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Comorbidity Index and Comprehensive Geriatric Assessment in Treatment Decision
Invited Speaker Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S1–S4
7.
Della Porta MG, Gallì A, Bacigalupo A, Zibellini S, Bernardi M, Rizzo E, et al Clinical Effects of Driver Somatic Mutations on the Outcomes of Patients With Myelodysplastic Syndromes Treated With Allogeneic Hematopoietic StemCell Transplantation. J Clin Oncol. 2016 Sep 6. [Epub ahead of print]. 8. Lindsley RC, Saber W, Mar BG, Redd RA, Haagenson MD, Grauman PV, et al Genetic Alterations Predict Outcomes in Patients with Myelodysplastic Syndrome Receiving Allogeneic Hematopoietic Stem Cell Transplantation. N Engl J Med. 2017;376:536–547.
5 NEW AGENTS FOR ANEMIC PATIENTS: MODIFIED ACTIVIN RECEPTORS U. Platzbecker1 1 University Hospital Dresden, MDS Center Dresden, Dresden, Germany A distinct subtype of lower risk myelodysplastic syndromes display ring sideroblasts in the bone marrow, i.e., erythroid progenitors characterized by excessive iron deposited in the mitochondria. This morphological feature is frequently associated with somatic mutations in components of the splicing machinery that constitutes the underlying molecular principle of the disease. Conventional treatment regimen with erythropoiesis-stimulating agents often fails to induce sustained erythroid improvement in these patients that harbor defects in late-stage erythroblasts downstream of erythropoietin action. The activin receptor ligand traps sotatercept and luspatercept represent promising alternatives that promote late-stage erythroid maturation and alleviate anemia in these patients. Experimental and clinical studies are ongoing to further delineate the molecular basis and the clinical implications of this novel therapeutic approach.
6 COMORBIDITY INDEX AND COMPREHENSIVE GERIATRIC ASSESSMENT IN TREATMENT DECISION F. Ramos1 1 Dept. Hematology, University Hospital, Leon, Spain During the last few years the hematological community has become progressively aware of the clinical relevance of comorbidity in the prognostic evaluation and management of the patients diagnosed with hematological diseases. At present time, we have a number of tools to measure the multi-morbidity of our MDS patients, ranging from the more specific (such as the MDS Comorbidity Index) to the most generic ones (such as the Charlson Comorbidity Index). In between, there are a lot of possible choices, but in the end the most important thing is to incorporate at least one of them into our daily practice. Elderly patients are becoming more and more frequent in our practices and pose a great challenge for the hematologist. Their complexity is mediated by a huge heterogeneity and any simple approach to these patients is doomed to failure. The Comprehensive Geriatric Assessment is the gold-standard for the clinical evaluation of the elderly patients, and the scientific evidence of its impact in the hematological diseases is growing steadily. Nevertheless, the hematologists call for more straightforward tools to be used in daily practice, something that has been recently addressed in Spain with the development of the Geriatric Assessment in Hematology (GAH scale). The aging process is a continuum and patients aged over 50 may be considered older adults. Although most patients in their fifties or sixties do not need at all a formal evaluation by a geriatric team,
S3
they may well be showing the first signs of functional decline. A number of indices for older adults are available, such as the Lee Index. This index is much less demanding for the health team than a CGA and much more straightforward. It considers age, gender, comorbidities, functional performance and other relevant dimensions and generates a score easy to incorporate as a covariate into either the clinical practice or research studies. The Spanish MDS Group (GESMD) has recently checked this index in a prospective cohort of MDS patients and found that it may be an interesting addition to the IPSS-R. Although no tool is perfect, the use of any index that considers general patient condition may help to (i) see the patient as a whole, (ii) adjust for the “noise” attributable to other concomitant diseases, and (iii) allow a better fit of the treatment to the individual patient.
7 HOW DO I DIAGNOSE MDS USING CURRENTLY AVAILABLE TOOLS? T. Haferlach1 1 MLL Munich Leukemia Laboratory, MLL, Munich, Germany The diagnosis of MDS is one of the most difficult tasks in hematology. This is caused by in some cases only minor phenotypic changes in the peripheral blood or bone marrow morphology and with a broad range of inter- and intraobserver reproducibility. This is not only true for the percentage of blasts in the cytomorphology of peripheral blood and bone marrow smears, accompanied by trephine biopsies, but especially with respect to the investigation of dysplasia in granulopoiesis, erythropoiesis and megakaryopoiesis. Further, ringsideroblasts have to be examined. To minimize uncertainty for the phenotype, i.e. cytomorpholgy and histology, both techniques should be applied in the peripheral blood (cytomorphology) and in the bone marrow. In case of differing results the findings should be discussed. If there is still uncertainty about the diagnosis of MDS versus reactive or toxic etc. the biopsy should be repeated in 4-8 weeks. The recent WHO-classification and IPSS-R depend on sufficient phenotypic investigation by cytomorphology and histology. This is mandatory. In addition, not only for diagnostic reasons but more for prognostication and treatment guidance cytogenetics from bone marrow, anticoagulated with heparin, needs to be performed. However, as around 30–40% of patients at diagnosis in a standard cohort only demonstrate cytogenetic changes and the others show a normal karyotype, cytogenetic is not a tool in all cases to substantially support the diagnosis of MDS or exclude it. In recent years several molecular markers have been shown to be of clinical importance in MDS. Therefore in patients with clinical relevant decisions such as allogeneic transplantation vs. watchand-wait these markers may be added to the mandatory techniques of cytomorphology and cytogenetics. Further, immunophenotyping may also contribute to diagnosis of MDS with respect to grading of dysplasia and percentage of blasts. In conclusion, cytomorphology, histology and cytogenetics are mandatory at the diagnosis of MDS. Molecular genetic investigations and immunophenotyping may further support clinical decisions and diagnostic approaches for patients with MDS.
7.
Della Porta MG, Gallì A, Bacigalupo A, Zibellini S, Bernardi M, Rizzo E, et al Clinical Effects of Driver Somatic Mutations on the Outcomes of Patients With Myelodysplastic Syndromes Treated With Allogeneic Hematopoietic StemCell Transplantation. J Clin Oncol. 2016 Sep 6. [Epub ahead of print]. 8. Lindsley RC, Saber W, Mar BG, Redd RA, Haagenson MD, Grauman PV, et al Genetic Alterations Predict Outcomes in Patients with Myelodysplastic Syndrome Receiving Allogeneic Hematopoietic Stem Cell Transplantation. N Engl J Med. 2017;376:536–547.
5 NEW AGENTS FOR ANEMIC PATIENTS: MODIFIED ACTIVIN RECEPTORS U. Platzbecker1 1 University Hospital Dresden, MDS Center Dresden, Dresden, Germany A distinct subtype of lower risk myelodysplastic syndromes display ring sideroblasts in the bone marrow, i.e., erythroid progenitors characterized by excessive iron deposited in the mitochondria. This morphological feature is frequently associated with somatic mutations in components of the splicing machinery that constitutes the underlying molecular principle of the disease. Conventional treatment regimen with erythropoiesis-stimulating agents often fails to induce sustained erythroid improvement in these patients that harbor defects in late-stage erythroblasts downstream of erythropoietin action. The activin receptor ligand traps sotatercept and luspatercept represent promising alternatives that promote late-stage erythroid maturation and alleviate anemia in these patients. Experimental and clinical studies are ongoing to further delineate the molecular basis and the clinical implications of this novel therapeutic approach.
6 COMORBIDITY INDEX AND COMPREHENSIVE GERIATRIC ASSESSMENT IN TREATMENT DECISION F. Ramos1 1 Dept. Hematology, University Hospital, Leon, Spain During the last few years the hematological community has become progressively aware of the clinical relevance of comorbidity in the prognostic evaluation and management of the patients diagnosed with hematological diseases. At present time, we have a number of tools to measure the multi-morbidity of our MDS patients, ranging from the more specific (such as the MDS Comorbidity Index) to the most generic ones (such as the Charlson Comorbidity Index). In between, there are a lot of possible choices, but in the end the most important thing is to incorporate at least one of them into our daily practice. Elderly patients are becoming more and more frequent in our practices and pose a great challenge for the hematologist. Their complexity is mediated by a huge heterogeneity and any simple approach to these patients is doomed to failure. The Comprehensive Geriatric Assessment is the gold-standard for the clinical evaluation of the elderly patients, and the scientific evidence of its impact in the hematological diseases is growing steadily. Nevertheless, the hematologists call for more straightforward tools to be used in daily practice, something that has been recently addressed in Spain with the development of the Geriatric Assessment in Hematology (GAH scale). The aging process is a continuum and patients aged over 50 may be considered older adults. Although most patients in their fifties or sixties do not need at all a formal evaluation by a geriatric team,
S3
they may well be showing the first signs of functional decline. A number of indices for older adults are available, such as the Lee Index. This index is much less demanding for the health team than a CGA and much more straightforward. It considers age, gender, comorbidities, functional performance and other relevant dimensions and generates a score easy to incorporate as a covariate into either the clinical practice or research studies. The Spanish MDS Group (GESMD) has recently checked this index in a prospective cohort of MDS patients and found that it may be an interesting addition to the IPSS-R. Although no tool is perfect, the use of any index that considers general patient condition may help to (i) see the patient as a whole, (ii) adjust for the “noise” attributable to other concomitant diseases, and (iii) allow a better fit of the treatment to the individual patient.
7 HOW DO I DIAGNOSE MDS USING CURRENTLY AVAILABLE TOOLS? T. Haferlach1 1 MLL Munich Leukemia Laboratory, MLL, Munich, Germany The diagnosis of MDS is one of the most difficult tasks in hematology. This is caused by in some cases only minor phenotypic changes in the peripheral blood or bone marrow morphology and with a broad range of inter- and intraobserver reproducibility. This is not only true for the percentage of blasts in the cytomorphology of peripheral blood and bone marrow smears, accompanied by trephine biopsies, but especially with respect to the investigation of dysplasia in granulopoiesis, erythropoiesis and megakaryopoiesis. Further, ringsideroblasts have to be examined. To minimize uncertainty for the phenotype, i.e. cytomorpholgy and histology, both techniques should be applied in the peripheral blood (cytomorphology) and in the bone marrow. In case of differing results the findings should be discussed. If there is still uncertainty about the diagnosis of MDS versus reactive or toxic etc. the biopsy should be repeated in 4-8 weeks. The recent WHO-classification and IPSS-R depend on sufficient phenotypic investigation by cytomorphology and histology. This is mandatory. In addition, not only for diagnostic reasons but more for prognostication and treatment guidance cytogenetics from bone marrow, anticoagulated with heparin, needs to be performed. However, as around 30–40% of patients at diagnosis in a standard cohort only demonstrate cytogenetic changes and the others show a normal karyotype, cytogenetic is not a tool in all cases to substantially support the diagnosis of MDS or exclude it. In recent years several molecular markers have been shown to be of clinical importance in MDS. Therefore in patients with clinical relevant decisions such as allogeneic transplantation vs. watchand-wait these markers may be added to the mandatory techniques of cytomorphology and cytogenetics. Further, immunophenotyping may also contribute to diagnosis of MDS with respect to grading of dysplasia and percentage of blasts. In conclusion, cytomorphology, histology and cytogenetics are mandatory at the diagnosis of MDS. Molecular genetic investigations and immunophenotyping may further support clinical decisions and diagnostic approaches for patients with MDS.