ALBERT

Description: Key Points rVIII-SingleChain is a novel rFVIII, designed to have high stability and high binding affinity for VWF. In severe hemophilia A patients, rVIII-SingleChain was well tolerated and resulted in low bleeding rates, when dosed twice per week.

Description: Key Points After DR3 activation, CD4+Foxp3+ regulatory T cells showed a distinct immune phenotype and function in acute GVHD. Prophylactic treatment with agonistic DR3 antibody to recipient mice abrogated the lethal acute GVHD in a time-dependent manner.

Description: Pediatric cancers are distinct from adult cancers in both their genomic alterations and therapeutic responses. Fms-like tyrosine kinase 3 (FLT3) mutations, especially internal tandem duplications (ITD), are among the most common mutations in acute myeloid leukemia (AML). FLT3-ITD mutations occur in approximately 15% of pediatric and 25-30% of adult AML, and are generally associated with poor prognosis. However, a number of studies have suggested that FLT3-ITD-positive(+) AML requires additional cooperative mutations. The objective of this study was to characterize the mutational landscape in a cohort of FLT3-ITD+ pediatric AML patients (median age,12.6 years; range, 2.8-19.2 years) enrolled to the AML02 and AML08 trials using samples obtained at diagnosis (n=34) and paired diagnosis/relapse samples (n=5). Children with promyelocytic leukemia were excluded. Samples were analyzed by RNASeq, a targeted 95 gene next generation sequencing (NGS) panel, and whole exome sequencing (WES). At diagnosis, 58.8% of the samples contained fusion genes; 41.2% were NUP98-NSD1, 11.8% were novel fusions (NSD1-CAPRIN1, NSD1-RALBP1, RUNX1-BCL11B, ZEB2-BCL11B), and 5.9% were previously reported fusions (CBFB-MYH11, DEK-NUP214). The NGS panel identified that WT1 and NPM1 were routinely mutated at a frequency of 32.4% and 20.6% respectively. While the NPM1 mutation was either a 4bp insertion at amino acid (a.a.) 287 or 288, WT1 mutations were heterogenenous with missense mutations, insertions and deletions all being reported. WT1 mutations and NUP98-NSD1 co-associated in 7 patients, 1 patient also harbored a TYK2 mutation; in the remaining 7 patients with NUP98-NSD1 fusions, a mutation in RAD21 or NRAS was observed in 2 patients. For samples with other fusions (n=6), we detected an average of 1 additional mutation per sample, which included mutations (variant allele frequency; VAF) in DNMT3A (0.44), IDH2 (0.49), KIT (0.37), NPM1 (0.51), PLCG2 (0.44), RAD21 (0.55), and SMC1A (0.47). No fusion genes were observed in 13 patients. In this latter subset, mutations in NPM1 (n=6) and WT1 (n=3) were observed. Other alterations that were identified in these samples included mutations in DNMT3A, IDH2, PLCG2, and PRKCB, which co-occurred with NPM1 mutations. Three patients did not harbor a fusion gene or a gene mutation by our analysis. When looking at cumulative incidence of relapse or resistant disease, our study results are concordant with previous reports where a NUP98-NSD1 fusion associated with worse prognosis (hazard ratio [HR] = 3.2, p = 0.02), but FLT3-ITD allelic ratio 〉0.4 was not prognostic (HR = 1.1, p=0.87). NPM1 mutations were not significantly associated with better prognosis (HR = 0.2, p = 0.11). We next sought to identify relapse specific alterations by analysis of paired diagnosis/relapse samples by RNASeq, NGS panel, and WES. Notably, the FLT3-ITD mutation was maintained at relapse in all samples. From the NGS panel, we observed the emergence of a MED12 mutation (P1751Q, VAF 0.37) and WT1 mutation (p.S152*, VAF 0.19) at relapse; a mutational switch in WT1 from diagnosis to relapse was also observed (5bp insertion at a.a. 157 to 2bp insertion at a.a. 158). By RNASeq analysis, we found a novel relapse specific fusion gene, LUZP6-OSBL1A. From exome sequencing, mutations in transcription factors were observed at relapse such as CREBBP, GLI3, and TBX20. Our analysis of relapse specific genes showed recurrent mutations in HUWE1, OGT, NACAD, and UNC13A. Intriguingly, both OGT and HUWE1 have been implicated in cancer metabolic reprogramming, and regulate MYC transcriptional programs. OGT is an O-Linked β-N-acetylglucosamine (O-GlcNAc) transferase involved post-translational modification of serine and threonine residues. HUWE1 is an E3 ubiquitin ligase that has been established as a tumor suppressor and previously reported to be mutated in AML. In conclusion, we demonstrate that additional genomic alterations are observed in the majority of pediatric FLT3-ITD+ AML samples evaluated, with a high proportion of samples containing fusion genes, WT1 and NPM1 mutations. We also identified novel fusion genes and mutations that have not been previously reported in pediatric FLT3-ITD+ AML, including relapse specific mutations. These results provide further biological insight into the genomic heterogeneity of pediatric FLT3-ITD+ AML, warranting further investigations in larger patient cohorts. Disclosures Inaba: Arog: Research Funding.

Description: Background : CD4+Foxp3+ regulatory T cells (Treg) are a subpopulation of T cells, which regulate the immune system and enhance immune tolerance after transplantation. Donor-derived Treg prevent the development of lethal acute graft versus host disease (GVHD) in murine models of allogeneic hematopoietic cell transplantation (HCT). We recently demonstrated that a single treatment of the agonistic antibody to DR3 (Death receptor 3, aDR3) to donor mice resulted in the expansion/activation of donor derived Treg and prevented acute GVHD (Blood 126:546, 2015), although the precise role of DR3 signaling in GVHD has not been elucidated. In this study, we investigated the efficacy of αDR3 treatment to recipient mice in model of murine GVHD. Methods To analyze the DR3 expression in immune cells with or without TCR stimulation, we comprehensively analyzed the cells with multicolor cytometry using viSNE (visualization of stochastic neighbor embedding algorithm). In transplantation experiments, 5x10e6 T cell depleted bone marrow (from WT C57BL/6 mice, H2kb) and 1x10e6 T cells (C57BL/6-Luciferase mice, H2kb) were injected intravenously into lethally irradiated (8Gy in total) BALB/c recipient mice (H2kd). aDR3 was intraperitonealy injected at different time point after transplantation. The transplanted mice were monitored by clinical GVHD score, weight, bioluminescence imaging (BLI) for donor T cell trafficking, and survival time. To investigate the role of donor or recipient derived Treg in this model, in vivo Treg depletion using B6-Foxp3DTR mice was also performed. Results viSNE analysis demonstrated that DR3 was preferentially expressed on resting-Treg (79%), although a subpopulation of CD4+Foxp3-T cells (59%), CD8+T cells (24%), and NK1.1+TCRb+NKT celsl (42%) also expressed DR3. However, DR3 expressions in CD4+Foxp3-T cells and CD8+T cells were elevated after TCR stimulation in vitro (p

Description: Hereditary spherocytosis (HS) is the most common congenital hemolytic anemia in Caucasians. Patients with HS show a high degree of phenotypic variability from asymptomatic to transfusion dependence. Much of this variability stems from HS not being a single uniform disorder but instead being a collection of disorders involving mutations in 5 different genes (ANK1, SPTB, SPTA1, SLC4A1, and EPB42 ) encoding for the 5 major cytoskeletal proteins in red blood cells (ankyrin, β and α spectrin, band 3, and protein 4.2 respectively). These proteins are responsible for maintaining the biconcave disk morphology of red blood cells. Traditionally the diagnosis of HS has been made without genetic testing. We believe that knowledge of the HS subtype may impact future clinical management decisions, e.g. what type of splenectomy to perform-partial vs total and impact on genetic counseling needs. As a result we are now pursuing genetic testing on all our patients with HS. Over the past 16 years at Sick Kids Hospital (Toronto, Canada), we have followed 257 children with HS. In the past year we have also been offering genetic testing (following informed consent) to all children (T in SPTA1 (referred to as the αLEPRA mutation) in 4 children/2 families with an α spectrin form of HS, and in another 2 children (1 family) with an ankyrin form of HS; 2) an ANK1 c.5097-33G〉A (8 children/6 families); 3) an ANK1 c.1405-9G〉A (4 children/3 families); 4) SPTB c.6037C〉T (3 children/2 families); and 5) SPTB c.5266C〉T (3 children/2 families). The ANK1 c.5097-33G〉A mutation had not been previously identified and yet was the most frequently detected mutation in our HS population. Most children (68/103) were found to have autosomal dominant (AD) HS: 33 children with the ankyrin subtype, 26 with the β spectrin subtype, 4 with the band 3 subtype and 5 in whom no mutation could be found but where there was a clear history of AD inheritance. Autosomal recessive (AR) inheritance was confirmed in 7 children - all 6 with α spectrin form of HS and 1 with a β spectrin form of HS. Twenty-eight children were spontaneous new mutations for HS: ANK (n=17), β spectrin (n=5), band 3 (n=3) and 3 in whom no mutation could be found. In all AR forms of HS, the index case had initially been thought to be a spontaneous new mutation for an AD form of HS; genetic testing resolved the inheritance pattern. Patients were categorized according to disease severity, primarily on the basis of their need for transfusions (a reflection of baseline hemoglobin) and splenectomy. The proportion of children that have required transfusions and needed splenectomies was: 83%/83% (α spectrin); 48%/18% (ankyrin), 23%/10% (β spectrin) and 29%/0% (band 3). Most children in our center undergoing splenectomy have undergone partial splenectomy; few have required subsequent total splenectomy. However, of the 5/6 children with α spectrin form of HS that underwent partial splenectomy 3 have subsequently needed, or are being considered for, total splenectomy. This suggests that due to the extreme severity of the α spectrin subtype of HS, children with this form of HS may not do well long-term with partial splenectomy and are likely to eventually require a total splenectomy. Our study to date represents one of the largest and most comprehensive genetic analyses of a cohort of HS patients. Our findings will add to the growing understanding of the disease, and will be important to provide comprehensive genetic counseling and possibly in the future to guide management of selected cases. Disclosures Drury: Prevention Genetics: Employment.

Description: Background:Dexrazoxane (DRZ) has been shown to have cardioprotective effects among doxorubicin-treated childhood cancer survivors up to 5-years after therapy completion, including effects on fractional shortening (FS%) and other parameters of left ventricular anatomy and function. However, data on longer-term effects are lacking. Methods: COG protocols P9404 (T-cell acute lymphoblastic leukemia/lymphoma; cumulative doxorubicin 360 mg/m2), P9425 (advanced stage Hodgkin lymphoma; cumulative doxorubicin 180-300 mg/m2), and P9426 (low/intermediate stage Hodgkin; cumulative doxorubicin 100-200 mg/m2) were phase 3 randomized clinical trials conducted between 1996 and 2001. Patients were randomly assigned to treatment with or without DRZ (10:1 mg dose ratio of DRZ:doxorubicin); DRZ was given as an intravenous bolus before each doxorubicin dose. Beginning in 2014, a subset of COG institutions began prospectively reassessing the cardiovascular health of long-term survivors in first complete remission treated on these 3 protocols, including echocardiography and selected blood biomarkers (e.g., high-sensitivity troponins, b-type natriuretic peptides [BNP], N-terminal [NT] proBNP). Echocardiograms and blood analytes were all processed centrally, with DRZ status masked. Results: To date, 94 participants (54% DRZ+; 57% male; average doxorubicin dose 279 mg/m2; current mean age 28 years and 16 years since cancer diagnosis) have been recruited from 30 institutions. Participants were similar with respect to demographic and treatment characteristics when compared by DRZ status. Overall, compared with DRZ+ participants, DRZ- participants had non-significantly reduced FS% (mean±SD: 33.0±4.8 vs. 34.8±4.6; p=0.10), but greater myocardial wall stress and dysfunction as measured by BNP (mean±SD: 18.3±14.7 vs. 11.3±10.6 pg/mL; p=0.02) and NT-proBNP (64.8±55.5 vs. 44.5±39.0 pg/mL; p=0.06). When the analysis was restricted to those who received the greatest doxorubicin exposure (P9404 participants, n=41), differences all became statistically significant (FS%: 31.3±3.9 vs. 34.9±3.7, p

Description: Introduction: Nearly 40% of adolescent women experience heavy menstrual bleeding (HMB), and identifiable bleeding disorders are diagnosed in only 20-60% of these patients. We suspect that qualitative platelet disorders contribute to HMB, but are under-diagnosed. A pilot study was conducted to evaluate platelet function in adolescent women with HMB employing four novel, small-volume, whole blood platelet function assays. In addition, primary and secondary hemostasis, bleeding phenotype, and quality of life were assessed. Methods: Patients referred to the Young Women's Hematology Clinic at Oregon Health & Science University for evaluation of HMB were offered participation in the study. Participants underwent standard review of their medical and family history and physical exam. Standard lab evaluation included CBC, PT, PTT, fibrinogen, thrombin time, Von Willebrand Panel, PFA-100, and iron studies with platelet aggregation or phenotyping performed if clinically indicated. Using less than 0.5 mL of whole blood, platelet function was assessed with four novel platelet function assays: assessment of platelet activation, secretion, and aggregation was assessed by flow cytometry analysis, while platelet adhesion and aggregation was assessed under shear in a capillary tube. Quality of life (QOL) was assessed using the PedsQL tool. Bleeding phenotype was assessed with the ISTH Bleeding Assessment Tool (ISTH BAT). Menorrhagia was assessed with the Pictorial Bleeding Assessment Chart (PBAC), the Philipp Tool and the clinical history. Results: Nine participants have enrolled on study to date, with 2 completing the 3-month visit. The median age of the cohort was 16 years (14-18 years). Eight out of nine categorized their period as heavy, 6 also had epistaxis, and 7 reported excessive bruising. The median ISTH BAT score was 4 (3-7). Of the 7 patients who had a Philipp Score obtained, 5 were positive. Median PBAC score was 161 (64-196). Median ferritin was 13 ng/mL (4-65 ng/mL). Median QOL psychosocial score was 70 (68.36-88.25), comparable to that of pediatric patients with cancer. Of the 9 participants, 6 had platelet aggregation and phenotyping. Four participants did not receive a bleeding disorder diagnosis, 1 was diagnosed with Type 1 VWD, 1 was diagnosed with bleeding disorder, NOS, and 1 was diagnosed with Ehlers Danlos Syndrome. Two participants were diagnosed with a qualitative platelet disorder (QPD): one based on platelet aggregation and one based on thromboelastography. The four novel platelet function assays confirmed platelet function abnormalities in the participants diagnosed with QPD's (Figure 1&2). Impaired platelet response to agonist stimulation was also observed in participants with non-platelet disorder bleeding disorder diagnoses and in participants without a bleeding disorder diagnosis. Conclusions: In this pilot study, the etiology of HMB in adolescent women was evaluated with four novel platelet assays in addition to standard assays of hemostasis. A bleeding disorder diagnosis was not made with standard evaluations in 4 out of 9 participants. The novel assays detected platelet abnormalities not observed using currently available clinical labs, and confirmed the presence of abnormal platelet function in participants with abnormal platelet function testing. These assays require significantly less blood volume than currently available assays and expand investigation of platelet function to platelet adhesion and platelet interactions in whole and flowing blood. Further work is needed to determine the sensitivity and specificity of the novel assays in detecting platelet dysfunction. Continued investigation into the impact of HMB on the adolescent female population is needed. Disclosures Haley: CSL Behring: Honoraria; Baxalta: Membership on an entity's Board of Directors or advisory committees. Recht:Biogen: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding; Genentech: Research Funding; Novo Nordisk: Research Funding; Baxalta: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Description: Background: Chronic graft versus host disease (CGVHD) remains a notable cause of post transplant morbidity and mortality, limiting quality of life and survival in the allogeneic transplant survivor. CD4+CD25+CD127dimFoxP3+ regulatory T cells (Treg) are a naturally occurring cell population isolatable in the peripheral blood (PB) with key immune regulatory function. Treg have been shown to protect against GVHD in a number of murine models and in patients. Further, clinical correlations have been observed between the presence of CGVHD and a decreased frequency of Treg post allogeneic hematopoietic cell transplant (HCT) as well as the use of low dose IL-2 resulting in clinical responses with an associated increase in Treg. Based on these observations we embarked on a phase I safety and tolerability trial of the treatment of steroid-refractory or dependent CGVHD with infusion of donor Treg in matched related donor recipients. Methods: Eligible patients were ³ 18 years of age with steroid refractory or dependent CGVHD with a matched related HCT donor. All patients were on systemic immunosuppression at the time of enrollment. Donor derived Treg were enriched from a non-mobilized PB apheresis product over 2 days of apheresis. The fresh apheresis product underwent enrichment by CD25+ immunomagnetic selection on the CliniMACS¨ Cell Selection System (Miltenyi Biotec) and Treg were purified by high-speed flow cytometry and gated on the CD4+CD127dim population. The functional activity of the Treg product was assessed via a mixed lymphocyte reaction (MLR). The trial dosing was through a 3+3 dose escalation design with three Treg dose cohorts: 1 x 10E5 Treg/kg, 5 x 10E5 Treg cells/kg and 1.5 x 10E6 Treg cells/kg. Results: Ten patients were enrolled and received donor Treg cell infusions. Isolation of highly purified Treg was successful from all donors. A median of 1.9x10E8 (range 0.9-2.78x10E8) Treg were collected with a purity that ranged from 87.1-99.3% FoxP3+ (Table 1). Function of the Treg enriched apheresis product confirmed Treg suppressive activity with a median suppression of 69.1% (48.7-77.2%) at a ratio of responder cells:CD4+/CD8+:Treg cells of 1:2:1, with sustained suppression to a ratio of 1:2:0.1. All 10 pateints were treated with three patients treated on all three dose cohorts and an additional patient was treated on the third cohort due to the planned cell dose being not reached with the third patient-donor pair. There were no adverse toxicities with the Treg infusion and no incidence of acute GVHD or acute exacerbation of CGVHD. The ratio of Treg/CD4+ cells in the patients' PB ranged from 2-4.4% at the time of the infusion and remained stable

Description: Red cells synthesize large quantities of heme during terminal differentiation. Central to erythropoiesis is heme synthesis, which requires tight coordination between mitochondrial iron import and synthesis of protoporphyrin IX (PPIX). Most individuals with erythropoietic porphyria carry loss of function mutations in FECH, or gain of function mutations in ALAS2, resulting in protoporphyrin IX accumulation. We performed whole exome sequencing to identify novel mutations in an individual exhibiting symptoms in whom FECH and ALAS2 mutations were absent (Fig. A, asterisk). We identified a novel CLPX point mutation in this individual (III.2), her father (II.4) and her paternal uncle (II.2), who also exhibited increased porphyrin levels relative to healthy individuals. The individual's mother was healthy and had a wild-type CLPX genotype (Fig. A). CLPX encodes a mitochondrial protein unfoldase that partially unfolds ALA synthase (ALAS) to allow efficient incorporation of its cofactor, pyridoxal phosphate (Kardon et al. 2015 Cell). This greatly stimulates the synthesis of d-aminolevulinic acid (ALA), the first step in heme biosynthesis. To determine if the CLPX mutation was causative for porphyria, we expressed mutant CLPX in HEK293T embryonic kidney cells and Friend mouse erythroleukemia (MEL) cells. Mutant CLPX expression (MUT) caused a significant increase in ALAS1 (non-erythroid isoform) (Fig. B) and ALAS2 (erythroid isoform) (Fig. C) activity relative to control and wild-type CLPX expressing samples (WT). This increase in ALAS enzymatic activity translated to an increase in PPIX levels (Fig. D, E), consistent with the porphyria phenotype observed in the individuals in this study. We observed that MUT-expressing samples had increased levels of ALAS1 and ALAS2. To determine if mutant CLPX altered ALAS protein stability, we transfected WT or MUT CLPX into HEK293T and MEL cells. Cells were treated with cycloheximide to block translation. We quantitated degradation rate of ALAS by western blot analysis of cell lysates obtained at several time points after cycloheximide treatment (chase). Expression of MUT CLPX stabilized both ALAS1 and ALAS2, accounting for the increase in ALAS protein levels, activity and downstream production of PPIX. The control of ALAS enzymatic activity and protein stability by CLPX unveils a novel cause of protoporphyria and insights revealing the ways in which mitochondrial physiology and heme synthesis are interdependent. Our results reveal an important regulatory node where the mitochondrial protein quality control machinery intersects with a key step in heme synthesis and provides an important genetic tool for understanding the pathology of porphyrias. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Background: Studies have shown that hypomethylating agents (HMAs), including 5-AZA and decitabine (Dac) are well-tolerated antileukemic agents (Kantarjian et al, JCO, 2012). Despite its myelosuppressive effect, Dac has low extramedullary toxicities, making it an attractive drug for allogeneic hematopoietic cell transplant (HCT). Reports suggest that HMAs selectively upregulate tumor associated antigens (TAAs) on malignant cells without expression in healthy tissue (Cruijsen, 2016). We previously reported on a series of 20 patients (pts) in a phase I study of 5-day Dac plus mini fludarabine and busulfan (DacMiniFluBu) in elderly or medically infirm pts (Baker et al, Blood, 2012). In the current analysis, we compared updated results from our DacFluBu study with a historical MiniFluBu control group in pts with MDS or AML. Methods: Pts were evaluated to assess engraftment, toxicity, disease response, PFS and OS. Pts received Dac 20 mg/m2/day on days (d) -15 to -11, Flu 30 mg/m2/day, on d -7 to -3 and Bu 130 mg/m2 on d -4 and -3. The control group received Flu 30 mg/m2 on d -6 to -2 and Bu 130 mg/m2 on d -3 and -2. Both groups received thymoglobulin 2 mg/kg IV on d -3, -2 and -1, followed by infusion of donor stem cells on d 0. Immunosuppression consisted of tacrolimus starting on d -2 and MTX 5 mg/m2 IV on d +1, 3, 6, and 11. Results: 107 pts were analyzed between 5/2009 and 8/2015; 36 pts received DacMiniFluBu; 17 with MDS, and 19 with AML. 23 (64%) had unrelated donors (URD); 13 (36%) had sibling donors. 71 pts were included in the MiniFluBu control group for comparison; 33 with MDS, and 38 with AML. 53 (75%) had URD; 18 (25%) had sibling donors. Median age was 68.5 yrs compared to 66 yrs, respectively. Cohorts were comparable for gender, disease and graft source. The incidence of severe (gr III/IV) acute GVHD (aGvHD) was 22% compared to the control group of 6% (p=0.0195). Moderate or severe cGVHD was seen in 7 pts vs 22 in the control group (p=0.2535). The median follow-up in the DacMiniFluBu group was 262 d, OS was 35%, relapse incidence was 28%, and NRM at 6 mos was 22%. In the control group, the median follow-up was 424 d (p=0.2213), OS was 34%, relapse was 41%, and NRM was 15%. Median time to relapse in the study vs control group was 142 and 149 d (p=0.8722). There were 22 deaths after DacMiniFluBu and 43 after MiniFluBu (p=0.7382). 6 pts in the study group received DLI at a median of 170 d post HCT for either relapse (n=3) or falling chimerism (n=3) compared to 16 pts in the control group at a median of 183 d. Multivariate analysis was performed to estimate the cumulative incidence of severe aGvHD by regimen. Results showed that conditioning regimen (HR=3.98, 95% CI, p=0.0197), degree of match (HR=1.365, p=0.039) and non-hematologic (heme) gr IV events (HR= 4.266, p=0.029) were all significant independent factors predicting a higher incidence of severe aGvHD. Conclusions: There were no significant differences in the cumulative incidences of relapse or survival between pts receiving DacMiniFluBu and MiniFluBu. However, the risk of severe aGvHD was 4 times greater in DacMiniFluBu recipients when controlling for infections, degree of match, and non-heme gr IV events. Findings were confirmed in univariate and multivariate analyses. This may be explained by the increased expression of TAAs in healthy tissues in response to Dac, which evoke T cell responses. This is the first report showing that adding Dac to the MiniFluBu regimen was an independent risk factor for severe aGvHD. Other findings in our analysis linking age, risk stratification, and degree of match to GvHD are consistent with prior reports. The differences between our results and those of other studies warrant larger validation analyses. Dac as part of a conditioning regimen should only be used in context of a clinical trial. Table Table. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Skarbnik: Genentech: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Vesole:Amgen: Speakers Bureau; Novartis: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; Takeda: Speakers Bureau. Goy:Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Johnson & Johnson: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Writing support, Speakers Bureau.