Reinhard Stauder

New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients

We have generated a large, unique database that includes morphologic, clinical, cytogenetic, and follow-up data from 2124 patients with myelodysplastic syndromes (MDSs) at 4 institutions in Austria and 4 in Germany. Cytogenetic analyses were successfully performed in 2072 (97.6%) patients, revealing clonal abnormalities in 1084 (52.3%) patients. Numeric and structural chromosomal abnormalities were documented for each patient and subdivided further according to the number of additional abnormalities. Thus, 684 different cytogenetic categories were identified. The impact of the karyotype on the natural course of the disease was studied in 1286 patients treated with supportive care only. Median survival was 53.4 months for patients with normal karyotypes (n = 612) and 8.7 months for those with complex anomalies (n = 166). A total of 13 rare abnormalities were identified with good (+1/+1q, t(1q), t(7q), del(9q), del(12p), chromosome 15 anomalies, t(17q), monosomy 21, trisomy 21, and -X), intermediate (del(11q), chromosome 19 anomalies), or poor (t(5q)) prognostic impact, respectively. The prognostic relevance of additional abnormalities varied considerably depending on the chromosomes affected. For all World Health Organization (WHO) and French-American-British (FAB) classification system subtypes, the karyotype provided additional prognostic information. Our analyses offer new insights into the prognostic significance of rare chromosomal abnormalities and specific karyotypic combinations in MDS.

New Comprehensive Cytogenetic Scoring System for Primary Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia After MDS Derived From an International Database Merge

PURPOSE The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the International Prognostic Scoring System (IPSS) in 1997, knowledge concerning the prognostic impact of abnormalities has increased substantially. The present study proposes a new and comprehensive cytogenetic scoring system based on an international data collection of 2,902 patients. PATIENTS AND METHODS Patients were included from the German-Austrian MDS Study Group (n = 1,193), the International MDS Risk Analysis Workshop (n = 816), the Spanish Hematological Cytogenetics Working Group (n = 849), and the International Working Group on MDS Cytogenetics (n = 44) databases. Patients with primary MDS and oligoblastic acute myeloid leukemia (AML) after MDS treated with supportive care only were evaluated for overall survival (OS) and AML evolution. Internal validation by bootstrap analysis and external validation in an independent patient cohort were performed to confirm the results. RESULTS In total, 19 cytogenetic categories were defined, providing clear prognostic classification in 91% of all patients. The abnormalities were classified into five prognostic subgroups (P < .001): very good (median OS, 61 months; hazard ratio [HR], 0.5; n = 81); good (49 months; HR, 1.0 [reference category]; n = 1,809); intermediate (26 months; HR, 1.6; n = 529); poor (16 months; HR, 2.6; n = 148); and very poor (6 months; HR, 4.2; n = 187). The internal and external validations confirmed the results of the score. CONCLUSION In conclusion, these data should contribute to the ongoing efforts to update the IPSS by refining the cytogenetic risk categories.

Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet

Within the myelodysplastic syndrome (MDS) work package of the European LeukemiaNet, an Expert Panel was selected according to the framework elements of the National Institutes of Health Consensus Development Program. A systematic review of the literature was performed that included indexed original papers, indexed reviews and educational papers, and abstracts of conference proceedings. Guidelines were developed on the basis of a list of patient- and therapy-oriented questions, and recommendations were formulated and ranked according to the supporting level of evidence. MDSs should be classified according to the 2008 World Health Organization criteria. An accurate risk assessment requires the evaluation of not only disease-related factors but also of those related to extrahematologic comorbidity. The assessment of individual risk enables the identification of fit patients with a poor prognosis who are candidates for up-front intensive treatments, primarily allogeneic stem cell transplantation. A high proportion of MDS patients are not eligible for potentially curative treatment because of advanced age and/or clinically relevant comorbidities and poor performance status. In these patients, the therapeutic intervention is aimed at preventing cytopenia-related morbidity and preserving quality of life. A number of new agents are being developed for which the available evidence is not sufficient to recommend routine use. The inclusion of patients into prospective clinical trials is strongly recommended.

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)

The international prognostic scoring system (IPSS) is considered the gold standard for risk assessment in primary myelodysplastic syndromes (MDS). This score includes several prognostic factors except serum lactate dehydrogenase (LDH). We evaluated the prognostic power of LDH as an additional variable in IPSS-based risk assessment. For this purpose, a total of 892 patients with primary MDS registered by the Austrian–German cooperative MDS study group was analyzed retrospectively. Multivariate analysis confirmed the value of established parameters such as medullary blasts, karyotype and peripheral cell counts and showed that elevated LDH was associated with decreased overall survival (P<0.00005) and increased risk of AML development (P<0.00005), independent of the system used to classify MDS (FAB or WHO). Moreover, elevated LDH was found to be a significant predictor of poor survival within each IPSS risk group and within each FAB group except RAEB-T. To exploit these results for refined prognostication, each IPSS risk group was split into two separate categories (A=normal LDH vs B=elevated LDH). Using this LDH-assisted approach, it was possible to identify MDS patients with unfavorable prognosis within the low and intermediate IPSS risk groups. We propose that the IPSS+LDH score should improve clinical decision-making and facilitate proper risk stratification in clinical trials.

Coalesced Multicentric Analysis of 2,351 Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics of Myelodysplastic Syndromes in the International Prognostic Scoring System

PURPOSE The International Prognostic Scoring System (IPSS) remains the most commonly used system for risk classification in myelodysplastic syndromes (MDSs). The IPSS gives more weight to blast count than to cytogenetics. However, previous publications suggested that cytogenetics are underweighted in the IPSS. Here we investigate the prognostic impact of cytogenetic subgroups compared with that of bone marrow blast count in a large, multicentric, international patient cohort. PATIENTS AND METHODS In total, 2,351 patients with MDS who have records in the German-Austrian and the MD Anderson Cancer Center databases were included and analyzed in univariate and multivariate models regarding overall survival and risk of transformation to acute myeloid leukemia (AML). The data were analyzed separately for patients treated with supportive care without specific therapy, with AML-like chemotherapy, or with other therapy regimens (low-dose chemotherapy, demethylating agents, immune modulating agents, valproic acid, and cyclosporine). RESULTS The prognostic impact of poor-risk cytogenetic findings (as defined by the IPSS classification) on overall survival was as unfavorable as an increased (> 20%) blast count. The hazard ratio (compared with an abnormal karyotype or a bone marrow blast count < 5%) was 3.3 for poor-risk cytogenetics, 4.8 for complex abnormalities harboring chromosomes 5 and/or 7, and 3.1 for a blast count of 21% to 30% (P < .01 for all categories). The predictive power of the IPSS cytogenetic subgroups was unaffected by type of therapy given. CONCLUSION The independent prognostic impact of poor-risk cytogenetics on overall survival is equivalent to the impact of high blast counts. This finding should be considered in the upcoming revision of the IPSS.

Comorbidity as prognostic variable in MDS: comparative evaluation of the HCT-CI and CCI in a core dataset of 419 patients of the Austrian MDS Study Group

BACKGROUND The evaluation of comorbidity is of increasing importance in patients with hematologic disorders. PATIENTS AND METHODS In the present study, the influence of comorbidity on survival and acute myeloid leukemia (AML) evolution was analyzed retrospectively in 419 patients with de novo myelodysplastic syndromes (MDS) (observation period: 1985-2007). The median age was 71 years (range 24-91 years). Two different scoring systems, the hematopoietic stem-cell transplantation-specific comorbidity index (HCT-CI) and the Charlson comorbidity index (CCI) were applied. RESULTS The HCT-CI was found to be a significant prognostic factor for overall survival (OS, P < 0.05) as well as event-free survival (EFS, P < 0.05) in our patients, whereas the CCI was of prognostic significance for OS (P < 0.05), but not for EFS. For AML-free survival, neither the HCT-CI nor the CCI were of predictive value. A multivariate analysis including age, lactate dehydrogenase, ferritin, karyotype, number of cytopenias, French-American-British groups, and comorbidity was applied. Comorbidity was found to be an independent prognostic factor in patients with low- or int-1-risk MDS (P < 0.05) regarding OS and EFS. CONCLUSIONS Together, our data show that comorbidity is an important risk factor for OS and EFS in patients with MDS.

Impact of adjunct cytogenetic abnormalities for prognostic stratification in patients with myelodysplastic syndrome and deletion 5q.

This cooperative study assessed prognostic factors for overall survival (OS) and risk of transformation to acute myeloid leukemia (AML) in 541 patients with de novo myelodysplastic syndrome (MDS) and deletion 5q. Additional chromosomal abnormalities were strongly related to different patients’ characteristics. In multivariate analysis, the most important predictors of both OS and AML transformation risk were number of chromosomal abnormalities (P<0.001 for both outcomes), platelet count (P<0.001 and P=0.001, respectively) and proportion of bone marrow blasts (P<0.001 and P=0.016, respectively). The number of chromosomal abnormalities defined three risk categories for AML transformation (del(5q), del(5q)+1 and del(5q)+⩾2 abnormalities) and two for OS (one group: del(5q) and del(5q)+1; and del(5q)+⩾2 abnormalities, as the other one); with a median survival time of 58.0 and 6.8 months, respectively. Platelet count (P=0.001) and age (P=0.034) predicted OS in patients with ‘5q−syndrome’. This study demonstrates the importance of additional chromosomal abnormalities in MDS patients with deletion 5q, challenges the current ‘5q−syndrome’ definition and constitutes a useful reference series to properly analyze the results of clinical trials in these patients.

The relevance of a geriatric assessment for elderly patients with a haematological malignancy - A systematic review

BACKGROUND Geriatric assessment is increasingly used to assess the health status of older cancer patients. We set out to assemble all available evidence on the relevance of a geriatric assessment in the treatment of older patients with haematological malignancies. METHODS A systematic Medline and Embase search for studies in which a geriatric assessment was used to detect health issues or to address the association between baseline geriatric assessment and outcome. RESULTS 18 publications from 15 studies were included. The median age of patients was 73 years (range 58-86). Despite generally good performance status, the prevalence of geriatric impairments was high. Geriatric impairments were associated with a shorter overall survival in a relevant proportion of studies (instrumental activities 55%, nutritional status 67%, cognitive capacities 83%, objectively measured physical capacity 100%). Comorbidity, physical capacity and nutritional status retained their significance even in multivariate analyses in 50%, 75%, and 67% of analyses respectively, whereas age and performance status lost their predictive value in most studies. One study found an association between comorbidity and chemotherapy-related non-haematological toxicity. In another study a pronounced association between summarised outcome of geriatric assessment and chemotherapy-related toxicity as well as response to treatment was described. CONCLUSION This review demonstrates that a geriatric assessment can detect multiple health issues, even in patients with good performance status. Impairments in geriatric domains have predictive value for mortality and also appear to be associated with toxicity and other outcome measures and should thus be integrated in individualised treatment algorithms.

Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): A multicenter study

Myelodysplastic syndromes (MDS) with del(5q) are considered to have a benign course of the disease. In order to address the issue of the propensity of those patients to progress to acute myeloid leukemia (AML), data on 381 untreated patients with MDS and del(5q) characterized by low or intermediate I International Prognostic Scoring System (IPSS) risk score were collected from nine centers and registries. Median survival of the entire group was 74 months. Transfusion-dependent patients had a median survival of 44 months vs 97 months for transfusion-independent patients (P<0.0001). Transfusion need at diagnosis was the most important patient characteristic for survival. Of the 381 patients, 48 (12.6%) progressed to AML. The cumulative progression rate calculated using the Kaplan–Meier method was 4.9% at 2 years and 17.6% at 5 years. Factors associated with the risk of AML transformation were high-risk World Health Organization adapted Prognostic Scoring System (WPSS) score, marrow blast count >5% and red-cell transfusion dependency at diagnosis. In conclusion, patients with MDS and del(5q) are facing a considerable risk of AML transformation. More detailed cytogenetic and molecular studies may help to identify the patients at risk of progression.

Blood levels of angiogenin and vascular endothelial growth factor are elevated in myelodysplastic syndromes and in acute myeloid leukemia.

Angiogenesis is of prognostic importance not only in solid tumors but also in malignant blood diseases. We measured levels of vascular endothelial growth factor (VEGF), angiogenin (ANG), and basic fibroblast growth factor (bFGF) in peripheral blood samples from 65 patients with myelodysplastic syndrome (MDS), from 25 patients with de novo acute myeloid leukemia (AML), and from 50 healthy donors. In matched samples, VEGF levels in serum were substantially higher than VEGF levels in plasma (380.7 +/- 56 pg/ml vs. 45.3 +/- 4.5 pg/ml, mean +/- SEM, p < 0.001), whereas serum and plasma levels of ANG were comparable and significantly correlated (r = 0.8; p < 0.01). Compared to normal controls (1.3 +/- 0.09 pg), serum levels of VEGF corrected for the peripheral blood platelet count (VEGF/10(6) platelets, VEGF(PLT)) were elevated in patients with refractory anemia (RA; 3.1 +/- 0.8 pg, p < 0.01), and reached maximal values in patients with advanced stage MDS (RAEB, RAEB-t) (3.5 +/- 0.6 pg, p < 0.001), de novo AML (3.6 +/- 1.1 pg, p < 0.05), and chronic myelomonocytic leukemia (CMML; 3.7 +/- 0.9 pg; p < 0.001). Levels of soluble ANG were elevated in RA (351 +/- 25.7 ng/ml, p < 0.001), in RAEB/RAEB-t (402 +/- 17.9 ng/ml; p < 0.001), in CMML (413.8 +/- 29.5 ng/ml; p < 0.001), and in patients with AML (305.1 +/- 17.1 ng/ml; p < 0.01, controls 255.4 +/- 8.1 ng/ml). Serum bFGF was neither elevated in MDS nor in AML patients. These results suggest that VEGF(PLT) is a marker of disease progression in MDS. Moreover, we show for the first time that elevated blood levels of ANG can be found in patients with myeloid malignancies, suggesting a role of ANG in the pathogenesis of these diseases.