ALBERT

Description: Background:Novel insights into the biology of myeloma cells have led to the identification of relevant prognosis factors.Cytogenetic abnormalities (CA) has become one of the most important prognostic factors, and the presence of t(4;14), t(14;16) or del(17p) are associated with poor prognosis. Although there are some reports indicating that 1q gains may be considered as a poor-risk feature, the information is not uniform. Furthermore, there are important controversies about whether or not novel agents-based combinations are able to overcome the poor prognosis of CA. In the relapse setting, the combinations including proteasome inhibitors and immunomodulatory drugs have shown to improve, and some of them to overcome, the outcome of patients with high-risk CA. Here we report a preplanned analysis, in a series of elderly newly diagnosed myeloma patients included in the Spanish GEM2010 trial and receiving VMP and Rd, in a sequential or alternating approach, in order to evaluate the influence of CA by FISH on the response rate and outcome. Patients and methods: 242 pts were randomized to receive a sequential scheme consisting of 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the IV administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2once daily on days 1-4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. FISH analysis for t(4;14), t(14;16), del(17p) and 1q gains was performed at diagnosis according to standard procedures using purified plasma cells. Results: In 174 out of the 233 patients evaluable for efficacy and safety, FISH analysis at diagnosis were available and two groups were identified: high-risk group (n= 32 patients with t(4;14) and/or t(14;16) and/or del(17p)) and standard-risk group (n=142 patients without high-risk CA). The rates of CA was similar in both treatment arms. Response Rates (RR) were no different in the high-risk vs standard-risk groups, both in the sequential (74% vs 79% RR and 42% vs 39% CR) and alternating arms (69% vs 86% RR and 39% vs 38% CR). After a median follow-up of 51 months, high-risk patients showed shorter PFS as compared to standard risk in the alternating arm (24 versus 33 months, p=0.03) and this also translated into a significantly shorter OS (38.4m vs not reached, p=0.002). However, in the sequential arm, high-risk and standard-risk patients showed similar PFS (29.5 months vs 31.5 months, p=0.9) and OS (46m vs 63m, p=0.1). This beneficial effect observed in the sequential arm applied to both t(4;14) or del(17p). As far as 1q gains is concerned, 151 patients had 1q information and 76 of them had 1q gains (50.3%), defined as the presence of more than 3 copies in at least 10% of plasma cells. The rate of 1q gains was well balanced in both sequential and alternating arms. The ORR was similar in patients with or without 1q gains (83% vs 80%) as well as the CR rate (45% vs 31%), and no differences were observed between sequential and alternating arms. Patients with or without 1q gains had a similar PFS (36 months vs 29 months) and 4-years OS (63% vs 68%) in the whole series and no differences were observed between the sequential and alternating arms. This effect has been observed in patients with 1q gains as isolated CA and the outcome was slightly but not significantly worse when 1q gains were present plus either t(4;14) and/or del17p. Conclusions: The total therapy approach including VMP and Rd administered in a sequential approach is able to overcome the poor prognosis of the presence of high-risk CA in elderly patients with newly diagnosed MM. The presence of 1q gains has no impact in the PFS and OS of elderly patients treated with VMP and Rd. Disclosures Mateos: Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Martínez-López:Novartis: Honoraria, Speakers Bureau. Oriol:Celgene: 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; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Paiva:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding.

Description: Abstract 2825 Mantle cell lymphoma (MCL) constitutes one of the lymphomas with poorest prognosis at relapse and there are no effective salvage. The activity shown by the combination Gemcitabine and Oxaliplatin in several types of limfoma, along with its “in vitro” synergistic effect, made this regimen an attractive regimen for salvaging patients with MCL. Against this background, we performed an off-label pilot study in order to assess efficacy and toxicity of the combination R-GemOx in relapsed or refractory patients with MCL. For this, 27 patients (70% male, median age 70 years) diagnosed with MCL between November 2004 and January 2010 were included in this study. Inclusion criteria were adequate performance status, confirmed diagnosis of MCL and relapse or refractoriness to the previous treatment. The regimen consisted of Rituximab 375 mg/m2 on day 1, Gemcitabine 1000 mg/m2 and Oxaliplatin 100 mg/m2 on day 2, every 14 days, up to 8 cycles. Dose and interval were adjusted according to hematological and extrahematological toxicities. Median number of previous regimens was 1 (range 1 to 3), being EPOCH-R (n=14), R-CHOP (n=6), and RFC (n=3) the most frequently used induction therapies. Twelve patients relapsed after prior CR, 10 progressed after achieving a PR, whereas 5 were refractory to therapy. At inclusion, 85% of patients were in advanced (III/IV) clinical stage, 40% had bone marrow infiltration, 28% gastrointestinal involvement, and 17% cavum infiltration. Median number of cycles administered was 8 (range, 3 to 8). Doses were reduced in 9 cycles and delayed in 15 cycles. Neutropenia grade 3–4 was observed in 9 cycles and thrombocytopenia grade 3–4 in 6. Hepatotoxicity grade 1–2 in 5 pts and grade 3 in 1, sensitive neurotoxicity grade 1–2 in 12 pts, and renal impairment grade 2 in 1 patient. After completion of the treatment, 21 pts (77%) were considered in CR/uCR, 1 (4%) achieved a PR, 1 a SD, whereas 4 PD. Six patients subsequently received a stem-cell transplantation (4 allogeneic, 2 autologous). Thirteen pts are still alive and out of progression. Ten pts have died (8 due to progression and 2 due to acute GVHD). With a median follow-up of 23 months (range: 3–57), PFS and OS at 2 years are 41% and 58%, respectively. The R-GemOx combination showed a significant activity in relapsed or refractory pts with MCL with a very acceptable toxicity profile. These results prompted us to conduct a multicenter phase II clinical trial that is now ongoing. Disclosures: López: Roche Farma: Research Funding, Travel Support. Bosch:Roche Farma: Research Funding.

Description: Introduction: Disease control at five years would be a desirable endpoint for elderly multiple myeloma (MM) patients; however, the percentage of cases reaching this objective as well as the biomarkers to predict it, are not well defined. Objective and design: In order to gain further insight about long-term disease control (〉5 years progression-free) in elderly MM we have analyzed a homogeneous population of 435 newly-diagnosed transplant-ineligible (TNE) patients enrolled in two consecutive Spanish clinical trials (GEM2005MAS65, GEM2010MAS65), that included both proteasome inhibitors and immunomodulatory drugs. Results: Amongst the 435 patients included in this post-hoc study, only 18.8% remained alive and progression-free after five years of initiating treatment. Noteworthy, in these patients the overall survival (OS) rate at 10-years was 69.4%, as compared to 11.4% for those patients progressing during the first five years (p〈 0.001). Baseline variables significantly associated with long-term progression free survival in the univariate analysis were younger age, ISS 1, R-ISS 1, hemoglobin ≥ 12g/dl, normal LDH, and standard-risk cytogenetic abnormalities and the presence of a monoclonal gammopathy of unknown significance (MGUS)-like immunophenotypic profile in the bone marrow. Complete responses (CR) and minimal residual disease (MRD) negativity were also associated with long-term progression free survival. In the multivariate analysis, an hemoglobin level ≥12g/dl (OR 2.61; 95% CI 1.47 - 4.61, p=0.001) and a MGUS-like immunophenotypic profile in the bone marrow (OR 3.33; 95% CI 1.30 - 8.54, p=0.002) were the two baseline variables significantly and independently associated with a higher probability of long-term disease-free survival. When the depth of response (including MRD) was included in the logistic regression model, Hb level ≥12g/dl (OR 2.18; p=0.010) and the MGUS-like signature (OR 4.99, p

Description: Abstract 3591 ZAP-70 (ξ-associated protein) is a protein tyrosine kinase of the Syk/ZAP family that plays a crucial role in cellular activation in T and NK cells. High expression of ZAP-70 protein in malignant cells from Chronic Lymphocytic Leukemia (CLL) correlates with adverse clinical prognostic features, such as unmutated IgHV genes, short time to progression, and short survival. Moreover, ZAP-70 protein has been related to aggressive features of the CLL cells, such as enhanced B-cell receptor (BCR) signaling and higher migration capacity. To further investigate into the mechanisms by which ZAP-70 protein influences the clinical outcome of patients with CLL, we analyzed the functional consequences of ZAP-70 ectopic expression in malignant B-cells. For this, Ramos and Raji (Burkitt) B-cell lines were stably transfected with a ZAP-70 expressing vector (pEGFP-N2ZAP-70) and the effects in BCR signaling and migration were studied. BCR-expressing B-cells (Ramos) where stimulated with F(ab’)2 anti-IgM or F(ab’)2 anti-IgD. IgM but not IgD stimulation induced ZAP-70 activation and mobilization to the membrane, which, in turn, enhanced signaling through phosphorilation of AKT and ERK1-2 kinases. The presence of ZAP-70 also inhibited IgM and CD79b internalization after BCR stimulation, thus allowing for a longer and sustained stimulation. In Raji B-cells, which did not express BCR, ZAP-70 was constitutively phosphorilated, which induced a higher level of ERK1-2 phosphorilation only, suggesting that AKT phosphorilation in Ramos expressing ZAP-70 after IgM stimulation was depending on additional factors. BCR stimulation in Ramos B cells changed the expression pattern of several cytokine receptors such as CXCR4 and CXCR3 (downregulated) and CCR7 (upregulated). Interestingly, ZAP-70 activation was involved in the induction of CCR7 expression, which was significantly upregulated upon BCR stimulation in ZAP-70 expressing B-cells. This upregulation was also confirmed in Raji B cells upon ZAP-70 expression and activation. The relationship between ZAP-70 and CCR7 was also seen in neoplastic B-lymphocytes from patients with CLL where there was a linear correlation between the expressions of the two molecules. The increased CCR7 expression in ZAP-70 expressing B-cell lines translated into an enhanced signaling though CCR7 upon CCL21 addition and an enhanced migration towards a CCL21-containing medium in vitro. In conclusion, ZAP-70 ectopic expression leaded to an enhanced signaling through the BCR after IgM stimulation while it did not participate in the signaling through IgD. Moreover, ZAP-70 expression induced the upregulation of the chemokine receptor CCR7, thus giving the cells the ability to better respond and migrate towards CCL21. These results give further insight into the functional role of ZAP-70 protein in the aggressiveness of CLL cases with an increased expression of ZAP-70. Disclosures: No relevant conflicts of interest to declare.

Description: Background: MM usually affects elderly patients and although novel agents-based combinations have substantially improved MM outcome, it is possible that this benefit would be particularly relevant for the "youngest-elderly" patients (65-80y). According to the frailty score published by IMWG, the chronological age ≥80 years identifies itself a frail patient population with poor outcome and we have here evaluated the efficacy, safety and outcome of patients included in the GEM2010 trial according to the age to identify the group of patients who benefit most of this total therapy approach. Patients and methods: 242 patients were randomized to receive a sequential scheme consisting on 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the iv administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1-4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. Results: 233 pts were evaluable for safety and efficacy (118 in the sequential and 115 in the alternating arm). One hundred and fifteen patients (49%) were between 65-75 years, 69 patients (30%) were aged between 75-80 years and 49 patients (21%) were older than 80 years. The allocation in both sequential and alternating arms was well balanced. There were not significant differences in the baseline characteristics of the three subgroups of patients. The ORR was similar in both patients aged 65-75 and 75-80 (80% and 83%), but significantly lower in patients older than 80 years (68%) (p=0.007). The CR rate was also almost identical in patients between 65-75 (45%) and 75-80 (49%), but significantly lower in those aged over 80 years (10%) (p

Description: Introduction: In MM, there is growing body of evidence showing the importance of MRD monitoring particularly among transplant-eligible patients. However, it is perhaps in elderly MM, the major patient subgroup and in which optimal balance between efficacy and toxicity is critical, that sensitive response assessment could help to tailor patients' treatment. Methods: We used an 8-color second-generation flow assay to monitor MRD among elderly MM patients (n=163) included in the PETHEMA/GEM2010MAS65 trial (sequential chemotherapy with 9 cycles of bortezomib-melphalan-prednisone (VMP) followed by 9 cycles of lenalidomide-low dose dexamethasone (Rd), or alternating cycles of VMP and Rd up to 18 cycles). A single 8-color antibody combination (CD45-PacB/CD138-OC515/CD38-FITC/CD56-PE/CD27-PerCPCy5.5/CD19-PECy7/CD117-APC/CD81-APCH7) was used to detect phenotypically aberrant clonal plasma cells (PCs), and MRD-negativity was defined when

Description: Multiparameter flow cytometry (MFC) is commonly used to monitor minimal residual disease (MRD) in MM due to its widespread availability, fast turnaround, and the amount of information obtained upon enumeration of different cell populations and their corresponding antigen expression levels. Thus, MFC could potentially be used not only to monitor MRD, but also to offer additional prognostic information based on MM plasma cell (PC) phenotypes. However, in MM there is lack of consensus about which markers are prognostically relevant because of technical variability between centers and the paucity of studies in large series of patients. Before investigating the prognostic value of those antigens evaluated in MRD studies, we first demonstrated their stability over time by comparing the phenotypic profile of MM-PCs from diagnosis to the MRD stage using principal component analysis (PCA). Accordingly, PCA of merged diagnostic and MRD profiles showed phenotypic overlap between both (MM-PC references in red and blue, respectively; Panel A), that was also demonstrable at the individual patient level [Panel B, in which diagnostic and MRD phenotypic profiles from individual patients (n=14) are represented with the same color]. After demonstrating antigen stability from diagnosis to the MRD stage, we then investigated their prognostic value in a large series of 1265 newly-diagnosed patients enrolled in four consecutive GEM/PETHEMA clinical trials (GEM2000 and GEM2005MENOS65 for transplant-eligible, GEM2005MAS65 and GEM2010 for elderly patients). As compared to cases with bright CD38 expression, patients with aberrantly low CD38 had inferior PFS (medians of 38 vs 30 months; P

Description: Abstract 1627 Front line treatment with chemoimmunotherapy in mantle cell lymphoma (MCL) is able to obtain a high CR rate. Regrettably, all patients with MCL eventually relapse, a situation for which no effective therapies are available. Gemcitabine plus Oxaliplatin have shown promising results in “in vitro” and in clinical studies for several types of lymphoma, its activity being improved by the addition of rituximab. Against this background, we conducted a pilot study aimed to assess the efficacy and toxicity of the combination of Rituximab, Gemcitabine and Oxaliplatin (R-GemOx) in pts with relapsed/refractory MCL. Inclusion criteria were age 〉 18 years and a histologically proved MCL that relapsed or was refractory to previous treatment. Patients were excluded if they had neutrophil count 〈 1,500 μL, platelet count 〈 100,000 μL, creatinine 〉 2.5 mg/dL, 〉 3 times the upper limit of laboratory normal for AST and ALT, or bilirubin 〉 3 mg/dL. The regimen consisted of Rituximab 375 mg/m2 day 1, Gemcitabine 1000 mg/ m2 and Oxaliplatin 100 mg/ m2 day 2, every 14 days for a total of 8 cycles. Dose and interval adjustment was done according hematological and extrahematological toxicities. Twenty-eight patients (71% male, median age 68 years, range 41–84 years) were included in this study. Median number of previous treatments was one (range: 1–4). Fifteen (53%) pts had relapsed after previous CR/uCR, 10 (36%) had progressed after a PR, and three (11%) were refractory to the previous treatment. Bone marrow infiltration was observed in 85% of evaluated patients. Median number of cycles administered was 8 (range 2–8). Toxicity was mainly hematological, with a grade 3–4 neutropenia and thrombocytopenia observed in 9 (4.7%) and five (2.6%) cycles, respectively. Main non-hematologic toxicities were hepatotoxicity grade 1–2(21%), sensitive neurotoxicity grade 1–2 (43%), and nefrotoxicity grade 2 (4%). Dose reduction was performed in only two pts for a total of eight cycles, and treatment was delayed in six pts for a total of 17 cycles. After completion of treatment, 21 pts (75%) achieved a CR/uCR, 1 (3.5%) a PR, 1 (3.6%) SD and 5 (17.8%) progressed. Stem-cell transplantation was subsequently performed in nine pts (6 allogeneic and 3 autologous). After a median follow-up of 23 months, 4 patients are alive without progression, 7 relapsed, and 17 died (13 due to progression, 2 due to aGVHD, and 2 due to post-transplant infection). Median PFS and OS of this series were 18 and 30 months, respectively. In conclusion, the R-GemOx combination showed an encouraging efficacy in relapsed/refractory pts with MCL. Hematological and non-hematological toxicity were mild. This is a feasible combination to be employed in salvaging pts prior stem-cell transplantation. Based on the above mentioned data from this pilot study, a national prospective multicenter phase II clinical trial is currently ongoing. Disclosures: No relevant conflicts of interest to declare.

Description: Ocular adnexal lymphomas (OAL) represent up to 55% of all orbital tumors, being extranodal marginal zone lymphoma (OAMZL) the most frequent histological subtype reported in approximately 50% of patients and its etiology and pathogenesis are still not well understood. There are conflicting reports regarding the association between C. Psittaci infection and ocular adnexal lymphoma (OAMZL), in part because this association may vary between different geographical regions. Herein, we analyzed the clinical features and the presence of C. Psittaci infection in a cohort of 28 patients with OAMZL diagnosed from a single Spanish institution. All tumor samples were centrally reviewed by two pathologists, and C. Psittaci infection was determined in tumor specimens by a Semi-nested PCR method. Between January 1984 and April 2009, 28 patients were diagnosed with primary OAMZL. The median age was 70 years (range: 31- 89) and 40% were male. The great majority of patients (79%) were diagnosed in stage I-extranodal (IE), and six patients (21%) had bilateral ocular involvement. IgH rearrangement was confirmed in 25 out of 28 cases with OAMZL. PCR for C. Psittaci infection was negative in all 28 tumor specimens analyzed. Most patients (82%) were treated with immunochemotherapy combinations, being chlorambucil based regimens the most frequently used. Overall, 18 out of 24 patients (75%) achieved a complete response after first-line treatment. Median PFS was of 79 months (IC 95% 36 - 121). Whereas C. Psittaci infection in OAMZLs has been proved in up to 90% of patients in Northern Italy, in this Spanish cohort OAMZLs were not associated with C. Psittaci infection. These findings confirm that the association between C. Psittacci infection and OAML is highly heterogeneous even between the same geographic regions. In these regions where C. Psittaci infection is not prevalent, the search for alternative antigenic stimuli driving the appearance of this lymphoma is warranted. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: Standard of care for previously untreated patients (pts) with diffuse large B-cell lymphoma (DLBCL) is rituximab (R) plus 6-8 cycles of CHOP (R-CHOP). While the RICOVER trial (Pfreundschuh et al. Lancet Oncol 2008) showed no benefit of 6 versus 8 cycles of R-CHOP administered at 2-weekly intervals, this has not been assessed with the standard 3-weekly regimen, and many centers continue to administer 8 cycles. GOYA (NCT01287741) was an open-label, randomized, Phase III study of the efficacy and safety of R-CHOP versus obinutuzumab (GA101; G) plus CHOP in previously untreated pts with DLBCL. The current exploratory analysis compared investigator (INV)-assessed progression-free survival (PFS) and overall survival (OS) in pts receiving 6 or 8 cycles of CHOP in combination with 8 cycles of R in GOYA. Methods: Eligible pts were aged ≥18 years with histologically documented, CD20-positive DLBCL and ≥1 bi-dimensionally measurable lesion, ECOG PS 0-2, IPI score ≥2, and adequate hematologic function. Low-risk pts with IPI score 1 not due to age alone or 0 with bulky disease (1 lesion ≥7.5cm) were also eligible. Pts who were randomized to R-CHOP received 8 cycles of R (375mg/m2) in combination with 6 (CHOP6) or 8 (CHOP8) cycles of CHOP. Centers elected upfront to administer either 6 or 8 CHOP cycles to all pts enrolled at that site. Efficacy was evaluated in all pts who were randomized to R-CHOP (intent-to-treat population; data cut-off: January 31, 2018). Safety was assessed in all pts who completed the 6th treatment cycle and received R in the 7th cycle (CHOP6 safety population: no additional CHOP cycles; CHOP8 safety population: at least 7 or 8 CHOP cycles received). Only AEs starting during or after the 7th cycle were considered. Statistical analyses included Kaplan-Meier estimates and Cox-regression, with and without propensity score adjustment to correct for baseline imbalances. Results: Results are reported for 712 pts who were randomized to R-CHOP (CHOP6, n=526; CHOP8, n=186; safety population: CHOP6, n=461; CHOP8, n=144). In the CHOP6 group, 55% were male and median age was 62 years (range 54-70). In CHOP8, 49% were male and median age was 60 years (range 47-67). Baseline characteristics were broadly comparable across treatment groups, except for geographic region (CHOP6 vs CHOP8: Asia, 32% vs 49%, respectively; Eastern Europe, 10% vs 24%; Western Europe, 36% vs 13%; North America, 18% vs 8%; other, 4% vs 5%). In CHOP6, 89% completed 6 cycles of R-CHOP, while in CHOP8, 76% completed 8 cycles. Three-year INV-assessed PFS rates were comparable between groups: 68.7% in CHOP6 versus 66.8% in CHOP8 (HR 0.92; 95% CI: 0.69, 1.23; Figure 1a). Three-year OS rates appeared higher in the CHOP6 group (83.2% vs 76.2% in CHOP8; HR 0.65; 95% CI: 0.46, 0.91; Figure 1b). PFS and OS comparisons were unchanged after propensity score adjustment for the prespecified baseline characteristics, including age, gender, disease stage, geographic region, IPI score, extranodal sites, body surface area, bulky disease, LDH, and COO (PFS: HR 0.96, 95% CI: 0.70, 1.32; OS: HR 0.66, 95% CI: 0.45, 0.97). Interim treatment response (by CT) did not influence these findings. Model-based subgroup analysis according to baseline pt characteristics did not identify any pt subgroups benefitting from 8 versus 6 cycles of CHOP (Figure 1c). Incidence of grade 3-5 adverse events (AEs) was lower in the CHOP6 group than in the CHOP8 group (17.8% vs 38.9%, respectively); cardiac AEs (all grade: 2.4% vs 6.3%; grade 3-5: 1.3% vs 3.5%) and infections (all grade: 10.6% vs 23.6%) were also less common. In support of these findings, similar results were achieved after repeating the same efficacy analysis in pts who received 6 or 8 cycles of CHOP in combination with 8 cycles of obinutuzumab. Conclusions: In this exploratory analysis of 712 previously untreated DLBCL pts in GOYA, in which the number of CHOP cycles was selected upfront by each site, no additional PFS benefit was observed with 8 cycles of R-CHOP compared with 6 cycles of R-CHOP plus 2 cycles of R, even after adjusting for baseline differences, including COO and IPI. Slow response, assessed by interim CT, did not influence these findings. Furthermore, incidence of grade 3-5 AEs (including cardiac) and any grade infections was markedly higher in pts receiving 8 cycles of CHOP versus 6 cycles. These results suggest that rituximab with 6 cycles of 3-weekly CHOP should be considered standard of care. Disclosures Sehn: Janssen: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Culligan:JAZZ: Honoraria; Celgene: Other: Support to attend conferences; Takeda: Honoraria, Other: Support to attend conferences; Daiichi-Sankyo: Other: Support to attend conferences; Abbvie: Other: Support to attend conferences; Pfizer: Honoraria; Merck Sharp & Dohme (MSD): Honoraria. Ogura:Cellgene: Honoraria; Celltrion: Research Funding; Takeda: Honoraria; SymBio: Research Funding. Launonen:Roche: Employment, Other: Travel, accommodation, expenses; Novartis: Consultancy, Equity Ownership, Other: Ownership interests none PLC; Travel. accommodation, expenses; Launonen: Other: Ownership interests none PLC; Travel, accommodation, expenses. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Sellam:Roche: Employment. Trněný:Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Sandoz: Honoraria; Abbvie: Honoraria, Research Funding. Vitolo:Gilead: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sandoz: Speakers Bureau. Martelli:Servier: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; F. Hoffman-La Roche: Membership on an entity's Board of Directors or advisory committees.