Flow Cytometric Score Correlates with Clinical Response to Azacitidine In Intermediate-2 and High Risk Myelodysplastic Syndrome Patients

Abstract Abstract 441 New treatment strategies that potentially change the natural course of intermediate (int)-2 and high risk myelodysplastic syndromes (MDS), such as azacitidine, are emerging. Recently, we reported that flow cytometric analysis of bone marrow (BM) in low and int-1 risk MDS is instrumental to identify clinically relevant subgroups. (Westers et al, Blood 2010) Moreover, it was reported that a flow cytometric scoring system (FCSS) is predictive for worse outcome in MDS. (Wells et al, Blood 2003, van de Loosdrecht et al, Blood 2008) The FCSS is a scoring system that allows for a numerical display of immunophenotypic aberrancies in the (im)mature myelo-monocytic lineage. Scores are generated by enumerating abnormalities; e.g. high scores reflect a high number of aberrancies. The current study aimed to investigate the role of this flow cytometry-based scoring system to assess and monitor response to treatment in int-2 and high risk MDS patients treated with azacitidine. Bone marrow aspirates were analyzed by flow cytometry in 18 MDS patients who were treated with azacitidine. Aspirates were drawn before treatment and after every third cycle of azacitidine. Response to treatment was evaluated using IWG-2006 criteria. The median age was 71 (range 50–78). Distribution over WHO 2001 categories was RCMD-RS n=2, RAEB-2 n=7, AML with 20–30% blasts n=6 and MDS/MPD n=3. International prognostic scoring system (IPSS) categories comprised int-2 n=8 and high n=5. In 5 patients the IPSS score could not be assessed due to lack of cytogenetics, these patients were at least int-2 MDS patients. Flow cytometric follow up was available in 12 patients due to short follow up, i.e. in 4 responders, 4 progressive disease (PD) and 4 stable disease (SD) patients; 3 patients stopped due to non-hematologic toxicity, 4 patients died of PD. Median follow up was 7 months (range 3–12). Median pre-treatment Hb was 6.7 mmol/L, platelets 35.5*10e9/L and absolute neutrophil count (ANC) 0.82*10e9/L. Responders had a significant increase in Hb (median 7.8 mmol/L, p=0.04), platelets (291.5 *10e9/L, p=0.03) and ANC (1.4*10e9/L, p=n.s. compared with baseline values). SD and PD patients had a median Hb of 6.5 mmol/L, platelets 69*10e9/L and ANC 0.77*10e9/L. The median pre-treatment flow score was 6 (range 3–8). Interestingly, responders had a significant decrease in flow score from median 5 to median 2 (range 1–3, p=0.005) after 3 months of treatment. No change in flow scores was seen in PD and SD patients after 3 months of treatment (median=6, range 4–8 and pre-treatment FCSS median=6.5, range 3–8). A sustained decrease in flow score was seen in 4 responders after 6 months of treatment (median 2, range 1–3) parallel to a further increase in median Hb (9.0 mmol/L), platelets (278.5 *10e9/L) and ANC (1.7*10e9/L). After 9 cycles of azacitidine, 3 patients were still responsive to treatment (median Hb 9.9 mml/L, platelets 169, ANC 4.07, median flow score 5, range 2–4). The majority of SD and PD MDS patients had aberrant marker expression on myeloid progenitors, such as CD5, CD7 and/or CD56 compared with responsive MDS patients, (63% (5/8) vs 25% (1/4). Moreover, initial loss of aberrant marker expression on myeloid progenitors was detected in one patient who responded to azacitidine treatment. At 9 months, this initially responsive patient and a patient from the stable disease group developed progressive disease. Interestingly, the initially responsive patient showed an increase in the percentage of myeloid progenitors with an aberrant immunophenotype at 6 months; of note, the total percentage of CD34+ cells was less than 3% by flow cytometry. The initial loss of aberrant marker expression on myeloid progenitors might be caused by a relative increase of normal progenitors and decrease of malignant progenitors caused by azacitidine treatment. In conclusion, our data indicate that flow cytometry identifies MDS patients who may benefit from azacitidine treatment by detection of aberrant marker expression on myeloid progenitors. Moreover, the data indicate that the FCSS may be instrumental in selection of SD patients who may benefit from prolonged treatment with azacitidine. Disclosures: Ossenkoppele: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van de Loosdrecht:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Validation of a Flow Cytometric Scoring System for the Prognostication of the Myelodysplastic Syndromes: a Retrospective Cohort Study

Blood ◽

10.1182/blood.v116.21.4012.4012 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4012-4012

Author(s):

Canan Alhan ◽

Theresia M. Westers ◽

Claudia Cali ◽

Gert J. Ossenkoppele ◽

Arjan A. Van de Loosdrecht

Keyword(s):

Healthy Volunteers ◽

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Scoring System ◽

Research Funding ◽

Classification Systems ◽

Prognostic Information ◽

Advisory Committees ◽

Flow Cytometric ◽

Myeloid Progenitors

Abstract Abstract 4012 The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders, characterized by cytopenia(s), dysplasia and a propensity to evolve into acute myeloid leukemia. The International Prognostic Scoring System (IPSS) and WHO-based prognostic scoring system provide prognostic information. However, even if patients are allocated in the same risk category their clinical course remains heterogeneous. Recent developments in the treatment of MDS require refinement of prognostication and identification of patients who might benefit from treatment with potentially disease modifying agents such as lenalidomide or azacitidine. Flow cytometry (FC) is emerging as a valuable technique for the diagnosis and prognosis of MDS. Recently, we demonstrated that flow cytometric analysis of BM in low and int-1 risk MDS is instrumental to identify clinically relevant subgroups. (Westers et al, Blood 2010) Previously, it was reported that a flow cytometric scoring system (FCSS) is predictive for worse outcome in MDS. (Wells et al, Blood 2003, van de Loosdrecht et al, Blood 2008) The FCSS is a scoring system that allows for a numerical display of immunophenotypic aberrancies in the (im)mature myelo-monocytic lineage. Scores are generated by enumerating abnormalities; a high score reflects a high number of aberrancies. The current study aimed to validate the FCSS for identification of prognostic subgroups in MDS. We analyzed aberrancies in (im)mature myelo-monocytic cells by FC in BM of 102 MDS patients, including 48 MDS patients from the previous cohort. The diagnoses according to WHO 2001 classification were RA(RS) n=19, RCMD(RS) n=54, RAEB-1 n=11, RAEB-2 n=13, MDS-U n=5 and also age-matched healthy volunteers (n=39) were included. The median age of MDS patients was 66 and of healthy volunteers 57. The FCSS in RA(RS) (median=3, range 1–6) patients was significantly higher compared with healthy controls (median=1, range 0–2, p<0.001). In contrast to our previous results the FCSS for RA(RS) and RCMD(RS) patients did not differ. This is a remarkable finding, since by morphology RA(RS) patients have unilineage dysplasia, in contrast to flow cytometric findings, where 84% (16/19) of the RA(RS) patients had two or more aberrancies in the (im)mature myelomonocytic compartment. The FCSS was higher in RAEB-1 (median=6, range 2–7) and RAEB-2 (median=6, range 4–8) compared with RCMD(RS) (median=3, range 0–6, p=0.02 and p<0.0001, respectively). Overall, the FCSS correlated significantly with WHO 2001 classification (p<0.0001). The FCSS showed a significant correlation with IPSS categories low, int-1, int-2 and high (p<0.0001). Remarkably, the FCSS was not correlated with cytogenetic risk categories low, intermediate and poor. The new German-Austrian Cytogenetic Prognostic Scoring System for MDS was also not correlated with the FCSS. This indicates that the FCSS and cytogenetics might provide separate prognostic information in MDS. Neutrophil granularity corresponding with side scatter by FC was significantly decreased in MDS patients compared with healthy volunteers (p<0.0001). In the RA(RS) and RCMD(RS) category, 40% (29/73) of patients expressed an aberrant marker such as CD5, CD7 and/or CD56 on myeloid progenitors. Transfusion data was available of 51 patients. Interestingly, the majority of MDS patients who were transfusion dependent or progressive, had aberrant expression of CD5, CD7 and/or CD56 on myeloid progenitors compared with MDS patients without aberrant marker expression (64% (16/25) vs 31% (8/26), respectively p=0.04). When the cumulative amount of all aberrancies in the (im)mature myelo-moncytic cells were taken into account, transfusion dependent patients had significantly more aberrancies than transfusion independent MDS patients, (median 6.5 vs 4, respectively, p=0.006). In conclusion, we here confirmed our previous findings in a larger cohort. The majority of RA(RS) patients already has multilineage dysplasia as detected by FC, which might be of prognostic relevance. Although the FCSS correlates with current prognostic systems, a striking heterogeneity remains within prognostic subgroups. Therefore, the FCSS and detection of aberrant myeloid progenitors can provide refined prognostication by identification of patients at risk for transfusion dependency and adverse clinical outcome, independent of current classification systems. Disclosures: Ossenkoppele: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van de Loosdrecht:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Five Parameter Based Flow Cytometric Scoring System Refines the Revised International Prognostic Scoring System for Myelodysplastic Syndromes

Blood ◽

10.1182/blood.v120.21.3849.3849 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3849-3849

Author(s):

Canan Alhan ◽

Theresia M. Westers ◽

Eline M.P. Cremers ◽

Claudia Cali ◽

Gert J Ossenkoppele ◽

...

Keyword(s):

Flow Cytometry ◽

Multivariate Analysis ◽

Myelodysplastic Syndromes ◽

Scoring System ◽

Risk Group ◽

Myeloid Cells ◽

Low Risk ◽

Added Value ◽

Flow Cytometric ◽

Myeloid Progenitors

Abstract Abstract 3849 The International Prognostic Scoring System (IPSS) has found widespread application in the clinical practice of myelodysplastic syndromes (MDS) for estimation of prognosis and treatment decision making. Increasing knowledge on components that encompass the IPSS has led to the design of the revised IPSS (IPSS-R, Greenberg, Blood 2012). Furthermore, it was recognized that techniques such as flow cytometry and molecular analyses should be validated for their prognostic value in MDS; once proven the added value, they might be part of future prognostic scoring systems. Over the past years, flow cytometry based scoring systems have been proposed to refine prognostication of MDS (Wells, Blood 2003; Matarraz, Cytometry 2010). The aim of our study was to construct a simple and widely applicable hazard-adapted flow cytometry based scoring system for the prognosis of myelodysplastic syndromes and investigate whether it is of added value to the IPSS-R. Bone marrow of 96 patients with MDS was analyzed by flow cytometry. Patients were assigned to an IPSS-R category based on bone marrow blast count, cytogenetics and depth of cytopenias. Patients that received a hematopoietic stem cell transplantation or chemotherapy were censored from start of treatment. All samples were processed according to European LeukemiaNet guidelines (van de Loosdrecht, Haematologica 2009 and Leukemia 2012). Aberrancies with regard to count, expression level of markers and lineage infidelity marker expression on myeloid progenitors, B cell progenitors, maturing erythroid, monocytic and myeloid cells were analyzed. The optimal cut-off level per variable was determined based on significance and hazard ratio (HR) of overall survival (OS) and univariate analysis. In the second step, multivariate analysis was performed with the variables that had a p-value ≤0.1. The parameters that were most predictive of OS from multivariate analysis were increased CD45 expression of myeloid progenitors, asynchronous expression of CD11b on myeloid progenitors, percentage of CD34negCD117pos mature myeloid cells, percentage of mature myeloid cells with CD14 expression and CD45 expression on monocytes. In the next step, a flow cytometric scoring system based on these five parameters was constructed. Each variable was scored for in a weighed manner and the weight was determined by the size of the HR. From this a MDS flow cytometric scoring system (MFCS) was designed that identified four risk groups. i.e. patients with a normal flow score (0–0.5 points), low (1 point), intermediate (>1–2 points) and patients with a high score (>2–4.5 points). The MFCS identified patients with significantly different OS, normal score, median OS 60.6 months (range 0.6–198.6 months), vs. low score, median OS 26.8 months (range 2.5–89.2 months), vs. intermediate score, median OS 19.1 months (range 1.6–62.3 months), vs. high score, median OS 7.9 months (range 0.5–15.1 months), p<0.001. In concordance with the IPSS-R cohort, the largest number of patients was within the low risk group, 41.7% (40/96). Interestingly, within this IPSS-R risk group, the MFCS was able to identify prognostic subgroups. The median OS of IPSS-R low risk patients with a normal MFCS score was not reached, compared with low risk patients with a low MFCS, median OS 40.6 months (range 22.5–89.2 months) and compared with intermediate MFCS, median OS 19.1 months (range 12.5–43.6 months), p<0.001. In a multivariate analysis the MFCS combined with the IPSS-R were best predictive for OS rather than the scores alone (p=0.002 and p=<0.001, respectively). In conclusion, we designed a simple, five parameter MDS flow cytometric (MFCS) score based on hazard. The MFSC score was able to identify prognostic subgroups within a well defined IPSS-R risk group. Furthermore, the MFCS combined with the IPSS-R offered refined prognostication for MDS. This implies that flow cytometric analysis has an added value for prognostication and should be part of a prognostic scoring system for MDS. In a currently ongoing prospective multi center study, these new scoring models will be validated. Disclosures: Alhan: Celgene: Honoraria. Ossenkoppele:Celgene: Consultancy, Honoraria. van de Loosdrecht:Celgene: Consultancy, Honoraria.

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Next Generation Myelofibrosis Risk Analysis in the Electronic Health Record

Blood ◽

10.1182/blood-2018-99-113692 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3038-3038

Author(s):

Andrew Sochacki ◽

Cosmin Adrian Bejan ◽

Shilin Zhao ◽

Travis Spaulding ◽

Thomas Stricker ◽

...

Keyword(s):

High Risk ◽

Median Survival ◽

Scoring System ◽

Low Risk ◽

International Prognostic Scoring System ◽

Proportional Hazard ◽

Next Generation ◽

Advisory Committees ◽

Cox Proportional Hazard

Abstract Background: Myelofibrosis (MF) is a devastating myeloproliferative neoplasm that is hallmarked by marrow fibrosis, symptomatic extramedullary hematopoiesis, and risk of leukemic transformation, most commonly driven by janus kinase 2 (JAK2) pathway mutations. MF risk classification systems guide prognosis, decisions regarding allogeneic stem cell transplantation, and disease modifying agents. Key systems include the Dynamic International Prognostic Scoring System (DIPSS) 2009, DIPSS plus 2010, Genetics-Based Prognostic Scoring System (GPSS) 2014, and Mutation-Enhanced International Prognostic Scoring System (MIPSS) 2014. System contributions include dynamic scoring (DIPSS), cytogenetics (DIPSS Plus), and high risk molecular mutations (GPSS and MIPSS). To power the next generation of MF risk prognostication, and ascertain new prognostic factors, large scale electronic health record (EHR) and genomic data will need integration. As a proof of concept, we leveraged our de-identified research EHR (2.9 million records) and linked genomic biobank (288,000 patients) to develop an all-inclusive phenotype-genotype-prognostic system for MF and recapitulate DIPSS, DIPSS Plus, GPSS and MIPSS. Methods: Our previously described methods (Bejan et al. AACR 2018) utilized natural language processing to algorithmically identify 306 MF patients. A subset (N=125) had available DNA for genotyping. We automatically extracted: age greater than 65, leukocyte count (WBC) greater than 25x109/L, hemoglobin (Hgb) less than 10g/dL, platelets (PLT) less than 100 x 109/L, circulating myeloid blasts ≥ 1%, and 10% weight loss compared to baseline as a proxy for constitutional symptoms. Transfusion data was not included. Karyotype data was manually reviewed. Next generation sequencing (NGS) was performed on biobanked peripheral blood DNA with the Trusight Myeloid Panel (Illumina®). Genotyped samples were restricted to dates after MF diagnosis. Multivariate Cox proportional hazard analysis was performed on all clinical and genomic variables. DIPSS plus was calculated without adjustment but lacked transfusion data. DIPSS, GPSS and MIPSS scores were calculated by published methods. Results: Multivariate Cox proportional hazard regression identified Hgb (HR=6.4; P=0.006), myeloid blasts (HR=3.8; P=0.03), and ASXL1 (HR=5.2; P=0.02) as significant in our cohort with regard to overall survival (OS). We noted a strong trend for high risk karyotype (HR=5.6; P=0.07). Our DIPSS model median survival (N=120) for each subgroup; low risk (median survival not met), intermediate-1 (108 months), intermediate-2 (47 months) and high risk (6 months) P=0.0002 (Figure 1a). DIPSS Plus (N=122) integrated karyotype data and PLT count with similar survival with the exception of high risk (4 months) P=0.00003 (Figure 1b). The percentage of patients with driver mutations in JAK2V617F (57%), CALR (3%) and MPLW515 (7.2%); JAK2WT, CALRWT and MPLWT triple negative (34%); high molecular risk ASXL1 (15%), EZH2 (6%), IDH1/2 (7%), SRFS2 (17%); other variants of interest TET2 (9.6%), TP53 (29%) and DNMT3A (16.8%). MIPSS (N=125; 48 months follow up) noted low risk, intermediate-1, and intermediate-2 (median survival not met) and high risk (32 months) P=0.0001 (Figure 1c). GPSS (N=125; 48 months follow up) did not demonstrate statistical separation among groups (Figure 1d). Discussion: This proof of concept transformed raw EHR records into clinical risk scores for MF. The addition of retrospective DNA analysis via NGS opens the possibility of multi-institutional EHR-biobank studies to most accurately create a system to define MF risk. Our sample size limited the significance of age, PLTs, poor risk mutations and other variables previously shown to impact OS. Likewise, we lacked the capacity to track transfusion dependence, previously shown to have prognostic relevance. Still, prognostication via the EHR mimics common scoring systems in MF and supports correct MF case selection, accurate laboratory extraction and reproducible genotyping of biobanked samples. Similar to the original GPSS report, our low risk cohort was small (N=2) and will benefit from expansion of genotyping underway. Finally, this phenotype-genotype-prognostic paradigm represents a technical advance and a unique opportunity to deploy patient specific comorbidities from lifetime EHR records to further refine risk across all myeloid disease. Disclosures Savona: Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Novel Machine Learning-Derived Dynamic Scoring System Predicts Risk of Thrombosis in Polycythemia Vera (PV) Patients

Blood ◽

10.1182/blood-2021-149098 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3619-3619

Author(s):

Ghaith Abu-Zeinah ◽

Spencer Krichevsky ◽

Richard T. Silver ◽

Elwood Taylor ◽

Douglas Tremblay ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Scoring System ◽

Research Funding ◽

External Validation ◽

Risk Groups ◽

Advisory Committees ◽

Thrombosis Risk ◽

Dynamic Scoring

Abstract Introduction: Thrombosis remains a leading cause of morbidity and early mortality in PV. The European LeukemiaNet (ELN) classifies patients (pts) at diagnosis as high-risk according to age ≥60 years (yr) and/ or prior thrombosis, but dynamic models predicting short-term risk of initial or recurrent thrombosis are unavailable. We utilized machine learning (ML) to develop a dynamic scoring system that predicts thrombosis in PV pts using the most important of 60 clinicopathologic features. Methods: A Random Forests ML model was trained to classify instances (3-month follow-up intervals of PV pts) as predictive or non-predictive of thrombosis, arterial or venous, in subsequent 3-6 months based on 60 features: 4 demographic, 11 history & physical, 13 treatments, 18 laboratory, and 14 pathology and molecular. The dataset was derived from Weill Cornell Medicine (WCM) Research Database Repository as previously described (Abu-Zeinah et al. Leukemia 2021) and split into training (75%) and testing (25%) sets. Hyperparameter tuning was performed to optimize model training. Synthetic minority oversampling technique (SMOTE) was implemented to reduce class imbalance since instances predictive of thrombosis were a minority. Missing data were imputed using multiple imputation by chained equations (MICE). The scoring system was developed based on ML-derived features of highest importance and confirmed by logistic regression multivariable analysis (MVA). Cumulative incidence (CI) of thrombosis was compared between risk groups using Fine-Gray model. External validation of the ML model and scoring system is underway using the Mount Sinai School of Medicine (MSSM) PV dataset. Statistical analyses and plots were performed in RStudio software v 1.4.1106. Results: 470 PV pts at WCM were included with baseline features shown in Fig 1A. During follow-up, 159 thromboses (88 venous, 71 arterial) occurred in 115 pts. CI of thrombosis was significantly higher shortly after diagnosis, as previously appreciated (Hulcrantz et al. Ann Intern Med. 2018), and following a thrombotic event (Fig 1B-C). Bilinear fitting to CI curves identified a 2-yr breakpoint that marked the transition from a high to a much lower long-term risk after diagnosis (incidence rate (IR), per year, of 4.4% vs 1%, respectively) and after thrombosis (IR of 9.7% vs 1.8%). Of the ML model's top 10 features, 5 that independently predicted thrombosis in MVA were selected for a clinically convenient scoring system to estimate thrombosis risk (Fig 1D-E). One point was assigned for each of age ≥60 yr, prior thrombosis, WBC ≥12 x 10 9/L, peri-diagnosis (<2 yr from diagnosis), and peri-thrombosis (<2 yr from last thrombosis). Using this scoring system, we found that high-risk (Hi) and intermediate-risk (Int) pts (score ≥2 and =1) were 6.5 and 2.3 times more likely to have thrombosis, respectively, than low-risk (Lo) pts (score = 0) (p<0.001 and p=0.014). Probability of thrombosis was significantly different for Lo, Int, and Hi at 1 yr (0%, 1%, and 6%), 2 yrs (1%, 3%, and 10%), and 5 yr (2%, 9% and 21%) (Fig 1F & 1H). In contrast, ELN high-risk pts were only 2.2 times more likely to have thrombosis than ELN low-risk pts (Fig 1G-H). The concordance (C-index) of the ML-derived model (0.7± se 0.02) was higher than ELN (0.59 ± se 0.03). External validation using the MSSM PV data (Fig 1A) is ongoing. Discussion: We applied ML to our large PV-WCM dataset to identify most important clinicopathologic features predicting thrombosis. In contrast to linear models, ML has little penalty for increasing number of parameters tested and can easily accommodate high-dimensional data to improve predictions. Because "big data" is not routinely available to caregivers, we developed a simple, dynamic scoring system predicting the risk of thrombosis in PV based on 5 most important features identified by ML. This new and dynamic scoring system outperformed ELN stratification and may prove useful in guiding treatment and improving selection of pts for clinical trials aimed at preventing thrombosis in PV pts. Conclusion: The risk of thrombosis in PV pts is temporally non-linear and strongly influenced by proximity to diagnosis and recent thrombosis. A simple ML-derived dynamic scoring system is presented that better classifies pts into distinct Lo, Int, and Hi thrombosis risk groups based on age, prior thrombosis, WBC, peri-diagnosis, and peri-thrombosis. Figure 1 Figure 1. Disclosures Abu-Zeinah: PharmaEssentia: Consultancy. Silver: Abbvie: Consultancy; PharamEssentia: Consultancy, Speakers Bureau. Mascarenhas: Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Galecto: Consultancy; Geron: Consultancy; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prelude: Consultancy; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merus: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forbius: Research Funding; Geron: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scandura: MPN-RF (Foundation): Research Funding; CR&T (Foudation): Research Funding; European Leukemia net: Honoraria, Other: travel fees ; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Research Funding.

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Prognostic Factors for Developing Thrombosis in Polycytemia Vera: A Retrospective Analysis of 331 Patients with Long-Term Follow-up Highlights the Importance of White Blood Cells Levels

Blood ◽

10.1182/blood-2020-139431 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 48-49

Author(s):

Samantha Ferrari ◽

Chiara Pagani ◽

Mariella D'Adda ◽

Nicola Bianchetti ◽

Annamaria Pelizzari ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

High Risk ◽

Board Of Directors ◽

Advisory Board ◽

Advisory Committees ◽

Risk Status ◽

History Of ◽

Wbc Count

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P=<0.0001) predicted for arterial thromboses, while only a history of prior thrombosis (P=0.03) predicted for venous ones. In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: 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; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

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Weight Loss Predicts Inferior Outcome in Polycythemia Vera Patients

Blood ◽

10.1182/blood-2020-134801 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 22-23

Author(s):

Albert Jang ◽

Hussein Hamad ◽

Sarvari Venkata Yellapragada ◽

Iberia R. Sosa ◽

Gustavo A. Rivero

Keyword(s):

Weight Loss ◽

High Risk ◽

Blood Cell ◽

Polycythemia Vera ◽

Board Of Directors ◽

Clinical Variable ◽

Advisory Committees ◽

Wbc Count

Background: Conventional risk factors for inferior outcomes in polycythemia vera (PV) include elevated hematocrit, white blood cell (WBC) count, age, and abnormal karyotype. Weight loss adversely impacts survival in cancer patients. JAK2 myeloproliferative neoplasms (MPN) upregulate tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), and IL-8 and induce decreased leptin levels leading to weight loss. The impact of weight loss in PV patients receiving best supportive care (i.e. frontline hydroxyurea [HU] therapy, phlebotomy) on overall survival (OS) is largely unknown. In this study, we seek to investigate: (1) differential effect on survival for weight loss, and (2) variables with predictive value for weight loss among JAK2 inhibitor-naïve PV patients. Methods: After IRB approval, 46 patients at the Michael E. DeBakey VA Medical Center diagnosed with PV between 2000 and 2016 were selected for analysis. Our outcome of interest was OS among PV patients exhibiting weight loss versus patients who maintained, gained weight or had minor weight loss. To objectively estimate weight changes overtime, the difference between baseline BMI [BMI-B] at the time of diagnosis and BMI at last follow-up (BMI-L) was obtained for each patient. Survival analysis was performed for PV patients exhibiting more than 10% weight loss (>10%) versus all other patients (less than 10% loss, stable and increased weight) (<10%) over time. Kaplan-Meier (KM) method was used to determine OS. Cox regression model was performed to assess independent role of different variables including age, blood cell counts and ferritin level Statistical analysis was performed using SAS software. Results: Median BMI loss was 10% (0.03-36.72%); 33/46 (71.7%) and 13/46 (28.2%) patients developed <10% and >10% BMI loss, respectively. Baseline characteristics are summarized in Table 1. Median BMI at last follow up was 21 for PV patients exhibiting >10% BMI loss and 27.7 for PV patients exhibiting <10% BMI loss (p<0.01). Median age was higher among patients exhibiting >10% BMI loss (68 vs 56 y, respectively, p=0.006). A non-significant clinical trend for higher WBC was observed among patients losing >10% BMI (10.9 vs 7.6 K/uL, p=0.08). Median Hemoglobin (Hb), hematocrit (Hct) and ferritin were intriguingly lower in the >10% loss group at 16 vs 18.3 g/dL (p=0.01), 49.3 vs 54.2% (p=0.04) and 29.8 vs 50.6 ng/mL (p=0.09) respectively, while median RDW was higher at 18 vs 15.1% (p=0.01). OS was 9125 days vs 5364 days, in patients with <10% and >10% BMI loss, respectively (p=0.02, HR=0.20; CI 95% 0.04-0.84) (Figure 1). On multivariate analysis, age (hazard ratio [HR], 1.34; p<0.02) and WBC count (HR, 1.57; p<0.01), were predictive of OS. Conclusions: A subgroup of PV patients exhibit progressive weight loss. Over 10% BMI reduction is associated with decreased survival, suggesting that "early weight loss" is an independent clinical variable that predicts high risk PV. While a larger study is needed to validate this observation, this small study highlights the role of leukocytosis, advanced age and weight loss in PV. Confirmation of the observations reported here could unveil an important role for pharmacologic and/or dietary interventions to improve survival among high-risk PV patients. Disclosures Rivero: agios: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

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CD161 Is Expressed in a Subset of T-Cell Prolymphocytic Leukemia Cases and Is Useful for Disease Follow-up

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqz060 ◽

2019 ◽

Vol 152 (4) ◽

pp. 471-478

Author(s):

Scott R Gilles ◽

Sophia L Yohe ◽

Michael A Linden ◽

Michelle Dolan ◽

Betsy Hirsch ◽

...

Keyword(s):

Flow Cytometry ◽

T Cell ◽

Nk Cells ◽

Retrospective Review ◽

T Cell Subsets ◽

Prolymphocytic Leukemia ◽

Flow Cytometry Data ◽

Flow Cytometric ◽

Flow Cytometric Evaluation

AbstractObjectivesCD161 (NKRP1) is a lectin-like receptor present on NK cells and rare T-cell subsets. We have observed CD161 expression in some cases of T-cell prolymphocytic leukemia (T-PLL) and found it to be useful in follow-up and detection of disease after treatment.MethodsRetrospective review of T-PLL cases with complete flow cytometry data including CD161.ResultsWe identified 10 cases of T-PLL with flow cytometric evaluation of CD161 available. Six of these cases were positive for CD161 expression. All CD161-positive cases were positive for CD8 with variable CD4 expression, whereas all CD161-negative cases were negative for CD8. In a case with two neoplastic subsets positive and negative for CD8, only the former expressed CD161.ConclusionsThese novel results suggest that CD161 is often aberrantly expressed in a defined subset of T-PLL positive for CD8. We are showing the utility of this immunophenotype in diagnosis and follow-up.

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Flow cytometric DNA analysis in conservatively treated renal tumours

Urologia Journal ◽

10.1177/039156039506201s39 ◽

1995 ◽

Vol 62 (1_suppl) ◽

pp. 141-143

Author(s):

P. Beltrami ◽

M. Lazzarotto ◽

G. Giusti ◽

C. Tallarigo ◽

G. Malossini ◽

...

Keyword(s):

Flow Cytometry ◽

Dna Analysis ◽

Tumour Size ◽

Prognostic Significance ◽

Dna Flow Cytometry ◽

Additional Parameter ◽

Flow Cytometric ◽

Renal Tumours ◽

Dna Histograms

— The DNA histograms of 21 conservatively resected renal tumours were studied using DNA flow cytometry. Five patients had an imperative and sixteen an elective indication for conservative resection of the renal tumour. On the basis of DNA histograms twelve aneuploid tumours were pointed out. A mean follow-up of 34.2 months was considered to see whether the ploidy would provide criteria with a prognostic significance, to be useful as an additional parameter. None of the twenty-one patients had local recurrence or distant metastasis: in our series the DNA analysis had no influence on the prognosis of this group of patients. The tumour size seems to be the only selective parameter for choosing renal-conserving surgery.

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ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽

10.1182/blood-2019-128198 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1565-1565 ◽

Cited By ~ 1

Author(s):

Patrizia Mondello ◽

Irene Dogliotti ◽

Jan-Paul Bohn ◽

Federica Cavallo ◽

Simone Ferrero ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advanced Stage ◽

Advisory Committees ◽

Free Survival ◽

High Risk Patients ◽

Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with >90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= <0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS <3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, 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, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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