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Objectives: Molecular biomarker tests can inform the clinical management of genomic heterogeneous hematological malignancies, yet their availability in routine care largely depends on the supporting health economic evidence. This study aims to systematically review the economic evidence for recent molecular biomarker tests in hematological malignancies. Methods: We conducted a systematic search in five electronic databases for studies published between January 2010 and October 2020. Publications were independently screened by two reviewers. Clinical study characteristics, economic methodology, and results were extracted, and reporting quality was assessed. Results: Fourteen studies were identified, of which half (n = 7; 50%) were full economic evaluations examining both health and economic outcomes. Studies were predominantly conducted in a first-line treatment setting (n = 7; 50%) and adopted a non-lifetime time horizon to measure health outcomes and costs (n = 7; 50%). Five studies reported that companion diagnostics for associated therapies were likely cost-effective for acute myeloid leukemia, chronic myeloid leukemia, diffuse large B-cell lymphoma, and multiple myeloma. Four studies suggested molecular biomarker tests for treatment monitoring in chronic myeloid leukemia were likely cost-saving. Conclusions: Although there is initial confirmation of the promising health economic results, the present research for molecular biomarker tests in hematological malignancies is sparse with many applications of technological advances yet to be evaluated.

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.

Key Points Therapy resistance to both individual and sequential BTK and BCL2 inhibition is clonally complex and most commonly oligoclonal.Single-agent resistance mutations occur in mutually exclusive clones; resistance mutations to sequential monotherapies variably co-occur., The genomic landscape of resistance to targeted agents (TAs) used as monotherapy in chronic lymphocytic leukemia (CLL) is complex and often heterogeneous at the patient level. To gain insight into the clonal architecture of acquired genomic resistance to Bruton tyrosine kinase (BTK) inhibitors and B-cell lymphoma 2 (BCL2) inhibitors in CLL, particularly in patients carrying multiple resistance mutations, we performed targeted single-cell DNA sequencing of 8 patients who developed progressive disease (PD) on TAs (either class). In all cases, analysis of single-cell architecture revealed mutual exclusivity between multiple resistance mutations to the same TA class, variable clonal co-occurrence of multiple mutations affecting different TAs in patients exposed to both classes, and a phenomenon of multiple independent emergences of identical nucleotide changes leading to canonical resistance mutations. We also report the first observation of established BCL2 resistance mutations in a patient with mantle cell lymphoma (MCL) following PD on sequential monotherapy, implicating BCL2 as a venetoclax resistance mechanism in MCL. Taken together, these data reveal the significant clonal complexity of CLL and MCL progression on TAs at the nucleotide level and confirm the presence of multiple, clonally independent, mechanisms of TA resistance within each individual disease context.

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.

Multi-parametric flow cytometry (MFC) has a well-established role in measurable residual disease (MRD) monitoring in patients with B-lymphoblastic leukemia (B-ALL). However, the optimal time-point (TP) for early MRD testing and associated prognostic impact remain undefined in adult B-ALL patients receiving Hyper-CVAD induction chemotherapy. To evaluate the utility of MRD analysis after one cycle (TP1) in comparison to MRD analysis after two cycles (TP2) of induction treatment with Hyper-CVAD chemotherapy, we studied 49 adult B-ALL patients over a 10-year period (2010-2020) who had available bone marrow samples for morphological and MFC MRD assessments at the two separate TPs. Median times to TP1 and TP2 relative to start of treatment were 21 and 45 days, respectively. When censored at transplant, achievement of MRD negativity at TP1 was not associated with a statistically significant improvement in either event-free survival (EFS) (p = .426) or overall survival (OS) (p = .335) when compared to patients with MRD positivity. In contrast, achieving MRD negativity at TP2 was associated with a statistically significant improvement in both EFS (p = ·005) and OS (p = .047) over patients who remained MRD positive. Multivariate analysis demonstrated that KMT2A-rearrangement and MRD positivity at TP2 were the only significant predictors of outcome, correlating with worse EFS and OS. Therefore, in the absence of residual morphologic disease, MRD analysis after one cycle of Hyper-CVAD induction chemotherapy did not provide additional benefit with regard to risk stratification or correlation with survival outcomes when compared to MRD testing after two cycles of Hyper-CVAD in adult B-ALL patients.

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.

As part of this special issue on validity, this essay addresses practices for research in both measurement and methodology through the lens of the philosophy of science. The essay has three primary...

As artificial intelligence (AI) technologies become more common and capable interaction partners (human-machine communication; HMC), understanding how people perceive and interact with them becomes...

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.

This study investigated preference for delivering feedback, including preferred channels, degree of privacy, and degree of synchronicity. Participants were asked to rate their preferences for vario...

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.

Exemplification theory postulates that iconic, emotional, and arousing depictions are potent in impacting judgments and impression formation. Previous research has examined how exemplification proc...

The current study builds upon our previous research on the human-to-human interaction script, which suggests that people expect to interact with other humans when encountering an initial interaction. This expectation impacts the initial impressions people have when interacting with social robots. The current experiment examined how short interactions might change those initial impressions. Participants were less uncertain and perceived greater social presence after a single brief interaction with a humanoid social robot. Social presence decreased after a short interaction with a human. These data suggest that initial impressions based on the human-to-human interaction script may impact actual interaction and the impressions that result from it. Open-ended responses suggest the potential for hyperpersonal communication in human-robot interaction. These findings are further discussed, as are limitations and directions for future research. The paper concludes with an agenda for applying constructivist interpersonal communication frameworks to human-robot interaction studies.

The way humans and robots interact is no longer in the realm of fiction, because robots have seemingly gained the ability to respond to others, including humans. Communication research can be at th...

This virtual half-day workshop will explore human-machine communication (HMC) and communication studies/science theories as used in HRI studies. Submitted papers can include a 1) discussion of theories from the disciplines of media and communication that can guide HRI studies and vice versa, 2) analysis of related constructs (variables) that intersect both fields but with different nomenclatures (e.g., credibility vs. trust, presence vs. im- mediacy), or 3) exploration of quantitative and qualitative study designs from media and communication and their application to HRI. For more information and submission information, go to https://www.combotlabs.org/hmchri2021.html

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.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare form of T-cell lymphoma that occurs after implantation of breast prostheses. We performed comprehensive next generation sequencing based genomic characterization of 11 cases of BIA-ALCL including sequence variant detection on 180 genes frequently mutated in haematological malignancy, genome-wide copy number assessment, structural variant detection involving the T-cell receptor loci and TRB deep-sequencing. We observed sequence variants leading to JAK/STAT activation in 10 out of 11 patients. We also observed germline TP53 mutations in two cases. In addition we detected a recurrent copy number loss involving RPL5 as well as copy number amplifications involving TNFRSF11A [RANK] (in 2 cases), MYC, P2RX7, TMEM119 and PDGFRA. In summary, our comprehensive genomic characterisation of 11 cases of BIA-ALCL has provided insight into potential pathobiological mechanisms (JAK/STAT, MYC and TP53) as well as identifying targets for future therapeutic intervention (TNFRSF11A, PDGFRA) in this rare entity.

This study investigated how player-avatar interaction (PAX) and player-avatar relationship (PAR) are associated with spatial presence, social presence, and self-presence in video games, and additionally how the associations differ between Chinese and American players. American and Chinese players were recruited to answer a survey king about these variables. The survey was translated from English to Chinese for the different samples. Regression models and ANOVA analysis were used to analyze data, and the results revealed several significant associations between dimensions of PAX and the three types of presence. Additionally, results indicated that player-avatar relationships characterized by identity play and extension are generally associated with higher level of presence than the other two relationship types. Cultural differences were also found, with American and Chinese players differing in how PAR associated with social presence. Thus, the present study adds more understanding to presence in video game, avatar-moderated gameplay, and cross-cultural differences in video gaming, and suggests avenues for future research.

The purpose of this research is to increase understanding of Taylor’s six-segment strategy wheel (SSSW) by exploring how message strategy makes use of commenters’ parasocial interactions (PSIs) wit...

Replications are an important part of the research process because they allow for greater confidence in the findings of communication research. However, engaging in replications is often undervalue...

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.

Genomic markers define molecular subtypes and measurable residual disease (MRD) targets in B-cell acute lymphoblastic leukemia/lymphoma (B-ALL) and are essential determinants of treatment. Current diagnostic approaches typically involve serial multi-step testing utilizing conventional cytogenetics (CC)/FISH and molecular genetic (RT-qPCR, MLPA, clonality PCR, NGS panel) techniques which are time and sample consuming and ultimately may not adequately identify genomically complex B-ALL subtypes. In contrast, single-step comprehensive genomic profiling by whole genome and whole transcriptome sequencing (WGS/WTS) may be more efficient for the molecular classification of established and newly described entities which are of increasing therapeutic relevance. We have instituted a multimodal platform for molecular testing in B-ALL performing WGS/WTS in parallel with deep NGS-based immunoglobulin (IG) rearrangement MRD and exploratory DNA-breakpoint based MRD assays. We aimed to determine the utility of this approach for subtype classification compared to a standard-of-care diagnostic approach of CC/FISH testing. Forty-two consecutive adult patients underwent both standard-of-care diagnostic testing and WGS/WTS. 20/42 (48%) patients had an abnormal CC/FISH result supporting classification into recognized molecular subgroups. WGS/WTS assessment incorporating somatic coding and non-coding mutations, structural variants, fusions, copy number abnormalities and gene expression subtype prediction (ALLSorts, https://github.com/Oshlack/ALLSorts) was performed with concordant results in all 20 patients. 16/22 patients that were unclassified by CC/FISH were successfully reclassified by WGS/WTS including subtypes enriched for cryptic rearrangements (Ph-like, DUX4, MEF2D) and groups characterized by heterogeneous genomic alterations or a distinctive gene expression signature (PAX5alt, ZEB2/CEBP). A low hypodiploid karyotype was observed in two cases with an apparently normal karyotype by CC. The six patients who remained without a subtype defining driver genetic alteration after comprehensive testing frequently harbored novel IGH translocations or a Ph-like expression signature but without a described fusion. In order to understand the relative contribution from WGS versus WTS, analysis of 36 patients was performed using a truth classification. WGS and WTS produced equivalent classifications for 22 cases. Two cases were based solely on WGS findings (iAMP21 and ZEB2/CEBP) and three cases were based solely on WTS findings (DUX4). Importantly the combination of both WGS and WTS was critical to correctly classify nine cases (Ph-like and PAX5alt). MRD was assessed by a sensitive NGS assay to IG rearrangements (Adaptive Biotechnologies) and by quantitative probe-based droplet digital PCR (ddPCR) assays designed to structural rearrangement DNA breakpoints from genome data (analytical sensitivity 10 -4). Patient-specific ddPCR assays were designed to eight structural variants (KMT2A and IGH translocations, and IKZF1 deletions) in seven patients and assessed in 36 remission samples with parallel testing by multiparametric flow cytometry (MFC). Concordant MFC and ddPCR was observed in 30/36 samples (19 MRD pos, 11 MRD neg). Discordances included two MRD pos by MFC-only and four MRD pos by ddPCR-only; the latter often occurring in the setting of antigen directed therapy or in ALL with a less informative immunophenotype, demonstrating the additional utility of non-MFC based MRD assessment in specific clinical settings. 27/42 patients in our cohort had ≥1 genomic structural rearrangement identified by WGS that could be used for patient-specific MRD monitoring to complement existing MRD assessment. In conclusion WGS/WTS provided a molecular subtype classification in 86% of our cohort compared to 48% by standard-of-care diagnostic testing highlighting that CC/FISH alone is inadequate for contemporary molecular classification of B-ALL, which may have implications for treatment decisions. Importantly, the combination of WGS and WTS was superior to WGS-only or WTS-only for correct molecular subtype assignment. This approach has the potential to improve risk assessment in adult B-ALL and the routine feasibility, improvement in clinical outcomes and health economic impact warrant further assessment. Disclosures Bajel: Abbvie, Amgen, Novartis, Pfizer: Honoraria; Amgen: Speakers Bureau. Dickinson: Janssen: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Research Funding; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Tiong: Servier: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Pfizer: Consultancy.

Tandem advances in mobile technologies and social networks have given rise to app-initiated romantic relationships. Little is understood, however, about the role of the device in this initiation. This experimental study explored the impact of “mere holding” of mobile devices on impressions formed when consuming dating app content. Mere holding (compared to no-touch viewing) was associated with reduced attraction, ascribed personhood, and psychological ownership. Findings suggest that holding may be experienced as a false realization of potential relationships through physical engagement of devices; theoretically, this realization may be understood as an inversion of interpersonal haptic nonverbals, as holding is less about interpersonal intimacy and more about heuristic engagement with the other as an object.

Massively parallel sequencing (MPS) technology has become routinely available for diagnosis, prognostication and therapeutic decision-making in haematological malignancies. However, increased throughput and wider coverage of genes can have unintended consequences. Germline variants of potential clinical significance (GVPCSs) detected during cancer testing may have implications for patients and families beyond the biological evaluation of a specific tumour. 721 reports generated from MPS panels used in the routine testing of myeloid and lymphoid malignancies were reviewed and variants within genes of potential germline relevance (TP53, RUNX1, GATA2 and WT1 in all contexts and CBL, KRAS and NRAS in the setting of juvenile myelomonocytic leukaemia) were analysed. A variant allele fraction threshold of ≥33.09% for considering germline origin of variants within cancer samples was established. The detection rate of incidental, pathogenic germline variants was 0.42%. Patient education and confirmatory germline sample testing of GVPCSs in appropriate circumstances are recommended.

The diagnosis and monitoring of myelodysplastic syndromes (MDSs) are highly reliant on bone marrow morphology, which is associated with substantial interobserver variability. Although azacitidine is the mainstay of treatment in MDS, only half of all patients respond. Therefore, there is an urgent need for improved modalities for the diagnosis and monitoring of MDSs. The majority of MDS patients have either clonal somatic karyotypic abnormalities and/or gene mutations that aid in the diagnosis and can be used to monitor treatment response. Circulating cell-free DNA is primarily derived from hematopoietic cells, and we surmised that the malignant MDS genome would be a major contributor to cell-free DNA levels in MDS patients as a result of ineffective hematopoiesis. Through analysis of serial bone marrow and matched plasma samples (n = 75), we demonstrate that cell-free circulating tumor DNA (ctDNA) is directly comparable to bone marrow biopsy in representing the genomic heterogeneity of malignant clones in MDS. Remarkably, we demonstrate that serial monitoring of ctDNA allows concurrent tracking of both mutations and karyotypic abnormalities throughout therapy and is able to anticipate treatment failure. These data highlight the role of ctDNA as a minimally invasive molecular disease monitoring strategy in MDS.

Previous research has found that parasocial relationships mirror actual social relationships. The purpose of this study is to determine how people reacted to the end of a parasocial relationship pe...

Several novel therapeutics are poised to change the natural history of chronic lymphocytic leukaemia (CLL) and the increasing use of these therapies has highlighted limitations of traditional disease monitoring methods. Here we demonstrate that circulating tumour DNA (ctDNA) is readily detectable in patients with CLL. Importantly, ctDNA does not simply mirror the genomic information contained within circulating malignant lymphocytes but instead parallels changes across different disease compartments following treatment with novel therapies. Serial ctDNA analysis allows clonal dynamics to be monitored over time and identifies the emergence of genomic changes associated with Richter's syndrome (RS). In addition to conventional disease monitoring, ctDNA provides a unique opportunity for non-invasive serial analysis of CLL for molecular disease monitoring., Disease monitoring of chronic lymphocytic leukaemia (CLL) is a challenge. Here, the authors show that serial ctDNA analysis in 32 CLL patients allows monitoring of clonal dynamics over time, and identifies the emergence of genomic changes associated with Richter's syndrome.

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.