Abstract: Myelodysplastic Syndromes (MDS) are hematopoietic stem cell disorders, which are characterized by marrow failure and a substantial risk of developing Acute Myeloid Leukemia (AML). While some patients gradually progress to more advanced MDS subtypes, others experience an apparently immediate AML onset without any transition period. In order to get a better understanding of these different types of MDS progression, we retrospectively analyzed the data of 3213 patients included into the MDS registry Düsseldorf. As assessed by bone marrow examination a disease progression to AML or to advanced MDS subtype was observed in 24,5% of the patients. The progression rate was lowest in the unilineage dysplasia group (RA/RARS: 9%) as compared to 5q- (26%), multilineage dysplasia (16%), RAEB I (26%) and RAEB II (37%). The progression rate in CMML I was 17%, in CMML II 31%, in RARS-T 9% and in the former RAEB-T group 57%. We then evaluated the survival-time of the progressive patients. In the entire group, patients who progressed had a median survival of 17 months compared to 30 months in those with stable disease (p=0.0005). In the group of patients with less than 5% of medullary blasts at time of diagnosis, those who progressed had a median survival of 28 months compared to 48 months in those who did not progress (p=0.00005). Interestingly, in this group of patients disease progression into an advanced MDS subtype did not affect survival (4% progression in advanced subtype, 46 vs. 48 months, p= n.s.), whereas disease progression into AML was associated with a shorter survival (11% progression into AML, 23 vs. 48 months, p=0,0005) In the group of patients who had & gt;5% of medullary blasts at diagnosis, the progression did not influence survival substantially (14 vs.15 months, p=0.01). The cumulative risk of AML evolution at 2 and 5 years after initial diagnosis was lowest in unilineage dysplasia (4% and 8%), multilineage dysplasia (11% and 19%), 5q- (10% and 18%), RAEB I (26% and 44%), RAEB II (50% and 74%), CMML I (14% and 24%), CMML II (33% and 74%), RARS-T (5% and 5%) and RAEB –T (70% and 77%). In the following we investigated the course of MDS progression in those patients who did not develop AML. Fifty-three % of the patients in the unilineage group (RA/RARS) progressed to RAEB I or RAEB II, 10% to RCMD and 3% developed a 5q- syndrome. In the multilineage group 41% of the patients transformed into RAEB I or II, while 40% of the patients with 5q- progressed to RAEB I or RAEB II. In the RAEB I group, 28% of the patients developed RAEB II and 18% of the CMML I patients ended up as CMML II. Finally, we analyzed the effect of progression within the IPSS groups with regard to survival. Patients within the low risk group who progressed (22%) had a median survival of only 46 months, compared to 88 months among those who did not progress (p=0.00005). This correlation was also significant among patients within the intermediate I group (29% progressive patients, 26 vs. 36 months, p=0.0004). In both, the intermediate II and the high risk group progression was not associated with a shorter survival. Conclusions: About 25% of the patients progress to a more advanced MDS type or to AML. A substantial part of the patients with 5q- Syndrome as well as patients with multilineage dysplasia and RAEB types show disease progression. Progression is only associated with a shorter survival among patients within the IPSS low and Intermediate I risk group. In patients with less than 5% of marrow blasts at time of diagnosis only progression into AML is associated with a shorter survival.

Abstract: The current classification system for Myelodysplastic Syndromes lumps all therapy-related (tMDS) into one subgroup assuming all tMDS had the same poor prognosis. We have put together a database including 2032 patients with a diagnosis of tMDS from several different IWG centers and the MDS clinical research consortium. With the idea of developing an individual scoring system for tMDS, we decided to start by optimizing the cytogenetic part of the IPSSR. First, we did an extensive review of karyotypes. Finally, 1245 patients had complete data and correct ISCN formula to be used for score development. We could show regarding karyotypes there are very limited differences between primary and tMDS. Mainly the distribution of risk groups differs with complex occurring more (37%) and normal karyotypes occurring less frequent, although still accounting for 30%. There are few exceptions that are relatively special for tMDS, like translocations including 11q23. A few karyotypes are less frequent; therefore, we could not evaluate the value of IPSS-R cytogenetics for all karyotypes. However, if we apply IPSS-R cytogenetics to our patient cohort, we can separate 5 different risk groups as in pMDS. We tested the performance of the score by using the Dxy. As main endpoint we chose transformation-free survival giving better information about the severity of the disease compared to the single endpoints survival and AML transformation that where calculated for completeness as well. The Dxy for the IPSS-R cytogenetic part is 0.31 for transformation-free survival. This indicates an effective prognostic performance although not as good as in pMDS. Several attempts were done to develop a tMDS specific cytogenetic score. The best draft scoring component achieves a Dxy of 0.33. Counting the number of aberrations achieves a score of 0.30. If normal clone present or not is added, the performance of this very simple model is improved with a Dxy of 0.32. As we could show, all these different approaches lead to a comparable performance. One can argue that still regarding a few karyotypes the prognostic impact is slightly different between p and tMDS (e.g. +8). On the other hand, the most practical approach seems to be to adopt the original cytogenetic part of the IPSS-R for further score development since clinicians do not need to use different scoring systems for different MDS subtypes. While the final analyses for the development of a tMDS specific risk score are currently under way, extensive calculations regarding the performance of different scores like WHO- (Dxy 0.24), FAB-classification (Dxy 0.19), WPSS-R (Dxy 0.35), IPSS-R (Dxy 0.37), and IPSS-R+age (Dxy 0.36), show all these systems can separate different risk groups within our cohort. However, these results also show an inferior performance of the scoring systems in t compared to pMDS. There are multiple possible reasons for this. The most important seem to be tMDS patients are often not cured from the primary disease and its disease specific risk of death should ideally be considered. Unfortunately, we don't have that data. And second, we included treated as well as untreated patients. It seems not to be feasible otherwise since the selection bias for old unfit patients would be unacceptable. We could show already in pMDS that the score performances are considerably worse if we analyze treated patients and the score performance in our cohort is better if limited to untreated patients. To conclude, we can say existing classification and scoring systems work in tMDS and can separate groups with clearly different risk for death and transformation. Although we could not develop a tMDS specific cytogenetic score this could be seen positively since it underlines tMDS do not seem to be much different regarding disease specific risk. This should initiate a discussion of a revision of the WHO-classification and encourage clinicians to use the existing tools for risk assessment and treatment decisions. A simple solution could be to use the WHO classification for pMDS and precede each subgroup with a t, like tMDS-SLD, and so on. Such an approach would be of importance for patients falsely classified as tMDS. After all this classification is done according to anamnestic information only and sporadic cases cannot be excluded. Until now, in the first analyzes performed with the final tMDS-database, we did not find any indication that risk factors established in pMDS would lose or change their meaning in tMDS. Figure. Figure. Disclosures Komrokji: Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. List:Celgene: Research Funding. Roboz:Orsenix: Consultancy; Eisai: Consultancy; Novartis: Consultancy; Celltrion: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Janssen Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Argenx: Consultancy; Janssen Pharmaceuticals: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Daiichi Sankyo: Consultancy; Sandoz: Consultancy; Otsuka: Consultancy; Daiichi Sankyo: Consultancy; Eisai: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Novartis: Consultancy; Celltrion: Consultancy; Celgene Corporation: Consultancy; Cellectis: Research Funding; Orsenix: Consultancy; Aphivena Therapeutics: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; AbbVie: Consultancy; Bayer: Consultancy; Bayer: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy. Döhner:Jazz: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Pfizer: Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Celator: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Astellas: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Amgen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pfizer: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Valent:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Platzbecker:Celgene: Research Funding. Lübbert:TEVA: Other: Study drug; Celgene: Other: Travel Support; Cheplapharm: Other: Study drug; Janssen: Honoraria, Research Funding. Díez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Stauder:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva: Research Funding. Germing:Janssen: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Abstract: Introduction The LenaMain study is a prospective, randomized, open label, multicenter phase III trial which included 188 patients 3 months after first-line high dose treatment and autologous stem cell transplantation (NCT number: NCT00891384). Patients were equally randomized to receive either 25 (n = 94, arm A) or 5 mg (n = 94, arm B) lenalidomide maintenance until disease progression following a uniform 6 months of 25 mg lenalidomide consolidation. Final analysis after follow-up of 46.7 months was presented at ASCO 2018 (#8016) demonstrating an extended event-free survival for arm A (11.8 months, p=0.032) and an about 10% increase of grade 3/4 infections per year as main toxicity. Here we report analysis of quality of life (QoL) data as secondary endpoint of the study. Materials & Methods The EORTC Quality of Life Questionnaire C30 (QLQ-C30) was collected at baseline and then monthly at every new cycle. The Global Health Status/Quality of Life (GHS/QoL) scale, the utility score and seven subscales (fatigue, nausea and vomiting, pain, physical functioning, role functioning, disease symptoms, and adverse effects of treatment) were compared between groups using a mixed model for repeated measures. Results Baseline questionnaire compliance was excellent (95.7%) and declined over time (82%, 76%, 71%, 54%, 49% after consolidation and after year 1, 2, 3 and 4 of maintenance, respectively). At baseline, GHS/QoL (67/67) and utility (0.73/0.72) scores for arm A/B were generally high and did not differ between both arms. The median GHS/QoL change between consolidation baseline and maintenance baseline was -1%. GHS/QoL scores appear constant for both treatment arms at most time points in the first 2 years of maintenance. Relevant improvements ≥ 5 points were observed in 30% of patients while improvements ≥ 15 points were observed in 20% of patients. During the same time a similar percentage of patients had relevant ≥ 5 and ≥15 point deteriorations, with a general tendency for a slight increase at the end of year 2. Notably, a greater number of deteriorations was found in the 5 mg lenalidomide arm. Mean GHS/QoL was constant during maintenance with a slight decrease of 〈 2 over the 1st year, reaching borderline relevance after the 2nd year with a mean change of -6 which was mainly driven by the 5 mg lenalidomide treatment arm (25 mg arm: -4 vs. 5 mg arm: -8). Utility values remained constant during maintenance (change from baseline 0.003, p=0.9 at year 1; 0.02, p=0.7 at year 2) and the overall pattern in the change over time does not appear to show any clear differences between the two treatment arms. Looking at QLQ-C30 subgroup domains after two years of maintenance, we observed a significantly higher change from baseline for diarrhea in the 25 mg lenalidomide arm, which may be a long-term drug-related effect. Conversely, role functioning was also significantly better in patients treated within the 25 mg lenalidomide arm. Other subgroups did not show significant differences after the second year. Overall GHS/QOL scores were not significantly different in patients with CR vs. ≥ vgPR. Similarly, there was no statistical difference in patients on treatment for 1, 2, 3 or 4 years of maintenance or in patients suffering from grade 3/4 adverse events or not. Thus, neither disease activity, nor duration of treatment nor high-grade toxicity biased our results. Conclusion The LenaMain trial shows that maintenance treatment with 25 mg lenalidomide vs. 5 mg significantly prolongs event-free survival. QoL, as secondary objective, was not different between both treatment arms, even showing a trend for improved QoL in the 25 mg lenalidomide treatment arm. Thus, QoL was not governed by the higher rate of infectious toxicity during high-dose lenalidomide maintenance. Disclosures Boquoi: Amgen: Honoraria, Other: Travel grant; Bristol-Myers Squibb: Honoraria; Janssen: Other: Travel grant; Celgene: Other: Travel grant. Goldschmidt:Celgene: Consultancy, Honoraria, Research Funding; Chugai: Honoraria, Research Funding; ArtTempi: Honoraria; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy. Rummel:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria; Celgene: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Symbio: Honoraria. Kroeger:Sanofi: Honoraria; JAZZ: Honoraria; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding. Mai:Celgene: Other: travel grant; Janssen: Honoraria, Other: Travel grant; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grant, Research Funding; Onyx: Other: travel grant; Mundipharma: Other: travel grant. Kobbe:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Fenk:Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Other: Travel grant, Research Funding; Bristol-Meyers Squibb: Honoraria, Other: travel grant; Janssen: Honoraria.

Abstract: In the current WHO classification patients (pts) with therapy-associated MDS are merged into a subgroup of AML, termed “AML with MDS, therapy-related”, regardless of dysplastic features, medullary blast count or cytogenetics. To validate the appropriateness of this approach, we combined the MDS/AML data sets of the Duesseldorf as well as the Goettingen data base. We identified 305 pts with t-MDS or t-AML. There were 138 males and 167 females, median age was 64 (22–90). When classified according to the WHO proposals for primary MDS (pMDS), 38% of the pts had AML (28% blast count & gt;30%, 10% blast count 20–30% (RAEB-T)), 10% had RAEB II, 8% RAEB I, 2% CMML II, 3% CMML I, 6% RA, 1.5% RARS, 20% RCMD, 11% RCMD-RS and 0.5% had 5q- Syndrome. 60% of pts had received chemotherapy only, 12% radiotherapy, and 28% underwent combined radiochemotherapy prior to t-MDS/AML diagnosis. The median latency between treatment and diagnosis was 116 months in pts who received radiotherapy as compared to 81 months in pts treated with chemotherapy alone or in combination with radiation (p= 0.0005). Cytogenetics were available in 192 pts (63%). 58% had an abnormal karyotype, the median number of aberrant chromosomes was 2 (0–12). The most frequent aberrant chromosome was chromosome 5 (18%), followed by 7 (14%), 20 (7%) and 17 (7%). 48% of the pts had a low-risk, 18% an intermediate-risk, and 33% a high-risk karyotype according to IPSS. Median survival of the entire group was 10 months compared to 26 months in pMDS in our registry (p=0.00005). Important prognostic parameters for pMDS, like age, hemoglobin level, platelet count, neutrophile count, as well as classification and scoring systems (FAB, WHO, IPSS) could not show an impact on outcome in t-MDS/AML. Pts with & lt;5% medullary blasts had a median survival of 16 months, with 5–9% of 8 months, with 10–19% of 8 months, with 20–29% of 6 months and pts with a blast count & gt;30% had a median survival of 12months (p=n.s.). When we compared pts with a medullary blast count & lt;5 vs ≥5 months the survival difference (15 vs 7 months) became significant (p=0,013). Pts with an elevated LDH level had a median survival of 7 as compared to 17 months in pts with normal LDH (p=0.0006). The karyotype subgroups (IPSS) showed significant survival differences between each of the groups: low-risk -34 months, intermediate-risk -25 months, high-risk -8 months. In a multivariate analysis only karyotype (p=0,011) and LDH level (p=0,014) remained independent prognostic parameters (blast count: p=0,961). These two variables can be combined in a score: LDH elevated= 1 point, high-risk karyotype= 1 point. This score leads to 3 subgroups (0, 1, or 2 points) with a significantly different prognosis of 42, 15, and 7 months (p=0,01). Our analysis shows that there is no substantial difference in survival between t-MDS and t-AML, justifying the combination of both entities in one AML subgroup. Current morphology based classification systems offer no prognostic information. On the other hand the established karyotype classification according to IPSS remains relevant for prognosis and combining this information with the LDH level leads to a simple score that is able to separate prognostically different risk-groups and thus should be validated further. 0%