ALBERT

Description: Prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1+ ALL) has been considerably improved since the beginning of the BCR-ABL1 tyrosine kinase inhibitors (TKI) era 20 years ago. However, the prognosis of patients with a refractory/relapsed (including molecular relapse) disease is still very dismal. New drugs or combination of new drugs may improve outcomes of these patients. For example, ponatinib, a 3rd-generation oral TKI, known to have activity against BCR-ABL1 T315I mutations, has shown some efficacy in this context. Similarly, a recent study has reported very encouraging results of the bispecific anti-CD3/CD19 monoclonal antibody blinatumomab as single-agent in refractory/relapsed Ph1+ ALL. Data regarding the efficacy and tolerance of a combination of blinatumomab+ponatinib (blina/pona) are still scarce. This was a retrospective study with the aim to report outcomes of patients receiving a combination of blina/pona for refractory/relapsed Ph1+ ALL in France. Fifteen adults from 8 French centers were identified and data were collected by physicians of each centers, then gathered for the purpose of this study. There were 9 males and 6 females, with a median age of 53 years (range:17-72). All patients, but 2 with blast crisis of chronic myeloid leukemia, had de novo Ph1+ ALL. Four cases had BCR-ABL1 T315I mutation. Patients received the blina/pona combination, either after a first (n=8) or a second (n=7) cytologic relapse. There was no refractory patient in theses series. Previous allograft and autograft has been performed in 7 and 2 patients, respectively. The majority of patients (n=12) had previously received 2 or more lines of TKI. The median time between the first cycle of blina/pona and diagnosis was 14 months (range: 8-40). The median number of blinatumomab cycle (28 mg/day by continuous infusion for 28 days every 6 weeks) administered per patient was 3 (range: 1-6) while ponatinib was concomittantly administered continuously at an initial dose of 45 mg once daily in 11 pts (73%) and 30 mg in 4 pts (27%). Median duration of ponatinib administration was 4 months (range: 1.1-10.9) from first blinatumomab cycle. The toxicity profile was safe: all patients received a complete first cycle without grade 3-4 adverse events. After cycle 1, blinatumomab was stopped in 47% of cases because of neurologic events in 4 and infections in 3; ponatinib was stopped in 33% of cases because of neurologic events in 3, fluid retention in 1 and severe arteriopathy in 1 patient with other vascular disease risk factors. All neurologic events resolved after stopping blinatumomab or ponatinib. The majority of patients were evaluated after one cycle (n=11, after cycle 2 n=3, after cycle 3 n=1). All but one patients (93%) obtained a cytologic complete remission (CR), of whom 12/14 (86%) achieved a complete molecular response. However, 2 patients were documented with CNS relapse at the time of blina/pona evaluation although in bone marrow molecular remission. Both obtained clearance of leukemic blasts after intrathecal infusion of chemotherapy. Then, 5 patients underwent allogeneic transplant (including 2 patients already allotransplanted before blina/pona) and 1 patient received donor lymphocyte infusion. Seven cases pursued maintenance therapy with ponatinib as single agent after stopping blinatumomab. With a median follow-up of 8 months (range: 2.6-30.2) for alive patients, median overall and leukemia-free survivals from first cycle of blina/pona were 8.5 months (range: 1.7-30.2) and 8 months (range: 1.3-30.2), respectively. At last follow-up (July 2018), only 4 relapses had occurred at a median of 3.3 months (range: 1.3-8.3) from first blina/pona cycle and 6 patients had died (3 bacterial infections, 1 fungal infection, 1 secondary cancer and 1 ALL relapse). All alive patients (n=9) but one (cytologic CR but detectable minimal residual disease) are in complete molecular response. Four patients are still under ponatinib medication at last follow-up. The combination of blinatumomab+ponatinib appears effective and tolerable in relapsed Ph1+ALL patients and may replace chemotherapy salvage regimens. The combination should be tested in first-line therapy in the future. Our results have also to be confirmed prospectively on a larger cohort of patients. Disclosures No relevant conflicts of interest to declare.

Description: Hypomethylating agents (HMA) azacitidine (AZA) and decitabine are approved low-intensity frontline therapy for AML pts, but patient selection between intensive versus low-intensity therapy remains mater of debate. To date, description of biomarker of response to HMA has brought few convincing findings. Most studies have focused on somatic mutations in candidate epigenetic genes such as DNMT3A, TET2, and IDH1/2 or tumor suppressor TP53 and led to controversies with none of this gene currently used to guide therapy decision in clinical practice. We performed an hypothesis-free, innovative, exome sequencing study to identify predictive biomarkers of outcome of AML pts treated with AZA. From Jan 2007 to Dec 2016, 279 newly diagnosed non-M3 AML pts were consecutively treated with AZA in the regional cancer network ONCOMIP. The median age was 76 yrs (45-93 yrs). Median follow-up was 5.5 yrs. AML was secondary of MDS, MPN or therapy related in 141 pts (50.5%). Karyotype was adverse in 135 pts (49.1%). Median WBC count was 2.7 G/L. Overall, 54 pts obtained CR/CRi (19,4%) and median OS was 10.6 months. Among the 279 pts, we identified a discovery cohort of 49 pts with extreme phenotype consisting in 26 pts achieving CR/CRi versus 23 pts in failure despite at least 3 cycles of AZA, and a validation cohort of 175 pts with baseline DNA sample and evaluable for response. Adverse karyotypes were more frequent in the validation set (30% vs 53% respectively, p=.004), which was likely due to an enrichment of responders pts in the discovery cohort. For exome sequencing of the discovery cohort, libraries were captured from baseline DNA BM samples with Sureselect all-exome V4 kit (Agilent) followed by paired-end, 150bp reads sequencing on a NextSeq sequencer (Illumina). Sequences were aligned with Nextgene and non-synonymous SNV were filtered according to 3 different patterns defined on gene function (nucleotide analogs metabolism/COSMIC census genes/AML genes), read depth, variant allele frequency and recurrence. An elastic-net regularization combining LASSO and Ridge penalties simultaneously (Zou & Hastie, 2005) was used to identify association between variants and clinical response. Using a resampling approach, bootstrap stability selection (BSS) were computed for each variant and only those with a BSS≥75% were selected. The exon capture baits targeted 98% of genes in the Consensus CDS database. A mean coverage depth of 85× per sample was achieved, with 92.5% of targets covered at ≥ 20× depth. From the 3 gene/SNV filtering patterns, bootstrapping of the data obtained with elastic-net regularization identified 4 candidate SNV in C11orf80, DZIP, ZNF543 and MECOM genes. Inspection of the exome-seq data for MECOM revealed that 11 of the 26 individuals in the responders sample had an heterozygous missense variant in the coding sequence of MECOM at position 169098992 (rs7622799; encoding p.Pro120Ser; MAF = 0.13 in the Exome Aggregation Consortium[ExAC]). We screened the 4 candidates SNV by targeted sequencing in the validation set and identified MECOM rs7622799, in 34/175 pts (19.4%). Response rates did not differ between pts with rs7622799 (8.8% CR/CRi) and without rs7622799 (9.2% CR/CRi, p=1.00). We then assessed whether genotype rs7622799 predicted OS in time dependent analysis using a Piecewise Cox model and demonstrated that pts with rs7622799 had improved OS from 3 months after diagnosis compared with non-rs7622799 (HR 0.56 95%CI[0.34;0.93]; p=0.024). The 3 other SNVs were not associated with patient outcome. We used an extreme phenotype study design, to discover that the missense variant rs7622799 of MECOM is correlated in time dependent analysis with the overall survival of older AML pts treated with AZA. MECOM is a complex locus gene which encodes for several isoforms namely EVI1, a very aggressive oncogene when overexpressed in AML, and MDS1-EVI1 (or PRDM3), which has epigenetic function as histone methyltransferase activity. Both isoforms directly interact with epigenetic modifiers (HDAC, DNMT3A). Further analyses are needed to best understand the functional impact of rs7622799. Although our findings could indicate that rs7622799 is associated with outcome of older AML pts in the setting of AZA, it remains unknown if it could be used to stratify pts between intensive and low-intensity therapy. Targeted sequencing of this SNV in a control cohort treated with intensive chemotherapy is ongoing Disclosures Fornecker: Takeda: Honoraria; Servier: Honoraria.

Description: Frontline therapy for newly diagnosed AML in older adults can be classified as "more" or "less" intensive. Assignment of patients (pts) to intensive chemotherapy (ICT) or low-intensity therapy (LIT) such as hypomethylating agents (HMA), low-dose aracytine (LDAC) or best supportive care (BSC), should be based on patient- and disease-related prognosis factors. Although scoring systems have been proposed to rationalize this clinical decision-making, there is a strong heterogeneity in clinical practice. Cancer management study mainly focused on patients' determinants of care but very few have assessed the influence of physicians' characteristics and none in AML. In behavioral sciences, attitudes towards risk and ambiguity are psychological traits that may explain medical choices. These traits are connected with theoretical models of decision under uncertainty that can be divided in Expected Utility (EU) and Non-Expected Utility (Non-EU) models where the former is often considered as a benchmark of "economic rationality". Choice patterns in decision task known as Allais paradox allow classifying individuals in these two classes of models. In addition, behavioral consequences when the probabilities of uncertain events are unknown are defined as ambiguity attitudes. Our study investigated the impact of physician's characteristics on their medical decisions regarding 6 clinical vignettes of older AML pts that highlight distinct and difficult situations derived from clinical practice. Physicians' demographical and occupational characteristics were collected through a national cross-sectional web survey among French hematologists. We categorized physicians as EU or non-EU using their responses to the binary lottery choice questions of the Allais paradox (Kahneman & Tversky, 1979). A last question elicited a certainty equivalent (sure gain between 0 and 500 euros) of an ambiguous lottery (Abdellaoui & al, 2011) as a proxy of physicians' ambiguity tolerance. Physicians were asked to decide how to treat (ICT, LIT or BSC) elderly AML pts presented in 6 vignettes (table1). Assessable respondents included those who answered all cases. We used k-means clustering method in order to define clinician's groups with homogeneous pattern of responses to the clinical cases. Among the 230 physicians with assessable answers, the median age was 42 years [standard deviation (SD)± 11.2], 123 were male (54%), 160 were consultant or professor (70%), 166 worked in an academic center (72%), 197 were specialized in hematology (86%), and the mean number of older AML pts treated a year per physician was 20.7 (SD ± 17.1). Regarding the Allais paradox, EU, non-EU and undefined represented respectively 101 (43.9%), 109 (47.3%) and 20 (8.7%) respondents. Regarding ambiguity tolerance, the mean of the certainty equivalent was 241 euros (SD ±136). From the pattern of responses to the vignettes, the K-means clustering yielded two distinct groups identified as (1) clinicians who were more prone to prescribe "more" intensive therapy (ICT), and (2) clinicians who were more prone to prescribe "less" intensive therapy (LIT or BSC). We studied the factors associated with the probability of belonging to the "more intensive" category of physicians. A multivariate model (n=210) on variables identified from the bivariate analyses systematically adjusted for age and gender highlighted the following effects and trend:ambiguity tolerant physicians prescribe significantly less ICT (OR 0.87 [for each 50 euros-increase]; 95%CI, 0.77-0.99, p=0.039), physicians not conforming to expected utility ("economically irrational") recommend more ICT (OR 1.85; 95%CI, 0.92-3.73, p=0.084) and female physicians tend to prescribe less ICT (OR 0.58; 95%CI, 0.28-1.20, p=0.14). Physicians' age, hierarchical status, hospital facility or volume of older AML pts treated a year were not associated with the clusters. Final results of national cross-sectional study performed on French hematologists, show that physicians' attitudes towards risk and ambiguity, i.e. physicians' nonprofessional characteristics, may influence their medical decision making process between "more" and "less" intensive therapy for older AML patients. The extension of this study in different countries is planned to test the cross-cultural robustness of our results and increase our knowledge on psychological traits that could influence physicians' practice. Disclosures Malak: Novartis: Membership on an entity's Board of Directors or advisory committees. Recher:Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding; Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees.

Description: Validated therapies for older pts with AML could rely on intensive or low-intensity strategies. Patient selection for these options remains controversial. There is currently no validated biomarker which can been used to guide therapeutic decision. TP53 mutations which are known to negatively impact AML pts outcome when treated with ICT, have been recently described as a positive prognosis factor for blast clearance with a 10-days regimen of decitabine (Welch, NEJM 2016). To date, it remains unclear whether AML pts with TP53 mutation represent a clinically homogeneous group. Several classification systems of p53 mutant, derived from in vitro or in vivo data, have been validated in solid tumors and aggressive lymphomas as predictors of p53 mutant functional impact or patient outcome. We retrospectively evaluated the impact of TP53 mutational status on the outcome of a real-world cohort of pts, treated frontline with standard doses of azacitidine (AZA). We further hypothesized that functional characterization of TP53 mutations could define a subgroup of pts with specific outcome with AZA From Jan 2007 to Dec 2016, we identified 279 AML pts enrolled in the regional cancer network ONCOMIP registry, treated frontline with AZA. Median age was 76 yrs (45-93), karyotype was adverse in 135 pts (49.1%), including 54 pts with -17 or del17p (19.4%). AML was secondary to MDS in 71 pts (25.4%), to MPN in 24 (8.6%) and therapy related in 46 pts (16.5%). Pts received a median of 6 cycles (1-67). Overall, 54 pts obtained CR/CRi (19.4%) and median OS was 10.6 months (95%CI ,9.7-12.1). For 224 pts with an available bone marrow baseline DNA sample, TP53 mutations were screened with next-generation sequencing on an Illumina® MiSeq sequencer. Sequencing results were filtered with the IARC TP53 mutations database and a variant allele frequency (VAF) 〉10%, strengthening the specificity of the data of this cohort. Of the 224 analyzed cases, 55 cases (24.6%) contained TP53 mutations. Response rates did not significantly differ between TP53mut (21.8% CR/CRi) and TP53wt (17.8% CR/CRi, p=.50) nor between pts with TP53mut and/or -17/del17p (19.1% CR/CRi) and pts without TP53 abnormality (18.6%CR/CRi, p=.93). Median OS was 7.9 months in pts with TP53mut and 12.6 months in TP53wt (p1 TP53 mutation, we selected the mutation with the predicted highest impact: 15 pts had disruptive mutations (i.e. missense mutation in L2/L3 helix of the DNA binding domain or truncating mutation) versus 40 pts with non-disruptive mutations (Poeta M, NEJM 2007), which was not associated with clinical response (25% in CR/CRi vs 27.9% in failure; p=1.00) nor with 6mOS (46.7% vs 55%, respectively; p=.79)Mutant p53 transactivation activity assessed with a 0-100 evolutionary score (Neskey D, Cancer Research 2015), was not associated with response (median score of 79.3[28-90] in CR/CRi vs 73.3 [49-96] in failure, p=1.00) nor with OS (HR 1.01; 95% CI, 0.99-1.03, p=.51).Relative fitness score (on a log2 scale) which was recently reported as a proxy of p53 mutant in vitro and in vivo cell proliferation advantage (Kotler E, Molecular cell 2018) was not associated with response (median score in CR/CRi of 0.094 [-0.79-0.58] vs 0.094 [-2.52-0.84] in failure, p=.68) nor with OS (HR 0.75; 95% CI, 0.45-1.22, p=.24) Overall, the response rate was not influenced by the TP53mut status, but median OS was negatively impacted by the TP53mut status in the entire cohort and in the sub-group of pts with adverse karyotype. None of the mutant p53 classification systems validated in other neoplasms succeed in identifying a subset of AML pts who specifically benefit from AZA suggesting a rather homogenous functional impact of TP53 mutations in this setting Disclosures Fornecker: Takeda: Honoraria; Servier: Honoraria.

Description: Cyclosporine A (CsA) alone or in combination with mycophenolate mofetil (MMF) has been used as graft-versus-host-disease (GvHD) prophylaxis since the early development of reduced intensity conditioning (RIC). The association of CsA+MMF, while commonly used after transplantation from a matched unrelated donor (MUD), has never been tested in a large randomized prospective trial. We retrospectively investigated the outcomes of adult patients with AML in complete remission (CR) undergoing a MUD transplant using CsA+MMF or CsA alone as GvHD prophylaxis, transplanted between 2007-2017 and registered with the ALWP of the EBMT. Of the 497 patients who were evaluated, 183 received CsA alone and 314 received CsA+MMF. The median age at transplant was similar, being 59 (range, 20-75) years in the CsA group and 60 (range, 21-75) years in the CsA+MMF group. All patients underwent a RIC regimen with fludarabine and busulfan and received anti-thymocyte globulin as part of the conditioning. The median follow-up was 33 (range, 18-60) months in the CsA group and 34 (range, 18-75) months in the CsA+MMF group. Disease status at transplant was first complete remission (CR1) for 81% (n=149) in CsA group and 86% (n=268) in CsA+MMF group (p=NS). Poor risk cytogenetics was reported for 19% of patients who received GvHD prophylaxis with CsA alone and for 15% of patients receiving CsA+MMF (p=NS). Peripheral blood stem cells (PBSC) was the graft source in 93% of patients receiving CsA alone and in 96% of patients who received CsA+MMF (p=0.17). Female to male mismatch was present in 13% and 15% of patients in the CsA goup and CsA+MMF group respectively, (p=NS). All but 2 patients engrafted. The 100 day cumulative incidence (CI) of grade II-IV and grade III-IV GvHD were 30% and 10%, respectively. The 2-year CI chronic GvHD was 35% and CI of extensive cGvHD was 15%. The 2-year CI of non-relapse mortality (NRM) and relapse were 19% and 25%, respectively. Of the 81 patients who died in the CsA group, disease recurrence (n=31), GvHD (n=20) and infection (n=17) were the most common causes of death. One hundred twenty seven patients died in the CsA+MMF group; cause of death was relapse for 53, GvHD for 28 and infection for 28 of them. The 2-year GVHD-free relapse-free survival (GRFS), leukemia- free survival (LFS), and overall survival (OS) were 45%, 56% and 60%, respectively. On multivariate analysis (MVA), no statistically significant differences were found among the two GvHD prophylaxis groups with respect to relapse, NRM, LFS, OS, acute and chronic GvHD. A positive cytomegalovirus serology of the donor was associated with higher NRM [HR=2.03, p

Description: The IKZF1 gene, which encodes the Ikaros transcription factor, is frequently deleted or mutated in patients with B-cell precursor acute lymphoblastic leukemias that express oncogenes, like BCR-ABL, which activate the JAK-STAT5 pathway. Ikaros functionally antagonizes the transcriptional programs downstream of IL-7/STAT5 during B cell development, as well as STAT5 activity in leukemic cells. However, the mechanisms by which Ikaros interferes with STAT5 function is unknown. We studied the genomic distribution of Ikaros and STAT5 on chromatin in a murine pre-B cell line, and found that both proteins colocalize on 〉60% of STAT5 target regions. Strikingly, Ikaros activity leads to widespread loss of STAT5 binding at most of its genomic targets within two hours of Ikaros induction, suggesting a direct mechanism. Ikaros did not alter the level of total or phosphorylated STAT5 proteins, nor did it associate with STAT5. Using sequences from the Cish, Socs2 and Bcl6 genes that Ikaros and STAT5 target, we show that both proteins bind overlapping sequences at GGAA motifs. Our results demonstrate that Ikaros antagonizes STAT5 DNA binding, in part by competing for common target sequences. Our study has implications for understanding the functions of Ikaros and STAT5 in B cell development and transformation.

Description: Introduction: Therapy-related myeloid neoplasms (t-MNs) account for about 10 to 20% of all cases of AML and MDS. Allogenic hematopoietic cell transplantation (allo-HCT) is considered as the only curative treatment in this high-risk setting. Given the rise of long-term cancer survivors, an increasing number of patients are expected to become transplant candidates. Physicians are concerned about the frailty and the risk of recurrence of primary cancer. In this retrospective registry-based study, we focused on patients with t-MN secondary to breast cancer radio- and/or chemotherapy, and collected information about the outcomes and complications after allo-HCT. Methods and results: In the EBMT registry we identified 252 female adult patients who underwent an allo-HCT between 2006 and 2016 for t-MN secondary to breast cancer treatment. Median age at transplantation was 57 years, and the median time from the breast cancer diagnosis to t-MN diagnosis and subsequent allo-HCT were 3.7 and 4.6 years, respectively. The indication for allo-HCT was AML and MDS in 77% and 23% of cases, respectively. Sixty-seven% of patients were in complete remission (CR) of their t-MN at the time of transplant. Abnormal karyotype was recorded in 40% of cases. A reduced Karnofsky performance status (KPS

Description: COVID-19 is a severe infectious complication in patients with underlying medical conditions such as having undergone hematopoietic stem cell transplantation (HCT). This prospective survey reports outcome on 272 COVID-19 patients from 19 countries having undergone allogeneic (n = 175) or autologous (n = 97) HCT reported to the EBMT registry or to the GETH. All patients had the diagnosis of SARS-CoV-2 documented by PCR. Patients were included in this analysis if COVID-19 diagnosis was before April 10, 2020. The overall survival was estimate by using the Kaplan Meier methods, considering the death due to any cause as an event and the time from COVID-19 infection to the latest follow-up as survival time; difference between groups were tested by the log-rank test. Univariate and multivariate risk factor analysis for overall survival were performed with the Cox regression model. The median age was 54.4 years (1.0 - 80.3) for allogeneic and 60.9 years (7.7 - 73.4) for autologous HCT patients. 20 patients were children (〈 18 years of age; median age 11.3 (1.0 - 16.9)). The median time from HCT to diagnosis of COVID-19 was 13.7 months (0.2 - 254.3) in allogeneic and 25.0 months (-0.9 - 350.3) in autologous recipients. Lower respiratory tract disease (LRTD) developed in 84.8% and 21.5% were admitted to an intensive care unit (ICU). At the time of analysis, 68/238 (28.6%) patients had died (47/155 allogeneic patients; 21/83 autologous patients). No follow-up had been received on 34 patients. The median time from infection to death was 19 days (0-102). Five patients were reported to have other primary causes of death than COVID-19. Of the patients reported to be alive, the median follow-up was 44 days. 144 (84.7%) patients (93 allogeneic; 51 autologous) had virologic resolution of the COVID-19 infection having at least one negative PCR. 26 patients were alive and known to be still COVID-19 positive (15 allogeneic; 11 autologous). For 34 patients the resolution status was unknown. Factors influencing the likelihood of resolution in multivariate analysis were underlying diagnosis (p=.01) and longer time from transplant to diagnosis of COVID-19 (p=.035). Overall survival at 6 weeks from COVID-19 diagnosis was 76.8% and 83.8% in allogeneic and autologous HCT recipients (p =ns), respectively (figure 1). Children (n=20) tended to do better with a 6-week survival of 95.0% although the difference was not significantly different (p =.12). In multivariate analysis of the total population older age (HR 1.26; 95% CI 1.05 - 1.51; p = .01) increased the risk and better performance status decreased the risk for fatal outcome (HR 0.79; 95% CI 0.69 - 0.90; p = .0003). The same factors had significant impact on overall survival in allogeneic HCT recipients (age HR 1.28; 95% CI 1.05 - 1.55; p=.01; performance status HR 0.79; 95% CI 0.68 - 0.92); p=.002) while only age impacted survival among autologous HCT patients (data not shown). Other transplant factors such as underlying diagnosis, time from HCT to diagnosis of COVID-19, graft-vs-host disease, or ongoing immunosuppression did not have a significant impact on overall survival. We conclude that HCT patients are at an increased risk compared to the general population to develop LRTD, require admission to ICU, and have increased mortality in COVID-19. Figure 1 Disclosures Duarte: Incyte Corporation: Other: Has received speaker and advisor fees. Kwon:Jazz: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Mielke:Novartis: Honoraria, Other: received via my institution, Speakers Bureau; Celgene/BMS: Honoraria, Other: received via my institution , Speakers Bureau; Bellicum: Honoraria, Other: received via my institution, Speakers Bureau; Kite/Gilead: Honoraria, Other: received via my institution , Speakers Bureau; Miltenyi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: received via my institution , Speakers Bureau; KIADIS Pharma: Honoraria, Other: received via my institution , Speakers Bureau; DNA Prime: Honoraria, Other: received via my institution , Speakers Bureau. López Jiménez:MSD: Speakers Bureau; Roche: Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Abbvie: Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau.