Page 28 - 2020_07-Haematologica-web

E. Hellström-Lindberg et al.
homozygous mutations in ERCC6L2 have been shown to predispose to the development of somatic TP53 mutations and severe AML.73 Mutations in DDX41 predispose to myeloid neoplasms at higher ages than most other predis- posing mutations, making this an important gene to ana- lyze in potential adult sibling donors.74
Determining the diagnosis of myeloid neoplasms with germline predisposition is of crucial clinical significance since it may tailor therapy, dictate the selection of donors and conditioning regimens for allogeneic hematopoietic SCT, and enable relevant prophylactic measures and early intervention. The Nordic MDS group recently published a practical guideline program for diagnosis and manage- ment of such conditions.4
Risk assessment and prognostication
Clinical variables for risk-based classification
A number of disparate methods have been developed to clinically characterize MDS patients and evaluate their prognosis. These classification approaches incorporated a mixture of clinical features, including marrow blasts and cytogenetics, differing cytopenias, age, lactate dehydroge- nase levels, and cytogenetic abnormalities. The International MDS Risk Analysis Workshop clarified these features and generated the consensus International Prognostic Scoring System for MDS (IPSS), dividing patients with MDS into four risk categories based on their cytopenias, marrow blast percentage and cytogenetic sub- group, with median survivals ranging from 0.4 to 5.7 years.75 This classification method proved useful for prog- nostic evaluation and clinical trial design.
Over the ensuing 15 years, additional features were sug- gested to provide prognostic information in MDS, includ- ing ferritin and β2-microglobulin levels, marrow fibrosis, the patient’s comorbidities and performance status, and novel cytogenetic subgroups as well as refined morpho- logical assessment of MDS.2,76-81 To examine the prognostic impact of these variables, the coalescence of data from a new set of untreated primary MDS patients from multiple international institutions provided another global data- base of 7,012 patients via the International Working Group for Prognosis in MDS (IWG-PM) project. This data- base generated the Revised-IPSS (IPSS-R) allowing for a more comprehensive cytogenetic analysis, providing five cytogenetic subgroups based on an increased number of specific prognostic chromosomal categories (n=15)12 com- pared to the six in the IPSS.75 In addition and importantly, the revised system incorporated depth of cytopenias and differing marrow blast percentages. The revised model demonstrated five major prognostic categories (Figure 2). Some patients in the IWG-PM project were also assessed by the WHO classification-based Prognostic Scoring System (WPSS) parameters, including red cell transfusion dependence and WHO-defined clinical subgroups, with similar prognostic efficacy.82
Since 2012, the IPSS-R has been a standard for evalua- tion of risk-based clinical outcomes, and design of thera- peutic strategies and clinical trials based on prognostic risk-based features. The European LeukemiaNet and the American NCCN MDS practice guidelines recommend treatment based on the IPSS-R, age and performance sta- tus.9,83 The IPSS-R has been confirmed to be a valuable method for risk-classifying MDS patients, albeit with some degree of variablity.84-88
Figure 2. Clinical outcomes of patients with myelodysplastic syndrome in relation to Revised International Prognostic Scoring System prognostic risk-based cate- gories. Survival, n = 7012, P<0.001. Evolution to acute myeloid leukemia, n = 6485, P<0.001.12 IPSS-R: Revised International Prognostic Scoring System; AML: acute myeloid leukemia.
1770
haematologica | 2020; 105(7)