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The global incidence of myelodysplastic syndromes (MDS) has been estimated as 0.06 to 0.26/100,000. Since their introduction, hypomethylating agents have played a central role in the treatment of MDS, with heterogeneous real-world outcomes.We assessed and synthesized clinical outcomes of azacitidine (AZA) monotherapy in treatment-naïve patients with higher-risk MDS. A systematic literature review was conducted by searching MEDLINE, Embase, and CENTRAL to identify randomized clinical trials (RCTs) and observational studies, both prospective and retrospective, reporting complete remission (CR), partial remission (PR), overall survival (OS), duration of response (DOR), time-to-response (TTR), and myelosuppressive adverse events (AEs) for patients treated with AZA monotherapy. Noncomparative meta-analyses were used to summarize effects.The search identified 3250 abstracts, of which 34 publications describing 16 studies (5 RCTs, 3 prospective, and 8 retrospective observational) were included. Across all studies, pooled CR was 16%; PR was 6%; Median OS was 16.4 months; median DOR was 10.1 months; median TTR was 4.6 months. Proportions of grade 3/4 anemia and thrombocytopenia AEs were 10% and 30%.The effectiveness and efficacy of AZA monotherapy-as measured by CR and median OS-was limited. These findings highlight a significant unmet medical need for effective treatments for patients with higher-risk MDS.

Magrolimab is a monoclonal antibody that blocks CD47, a ‘do not eat me’ signal overexpressed on tumor cells. CD47 is overexpressed in multiple myeloma (MM), which contributes to its pathogenesis. Preclinical studies have shown that CD47 blockade induces macrophage activation, resulting in elimination of myeloma cells, and that there is synergy between magrolimab and certain anticancer therapies. These findings suggest that magrolimab-based combinations may have a therapeutic benefit in MM. This phase II study investigates magrolimab in combination with commonly used myeloma therapies in patients with relapsed/refractory MM and includes a safety run-in phase followed by a dose-expansion phase. Primary end points include the incidence of dose-limiting toxicities and adverse events (safety run-in) and the objective response rate (dose expansion).

Idelalisib is a phosphatidylinositol 3-kinase δ inhibitor approved for relapsed/refractory follicular lymphoma, a type of indolent non-Hodgkin lymphoma (iNHL), and chronic lymphocytic leukemia (CLL). Idelalisib-triggered adverse events (AEs) may be managed with treatment interruption and/or dose reduction, potentially extending therapy duration and increasing the likelihood of continued response.Post hoc analyses were conducted to evaluate clinical outcomes after AE-induced idelalisib interruption for 125 patients with iNHL and 283 with CLL.Progression-free survival (PFS) was longer for patients with iNHL who experienced ≥ 2 interruptions versus those with 0 interruptions who discontinued idelalisib or study because of AEs (hazard ratio 0.33; P = .0212). Both PFS and overall survival were longer for patients with CLL with ≥ 2 interruptions versus 0 interruptions in those who discontinued therapy because of an AE (hazard ratio PFS 0.50, overall survival 0.41; P .005). Clinical benefits persisted for patients with CLL who experienced treatment interruption after receiving idelalisib for ≥ 6 months. Supplementing interruption with dose reduction did not worsen clinical outcomes. However, time off therapy of ≥ 8% may diminish the clinical benefit of treatment interruption.Idelalisib interruption and dose reduction were associated with enhanced clinical outcomes for patients with relapsed/refractory iNHL or CLL who experienced an AE, supporting this management strategy when indicated.

Trial Information Lessons Learned Although this study of idelalisib in patients with PDAC was limited in size and duration because of early termination, idelalisib exposure resulted in an overall safety profile consistent with studies in hematological malignancies, except that the incidences of diarrhea and colitis were reduced in patients with PDAC. Preclinical studies of the PI3K pathway in PDAC and positive clinical results of PI3K inhibition in other cancers support the continued development of PI3K inhibitors in PDAC. Background Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal solid tumors and is often refractory to treatment. Phosphatidylinositol-3 kinase (PI3K) δ inhibition influences regulatory immune cell function and improves survival in preclinical PDAC models. Here, idelalisib, an inhibitor of PI3Kδ, was investigated as treatment for metastatic PDAC. Methods This was an open-label, multicenter, phase Ib, nonrandomized, dose-escalation study. Study aims were to investigate the maximum tolerated dose, safety, pharmacokinetics/pharmacodynamics, and efficacy of idelalisib alone and in combination with chemotherapeutics—nab-paclitaxel and modified (m)FOLFOX6. Results Because of early termination, only 16 patients were enrolled in the single-agent idelalisib arm, 12 of whom received at least one dose of idelalisib. The most common treatment-emergent adverse events (≥25%) related to idelalisib (n = 12) were increased aspartate aminotransferase, pyrexia, and maculopapular rash. One patient presented with diarrhea; no cases of colitis were reported. One patient discontinued treatment because of pyrexia and maculopapular rash; two patients died because of disease progression. Conclusion This study was terminated because factors contributing to safety concerns in phase III studies of idelalisib for hematological malignancies were not fully understood. In this small sample of patients with metastatic PDAC, exposure to idelalisib resulted in safety findings consistent with previous studies, with reduced diarrhea/colitis.

Introduction: Idelalisib, a selective oral inhibitor of PI3Kδ, was approved by the FDA and EMA as monotherapy for patients with advanced follicular lymphoma (FL) based on positive efficacy and safety results from the registration phase 2 trial in patients with indolent non-Hodgkin lymphoma (iNHL) refractory to 2 prior regimens (NCT01282424; 101-09). Phase 3 studies of idelalisib in earlier lines of treatment for iNHL were terminated prematurely due to an increased risk of death and higher incidence of serious adverse events (AEs) associated with idelalisib. Herein, we present the preplanned interim results as of June 8, 2020, of the safety of idelalisib monotherapy in patients with refractory FL treated in the EU from one of the largest noninterventional trials of idelalisib. Methods: This was a noninterventional, partially retrospective cohort study conducted in 10 European countries (EUPAS19618; NCT03568929). Eligible patients were adults aged ≥18 years treated with idelalisib for refractory FL, per the Summary of Product Characteristics and treatment guidelines, in routine clinical practice. Data was collected from patients' medical records and anonymized. Safety events were evaluated and included treatment-emergent AEs (TEAEs), health outcomes of interest (HOIs) requested by the EMA (bowel perforations, Grade ≥3 diarrhea/colitis, progressive multifocal leukoencephalopathy, pneumonitis, Grade ≥3 rash, infections, Stevens-Johnson syndrome, transaminase elevations, and hepatocellular injury), and deaths. TEAEs were defined as AEs that occurred between first dose and 30 days after last dose. Data were summarized using descriptive statistics. Rates per person-year were calculated as the number of patients experiencing an AE divided by the person-time at risk. Results: For the 158 patients included in this analysis, median age was 67 years and 84 (53%) were male. A summary of patient and disease characteristics at baseline are presented in Table 1. At treatment initiation, 47 (30%) patients had grade 2 FL and 105 (66%) had Ann Arbor stage III/IV disease, though these characteristics were not captured for 42% and 20% of patients, respectively; 149 (94%) had ≥2 prior therapies. The median duration of idelalisib exposure was 165 (range 11-1321) days, and patients were observed for a median of 323 (range 12-1676) days. In total, 144 (91%) patients experienced a TEAE, with a rate of 3.36 per person-year. The proportion of patients experiencing Grade 3/4, severe, common, and HOI TEAEs are presented in Table 2. Diarrhea of any grade was the most common TEAE, and infections were the most common treatment-emergent HOI. During the TEAE period, 19 (12%) patients died (Table 2). The proportion of common TEAEs reported in this analysis were lower compared with a subgroup analysis of patients with FL from the registration trial (Salles Haematologica 2017; DOI: 10.3324/haematol.2016.151738), including diarrhea 27% vs 51%, cough 9% vs 32%, fever/pyrexia 10% vs 29%, pneumonia 5% vs 11%; treatment-emergent Grade 3/4 diarrhea/colitis and transaminase elevations were also lower in this analysis: 8% vs 17% and 4% vs 14%. This comparison is limited due to differences in study populations, namely that patients in the registration trial had more advanced disease (stage III/IV, 66% vs 83%) and had a higher median number of prior therapies (3 vs 4). Conclusions: This interim analysis of the safety of idelalisib in patients with refractory FL in this large noninterventional safety study provides an estimate of potential final study findings. The AE profile from this study appears to corroborate the known safety profile of idelalisib. No new safety signals were detected. Disclosures Salles: Bristol Myers Squibb: Consultancy, Other; Genmab: Consultancy; Gilead: Consultancy, Honoraria, Other: Participation in educational events; Epizyme: Consultancy; Abbvie: Consultancy, Honoraria, Other: Participation in educational events; Autolus: Consultancy; Amgen: Honoraria, Other: Participation in educational events; Celgene: Consultancy, Honoraria, Other: Participation in educational events; Debiopharm: Consultancy; Takeda: Consultancy, Honoraria, Other; Novartis: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria, Other; Janssen: Consultancy, Honoraria, Other: Participation in educational events; Karyopharm: Consultancy; Kite: Consultancy, Honoraria, Other; MorphoSys: Consultancy, Honoraria, Other. Pettengell:Celgene: Honoraria; MEI Pharma: Honoraria; Roche Ltd: Honoraria; Takeda: Honoraria. Vandenberghe:Celgene: Other: sponsorship to attend Lugano lymphoma meeting in 2019; Abbvie: Other: travel grants, Research Funding; Gilead: Other: travel grants, Research Funding; Janssen: Other: travel grants; Roche: Other: travel grants, Research Funding. Corradini:Kiowakirin: Consultancy, Honoraria; Incyte: Consultancy; Gilead: Consultancy, Honoraria, Other; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other; BMS: Other; Servier: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other; Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Other; AbbVie: Consultancy, Honoraria, Other. De Belder:Gilead Sciences Europe, Ltd.: Current Employment. Shah Gupta:Gilead Sciences, Ltd.: Current Employment. van Troostenburg:Gilead Sciences GmbH: Current Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Current Employment. Ramroth:Gilead Sciences, Ltd.: Current Employment.

Idelalisib is associated with increased occurrence of immune-related adverse events (irAEs). Clinical observations suggest a correlation between immune checkpoint inhibitor–induced irAEs and survival outcomes in patients with solid tumors; however, this relationship in hematologic malignancies is not well understood. In a post hoc analysis of 3 registrational trials, we explored the relationship between Grade ≥3 diarrhea/colitis and alanine/aspartate transaminase (ALT/AST) elevation incidences and efficacy endpoints in patients with indolent non-Hodgkin’s lymphoma (iNHL), follicular lymphoma (FL), and chronic lymphocytic leukemia treated with idelalisib. Grade ≥3 diarrhea/colitis was associated with higher overall response rate (ORR) and longer progression-free survival (PFS) for all subgroups. Grade ≥3 ALT/AST elevations were associated with improved duration of response and overall survival for all subgroups and improved ORR and PFS for patients with FL or iNHL. Our analysis in hematologic malignancies showed a trend correlating idelalisib-induced Grade ≥3 irAEs with improved efficacy.

B-cell receptor (BCR) signaling pathway inhibitors (including Bruton’s tyrosine kinase [BTK] inhibitors, and phosphatidylinositol-3 kinase inhibitors [PI3Ki]) have shown clinical efficacy in non-Hodgkin lymphoma (NHL). However, responses to these agents have been limited in depth and duration. This may be due to resistance to PI3Kδ and BTK inhibitors as monotherapy [1,2,3,4,5]. The emergence of resistant clones may be addressed by combining these 2 classes of drugs. Furthermore, tolerability of these drug classes has been a concern. Combination therapy using lower doses of one or more classes of inhibitors may address some limitations.

e19062 Background: AZA is a standard of care for patients who have HR-MDS. Given the limited availability of large datasets describing outcomes in the current treatment paradigm of HR-MDS, this analysis aimed to aggregate clinical outcomes associated with AZA monotherapy for treatment-naïve HR-MDS. Methods: CENTRAL, EMBASE, and MEDLINE were searched to identify interventional, prospective, and retrospective observational studies in treatment-naïve HR-MDS (defined as intermediate-2 or high risk by IPSS or intermediate to very high risk by IPSS-R) using AZA monotherapy. Inclusion of observational studies was limited to those with n >20 in the AZA arm. Responses according to IWG 2000 or IWG 2006 including complete remission (CR) rate, overall response rate (ORR; defined as CR, marrow CR [mCR], partial response, and hematologic improvement), overall survival (OS), duration of response (DOR), and time to response (TTR) were extracted. Response rates were synthesized using random-effects models; median of medians was used for OS, DOR, and TTR. Results: Of 3250 abstracts identified, 34 publications describing 16 studies met inclusion criteria: 5 randomized controlled trials (RCTs), 3 prospective studies, and 8 retrospective studies. None of the response endpoints were reported in all studies (see Table). The pooled ORR ranged from 44% to 55% across RCTs, prospective, and retrospective studies. The pooled CR rates, reported in 2 RCTs (n=55), 1 prospective study (n=27), and 3 retrospective studies (n=509), were 14%, 11%, and 16%, respectively. The pooled CR rate across all studies (n=591) was 16% (95% CI: 13%, 19%). Pooled median OS (mOS) was 16.7 months (mo) in the 3 RCTs (n=161), 16.5 mo in a single prospective study (n=34), and 14.4 mo in the 5 retrospective studies (n=1472). Pooled mOS across all studies (n=1667) was 16.4 mo (95% CI: 12.0, 17.3). The pooled median DOR was 10.1 mo (95% CI: 9.1, 11.0), and the median TTR was 4.6 mo (95% CI: 3.0, 9.0). Conclusions: These findings provide evidence that benefit from AZA monotherapy in treatment-naïve HR-MDS patients is limited. Opportunity exists for novel therapies to increase response rates, improve the duration of responses, and prolong survival. [Table: see text]

2566 Background: We have previously shown that systemic administration of GS-3583, a Fms-like tyrosine kinase 3 (FLT3) agonist Fc fusion protein leads to expansion of conventional dendritic cells (cDC), both subtype 1 (cDC1) and subtype 2 (cDC2), in the periphery of healthy volunteers (Rajakumaraswamy N, et al. J Clin Oncol. 2021;39[suppl_15]:2559.). This mechanism may increase cDC in the tumor microenvironment and promote T cell mediated antitumor activity in patients with solid tumors. Methods: This ongoing, Phase 1b, open label study is investigating the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of escalating multiple doses of GS-3583 monotherapy in adult patients with advanced solid tumors using a standard 3 + 3 design. GS-3583 was administered intravenously on Days 1 and 15 of Cycle 1 and on Day 1 of each subsequent 28-day cycle for up to 52 weeks or until progressive disease or unacceptable toxicity. Dose-limiting toxicity (DLT) was evaluated during the first 28 days of GS-3583 therapy at each dose level. Results: At the time of the Dec 3, 2021 data cut-off, 9 patients have enrolled in 3 dose escalation cohorts. Median (range) age was 71 (44-79); 4 (44%) patients were male. Tumor types were pancreatic (n=3), ovarian (n=4), and rectal (n=2). To date, no DLTs or discontinuation due to adverse events (AE) have been observed. Three patients had Grade ≥3 AEs which were also recorded as serious AEs, none of which were considered related to GS-3583. Dose dependent increase in GS-3583 exposure was observed in the evaluated dose range 2 to 12 mg with target-mediated drug disposition appearing to be saturated at doses above Dose Level 2. GS-3583 accumulation was observed at higher dose levels. GS-3583 treatment resulted in expansions of cDC1 and cDC2 at all 3 doses (Table); a dose-dependent trend in the magnitude and the durability of cDC expansion was observed. At the highest dose evaluated, GS-3583 produced ≥100-fold expansion of both cDC1 and cDC2 at multiple time points. Dose escalation on the study is still ongoing. Conclusions: GS-3583 was safe and well tolerated and induced dose-dependent expansion of cDCs in the periphery in patients with advanced solid tumors up to doses of 12 mg. These findings support further dose escalation and clinical development of GS-3583 in combination with agents that would stimulate the expanded cDCs to produce anti-tumor responses. Clinical trial information: NCT04747470. [Table: see text]

BackgroundConventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor specific CD8+ T cells and their recruitment to tumor microenvironment (TME). However, cDC1s are often underrepresented in the TME. Systemic administration of Fms-like tyrosine kinase 3 ligand (FLT3L), a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to expansion of cDC1s in the periphery which can then be recruited into the TME. FLT3 pathway stimulation using GS-3583, a novel FLT3 agonistic Fc fusion protein, has the potential to promote T cell mediated anti-tumor activity. We sought to evaluate the pharmacodynamic (PD) effect of a single dose of GS-3583 in healthy volunteers alongside its safety. Herein, we present the updated results of the study.MethodsThis was a first-in-human, placebo-controlled study of GS-3583 in healthy volunteers to evaluate the safety, pharmacokinetics (PK), and PD of escalating single doses (ranging from 75 micrograms to 2000 micrograms) of GS-3583. The study was blinded to the subjects and the investigator. Each dose cohort enrolled 8–12 healthy subjects who received GS-3583 or placebo as single IV infusion at 3:1 ratio. Subjects were observed in the phase 1 unit for 15 days and then for 12 weeks as outpatients. As part of the PD evaluation, we investigated the changes in the number of cDC1 and cDC2 cells.ResultsAs of 2nd July 2021, selected safety, PK and PD data from all 4 cohorts were available. GS-3583 was well tolerated and all subjects had been discharged. To date, there have been no serious or grade 3 or higher adverse events. Preliminary PK analysis suggested dose-dependent increase in GS-3583 exposure (AUC and Cmax). Preliminary PD analysis shows that administration of GS-3583 resulted in temporary, dose-dependent increases in cDC1/cDC2 cells that peaked between days 5–11 (higher doses resulted in later peaks) and returned to baseline within 3 weeks of drug administration (table 1, figure 1).Abstract 380 Table 1Selected subject characteristics and pharmacodynamic resultsAbstract 380 Figure 1A) Comparison of cDC1 cell quantitative changes in cohorts 1–4; B) Comparison of cDC2 cell quantitative changes in cohorts 1–4ConclusionsGS-3583 infusion was well tolerated and induced dose dependent expansion of dendritic cells in the periphery in healthy volunteers. In patients with cancer, this increase in dendritic cells can be utilized to enhance anti-tumor therapeutic effects of immuno-oncology therapies.AcknowledgementsFunding provided by Gilead Sciences, Inc.Ethics ApprovalThe study received study site IRB/Ethics Committee approval prior to enrollment of subjects.

The phase 2 study of idelalisib monotherapy for indolent non-Hodgkin lymphomas (iNHLs) was completed in 2018; final efficacy and safety data with up to 6.7 years long-term follow-up are reported. Patients with iNHL refractory to both rituximab and an alkylating agent were enrolled and received 150 mg idelalisib twice daily (

Idelalisib (IDL) is an oral first-in-class phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor approved for chronic lymphocytic leukaemia (CLL) alongside rituximab (R) since 2014. However, little data exist on routine practice. The RETRO-idel was a protocol-led, retrospective study of 110 patients [n = 27 front-line (1L)] who received IDL-R. The primary end-point was clinical overall response rate (ORR). The median (range) follow-up of the whole cohort was 30·2 (0·1-51·9) months. The median (range) age was 72 (48-89) years. Tumour protein p53-disruption was common [100% 1L, 32·5% relapsed/refractory (R/R)]. The best ORR (intention-to-treat) was 88·2% (1L 96·3%, R/R 85·5%). Overall, the median event-free survival (mEFS) was 20·3 months and time-to-next treatment was 29·2 months. The mEFS for 1L patients was 18·7 months and R/R patients was 21·7 months. The 3-year overall survival was 56·1% (95% confidence interval 45·7-65·3). IDL was discontinued in 87·3% (n = 96). More patients discontinued due to adverse events in the front-line setting (1L 63·0% vs. R/R 44·6%) and due to progressive disease in R/R patients (20·5% vs. 3·7% in 1L). Lower respiratory tract infection/pneumonia were reported in 34·5% (Grade ≥3, 19·1%), diarrhoea in 30·9% (Grade ≥3, 6·4%), and colitis in 9·1% (Grade ≥3, 5·5%). Overall, these data describe clear efficacy for IDL-R in routine practice. No new safety signals were identified, although careful management of known toxicities is required.

Background: Malignant lymphoid cells are characteristically dependent on signals mediated by the phosphatidylinositol 3-kinase delta isoform (PI3Kδ). Idelalisib is an oral, selective, PI3Kδ inhibitor approved by the FDA and EMA as monotherapy for the treatment of advanced follicular lymphoma (FL). The approval was based on a phase 2 trial in patients with indolent non-Hodgkin lymphoma including 72 patients with FL who were refractory to at least 2 prior regimens (NCT01282424; Study 101-09). Interim safety analysis of this large, pan-European, noninterventional study of refractory FL patients treated with idelalisib monotherapy (EUPAS19618; NCT03568929) showed that the adverse event (AE) profile in clinical practice corroborates the known safety profile of idelalisib reported from clinical trials. Herein, we report the effectiveness and updated safety analysis from this study. Methods: This was a non-interventional, retrospective, cohort study. Adult patients treated with idelalisib for FL in routine clinical practice in 10 European countries were included. Data were collected retrospectively from sites by study personnel from remotely source data-verified medical records using electronic case report forms. Safety and effectiveness data for each patient were collected from time of idelalisib initiation until 6 months post-discontinuation of idelalisib, start of next treatment, or death. For this analysis, the data cut-off date was 16 June 2021. Effectiveness of idelalisib was assessed by overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS). The overall safety profile of idelalisib was assessed by estimating the incidence of AEs, serious AEs, adverse drug reactions (ADRs), and serious ADRs. Focus was given to special health outcomes of interest (HOIs), including transaminase elevation, hepatocellular injury, severe diarrhea/colitis, pneumonitis, neutropenia, rash, Stevens-Johnson syndrome, and serious infections. Multivariate Poisson regression analyses are used to estimate rates of ADRs, serious ADRs, and HOIs, and are adjusted for potential confounders. Time-to-event data were analyzed using Kaplan-Meier methods. Results: Overall, there were 257 eligible patients in the study from 85 sites. The Full Analysis Set (FAS) consisted of 242 patients excluding those with deviations (n=10) or those without any data contribution at the cut-off date (n=5). Of the 242 patients, 183 initiated idelalisib at least 12 months prior to data cut-off date and were included in the Effectiveness Analysis Set (EAS; n=49 patients did not have effectiveness data recorded, and 10 did not meet effectiveness inclusion criteria). For the 183 patients in the EAS, median age was 67 years and 54.6% (n=100) were male (Fig. 1A). Median number of prior therapies was 3 (range 1-10) and median time since diagnosis was 5.8 years (range: 0.4-32). At treatment initiation, 64% (n=117) had Ann Arbor stage III/IV disease. Median duration of idelalisib exposure was 6.8 months (IQR 3.0-15.6); 41.5% (n=76) had dose interruptions. Patients received doses of 150 mg only (67.8%), both 150 mg and 100 mg (28.4%), or 100 mg only (3.8%). Patients were observed for a median of 9.8 months (IQR 5.2-19.3). In the EAS, 103/183 patients achieved a response with 30 patients (16.4%) achieving a complete response (CR) and 73 (39.9%) achieving a partial response (PR), yielding a best ORR of 56.3% (95% CI: 48.8-63.6; Fig. 1B). Median DOR, PFS, and TTNT were 22.5 (95% CI: 15.1-27.9), 11.1 (95% CI: 8.1-18.1) and 15.4 months (95% CI: 9.9-22.2), respectively (Fig. 1B, C). Median OS had not been reached at the time of data cut-off (Fig. 1D). Updated safety information was available from the 242 patients in the FAS. The most frequent AEs recorded were infections, diarrhea and/or colitis, and transaminase elevation. The proportion of patients in the FAS experiencing Grade 3/4, severe, common, and HOI TEAEs are presented in Fig. 1E. Conclusions: We report to our knowledge the largest cohort of FL patients treated with idelalisib outside of the clinical trial setting. Our effectiveness findings are remarkably similar to those from the registrational study 101-09 (Gopal 2014 N Engl J Med). Safety profile of idelalisib was consistent with trial experience, and no new safety signals were identified. Idelalisib remains an effective treatment option for FL patients. Figure 1 Figure 1. Disclosures Gyan: Gilead Sciences, Inc.: Consultancy; Novartis: Research Funding; Mundipharma: Research Funding; Fresenius Kabi: Research Funding; Sanofi: Honoraria; AbbVie: Other: Hospitality; AstraZeneca: Honoraria. Tisi: Incyte: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Merli: Takeda: Consultancy; Janssen Pharmaceuticals: Consultancy; Gilead Sciences, Inc.: Consultancy; Novartis: Consultancy. Di Raimondo: Amgen: Honoraria; AbbVie: Honoraria; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria; Janssen Pharmaceuticals: Honoraria; Jazz Pharmaceutical: Honoraria. Mercadal: Gilead Sciences, Inc.: Honoraria, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Puccini: Takeda: Membership on an entity's Board of Directors or advisory committees. Vandenberghe: Janssen Pharmaceuticals: Honoraria; AbbVie: Honoraria. Boland: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Shah Gupta: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. van Troostenburg: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Dunnill: Gilead Sciences, Inc.: Current equity holder in publicly-traded company, Other: Contractor. Ramroth: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Rajakumaraswamy: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Salles: Genentech/Roche: Consultancy; Incyte: Consultancy; Regeneron: Consultancy, Honoraria; Miltneiy: Consultancy; Genmab: Consultancy; Epizyme: Consultancy, Honoraria; Velosbio: Consultancy; Novartis: Consultancy; Ipsen: Consultancy; Morphosys: Consultancy, Honoraria; Allogene: Consultancy; Debiopharm: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; Loxo: Consultancy; Takeda: Consultancy; Rapt: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

TPS3147 Background: Productive antitumor immune responses in nonclinical models depend on a type of dendritic cell (DC), conventional DC subtype 1 (cDC1), which in the context of cancer, primes tumor-reactive T cells through presentation of tumor-derived antigens. FMS-related tyrosine kinase 3 ligand (FLT3L) is a hematopoietic growth factor that binds to and activates FLT3 on terminally differentiated DCs. Activated FLT3 promotes proliferation, inhibits cell death, and is required for the differentiation, expansion, and maintenance of DCs in peripheral and lymphoid organs. GS-3583 is a fusion protein composed of the extracellular domain of recombinant human FLT3L fused to an engineered fragment crystallizable (Fc) region of human immunoglobulin G4. GS-3583 has PK properties that support sustained cDC in patients and potential combination with established immunotherapies. This phase 1b, open-label, multicenter, dose-finding study will evaluate safety, tolerability, PK, and preliminary efficacy of GS-3583 monotherapy in patients with advanced solid tumors (NCT04747470). Methods: Approximately 33 adults aged ≥18 years with a histologically or cytologically confirmed locally advanced or metastatic malignant solid tumor that is refractory to or intolerant of standard therapy or for which no standard therapy is available will be enrolled. The study employs a 3+3 dose escalation design in which GS-3583 is administered intravenously for up to 52 weeks or until progressive disease or unacceptable toxicity. Up to five dose escalation cohorts have been planned. The maximum tolerated dose is the highest dose with incidence of DLT in < 33% of 6 or more patients in the first 28 days of GS-3583 dosing; recommended phase 2 dose will be determined. Assessments include safety, PK, pharmacodynamics including cDCs, immunogenicity, and efficacy by RECIST 1.1 in CT/MRI imaging conducted every 8 weeks. Accrual at approximately 3-4 centers in the US is ongoing. Clinical trial information: NCT04747470.

2559 Background: Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor specific CD8+ T cells and their recruitment to tumor microenvironment (TME). However, cDC1s are often underrepresented in the TME. Systemic administration of Fms-like tyrosine kinase 3 ligand (FLT3L), a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to expansion of cDC1s in the periphery which can then be recruited into the TME. We hypothesize that FLT3 pathway stimulation using GS-3583, a FLT3 agonist Fc fusion protein, has the potential to promote T cell mediated anti-tumor activity. Methods: This was a first-in-human placebo-controlled study of GS-3583 in healthy volunteers to evaluate the safety, PK, and PD of escalating single doses (ranging from 75μg to 2000μg) of GS-3583. The study was blinded to the subjects and the investigator. Each dose cohort enrolled 8-12 healthy subjects who received GS-3583 or placebo as single IV infusion at 3:1 ratio. Subjects were observed in the phase 1 unit for 15 days and then for 12 weeks as outpatients. As part of the PD evaluation, we investigated the changes in the number of cDC1s and cDC subtype 2 (cDC2) cells. Results: As of 8th Feb 2021, selected safety, PK and PD data from the first 3 cohorts were available. GS-3583 was well tolerated and all subjects had been discharged. To date, there have been no serious or grade 3 or higher adverse events. Preliminary PK analysis suggested dose-dependent increase in GS-3583 exposure (AUC and Cmax). Preliminary PD analysis shows that administration of GS-3583 resulted in dose-dependent increases in cDC1/cDC2 cells that peaked at day 5 or day 8 and returned to baseline within three weeks of drug administration. Conclusions: GS-3583 was safe and well tolerated and induced dose dependent expansion of dendritic cells in the periphery. In patients with cancer, this increase in dendritic cells can be utilized to enhance anti-tumor responses to immuno-oncology therapies.[Table: see text]

The safety of trial subjects is the tenet that guides the regulatory assessment of a Clinical Trial Authorization application and applies equally to trials involving small molecules and those with biological/biotechnological products, including Advanced Therapy Medicinal Products. The objective of a regulator is to ensure that the potential risk faced by a trial subject is outweighed by the potential benefit to them from taking part in the trial. The focus of the application review is to assess whether risks have been identified and appropriate steps taken to alleviate these as much as possible. Other factors are also taken into account during a review, such as regulatory requirements, and emerging non-clinical and clinical data from other trials on the same or similar products. This paper examines the regulatory review process of a Clinical Trial Authorization application from the perspectives of Quality, Non-Clinical and Clinical Regulatory Assessors at the Medicines and Healthcare products Regulatory Agency. It should be noted that each perspective has highlighted specific issues from their individual competence and that these can be different between the disciplines.

Background Idelalisib, an oral, first-in-class, selective phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, is approved in the US and Europe as monotherapy for relapsed/refractory follicular lymphoma (FL). Its safety and efficacy were primarily established from a Phase 2 study in patients with double-refractory FL, which carries a poor prognosis and has no current standard of care. As this was a single-arm trial, data regarding the relative efficacy of idelalisib compared to other regimens used in this population are limited. Therefore, we conducted a Matching-Adjusted Indirect Comparison (MAIC) to derive measures of relative efficacy of idelalisib versus other therapies in double-refractory FL using a well-established registry. Methods Study 101-09 was a Phase 2, multi-centre, single-arm, open-label trial of 125 patients with relapsed or refractory indolent non-Hodgkin's lymphoma (iNHL) treated with idelalisib monotherapy which included 72 patients (58%) with FL. Summary data from this Phase 2 trial were compared with individual level patient data from the HMRN (Haematological Malignancy Research Network). HMRN is an ongoing population-based cohort registry in the Northern UK that includes a population of 3.8 million and collects information on all haematological malignancies in the region. This analysis included all patients newly diagnosed with FL from 1st Sep 2004 to 31st Aug 2013. Outcomes in patients who had received ≥ 2 prior lines of chemo/immuno-chemotherapy and were refractory to both rituximab and an alkylating agent, or had a relapse within 6 months after receipt of those therapies and were subsequently treated, were examined. MAICs were conducted in order to match to the characteristics reported of the trial population using previously described methodology. Results In total, 1,007 patients were newly diagnosed with FL during the index period, of whom 675 received treatment either from time of diagnosis (n=556) or after a period of 'watch and wait' (n=119); the majority of patients were treated with chemotherapy (n=520), with 155 receiving radiotherapy. The most common regimen at first line was R-CVP (n=304) followed by R-CHOP (n=135). Number of patients receiving second line therapy was 185 either due to relapse (n=136) or being refractory to first line therapy (n=49), the most common regimens were R-CVP, R-CHOP and other agents such as DHAP or bendamustine. Overall, 68 patients received third line treatment, the most common being chlorambucil-based (19.1%), fludarabine-based (6.8%) and DHAP (20.6%); the overall response rate was 58.8%. In the 675 patients treated with therapy, survival diminished by treatment line with respective 5-year OS being 74.7% in first line, 50.6% in second line and 39.3% in third line. Twenty-six patients had received two or more prior regimens, were refractory to both rituximab and an alkylating agent, or had a relapse within 6 months of those therapies and were subsequently treated with chemotherapy - this cohort was used for MAIC against the 101-09 study population. Demographically, both populations were relatively similar. Since HMRN included patients as soon as they reached the eligibility criteria, differences were seen in time since diagnosis and the median prior therapies, suggesting that patients with higher risk disease and a poorer prognosis may have been identified. Accordingly, HMRN patients had a poorer 2-year OS than trial patients (46.2% vs 69.8%). The variables included were: age (62 < or ≥62), sex, stage III/IV disease, bulky disease and time from diagnosis (< or ≥4.7y). The results of the MAIC analyses pre and post matching were as follows: 2 year OS decreased from 46.2% to 19.8% after matching and 1-year PFS decreased from 57.7% to 24.7%; the respective 2-year OS of the trial population was 69.8% and 1-year PFS of 43.0% demonstrating favourable efficacy of idelalisib in this population. Conclusion This MAIC analysis using real-world data suggests that idelalisib provides superior efficacy relative to the other therapies used for the treatment of patients with FL who are refractory to two prior lines. The small effective sample size is a potential limitation of this analysis, along with the possible converse effect on prognosis associated with time since diagnosis between the two studies. However, the favourable efficacy of idelalisib remained when the analysis was repeated excluding time from diagnosis (2-year OS 39.9%). Disclosures Rajakumaraswamy: Gilead Sciences: Employment. Lovato:Gilead Sciences: Employment. Smith:Gilead Sciences: Employment. Bagguley:Gilead Sciences: Consultancy. Smith:Jazz Pharmaceuticals: Research Funding; Johnson & Johnson: Research Funding; Novartis: Research Funding; Gilead Sciences: Consultancy. Patmore:Roche: Consultancy; Gilead Sciences: Consultancy. Marcus:Gilead Sciences: Consultancy; Roche/ Genentech: Consultancy, Honoraria.

Although alpha(2)-adrenoceptor agonists are widely used for analgesia, anxiolysis, sedation, sympatholysis and as anaesthetic-adjuncts for many years, their potential use as neuroprotectants has so far been confined to laboratory experiments. Despite the large body of evidence from both in vivo and in vitro studies, their exact neuroprotective mechanisms remain elusive. Herein, we review the available literature pertaining to the neuroprotective effect of alpha(2)-adrenoceptor agonists and the possible biochemical and physiological cascades involved in their mechanisms of action. The remarkable safety profile of alpha(2)-adrenoceptor agonists and their high potency of neuroprotection should prompt clinical trials to evaluate their neuroprotective efficacy in humans.

Which of the three alpha2-adrenoceptor subtypes of alpha2A, alpha2B, or alpha2C mediates the neuroprotective effect of dexmedetomidine was examined in cell culture as well as in an in vivo model of neonatal asphyxia. Dexmedetomidine dose-dependently attenuated neuronal injury (IC50=83+/-1 nM) in neuronal-glial co-cultures derived from wild-type mice; contrastingly, dexmedetomidine did not exert neuroprotection in injured cells from transgenic mice (D79N) expressing dysfunctional alpha2A-adrenoceptors. An alpha2A-adrenoceptor subtype-preferring antagonist 2-[(4,5-Dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL44408) completely reversed dexmedetomidine-induced neuroprotection, while other subtype-preferring antagonists 2-[2-(4-(2-Methoxyphenyl)piperazin-1-yl)ethyl]-4,4-dimethyl-1,3-(2H,4H)-isoquinolindione dihydrochloride (ARC239) (alpha2B) and rauwolscine (alpha2C) had no significant effect on the neuroprotective effect of dexmedetomidine in neuronal-glial co-cultures. Dexmedetomidine also protected against exogenous glutamate induced cell death in pure cortical neuron cultures assessed by flow cytometry and reduced both apoptotic and necrotic types of cell death. Likewise this neuroprotective effect was antagonised by BRL44408 but not ARC239 or rauwolscine. Dexmedetomidine exhibited dose-dependent protection against brain matter loss in vivo (IC50=40.3+/-6.1 microg/kg) and improved the neurologic functional deficit induced by the hypoxic-ischemic insult. Protection by dexmedetomidine against hypoxic-ischemic-induced brain matter loss was reversed by the alpha2A-adrenoceptor subtype-preferring antagonist BRL44408; neither ARC239 nor rauwolscine reversed the neuroprotective effect of dexmedetomidine in vivo. Our data suggest that the neuroprotective effect of dexmedetomidine is mediated by activation of the alpha2A adrenergic receptor subtype.

The safety of trial subjects is the tenet that guides the regulatory assessment of a Clinical Trial Authorization application and applies equally to trials involving small molecules and those with biological/biotechnological products, including Advanced Therapy Medicinal Products. The objective of a regulator is to ensure that the potential risk faced by a trial subject is outweighed by the potential benefit to them from taking part in the trial. The focus of the application review is to assess whether risks have been identified and appropriate steps taken to alleviate these as much as possible. Other factors are also taken into account during a review, such as regulatory requirements, and emerging non-clinical and clinical data from other trials on the same or similar products. This paper examines the regulatory review process of a Clinical Trial Authorization application from the perspectives of Quality, Non-Clinical and Clinical Regulatory Assessors at the Medicines and Healthcare products Regulatory Agency. It should be noted that each perspective has highlighted specific issues from their individual competence and that these can be different between the disciplines.

Xenon, an NMDA receptor antagonist and dexmedetomidine (Dex), an alpha(2)-adrenoceptor agonist, both exhibit neuroprotective effects. We investigated the nature of their interaction. In vitro: a primary co-culture of neuronal and glial cells derived from neonatal mice was exposed to oxygen and glucose deprivation (OGD) and the resulting neuronal injury was assessed by the release of lactate dehydrogenase (LDH). In vivo: Postnatal rats aged 7 days underwent right common carotid artery ligation followed by 90 min of hypoxia. The area of infarction was assessed at four days post-injury by morphological criteria. Long-term neurological function was evaluated at 30 days post-injury by testing co-ordination on rotarod. Both xenon and Dex concentration-dependently reduced LDH release with IC50 values of 42% atm (95% CI: 35-52) and 0.10 microM (95% CI: 0.08-0.16), respectively. Isobolographic analysis showed that combined effect of xenon and Dex in vitro was additive. In vivo, a combination of xenon and Dex, at doses that are individually not neuroprotective, produced significant neuroprotective effect as measured by reduction in area of infarction. The long-term neurological function data corroborated these morphological data. Our study demonstrates that the combination of xenon and Dex offers neuroprotection additively in vitro and synergistically in vivo.

BECAUSE the fetus and neonate are capable of sensing painful stimuli, and nociceptive-induced neuronal plasticity has long-term psychological and physiologic sequelae, including hyperalgesic states and worse perioperative morbidity and mortality, effective analgesia in the young is critical. In addition, neonatal pain processing pathways differ from mature systems, and therefore, one cannot assume that an analgesic in an adult model will be effective in younger age groups. Indeed, some anesthetics, e.g., nitrous oxide, seem to be ineffective because they requires the participation of a pathway that is immature before the toddler stage. Xenon, a noble gas with anesthetic properties, exerts an analgesic effect in adult humans and animals, consistent with its profile as an N-methyl-D-aspartate (NMDA) antagonist. However the efficacy of xenon analgesia in younger age groups has not previously been tested. Previous studies revealed that xenon suppressed wide dynamic range neurons within the intact spinal cord and was still effective in a spinal cord transection model, suggesting that xenon exerts an effect directly at the spinal cord, without requiring involvement of higher supraspinal centers. Therefore, we hypothesized that xenon could exert an antinociceptive effect in the presence of immature pain processing pathways that lack functional connectivity to supraspinal centers, as long as these express functional NMDA receptors. In this report, we investigate the efficacy of xenonversus formalin-induced nociception as reflected by behavior and c-Fos expression (a marker of neuronal activation) in cohorts of rats at various ages.

A 30 year old woman booked for antenatal care of a much wanted pregnancy at nine weeks' gestation. She had previously undergone three surgical terminations of pregnancy at 15, 12, and 10 weeks. She was otherwise fit and healthy and the pregnancy was progressing normally. A routine ultrasound scan was done at 19 weeks (figure). 1. What does the ultrasound scan show and what are the implications for the pregnancy? 2. What are the causes of this condition? 3. How should this woman be managed? What are the risks? 1. The scan shows “beaking” or “funnelling” of the internal cervical os, which could be a sign of cervical incompetence. Cervical incompetence can lead to a midtrimester miscarriage. 2. Cervical surgery, such as cone biopsy (where a small piece of the cervix is removed for testing), forceful dilatation of the cervix (especially in late surgical terminations), trauma during labour, congenital malformations (for example, hypoplastic cervix), and connective tissue disorders (for example, Marfan's syndrome) can all cause cervical …

Using their experiences of transferring between universities, Nishanthan Rajakumaraswamy, Iqbal Toor, and Geraint Thomas explore the options for medical students wanting to study somewhere else

Background: Magrolimab is a humanized monoclonal antibody that blocks the immune checkpoint CD47, a "do not eat me" signal, overexpressed on tumor cells. The binding of magrolimab to CD47 leads to phagocytosis of cancer cells from human solid tumors and hematologic malignancies. The overexpression of CD47 contributes to the pathogenesis of multiple myeloma (MM) and blocking CD47 induces immediate activation of macrophages and elimination of myeloma cells (Sun et al). Hence, a blockade of CD47 with magrolimab may have therapeutic benefit in patients with MM. Combination therapies are more effective than single-agent therapy for both newly diagnosed and relapsed/refractory MM (RRMM). In vitro studies show synergy between magrolimab and daratumumab on MM cell line phagocytosis, and complimentary mechanisms suggest potential enhanced efficacy in other combinations. The current study (NCT04892446) is investigating the efficacy of magrolimab in combination with commonly used myeloma therapies in patients with RRMM. Design and Methods: This phase 2, multi-arm study includes patients aged ≥18 years currently requiring treatment for RRMM; all participants must have received at least 3 previous lines of therapy for MM, including an immunomodulatory drug and a proteasome inhibitor. This study includes 2 phases: a safety run-in cohort and a dose-expansion cohort (Figure 1). The primary objectives of the safety run-in cohort are to evaluate the safety and tolerability of magrolimab in combination with other anticancer therapies using the occurrence of dose-limiting toxicities (DLTs) as the primary endpoint, and to determine the recommended phase 2 dose (RP2D) of magrolimab in the following combinations: magrolimab+daratumumab; magrolimab+pomalidomide+dexamethasone; and magrolimab+bortezomib (maximum of 8 prior cycles in those who previously received bortezomib)+dexamethasone. Dose expansion cohorts will evaluate the efficacy of magrolimab combinations with objective response rate (ORR) as the primary endpoint. Secondary endpoints include duration of response, progression-free survival, and overall survival. Minimal residual disease negativity, biomarker changes from baseline, immune cell signaling alterations, and the mutational profile of plasma cell clones will also be explored. Magrolimab is administered intravenously (IV) with an initial priming dose, followed by a maintenance dose on days 8, 15, 22, and 29 during cycle 1 (35 days) and days 1, 8, 15, and 22 from cycle 2 (28 days) onwards. Daratumumab, pomalidomide, dexamethasone, and bortezomib will be administered according to manufacturer's prescribing information. Dose de-escalation may occur based on DLTs per protocol. Patients will continue treatment until unacceptable toxicity, progressive disease, or patient/investigator choice to discontinue. Planned enrollment is approximately 153 patients. Status: Recruitment is ongoing. Reference: Sun J, Muz B, Alhallak K, Markovic M, Gurley S, Wang Z, Guenthner N, Wasden K, Fiala M, King J, Kohnen D, Salama NN, Vij R, Azab AK. Targeting CD47 as a novel immunotherapy for multiple myeloma. Cancers (Basel). 2020;12(2):305. Figure 1 Figure 1. Disclosures Paul: Amgen Inc.: Speakers Bureau; Bristol Myers Squibb: Divested equity in a private or publicly-traded company in the past 24 months; Genentech: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Regeneron: Membership on an entity's Board of Directors or advisory committees. Liedtke: Celgene: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Monge: Karyopharm Therapeutics: Research Funding; Bristol Myers Squibb: Consultancy. Rifkin: Takeda: Membership on an entity's Board of Directors or advisory committees; Fresenius-Kabi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; McKesson: Current Employment, Current equity holder in publicly-traded company; Coherus: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb (Celgene): Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Gandhi: Karyopharm Therapeutics: Honoraria; TG Therapeutics: Honoraria; GlaxoSmithKline: Honoraria. Kovacsovics: Janssen Pharmaceuticals: Research Funding; Amgen Inc.: Research Funding; Stemline: Honoraria; Jazz Pharmaceutials: Honoraria; Novartis: Research Funding; AbbVie: Research Funding. Levy: Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Novartis: Consultancy, Other: Promotional speaker; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Dova: Consultancy, Other: Promotional speaker. Siegel: Karyopharm: Honoraria; Celularity: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Speakers Bureau; Takeda: Honoraria; Bristol Myers Squibb: Honoraria, Speakers Bureau; Amgen Inc.: Honoraria; Janssen: Honoraria, Speakers Bureau. Silbermann: Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Byrne: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Ncube: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Murphy: Gilead Sciences, Inc.: Current Employment, Current holder of stock options in a privately-held company. Gu: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Rajakumaraswamy: Gilead Sciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Chao: Gilead Sciences, Inc.: Current Employment; TigaTx: Membership on an entity's Board of Directors or advisory committees; Stanford University: Patents & Royalties; Hepatx Inc: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Iconovir Bio: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Stanford University Medical School: Membership on an entity's Board of Directors or advisory committees; Foresite capital: Consultancy; Bioverge: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Chimera Bioengineering: Current equity holder in publicly-traded company. Usmani: Sanofi: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; EdoPharma: Consultancy; GSK: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Array BioPharma: Consultancy, Research Funding; SkylineDX: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Janssen Oncology: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Abbvie: Consultancy. OffLabel Disclosure: Magrolimab is an investigational therapy