Citations

Mucopolysaccharidosis type I (MPS I) is caused by the deficiency of α-l-iduronidase, leading to the storage of dermatan and heparan sulfate. There is a broad phenotypical spectrum with the presence or absence of neurological impairment. The classical form is known as Hurler syndrome, the intermediate form as Hurler–Scheie, and the most attenuated form is known as Scheie syndrome. Phenotype seems to be largely influenced by genotype. Patients usually develop several somatic symptoms such as abdominal hernias, extensive dermal melanocytosis, thoracolumbar kyphosis odontoid dysplasia, arthropathy, coxa valga and genu valgum, coarse facial features, respiratory and cardiac impairment. The diagnosis is based on the quantification of α-l-iduronidase coupled with glycosaminoglycan analysis and gene sequencing. Guidelines for treatment recommend hematopoietic stem cell transplantation for young Hurler patients (usually at less than 30 months of age). Intravenous enzyme replacement is approved and is the standard of care for attenuated—Hurler–Scheie and Scheie—forms (without cognitive impairment) and for the late-diagnosed severe—Hurler—cases. Intrathecal enzyme replacement therapy is under evaluation, but it seems to be safe and effective. Other therapeutic approaches such as gene therapy, gene editing, stop codon read through, and therapy with small molecules are under development. Newborn screening is now allowing the early identification of MPS I patients, who can then be treated within their first days of life, potentially leading to a dramatic change in the disease’s progression. Supportive care is very important to improve quality of life and might include several surgeries throughout the life course.

Giant cell tumor of bone (GCT) is a benign locally aggressive neoplasm composed of mononuclear cells admixed with innumerable osteoclast-type giant cells. H3F3A gene mutations producing mutant histone protein product H3.3 have been identified in 96% of GCT; mutant H3.3 is reliably demonstrated by immunohistochemistry. GCT may contain woven bone and rarely, neoplastic cartilage nodules which causes diagnostic challenges with aggressive neoplasms such as osteosarcoma. We describe the features of GCT with cartilage matrix and report the next-generation sequencing findings in a subset of tumors. Seventeen cases of GCT with cartilage matrix form the cohort: 7 males and 10 females, 13 to 55 (mean: 25) years old. Tumors involved the fibula (6), femur (6), and patella, tibia, humerus, S1, and scapula (1 case each). Tumors were radiolucent, circumscribed, lytic, and expansile. All contained classic GCT, foci of cartilage matrix, and trabeculae of woven bone. Immunohistochemistry showed diffuse staining for H3.3 in 9/9 cases and 1 case was positive for S100 and SOX9 in the cartilage areas. Next-generation sequencing showed a mutation in the H3F3A gene in 6/6 cases. On follow-up, 2 patients who underwent resection showed no disease after 12, and 7 months, respectively. Three patients had recurrences 10, 12, and 27 months after curettage; there were no metastases. GCT with cartilage matrix is uncommon. The cartilage matrix is associated with woven bone suggesting the neoplastic cells may differentiate into chondrocyte-like and osteoblast-like cells. Recognition of this neoplasm is important to prevent misdiagnosis and overtreatment of affected patients.

AbstractBackgroundThe AdaptivCRT (aCRT) algorithm continuously adjusts cardiac resynchronization therapy (CRT) according to intrinsic atrioventricular conduction, providing synchronized left ventricular pacing in patients with normal PR interval and adaptive BiV pacing in patients with prolonged PR interval. Previous analyses demonstrated an association between aCRT and clinical benefit. We evaluated the incidence of patient mortality and atrial fibrillation (AF) with aCRT compared with standard CRT in a real‐world population.Methods and ResultsPatients enrolled in the Medtronic Personalized CRT Registry and implanted with a CRT from 2013‐2018 were divided into aCRT ON or standard CRT groups based upon device‐stored data. A Frailty survival model was used to evaluate the potential survival benefit of aCRT, accounting for patient heterogeneity and center variability. Daily AF burden and first device‐detected AF episodes of various durations were recorded by the device during follow‐up.A total of 1814 CRT patients with no reported long‐standing AF history at implant were included. Mean follow‐up time was 26.1 ± 16.5 months and 1162 patients (64.1%) had aCRT ON. Patient survival probability at 36 months was 88.3% for aCRT ON and 83.7% for standard CRT (covariate‐adjusted hazard ratio [HR] = 0.71, 95% CI: 0.53‐0.96, P = .028). Mean AF burden during follow‐up was consistently lower in aCRT ON patients compared with standard CRT. At 36 months, the probability of AF was lower in patients with aCRT ON, regardless of which AF definition threshold was applied (6 minutes‐30 days, all P < .001).ConclusionUse of the AdaptivCRT algorithm was associated with improved patient survival and lower incidence of AF in a real‐world, prospective, nonrandomized registry.

In the murine venous thrombosis model induced by ligation of the inferior vena cava (IVCL), genetic deficiency of heme oxygenase-1 (HO-1) increases clot size. This study examined whether induction of HO-1 or administration of its products reduces thrombosis. Venous HO-1 upregulation by gene delivery reduced clot size, as did products of HO activity, biliverdin, and carbon monoxide. Induction of HO-1 by hemin reduced clot formation, clot size, and upregulation of plasminogen activator inhibitor-1 (PAI-1) that occurs in the IVCL model, while leaving urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA) expression unaltered. The reductive effect of hemin on clot size required HO activity. The IVCL model exhibited relatively high concentrations of heme that peaked just before maximum clot size, then declined as clot size decreased. Administration of hemin decreased heme concentration in the IVCL model. HO-2 mRNA was induced twofold in the IVCL model (vs. 40-fold HO-1 induction), but clot size was not increased in HO-2 −/− mice compared with HO-2 +/+ mice. Hemopexin, the major heme-binding protein, was induced in the IVCL model, and clot size was increased in hemopexin −/− mice compared with hemopexin +/+ mice. We conclude that in the IVCL model, the heme-degrading protein HO-1 and HO products inhibit thrombus formation, as does the heme-binding protein, hemopexin. The reductive effects of hemin administration require HO activity and are mediated, in part, by reducing PAI-1 upregulation in the IVCL model. We speculate that HO-1, HO, and hemopexin reduce clot size by restraining the increase in clot concentration of heme (now recognized as a procoagulant) that otherwise occurs. NEW & NOTEWORTHY This study provides conclusive evidence that two proteins, one heme-degrading and the other heme-binding, inhibit clot formation. This may serve as a new therapeutic strategy in preventing and treating venous thromboembolic disease.

Abstract Background The aim of this study was to review risk factors for conversion in a cohort of patients with rectal cancer undergoing minimally invasive abdominal surgery. Methods A retrospective analysis was performed of consecutive patients operated on from February 2005 to April 2018. Adult patients undergoing low anterior resection or abdominoperineal resection for primary rectal adenocarcinoma by a minimally invasive approach were included. Exclusion criteria were lack of research authorization, stage IV or recurrent rectal cancer, and emergency surgery. Risk factors for conversion were investigated using logistic regression. A subgroup analysis of obese patients (BMI 30 kg/m2 or more) was performed. Results A total of 600 patients were included in the analysis. The overall conversion rate was 9·2 per cent. Multivariable analysis showed a 72 per cent lower risk of conversion when patients had robotic surgery (odds ratio (OR) 0·28, 95 per cent c.i. 0·15 to 0·52). Obese patients experienced a threefold higher risk of conversion compared with non-obese patients (47 versus 24·4 per cent respectively; P &lt; 0·001). Robotic surgery was associated with a reduced risk of conversion in obese patients (OR 0·22, 0·07 to 0·71). Conclusion Robotic surgery was associated with a lower risk of conversion in patients undergoing minimally invasive rectal cancer surgery, in both obese and non-obese patients.

OBJECTIVE Traditionally, stent-assisted coiling and balloon remodeling have been the primary endovascular treatments for wide-necked intracranial aneurysms with complex morphologies. PulseRider is an aneurysm neck reconstruction device that provides parent vessel protection for aneurysm coiling. The objective of this study was to report early postmarket results with the PulseRider device. METHODS This study was a prospective registry of patients treated with PulseRider at 13 American neurointerventional centers following FDA approval of this device. Data collected included clinical presentation, aneurysm characteristics, treatment details, and perioperative events. Follow-up data included degree of aneurysm occlusion and delayed (> 30 days after the procedure) complications. RESULTS A total of 54 aneurysms were treated, with the same number of PulseRider devices, across 13 centers. Fourteen cases were in off-label locations (7 anterior communicating artery, 6 middle cerebral artery, and 1 A 1 segment anterior cerebral artery aneurysms). The average dome/neck ratio was 1.2. Technical success was achieved in 52 cases (96.2%). Major complications included the following: 3 procedure-related posterior cerebral artery strokes, a device-related intraoperative aneurysm rupture, and a delayed device thrombosis. Immediately postoperative Raymond-Roy occlusion classification (RROC) class 1 was achieved in 21 cases (40.3%), class 2 in 15 (28.8%), and class 3 in 16 cases (30.7%). Additional devices were used in 3 aneurysms. For those patients with 3- or 6-month angiographic follow-up (28 patients), 18 aneurysms (64.2%) were RROC class 1 and 8 (28.5%) were RROC class 2. CONCLUSIONS PulseRider is being used in both on- and off-label cases following FDA approval. The clinical and radiographic outcomes are comparable in real-world experience to the outcomes observed in earlier studies. Further experience is needed with the device to determine its role in the neurointerventionalist’s armamentarium, especially with regard to its off-label use.

Abstract The IGHV4-34 gene is very frequent (~10%) in the B cell receptor immunoglobulin (BcR IG) gene repertoire of chronic lymphocytic leukemia (CLL). Over 30% of IGHV4-34 CLL cases can be assigned to different subsets with stereotyped BcR IG. The largest is subset #4 which represents ~1% of all CLL and ~10% of IGHV4-34 CLL and is considered a prototype for indolent disease. The BcR IG of a great majority (~85%) of IGHV4-34 CLL cases carry a significant load of somatic hypermutation (SHM), often with distinctive SHM patterns. This holds especially true for stereotyped subsets and is suggestive of particular modes of interactions with the selecting antigen(s). In detail, subsets #4 and #16, both involving IgG-switched cases (IgG-CLL), exhibit the greatest sequence similarity in SHM profiles, whereas they differ in this respect from IgM/D subsets #29 and #201. Prompted by these observations, here we explored the extent that these subset-biased SHM profiles in different IGHV4-34 stereotyped subsets were reflected in distinct demographics, clinical presentation, genomic aberrations and outcomes. Within a multi-institutional series of 20,331 CLL patients, 1790 (8.8%) expressed IGHV4-34 BcR IG. Following established bioinformatics approaches for the identification of BcR IG stereotypy, 573/1790 IGHV4-34 CLL cases (32%) were assigned to stereotyped subsets; of these, 340 cases (19% of all IGHV4-34 CLL and 60% of stereotyped IGHV4-34 cases) belonged to subsets #4, #16, #29 and #201, all concerning IGHV-mutated CLL (M-CLL). Clinicobiological information was available for 275/340 patients: #4, n=150; #16, n=44; #29, n=39; and #201, n=42. Comparisons between subsets revealed no differences in gender and age distribution. Interestingly, however, 36-43% of each subset cases were young for CLL (defined as patients aged ≤55 years), which is higher compared to general CLL cohorts, where young patients generally account for ~25% of cases. In contrast, significant differences were identified between subsets regarding: (i) disease stage at diagnosis, with >90% of IgG subsets #4 and #16 diagnosed at Binet stage A versus 83% in subset #201 and 74% in subset #29 (p=0.029); (ii) CD38 expression, ranging from 1% in subset #4 to 10% in subset #201 (p=0.013); (iii) the distribution of del(13q), peaking at a remarkable 92% in subset #29 versus only 37% in subset #16 (p<0.0001). Regarding other genomic aberrations, they were either absent (NOTCH1 mutations) or rare (SF3B1 mutations, trisomy 12, del(11q), TP53 aberrations due to either del(17p) and/or TP53 mutations). The sole exception concerned a high frequency (14%) of TP53 aberrations in subset #29 (p<0.05 compared with the other subsets), which is notable for M-CLL cases in general. Time to first treatment (TTFT) could be analyzed in 228 cases. IgG subsets #4 and #16 had significantly (p=0.036) longer TTFT (median TTFT: not yet reached) compared to the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). In conclusion, we have identified distinct clinicobiological profiles for different stereotyped IGHV4-34 M-CLL subsets, highlighting subsets #4 and #16 as particularly indolent, which is important for both medical and social reasons, especially considering that a significant proportion of patients in these subsets are diagnosed at younger ages. Our findings support the notion that BcR IG stereotypy refines prognostication in CLL, superseding the crude immunogenetic distinction based on SHM load only. Additionally, the observed heterogeneity suggests that not all M-CLL are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management. Disclosures Tausch: Gilead: Other: Travel support. Shanafelt:Glaxo-Smith_Kline: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Polyphenon E Int'l: Research Funding; Hospira: Research Funding; Janssen: Research Funding; Pharmactckucs: Research Funding; Cephalon: Research Funding. Niemann:Gilead: Consultancy; Janssen: Consultancy; Roche: Consultancy; Novartis: Other: Travel grant. Langerak:InVivoScribe: Patents & Royalties: Licensing of IP and Patent on BIOMED-2-based methods for PCR-based Clonality Diagnostics.; DAKO: Patents & Royalties: Licensing of IP and Patent on Split-Signal FISH. Royalties for Dept. of Immunology, Erasmus MC, Rotterdam, NL; Roche: Other: Lab services in the field of MRD diagnostics provided by Dept of Immunology, Erasmus MC (Rotterdam). Hallek:Celgene: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; AbbVie: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Roche: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Boehringher Ingelheim: Honoraria, Other: Speakers Bureau and/or Advisory Boards; Pharmacyclics: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Mundipharma: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Janssen: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding; Gilead: Honoraria, Other: Speakers Bureau and/or Advisory Boards, Research Funding. Ghia:Janssen Pharmaceuticals: Research Funding.

Introduction: Patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) who failed treatment with the Bruton's tyrosine kinase inhibitor (BTKi) ibrutinib have a poor outcome and are difficult to treat. This ongoing, two-cohort, Phase II trial evaluates the safety and preliminary efficacy of tafasitamab (MOR208), an Fc-enhanced anti-CD19 monoclonal antibody in combination with idelalisib (IDE) (Cohort A) or venetoclax (VEN) (Cohort B) in R/R CLL pts previously treated with a BTKi. Preliminary results were published at EHA 2018 for Cohort A and at ASH 2018 for Cohort B. Here, we report the results of the primary analysis for both cohorts. Methods and Patients: Pts who either progressed or were intolerant to BTKi were enrolled at 12 sites in six countries in Europe and the US from Nov 2016 to Apr 2018. The primary endpoint is the incidence and severity of adverse events (AEs); secondary endpoints include overall response rate (ORR) as per investigator assessment according to International Workshop on CLL (IWCLL) 2008 guidelines. Complete response (CR) was confirmed by computed tomography assessment and by bone marrow (BM) biopsy. The exploratory endpoint minimal residual disease (MRD) was assessed centrally by quantitative allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in peripheral blood (PB) and BM. Each treatment cycle (C) lasts 28 days (D). Dose and administration: tafasitamab intravenous infusion, 12 mg/kg weekly in C1-C3, every other week in C4-C6 and monthly from C7D1; IDE orally, 150 mg twice daily; VEN orally, weekly ramp up starting on C1D8 at 20 mg to full daily dose of 400 mg. Patients: mean time since first CLL diagnosis was 135 months (mos) for pts in Cohort A and 105 mos in Cohort B. Median number of prior therapy lines was five (2-9) and three (1-5), respectively. All pts had received ibrutinib; one pt had subsequent acalabrutinib treatment as last prior therapy line. Mutations of BTK and PLCγ2 were assessed in nine pts in Cohort A and 13 pts in Cohort B. BTK/PLCγ2 mutations were centrally detected in 4/3 pts in Cohort A and in 2/3 pts in Cohort B, respectively. Complex karyotype was observed in six (54.5%) pts in Cohort A and 12 (92.3%) pts in Cohort B. Results with a data cut-off date of 9 Nov 2018 are presented. Results: Cohort A: Median time on study was 9.9 mos (95% confidence interval [CI]: 5.7-not reached). Eleven pts were enrolled and received tafasitamab and IDE. Two pts discontinued treatment due to AEs (aspartate-aminotransferase increased; acute pancreatitis), two due to progressive disease (PD) and one pt by physician's decision. One pt died due to PD and one pt due to cardiac failure. At the cut-off date, treatment was ongoing in four pts. Table 1 summarizes treatment-emergent adverse events (TEAEs) with neutropenia Grade ≥3 being most common (5 [46%]). Fourteen treatment-emergent serious AEs (SAEs) were reported in eight (72.7%) pts. ORR was 90.9% (CR=9.1%, partial response [PR]=81.8%), disease control was achieved in all 11 pts. One of eight pts (12.5%) assessed for MRD status reached MRD-negativity in PB at C14. Cohort B: Median time on study was 12 mos (95% CI: 2.8-not reached). Eleven of 13 enrolled pts received tafasitamab and VEN while two pts received tafasitamab only. Three pts discontinued treatment due to AEs (infusion-related reactions [two pts], diarrhea [one pt], one due to PD and one withdrew consent. At the cut-off date, treatment was ongoing in eight patients. Table 2 summarizes TEAEs, neutropenia Grade ≥3 was most commonly observed (six [46%] pts). Fourteen SAEs were reported in nine (69.2%) pts. The ORR in all 13 pts was 76.9% (CR=23.1%, PR=53.8%, not evaluable=23.1%). Six of seven pts assessed for MRD in PB (46.2% of 13 [100%] pts) reached negative status in PB by C7 at the latest. One of three pts assessed for MRD in BM (7.7% of 13 [100%] pts) reached MRD negative status in BM at C15. Conclusions: This trial demonstrates that in heavily pretreated pts with R/R CLL who failed prior BTKi, tafasitamab in combination with IDE or VEN is a potential therapeutic option. The safety profiles of the combinations are influenced by the combination partner, but both combinations are manageable. The response rates and MRD-negativity rates indicate that combinations of targeted agents with anti-CD19 tafasitamab have valuable antitumor activity and warrant further investigation of tafasitamab-based combinations in CLL. Disclosures Staber: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda-Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jurczak:Celtrion: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Research Funding; Celgene Corporation: Research Funding; Incyte: Research Funding; Servier: Research Funding; Roche: Research Funding; Novo Nordisk: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Gilead: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Brugger:AstraZeneca: Equity Ownership; MorphoSys: Employment. Chanan-Khan:Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; Xencor: Research Funding; AbbVie: Research Funding. Greil:Mundipharma: Honoraria, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Sanofi Aventis: Honoraria; Sandoz: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Eisai: Honoraria; Janssen-Cilag: Honoraria; Cephalon: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Boehringer Ingelheim: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Ratiopharm: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Dirnberger-Hertweck:MorphoSys: Employment. Kelemen:MorphoSys: Employment. Middeke:Janssen: Consultancy, Speakers Bureau; MSD: Consultancy; AbbVie: Consultancy, Speakers Bureau; Gilead: Consultancy; Roche: Speakers Bureau; Sanofi: Research Funding, Speakers Bureau. Montillo:Roche: Consultancy, Honoraria, Research Funding; Acerta: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Versatem: Membership on an entity's Board of Directors or advisory committees. Munir:Acerta: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Other: TBC; AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy. Parikh:Pharmacyclics: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; MorphoSys: Research Funding; Acerta Pharma: Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Research Funding. Stilgenbauer:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffmann La-Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Weirather:MorphoSys: Employment. Woyach:Janssen: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding; Karyopharm: Research Funding; Loxo: Research Funding; Morphosys: Research Funding; Verastem: Research Funding. Wendtner:AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Hoffman-La Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.