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The three main approaches to the metaphysics of intentionality can arguably be subjected to analysis in terms of grammatical point of view: the approach of the (internalist) phenomenal intentionality programme (plus productivism about linguistic content) may be regarded as first-personal; interpretationism, perhaps, as second-personal; and (reductive externalist) causal information theories (including teleosemantics) as third-personal. After making this plausible, the current paper focusses on the role of the interpreter (if any) in interpretationism. It argues that, despite some considerations from the publicity of meaning potentially suggesting the contrary, radical interpretation is not subject to epistemic constraint; nor should the interpretationist appeal to the idiosyncratic interests of actual interpreters, thereby rendering the approach irremediably relativistic. Instead, an appeal to the pure form of interestedness is all that is involved; this supports a methodologically non-reductive outlook on intentionality.

Key Points Treatment-naive and relapsed/refractory MDS patients receiving venetoclax and HMAs have an ORR of 59% with 63% of responders proceeding to transplant. Allogeneic stem cell transplantation after treatment with venetoclax in combination with HMA is associated with prolonged survival.

The central thesis of this paper is that fake news and related phenomena serve as defeaters for knowledge transmission via journalistic channels. This explains how they pose a threat to democracy; and it points the way to determining how to address this threat. Democracy is both intrinsically and instrumentally good provided the electorate has knowledge (however partial and distributed) of the common good and the means of achieving it. Since journalism provides such knowledge, those who value democracy have a reason to protect it. Hostile agents, however, can undermine both the effectiveness of democratic decision-making and faith in democracy itself, by deliberately promulgating fake news and hyper-partisan views; moreover, these effects can come about unintentionally on social media. I conclude that we may need to change, not just the way we process information online, but also the informational environment in which we operate.

Acute myeloid leukemia (AML) is predominantly a disease of older adults and the majority of affected patients succumb to the disease. After decades of slow progress, the last 5 years have witnessed remarkable progress in AML therapy with the approval of multiple highly active and well-tolerated novel therapies. Notable among these are agents targeting driver mutations including FLT3, IDH1/2 as well as the Bcl-2 inhibitor venetoclax. The combination of hypomethylating agents with venetoclax is highly active in AML and has become the standard of care for older patients as well as those with comorbidities. As a result of these advances, a larger proportion of AML patients now achieve complete remissions enabling them to undergo allogeneic hematopoietic cell transplantation with curative intent. Progress is also being made in the field of monoclonal antibodies targeting leukemia antigens and other immunotherapies and many such agents are currently under active investigation.

Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is characterized by anemia, ring sideroblast erythroid precursors, and persistent thrombocytosis. Case reports suggest lenalidomide may be effective in treating MDS/MPN-RS-T. We evaluated a large series of patients with MDS/MPN-RS-T to compare hematological improvement (HI) response rates among different drug therapies including lenalidomide. We identified 167 patients with MDS/MPN-RS-T. Among the patients tested, 84% had SF3B1 mutations and 43% had JAK2 V617F mutations. The median OS for the cohort was 81 months. Overall, 76 patients (46%) received erythropoiesis-stimulating agents (ESAs), 47 patients (28%) received lenalidomide, and 45 patients (27%) received hypomethylating agents (HMAs). The HI rates were 58%, 53%, and 24%, respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMAs. Rates of HI improvement were higher in patients with MDS/MPN-RS-T treated with ESAs or lenalidomide, in comparison to those treated with HMAs.

BACKGROUND Blinatumomab has demonstrated encouraging activity in relapsed/refractory (r/r) and minimal residual disease-positive (MRD+) acute lymphoblastic leukemia (ALL). Extramedullary disease (EMD) relapse or relapse with CD19- disease has been observed after blinatumomab therapy in patients with r/r or MRD+ ALL. However, the pathophysiology and risk factors of treatment failure are not fully understood. METHODS This study retrospectively reviewed the outcomes of adult patients with B-cell ALL treated with blinatumomab (n = 132) for either r/r (n = 103) or MRD+ disease (n = 29) at the authors' center (2013-2021) and analyzed factors associated with treatment response and EMD failure. RESULTS The overall response rate was 64%. A lower marrow blast burden before blinatumomab (P = .049) and no history of previous EMD (P = .019) were significantly associated with a higher response. Among the patients who responded to blinatumomab, 56% underwent consolidation with allogeneic transplantation. Blinatumomab failure was observed in 89 patients; 43% of these patients (n = 38) either progressed or relapsed at extramedullary sites. A history of extramedullary involvement (53% vs 24%; P = .005) and retention of CD19 expression at the time of relapse/progression (97% vs 74%; P = .012) were associated with a higher risk for extramedullary failure. Central nervous system (CNS) failure after blinatumomab was encountered in 39% of the patients with EMD. CONCLUSIONS A history of EMD predicted an inferior response to blinatumomab therapy with a higher risk for relapse/progression at extramedullary sites (particularly CNS). Consolidation with allogenic transplantation in patients who primarily responded to blinatumomab did not abrogate the risk of extramedullary relapse. The incorporation of extramedullary assessment and the intensification of CNS prophylaxis may help in addressing extramedullary failure. LAY SUMMARY Extramedullary failure is common during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. A history of extramedullary disease predicts an inferior response to blinatumomab therapy and a higher risk for relapse/progression at extramedullary sites. Most extramedullary failure cases retain CD19 expression.

What role, if any, should centered possible worlds play in characterizing the attitudes? Lewis (Philos Rev 88(4):513–543, 1979) argued (in effect) that, in order to account for the phenomena of self-location (Perry in Philos Rev 86(4):474–497, 1977, Nous 13(1):3–21, 1979), the contents of the attitudes should be taken to be centered propositions (i.e. sets of centered worlds). Stalnaker (Our knowledge of the internal world, Oxford University Press, Oxford, 2008, in: Brown, Cappelen (eds) Assertion: New philosophical essays, Oxford University Press, Oxford, 2011, Context, Oxford University Press, Oxford, 2014), however, has argued that while centered worlds are needed to characterize e.g. belief states, the contents of such states should be understood as ordinary, uncentered propositions (cf. Hintikka in Knowledge and belief, Cornell University Press, Ithaca, NY, 1962). But Stalnaker does not, as is common, provide a semantics of attitude ascriptions based on the models he develops of the attitudinal states themselves. This paper begins to explore the prospects for doing so. It argues that a simple but well-motivated approach does not yield the principles of knowledge and belief Stalnaker endorses; and that a modification which does brings with it worries of its own surrounding communication and learnability. A technical appendix contains novel and pertinent results in doxastic/epistemic logic.

7030 Background: Inactivation of p53 and overexpression of Mcl1 are common mechanisms that cancer cells use to evade apoptosis. BTX-A51 is a novel, oral, direct inhibitor of casein kinase 1α (CK1α) and cyclin dependent kinase 7 and 9 that robustly increases p53 protein levels via CK1α inhibition while preferentially decreasing super-enhancer transcription of Myc and Mcl1, enabling selective apoptosis of leukemia cells. Here, we report the interim results of the first-in-human (FIH) study of BTX-A51 in patients (pts) with R/R AML. Methods: The study utilizes a hybrid accelerated titration with single pt cohorts and a Bayesian optimal interval design in dose escalation. The primary objective is to determine the maximum tolerated dose and recommended Phase 2 dose (RP2D) of BTX-A51. Secondary objectives include evaluating the antileukemic activity, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 25 January 2022, 30 pts (28 with AML; 2 with HR-MDS) enrolled at dose levels between 1 and 42 mg; 2 pts remain on treatment. Monotherapy doses between 1 and 42 mg were administered orally 3 days/week (wk) (3 wk in a 28-day cycle) and at 21 mg (4 wk in a 28-day cycle). Baseline characteristics include median age 75 years, median number of prior therapies 3, 97% received prior treatment with venetoclax, 97% had prior HMA, and 43% had prior induction failure. The most common treatment-emergent AEs (TEAEs) were hypokalemia, nausea, vomiting, diarrhea, and hypotension. The most common Grade 3 or higher TEAEs were anemia, febrile neutropenia, platelet count decreased, and hypokalemia. DLTs included grade 3 hepatic failure at the 42 mg dose in 1 pt and grade 3 alkaline phosphatase elevation in 1 pt at the 21 mg dose. All events resolved after holding study drug. Plasma PK of BTX-A51 was roughly dose-proportional between 1 and 42 mg with accumulation based on AUC between Day 1 and Day 5. Estimated half-life was between 18 and 55 hours. Among the 30 pts with R/R AML and MDS, CR/CRi rate was 10% (3/30) with 1 pt at the 11 mg and 2 pts at the 21 mg dose levels attaining CRi. Bone marrow (BM) blast reduction > 50% occurred in 4 patients including the 3 responders, all at the 11 and 21 mg dose levels. All 4 pts with > 50% BM blast reduction had RUNX1 mutations; 9 pt with RUNX1 enrolled in the trial. The median duration of response for pts achieving CR/CRi was approximately 1.5 month. Responses were not observed in MDS pts. PD data will be provided in the full presentation. Based on the clinical data from dose escalation, the RP2D is 21 mg administered 3 days/wk for 4 wk of a 28-day cycle. Conclusions: In this FIH study, monotherapy BTX-A51 demonstrated an acceptable safety profile and promising antileukemic activity in pts with heavily pretreated R/R AML. The 21 mg dose administered 3x/wk for 4 wk was identified as the RP2D. RUNX1 mutations were enriched among responders and pts attaining > 50% BM blast reduction. Clinical trial information: NCT04243785.

TPS7065 Background: RARA-positive (RARA+) AML is a novel genomically defined patient subset with an actionable biological target for treatment with tamibarotene, an oral and selective RARα agonist (McKeown 2017). RARA+ patients can be selected by a blood-based biomarker test, with approximately 30% of newly diagnosed (ND) AML patients being RARA+ (Vigil 2017). As a biologically targeted agent for patients with RARA overexpression, tamibarotene has the potential to provide benefit irrespective of mutation or cytogenetic risk classification. In RARA+ ND AML patients ineligible for standard induction therapy, tamibarotene plus azacitidine (aza) led to a CR/CRi rate of 61% and a rapid onset of response (de Botton 2020). Approximately one-third of patients with ND unfit AML do not respond to front-line standard of care venetoclax (ven)/aza (DiNardo 2020). Translational data suggest RARA positivity enriches for monocytic features reported to be associated with ven resistance (Fiore 2020, Pei 2020). This data suggests the RARA biomarker selects for patients who may respond to tamibarotene and may be less likely to respond to ven/aza. Given that tamibarotene plus aza has been generally well tolerated, with no increase in myelosuppression compared to single agent aza (de Botton 2020), it is anticipated that tamibarotene can be administered safely in combination with ven/aza. Methods: This is a Phase 2, open-label, multi-center study in the U.S. and France comparing the clinical activity of tamibarotene/ven/aza to ven/aza in treatment-naive RARA+ AML patients ineligible for standard induction chemotherapy. The primary objectives are to characterize the safety of the combination and to compare the CR/CRi rate of tamibarotene/ven/aza vs. ven/aza, with secondary objectives to compare CR rate, CR/CRh rate, duration of response, and time to response. The overall response rate using tamibarotene/ven/aza following ven/aza treatment failure will be explored. Clinical activity will be characterized by ELN criteria (Dohner 2017). This 3-part trial includes a safety lead-in, randomized efficacy study, and salvage arm. Following the safety lead-in, approximately 80 patients will be randomized 1:1 to receive tamibarotene/ven/aza or ven/aza. Response rates and 95% exact binomial confidence intervals will be calculated by treatment group. In the salvage arm, tamibarotene will be added for study patients randomized to ven/aza who experience progressive disease, relapse, or treatment failure. Patients will be treated with aza at 75 mg/m2 IV/SC daily on days 1-7, ven on days 1-28 per VENCLEXA USPI, followed by tamibarotene at 6 mg twice per day by mouth on days 8-28 of each 28-day cycle. The SELECT AML-1 trial opened in July 2021 with ongoing enrollment. Clinical trial information: NCT04905407.

Clarke and Beck propose that the approximate number system (ANS) represents rational numbers. The evidence cited supports only the view that it represents ratios (and positive integers). Rational numbers are extensive magnitudes (i.e., sizes), whereas ratios are intensities. It is also argued that WHAT a system represents and HOW it does so are not as independent of one another as the authors assume.

Acute myeloid leukemia (AML) is predominantly a disease of older adults and the majority of affected patients succumb to the disease. After decades of slow progress, the last 5 years have witnessed remarkable progress in AML therapy with the approval of multiple highly active and well-tolerated novel therapies. Notable among these are agents targeting driver mutations including FLT3, IDH1/2 as well as the Bcl-2 inhibitor venetoclax. The combination of hypomethylating agents with venetoclax is highly active in AML and has become the standard of care for older patients as well as those with comorbidities. As a result of these advances, a larger proportion of AML patients now achieve complete remissions enabling them to undergo allogeneic hematopoietic cell transplantation with curative intent. Progress is also being made in the field of monoclonal antibodies targeting leukemia antigens and other immunotherapies and many such agents are currently under active investigation.

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome1,2. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient’s leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60–92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival. Preliminary results from the Beat AML umbrella trial demonstrates the feasibility and efficacy of applying prospective genomic profiling for matching newly diagnosed patients with AML with targeted therapies.