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The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.

Covalent Bruton tyrosine kinase inhibitors (BTKi’s) and the B-cell lymphoma 2 (BCL2) inhibitor venetoclax have significantly improved outcomes for patients with chronic lymphocytic leukemia (CLL), especially those with biologically adverse disease. Patients with CLL resistant to their first targeted agent (TA) can be effectively treated with the alternative class. However, relapses are expected with second-line TA therapy, and the clinical challenge of double class-resistant disease is now emerging with increasing frequency. To define the characteristics and outcomes of patients with double class-resistant disease, we retrospectively analyzed 17 patients who developed progressive disease (PD) on both TA classes for CLL (venetoclax, then BTKi, n=12; BTKi, then venetoclax, n = 5). The cohort was heavily pretreated (median lines of prior therapy, 4) and enriched for adverse disease genetics (complex karyotype, 12 of 12 tested [100%]; del(17p)/TP53 mutations, 15 of 17 [88%]). The median time to progression on prior venetoclax was 24 months (range, 6-94 months) and was 25 months (range, 1-55 months) on prior BTKi. Progression on second-line TA was manifest as progressive CLL in 11 patients and as Richter transformation in 6. The median overall survival after progression on second-line TA was 3.6 months (95% confidence interval, 2-11 months). Patients with double class-resistant CLL have a dismal prognosis, representing a group of high unmet need.

We reviewed haematological investigations for 43 patients treated at a single centre with alectinib, an inhibitor of anaplastic lymphoma kinase (ALK) which is considered standard first-line treatment for patients with ALK-rearranged advanced non-small cell lung cancer. Ninety-five percent of patients developed marked acanthocytosis, echinocytosis and/or spheroacanthocytosis, not observable with prior treatment with other ALK-inhibitors. Anaemia developed in 73% of patients (38%

Identification of patients at risk of initial & recurrent cytomegalovirus (CMV) reactivation following allogeneic stem cell transplant (alloSCT) may help guide prophylactic strategies. T-cell receptor beta (TRB) deep sequencing was used to identify and enumerate the T-cell repertoire harbouring TRB sequences with annotated specificity to CMV (pubCMVrep), as well as the overall T-cell receptor (TCR) repertoire diversity at day +30 & day +60 post-alloSCT for 65 patients. T-cells harbouring TRB sequences with annotated specificity for CMV were identifiable in all patients. 56% of patients required CMV treatment and 23% of the cohort developed recurrent CMV. PubCMVrep size at day +30 was not associated with reactivation, however amongst patients with antecedent CMV viremia a low day +60 pubCMVrep was associated with a greater incidence of recurrent CMV (75% vs. 21%, HR 6.16, 95% CI 1.29-29.40, P = 0.0008). Moreover, patients with high pubCMVrep only developed recurrent CMV in the setting of GVHD. Low TCR diversity at day +30 was associated with a greater incidence of initial CMV reactivation (71% vs. 22%, HR 5.39, 95% CI 1.70-17.09, p = 0.0002). pubCMVrep and TCR diversity are promising biomarkers to identify patients at risk of initial & recurrent CMV who may benefit from novel prophylactic strategies.

The highly selective BCL2 inhibitor venetoclax achieves deep responses in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL), including undetectable minimal residual disease (uMRD). We retrospectively reviewed 62 patients with CLL treated with venetoclax to investigate the performance of peripheral blood (PB) compared with bone marrow (BM) assessment of MRD; the kinetics, clinicopathological associations, and longer-term outcomes of uMRD attainment and recrudescence; and the ability of venetoclax dose escalation to deepen responses. Among 16 patients who achieved PB uMRD and had contemporaneous BM assessments, 13 (81%) had confirmed BM uMRD, and patients with PB uMRD had outcomes at least as favorable as those with BM uMRD for time to progression, overall survival, and MRD recrudescence. Excluding 2 patients lacking earlier assessment, the median time to PB uMRD was 18 (range, 5-26) months, with 90% of instances achieved by 24 months. There was no new PB uMRD attainment after 24 months without treatment intensification. The dominant association with earlier attainment of uMRD was concurrent rituximab (P = .012). Complex karyotype was associated with inferior uMRD attainment after 12 months of therapy (P = .015), and patients attaining uMRD whose disease harbored TP53 abnormalities demonstrated a trend toward earlier recrudescence (P = .089). Of patients who received venetoclax dose escalations, 4 (27%) of 15 achieved improvements in response. For patients with R/R CLL receiving venetoclax, PB uMRD commonly correlates with BM uMRD and is associated with a comparable longer-term prognosis. Concurrent rituximab augments uMRD attainment, but dose escalation and further treatment beyond 24 months infrequently deepen responses.

BACKGROUND Measurable residual disease (MRD) monitoring in acute lymphoblastic leukemia (ALL) is an important predictive factor for patient outcome and treatment intensification. Molecular monitoring, particularly with quantitative polymerase chain reaction (qPCR) to measure immunoglobin heavy or kappa chain (Ig) or T-cell receptor (TCR) gene rearrangements, offers high sensitivity but accessibility is limited by expertise, cost, and turnaround time. Flow cytometric assays are cheaper and more widely available, and sensitivity is improved with multi-parameter flow cytometry at eight or more colors. METHODS We developed a 10-color single tube flow cytometry assay. Samples were subject to bulk ammonium chloride lysis to maximize cell yields with a target of 1 × 106 events. Once normal maturation patterns were established, patient samples were analyzed in parallel to standard molecular monitoring. RESULTS Flow cytometry was performed on 114 samples. An informative immunophenotype was identifiable in all 22 patients who had a diagnostic sample. MRD analysis was performed on 87 samples. The median lower limits of detection and quantification were 0.004% (range 0.0005%-0.028%) and 0.01% (range 0.001%-0.07%) respectively. Sixty-five samples had concurrent molecular MRD testing, with good correlation (r = 0.83, p

Visual disturbance is a common complaint in patients with multiple myeloma, both at diagnosis and later in their course, and has a broad differential. Here, we report a novel cause of visual disturbance, namely retinal ischemia due to extramedullary plasmacytomas of the orbit. A 69 year-old male patient with known multiple myeloma presented with reduced vision in his left eye. The patient had been initially diagnosed with IgG myeloma 9 months earlier and multiples lines of medical therapy had been unsuccessful. Ophthalmology review was organised and fundoscopic examination showed evidence of retinal ischemia. Computed tomography of the orbits demonstrated multiple enhancing masses within both orbits, consistent with extramedullary plasmacytomas. The presence of retinal ischemia was thus attributed to mass effect on the orbital vessels. Extramedullary plasmacytomas within the orbit are a rare manifestation of multiple myeloma, but important to consider as a possible cause of visual disturbance.

Peptide receptor radionuclide/chemoradionuclide therapy (PRRT/PRCRT) is an effective therapy for metastatic neuroendocrine neoplasia (NEN), but therapy-related myeloid neoplasms (t-MN) remain of concern. The study reviewed the clinicopathological features and outcomes of patients who developed t-MN. Retrospective analysis of all patients diagnosed with t-MN by 2016 WHO classification, from a cohort of 521 patients who received PRRT/PRCRT over a 12-year period. Molecular next-generation sequencing using an in-house 26-gene panel was performed. Twenty-five of 521 (4.8%) patients were diagnosed with t-MN, including six acute myeloid leukaemia (AML) and 19 myelodysplastic syndrome (MDS). The median time from first cycle PRRT/PRCRT to diagnosis of t-MN was 26 months (range 4–91). Twenty-two of 25 (88%) patients had grade 1–2 pancreatic or small bowel NEN with moderate metastatic liver burden. Six patients (24%) had prior chemotherapy. Median number of PRRT cycles = 5 (22/25 (88%) with concomitant radiosensitising chemotherapy). All 25 patients achieved disease stabilisation (68%) or partial response (32%) on RECIST 1.1 at 3 months post-PRRT. At t-MN diagnosis, all patients presented with thrombocytopenia (median nadir 33 × 109/L, range 3–75) and 17 (68%) remained NEN progression-free. Marrow genetic analysis revealed unfavourable karyotype in 16/25 (66%) patients with tumour protein 53 (TP53) mutation in nine (36%). Azacitidine therapy was utilised in ten eligible patients, while four received induction chemotherapy for AML. The median overall survival from first PRRT was 62 months (19–94), but from t-MN diagnosis was only 13 months (1–56), with death due primarily to haematological disease progression. The diagnosis of t-MN after PRRT/PRCRT is an infrequent but serious complication with poor overall survival. Most patients present with thrombocytopenia; unfavourable genetic mutations have a poor response to t-MN treatment. Prospective data are needed to explore potential pre-existing genetic factors and predictive biomarkers to minimise the risk of t-MN.

Cues delivered by agents are known to trigger mental shortcuts associated with ontological category or the kind of thing an agent is. Two such heuristics are key to considering organic and machine agents, and result in biased evaluations: the machine heuristic (MH) (if machine, then systematic/unbiased, therefore its products are good) and the nature heuristic (NH) (if natural, then pure/innate, therefore good). As machine agents such as robots are increasingly integrated into human spheres, it is yet unknown (a) if invocation of agent-cued heuristics is inherently tied to activities and (b) whether either/both heuristics are evoked when agents exhibit both organic and machinic properties (as with cyborgs). To investigate these open questions, a 3 × 2 experiment tasked individuals with considering a magazine article about an agent (organism, cyborg, robot) performing behaviors (natural, technical) to solve a widespread problem, and then evaluating the agent and its solution for markers of machine and NHs. Findings indicate that the NH may be dominant over the MH; however, this primacy may be driven by operational contexts.

The BCL2 inhibitor venetoclax has complete response rates of up to 50% in chronic lymphocytic leukemia patients, but secondary resistance reflecting acquired mutations in BCL2 can lead to treatment failure. Blombery et al report that an unexpectedly large number of patients carry multiple BCL2 mutations with subclonal variation in their occurrence.

Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma. Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination.We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood.The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P0.001). The rate of complete response as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months. The tumor lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%).In this study involving historical controls, dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .).

The diagnostic criteria for CLL rely on morphology and immunophenotype. Current approaches have limitations affecting reproducibility and there is no consensus on the role of new markers. The aim o ...

Background: Myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis leading to cytopenias, including anemia and thrombocytopenia. KER-050, a modified activin receptor type IIA inhibitor, is designed to target transforming growth factor-β ligands, including activin A. In preclinical studies, KER-050 promoted the maturation of progenitors across the full spectrum of erythropoiesis and thrombopoiesis and elicited bone anabolic effects. In a Phase 1 study in healthy participants, KER-050 treatment resulted in robust and sustained increases in reticulocytes (RETs), hemoglobin (HGB), and platelets. Increases in the bone formation marker bone specific alkaline phosphatase were also observed. Here we report results of an ongoing Phase 2 study to evaluate whether KER-050 provides therapeutic benefit in MDS patients with anemia. Aims: Evaluate safety, tolerability, pharmacodynamics and efficacy of ascending doses of KER-050 in participants with MDS in an open-label, 2-part Phase 2 study. Methods: IPSS-R very low-to-intermediate risk MDS patients (both RS+ and non-RS) with anemia (HGB Results: At data cut-off (July 10, 2021) with median follow-up of 140 days (range 1 to 169 days), 17 participants had received ≥1 dose of KER-050 across 3 dose levels: 0.75 mg/kg, 1.5 mg/kg and 2.5 mg/kg. Baseline characteristics are described in Table 1. No related serious AEs, dose-limiting toxicities, or dose modifications were reported. One participant developed grade 2 maculopapular rash after the first dose which was considered treatment related, resolved and did not recur with subsequent doses. No other related AEs were reported. Two discontinued study drug prior to end of treatment: 1 due to participant decision, 1 due to death unrelated to study drug. None developed high risk MDS or AML. In 10 efficacy-evaluable participants, overall erythroid response rate was 60% (n=6/10). 33% (n=1/3) NT participants had a HGB increase of ≥1.5g/dL sustained ≥ 8 weeks. 5 of 7 transfused participants (71%) (n=1/2 LTB and n=4/5 HTB; n=2/3 non-RS and n=3/4 RS+) had erythroid responses sustained ≥8 weeks (range 8-20 weeks, ongoing) and 57% (n=4/7) achieved TI (Figure 1, Panel A). Maximum increase from baseline in RETs observed in transfused responders (TR) (n=5) was 24.6 x10 9/L (mean), range 10.5- 41.6 x10 9/L from day 1-29 with increases in RETs seen after each dose (Panel B). Maximum reduction in serum ferritin in TR was 40.4% (mean), range 10-66%, and maximum increase in soluble transferrin receptor (sTfR) was 52.8% (mean), range 29.8-116.4%. Increases in platelets were observed in TR (Panel C). Mean baseline platelet count for TR was 234 x10 9/L (range 104-401 x10 9/L), and maximum increase from baseline was 130 x10 9/L (mean), range 32-235 x10 9/L. No participants required dose reduction due to thrombocytosis. Summary: Erythroid responses have been observed in RS+ and non-RS MDS patients including reduction in transfusion burden at the initial dose levels. Observed increases in RETs and sTfR and observed decreases in ferritin suggest that KER-050 treatment is potentially associated with increased erythropoiesis. Increases in platelets have been observed in TR. These data support the potential of KER-050 as a treatment for multilineage cytopenias in MDS by potentially targeting multiple stages of hematopoiesis. As of data cut-off, KER-050 has been well tolerated. Dose escalation is ongoing in this Phase 2 study of anemic patients with MDS; data from planned cohorts from Part 1 will be presented. Part 2 dose expansion phase is expected to initiate prior to the meeting. Figure 1 Figure 1. Disclosures Ross: Bristol Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Keros Therapeutics: Consultancy, Honoraria. Arbelaez: Amgen: Other: Travel, Accommodations, Expenses. Chee: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Fong: AbbVie: Consultancy; Amgen: Consultancy; Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Speakers Bureau; Phizer: Consultancy; Novotech: Honoraria; Specialised Therapeutics: Honoraria. Hiwase: Novartis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Wight: Jannsen: Honoraria, Other: Travel subsidies; Abbvie: Honoraria, Other: Travel subsidies. Rovaldi: Keros Therapeutics: Current equity holder in publicly-traded company. Furutani: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gaggi: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Jiang: Keros Therapeutics: Current Employment, Current holder of stock options in a privately-held company. Lachey: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Natarajan: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company. Ordonez: Keros Therapeutics: Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Background Mantle cell lymphoma (MCL) is a clinically and pathogenetically distinct B-cell non-Hodgkin lymphoma that presents at a median age of 65 years and typically at an advanced stage. High dose chemotherapy and stem cell transplantation can achieve durable responses, but disease eventually relapses in most patients. Allogeneic transplantation can achieve a cure in some but is only suitable for a minority of younger, fitter patients who achieve remission to salvage but carries risks of GVHD. Bruton tyrosine kinase inhibitors (BTKi) are active in relapsed MCL but the median PFS is generally less than 2 years and ibrutinib failure is associated with particularly poor outcomes (Cheah et al., Ann Oncol 2015). Mutations of TP53 are associated with refractoriness to both chemotherapy and novel agents (Eskelund et al., Blood 2017), and patients with disease harboring these mutations are in particular need of more effective therapies. Promising activity has recently been demonstrated with chimeric antigen receptor T-cells (CAR T), albeit with significant rates of cytokine release syndrome (CRS) and neurotoxicity (Wang et al., New England Journal of Medicine 2020), resulting in FDA approval of brexucabtagene autoleucel in MCL. Rationale Tisagenlecleucel (Novartis) is a CAR T-cell product directed against CD19 that is approved in many countries for the treatment of relapsed DLBCL and ALL. MCL consistently expresses CD19 at diagnosis and relapse and is therefore a promising target. Pre-clinical data suggests synergistic effects if tisagenlecleucel is combined with the BTKi ibrutinib. The proposed mechanism includes enhancing T cell activation and expansion (Fraietta et al., Blood 2016), disrupting the MCL nodal environment (Long et al., The Journal of Clinical Investigation 2017) and mitigating CRS (Ruella et al., Clin Cancer Res 2016). Clinical trials in CLL show that the combination is safe and effective, including deep minimal residual disease negative responses (Gill et al., Blood 2018, Gauthier et al., Hematological Oncology 2019). We hypothesise that combination treatment will be tolerable and improve outcomes in a poor risk MCL population. Combination, time-limited therapy would also avoid the burdens of continuous treatment. Study Design and Methods 20 adult patients with MCL that has relapsed following front-line therapy, or those patients with MCL with TP53 aberrations who have achieved less than complete response on PET imaging after 2 cycles of induction will be enrolled (See Fig 1. for inclusion and exclusion criteria). Treatment consists of 560mg oral ibrutinib followed by a single infusion of tisagenlecleucel. Autologous lymphocytes for CAR T manufacture will be collected after a minimum of 7 days of continuous ibrutinib therapy. Ibrutinib will be continued during CAR T manufacture and for 6 months after infusion (see Fig 2.) Patient characteristics will be presented using descriptive statistics, response rates will be calculated as percentages using exact methods from the binomial distribution, and progression-free survival, duration of response and overall survival will be described using the Kaplan-Meier method. The primary objective is to estimate the complete response (CR) rate at month 4 following tisagenlecleucel infusion in combination with ibrutinib with the primary endpoint being CR rates at month 4 post tisagenlecleucel using the Lugano criteria. Secondary objectives include estimating MRD negative response rates, response rates according to TP53 status, and safety of the combination. Exploratory translational studies include studies of T cell repertoire and phenotype during ibrutinib exposure and after tisagenlecleucel infusion. The role of circulating tumour DNA monitoring in the management of MCL is also being evaluated. The trial is investigator led, sponsored by the Peter MacCallum Cancer Centre, with additional sites throughout Australia. The study was initiated in April 2020 and is actively recruiting patients. The trial is registered at ClinicalTrials.gov: NCT04234061. Disclosures Hamad: Abbvie: Honoraria; Novartis: Honoraria. Blombery:Janssen: Honoraria; Amgen: Consultancy; Invivoscribe: Honoraria; Novartis: Consultancy. Seymour:Nurix: Honoraria; Morphosys: Consultancy, Honoraria; Mei Pharma: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Tam:Pharmacyclics LLC, an AbbVie Company: Honoraria; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Dickinson:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck Sharp & Dohme: Consultancy. OffLabel Disclosure: Tisagenlecleucel is not currently approved for use in MCL.

Progression of chronic lymphocytic leukemia (CLL) on venetoclax (VEN) and BTK inhibitors (BTKi) is associated with acquired genomic variants in BCL2/MCL1/BCL2L1 and BTK/PLCG2, respectively, in some patients. We aimed to assess the clonal structure and evolution of resistance in patients (pts) with progressive disease treated with single agent VEN or BTKi (or both as sequential monotherapies) using next generation sequencing (NGS) and single cell sequencing. Seven pts with CLL and 1 with mantle cell lymphoma (MCL) with disease progression on VEN, ibrutinib (IBR) or zanubrutinib (ZANU) were identified from patients treated at our institutions. Pts were selected on the basis of multiple known resistance mechanisms from previous analysis of mutations (muts) and copy number changes detected using clinical bulk NGS targeting genes of interest including BCL2, MCL1, BCL2L1, BAX, BAK1, BTK, PLCG2, CXCR4, as well as TP53 and SF3B1. Of the 8 pts selected for single cell analysis, all had disease that was relapsed/refractory to chemotherapy prior to receiving either VEN (3 pts), BTKi (2 pts) or sequential VEN-BTKi (3 pts). 6,520-16,378 individual cells from 9 samples (8 pts) were analyzed (total 103,388 cells) using a custom panel targeting pt-specific muts on the Tapestri platform (Mission Bio). A summary of genomic abnormalities detected across the cohort is presented in Figure 1. We first evaluated the relationship between genomic resistance mechanisms within the context of single agent (VEN or BTKi) as well as sequential VEN-BTKi treatment. In CLL pts treated with a single agent, all BCL2 muts in VEN pts and BTK muts in IBR or ZANU pts were identified in different subclones consistent with an oligoclonal pattern of disease progression with independent clonal acquisition of resistance mechanisms. Both pts who received ZANU (either as a single agent or sequentially) harbored the BTK L528W mut (previously described as enriched in ZANU progressors; Handunnetti ASH 2019) in independent clones from BTK C481 muts. In pts who received sequential VEN-BTKi treatment, clones were observed that harbored established or novel dual genomic resistance mechanisms within the same cell (BTK mut/MCL1 amp in CLL, BTK/BAX muts in MCL). However, this was not observed in all clones or for all pts, suggesting the presence of further undetected resistance mechanisms (genetic or other). Given the unique ability of single cell sequencing to resolve mut context within a clonal hierarchy, we next assessed this phenomenon within our cohort utilizing other muts known to be present in these tumors. Analysis of TP53 muts exemplified the diversity of clonal patterns observed, with resistance muts being detected subclonally to parental TP53 muts in some pts and independently of TP53 muts in others. In addition, further evolution of resistant clones was observed through the development of TP53 muts within clones harboring acquired resistance muts, consistent with continued clonal evolution within the resistant disease compartment. In one pt, post-resistance clonal evolution was identified through the clonal acquisition of a CXCR4 mut within a BTK mutated population. Finally, to understand the contribution of BTK zygosity and gender to BTKi resistance (given its location on the X-chromosome), we performed single cell analysis on a disease specimen from a female pt with progressive MCL harboring multiple BTK mutations following treatment with sequential VEN-BTKi. Analysis revealed four clonally independent heterozygous BTK muts inferring the sufficiency of a single mutant allele to drive resistance in this context. Interestingly, this pt also harbored a BCL2 mut and a BAX mut, the latter co-occurring with a BTK mut (BCL2 not assessable). This pt therefore represents the first description of BCL2 or BAX muts occurring in a pt with progressive MCL on VEN and the first of a BTK L528W mut in MCL progressing on ZANU. In summary, these data highlight the significant clonal complexity of CLL progression on VEN and BTKi. Our data show that disease progression in this context is consistently oligoclonal with separate clones harboring distinct identifiable resistance mechanisms. These data have pt-specific implications for the potential utility of cycling back to previously efficacious targeted therapies as well as providing a strong rationale for the early use of disease-appropriate combination targeted therapies. Disclosures Anderson: Walter and Eliza Hall Institute: Patents & Royalties: milestone and royalty payments related to venetoclax.. Handunnetti:AbbVie: Other: Travel expenses; Roche: Honoraria; Gilead: Honoraria. Yeh:Novartis: Honoraria; Gilead: Research Funding. Tam:BeiGene: Honoraria; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Seymour:Morphosys: Consultancy, Honoraria; Mei Pharma: Consultancy, Honoraria; Gilead: Consultancy; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Nurix: Honoraria. Roberts:Janssen: Research Funding; Servier: Research Funding; AbbVie: Research Funding; Genentech: Patents & Royalties: for venetoclax to one of my employers (Walter & Eliza Hall Institute); I receive a share of these royalties. Blombery:Amgen: Consultancy; Novartis: Consultancy; Invivoscribe: Honoraria; Janssen: Honoraria.

Background/Aim An effective T cell response is necessary for the control of cytomegalovirus (CMV) reactivation after allogeneic stem cell transplant (alloBMT) - CMV is associated with significant morbidity, especially in patients (pts) who require recurrent episodes of antiviral therapy & those who develop associated end organ dysfunction (CMV disease). We sought to determine whether deep sequencing of T cell receptor beta (TRB) loci could identify & quantitate T cell clonotypes with specificity for CMV epitopes in the early post-alloBMT period and assess association with virus related outcomes. Methods TRB deep sequencing was performed using LymphoTrack TRB (Invivoscribe) on stored DNA samples, extracted from CD3+ selected peripheral blood samples taken at Day+30 & Day+60 from 65 consecutive pts receiving alloBMT at our institution, who were donor (D) &/or recipient (R) CMV seropositive. Sequence assembly, annotation & error correction was performed by MiXCR/VDJtools. Epitope specificity was assessed using a curated database of T cell clonotype/epitope specificity (VDJdb). Statistical analysis was performed using the Kaplan-Meier method for time to event endpoints, Fisher's exact test for discrete variables & the Mann Whitney U test for continuous variables. Results CMV specific T cells were identifiable in 97% samples at D+30 & 100% samples at D+60 - the proportion of the T cell repertoire comprising CMV specific T cells (CMV-Trep%) was median (IQR) 0.15% (0.04-0.55%) & 0.12% (0.05-0.66%) respectively. Antecedent viremia was associated with a higher CMV-Trep% at both time points (D+30: 0.45% vs, 0.095%, p=0.01; D+60: 0.20% vs. 0.07%, p=0.02), as was D+R+ serostatus at D+60 (0.28%, p=0.003). Pts who developed detectible viremia between the two sample timepoints had a median 2.1-fold increase in CMV-Trep% (vs. 0.1-fold decrease for those without viremia, p=0.03). 45% of pts had at least 1 episode of anti-CMV therapy, 52% of whom required >1 episodes of treatment. CMV disease developed in 11% of pts. Time to first antiviral treatment was associated with ATG (HR 2.5, p Conversely, following initial reactivation requiring antiviral therapy, pts with CMV-Trep >0.1% at D+60 were significantly less likely to require additional episodes of antiviral therapy (HR 0.32, p=0.05) or develop CMV related organ dysfunction (HR 0.15, p=0.02). No clinical factor was associated with these outcomes. Conclusion The degree of post-reactivation expansion of CMV specific T cells can be quantified using TRB deep sequencing. Identification of pts who fail to mount a T cell response to initial reactivation may be predictive of those at high risk for recurrent viremia & CMV disease, in whom secondary prophylactic interventions (e.g. antiviral or cellular therapy) could be used.

Background Minimal residual disease (MRD) assessment of hematopoietic neoplasia below 10-4 requires more leukocytes than is usually attainable by post-lysis preparation. However, not all laboratories are resourced for consensus Euroflow pre-lysis methodology. Our study aim was to validate a modified pre-lysis protocol against our standard post-lysis method for MRD detection of multiple myeloma (MM), chronic lymphocytic leukemia (CLL), and B-non Hodgkin lymphoma (B-NHL), to meet demand for deeper MRD assessment by flow cytometry. Method Clinical samples for MRD assessment of MM, CLL, and B-NHL (50, 30, and 30 cases, respectively) were prepared in parallel by pre and post-lysis methods for the initial validation. Total leukocytes, MRD, and median fluorescence intensity of antigen expression were compared as measures of sensitivity and antigen stability. Lymphocyte and granulocyte composition were compared, assessing relative sample processing stability. Sensitivity of the pre-lysis assay was monitored post validation for a further 18 months. Results Pre-lysis achieved at least 10-4 sensitivity in 85% MM, 81% CLL, and 90% B-NHL samples versus 24%, 48%, and 26% by post-lysis, respectively, with stable antigen expression and leukocyte composition. Post validation over 18 months with technical expertise improving, pre-lysis permitted 10-5 MRD assessment in 69%, 86%, and 82% of the respective patient groups. Conclusion This modified pre-lysis procedure provides a sensitive, robust, time efficient, and relatively cost-effective alternative for MRD testing by MFC at 10-5 , facilitating clinically meaningful deeper response assessment for MM, CLL, and B-NHL. This method adaptation may facilitate more widespread adoption of highly sensitive flow cytometry-based MRD assessment.

Prevention of cancer-associated thromboembolism (TE) remains a significant clinical challenge and priority world-wide safety initiative. In this prospective non-small cell lung cancer (NSCLC) cohort, longitudinal TE risk profiling (clinical and biomarker) was undertaken to develop risk stratification models for targeted TE prevention. These were compared with published models from Khorana, CATS, PROTECHT, CONKO, and CATS/MICA. The NSCLC cohort of 129 patients, median follow-up 22.0 months (range 5.6&mdash, 31.3), demonstrated a hypercoagulable profile in &gt, 75% patients and TE incidence of 19%. High TE risk patients were those receiving chemotherapy with baseline fibrinogen &ge, 4 g/L and d-dimer &ge, 0.5 mg/L, or baseline d-dimer &ge, 1.5 mg/L, or month 1 d-dimer &ge, 1.5 mg/L. The model predicted TE with 100% sensitivity and 34% specificity (c-index 0.67), with TE incidence 27% vs. 0% for high vs. low-risk. A comparison using the Khorana, PROTECHT, and CONKO methods were not discriminatory, TE incidence 17&ndash, 25% vs. 14&ndash, 19% for high vs. low-risk (c-index 0.51&ndash, 0.59). Continuous d-dimer (CATS/MICA model) was also not predictive of TE. Independent of tumour stage, high TE risk was associated with cancer progression (HR 1.9, p = 0.01) and mortality (HR 2.2, p = 0.02). The model was tested for scalability in a prospective gastrointestinal cancer cohort with equipotency demonstrated, 80% sensitivity and 39% specificity. This proposed TE risk prediction model is simple, practical, potent and can be used in the clinic for real-time, decision-making for targeted thromboprophylaxis. Validation in a multicentre randomised interventional study is underway (ACTRN12618000811202).

Background: Peptide receptor radionuclide/chemoradionuclide therapy(PRRT/PRCRT) is an emerging therapy in patients with metastatic neuroendocrine neoplasia (NEN). However, therapy-related myeloid neoplasms (t-MN) remain a potential complication with substantial adverse outcomes. The study reviewed our PRRT/PRCRT patients who developed t-MN, with regard to their clinicopathological features and outcomes. Methods: Retrospective analysis of all patients diagnosed with t-MN, defined as per revised 2016 WHO classification, from this single centre cohort of 521 patients who received PRRT/PRCRT over a 12-year period. Molecular next generation sequencing using an in-house 26 gene panel were performed. Findings: Twenty-five (4.8%) patients were diagnosed with t-MN, including six acute myeloid leukaemia (AML) and 19 myelodysplastic syndrome (MDS). The median time from first cycle PRRT/PRCRT to diagnosis of t-MN was 26 months (range 4 - 91). Twenty-two of 25 (88%) patients had Grade 1-2 pancreatic or small bowel NEN with moderate metastatic liver burden. The majority, 22 of 25 (88%) received concomitant radiosensitising chemotherapy. All 25 patients achieved disease stabilisation (68%) or at least a partial response (32%) on RECIST 1.1 assessment at 3 months post-PRRT. At t-MN diagnosis, all patients presented with thrombocytopenia (median nadir 33 x 109/L, range 3 - 75) and 17 (68%) were NEN progression free. Marrow genetic analysis revealed unfavourable karyotype in 16/25 (66%) patients and tumour protein 53 (TP53) mutations in nine (36%). Azacitidine therapy was utilised in ten eligible patients, while four received induction chemotherapy for AML. The median overall survival from the time of t-MN diagnosis was 13 months (range 1 - 56), with cause of death due largely to haematological disease progression. Interpretation: The diagnosis of t-MN after PRRT/PRCRT is uncommon but a serious complication with poor overall survival. Most patients present with thrombocytopenia, unfavourable genetic mutations and poor response to t-MN treatment. Funding: No funding source involved. Declaration of Interest: RJH holds shares in Telix Pharmaceuticals on behalf of the Peter MacCallum Cancer Centre. MSH reports personal fees and non-financial support from Ipsen and Sanofi Genzyme, personal fees and other from Endocyte, outside the submitted work. All remaining authors declare no competing interests. Ethical Approval: The study was approved by the hospital’s medical ethics committee as a retrospective audit with approval of waiver for patient consent (HREC Project number 18/61R). All patients had provided written, informed consent for PRRT/PRCRT.

The main purpose of this study was to examine various potential influences (including mass media reporting, instructors/teachers, and personal experience) of students' attitudes toward both social media and face-to-face (FtF) communication. Such questions emerged from recent debates over the role of technology in the college classroom that commonly center on the comparison of FtF and computer-mediated communication (CMC). Of the 545 college students surveyed online, mass media and instructors/teachers emerge as primary sources of information about negative elements of social media, while friends and personal experience are primary sources about the benefits of CMC. Most all sources examined provide positive information about FtF benefits, and none were sources of negative elements of FtF interaction. These findings are discussed in terms of how educators and others might recognize the impact of how they frame and discuss social media in and out of their classrooms.

Advancements in wearable technology have allowed for extradyadic social cues to be inserted directly (albeit conspicuously) into face-to-face interactions. The current study simulated a fictitious “Looking Glass” program that (a) autodetects (via facial recognition) one’s partner and (b) displays that person’s last 12 social media posts on a pair of Google Glass. In a randomized case/control experiment, nonwearers were more likely to perceive Glass wearers as physically attractive and socioemotionally close, while feeling lower self-esteem and having higher mental and physical demand with the conversation. Open-ended data suggested Glass wearers to be less attentive to the conversation, and Glass-present conversations were less on topic. These data, while preliminary and based on a small sample of users, hold implications for future application and research on cyborgic face-to-face interactions.

IntroductionTwenty years ago, the Advertising Division of the Association for Education in Journalism and Mass Communication (AEJMC) launched the first journal to focus exclusively on teaching advertising (Marra & Avery, 1996). Since its beginning in the spring of 1996, the Journal of Advertising Education's (JAE) goal was to "help advertising faculty teach" (Marra & Avery, 1996, p. 4). James Marra and Jim Avery, the AEJMC Advertising Division heads who helped launch the journal, stated that before the first issue of JAE was published, "advertising education never could claim its own medium to embrace and then assist, guide, and refine the lofty mission of teaching" (Marra & Avery, 1996, p. 4).Since its first edition, journal contributors have explored a range of topics, and JAE has been publishing research in various areas of advertising education, including media planning, creative, account planning, marketing, student competitions, curriculum, and employment and internships. Contributors also have explored how pedagogical innovations can be applied to advertising education. In addition to exploring an array of topics, JAE has embraced a variety of methods, ranging from surveys and quasi-experimental studies to interviews and case studies.JAE is a peer-reviewed scholarly publication that addresses issues related to instruction, curriculum and leadership in advertising education. The journal is unique because it has always been self-published by the AEJMC Advertising Division. Advertising professors, administrators and graduate students in the United States constitute the journal's audiences (JAE, n. d.).This study's objective is to examine JAE's 20 years of contributions to advertising education research, while also providing an in-depth look at the research trends and practices that have shaped the journal with regard to methods, authorship and content focus. This article will also explore the dynamics of the institutions and authors who have made this journal a resource for advertising educators. To achieve these goals, this research reviews 20 years of JAE content inductively to identify research trends. Then, the study quantitatively content analyzes JAE according to research topic, method, Carnegie Classification and authorship practice. The analysis concludes by comparing JAE with its peer publications.Literature ReviewSince 1996, JAE's first year of publication, the advertising profession and, consequently, the practices in advertising education have rapidly evolved. JAE content has kept pace with this evolution on several fronts. Kim, Hayes, Avant and Reid (2014) analyzed advertising research trends from 1980-2010 that parallel trends in advertising practice. The most frequently studied areas in the field included advertising practice, effects, social issues, content and methodology. Although Web-focused research has recently increased in popularity, advertising scholars have traditionally focused on print media analysis (Kim et al, 2014). JAE was quick to adapt to Webbased media innovations, with many articles exploring Internet-related issues in its earliest years (Barnes, 1996; Everett, Siegel & Marchant, 1999; Frisby, 2000). JAE is distinct in its methodological innovation and diversity. JAE embraces a variety of qualitative methodologies, including interviews, textual analysis and personal narratives, although advertising and marketing research tends to be primarily empirically and quantitatively focused (Kim et al, 2014).In addition to matching their research to industry trends and being quick to innovate, advertising professors publishing in JAE also work to establish state-of-the-art industrycentered curricula and coursework. JAE has a history of publishing articles on teaching industry-related skills as they apply to creative (Barnes & Lloyd, 1997; Beard & Tarpenning, 2001; Blakeman & Haley, 2005; Duke, 2001; Habib, 2015; Johnson & Jones, 2010; Robbs, 2010; Stuhlfaut, 2007), media (Kim & Patel, 2012; Kinsky, 2015; Martin, 2002; Slater, Robbs & Lloyd, 2002), account planning (Lavery, 2000; Morrison, Christy & Haley, 2003), internships and employment (Kendrick & Fullerton, 2002; Kendrick & Fullerton, 2003; Maynard & Saewitz, 2008; McMillan, Sheehan, Heinemann & Frazier, 2001; Perlmutter & Fletcher, 1999; Roznowski & Wrigley, 2003; Taylor & Sheehan, 1997; Yoo & Morris, 2015) and student competitions (Fullerton, Kendrick & Frazier, 2009; Marra, Avery & Grabe, 1997; Parker, 2000; Spuler & Marold, 2015; Weir, 1999). …

BCL2 blunts activation of the mitochondrial pathway to apoptosis, and high-level expression is required for chronic lymphocytic leukemia (CLL) survival. Venetoclax (ABT-199) is a small-molecule selective inhibitor of BCL2 currently in clinical trials for CLL and other malignancies. In conjunction with the phase 1 first-in-human clinical trial of venetoclax in patients with relapsed or refractory CLL (M12-175), we investigated the mechanism of action of venetoclax in vivo, explored whether in vitro sensitivity assays or BH3 profiling correlated with in vivo responses in patients, and determined whether loss of TP53 function affected responses in vitro and in vivo. In all samples tested, venetoclax induced death of CLL cells in vitro at concentrations achievable in vivo, with cell death evident within 4 hours. Apoptotic CLL cells were detected in vivo 6 or 24 hours after a single 20-mg or 50-mg dose in some patients. The extent of mitochondrial depolarization by a BIM BH3 peptide in vitro was correlated with percentage reduction of CLL in the blood and bone marrow in vivo, whereas the half lethal concentration derived from standard cytotoxicity assays was not. CLL cell death in vitro and the depth of clinical responses were independent of deletion of chromosome 17p, TP53 mutation, and TP53 function. These data provide direct evidence that venetoclax kills CLL cells in a TP53-independent fashion by inhibition of BCL2 in patients and support further assessment of BH3 profiling as a predictive biomarker for this drug.

Systemic anaplastic large cell lymphoma (sALCL) is an aggressive T-cell non Hodgkin lymphoma which is divided into two categories based on the expression of the anaplastic lymphoma kinase (ALK) protein (i.e. ALK-positive ALCL and ALK-negative ALCL). ALK-negative sALCL typically presents with

Myelodysplastic syndromes (MDS) are a group of clonal marrow stem cell disorders characterized by progressive peripheral cytopenias and ineffective hematopoiesis with an associated risk of progress...

Flow cytometry is the most accessible method for minimal residual disease (MRD) detection due to its availability in most haematological centres. Using a precise combination of different antibodies, immunophenotypic detection of MRD in acute leukaemia can be performed by identifying abnormal combinations or expressions of antigens on malignant cells at diagnosis, during and post treatment. These abnormal phenotypes, referred to as leukaemia-associated immunophenotypes (LAIPs) are either absent or expressed at low frequency in normal bone marrow (BM) cells and are used to monitor the behaviour and quantitate the amount of residual disease following treatment. In paediatric acute lymphoblastic leukaemia (ALL), the level of MRD by multiparametric flow cytometry (MPFC) during therapy is recognised as an important predictor of outcome. Although less extensively studied, adult ALL and adult and paediatric acute myeloid leukaemia (AML) have also demonstrated similar findings. The challenge now is incorporating this information for risk-stratification so that therapy can be tailored individually and ultimately improve outcome while also limiting treatment-related toxicity. In this review we will elaborate on the current and future role of MPFC in MRD in acute leukaemia while also addressing its limitations.

The BCL2 inhibitor venetoclax induces high rates of durable remission in patients with previously treated chronic lymphocytic leukemia (CLL). However, despite continuous daily treatment, leukemia recurs in most patients. To investigate the mechanisms of secondary resistance, we analyzed paired pre-venetoclax and progression samples from 15 patients with CLL progression enrolled on venetoclax clinical trials. The novel Gly101Val mutation in BCL2 was identified at progression in 7 patients, but not at study entry. It was first detectable after 19 to 42 months of therapy, and its emergence anticipated clinical disease progression by many months. Gly101Val reduces the affinity of BCL2 for venetoclax by ∼180-fold in surface plasmon resonance assays, thereby preventing the drug from displacing proapoptotic mediators from BCL2 in cells and conferring acquired resistance in cell lines and primary patient cells. This mutation provides new insights into the pathobiology of venetoclax resistance and provides a potential biomarker of impending clinical relapse. Significance: Why CLL recurs in patients who achieve remission with the BCL2 inhibitor venetoclax has been unknown. We provide the first description of an acquired point mutation in BCL2 arising recurrently and exclusively in venetoclax-treated patients. The mutation reduces venetoclax binding and is sufficient to confer resistance. See related commentary by Thangavadivel and Byrd, p. 320. This article is highlighted in the In This Issue feature, p. 305

Cytotoxic chemotherapy has inherent mutagenic potential and alters the bone marrow microenvironment after therapy. In some cases, this potentiates expansion of an aberrant clone and may lead to a therapy-related myeloid neoplasm if the clone overcomes selective pressure. We present the case of a 43-year-old woman diagnosed with an indolent, therapy-related myeloid neoplasm with an isolated chromosome 6p abnormality following treatment for de novo Acute Myeloid Leukaemia (AML), who manifest a sustained spontaneous cytogenetic remission two years later, possibly due to an ineffectual or non-dominant founding clone. This case reminds us to be mindful of the possibility that clonal haematopoiesis may not always equate to clinically relevant disease, even in the setting of an abnormal clonal karyotype.

The diagnostic landscape of hematological malignancies including myelodysplastic syndromes (MDS) is evolving rapidly. Peripheral blood (PB) and bone marrow (BM) morphology has been the gold standar...

Context Detection of measurable residual disease after therapy is an important predictor of outcome in acute myeloid leukemia. Objective To investigate the feasibility of using next-generation sequencing (NGS) in the diagnostic laboratory to perform quantitative NPM1 mutation assessment using ultradeep (approximately 300 000×–500 000×) sequencing (NGS-qNPM1) as a method of assessing residual disease burden in patients with acute myeloid leukemia. Design A flexible NGS-based assay for the detection and quantitation of NPM1 mutations was developed by polymerase chain reaction amplification of target DNA sequences, sequencing on an Illumina (San Diego, California) MiSeq, and analyzing data with an in-house–designed bioinformatic pipeline. NGS-qNPM1 was compared with current NPM1 quantitation methods (real-time quantitative-polymerase chain reaction and multiparameter flow cytometry). Results The NGS-qNPM1 assay had a sensitivity of between 10−4 and 10−5 and showed high concordance and correlation with reference methodologies. Moreover, the NGS-qNPM1 assay was able to be integrated into the laboratory's existing, targeted amplicon-based sequencing workflow. Conclusions An NGS-based, quantitative NPM1-mutation assessment can be used to monitor patients with acute myeloid leukemia, and it has some practical advantages over existing modalities.

The peripheral T-cell lymphomas (PTCL) comprise a diverse range of hematological neoplasms, accounting for 10–15% of all non-Hodgkin lymphomas diagnosed in adults [1] and typically possessing an ag...

Despite the availability of safe and efficacious antithrombotic agents, as well as the vast clinical experience justifying their use, thromboembolism (TE) remains a frequent complication among canc...

Humans often prefer representations that are cognitively easier to store, and such representations are easier to retrieve later to make judgments about the social world. Exemplification theory draws on physiological memory mechanisms and argues that simple, iconic, concrete, and emotionally arousing depictions of events (exemplars) are favored and thus more likely to be stored and used than are abstract, inconsequential depictions or representations. Inconsequential information or representations are forgotten because they are not processed as being essential for survival. Exemplified events vary on a continuum of how accurately they represent a larger occurrence of events. Through specific uses of pictures, quotes and other depictive strategies, concrete, iconic, and emotionally arousing information is often added to a story. Research has documented the strength of specific exemplars in creating inaccurate estimations of events and perceptions of severity and susceptibility. Moreover, in the presence of a risk, portrayals with exemplars have been shown to motivate individuals to intend to change behavior. Exemplification is a strong theory that is understudied and underutilized. The theory has strong explanatory, predictive, and organizing power, and it has application to phenomena in contexts such as media effects, persuasion, crisis and risk communication, health communication and public relations.

The BCL2 inhibitor venetoclax achieves responses in ∼79% of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL), irrespective of risk factors associated with poor response to chemoimmunotherapy. A limitation of this targeted therapy is progressive disease (PD) in some patients. To define the risk factors for progression, the clinicopathological features of PD, and the outcomes for patients after venetoclax failure, we analyzed 67 heavily pretreated patients on 3 early phase clinical trials. Investigations at progression included positron emission tomography scan and biopsy. Twenty-five (37%) patients manifested PD on therapy: 17 with Richter transformation (RT) and 8 with progressive CLL/SLL. RT occurred significantly earlier (median 7.9 months) than progressive CLL (median 23.4 months) (P = .003). Among patients who received the recommended phase 2 dose of venetoclax or higher (≥400 mg/d), fludarabine refractoriness and complex karyotype were associated with progression (hazard ratio 7.01 [95% confidence interval 1.7-28.5]; P = .002 and 6.6 [1.5-29.8]; P = .005, respectively), whereas del(17p) and/or TP53 mutation were not (P = .75). Median postprogression survival was 13 (

The safety, kinetics and efficacy of plerixafor+pegfilgrastim for hematopoietic stem and progenitor cell (HSPC) mobilization are poorly understood. We treated 12 study patients (SP; lymphoma n=10 or myeloma n=2) with pegfilgrastim (6 mg SC stat D1) and plerixafor (0.24 mg/kg SC nocte from D3). Six SP were 'predicted poor-mobilizers' and six were 'predicted adequate-mobilizers'. Peripheral blood (PB) CD34(+) monitoring commenced on D3. Apheresis commenced on D4. Comparison was with 22 historical controls (HC; lymphoma n=18, myeloma n=4; poor mobilizers n=4), mobilized with pegfilgrastim alone. Eight (67%) SP had PB CD34(+) count ⩽5 × 10(6)/L D3 post pegfilgrastim; all SP surpassed this threshold the morning after plerixafor. In SP, PBCD34(+) counts peaked D4 6/12 (50%), remaining ⩾5 × 10(6)/L for 4 days in 8/12 (67%). All SP successfully yielded target cell numbers (⩾2 × 10(6)/kg) within four aphereses. After maximum four aphereses, median total CD34+ yield was higher in SP than HC; 8.0 (range 2.4-12.9) vs 4.8 (0.4-14.0) × 10(6)/kg (P=0.04). Seven of twelve (58%) SP achieved target yield after one apheresis. Flow cytometry revealed no tumor cells in PB or apheresis product of SP. Plerixafor+pegfilgrastim was well tolerated with bone pain (n=2), diarrhoea (n=2) and facial paraesthesiae (n=3). Plerixafor+pegfilgrastim is a simple, safe and effective HSPC mobilization regimen in myeloma and lymphoma, in both poor and good mobilizers, and is superior to pegfilgrastim alone.

The optimum follow-up of patients with transformed indolent lymphoma (TrIL) is not well defined. We sought to determine the utility of surveillance positron emission tomography-computed tomography (PET-CT) in patients with TrIL achieving complete metabolic remission (CMR) after primary therapy. We performed a retrospective analysis of patients with TrIL treated at Peter MacCallum Cancer Centre between 2002 and 2012 who achieved CMR after primary therapy who had ≥1 subsequent surveillance PET-CT. Of 55 patients with TrIL, 37 (67 %) received autologous stem cell transplantation as consolidation following chemoimmunotherapy. After a median follow-up of 34 (range 3-101) months, the actuarial 3-year progression-free (PFS) and overall survival (OS) were 77 % (95 %CI 62-86 %) and 88 % (75-94 %), respectively. Of 180 surveillance PET-CT scans, there were 153 true negatives, 4 false positives, 1 false negative, 7 indeterminate and 15 true positives. Considering indeterminate scans as false positives, the specificity of PET-CT for detecting relapse was 94 %, sensitivity was 83 %, positive predictive value was 63 % and negative predictive value was 98 %. All seven subclinical (PET detected) relapses were of low-grade histology; in contrast, all nine relapses with diffuse large B cell lymphoma (DLBCL) were symptomatic. In our cohort of patients with TrIL achieving CMR, PET-CT detected subclinical low-grade relapses but all DLBCL relapses were accompanied by clinical symptoms. Thus, surveillance imaging of patients with TrIL achieving CMR is of limited clinical benefit. PET-CT should be reserved for evaluation of clinically suspected relapse.

The BCL2 Gly101Val mutation may be acquired in patients with chronic lymphocytic leukaemia (CLL) treated with venetoclax (VEN), leading to reduced drug binding affinity and secondary resistance. In the majority of patients, the Gly101Val mutation is subclonal within the CLL compartment consistent with the presence of alternative resistance mechanisms in CLL cells not harboring the Gly101Val mutation. To date, two Gly101Val mutated patients have been identified with co-existing candidate resistance mechanisms in Gly101Val non-mutated cells; one with BCL-XL over-expression (Blombery et al, Cancer Discov., 2019) and another with a second subclonal candidate BCL2 resistance mutation - Asp103Tyr (Tausch et al, Haematologica 2019). Given the possibility of additional resistance mechanisms, we investigated patients with progressive CLL on VEN harboring the Gly101Val mutation for the presence of additional acquired resistance mutations in BCL2. Ten patients with progressive CLL on VEN with Gly101Val mutations were identified by sensitive allele-specific droplet digital PCR. To further assess for alternative BCL2 mutations in this cohort we performed ultra-deep amplicon-based next generation sequencing (NGS) (median depth ~50,000X) targeting BCL2. An amplicon variant caller (Canary) specifically designed for low level variant calling was used (Doig et al, BMC Bioinformatics, 2017). To achieve enhanced specificity we performed digital NGS with PCR error-correction using unique molecular indexes (UMI) (QiaSEQ Targeted DNA Panel). Given the high GC content of BCL2 we also used hybridization-based NGS using a custom targeted panel (Blombery et al, BJH 2017) combined with a sensitive unpaired variant caller (GATK4/Mutect2). In 7/10 (70%) patients, BCL2 mutations in addition to the Gly101Val were detected. Recurrent mutations (detected in more than one patient) were Asp103Tyr, Asp103Glu, Arg107_Arg110dup, and Val156Asp. All additional recurrent mutations were confirmed to be absent prior to commencing VEN (sensitivity 1% variant allele frequency[VAF]). Phase-analysis of NGS reads was consistent with the presence of the additional recurrent mutations on different alleles (and therefore cells, assuming heterozygosity) to both each other and to Gly101Val. Multiple addition recurrent mutations were observed in patients in the cohort with one patient harboring three recurrent mutations in addition to the Gly101Val (Asp103Tyr, Asp103Glu, Val156Asp). In multiple patients in the cohort, the VAF of non-Gly101Val mutations exceeded that of the Gly101Val mutation. Importantly, in all patients a significant (albeit variable) proportion of CLL cells were found to be BCL2 wild-type consistent with the presence of as yet unidentified resistance mechanisms unrelated to BCL2 mutations. In one patient, two additional non-recurrent mutations were observed (Ala113Gly and Arg129Leu) in addition to Gly101Val and Val156Asp. Again, all four mutations in this patient were observed to be in mutually exclusive NGS reads. Strikingly, all of the recurrent acquired BCL2 mutated residues identified in our cohort are situated in the BCL2 binding groove that binds VEN (Figure 1). The Asp103 codon in the P4 pocket is critical for VEN binding through hydrogen bonding between its sidechain and the azaindole moiety of VEN. The Asp103Glu mutation is noteworthy given that the equivalent residue to Asp103 in BCL-XL is a Glu, which reduces VEN binding to BCL-XL. The Val156 mutation situated at the base of the P2 pocket is close to the chlorophenyl moiety of VEN and a change to Asp in this position may disrupt VEN binding. Ongoing binding experiments and modeling in cellular systems will further elucidate the mechanism and contributions of these new recurrent mutations to VEN resistance. In summary, we have extended the landscape of acquired candidate resistance mutations occurring in patients treated with VEN to include four novel recurrent BCL2 mutations. Moreover, our data are consistent with the emerging observation of multiple acquired resistance mechanisms operating in different CLL cells in a single patient contributing to an "oligoclonal" pattern of clinical relapse on VEN therapy. Figure 1 - BCL2 protein structure surface bound to venetoclax (VEN) in orange. The Asp103Tyr, Asp103Glu and Val156Asp mutation sites are shown in red and Arg107_Arg110dup region in blue Disclosures Blombery: Janssen: Honoraria; Invivoscribe: Honoraria; Novartis: Consultancy. Anderson:Walter and Eliza Hall Institute: Employment, Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.. Seymour:Acerta: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy. Huang:Genentech: Patents & Royalties: DCSH is an employee of the Walter and Eliza Hall Institute which receives milestone and royalty payments related to venetoclax. Roberts:AbbVie: Other: Unremunerated speaker for AbbVie, Research Funding; Australasian Leukaemia and Lymphoma Group: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Walter and Eliza Hall Institute: Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.; BeiGene: Research Funding.

Background: Marginal zone lymphoma (MZL) is an incurable but heterogeneous disorder for which there is no standard of care treatment in the relapsed/refractory (R/R) setting. The BTK inhibitor, ibrutinib (IB) is well tolerated with an overall response rate (ORR) of 48% as monotherapy in R/R MZL but rarely complete remission (Noy et al, Blood, 2017). The BCL-2 inhibitor, venetoclax (VEN) has also been evaluated in a small number of R/R MZL patients (pts) with evidence of activity and tolerability (Davids et al, JCO, 2017). We sought to evaluate the efficacy and safety of combination IB and VEN in pts with MZL based upon the rationale of (1) distinct mechanisms of action, (2) activity as monotherapies in MZL, and (3) acceptable non-overlapping toxicity profiles. We report preliminary results of the MZL cohort of an investigator-initiated phase II trial of combination IB and Ven (NCT02471391). Methods: Pts with MZL by WHO 2008 criteria who were R/R or treatment naïve but considered inappropriate for treatment with chemotherapy were enrolled. Pts commenced treatment with IB monotherapy at a dose of 560mg per day. After 4 weeks, VEN was added to IB treatment, in weekly step-wise dose escalation over 6 weeks to a target dose of 800mg per day in the initial cohort (n = 4), amended to 400mg per day, due to a reported IB-VEN drug interaction in a similar trial (NCT02910583). The primary endpoint was the complete remission rate (CRR) at 16 weeks. The secondary endpoints were to determine ORR and CRR, to determine minimal residual disease (MRD) elimination rates, to describe progression free survival (PFS), overall survival, duration of response, time to progression and frequency and severity of adverse events. Investigator-assessed response assessments, based on IWG criteria (Cheson et al, JCO, 2007), were performed with CT at 4, 16, 28, 40 and 56 weeks, PET/CT at weeks 16 and 56, and bone marrow (BM) aspirate and trephine, and MRD assessments by flow cytometry at all time-points. Results: Fourteen of 15 planned pts were enrolled at the time of data cut-off (May 2019), of whom 12 had reached the week 16 primary endpoint or discontinued and are reported here. Two remain on study for The CRR with CT assessment at week 16 was 25% (3/12). The CRR including PET assessment was 42% (5/12) at week 16. The ORR at this time-point was 58% (7/12) by CT and 84% (10/12) by PET (historical control with IB monotherapy is 3%; Noy et al, Blood, 2017). MRD clearance (10^-4 sensitivity) in BM was confirmed in 1 of 7 evaluable pts. Two pts have developed PD after 7 and 11 months of treatment commencement. No deaths have occurred. Safety analysis shows no cases of tumour lysis syndrome, and only one (8%) discontinuation due to toxicity. Grade 1-2 atrial fibrillation (AF) occurred in 2 pts (17%), suspected to be related to IB. The most common non-hematologic toxicities were diarrhea, bruising, fatigue and nausea, and were largely low grade. The most common hematologic toxicities were neutropenia (n=6) and thrombocytopenia (n=5) including grade 3-4 events (2 and 1 events, respectively). Serious adverse events (SAE) occurred in 5 subjects (1 pt had 2 SAE's), including 2 events attributable to trial therapy. Overall 2 pts (17%) required permanent dose reduction of IB to 420mg, due to grade 2 AF and due to grade 3 febrile illness in these cases. One pt (8%) required permanent dose reduction of VEN to 300mg, due to grade 4 neutropenia lasting >7 days despite use of G-CSF. Conclusions: Combination IB and VEN is a promising safe and efficacious treatment for MZL. Our preliminary data, demonstrating high response rates including frequent CR, warrants further investigation in a larger study. Disclosures Handunnetti: Gilead: Honoraria; Abbvie: Other: Travel Grant. Khot:Amgen: Speakers Bureau; Kyowa Hakko Kirin: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Celgene: Consultancy. Anderson:Walter and Eliza Hall Institute: Employment, Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.. Blombery:Novartis: Consultancy; Janssen: Honoraria; Invivoscribe: Honoraria. Ritchie:Sanofi: Honoraria; Novartis: Honoraria; Imago: Research Funding; Beigene: Research Funding; Takeda: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding. Hicks:Telix Pharmaceuticals: Equity Ownership; Ipsen: Research Funding; Clarity: Research Funding. Bressel:Regeneron Pharmaceuticals: Consultancy. Roberts:Australasian Leukaemia and Lymphoma Group: Membership on an entity's Board of Directors or advisory committees; Walter and Eliza Hall Institute: Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.; AbbVie: Other: Unremunerated speaker for AbbVie, Research Funding; Janssen: Research Funding; BeiGene: Research Funding. Seymour:Janssen: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy; Acerta: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Tam:Novartis: Honoraria; Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria; Roche: Honoraria; Pharmacyclics LLC, an AbbVie company: Honoraria. OffLabel Disclosure: Discussion of off-label use: Venetoclax and combination venetoclax and ibrutinib are not approved in the US for use in marginal zone lymphoma.

Background: The phase II AIM trial (Tam et al, NEJM 2018; NCT02471391), using combination BTK inhibitor ibrutinib (IB) and BCL-2 inhibitor venetoclax (VEN) therapy achieved excellent 16 week complete remission rates (CRR) (primary endpoint; 62%) in patients (pts) with poor prognosis mantle cell lymphoma (MCL), higher than currently approved second line IB monotherapy. Additionally, overall response rate (ORR) by PET of 71%, with attainment of minimal residual disease (MRD) negativity was reported. At the time of primary endpoint analysis (median follow up 15.9 months), median progression free survival (PFS), duration of response (DOR), time to progression (TTP) and overall survival (OS) had not been reached. Herein, we update our results with an additional 21.6 months of follow-up and report the outcomes of pts who electively interrupted treatment. Methods: Pts with MCL who had relapsed or refractory disease (R/R; n=23) or were treatment naïve but inappropriate for chemotherapy (n=1) were enrolled. Pts commenced treatment with IB 560mg/d for 4 weeks, followed by weekly ramp-up of VEN to 400mg/d. Initially, pts were intended to continue IB and VEN until progressive disease or unacceptable toxicity; a later amendment allowed pts to electively interrupt both drugs if MRD-negative CR was reached. Pts who elected to interrupt therapy were closely monitored by peripheral blood flow MRD testing and regular CT scans, and were allowed to recommence both study drugs at MRD recrudescence or clinical progression. Results: Median age was 68 years (range, 47-81), median number of previous treatments was 2 (range, 0 to 6), and 50% had aberrations of TP53. As previously reported, the flow MRD-negative and ASO-PCR MRD-negative rates were 67% and 38%, respectively. For the current analysis, the median follow-up was 37.5 months (range, 1.4-45.3).The median DOR and TTP had not been reached and were estimated to be 74% and 60% at 30 months, respectively. The median PFS was 29 months (95% CI of 13-NE) (Figure 1), and the median OS was 32 months (95% CI of 27-NE) (Figure 2). For pts with TP53 aberrant MCL (n=12), the CRR was 50% (95% CI 21-79) with and without PET. In this group the ORR was 58% (95% CI 28-85) without PET and 50% (CI 21-79%) with PET. The DOR in 6 responders with TP53 aberrant MCL (excluding one pt with CRu) was 12+, 24+, 26+, 35+, 36+ and 38+ months from study commencement. In contrast, pts with ATM aberrant MCL (n=10) the CRR was 90% (95% CI 55-100) with and without PET, and the ORR was 90% (95% CI 55-100) with and without PET. Of the 9 responders with ATM aberrant MCL, the DOR was 9+, 9+, 12+, 24+, 31+, 35+, 36+, 37+ and 38+ months from study commencement. Of 13 deaths, 8 were due to PD. Of the other 5 deaths, 2 were due to infection, and 1 each to cardiac failure, glioblastoma, and graft versus host disease after an allograft that occurred after PD on trial. Five pts in MRD negative PET-confirmed CR electively interrupted treatment after a median 18.5 months (range 18-33) of therapy: one pt had radiological progression after 7 months, and the other 4 remained free of clinical or MRD progression after 6, 13, 17 and 18 months off therapy. Conclusions: The median PFS for the IB-VEN combination was 29 months. Treatment interruption was feasible for pts in MRD-negative complete remissions, raising the prospect of limited duration targeted-agent therapy in the management of R/R MCL. Disclosures Handunnetti: Gilead: Honoraria; Abbvie: Other: Travel Grant. Anderson:Walter and Eliza Hall Institute: Employment, Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.. Hicks:Clarity: Research Funding; Ipsen: Research Funding; Telix Pharmaceuticals: Equity Ownership. Bressel:Regeneron Pharmaceuticals: Consultancy. Koldej:NanoString Technologies: Other: Travel grant. Ritchie:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Novartis: Honoraria; Sanofi: Honoraria. Seymour:Roche: Consultancy, Research Funding, Speakers Bureau; Acerta: Consultancy; Takeda: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau. Roberts:Walter and Eliza Hall Institute: Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.; AbbVie: Other: Unremunerated speaker for AbbVie, Research Funding; Janssen: Research Funding; Australasian Leukaemia and Lymphoma Group: Membership on an entity's Board of Directors or advisory committees; BeiGene: Research Funding. Tam:AbbVie: Honoraria, Research Funding; Roche: Honoraria; BeiGene: Honoraria; Novartis: Honoraria; Pharmacyclics LLC, an AbbVie company: Honoraria; Janssen: Honoraria, Research Funding. OffLabel Disclosure: While ibrutinib is FDA approved for use in relapsed and refractory mantle cell lymphoma, venetoclax and combination venetoclax and ibrutinib are not licensed for use in mantle cell lymphoma. The use of venetoclax and ibrutinib for this indication is investigational.

Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) to a high-grade B-cell lymphoma and is associated with an aggressive clinical course and poor prognosis. Conventional treatment options for RS are generally associated with low response rates and limited durability making this entity an area of significant unmet therapeutic need. Immune checkpoint inhibitor therapy has shown promise in the treatment of some aggressive lymphoma subtypes. In RS, modest benefits have been reported in small phase two trials of anti-PD-1 monotherapy and in combination with ibrutinib, however larger scale studies are lacking (Ding et al Blood, 2017; Jain et al Blood, 2016). We sought to characterise the immune-evasion phenotype of RS focussing on potential genetic biomarkers which may inform the selection of patients who are most likely to benefit from immune-directed therapies. We first assessed the gene expression of immune-checkpoint molecules given their potential clinical relevance and ability to be targeted by available therapeutic agents. Given immunohistochemical (IHC) assessment of immune-checkpoint molecules is recognized to be associated with high inter-observer variability and there is a high correlation between gene expression of immune-checkpoint molecules and IHC, we performed gene expression quantification using the Nanostring nCounter Human Immunology V2 panel (Nanostring Technologies, USA). Nanostring analysis was performed on samples from 17 patients with histologically confirmed RS (DLBCL subtype) and compared to 73 cases of de novo (non-transformed) DLBCL. Significant differences in the gene expression of checkpoint molecules was observed between RS and DLBCL biopsies, including higher expression of LAG3, PD1 and TIGIT in RS (p=0.0001, logFC 1.9; p=0.0017, logFC 1.1 and p=0.0437, logFC 0.7 vs DLBCL, respectively). PD-L2 and TIM3 gene expression were both significantly lower in RS compared to DLBCL (p = 0.0059, logFC 0.8; p = 0.012, logFC 0.8). PDL1 and CTLA4 gene expression did not significantly differ between RS and DLBCL. We next assessed the gene expression of T- and NK- cell markers (including CD3, CD4, CD8, FOXP3 and CD56) and the ratios of these markers to malignant B-cells (CD19). We observed no significant difference between RS and DLBCL, consistent with a similar relative quantity of immune cell infiltration between the two entities. Significantly higher gene expression of CD39, a marker of CD8+ T-cell exhaustion, was observed in RS than DLBCL (p = 0.031; logFC 0.5). Additional immune-related genes were next assessed, including those involved in antigen presentation (e.g. B2M, HLA molecules, TAP), immunosuppressive cytokine generation (e.g. ARG1, IDO1) and apoptosis resistance (e.g. FAS) which showed no significant differences in expression between RS and DLBCL. To assess whether these findings were consistent across other transformed lymphoma subtypes, we compared RS to a cohort of transformed follicular lymphoma (tFL, n=16) and transformed marginal zone lymphoma (tMZL, n=25). LAG3 expression was significantly higher in RS compared to both tFL and tMZL (p=0.0002, logFC 2.7; p=0.019, logFC 1.7). PD1 expression was also significantly higher in RS than tFL but not tMZL (p=0.0045, logFC 1.7; p=0.39, logFC 0.4). Given the established association of copy number amplifications involving immune checkpoint molecules (e.g. PD-L1/PD-L2 on 9p24.1) representing a potential predictive biomarker of response in other lymphomas, we performed hybridization-based NGS with whole genome copy number assessment to evaluate immune checkpoint gene loci in the three cohorts. No significant focal amplifications were detected in RS samples with overexpressed immune-checkpoint molecules. In contrast, three patients in the DLBCL/transformed cohort had focal copy number amplifications involving PD-L1. No copy number amplification of LAG3 was observed in either RS or DLBCL. In summary, we have observed significantly increased gene expression of LAG3, PD1 and TIGIT in RS compared to de novo DLBCL. Combined with increased gene expression of the exhausted cytotoxic T-cell marker CD39, these data provide a strong biological rationale for pursuing LAG3 inhibition either alone or in combination with other immune checkpoint blockade to enhance anti-tumour T cell responses in this difficult-to-treat entity. CG/JL/YK co-first authors Disclosures Gould: NovoNordisk: Other: Travel funding - domestic flights to attend education, May 2018. Villa:Roche, Abbvie, Celgene, Seattle Genetics, Lundbeck, AstraZeneca, Nanostring, Janssen, Gilead: Consultancy, Honoraria. Tam:Abbvie, Janssen: Research Funding; Abbvie, Janssen, Beigene, Roche, Novartis: Honoraria. Neeson:Roche Genetech: Research Funding; Allergan: Research Funding; Juno/Celgene: Research Funding; Compugen: Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Seymour:Roche: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Acerta: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding. Dickinson:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck Sharpe and Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Blombery:Invivoscribe: Honoraria; Novartis: Consultancy; Janssen: Honoraria.

Social media are increasingly being used as an information source, including information related to risks and crises. The current study examines how pieces of information available in social media impact perceptions of source credibility. Specifically, participants in the study were asked to view 1 of 3 mockTwitter.compages that varied the recency with which tweets were posted and then to report on their perceived source credibility of the page owner. Data indicate that recency of tweets impacts source credibility; however, this relationship is mediated by cognitive elaboration. These data suggest many implications for theory and application, both in computer-mediated communication and crisis communication. These implications are discussed, along with limitations of the current study and directions for future research.

In a phase I study of autologous chimeric antigen receptor (CAR) anti-LeY T-cell therapy of acute myeloid leukemia (AML), we examined the safety and postinfusion persistence of adoptively transferred T cells. Following fludarabine-containing preconditioning, four patients received up to 1.3 × 109 total T cells, of which 14–38% expressed the CAR. Grade 3 or 4 toxicity was not observed. One patient achieved a cytogenetic remission whereas another with active leukemia had a reduction in peripheral blood (PB) blasts and a third showed a protracted remission. Using an aliquot of In111-labeled CAR T cells, we demonstrated trafficking to the bone marrow (BM) in those patients with the greatest clinical benefit. Furthermore, in a patient with leukemia cutis, CAR T cells infiltrated proven sites of disease. Serial PCR of PB and BM for the LeY transgene demonstrated that infused CAR T cells persisted for up to 10 months. Our study supports the feasibility and safety of CAR–T-cell therapy in high-risk AML, and demonstrates durable in vivo ­persistence.

In an online survey with two cohorts (2009 and 2011) of undergraduates in dating relationshi ps, we examined how attachment was related to communication technology use within romantic relation ships. Participants reported on their attachment style and frequency of in-person communication as well as phone, text messaging, social network site (SNS), and electronic mail usage with partners. Texting and SNS communication were more frequent in 2011 than 2009. Attachment avoidance was related to less frequent phone use and texting, and greater email usage. Electronic communication channels (phone and texting) were related to positive relationship qualities, however, once accounting for attachment, only moderated effects were found. Interactions indicated texting was linked to more positive relationships for highly avoidant (but not less avoidant) participants. Additionally, email use was linked to more conflict for highly avoidant (but not less avoidant) participants. Finally, greater use of a SNS was positively associated with intimacy/support for those higher (but not lower) on attachment anxiety. This study illustrates how attachment can help to explain why the use of specific technology-based communication channels within romantic relationships may mean different things to different people, and that certain channels may be especially relevant in meeting insecurely attached individuals’ needs.

BACKGROUND: The effectiveness of platelet transfusions to prevent bleeding in patients with hematologic cancers remains unclear. This trial assessed whether a policy of not giving prophylactic platelet transfusions was as effective and safe as a policy of providing prophylaxis. METHODS: We conducted this randomized, open-label, noninferiority trial at 14 centers in the United Kingdom and Australia. Patients were randomly assigned to receive, or not to receive, prophylactic platelet transfusions when morning platelet counts were less than 10×10(9) per liter. Eligible patients were persons 16 years of age or older who were receiving chemotherapy or undergoing stem-cell transplantation and who had or were expected to have thrombocytopenia. The primary end point was bleeding of World Health Organization (WHO) grade 2, 3, or 4 up to 30 days after randomization. RESULTS: A total of 600 patients (301 in the no-prophylaxis group and 299 in the prophylaxis group) underwent randomization between 2006 and 2011. Bleeding of WHO grade 2, 3, or 4 occurred in 151 of 300 patients (50%) in the no-prophylaxis group, as compared with 128 of 298 (43%) in the prophylaxis group (adjusted difference in proportions, 8.4 percentage points; 90% confidence interval, 1.7 to 15.2; P=0.06 for noninferiority). Patients in the no-prophylaxis group had more days with bleeding and a shorter time to the first bleeding episode than did patients in the prophylaxis group. Platelet use was markedly reduced in the no-prophylaxis group. A prespecified subgroup analysis identified similar rates of bleeding in the two study groups among patients undergoing autologous stem-cell transplantation. CONCLUSIONS: The results of our study support the need for the continued use of prophylaxis with platelet transfusion and show the benefit of such prophylaxis for reducing bleeding, as compared with no prophylaxis. A significant number of patients had bleeding despite prophylaxis. (Funded by the National Health Service Blood and Transplant Research and Development Committee and the Australian Red Cross Blood Service; TOPPS Controlled-Trials.com number, ISRCTN08758735.).