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Many writers and artists have been interested in the aesthetic beauty and the language of maps. Katherine Harman, author of You Are Here: Personal Geographies and Maps of the Imagination, argues th...

Background: CML is managed by life-long TKI therapy in most pts which can be associated with chronic toxicities and substantial costs. Discontinuation of TKI in some pts can result in sustained therapy-free remission (TFR); however only a minority are candidates for discontinuation approaches; of those most still relapse and must restart TKI. High expression of programmed death receptor-1 (PD-1) and its ligand PD-L1 on CML-specific cytotoxic T-cells and CML cells, respectively, suggests that PD-1/PD-L1-mediated immune escape contribute to CML persistence and relapse after TKI discontinuation. We designed the BLAST MRD CML trial (NCT#03516279) to study whether adding anti-PD-1 antibody pembrolizumab to TKI therapy is safe and tolerable and increases rate of conversion to undetectable minimal residual disease (UMRD). We present data from the early safety cohort from this ongoing trial with a data cut-off date June 15th, 2021. Methods: BLAST MRD CML-1 is an ongoing national, ECOG-sponsored, single-arm pilot phase II clinical trial that enrolls adults with chronic phase CML who achieved a major molecular response (MR 3) but not UMRD while on a stable dose of up to three lines of TKI therapy. UMRD was defined as an undetectable BCR-ABL by central RQ-PCR (assay sensitivity of 4.5 [MR 4.5]) on 2 consecutive samples separated by ≥4 weeks. Once enrolled, pts continue on TKI and concurrently receive pembrolizumab 200mg IV on day (D)1 of each 21-D cycle with central MRD assessment every 4 cycles for 17 cycles. Pts who achieve UMRD at or prior to C17 discontinue pembrolizumab, while those with persistent MRD continue TKI + pembrolizumab for another 18 cycles. TKI is discontinued one year following first documentation of UMRD. After TKI discontinuation, BCR-ABL is monitored at defined intervals for 24 months. Primary endpoint is proportion of CML pts on stable-dose TKI who convert to UMRD within 2 years (yrs) of combined TKI + pembrolizumab therapy. Secondary endpoints include rates of TKI discontinuation and proportion of pts achieving 2-year TFR, MRD kinetics, and safety. Immune related and other adverse events (AE) were assessed and graded according to CTCAE v 5.0. Results: As of cut-off date, 6 pts enrolled in safety cohort. Median age was 43 yrs (range 32-65). TKIs received on trial included imatinib (N=2), dasatinib (N=3), and nilotinib (N=1). All 6 pts were on 2 nd line TKI. Median exposure to pembrolizumab was 20 doses (range, 5-36). Five pts were still on combined pembrolizumab + TKI treatment, while the 6 th pt has completed combined therapy for 2 yrs and then continued TKI monotherapy on trial after achievement of UMRD (pt has to be in UMRD for 1 yr before TKI can be discontinued). The combination of TKI and pembrolizumab was safe and well tolerated (Table 1). Only 3 pts experienced grade (G) 1/2 AEs as the worst non-hematologic AE while on trial. Hematologic toxicity reported was also generally minimal with only one G 1/2 anemia AE. The only reported G3 AE was a lipase elevation (283 U/L, normal range 11 - 55 U/L) noted on routine laboratory assessment in a pt receiving nilotinib at 400mg BID dose after 48 weeks of starting on trial combined therapy. Amylase was also elevated at G2. No baseline lipase levels were available as protocol at that time did not require baseline assessments. The pt had no symptoms and CT imaging showed no radiologic evidence of pancreatitis. The lipase and amylase levels normalized with holding of both nilotinib and pembrolizumab for 7 weeks, and the AE did not recur with resumption of combined therapy at same dose of pembrolizumab but with nilotinib reduced to 400mg daily. No G4 or 5 AEs occurred. No other dose-adjustments or treatment discontinuation/interruptions due to AEs occurred. No immune-related AEs (IRAEs) have been reported. Discussion: Data from the early safety cohort suggest that the combination of TKI and pembrolizumab is safe and well tolerated. The AEs observed were mild and generally G1/2. No pt discontinued trial therapy due to AEs. Only one G3 AE (asymptomatic lipase elevation) was reported, which could have been related to nilotinib therapy and could have predated trial entry as no baseline lipase value was available and was fully reversible with a temporary hold of therapy. No IRAEs have been reported to date. Work is ongoing on an amendment to study protocol to enhance accrual. Efficacy results will be reported as they mature. Figure 1 Figure 1. Disclosures Zeidan: Boehringer Ingelheim: Consultancy, Research Funding; Ionis: Consultancy; Gilead: Consultancy, Other: Clinical Trial Committees; Loxo Oncology: Consultancy, Other: Clinical Trial Committees; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Astex: Research Funding; Jasper: Consultancy; Cardiff Oncology: Consultancy, Other: Travel support, Research Funding; Aprea: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; BeyondSpring: Consultancy; BMS: Consultancy, Other: Clinical Trial Committees, Research Funding; Acceleron: Consultancy, Research Funding; Novartis: Consultancy, Other: Clinical Trial Committees, Travel support, Research Funding; Genentech: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; BioCryst: Other: Clinical Trial Committees; Janssen: Consultancy; Kura: Consultancy, Other: Clinical Trial Committees; Geron: Other: Clinical Trial Committees; Astellas: Consultancy; ADC Therapeutics: Research Funding; Agios: Consultancy; Jazz: Consultancy; Pfizer: Other: Travel support, Research Funding; AbbVie: Consultancy, Other: Clinical Trial Committees, Research Funding. Radich: Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Bhatt: National Marrow Donor Program: Research Funding; Tolero Pharmaceuticals, Inc: Research Funding; Pfizer: Research Funding; Incyte: Consultancy, Research Funding; Jazz: Research Funding; Abbvie: Consultancy, Research Funding; Partnership for health analytic research, LLC: Consultancy; Servier Pharmaceuticals LLC: Consultancy; Rigel: Consultancy; Abbvie: Consultancy, Research Funding; Genentech: Consultancy. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Litzow: Omeros: Other: Advisory Board; Astellas: Research Funding; Jazz: Other: Advisory Board; Amgen: Research Funding; Pluristem: Research Funding; Biosight: Other: Data monitoring committee; Actinium: Research Funding; AbbVie: Research Funding. OffLabel Disclosure: Pembrolizumab has not been approved for the treatment of CML

Study Background: Survival outcomes of older patients with AML are dismal with a 3-year survival of < 10%. The combination of hypomethylating agents (HMA) with venetoclax has emerged as the new standard of care for older unfit patients with AML, but median survival remains less than 15 months. Patients with undetectable MRD after this regimen seem to have the best long-term clinical outcomes. In this randomized phase 2 trial, the goal with combining pembrolizumab is to facilitate a more effective CTL mediated destruction of leukemic blasts resulting in improved rates of CR without MRD, which would hopefully increase duration of response and lower relapse rates. Here we report on the design of the first randomized multi-center clinical trial of HMA+venetoclax +/- ICPI in unfit AML patients. Methods: The primary objective of this Cancer Therapy Evaluation Program-approved multi-institutional, randomized phase II study (NCT04284787) is to assess the percentage of patients with MRD negative CR (MRD- CR) as measured by flow cytometry with chemotherapy + pembrolizumab during the first 6 cycles and compare between the two study arms (See study Schema). Secondary objectives include rates of CR / complete remission with incomplete count recovery (CRi), complete remission with partial recovery count (CRh) and Hematologic improvement (HI) to red blood cells and platelets, MRD negativity at Day 14, MRD-negative CR at end of induction therapy and MRD negative CR after last consolidation cycle, event free survival (EFS), relapse free survival (RFS), duration of response (DOR), and overall survival (OS), and proportion of patients who develop severe toxicity. Important exploratory objectives include MRD assessment by duplex sequencing (DS), and comparing DS and multiparameter flow cytometry for MRD detection. A total of 76 patients will be included (38 patients in the intervention arm and 38 patients in the control arm). Planned stratification factors include 1) cytogenetics (intermediate/unknown vs. adverse karyotype) 2) antecedent hematologic disorder defined as prior MDS, MPN, or aplastic anemia (present vs. absent); and 3) reason to not receive intensive chemotherapy (ineligibility vs refusal). All patients will receive azacitidine at 75 mg/m2 IV over 10-40 minutes or SQ x 7 days on Days 1-7 or Days 5-2 (to avoid weekend administration) and, including a ramp-up phase to 400 mg /day venetoclax on Days 1-4. Venetoclax will be administered at 400 mg/day on the remaining days of the cycle for the first cycle and on Days 1-21 or 1-28 for subsequent cycles (depending on count recovery). Half of the patients will receive pembrolizumab intravenously starting on Day 8 of the first cycle and then q 3 weeks in cycles 2-6 (intervention arm), up to 2 years of maintenance. The other half will not receive pembrolizumab (control arm). After 15 efficacy-evaluable patients in each of the two study arms have had their primary endpoint results available, a formal futility and toxicity analysis will be conducted. Follow up will continue up to 2 years after the last patient is randomized Eligible patients are aged ≥60 years with newly diagnosed and pathologically-confirmed AML, including secondary AML arising from prior MDS and therapy-related AML, who are deemed ineligible for intensive chemotherapy according to treating physician's assessment or who refuse intensive chemotherapy. Candidates with high risk MDS and secondary AML arising from myeloproliferative neoplasm or other hematologic disorders are not allowed. Additional exclusion criteria include CBF-AML, prior allogeneic stem cell transplant, receipt of prior hypomethylating therapy for antecedent MDS, active infection requiring systemic therapy, and use of corticosteroids. Responses in AML patients will be assessed using European Leukemia Net 2017 response criteria. EFS will be calculated as the time from initial treatment to either disease relapse or death. OS will be calculated from time from initial treatment to death. Biomarker analyses will include an extensive array of immunologic and correlative studies that will evaluate PD-1 and PD-L1 expression, immune cell subset analysis, leukemia specific T-cell response, cytokine level, T-cell receptor (TCR) repertoire, as well as RNA-seq, gut microbiome characterization and metabolomics, and whole exome sequencing for tumor and germline DNA. Disclosures Zeidan: Abbvie: Consultancy, Honoraria, Research Funding; MedImmune/Astrazeneca: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Cardiff Oncology: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Leukemia and Lymphoma Society: Other; CCITLA: Other; Astex: Research Funding; Aprea: Research Funding; ADC Therapeutics: Research Funding; Taiho: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria. Radich:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Jazz: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding.

Study Background: The presence of minimal residual disease (MRD) after IC in AML patients is often a harbinger of relapse, and therapeutic targeting of MRD has emerged as an important strategy to improve long-term outcomes. The importance of the PD-1/PD-L1 pathway in immune evasion of AML has been demonstrated in murine AML models whereby PD-L1 and PD-1 were upregulated in leukemia cells, and PD-1 blockade suppresses invivo leukemia cell proliferation and improved survival in AML bearing mice (Zhang et al., 2009; Zhou et al., 2010). Combining IC with immune checkpoint inhibition (ICPI) has resulted in a significant clinical activity in some advanced solid malignancies including non-small-cell lung cancer. A recent single-arm phase 2 study combining IC with nivolumab showed the combination was feasible and resulted in undetectable MRD in 53% of patients with Complete response (CR)/CR with incomplete count recovery (CRi) (Ravandi et al, 2019). Here we report on the design of the first randomized multi-center clinical trial of IC+ICPI in fit AML patients. Methods: The primary objective of this investigator-initiated Cancer Therapy Evaluation Program (CTEP)-sponsored multi-institutional, randomized phase II study (NCT04214249) is to assess the percentage of patients with MRD negative CR (MRD- CR) as measured by flow cytometry at the end of first cycle of consolidation therapy with IC+ pembrolizumab and compare between the two study arms (Figure 1). Secondary objectives include rates of CR/CRi, complete remission with partial recovery count (CRh) and hematologic improvement (HI) to red blood cells and platelets, MRD negativity at Day 14, MRD-negative CR at end of induction therapy and MRD negative CR after last consolidation cycle, event free survival (EFS), relapse free survival (RFS), duration of response (DOR), and overall survival (OS), and proportion of patients who develop severe toxicity. Important exploratory objectives include MRD assessment by duplex sequencing (DS) and comparing DS and multiparameter flow cytometry for MRD detection. The study will consist of an induction, consolidation, and maintenance phase of therapy. A total of 124 patients will be included (62 patients in the intervention arm and 62 patients in the control arm). Planned stratification factors include 1) age (younger than 65 vs. 65 and older), 2) cytogenetics by FISH or metaphase karyotype (presence vs. absence of core binding factor inversions and translocations), and 3) t-AML or AML arising from prior/antecedent MDS. All patients will receive cytarabine at 100 mg/m2/day continuous infusion on Days 1-7 and either idarubicin 12 mg/m2/day IV on Days 1-3 or daunorubicin 60 mg/m2/day IV on Days 1-3. on Day 8 of the induction chemotherapy, half of the patients will receive pembrolizumab IV (intervention arm), and continue Q3 weeks throughout Induction/Consolidation, and thereafter for up to 2 years from the start of maintenance. The other half will not receive pembrolizumab (control arm). After 31 efficacy-evaluable patients (patients who had a bone marrow biopsy done after the first consolidation cycle) in each of the two study arms have had their primary endpoint results available, a formal futility and toxicity analysis will be conducted. Follow up will continue up to 2 years after the last patient is randomized. Eligible patients are aged ≥18 and ≤75 years with newly diagnosed and pathologically-confirmed AML, including secondary AML arising from prior MDS and therapy-related AML. Patients with FLT3-mutated AML are excluded as well as those with prior allogeneic stem cell transplant, active infection requiring systemic therapy, and requiring use of high dose corticosteroids. Responses in AML patients will be assessed using European Leukemia Net 2017 response criteria. EFS will be calculated as the time from initial treatment to either disease relapse or death. OS will be calculated from time from initial treatment to death. Biomarker analyses will include an extensive array of immunologic and correlative studies that will evaluate PD-1 and PD-L1 expression, immune cell subset analysis, leukemia specific T-cell response, cytokine level, T-cell receptor (TCR) repertoire, as well as RNA-seq, gut microbiome characterization and metabolomics, and whole exome sequencing for tumor and germline DNA. Figure 1 Disclosures Zeidan: Epizyme: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Leukemia and Lymphoma Society: Other; Jazz: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Cardiff Oncology: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; MedImmune/Astrazeneca: Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Aprea: Research Funding; ADC Therapeutics: Research Funding; Astex: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Taiho: Consultancy, Honoraria; CCITLA: Other; Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria. Radich:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Jazz: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding.

Imperial power, and the policies of the Bush administration, are widely perceived as a distinct break with the modern world and the American past. In fact, elements of imperial power have been present since early modernity. The distinct nature of imperial sovereignty remains unclear. Negri and Hardt insist that imperial sovereignty constitutes a sharp break from modern nation-state sovereignty. However, if modern sovereignty is read from the standpoint of the exception, not liberalism, its ground and operation are the same as those of empire. What is new in empire is that global restraints still present in the nation-state order have disappeared. As a result, the state of exception today has become the rule. Only by recognizing that this relation is a product of imperial power, and not an external factor it seeks to counter, can we challenge the legitimating discourse of empire.

This essay examines Irigaray's analysis of politics and the political implications of her critique of sacrificial orders that repress difference/matter. I suggest that her descriptions of a fluid “feminine” can be read as an alternative symbolic not dependent on repression. This idea is politically promising in opening a possibility for justice and a nonantagonistic intersubjectivity. I conclude by assessing Irigaray's concrete proposals for sexuate rights and a civil identity for women.

Derrida has characterized his thought as an attempt to think a relationship to otherness such that the other is neither incorporated nor expelled, yet the relationship between thinking alterity and responding to present others remains ambiguous.' His earlier writings are predominantly concerned with the relation to a generalized and neutral alterity, while in the more recent Specters of Marx he turns explicitly to the question of the relation to the living other. He continues for the most part, however, to think that other according to the understanding of irreducible alterity he developed in his critique of the metaphysics of presence in "Differance." When transferred to a political context, such an insistence on the radical alterity of the other becomes dangerous by foreclosing the possibility of a lived encounter with the other, limiting deconstruction's capacity for political intervention. In the name ofthe relation to the other, Derrida has stated, much as Marx " called for the transformation to come of his own theses" (SP 13), that the "efficacity of the thematic of differance may very well, indeed must, one day be superseded." (MP 7).2This thought of differance or radical alterity has indeed shifted pieces of the metaphysical tradition that has obscured the role of the other in philosophy and politics. Differance, as a general play of forces from which every system forms itself, cannot be avoided and is an inescapable relation. Since differance is irreducible to every manner in which it might be determined within a system, it can never be fully appropriated. Just as clearly, this does not hold for a lived relation to the present other. Unlike differance, the other as a singularity is not an irreducible reserve. In the context of what Simon Critchley calls the ethical reception of deconstruction, an evaluation of deconstruction's ability to respond to the living other is necessary. Even those optimistic about the deconstructive approach toward ethics have expressed skepticism about its political efficacy.' Similarly, many feminists have accepted the broad paradigm of deconstructive ethics while questioning its use of feminine metaphors, and its habit of taking on the voice of women rather than listening to the voice of women.4 But for the most part the character of the ethics it points to have remained intact. Its political efficacy and indifference to the feminine are examined as if these were only epiphenomena or tangential flaws, with no effect on the structure of deconstruction as ethics. These weaknesses are nonetheless signs of deeper problems in the characterization of closure and the ethical response that interpretation implies. Even where Derrida refers to an other of unspecified gender, its inaccessibility makes a lived engagement with any other difficult to conceive. Irigaray's thinking, while influenced by Heidegger and Derrida, offers a different reading of the history of philosophy by taking into account the perspective of the excluded other. As she argues, the figuration ofthe other as an unrepresentable alterity registered in a trace has been the mode of appearance for the feminine within metaphysics. This subjects women to a double violence: they are rendered as objects serving the desire ofthe subject, and they are deprived of any location or desire of their own. Irigaray thus complicates Derrida's depiction of alterity as a disruptive force by emphasizing the exclusion experienced by the living other. In insisting on a materiality which metaphysics marginalized, and of which Derrida remains suspicious, she offers a thinking of otherness as tangible and accessible. The Other, Whose Other, What Price? Derrida's Narrative What then is the sense of this alterity that pervades both infinite and finite alterity in Derrida? The radicalness of deconstruction lies not in other-talk, nor in any discovery that postmetaphysical thinking is distinguished by the fracture of differance. …

9012^ Background: CTLA-4 and PD-1 are critical immune checkpoint receptors. In MEL pts, ipilimumab (anti-CTLA-4) prolonged survival in two phase III trials, and nivolumab (anti-PD-1) produced an objective response rate (ORR) of 31% (n=106) in a phase I trial. PD-1 is induced by CTLA-4 blockade, and combined blockade of CTLA-4/PD-1 showed enhanced antitumor activity in murine models. Thus, we initiated the first phase 1 study to evaluate nivolumab/ipilimumab combination therapy. Methods: MEL pts with ≤3 prior therapies received IV nivolumab and ipilimumab concurrently, q3 wk × 4 doses, followed by nivolumab alone q3 wk × 4 (Table). At wk 24, combined treatment was continued q12 wk × 8 in pts with disease control and no DLT. In two sequenced-regimen cohorts, pts with prior standard ipilimumab therapy were treated with nivolumab (q2 wk × 48). Results: As of Dec. 6, 2012, 69 pts were treated. We report efficacy data on 37 pts with concurrent therapy in completed cohorts 1-3 (Table); ORR was 38% (95% CI: 23-55). In cohort 2 (MTD), ORR was 47% and 41% of pts had ≥80% tumor reduction at 12 wk (Table) with some pts showing rapid responses, prompt symptom resolution, and durable CRs. Related adverse events (rAEs) for concurrent therapy were similar in nature with some higher in frequency than those typically seen for the monotherapies and were generally manageable using immunosuppressants. Cohort 3 exceeded the MTD (DLT: gr 3-4 ↑ lipase). At the MTD, gr 3-4 rAEs occurred in 59% of pts and included uveitis/choroiditis, colitis, and reversible lab abnormalities. Conclusions: Nivolumab and ipilimumab can be combined with a manageable safety profile. Clinical activity for concurrent therapy appears to exceed that of published monotherapy data, with rapid and deep tumor responses (≥80% tumor reduction at 12 wk) in 30% (11/37) of pts. A phase III trial is planned to compare concurrent combination dosing with each monotherapy. Clinical trial information: NCT01024231. [Table: see text]

White fat cells from normal rats treated with 200 μg of L-3,5,3’-triiodothyronine (T-3) exhibited an increased lipolytic response to norepinephrine and dibutyryl cyclic adenosine 3’, 5’-monophosphate. No increase in lipolytic response of T-3 treated cells was observed in the presence of growth hormone and dexamethasone. Cells from both hypophysectomized and normal rats treated with T-3 showed marked increases in accumulation of cyclic adenosine 3’,5’-monophosphate (cyclic AMP) and glycerol release as compared to control cells in the presence of catecholamine and theophylline. Little effect of T-3 treatment was seen on cyclic AMP accumulation in the presence of catecholamine alone or in the absence of lipolytic agents. The administration of 25 micrograms of T-3 to normal female rats 18 hours prior to sacrifice was equally as effective as 200 micrograms in stimulating cyclic AMP accumulation of fat cells incubated with catecholamines and theophylline. There was a lag period of about 5½ hours after subcutane...