Abstract: Not available.

Abstract: We provide a long‐term evaluation of patients enrolled in the EORTC/GIMEMA AML‐10 trial which included a total of 2157 patients, 15‐60 years old, randomized to receive either daunorubicin (DNR, 50 mg/m 2 ), mitoxantrone (MXR, 12 mg/m 2 ), or idarubicin (IDA, 10 mg/m 2 ) in addition to standard‐dose cytarabine and etoposide for induction chemotherapy and intermediate dose cytarabine for consolidation. Younger patients who reached complete remission with complete (CR) or incomplete (CRi) recovery were then scheduled to receive an allogeneic hematopoietic stem cell transplantation (HSCT). That was if they had a HLA‐identical sibling donor; in all other cases, an autologous HSCT had to be administered. At an 11‐year median follow‐up, the 5‐year, 10‐year and 15‐year overall survival (OS) rates were 33.2%, 30.1% and 28.0%, respectively. No significant difference between the three randomized groups regarding OS was observed ( P = .38). In young patients, 15‐45 years old, no treatment difference ( P = .89) regarding OS was observed, while in patients 46‐60 years old, MXR and IDA groups had a trend for a longer OS as compared to the DNR group ( P = .029). Among younger patients without a favorable MRC cytogenetic risk subgroup who achieved a CR/CRi after induction chemotherapy, those with a HLA‐identical sibling donor had higher 10‐year and 15‐year OS rates than those without. In older patients who reached CR/CRi, the long‐term outcomes of those with or without a donor was similar. In conclusion, long‐term outcomes of the study confirmed similar OS in the three randomized groups in the whole cohort of patients.

Abstract: Introduction Telomere length is shortened in patients with idiopathic aplastic anemia (AA) and other bone marrow failure disorders (BMFD) and predicts risk of clonal evolution (CE), relapse and overall survival (OS). Telomereopathies predominantly cause bone marrow failure, are multi-systemic disorders with variable penetrance, and may involve inter-play of other factors in disease manifestation and organ affliction. Telomere length (TL) in AA and other hypocellular BMFD, independent of mutations in telomere genes (TGC), has not been studied as a scoring tool, as well predicting the risk of affliction of other organ/systems in these disorders. We systematically review a large cohort of 472 patients in a single centre with AA/BMFD using TL and TGC analysis as a discriminator, to study risk of CE and OS, manifesting with liver/lung and skin complications, cancer predisposition and likelihood of a family member presenting with cytopenias. Methods We screened 1060 consecutive patients at a single centre from the years 2011-18, with AA or unexplained cytopenias for telomere length (TL) analysis using a multiplex qPCR methodology as described by Cawthon et al. 472 (44.5%) patients had TL less than the 25th centile, of whom 243 had 〈 1st centile, 122 had 〈 10th and 107 had TL between the 10-25th centile. These 472 patients underwent TGC mutation analysis on a customised panel of 12 TGC genes (TERT, TERC, DKC1, TINF2, NHP2, NOP10, RTEL1, CTC1, USB1, WRAP53, ACD and PARN) using deeply parallel sequencing and were studied alongside their clinical parameters, disease progression, treatments and OS. Results Table attached. The median age and gender across the 3 cohorts studied (TL 10-25th centile, 〈 10th centile and 〈 1st centile) were comparable, with a median age of 43 for the entire cohort. 127 (26.9%) of patients were detected to have a total of 142 mutation in the TGC. A third of patients with BMFD and TL 〈 1st centile had a TGC mutation, but the prevalence did not statistically differ with the other cohorts of TL 〈 10th centile and between 10-25th centile. Patients with TL 〈 1st centile can have mutations in 2 telomere genes, but this is less frequently seen when TL 〈 10th centile and not seen in the cohort with TL between 10-25th centile. TL does not correlate with the manifestation and presence of liver, respiratory and skin problems of telomere disease. TL in BMFD does not associate with increased predisposition to cancer, as their presence was not statistically significant across the 3 groups. Disease manifestation with bone marrow failure, haematological indices, need for blood transfusions, presence of a PNH clone and karyotypic abnormalities, including complex and monosomal karyotype were not dissimilar across the 3 TL cohorts. Not surprisingly, there were more family members with features of cytopenias and BMFD, on screening of patients with a confirmed TGC mutation. TL did not predict a difference in treatment strategies used across the 3 groups, although more patients with a TGC mutation received anabolic steroids. The risk of clonal evolution to PNH or MDS/AML and overall survival was again similar across the 3 TL cohorts with an OS of 93% at 1078 days follow-up for the entire cohort. Conclusion TL can reliably be used as a screening tool to investigate patients for further TGC mutation analysis in patients with AA or BMFD. Heterozygous state mutations in TERT are the commonest, and can be associated with mutations in other TGC genes, particularly RTEL1 and TERC. This may cause a compounding factor in shortening the TL further. However, TL 〈 1st centile does not associate with more severe cytopenias (BMFD) or predict more multi-system manifestation or increased cancer pre-disposition. Indeed, in our cohort it failed to show an increased risk of clonal evolution or decreased OS. Telomere biology is a dynamic process and assessments at different time points, from diagnosis to the time point of progression and transformation, may yield better understanding in pathogenesis of BMFD. TL and TGC mutation analysis in a single centre study from 2011-18. Table Disclosures Kizilors: Incyte biosciences: Research Funding. Mufti:Celgene: Consultancy, Research Funding.

Abstract: Eculizumab, the monoclonal antibody targeting C5, is the only licensed treatment for Paroxysmal Nocturnal Hemoglobinuria (PNH) in the UK. Inherent to the mechanism of action, C5 inhibitors increase patient susceptibility to encapsulated microorganisms, particularly Neisseria meningitidis. The PNH National service (UK), has 18 years of experience treating patients with PNH using complement inhibition. The risk of N. meningitidis is mitigated by vaccination, ciprofloxacin (500 mg bd) on days 1-13 since we moved to vaccination on day one of complement inhibitor therapy, followed by daily prophylaxis with penicillin (or erythromycin). Since a case of sepsis with penicillin-resistant meningococci was observed, patients also have a rescue course ciprofloxacin. Patient education, safety cards, prompt action in case of fever and a 24 hour on-call service for patients are equally important. Until 2010 patients were revaccinated with MenACWY every 3 years. Bexsero (MenB vaccine) vaccination (2 vaccines within first 6 months) with boosters every 5 years was added in 2015. In collaboration with the Public Health England Meningococcal Reference Unit in 2010 a program was developed to monitor antibody titers after vaccination and to revaccinate against MenACWY if titers declined to below protective levels. It is technically not possible to assay for meningoccal serogroup B antibody titers when on Eculizumab therapy. We present the outcome of this project. Methods: Antibody titers to serogroups ACWY were assayed following vaccination and then once per annum. Patients with unprotective antibody titers were revaccinated. We evaluate our practice and review the 9 meningococcal infections in 8 patients. We present disease characteristics, serogroup and outcome, vaccination history and antibody status. Results: Between May 2002 and July 2020, 324 patients commenced complement inhibitor treatment for PNH. 801 vaccinations with MenACWY were administered; median 2 vaccinations per patient (range 1 - 10). A total of 1,671 antibody titer assessments were conducted in 294 patients, median of 4 tests per patient (range 1 - 15). Every test assessed antibodies against all four serogroups. Titers were not assessed in 9% of patients (30), due to vaccination prior to change in practice or recent commencement on treatment. A protective antibody response to all serogroups after first vaccination was observed in 170 / 294 patients (57.8%) and a partial response (antibodies to 3 serotypes) in 51 /294 (17.3%). Revaccination of 51 partial responders resulted in an additional 21 patients with a full response. Revaccination of 73 non-responders (antibodies to 0-2 serotypes) resulted in 32 more partial or full responses. 287 of 324 patients received MenB vaccinations; median 2 vaccinations per patient (range 1 - 4). Eight of 324 (2%) patients with median age 22.5 years developed meningococcal sepsis (see table); patient 5 had 2 episodes. 3 of 5 cases with serogroup B infection were before serogroup B vaccination was introduced. The other 4 episodes in 3 patients were due to Y, C, W meningococci, in one the serogroup is unknown. All except patient 1 were compliant with antibiotic prophylaxis. Patient 7 died from meningococcemia, a delay in seeking medical attention may have contributed, however this was also a penicillin resistant strain. Discussion: We report the largest experience of managing meningococcal risk in patients on complement inhibitor therapy for PNH. Despite our proactive management we had 9 cases of meningococcal sepsis, with one fatal infection. Our most recently introduced practice of prompt treatment with ciprofloxacin if pyrexic on antibiotic prophylaxis will prevent cases like patient 7 with a penicillin resistant strain. Three patients had a meningococci sepsis with serogroups C, W and Y; whilst 1 patient had no check of titers due to recent commencement on treatment, the titres of the other 2 had suggested protective immunity. We demonstrated that a full antibody response can be obtained on a second vaccination in most patients if the first one failed. If no response is achieved upfront or revaccination then further MenACWY vaccination is not likely to be successful. Current practice significantly mitigates the risk of meningococcal disease, however it is essential patients remain vigilant for fever, seeking immediate medical attention stating their diagnosis of PNH on complement inhibitor therapy. Disclosures Arnold: Alexion Pharmaceuticals: Honoraria. Borrow:Pfizer: Research Funding; GlaxoSmithKline: Research Funding; Alexion pharmacueticals: Research Funding; Sanofi: Research Funding. Riley:Alexion: Honoraria. Munir:Alexion: Honoraria; F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Kelly:Alexion: Honoraria. Pike:Apellis: Research Funding. Hillmen:Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees.

Abstract: Introduction: There is strong evidence that the cytopenia(s) in MDS might be caused by excessive, cytokine induced, intramedullary apoptotic death of progenitor hematopoietic cells. TNFα is a key cytokine that may trigger and sustain the excessive apoptosis processes in early disease. Infliximab is a chimeric human-murine monoclonal antibody with high affinity for human TNFα. Infliximab effectively prevents TNFα specific signaling in immune mediated inflammatory diseases. The therapeutic potential of suppressing TNFα mediated apoptosis in MDS was investigated. Patients and methods: The EORTC LG conducted an open label 2-arm randomized, Simon 2-stage design, phase II study, with the primary objective of assessing the activity of two different dose levels of Infliximab, as single agent, in patients (pts) with low-/intermediate-risk MDS according to IPSS. Activity was assessed by response rate, using the International Working Group criteria: Complete Response (CR) + Partial Response (PR) + Hematological Improvement (HI). Toxicity was assessed as a secondary objective. Results: Between February 2004 and March 2006, 37 eligible/evaluable pts (targeted sample size for the analysis of first stage) were randomly assigned to receive Infliximab, 3 mg/kg (18 pts) vs 5 mg/kg (19 pts), intravenously on days 1 and 15, thereafter every 4 weeks, for a total of 8 courses. Baseline characteristics by treatment arm (3 mg/kg vs 5 mg/kg) were: median age (65 vs 69 years); IPSS risk score: low (2 vs 6 pts), Intermediate-1 (14 vs 10 pts), Intermediate-2 (2 vs 3 pts); cytogenetic risk group: good (9 vs 12 pts), intermediate (5 vs 4 pts), unknown (4 vs 3 pts). Treatment applicability (3 mg/kg vs 5 mg/kg): 20 pts (10 vs 10) completed the 8 cycles of therapy, and 17 pts (8 vs 9) stopped earlier due to: progressive disease (2 vs 4), excessive toxicity (3 vs 0), patient’s refusal (2 vs 2), death due to an unrelated cause (1 vs 1), other reasons (0 vs 2). Activity (3 mg/kg vs 5 mg/kg): 3 pts responded to treatment in the 3 mg/kg arm: 1 CR, 1 PR and 1 HI (neutrophils), while no patient responded in the 5 mg/kg arm. A total of 21 pts (7 vs 14) had stable disease, 11 pts (7 vs 4) had documented disease progression and 2 pts were inevaluable for response (1 vs 1). After a median follow-up of 1.5 years, 8 pts (6 vs 2) died. Adverse events: 3 out of 18 patients died due to infections in the 3 mg/kg arm vs 0/19 in the 5 mg/kg arm. Two of the lethal infections were considered likely related to protocol treatment: one patient developed a fatal mucormycosis during treatment and one patient developed a fatal sepsis shortly after the eighth Infliximab infusion and thereafter also had documented progression to AML. There were few other AE/toxicities. Conclusion: Infliximab in the 3 mg/kg dose/schedule showed some activity in this study. Infliximab has limited activity as single agent but may warrant further investigation in combination with other active agents. Patients must be monitored closely for occurrence of severe infections.

Abstract: Introduction In MDS-004, a phase 3, randomized, double-blind, placebo-controlled multicenter study, the efficacy and safety of LEN was evaluated in RBC transfusion-dependent pts with IPSS-defined Low-/Int-1-risk MDS and del(5q), with or without additional cytogenetic abnormalities (Fenaux P, et al. Blood. 2011;118:3765-76). LEN was recently approved in the European Union (EU) for RBC transfusion-dependent pts with IPSS-defined Low-/Int-1-risk MDS and isolated del(5q). This ad hoc analysis evaluated treatment responses, progression to acute myeloid leukemia (AML), overall survival (OS), and adverse events (AEs) in a subset of pts with isolated del(5q) from the MDS-004 study. Methods In MDS-004, pts were randomized to either LEN 10 mg/day on days 1–21 or LEN 5 mg/day on days 1–28 of each 28-day cycle; or placebo (PBO). Erythroid response was assessed at 16 weeks. Double-blind treatment continued until unacceptable toxicity, erythroid relapse, or disease progression. PBO or LEN 5 mg pts without response by 16 weeks crossed-over to open-label (OL) LEN 5 mg or 10 mg treatment, respectively. After 52 weeks, pts on double-blind treatment entered the OL phase at their current LEN dose (total study duration 156 weeks). The primary end-point was RBC-transfusion independence (TI) ≥ 182 days. Secondary end-points included duration of RBC-TI ≥ 182 days, cytogenetic response (CyR; IWG 2000), progression to AML, OS, and AEs. In this subset analysis of pts with isolated del(5q) at baseline from the MDS-004 study, RBC-TI ≥ 182 days and CyR were compared across treatment groups (LEN 10 mg vs PBO; and LEN 5 mg vs PBO). Progression to AML and OS were characterized by the Kaplan-Meier method from study randomization with differences evaluated by the log-rank test. Results A total of 135 of 205 pts randomized to treatment in the MDS-004 study had isolated del(5q) and were included in the intention-to-treat population for this analysis: LEN 10 mg (n = 47), LEN 5 mg (n = 43), and PBO (n = 45). Baseline characteristics were comparable across treatment groups; median age 69 years (range 36–86), 75% female, and median time since diagnosis 2.5 years (range 0.2–29.2). Median hemoglobin (Hb) level was 8.2 g/dL (range 5.6–11.2) and median transfusion burden was 6 units/8 weeks (range 1–25). Significantly more LEN 10 mg (57.4%) and LEN 5 mg (37.2%) pts achieved RBC-TI ≥ 182 days versus PBO (2.2%; both P 〈 0.001). Median duration of RBC-TI ≥ 182 days was not reached (NR) for the LEN 10 mg (95% CI 1.6 years–NR) and 5 mg groups (95% CI 0.8 years–NR). Median time to RBC-TI ≥ 182 days response was 4.3 weeks (95% CI 0.3–14.7) and 4.2 weeks (95% CI 0.3–12.3) for the LEN 10 mg and 5 mg groups, respectively. In pts with RBC-TI ≥ 182 days, median maximum Hb increases were 6.5 g/dL (range 8.8–14.4) and 5.4 g/dL (range 8.3–14.1) for the LEN 10 mg and 5 mg groups, respectively. CyR (major + minor response) was achieved in 56.8%, 23.1%, and 0% of pts in the LEN 10 mg, LEN 5 mg, and PBO groups, respectively (LEN 10 mg vs PBO, P 〈 0.001; LEN 5 mg vs PBO, P = 0.03). Of the pts randomized to PBO, 38 crossed over to LEN. In pts treated with LEN, the estimated 2-year cumulative risk of progression to AML was 13.8%. The rates for the estimated 2-year cumulative risk of progression to AML were 12.6% (95% CI 5.4–27.7), 17.4% (95% CI 8.7–33.3), and 16.7% (95% CI 8.3–32.0) in the LEN 10 mg, LEN 5 mg, and PBO groups, respectively (Figure 1A). Median OS was 4.0 years (95% CI 2.5–NR), 3.5 years (95% CI 1.7–4.8), and 2.9 years (95% CI 2.2–4.2) in the LEN 10 mg, LEN 5 mg, and PBO groups, respectively (Figure 1B). By landmark analysis (6 months), progression to AML was similar (P = 0.9883), but OS was longer (P = 0.0072) in LEN-treated pts who achieved RBC-TI ≥ 182 days versus non-responders. AEs included myelosuppression, with grade 3–4 neutropenia reported in 76.6%, 76.7%, and 17.8% of pts; and thrombocytopenia in 46.8%, 46.5%, and 2.2% of pts in the LEN 10 mg, LEN 5 mg, and PBO groups, respectively. Conclusions In this subset analysis of MDS-004 pts with isolated del(5q), LEN therapy was associated with a significant achievement of RBC-TI ≥ 182 days and CyR (57% of pts in the LEN 10 mg group for both RBC-TI and CyR), and had no negative impact on progression to AML or OS. The overall safety profile was well characterized and consistent with the known safety profile of LEN. These data support that LEN is beneficial for the treatment of RBC transfusion-dependent pts with Low-/Int-1-risk MDS and isolated del(5q). Disclosures: Giagounidis: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Mufti:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Mittelman:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sanz:Celgene Corp.: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Platzbecker:Celgene: Honoraria. Selleslag:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau. Beyne-Rauzy:Celgene Corporation: Research Funding; Roche: Research Funding. te Boekhorst:Novartis: Consultancy. del Cañizo:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Array: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Guerci-Bresler:Celgene: Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Amgen: Honoraria. Quesnel:Celgene: Research Funding. Bowen:Celgene: Honoraria. Schlegelberger:Celgene: Consultancy. Fu:Celgene: Employment, Equity Ownership. Benettaib:Celgene: Employment, Equity Ownership. Hellström-Lindberg:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Fenaux:Celgene: Honoraria.

Abstract: Abstract 3012 Poster Board II-988 PNH is a progressively debilitating and life-threatening disease characterized by chronic complement-mediated hemolysis. PNH evolves from a somatic mutation of the PIG-A gene in hematopoietic stem cells that leads to the loss of the GPI-anchored complement inhibitor proteins CD55 and CD59 on the surface of blood cells. The loss of complement inhibitors leads to complement-mediated hemolysis that underlies the life-threatening thrombosis, chronic kidney disease, pulmonary hypertension, and organ damage, as well as significant morbidities including impaired quality of life and anemia in PNH. PNH cells can be found in up to 70% of patients with aplastic anemia (AA), a bone marrow failure (BMF) syndrome, suggesting a common immune-mediated pathophysiology for the initial evolution of both PNH and AA. However, each disease is associated with different morbidities and mortality that requires distinct treatments. The aplasia of AA may be effectively treated with immunosuppressive therapy (IST). The unregulated terminal complement activation and hemolysis associated with PNH can be effectively treated with eculizumab, a humanized anti-C5 monoclonal antibody that inhibits terminal complement activation. We conducted a post hoc review of the PNH clinical trial database (N=195) to evaluate the efficacy and safety of eculizumab in a population of patients (n=17) receiving concomitant IST. In the first group, 12 patients (11 with AA; 1 pancytopenic) were started on cyclosporine A (CSA) from 9.8 to 160 months before eculizumab treatment. Patients were treated with CSA and concomitant eculizumab for a median of 2.5 years (8 patients maintained IST throughout the entire clinical program; 4 patients stopped IST). The median PNH granulocyte clone size was 88%. At baseline, despite IST, there was on-going hemolysis as measured by elevated LDH (median, 1,150 U/L), patients were severely fatigued (median FACIT-fatigue 22.8) and had substantial transfusion use (median 10 U/year per patient). The addition of eculizumab therapy significantly reduced hemolysis (P=0.002, 0.003, and 0.002 vs baseline, at 3, 6 and 12 months, respectively) and significantly improved fatigue (P=0.033, 0.042, and 0.024 vs baseline at 3, 6 and 12 months, respectively) in patients concomitantly treated with IST. Fatigue improved with eculizumab treatment without significant hemoglobin change and prior to a reduction in transfusion requirements (P=0.036 and 0.019 vs baseline at 6 and 12 months, respectively). In the second group, 5 patients started on IST treatment while already undergoing treatment with eculizumab. Patient medical history included 2 patients with pre-existing AA, 1 with pre-existing thrombocytopenia and 2 with no recorded pre-existing cytopenia. The median granulocyte clone size was 92 %. At the individual principal investigator's discretion, IST was started 1 to 19 months after the start of eculizumab.IST regimens included CSA alone (1), CSA/Azathioprine (1), CSA/ALG (1), CSA/ATG (1), or CSA/alemtuzmab (1). At the time of the first dose of IST, absolute neutrophil count (ANC) ranged from 0.9 to 1.1×109/L, platelet counts ranged from16 to 165 ×109/L and reticulocyte counts ranged from 1.9 to 7.5. Three of the five (60%) patients demonstrated a partial response to IST treatment added to eculizumab (Patient 1: Hgb increased +3.4 g/dL; Patient 2: platelet count increased 〉 2 fold, transfusion independent; Patient 3: ANC increased 〉 2 fold, transfusion independent). In both patient groups, the overall and infection-related adverse event rates and serious event rates (calculated as # events / patient / month) were similar to the overall clinical trial population and did not increase over time. In summary, PNH may be associated with some degree of bone marrow failure (frequently from mild cytopenia to severe AA). We show that patients with BMF and PNH treated with IST alone can continue to experience hemolysis, contributing to patient morbidities due to PNH. Patients with hemolysis who are already on IST can be given eculizumab, reducing hemolysis and subsequent morbidities. While eculizumab is approved to treat PNH patients with hemolysis it is not expected to affect the aplastic bone marrow component. A proportion of the patients who develop worsening cytopenias on eculizumab will respond to IST. Finally, we demonstrate that eculizumab appears well tolerated in patients requiring IST for their marrow failure. Disclosures: Schrezenmeier: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schubert:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Muus:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Socie:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Risitano:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hill:Alexion: Honoraria. Hillmen:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.