ALBERT

Description: In acute myeloid leukemia (AML) the subset with complex karyotype (CK) is traditionally regarded as the worst prognostic group. However, ≥ 3, ≥ 4, or ≥ 5 abnormalities have been variably used for its definition. Recently, monosomal karyotype (MSK) was suggested to indicate an even inferior outcome. We tested which definition fits best to identify the most unfavorable subgroup. After excluding patients with t(15;17)/PML-RARA, t(8;21)/RUNX1-RUNX1T1, inv (16)/t(16;16)/CBFB-MYH11, and normal karyotype, 824 patients with AML with cytogenetic abnormalities were analyzed. Patients with MSK or CK defined as ≥ 3, ≥ 4, or ≥ 5 abnormalities showed an inferior overall survival compared with the respective remaining patients not fulfilling these criteria (for all, P 〈 .001). Hazard ratios were 1.93, 1.68, 1.94, and 1.92. CK ≥ 4 as a single parameter identified the largest proportion of patients with very poor risk. However, combining CK ≥ 4 and MSK detected an even larger number of patients with very unfavorable outcome (261 of 824; 31.7%).

Description: Background: 6 cycles CHOP-like chemotherapy plus rituximab (6x R-CHOP) are the standard treatment for young patients with DLBCL. The MInT trial established a subgroup with favourable prognosis as defined as aaIPI=0 and no bulky disease [Pfreundschuh et al., Lancet Oncol 2006; 7: 379-391] with a 3-year EFS of 89%, PFS of 95% and OS of 98%. We hypothesized that 4 cycles of CHOP plus 6 applications of rituximab are non-inferior to the standard treatment of 6x R-CHOP in this population. Patients and Methods: 18 to 60 year-old patients, aaIPI =0 without bulky (≥7.5 cm) disease were randomized to receive 6x R-CHOP or 4x R-CHOP+2xR at 21-day cycles. Radiotherapy was not planned to be given except for prophylactic radiotherapy of the contralateral testis in patients with testicular lymphoma. The primary endpoint was progression free survival (PFS) with events defined as progressive disease, relapse or death. Assuming a 93% 3-years PFS for the 6x R-CHOP arm, it was planned to tolerate an impairment of 5.5% by reducing the number of courses to 4x R-CHOP+2xR to prove non-inferiority with a power of 80% and an alpha-error of 5% (one-sided). Results: Between 12/2005 and 10/2016, 592 patients were randomized in the international multi-center FLYER trial and 588 patients were evaluable for this final analysis. 295 patients were assigned to receive 6x R-CHOP and 293 were assigned to receive 4x R-CHOP+2xR. There were no relevant differences in demographics (median age: 48 years, 99% aaIPI=0, 1% aaIPI=1, 0.3% bulky disease), protocol adherence and toxicity between the two arms. PFS, EFS and OS after 4x R-CHOP+2xR were as good as after 6x R-CHOP. After 66 months median observation, the 3-year PFS rate of the patients receiving 4x R-CHOP+2xR was 96% vs. 94% of patients receiving 6x R-CHOP (p=0.760). The lower limit of the 95% CI of the difference between treatment arms was 0% and excludes -5.5% demonstrating the non-inferiority. The 3-year EFS was identical (89%) in both treatment arms. The 3-years OS was 99% in patients receiving 4x R-CHOP+2xR and 98% in patients receiving 6x R-CHOP. In a multivariable analysis adjusting for strata (stage and E-involvement), the hazard ratio of 4x R-CHOP+2xR compared to 6x R-CHOP was 1.0 (95% CI: 0.7-1.6; p=0.896) for EFS, 0.9 (95% CI: 0.5-1.6; p=0.797) for PFS, and 0.8 (95% CI: 0.4-1.9; p=0.671) for OS. With respect to relapse rate there was also no significant difference between the two treatment arms. 4% (95% CI 2-7%) of the patients in the 4x R-CHOP+2xR arm relapsed vs. 5% (95% CI 3-8%) of the patients in the 6x R-CHOP arm. 33% of relapses occurred in the first two years after study inclusion but continue to be seen with longer follow-up in both arms. Conclusion: In young patients with favourable prognosis DLBCL outcome after 4x R-CHOP+ 2xR is non-inferior compared to the previous standard 6x R-CHOP. Thus, chemotherapy can be spared without compromising prognosis in this population. Supported by Deutsche Krebshilfe Figure. Figure. Disclosures Poeschel: Roche: Other: Travel grants; Amgen: Other: Travel grants. Held:BMS: Consultancy, Other: Travel grants, Research Funding; Amgen: Research Funding; Roche: Consultancy, Other: Travel grants, Research Funding; MSD: Consultancy; Spectrum: Research Funding. Holte:Roche, Norway: Research Funding; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees. Viardot:Roche: Consultancy, Honoraria; Amgen: Consultancy; Gilead Kite: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Borchmann:Novartis: Consultancy, Honoraria. Keller:Celgene: Research Funding; BMS: Consultancy; Takeda: Consultancy, Research Funding; Janssen-Cilag: Consultancy, Equity Ownership; Roche: Consultancy; MSD: Consultancy. Schmidt:Gilead: Honoraria, Other: Travel Grants; Celgene: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants. Marks:Merck: Honoraria; BMS: Honoraria; Servier: Honoraria. Stilgenbauer:Boehringer-Ingelheim: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmcyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: 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, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffmann La-Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schmitz:Riemser: Honoraria, Other: Travel grants; Kite/Gilead: Honoraria, Other: Travel grants; Novartis: Honoraria, Other: Travel grants; Celgene: Other: Travel grants; Roche: Honoraria. Murawski:Takeda: Consultancy; Janssen: Other: Travel grants.

Description: Introduction: The PETAL trial is a multicenter randomized controlled study for patients with aggressive lymphomas of diverse histologies (EudraCT 2006-001641-33, NCT00554164). In the study population as a whole interim PET (iPET) reliably predicted time to treatment failure (TTTF) and overall survival (OS). Interim PET-based treatment changes, however, had no impact on outcome (ASH 2014, abstract 391). Here we report the exploratory analysis for aggressive B cell lymphomas. Methods: Pts. aged 18 to 80 yrs. with newly diagnosed aggressive lymphomas and a positive baseline PET received 2 cycles of rituximab (R), cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) followed by iPET. The conditions of iPET were strictly defined: 3-week interval between the 2nd R-CHOP cycle and iPET to avoid inflammatory reactions (Eur J Nucl Med Mol Imaging 30:682, 2003), no G-CSF after the 2nd cycle to avoid altered glucose biodistribution (J Nucl Med 47:950, 2006), standardized uptake value (SUV)-based PET interpretation to improve reproducibility (favorable iPET response: reduction of maximum SUV by 〉 66 % compared to baseline; J Nucl Med 48:1626, 2007). Pts. with CD20+ lymphomas and a favorable iPET were randomized to receive 4 more cycles of R-CHOP or the same treatment plus 2 extra doses of R (part A of the trial). Pts. with an unfavorable iPET were randomized to continue R-CHOP for 6 additional cycles or receive 6 blocks of a more complex methotrexate-, cytarabine- and etoposide-based regimen originally designed for Burkitt lymphoma (Blood 124: 3870, 2014; part B). R was omitted in pts. with CD20- lymphomas. Sample size of the entire study population was based on the empirically derived assumption that treatment failure after 2 yrs. (TF: progression, relapse, treatment discontinuation due to toxicity, start of alternative therapy, death of any cause) could be improved from 80 % to 90 % in part A and from 30 % to 45 % in part B (alpha=0.05, power=0.8). Secondary endpoints included OS and toxicity. Results: Fifty-seven oncological centers and 23 nuclear medicine institutions participated in the trial. Between 2007 and 2012 1072 pts. were registered, and 862 (80.4 %) had a positive baseline PET, received 2 cycles R-CHOP, underwent iPET and were allocated to one of the post-iPET treatment arms detailed above. Reference pathology was available in 98 %, and median follow-up is 52 months. All in all, there were 779 patients with CD20+ aggressive B-cell lymphomas (90.4 % of all treated pts.) of whom 606 had diffuse large B-cell lymphoma (DLBCL), 42 primary mediastinal B-cell lymphoma (PMBCL) and 42 follicular lymphoma grade 3 (FL3). Interim PET was favorable in 691 pts. (88.7 %) and unfavorable in 88 pts. with CD20+ lymphomas (11.3 %). It was highly predictive of TTTF for CD20+ lymphomas in general and for each of the DLBCL, PMBCL and FL3 subgroups (Table). In CD20+ lymphomas and DLBCL, the iPET response predicted TF independently of the International Prognostic Index, and it was also predictive of OS. The groups of PMBCL and FL3 were too small for multivariate analyses. In part A, adding 2 extra doses of R failed to improve TTTF and OS in all histological entities. Separate analyses for subgroups defined by sex, age (〈 vs. 〉 60 yrs.) or a combination of the two showed no statistically significant benefit of extra doses of R in any of the subgroups. In pts. with an unfavorable iPET response, a switch from R-CHOP to the Burkitt regimen failed to improve TTTF or OS in CD20+ lymphomas in general (Figure) and in the DLBCL, PMBCL and FL3 subgroups. In part B, the Burkitt protocol was associated with more grade 3/4 leukopenia (82 % vs. 57 %, p=0.02), thrombocytopenia (59 % vs. 18 %, p=0.0001), infection (41 % vs. 16 %, p=0.017) and mucositis (39 % vs. 7 %, p=0.0007) than R-CHOP, but treatment-related mortality was similar in both arms (1 death each). Conclusion: In this large multicenter trial iPET proved highly predictive of outcome in pts. with CD20+ aggressive B-cell lymphomas, DLBCL, PMBCL or FL3 treated with R-CHOP. In pts. with a favorable iPET response, addition of 2 extra doses of R to 6 cycles R-CHOP failed to improve outcome in CD20+ lymphomas in general and in subgroups defined by histology, sex or age. In pts. with an unfavorable iPET response, switching to a more aggressive protocol also failed to improve outcome in any of the entities. Novel strategies are required for aggressive B-cell lymphomas failing to respond to the first 2 cycles of R-CHOP. Table Table. Figure Figure. Disclosures Duehrsen: Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Giagounidis:Celgene Corporation: Consultancy. Grube:BMS, Sanofi: Consultancy. Klapper:Roche, Novartis, Amgen, Takeda: Research Funding. Hüttmann:Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria; Gilead, Amgen: Other: Travel cost.

Description: Introduction: The PETAL trial is a multicenter randomized controlled study for patients with aggressive lymphomas of diverse histologies (EudraCT 2006-001641-33, NCT00554164). In the study population as a whole interim PET (iPET) reliably predicted time to treatment failure (TTTF) and overall survival (OS). Interim PET-based treatment changes, however, had no impact on outcome (ASH 2014, abstract 391). Here we report the exploratory analysis for peripheral T cell lymphomas (PTCL). Methods: Pts. aged 18 to 80 yrs. with newly diagnosed aggressive lymphomas and a positive baseline PET received 2 cycles of rituximab (R), cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) followed by iPET. R was omitted in pts. with CD20-negative lymphomas. The conditions of iPET were strictly defined: 3-week interval between the 2nd (R-)CHOP cycle and iPET to avoid inflammatory reactions (Eur J Nucl Med Mol Imaging 30:682, 2003), no G-CSF after the 2nd cycle to avoid altered glucose biodistribution (J Nucl Med 47:950, 2006), standardized uptake value (SUV)-based PET interpretation to improve reproducibility (favorable iPET response: reduction of maximum SUV by 〉 66 % compared to baseline; J Nucl Med 48:1626, 2007). PTCL pts. with CD20-negative lymphomas and a favorable iPET uniformly received 4 additional cycles of CHOP (part A of the trial). Pts. with an unfavorable iPET were randomized to continue CHOP for 6 additional cycles or receive 6 blocks of a more complex methotrexate-, cytarabine- and etoposide-based regimen originally designed for Burkitt lymphoma (Blood 124: 3870, 2014; part B). Sample size of the entire study population was based on the empirically derived assumption that treatment failure after 2 yrs. (progression, relapse, treatment discontinuation due to toxicity, start of alternative therapy, death of any cause) could be improved from 30 % to 45 % in part B (alpha=0.05, power=0.8). Secondary endpoints included OS and toxicity. Results: Fifty-seven oncological centers and 23 nuclear medicine institutions participated in the trial. Between 2007 and 2012 1072 pts. were registered, and 862 (80.4 %) had a positive baseline PET, received 2 cycles (R-)CHOP, underwent iPET and were allocated to one of the post-iPET treatment arms detailed above. Reference pathology was available in 98 %, and median follow-up is 52 months. All in all, there were 76 pts. (8.8 % of all treated pts.) with T-cell lymphomas of whom 21 had ALK+ anaplastic large cell lymphoma (ALCL), 13 ALK- ALCL, 18 angioimmunoblastic T-cell lymphoma (AITL) and 20 PTCL not otherwise specified (NOS). Interim PET was favorable in 57 pts. (75 %) and unfavorable in 19 pts. with T-cell lymphomas (25 %). It was highly predictive of outcome, TTTF and OS being significantly higher in part A than B (2-year probability for TTTF: 63 % vs. 21 %; univariate hazard ratio (HR) for B 3.4, 95 % confidence interval (CI) 1.8 - 6.4, p

Description: Background: Administration of recombinant G-CSF has found extensive use in the support of chemotherapy-induced neutropenia in patients undergoing myelosuppressive chemotherapy. We retrospectively analyzed patients with acute myeloid leukemia (AML) who received either pegfilgrastim or lenograstim in this setting. Patients and Methods: Unselected patients with AML according to FAB, age 〉18 years, performance status ECOG 〈 3, excluding pregnancy received at least one cycle of chemotherapy. On day 1 after chemotherapy has ended G-CSF treatment was initiated with pegfilgrastim 6 mg once per cycle or lenograstim 5 micg/kg b.w. until leucocyte counts (LC) raised 〉 1,000/micL. Primary objective was the difference in the time to elevating LC 〉 1,000/micL in each G-CSF treatment groups if LC nadired 〈 1,000/micL and the difference in the substitution of packed red blood (PRB) and platelets (PLT). Results: Twenty-eight patients, 12 males and 16 females, aged median 61.4 years (range: 27–75 years) received 46 cycles. Six patients died due to the underlying disease. In four patients (two patients in the pegfilgrastim and two patients in the lenograstim group) G-CSF treatment failed to elevate LC 〉 1,000/micL. There was a difference in the time-to-recovery of leucocyte counts between pegfilgrastim 11.3 ± 3.8 days (range: 6 to 28 days) and lenograstim 13.3 ± 3.3 days (range: 6 to 22 days). The frequency of transfusions of PRB was 3.3 ± 2.6 in pegfilgrastim treated patients compared with 5.0 ± 2.9 in patients treated with lenograstim and the frequency of transfusions of PLT was 4.8 ± 2.5 vs. 6.0 ± 4.5. These differences received no statistical significance. Conclusion: In this retrospective analysis unselected patients received myelodepressive chemotherapy because of acute myeloid leukemia. Both G-CSF showed adequate recovery of leucocyte counts with a faster increase in those patients to whom pegfilgrastim was administered. No statistical difference in the frequency of donation of human blood products was recognized. This retrospective study was limited because of the small number of patients included, thus these promising results need to be confirmed in a larger, prospective trial.

Description: Introduction: The predictive value of 18-fluorodeoxyglucose PET performed after a few cycles of chemotherapy has been questioned in aggressive lymphomas. Inconsistent study results, however, may be due to procedural differences rather than an inability of the method to predict outcome. Whether changing treatment in pts. with an unfavorable interim PET (iPET) improves outcome, has not been determined in a randomized study. The PETAL trial (EudraCT 2006-001641-33, NCT00554164) was initiated to resolve these issues. Methods: Pts. aged 18 to 80 yrs. with newly diagnosed aggressive lymphomas and a positive baseline PET received 2 cycles of rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O) and prednisone (CHOP) followed by iPET. The conditions of iPET were strictly defined: 3-week interval between the 2nd R-CHOP cycle and iPET to avoid inflammatory reactions (Eur J Nucl Med Mol Imaging 30:682, 2003), no G-CSF after the 2nd R-CHOP cycle to avoid altered glucose biodistribution (J Nucl Med 47:950, 2006), standardized uptake value (SUV)-based PET interpretation to improve objectivity of evaluation (favorable iPET response: reduction of maximum SUV by 〉 66 % compared to baseline; J Nucl Med 48:1626, 2007). Pts. with CD20-positive lymphomas and a favorable iPET were randomized to receive 4 additional cycles of R-CHOP or the same treatment plus 2 extra doses of R (Part A of the trial). Pts. with an unfavorable iPET were randomized to continue standard R-CHOP for 6 additional cycles or receive 6 blocks of a more complex and more intensive protocol yielding excellent results in Burkitt and other aggressive lymphomas (Part B). Its main components were hyperfractionated alkylating agents (C, ifosfamide) and high doses of methotrexate and cytarabine, with dose reductions in pts. 〉 60 yrs. Other constituents were R, H, O, vindesine, etoposide and dexamethasone (Blood 120: abstr 667, 2012). R was omitted in pts. with CD20-negative lymphomas. Sample size was based on the empirically derived assumption that treatment failure after 2 yrs. (TF: progression, relapse, treatment discontinuation due to toxicity, start of alternative therapy, death of any cause) could be improved from 80 % to 90 % in Part A and from 30 % to 45 % in Part B (alpha=0.05, power=0.8). Complete remission (CR), overall survival (OS) and toxicity were secondary endpoints. Results: From 2007 to 2012 926 pts. were recruited by 57 participating oncological centers and analyzed by PET in 23 nuclear medicine institutions. With a median follow-up of 33 months 853 pts. are currently evaluable in the intent-to-treat population. 757 pts. had CD20-positive B cell lymphomas (80 % diffuse large B cell [DLBCL], 3 % primary mediastinal B cell, 8 % follicular lymphoma grade 3), 13 had CD20-negative B cell lymphomas and 83 had peripheral T cell lymphomas. Interim PET was favorable in 746 pts. (87 %) and unfavorable in 107 (13 %). It was highly predictive of outcome, time to TF being significantly higher in Part A than Part B (2-year probability: 79 % vs. 47 %; hazard ratio (HR) for B 3.4, 95 % confidence interval (CI) 2.6 – 4.6, p

Description: Vitamin D deficient patients suffering from diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP have lower overall survival. This especially applies for patients with vitamin D levels ≤8 ng/ml (Bittenbring et al. J Clin Oncol. 2014; 32:3242-8). Vitamin D up to 65 ng/ml may be necessary for optimal efficacy of R-CHOP (Neumann et al. Cancer Immunol Immunother. 2018; 67:1709-18). To study the clinical benefit of vitamin D substitution, we established a fast-track schedule to appropriately substitute patients to these vitamin D levels. The pre-treatment baseline vitamin D level was determined in 99 patients included in the ongoing, randomized, multicenter, phase-III, open-label OPTIMAL〉60 trial (NCT01478542) from November 2014 to July 2015. It was intended that patients reach a vitamin D level of 65 ng/ml. We calculated the dose needed using patient weight and baseline vitamin D: IU = 100 x ΔVitD3 x kg body weight (Van Groningen et al. Eur J Endocrinol. 2010; 162:805-11) and substitution started before treatment. Patients received 20.000 IU capsules of vitamin D, split over several days, with a daily maximum of 200.000 IU. Vitamin D level was checked again after substitution and at all restagings. Patients, who did not reach the intended vitamin D level of 65 ng/ml, received a second or third cycle of substitution. Baseline vitamin D level was 17.8±12.7 ng/ml. 14.3% of the patients reached the target value of up to 65 ng/ml after one substitution cycle with a mean dose of 386.000±137.000 IU. The average increase was 27.8 ng/ml, to a mean of 45.6±18.7 ng/ml. After the second substitution cycle with a median dose of 188.000±102.000 IU patients had vitamin D serum levels of 52.6±13.8 ng/ml. After a third substitution with 91.000±56.000 IU mean level of vitamin D was 56.0±9.6 ng/ml. By administering vitamin D in a dosage calculated by the van Groningen formula, we were able to increase the vitamin D level of our patients reliably after 2-3 cycles of substitution. After second and third substitution, a saturation effect was seen. The clinical effect of vitamin D substitution is the subject of the current study and the results are presently pending. The OPTIMAL〉60 trial is supported by Amgen, Roche, Acrotech. Disclosures Poeschel: Roche:Other: Travel, Accommodations, Expenses;Amgen:Other: Travel, Accommodations, Expenses;Abbvie:Other: Travel, Accommodations, Expenses.Habersang:Rheinlandklinikum Neuss:Current Employment.Mahlberg:Janssen:Other: Travel, Accommodations, Expenses;Mutterhaus der Borromaeerinnen, Trier:Current Employment;Novartis:Honoraria, Other: Travel, Accommodations, Expenses;Labor Synlab:Ended employment in the past 24 months;Abbvie:Other: Travel, Accommodations, Expenses;Roche:Honoraria;Amgen:Honoraria, Other: Travel, Accommodations, Expenses;Merck:Honoraria, Other: Travel, Accommodations, Expenses.Keller:Janssen-Cilag:Consultancy, Other: Travel, Accommodations, Expenses;Takeda:Consultancy, Other: Travel, Accommodations, Expenses;Celgene:Consultancy, Other: Travel, Accommodations, Expenses;BMS:Consultancy, Other: Travel, Accommodations, Expenses;Roche:Consultancy, Other: Travel, Accommodations, Expenses;Hexal:Consultancy;Novartis:Consultancy;MSD:Consultancy;Pfizer:Consultancy;Astra-Zeneca:Consultancy;Pentixapharm:Consultancy.Viardot:Kite/Gilead:Honoraria, Other: advisory board;Roche:Honoraria, Other: advisory board;Amgen:Honoraria, Other: advisory board;Novartis:Honoraria, Other: advisory board.Stilgenbauer:Novartis:Consultancy, Honoraria, Other, Research Funding;Pharmacyclics:Consultancy, Honoraria, Other, Research Funding;GlaxoSmithKline:Consultancy, Honoraria, Other: travel support, Research Funding;Janssen-Cilag:Consultancy, Honoraria, Other: travel support, Research Funding;Mundipharma:Consultancy, Honoraria, Other, Research Funding;Genzyme:Consultancy, Honoraria, Other: travel support, Research Funding;Genentech:Consultancy, Honoraria, Other: travel support, Research Funding;F. Hoffmann-LaRoche:Consultancy, Honoraria, Other: travel support, Research Funding;Celgene:Consultancy, Honoraria, Other: travel support, Research Funding;Gilead:Consultancy, Honoraria, Other: travel support, Research Funding;AbbVie:Consultancy, Honoraria, Other: travel support, Research Funding;Boehringer-Ingelheim:Consultancy, Honoraria, Other: travel support, Research Funding;Amgen:Consultancy, Honoraria, Other: travel support, Research Funding.Held:Roche:Consultancy, Other: Travel, Accommodations, Expenses, Research Funding;BMS:Consultancy, Other: Travel, Accommodations, Expenses, Research Funding;MSD:Consultancy;Acrotech:Research Funding;Spectrum:Research Funding;Amgen:Research Funding.Bittenbring:Gilead:Honoraria, Other: Travel, Accommodations, Expenses;Bluebird Bio:Honoraria, Other: Travel, Accommodations, Expenses;Roche:Honoraria, Other: Travel, Accommodations, Expenses, Advisory board;Celgene:Honoraria, Other: Travel, Accommodations, Expenses, Advisory Board;Pfizer:Honoraria, Other: Travel, Accommodations, Expenses.