In the current World Health Organization (WHO)-classification, therapy-related myelodysplastic syndromes (t-MDS) are categorized together with therapy-related acute myeloid leukemia (AML) and t-myelodysplastic/myeloproliferative neoplasms into one subgroup independent of morphologic or prognostic features. Analyzing data of 2087 t-MDS patients from different international MDS groups to evaluate classification and prognostication tools we found that applying the WHO classification for p-MDS successfully predicts time to transformation and survival (both p < 0.001). The results regarding carefully reviewed cytogenetic data, classifications, and prognostic scores confirmed that t-MDS are similarly heterogeneous as p-MDS and therefore deserve the same careful differentiation regarding risk. As reference, these results were compared with 4593 primary MDS (p-MDS) patients represented in the International Working Group for Prognosis in MDS database (IWG-PM). Although a less favorable clinical outcome occurred in each t-MDS subset compared with p-MDS subgroups, FAB and WHO-classification, IPSS-R, and WPSS-R separated t-MDS patients into differing risk groups effectively, indicating that all established risk factors for p-MDS maintained relevance in t-MDS, with cytogenetic features having enhanced predictive power. These data strongly argue to classify t-MDS as a separate entity distinct from other WHO-classified t-myeloid neoplasms, which would enhance treatment decisions and facilitate the inclusion of t-MDS patients into clinical studies.

The coexistence of autoimmune disorders (AD) in patients with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) has been widely recognized, although with distinct results regarding their prevalence and impact on the outcomes of the underlying hematological process. This study was aimed to analyze the prevalence, clinical characteristics, and outcomes of MDS with AD in a series of 142 patients diagnosed with MDS and CMML. AD was ascertained by both the presence of clinical symptoms or compatible serological tests. In total, 48% patients were diagnosed as having AD, being hypothyroidism the most commonly reported clinical AD (8%) and antinuclear antibodies the most frequent serological parameter identified (23.2%). The presence of AD was associated with female gender, lower hemoglobin levels, and higher IPSS-R. Overall survival for patients with AD was inferior to those with no AD (69 vs. 88% at 30 months; HR 2.75, P = 0.008). Notably, clinical but not isolated immune serological parameters had an impact on the outcomes of patients with AD. Finally, in a multivariate analysis, the presence of AD (HR 2.26) along with disease risk categories (very low and low vs. intermediate, high, and very high IPSS-R; HR 4.62) retained their independent prognostic value (P < 0.001). In conclusion, AD are prevalent in MDS and CMML patients and have prognostic implications, especially in lower-risk MDS patients.

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The 2017 European LeukemiaNet (ELN 2017) guidelines for the diagnosis and management of acute myeloid leukemia (AML) have become fundamental guidelines to assess the prognosis and post-remission therapy of patients. However, they have been retrospectively validated in few studies with patients included in different treatment protocols. We analyzed 861 patients included in the CETLAM-12 risk-adapted protocol, which indicates cytarabine-based consolidation for patients allocated to the ELN 2017 favorable-risk group, while it recommends allogeneic stem cell transplantation as a post-remission strategy for the ELN 2017 intermediate- and adverse-risk groups. We retrospectively classified patients according to the ELN 2017, with 327 (48%), 109 (16%) and 245 (36%) patients allocated to the favorable, intermediate and adverse risk group, respectively. The 2 and 5 year-overall survival (OS) were 77 and 70% for favorable risk patients, 52 and 46% for intermediate risk patients, and 33 and 23% for adverse risk patients, respectively. Furthermore, we identified a subgroup of patients within the adverse group (inv(3)/t(3;3), complex karyotype and/or TP53 mutation/17p abnormality) with a particularly poor outcome, with a 2-year OS of 15%. Our study validates the ELN 2017 risk stratification in a large cohort of patients treated with an ELN-2017 risk-adapted protocol, based on alloSCT after remission for non-favorable ELN subgroups, and identifies a genetic subset with a very poor outcome which warrants investigation of novel strategies.

Background: The International Prognostic Scoring System (IPSS) for MDS has recently been revised (IPSS-R). However both scoring systems were developed after exclusion of therapy-related cases and data on its usefulness in treatment-related MDS (tMDS) is limited. Aims and Methods: We analyzed 1837 pts from Spanish, German, Swiss, Austrian, US, Italian, and Dutch centers diagnosed 1975-2015. Complete data to calculate the IPSS/-R was available in 1511 pts. The impact of prognostic features was analyzed by uni- and multivariable models and estimated by a measure of concordance for censored data (Dxy). Results: Median age was 68 years. 1% of pts had 5q-syndrome, 13% RCUD, 4% RARS, 27% RCMD/-RS, 18% RAEB 1, 18% RAEB 2, 4% CMML 1, 2% CMML 2, 3% MDS-U, and 7% AML (RAEB-T) according to WHO-classification. Regarding cytogenetics 38% exhibited good, 14% intermediate, and 48% poor-risk according to IPSS, and 2% very good, 36% good, 17% intermediate, 15% poor, and 31% very poor according to IPSS-R. Prognostic risk groups were 12% IPSS low, 34% int 1, 36% int 2, and 18% high, while the IPSS-R was very low in 8%, low in 20%, intermediate in 17%, high in 23%, and very high in 32%. The most frequent primary diseases were NHL 28%, breast cancer 16%, myeloma 6%, prostate cancer 6%, Hodgkins disease 5%, and 4% gastrointestinal tumors. Patients received chemotherapy in 75% and radiotherapy in 47%. Regarding chemotherapeutic drugs, most pts received combination regimens containing alkylating agents in 65%, topoisomerase inhibitors in 44%, antitubulin agents in 26%, and antimetabolites in 26%. Median follow-up from MDS diagnosis was 59 months, median survival 16 months. Since a disease altering treatment is, at least in higher risk disease, which is overrepresented in tMDS, standard of care, we decided to analyze treated as well as untreated pts to avoid a selection bias. This included stem cell transplantation in 16% with a median survival of 24 months. Features with influence on survival and time to AML in univariable analysis included FAB, WHO, IPSS, IPSS-R, cytogenetics, hb, platelets, marrow and peripheral blasts, ferritin, LDH, fibrosis, ß2-microglobulin, and use of alkylating agents for the treatment of primary disease. For hemoglobin, platelets, LDH, fibrosis, and ß2-microglobulin the influence was stronger on survival. Year of diagnosis, age, gender, neutrophil count, WBC, use of chemo or radiotherapy as well as other chemotherapeutic agents had no marked influence on both outcomes. According to our results, both the IPSS (Dxy 0.29 for survival, 0.32 for AML) and IPSS-R (Dxy 0.34, 0.32 for AML) perform moderately in tMDS, but not as well as in primary MDS (pMDS). Therefore, existing prognostic models need to be adjusted to tMDS. However, this appears to be not without difficulties. The scores tested, as well as most prognostic variables themselves perform inferior compared to pMDS. It becomes even more complicated since tMDS in itself is even more heterogeneous than pMDS. Scores and variables perform differently depending on the primary disease or therapy. The IPSS/-R and its variables perform for example better in pts with solid tumors compared to hematologic diseases or in pts who have received radio- instead of chemotherapy, but also in pts after prostate compared to breast cancer. In addition to the integration of further variables, new cutoffs, or the weighting of existing variables, we are currently testing the possibility of separate score versions for different tMDS subgroups. Separate score versions for survival and time to AML would also give differing weights to most features. Hemoglobin, platelets and cytogenetics would get more weight for survival, while marrow blasts would be more important regarding AML. Conclusion: In contrast to early descriptions of tMDS, with poor risk cytogenetics in the vast majority of pts and a uniformly poor prognosis, surprisingly we find good risk karyotypes in a relatively large number of pts. Although, poor risk cytogenetics are still overrepresented, this indicates, different types of tMDS exist. Our analysis shows that many variables exhibit prognostic influence in tMDS and the IPSS or preferably IPSS-R can be applied in these pts. However, the prognostic power of both scores is inferior compared to pMDS, making an optimized tMDS score reasonable. Currently data from further IWG centers is integrated in our database and further analyses are performed to propose a tMDS specific score. Figure 1. Figure 1. Disclosures Komrokji: Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau; Incyte: Consultancy; Celgene: Consultancy, Research Funding. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Steensma:Celgene: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Onconova: Consultancy. Valent:Novartis: Consultancy, Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Platzbecker:Boehringer: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Esteve:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.