30
Karyotype* Good Intermediate Poor    
Cytopenias° 0 / 1 2 / 3      
International MDS risk classification (Blood 1997;89:2079-2088) pts: patients
International MDS risk classification (Blood 1997;89:2079-2088) pts: patients

Most of the scientific evidence on the efficacy and safety of the currently available therapeutic agents is derived from clinical studies adopting the IPSS as the reference score for including patients and analyzing results. As a consequence, evidence-based therapeutic recommendations refer to patients stratified according to IPSS.

In 2012 the revised IPSS (IPSS-R), based on 5 cytogenetic risk groups, refined categories for bone marrow blasts and peripheral blood cytopenias was published. The IPSS-R is recognized as relevant for hematopoietic stem cell transplantation eligibility.

 
Score 0 +0.5 +1 +1.5 +2 +3 +4
Cytogenetic Very good   Good   Intermediate Poor Very poor
bm Blasts % ≤2   >2 - <5   5 - 10% >10%  
Haemoglobin ≥10   8 - <10 <8      
Platelets ≥100 50 - <100 <50        
ANC ≥0.8 <0.8          
 
Risk group Total score
Very low ≤1.5
Low >1.5 - 3
Intermediate >3 - 4.5
High >4.5 - 6
Very high >6
Revised international prognostic scoring system for myelodysplastic syndromes: Survival and AML evolution (Blood. 2012;120:2454-65)
Revised international prognostic scoring system for myelodysplastic syndromes: Survival and AML evolution (Blood. 2012;120:2454-65)
Dynamic changes in cytopenias

Worsening of cytopenias and in particular thrombocytopenia may predict for a worse prognosis. It is therefore important to follow patients who are potential candidates for active therapy with an active “watch and wait” strategy.

Prognostic relevance of flow cytometry

Flow cytometry immunophenotyping may provide prognostic information: the combination of multiple flow cytometric abnormalities into numerical scores was shown to be of additive value to reference prognostic scoring systems. Although this approach cannot be recommended on a routine basis, flow cytometry immunophenotyping can be useful for identifying subsets of patients with a distinct clinical course and response to treatment.

Prognostic relevance of somatic mutations

The prognostic role of somatic mutations in MDS is a dynamically evolving field. MDS Right guidelines will therefore develop as the project generates more information on the subject. The present conservative version is limited to statements supported by multiple publications.

Integration of somatic mutations into prognostic scoring systems may provide more accurate risk stratification of individual patients and further refine clinical decision-making in MDS. Most published data is based on retrospective analyses and there is still a lack of validated information about which genes, platforms and interpretations to use. Cooperative studies are ongoing to clarify the role of specific mutation patterns for prognosis and treatment.

  • Patients with 5q deletion, a low or intermediate-1 IPSS score, and evidence of TP53 mutation have a significantly higher risk of transformation to AML than patients without TP53 mutation.
  • Patients with complex karyotypes have significantly worse prognosis if they also carry a TP53 mutation. They also have a worse outcome after SCT.
  • NGS significantly aids prognostic assessment and clinical decision-making in intermediate risk patients and in particular in patients with normal karyotype who are potential candidates for stem cell transplantation.
Recommendations for molecular genetics in the prognostic work-up

According to WHO 2016 and IPSS-R, NGS is not mandatory in the prognostic process for MDS and MDS MPN. NGS is therefore not mandatory but highly recommended in the MDS Right guidelines. It should however be noted that hematological departments at many university hospitals add NGS to the prognostic process in order to guide risk assessment and clinical decision-making.

The recommendation is to discuss NGS information in multiprofessional conferences and/or with experienced centers.

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Patient-related factors
General comments

This section will develop over the next years when larger datasets are analyzed with regard to the relative impact of different disease-related and patient-related factors.

Age and functional ability

Different factors related to individual general health status may affect clinical outcome and decision-making in patients with cancer. These include age, functional ability (performance status), comorbidity, physical reserves (frailty), nutritional status, and cognition.

  • Increasing age is an independent adverse prognostic factor in MDS, and age-adjusted estimates of survival probability have been provided in various prognostic scoring systems. However, chronological age may be distinct from biological or functional age.
  • Many scales for the measurement of individual functional ability (performance status) were tested in MDS, and used as a selection criterion to enter clinical trials. However, these functional assessment scores provide only small amounts of information pertinent to the management of elderly patients.
Extra-hematological comorbidity

The prognostic relevance of comorbidity may have important implications in the management of patients with MDS, and accounting for both disease- and patient-related factors considerably improves risk stratification according to disease-related criteria. Several comorbidity scores have been tested in the general MDS patient population. These include general measures, such as the Charlson comorbidity index or the Adult Comorbidity Evaluation-27, and disease-specific measures, such as the MDS-Specific Comorbidity Index.

 
Comorbidity HR obtained through a multivariable Cox survival analysis with NLD as a dependent covariate Variable weighted score (to be taken into account if the specific comorbidity is present)
Cardiac disease 3.57 (p<.001) 2
Moderate-to-severe hepatic disease 2.55 (p=.01) 1
Severe pulmonary disease 2.44 (p=.005) 1
Renal disease 1.97 (p=.04) 1
Solid tumor 2.61 (p=.001) 1
 
MDS-CI risk Sum of invididual variable scores Proprtion of patients in the learning cohort belonging to the risk group (%)
Low risk 0 546 / 840 (65%)
Intermediate risk 1 - 2 244 / 840 (29%)
High risk >2 50 / 840 (6%)

The Hematopoietic Cell Transplantation Comorbidity Index is an instrument that captures pre-transplantation comorbidities and should be used in predicting post-transplantation outcomes and stratifying patients with MDS.

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Risk assessment for allogeneic hematopoietic stem cell transplantation (HSCT)
Disease-related factors
  • Disease-risk scored according to the revised IPSS (IPSS-R) has been recognized as a relevant clinical variables for HSCT eligibility.
  • Patients with MDS and marrow fibrosis should be considered for HSCT before development of severe marrow fibrosis (recommendation level D).
Patient-related factors
  • Age, performance status (functional ability), frailty (reduced physical fitness or physical reserve), and comorbidities are important factors which determine outcome after HSCT. The impact of age per se is less evident, if other factors, including comorbidities are considered appropriately.
  • Comorbidities, graded according to the Hematopoietic Cell Transplantation Comorbidity Index has been recognized as a relevant clinical variables for HSCT eligibility.
 
Comorbidity HCT-CI weighted scores
Arrhythmia 1
Cardiac 1
Inflammatory bowel disease 1
Diabetes 1
Cerebrovascular disease 1
Psychiatric
disturbance		 1
Hepatic, mild 1
Obesity 1
Infection 1
Rheumatologic 2
Peptic ulcer 2
Moderate/severe
renal		 2
Moderate pulmonary 2
Prior solid tumor 3
Heart valve disease 3
Severe pulmonary 3
Moderate/severe hepatic 3
Risk stratification of patients with acute myeloid leukemia/myelodysplasia and receiving allogeneic hematopoietic cell transplantation (HCT). Group I (gray) included HCT-specific comorbidity index (CI) scores 0 to 2 plus low disease risk; group II (yellow) included HCT-CI scores 0 to 2 plus intermediate and high disease risks; group III (blue) included HCT-CI scores ≥ 3 plus low disease risks; and group IV (red) included HCT-CI scores ≥ 3 plus intermediate and high disease risks. NRM, nonrelapse mortality; OS, overall survival; RFS, relapse-free survival. JCO  2007, 25, 4246-4254.
Risk stratification of patients with acute myeloid leukemia/myelodysplasia and receiving allogeneic hematopoietic cell transplantation (HCT). Group I (gray) included HCT-specific comorbidity index (CI) scores 0 to 2 plus low disease risk; group II (yellow) included HCT-CI scores 0 to 2 plus intermediate and high disease risks; group III (blue) included HCT-CI scores ≥ 3 plus low disease risks; and group IV (red) included HCT-CI scores ≥ 3 plus intermediate and high disease risks. NRM, nonrelapse mortality; OS, overall survival; RFS, relapse-free survival. JCO  2007, 25, 4246-4254.

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References
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  • Malcovati L, et al. J Clin Oncol. 2007;25:3503-3510.
  • Greenberg P, et al. Blood. 2012;120:2454-65.
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  • Sorror ML, et al. J Clin Oncol. 2007;25:4246-4254.
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  • Jädersten M, et al. JCO 2011; 29:1971-9  
  • Itzykson R, et al. Blood Adv. 2018 Aug 28;2(16):2079-2089.