Abstract: Background In myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) achievement of complete remission (CR) is a prerequisite for potential cure. In AML, CR/CR with incomplete recovery (CRi) is deemed the major outcome associated with improved overall survival (OS); patients (pts) without CR/CRi are considered non-responders, and hematologic improvement (HI) without (assessment of) bone marrow (BM) blast clearance is considered treatment (trt) failure. Achievement of CR may not be necessary for prolonged OS in pts treated with azacitidine (AZA) (Pleyer L, Annals Hematol 2014, 1825; Schuh AC, ASH 2015, P575). Outside of clinical trials, BM evaluations (BME) are only performed in ~50% of pts (Dinmohamed, Leuk Res 2015, 177) when either response or progression are obvious from peripheral blood (PB) values, or when pts are unable or unwilling to have BME. Aims To assess of the impact of response type on AZA trt outcomes in multivariate adjusted analyses (MVA). Methods 1441 pts included in the Austrian Azacitidine Registry were analyzed (NCT01595295). Data cut-off was 1 July 21. Marrow response was assessed for MDS/CMML and AML at each BME; HI was assessed on day 1 of each AZA cycle (Döhner H, Blood 2017, 424; Cheson BD, Blood 2006, 419; Pleyer L, ASH 2019, P3821); peripheral blood complete remission (PB-CR) was defined as hemoglobin ³11 g/dL, platelet count ≥100 G/L, neutrophil count ³1.0 G/L, white blood cell count & lt;15 G/L, PB blasts =0%, and no transfusions. Response types were calculated from electronic case report form data. To identify which response type achieved by which AZA cycle had the highest impact on time-to-event endpoints, likelihood ratios (LR) of the Cox-regression model for OS or time to next treatment (TTNT) were calculated using the respective response types as covariates. Baseline characteristics with univariate p & lt;0·10 (n=23) for association with OS were included in the multivariate regression. After stepwise selection n=17 variables remained and were used for MVA. Assign Data Management and Biostatistics GmbH performed statistical analyses with SAS® 9.4. Results In total, 521, 135, and 785 pts had MDS, CMML and AML. Median year of initial diagnosis was 2012, median time to AZA start was 3·0 (IQR 1·0-13·2) months (mo), median follow-up time from AZA start was 10.6 (IQR 4·0-21·1) mo, 894 pts received AZA as first line trt, median age at AZA start was 73 (range 23-99) years. In total, 13956 AZA cycles were applied, median duration of AZA trt was 5·0 (IQR 1·9-12·1) mo, median AZA dose was 875 (IQR 700-1000) mg/cycle, AZA was applied for a median of 7 (IQR 5-7) days. Median time to best response was 3·7 (IQR 2·0-5·9) months. Early mortality was 5.5% within 30 days. During AZA trt 1225 BM evaluations (BME) were performed in 697 (48·4%) of pts. Of these, 204 achieved CR/CRi. Irrespective of BME, 622 (43%) of 1441 pts achieved an HI and 264 (18·3%) of 1441 pts achieved a PB-CR. Pts achieving CR had longer adjusted OS (23·7 vs 19·7 mo, p=0·0227; HR=0·621 [0·413-0·936]) and TTNT (19·4 vs 15·7 mo, p=0·0262; HR=0·644 [0·436-0·949] ) than pts achieving CRi. Among pts achieving CR, those additionally achieving PB-CR had longer adjusted OS (24·8 vs 16·3; p=0·0040; HR=0·256 [0·101-0·647]; Fig 1A) and TTNT (21·2 vs 11·0; p=0·0005; HR=0·219 [0·094-0·513] ; Fig 1B) than those who did not. Among pts not achieving CR, those additionally achieving PB-CR had longer adjusted OS (20·8 vs 14·1; p & lt;0·0001; HR=0·510 [0·397-0·657]; Fig 1A) and TTNT (17·7 vs 10·9; p & lt;0·0001; HR=0·485 [0·357-0·589]; Fig 1B) than those who did not. Among all pts, irrespective of BM blast count, achievement of PB-CR resulted in longer adjusted OS (21·7 vs 10·0 mo; p & lt;·0001; HR 0·363; Fig 1C) and TTNT (18.5 vs 7.8 mo; p & lt;0.0001; HR=0.346; Fig 1D) and provided added value to CR and CR/CRi. Among all response types and after MVA, the highest prognostic impact on both OS and TTNT was observed when achieving PB-CR or CR/CRi by cycle 9 or 10 (Fig 2A-B). Conclusions Above data indicate that achievement of PB-CR is a strong predictor of OS and TTNT that provides additional information to current response criteria. Inclusion of PB-CR in updated response criteria of pts with MDS, CMML or AML receiving non-intensive trt should be considered. The greatest advantage of PB-CR is that it can be easily, nearly painlessly and quickly assessed. Inclusion of PB-CR as an endpoint in clinical trials would be desirable for validation of these results. Figure 1 Figure 1. Disclosures Pleyer: AbbVie, BMS, Novartis: Honoraria, Other: Travel Sport. Pfeilstocker: BMS: Honoraria. Stauder: Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heibl: BMS: Honoraria. Sill: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hartmann: Celgene, Amgene, Janssen, AbbVie: Honoraria. Petzer: Kite-Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Saegen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Celgene-BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees. Geissler: BMS: Honoraria. Sperr: AbbVie, BMS-Celgene, Daiichi Sankyo, Deciphera, Incyte, Jazz, Novartis, Pfizer, StemLine, Thermo Fisher: Honoraria, Research Funding. Leisch: Honoraria from BMS, Celgene, Gilead, Takeda and Novartis; Travel support: Celgene and Novartis: Honoraria, Other: Travel support. Melchardt: Abbvie, Celgene, Novartis: Honoraria. Zebisch: Novartis: Consultancy; AbbVie: Consultancy; Celgene: Consultancy, Honoraria. Machherndl-Spandl: AbbVie, Celgene, BMS, Pfizer: Honoraria. Wolf: Roche: Honoraria, Research Funding; MSD: Honoraria, Research Funding; BMS-Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Gilead: Honoraria; Incyte: Honoraria; GEMOAB: Honoraria. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. OffLabel Disclosure: Azacitidine is approved for all types of MDS and CMML as well as low blast count AML by FDA, but not for all subtypes of MDS and CMML by EMA.

Abstract: Background The EuroQuol 5 Dimension (EQ5D) is a validated tool to assess health-related quality of life (HRQoL). The International Prognostic Scoring System (IPSS) and the revised IPSS (R-IPSS) are the gold standards of prognostication in patients (pts) with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and low blast count acute myeloid leukemia (AML). The EQ5D is the most used tool for patient reported outcome measures but is underused in MDS, CMML or AML, with only one report on the use of the updated 5 level (5L) published to date (Yu H, Qual Life Res 2021, 855). Aims 1) Compare HRQoL of pts with MDS, CMML or AML with a German population norm (Grochtdreis T, Eur J Health Econ 2019, 933) matched by age, sex and no. of comorbidities. 2) Assess the impact of baseline HRQoL on azacitidine (AZA) treatment (trt) outcomes. 3) Longitudinal analyses of EQ-5D/lab value pairs per AZA cycle. Methods Pts treated within the Austrian Azacitidine Registry were analyzed (NCT01595295, data cut-off 13 Dec 20). EQ5D and lab values were assessed at the start of AZA trt cycles. The EQ5D-5L German value set (Ludwig K, Pharmacoeconomics 2018, 663) and the reverse crosswalk tool provided by EuroQol were used for calculation of the EQ5D-index. Baseline characteristics with univariate p & lt;0.10 (n=10) for association with OS were included in the multivariate (MV) regression. After stepwise selection, 6 variables remained and were used for MV adjustment (MVA). Outcome endpoints were overall survival (OS), time with clinical benefit (TCB) and time to next treatment (TTNT). Assign Data Management and Biostatistics GmbH performed statistical analyses with SAS® 9.4 Results 1456 EQ5D (n=225 3L; n=1231 5L) questionnaires were analyzed; 129, 33 and 110 of 272 pts had MDS, CMML or AML. Pts reported more pronounced restrictions in usual activities (+28%, p & lt;·0001), anxiety/depression (+21%, & lt;·0001), selfcare (+18%, p & lt;·0001) and mobility (+15%, p & lt;·0001), as well as lower mean EQ5D-5L indices (0·81 vs 0·88, p & lt;·0001) and lower self-rated health on a visual analogue scale (VAS) (64 vs 72%, p & lt;·0001) than a matched reference population. Pts with an EQ5D available at AZA start (n=205) were stratified according to their Level Sum Score (LSS), EQ-VAS or EQ5D-index being & lt;/≥ the respective group median. After MVA, the EQ5D-index remained significant for OS (+5·0 mo; p=0·0143; HR=1·52 [1·09-2·13]), TCB (+3·0 mo; p=0·0258; HR=1·43 [1·04-1·95] ) and TTNT (+3·0 mo; p=0·0332; HR=1·42 [1·03-1·96]) (Fig 1). Thus, an EQ5D-index & lt;0·8845 at AZA start indicates an increased risk of death (+52%), shorter AZA trt duration (+43%) and a higher risk of requiring a next trt or dying (+42%) in MV adjusted analyses. In univariate logistic regression, LSS (p·0009), EQ-VAS (p=0·0237) and EQ5D-index (p=0·0110) were correlated with response to AZA. After MVA, LSS remained significantly predictive of AZA response (p=0·0160; odds ratio (OR)=0·451 [0·235-0·852]), and the EQ5D-index showed a trend (p=0·0627; OR=0·522 [0·296-1·032] ). A LSS of ≥8 at AZA start thus indicates a 0·45 times lower odds of responding to AZA. Increases of the likelihood ratio (LR) were observed after addition of 1) LSS to the IPSS (p=0·0068) or R-IPSS (p=0·0205); 2) EQ-VAS to the IPSS (p=0·0031) or R-IPSS (p=0·0058); 3) EQ5D-index to the IPSS (p=0·0015) or R-IPSS (p=0·0012), indicating that they provide added value to the IPSS and the R-IPSS. Up to 1432 "EQ5D response/clinical parameter" pairs revealed that hemoglobin level, platelet count, transfusion dependence, serum ferritin, creatinine, albumin, adverse events G3-4, AZA days and dose per cycle and hematologic improvement in erythrocytes and platelets significantly correlated with ≥5 of 8 EQ5D parameters. Conclusions These data indicate for the first time that: 1) Patients with MDS, CMML or AML have profound impairments in HRQoL compared to a German population norm. 2) Baseline EQ5D-index predicts adjusted OS, TCB and TTNT. 3) Baseline LSS significantly predicts response to AZA. 4) Baseline LSS, EQ-VAS and EQ5D-index significantly add value to the existing gold standards for prognostication (IPSS, R-IPSS). 5) EQ5D responses during AZA trt correlated significantly with lab values associated with response, toxicity and AZA dose and no. of trt days per cycle. Based on these results, we will continue to use the EQ5D-5L and recommend the longitudinal use of this brief questionnaire in both clinical trial- and real-world settings. Figure 1 Figure 1. Disclosures Pleyer: AbbVie, BMS, Novartis: Honoraria, Other: Travel support. Heibl: BMS: Honoraria. Leisch: Honoraria from BMS, Celgene, Gilead, Takeda and Novartis; Travel support: Celgene and Novartis: Honoraria, Other: Travel support. Melchardt: Abbvie, Celgene, Novartis: Honoraria. Wolf: Roche: Honoraria, Research Funding; MSD: Honoraria, Research Funding; BMS-Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; Gilead: Honoraria; Incyte: Honoraria; GEMOAB: Honoraria. Greil: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Stauder: Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: While azacitidine is approved for all patients with MDS, CMML and AML by the US FDA, it is not approved for all patients subsets by EMA.

Abstract: Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% ( n  = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.

Abstract: Chronic myeloid leukemia (CML) is usually diagnosed in chronic phase, yet there is a small percentage of patients that is diagnosed in accelerated phase or blast crisis. Due to this rarity, little is known about the prognosis of these patients. Our aim was to identify prognostic factors for this cohort. We identified 283 patients in the EUTOS population‐based and out‐study registries that were diagnosed in advanced phase. Nearly all patients were treated with tyrosine kinase inhibitors. Median survival in this heterogeneous cohort was 8.2 years. When comparing patients with more than 30% blasts to those with 20‐29% blasts, the hazard ratio (HR) was 1.32 (95%‐confidence interval (CI): [0.7‐2.6]). Patients with 20‐29% blasts had a significantly higher risk than patients with less than 20% blasts (HR: 2.24, 95%‐CI: [1.2‐4.0] , P = .008). We found that the blast count was the most important prognostic factor; however, age, hemoglobin, basophils and other chromosomal aberrations should be considered as well. The ELTS score was able to define two groups (high risk vs non‐high risk) with an HR of 3.01 (95%‐CI: [1.81‐5.00], P 〈  .001). Regarding the contrasting definitions of blast crisis, our data clearly supported the 20% cut‐off over the 30% cut‐off in this cohort. Based on our results, we conclude that a one‐phase rather than a two‐phase categorization of de novo advanced phase CML patients is appropriate.

Abstract: The current gold standard of response assessment in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) is morphologic complete remission (CR) and CR with incomplete count recovery (CRi), both of which require an invasive BM evaluation. Outside of clinical trials, BM evaluations are only performed in ~50% of patients during follow‐up, pinpointing a clinical need for response endpoints that do not necessitate BM assessments. We define and validate a new response type termed “peripheral blood complete remission” (PB‐CR) that can be determined from the differential blood count and clinical parameters without necessitating a BM assessment. We compared the predictive value of PB‐CR with morphologic CR/CRi in 1441 non‐selected, consecutive patients diagnosed with MDS ( n  = 522; 36.2%), CMML ( n  = 132; 9.2%), or AML ( n  = 787; 54.6%), included within the Austrian Myeloid Registry (aMYELOIDr; NCT04438889). Time‐to‐event analyses were adjusted for 17 covariates remaining in the final Cox proportional hazards (CPH) model. DeepSurv, a CPH neural network model, and permutation‐based feature importance were used to validate results. 1441 patients were included. Adjusted median overall survival for patients achieving PB‐CR was 22.8 months (95%CI 18.9–26.2) versus 10.4 months (95%CI 9.7–11.2) for those who did not; HR = 0.366 (95%CI 0.303–0.441; p   〈  .0001). Among patients achieving CR, those additionally achieving PB‐CR had a median adjusted OS of 32.6 months (95%CI 26.2–49.2) versus 21.7 months (95%CI 16.9–27.7; HR = 0.400 [95%CI 0.190–0.844; p  = .0161]) for those who did not. Our deep neural network analysis‐based findings from a large, prospective cohort study indicate that BM evaluations solely for the purpose of identifying CR/CRi can be omitted.

Abstract: Background: BM are generally associated with poor prognosis and with neurological impairments making BM a major limitation of life expectancy and quality of life in MBC. Real-world data are needed in order to quantify and better characterize this special clinical situation. Here, we present data from the MBC registry of the Austrian Study Group for Medical Tumor Therapy (AGMT-MBC-Registry). Methods: The AGMT-MBC-Registry is an ongoing multicenter registry for MBC patients in Austria. Patients with available hormone receptor and HER2 status and sufficient outcome data were included in this analysis. Unadjusted, univariate overall survival (OS) probabilities were calculated by the Kaplan-Meier method and compared by the log-rank test; multivariable adjusted hazard ratios (HR) were estimated by Cox regression models. HR were estimated with diagnosis of BM as time-dependent variable. Logistic regression was performed to investigate the probability of developing BM. Multivariable analyses included the following parameters: breast cancer subtype (luminal-like vs. HER2+ vs. TNBC), age at diagnosis of metastatic disease (continuous, in Cox regression as interaction with menopausal status), DFS (de novo metastatic or ≥ 24 months vs. & lt; 24 months), visceral disease (yes vs. no) and number of metastatic sites (1 vs 2-3 vs. ≥4) at diagnosis of metastatic disease. Results: As of 15/04/2021, 2024 patients were included in the registry. Out of 1691 evaluable patients, 306 (18.1%) had documented BM. The incidence at diagnosis of metastatic disease and the overall incidence during the course of disease was significantly higher in HER2+ (9.5% [13/137] and 36.5% [50/137] ) and triple-negative tumors (11.9% [38/318] and 27.7% [88/318] ) compared to luminal-like tumors (3.3% [41/1236] and 13.6% [168/1236] ) (both P & lt;0.001). Besides subtype, ≥4 metastatic sites at diagnosis of metastatic disease and age were statistically significant associated with BM in logistic regression analysis.Median time to BM calculated from the date of diagnosis of metastatic disease was 11.3 months (95%CI 9.3-13.3) in the total population with BM, 12.7 months (95%CI 7.3-16.0) in HER2+, 5.2 months (95%CI 1.8-10.3) in triple-negative and 15.4 months (95%CI 8.4-19.5) in luminal disease, respectively. Interestingly, 13.7% of patients (42/306) had BM as first metastatic site without extracranial disease. The median number of systemic therapy-lines before and after diagnosis of BM was 1 (range 0-8) and 1 (range 0-10), respectively. Most of the patients with BM (80.1%) received radiotherapy; 12.7% focal radiotherapy, 69.8% whole brain irradiation and 9.0% both types of radiotherapy (8.5% unknown). After a median follow-up of 72.3 months (95%-CI 68.6-80.0), patients with BM had a significantly shorter median OS (7.5 months) compared to patients without BM (38.4 months) both in univariate (HR 3.58; 95%CI 3.11-4.11; P & lt;.001) and multivariable analysis (HR 3.70; 95%CI 3.18-4.32; P & lt;.001). OS in patients with BM differed significantly between the three breast cancer subtypes with a median OS of 36.3 months (95%CI 30.5-47.9), 33.5 months (95%CI 22.9-45.5) and 13.2 months (95%CI 11.1-18.4) in luminal, HER2+ and TNBC, respectively (overall log-rank P & lt;0.001). Similarly, the time from diagnosis of BM and death was significantly shorter in TNBC (4.1 months; 95%CI 3.4-6.3) compared to luminal (9.7 months; 95%CI 6.8-13.7) and HER2+ breast cancer (10.7 months; 95%CI 9.1-26.2) (overall log-rank P & lt;0.001). Conclusion: Almost 20% of patients with MBC develop BM during their course of disease, with a higher incidence in HER2+ and triple-negative disease. Besides effective prevention strategies improved systemic and local therapies are needed to minimize morbidity and improve outcome in these patients. Citation Format: Simon Peter Gampenrieder, Gabriel Rinnerthaler, Christoph Tinchon, Andreas Petzer, Marij Balic, Sonja Heibl, August F Zabernigg, Daniel Egle, Margit Sandholzer, Florian Roitner, Johannes Andel, Petra Pichler, Christopher Hager, Michael Knauer, Michael Hubalek, Christian F Singer, Richard Greil. Brain metastases (BM) from breast cancer: Real-word data from the Austrian AGMT_MBC-registry [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-08.

Abstract: In older patients with chronic myelomonocytic leukaemia (CMML) and limited life expectancy due to age and or comorbidities, it is particularly important to consider the risk of transformation for individualised treatment decisions. There is limited information on potential differences between younger and older CMML patients regarding the cumulative risk of transformation as well as haematological, molecular and biologic characteristics. We analysed data from the Austrian Biodatabase for CMML (ABCMML) to compare these parameters in 518 CMML patients. Categorisation of patients into 3 age‐related groups: 〈 60 years, 60‐79 years and ≥80 years, showed a significantly lower risk of transformation at higher age by competing risk analysis, with a 4‐year risk of 39%, 23% and 13%, respectively ( P   〈  .0001). The lower probability of transformation was associated with a lower percentage of blast cells in the peripheral blood (PB) of older patients. Furthermore, we provide a simple score based on age, PB blasts and platelet counts that allowed us to define subgroups of CMML patients with a different cumulative transformation risk, including a low‐risk group with a transformation risk of only 5%. Our findings may facilitate reasonable treatment decisions in elderly patients with CMML.

Abstract: Introduction. Mutations in genes encoding the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and 2 are found in 10-20% of patients with acute myeloid leukemia (AML). Recently, IDH inhibitors have shown good clinical response in patient's refractory to standard treatments, providing evidence for a new treatment paradigm. Comprehensive real-world studies are needed to explore genotype-to-phenotype correlations and prognosis of IDH mutated AML, which may influence targeted treatment strategies. Patients. From a retrospective, European, real-word population (ClinicalTrials.gov Identifier: NCT04369287) we studied 477 IDH mutated patients and 954 IDH wild type patients matched for age, sex and type of treatment with a 1:2 ratio. Results. Median age of IDH mutated patients was 67 years; IDH1 mutations were found in 202 patients (89% carried R132 mutation), while IDH2 mutations were found in 275 cases (51% and 28% carried R140 and R172 mutations, respectively). At diagnosis, IDH mutated patients had lower neutrophil and higher platelet count and higher percentage of marrow blasts (P & lt;0.001). IDH mutations were more frequently observed in de novo AML vs. AML from previous myeloid malignancy (P=0.043). Considering cytogenetic risk according to ELN criteria, the great majority of IDH1 and IDH2 mutated patients had an intermediate cytogenetic risk (84% and 86%, respectively, P & lt;.001, most of them showing a normal karyotype). Considering IDH1 vs. IDH2 mutated population, deletion of chromosome 7 was more frequently reported in IDH2 mutated patients (P=.001). We then analysed the most common co-mutational patterns in IDH mutated patients. A total of 53% of IDH1 mutated patients carried NPM1 mutations (without FLT3 mutations), while the majority of IDH2 mutated patients had wild type NPM1 gene (P & lt;.001). IDH2 mutated patients more frequently presented with co-mutation in FLT3 gene (P & lt;.001); among IDH2/FLT3 co-mutated patients, the great majority of cases carried the R140 mutation (P & lt;.001). ASXL1 mutations were also more frequently associated with IDH2 mutations (P=.029). Most patients with CEBPA biallelic mutations carried IDH1 or 2 mutations (66%, P=.01), while core binding factor translocations, and mutations in TP53 and RUNX1 were rarely associated with IDH1 or 2 mutations. Median overall survival from diagnosis (OS) was 14 months for IDH1 mutated patients, 23 for IDH2 mutated patients and 19 for IDH wild type patients (P & lt;.001, figure 1); the independent negative effect on OS for IDH1 mutations was confirmed in a multivariable analysis on the whole study population including age, sex, ELN risk group, and type of treatment as covariates (HR was 1.65 vs. wild type population and 1.36 vs. IDH2 mutated patients, P & lt;.001), as well as in a specific analysis focused on patients belonging to intermediate ELN risk category (HR 1.75 vs. wild type population, P & lt;.001). Focusing on different mutational hotspots, survival analysis confirmed that IDH1 R132 mutation was associated with worse prognosis among IDH mutated patients (P & lt;.001). Moreover, we observed a reduced relapse-free survival (RFS) for both IDH1 and 2 mutated patients vs. wild type patients (P & lt;.001, figure 1). Multivariable analysis confirmed worse RFS for IDH1 and 2 patients vs. wild type patients (HR 3.8 and 1.4, respectively, P & lt;.001), as well as for IDH1 vs. IDH2 mutated patients (HR 1.5, P & lt;.001). IDH mutated patients receiving hypomethylating agents (n=211) had a lower response rate vs. wild type patients (56% vs. 36% of treatment failure, respectively, P=.04), while no significant different probability of response to intensive chemotherapy was noticed. In patients who received allogeneic transplantation (n=345), IDH1 mutated patients shower higher relapse rate vs. wild type and IDH2 mutated patients (53% vs. 34%, P & lt;.001). Conclusion. In a real world context, AML patients with IDH1 and 2 mutations have high marrow blasts percentage, frequently present normal karyotype and show specific co-mutational patterns with respect to NPM1, FLT3 and ASXL1 genes. IDH1 mutations were an independent predictor of unfavorable outcome with high rate of disease recurrence under currently available treatment options, and could be considered as an additional marker to improve personalized prognostic assessment within ELN risk groups. Dissection of prognosis of IDH mutated AML may influence targeted treatment strategies in clinical practice. Disclosures Voso: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Heibl:Takeda: Honoraria; AOP orphan: Consultancy, Honoraria, Research Funding; BMS/celgene: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria. Metzeler:Astellas: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharma: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding. Thiede:AgenDix GmbH: Other: Co-owner and CEO. Fracchiolla:ABBVIE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses, Speakers Bureau. Todisco:Jannsen, Abbvie, Jazz: Membership on an entity's Board of Directors or advisory committees. Passamonti:Novartis: Speakers Bureau; BMS: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support.

Abstract: Background: Patients with diffuse large B-cell lymphoma (DLBCL) relapsing early (within 12 months) or primary refractory to induction therapy with rituximab (R) and CHOP have a poor prognosis with a median overall survival (OS) of less than 2 years. Relapse immuno-chemotherapy followed by autologous stem cell transplantation is the standard of care, but response rates are still not satisfactory and a substantial number of patients are ineligible for transplant or aggressive therapies. Novel antibodies, small molecules and CAR-T cell therapies have been explored for this population. We initiated a study with obinutuzumab and venetoclax to evaluate the effect of a chemo-free regimen in these refractory or early relapsing DLBCL patients with the option to prepare these patients for cell therapy. Study design and Methods: Twenty-one patients with DLBCL (relapsed within 12 months or primary refractory), detectable Bcl-2 protein expression and CD20 positivity were included in this prospective, Fleming-design Phase II single-arm study. Obinutuzumab was given i.v. at a dose of 1000 mg on days 1, 8, 15 in cycle 1 and on day 1 of each following 21-day cycles. Venetoclax was given at 800mg daily p.o. Treatment was repeated for up to 3 cycles. Eligible patients were planned to either proceed to stem cell transplantation or receive up to 9 cycles of maintenance if ineligible for transplant. The primary endpoint was objective response rate by Lugano 2014 criteria after 3 cycles (investigator assessed). Secondary objectives included dose-limiting toxicities, response duration, progression-free and overall survival and ability to proceed to further stem cell transplantation. A biomarker program investigated histopathologic, genomic and biological factors associated with outcome. The trial was registered under Eudract Nr. 2016-001760-10 andNCT02987400. Results: The ITT population consisted of 21 patients (median age 64 years, 9 M, 12F) with refractory or early relapsed DLBCL after 1 (N=11) to 4 previous lines of therapy. The majority of patients received 3 cycles of obinutuzumab-venetoclax (range 1-8). The regimen was well tolerated. No DLTs were observed. Adverse events were observed in 85.7% with gastrointestinal disorders and administration site conditions being most prominent. Cytopenias were reported in 23.8% and infections in 19%. Severe adverse events were observed in 19%. The objective response rate was 38.1% (8/21 patients) with a best response of 5 CR (23.8%) and 3 PR (14.2%). Response duration was 83.3% at 84 days, with a progression-free survival of 38.8% at 84 days and 25.9% at 168 days and an overall survival of 59.3% at 168 days. All deaths were due to underlying disease. Three of 6 responding patients eligible for transplant went on to ASCT, while 2 CR patients refused. Overall, 6 patients received ASCT and 3 patients anti-CD19 CAR-T cells. Three patients received further maintenance cycles. At final visit, 20% of patients were still in CR while 73.3% of patients had progressed. Overall the data indicate that this therapy creates a response period of approximately 3 months in responding patients. Progressive disease was treated with various regimens including chemo-immunotherapy, bispecific agents, antibody-drug conjugates, immunomodulators or small molecules. To date, 7 patients have died. Characteristics of responding patients include very good or good R-IPI as well as low number of previous therapies (median=1). BCL2 expression and genomic features are currently being analysed and will be presented at the meeting. Conclusion: Obinutuzumab and Venetoclax represents a chemo-free relapse regimen with low toxicity for DLBCL with the ability to induce objective responses in 38.1% of patients including complete remissions. Its potential to serve as a "window-of-opportunity", relapse- or bridging-treatment in preparation for stem cell or CAR-T cell therapies will be further increased by identification of clinical or biological predictors of response. Supported by a grant from Roche Austria. Disclosures Jaeger: F. Hoffmann-La Roche: Honoraria, Research Funding; Karyopharm: Honoraria; CDR Life AG: Consultancy, Research Funding; Miltenyi: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; BMS/Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Heibl:BMS/celgene: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria; AOP orphan: Consultancy, Honoraria, Research Funding; Takeda: Honoraria. Willenbacher:AbbVie: Honoraria; Roche: Honoraria. Erlsbacher:Assign Data Management and Biostatistics GmbH: Current Employment. Larcher-Senn:Assign Data Management and Biostatistics GmbH: Current Employment. Fridrik:Roche: Consultancy, Other; AbbVie: Consultancy, Other. Greil:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; MSD Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Daiichi Sankyo, Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; Astra zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding; BMS/celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accomodations, expenses, Research Funding.