Kooperativer Bibliotheksverbund

In: Neuro-Ophthalmology, Informa UK Limited, Vol. 33, No. 5 ( 2009-09-25), p. 237-247

Type of Medium: Online Resource

ISSN: 0165-8107 , 1744-506X

URL: Article

DOI: 10.3109/01658100903226174

Language: English

Publisher: Informa UK Limited

Publication Date: 2009

detail.hit.zdb_id: 1475815-5

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 26-28

Abstract: We have recently shown that bone marrow (BM) RNA profiles stratify patients with acute myeloid leukemia (AML) into immune-infiltrated and immune-depleted subtypes and that type I/II interferon (IFN)-related gene signatures associate with complete response to flotetuzumab (FLZ), an investigational CD123×CD3 bispecific DART molecule. Within the AML tumor microenvironment CD8+ T cells exhibit features of immune exhaustion and senescence (IES). IES are dysfunctional states driven by metabolic alterations in the tumor microenvironment (TME) and emerging targets for cancer immunotherapy. The aim of the current study was to determine whether IES predicts response of relapsed-refractory (R/R) AML to FLZ in the CP-MGD006-01 clinical trial. Based on prior knowledge and gene set enrichment analysis, we derived a 61-gene IES signature score from RNA-sequencing datasets (TCGA and Beat-AML Master Trial; 162 and 281 patients, respectively). The immunotherapy cohort included 139 BM samples from 71 patients with R/R AML treated with FLZ at the RP2D of 500 ng/kg/day (NCT02152956). BM samples were collected at time of study entry (n=71; n=66 with response data) and longitudinally post-cycle (PC)1 (n=40), PC2 (n=18), PC3 and 4 (n=4) and end of treatment (n=6). AML status at study entry was classified as primary induction failure (PIF, defined as lack of response to at least 2 induction treatment cycles), and early (ER) or late relapse (LR), defined as complete remission (CR) of & lt;6-month or ≥6-month duration, respectively. Overall response rate (ORR), collectively complete response, was defined as & lt;5% BM blasts (CR, CRh, CRi or MLFS), and partial response (PR) was defined as & gt;50% decrease or decrease to 5-25% BM blasts. RNAs were profiled on the PanCancer IO 360™ gene expression panel on the nCounter® platform. Formalin-fixed paraffin embedded BM biopsies were profiled using the human IO protein and RNA panels on the GeoMx® digital spatial profiler (DSP). The 61 genes in the IES signature included T/NK-cell markers (granzymes, CD8A, KLRD1, KLRK1), immune checkpoints (ICOS, CTLA4, EOMES), IFNG and IFN-stimulated genes (CXCR6, IFIH1, IL10RA, GBP1), and were enriched in KEGG pathways related to Th1/Th2 differentiation, TCR signaling, cytokine-cytokine receptor interaction, NK-mediated cytotoxicity and CD28 costimulation (false discovery rate & lt;0.001 for all; Fig. 1A). Unsupervised hierarchical clustering of gene expression allowed the identification of BM samples with high, intermediate and low IES scores at time of study enrollment (Fig. 1B). Ninety-five percent (18/19) of patients in the IEShigh cluster had PIF/ER AML, congruent with prior studies showing enhanced immune infiltration and IFN signaling in the TME of patients with PIF. Notably, ORR to FLZ (complete response, n=18 or PR, n=5) were documented in 11/19 (58%), 10/32 (31.2%) and 2/15 (13.3%) of patients in the IEShigh, IESint and IESlow cluster, respectively (Fig. 1B). The IES signature score was significantly higher at baseline in patients who responded to FLZ compared with non-responders (P=0.0052; Fig. 1C). High-dimensional flow cytometry of sequential BM samples collected at time of study entry and PC1 of FLZ showed the on-treatment upregulation on both CD4 and CD8 T cells of early activation markers CD69 and CD38 (but not the late activation marker HLA-DR), as well as immune checkpoints LAG3 and Tim-3, and proliferation marker Ki-67, indicating FLZ-mediated modulation of the immune TME. To determine the variation in co-expression of T-cell markers associated with FLZ treatment, we also measured lymphocytes obtained from 21 BM samples prior to and post-FLZ using an unsupervised multivariate analysis. Qualitative comparisons of the principal component analysis (PCA) showed distinct phenotypic changes in BM samples post-treatment (Fig. 1D). Characterization of BM biopsies using GeoMx DSP showed distinct T-cell clustering in responders (Fig. 1E). PCA showed enhanced CD45, CD3, CD4 and PDL1 in situ RNA/protein expression (fold change 1.96, 2.83, 3.32, 4.7, respectively, P & lt;0.05 for all) at PC1 of FLZ in OR versus non-responders (Fig. 1F). In conclusion, features of IES were associated with response to FLZ. T-cell functional rejuvenation by FLZ could benefit patients with R/R AML by counteracting pre-existing immune dysfunction. Figure Disclosures Church: NanoString Technologies, Inc.: Current Employment. Uy:Pfizer: Consultancy; Agios: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas Pharma: Honoraria; Daiichi Sankyo: Consultancy. Emadi:Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; KinaRx: Other: co-founder and scientific advisor; Servier: Membership on an entity's Board of Directors or advisory committees. Walter:Aptevo Therapeutics: Research Funding. Foster:Bellicum Pharmaceuticals: Research Funding; Macrogenics: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Arellano:Cephalon Oncology: Research Funding; Hanmi: Research Funding; Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wieduwilt:Amgen: Research Funding; Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Macrogeneics: Research Funding. Michaelis:Jazz Pharmaceuticals: Research Funding. Stiff:Kite, a Gilead Company: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Delta-Fly: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Advani:Takeda: Research Funding; Immunogen: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; OBI: Research Funding. Wermke:MacroGenics: Honoraria. Erba:AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, PTC: Research Funding; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Agios, Amgen, Astellas, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy; Glycomimetics: Other: member of Scientific Steering Committee; Celgene: Other: chair of the Scientific Steering Committee; Covance (AbbVie): Other: chair of the Independent Review Committee. Ravandi:Orsenix: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Macrogenics: Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Topp:Amgen, KITE, Novartis, Regeneron, Roche: Consultancy; Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding. Muth:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Kaminker:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Gojo:Amgen: Research Funding; Merck: Research Funding; Amphivena: Research Funding; Genentech: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Luznik:AbbVie: Consultancy; WindMil Therapeutics: Patents & Royalties: Patent holder; Merck: Research Funding, Speakers Bureau; Genentech: Research Funding. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Davidson-Moncada:Macrogenics: Current Employment. Rutella:NanoString Technologies, Inc.: Research Funding; MacroGenics, Inc.: Research Funding; Kura Oncology: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-134921

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3905-3905

Abstract: Background: Less-fit patients with acute myeloid leukemia (AML) or high-risk myelodysplasia (MDS) age 60 years and older constitute the majority of patients with AML/MDS but are not well represented in clinical trials. DNA-methyltransferase inhibitor (HMA) monotherapy (e.g. azacitidine or decitabine) is usual. Overall response rates (ORR) are low; improvement in overall survival relative to supportive care alone is modest, highlighting the critical need for efficient identification of effective novel therapies. Blocking programed cell death protein-1 (PD-1) signaling with nivolumab may increase the sensitivity of AML cells to azacitidine and improve outcomes and is the focus of one arm of the S1612 trial. Signaling through PD-1 contributes to tumor immune evasion and growth in AML [Chen, Cancer Biol Ther 2008]. Increased expression of PD-1 (~40% of AML), is associated with poor HMA response [Ørskov, Oncotarget 2015] . A single center azacitidine/nivolumab non-randomized phase II study in relapsed/refractory AML reported ORR of 33% (23/70), including 22% complete remission/complete remission with incomplete hematologic recovery [Daver, Cancer Discovery 2018]. About 25% of the patients developed grade 2-4 immune toxicities; nivolumab immune-related adverse events led to treatment discontinuation in nearly 1 in 7 patients. Study Design and Methods:The S1612 trial [NCT03092674] is a platform randomized phase II/III clinical trial with a common azacitidine control arm (CA) and two currently active experimental arms (EA). Therapy is intended for community setting: azacitidine/nivolumab; and azacitidine/midostaurin. The innovative design utilizes a phase II go/no-go decision comparing each EA with the CA independently when there are 100 pts/arm and 104 deaths on the EA and CA combined. EAs will proceed to phase III if the null hypothesis (HR=1) is rejected in favor of the EA (15% one-sided alpha). When the two currently active EAs complete phase II accrual, a third EA (decitabine/cytarabine) will open. The CA stays open the entire length of the trial and only concurrently randomized patients will be compared across arms. If an EA proceeds to phase III, 200 additional patients (300 total patients) will be accrued. Phase III analysis occurs 1.5 years after accrual or at 414 deaths (in the respective EA and CA), whichever comes first. The phase III tests the null hypothesis with 4.5% two-sided alpha and 83% power for each EA to detect an improvement in median OS from 10.4 to 15.6 months. Eligible pts are age ≥60 years, newly diagnosed AML with ≥ 20% blasts or myelodysplastic syndrome with excess blasts-2 (MDS-EB-2); deemed by the treating physician unfit for standard cytotoxic chemotherapy; and no prior HMA permitted. Trial in Progress Issues:Between December 2017 and October 2018, 113 patients were screened and 78 randomized to study treatment (median/range age: 75/61-86 years; median/range performance status 1/0-3). Two concerns challenged this trial: 1) required administration of 7-day azacitidine at the enrolling sites created a burden for this population and 2) an early excess grade 5 toxicity signal in the azacitidine/nivolumab arm compared with the control arm. Without a control comparison, this safety signal likely would have been missed. Strategies to address these concerns were developed by the study team. Discussion with the sponsor and US Food and Drug Administration (FDA) focused on allowance of standard-of-care protocol-directed azacitidine administration in the patient's primary care doctor's office rather than at the oncology center. Because of the toxicity concern, the trial was placed on partial clinical hold for further evaluation and possible nivolumab-arm eligibility changes, along with new surveillance and pre-emptive action including prompt steroid initiation for suspected immune-related toxicities. The S1612 trial highlights special concerns when enrolling vulnerable populations onto leukemia clinical trials, and the importance of collaborative strategies including with the FDA to preserve clinical trial integrity for patient benefit. It also demonstrates the efficiency this novel platform design has for therapeutic investigation and, importantly, very early identification of serious toxicity. Updates on accrual and resolution and of these issues will be presented. Disclosures Hay: Kite: Research Funding; Gilead: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; MorphoSys: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Roche: Research Funding; Novartis: Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria. Walter:Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; New Link Genetics: Consultancy; Agios: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Seattle Genetics: Research Funding; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy. Foran:Agios: Honoraria, Research Funding. Radich:TwinStrand Biosciences: Research Funding; Novartis: Other: RNA Sequencing. Othus:Celgene: Other: Data Safety and Monitoring Committee; Glycomimetics: Other: Data Safety and Monitoring Committee. Erba:Astellas Pharma: Consultancy; Amgen: Consultancy; Amgen: Consultancy; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Pfizer: Consultancy; Pfizer: Consultancy; ImmunoGen: Consultancy, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Astellas Pharma: Consultancy; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Michaelis:Pfizer: Equity Ownership, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; TG Therapeutics: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; BMS: Research Funding; Bioline: Research Funding; ASTEX: Research Funding; Janssen: Research Funding; Millenium: Research Funding; Macrogeneics: Research Funding. OffLabel Disclosure: Off label experimental combination therapies in newly diagnosed AML/MDS will be discussed, including nivolumab and azacitidine.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-124320

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2347-2347

Abstract: Background: Outcomes of patients with relapsed/refractory AML (RR-AML) have remained poor. Therapy with venetoclax based combinations in this setting leads to CR/CRi rates of 21-49% (DiNardo CD et al. Am J Hematol 2018, Aldoss I et al. Haematologica 2018, Stahl M et al. Blood Adv 2020). Preclinical studies with BCL-2 inhibitors indicate potential mechanisms of drug resistance including overexpression of the anti-apoptotic protein MCL-1 (Konopleva et al. Cancer Cell. 2006). Pevonedistat is a first in class inhibitor of Nedd8 activating enzyme that induces the pro-apoptotic protein NOXA leading to neutralization of MCL-1 and apoptosis. Preclinical studies evaluating the combination of pevonedistat and venetoclax against AML cell lines have demonstrated a synergistic effect (Knorr KL et al. Cell Death Differ. 2015). Hence, we designed a phase I study to assess the safety and tolerability of adding pevonedistat to the combination of azacitidine and venetoclax in patients with RR-AML. Study design and methods: We conducted a phase I study with the combination of pevonedistat, venetoclax and azacitidine in patients with RR-AML. Patients aged 18 years or above with morphologically documented RR-AML, ECOG performance status 0-2 and adequate organ function were eligible. Major exclusion criteria were isolated extramedullary relapse, hematopoietic cell transplantation (HCT) within 100 days of enrollment, and active acute GVHD. Previous therapy with hypomethylating agents (HMA) or venetoclax was not an exclusion criterion. The dose escalation phase was conducted using 3+3 design. Treatment included azacitidine (75 mg/m 2 daily x 7 days), venetoclax (400 mg daily x 28 days), and pevonedistat in escalating doses (10-20 mg/m 2 IV days 1,3,5 of each cycle) with a cycle length of 28 days. Pevonedistat was given at 10 mg/m 2 dose in cohort 1, 15 mg/m 2 dose in cohort 2 and 20 mg/m 2 dose in cohort 3. The primary endpoint is to determine the recommended phase 2 dose (RP2D) and toxicity profile of pevonedistat, azacitidine and venetoclax. Other endpoints included determination of response rates, duration of response, survival, pharmacokinetics, correlation of response rates with AML genomic profile, correlation of pretreatment levels of BCL2, BCLXL, MCL1, BAX or BAK with response, determination of changes in NOXA (PMAIP1) mRNA and protein expression pre-and post-pevonedistat treatment, evaluation of BH3 mimetic profiling on bone marrow samples by flow cytometry and assessing the sensitivity of leukemia and leukemic stem/progenitor cells to pevonedistat ex vivo. Results: Thirteen patients participated in the dose escalation phase, 12 of whom were evaluable. Median age was 69 years (61-91), 30.8% had secondary/therapy related AML, 69.2% with adverse risk disease, 53.8% previously received venetoclax/HMA and 23.1% had relapse after prior allogeneic hematopoietic cell transplantation (HCT) (Table 1). Seven patients were enrolled into cohort 1 (pevonedistat 10 mg/m 2 dose) of which one was not evaluable, three patients enrolled into cohort 2 (pevonedistat 15 mg/m 2 dose), and three patients enrolled into cohort 3 (pevonedistat 20 mg/m 2 dose). Grade 3 or higher AEs included febrile neutropenia (23%), infection (15%), anemia (38%), neutropenia (54%), thrombocytopenia (38%). There was 1 dose limiting toxicity (DLT) in cohort 1 (atrial fibrillation) that triggered cohort expansion. However, subsequent patients did not experience DLT despite planned dose escalation. Of the 12 evaluable total patients, CR/CRi was observed in 5 (41.6%) patients. Notably, patients with RR-AML who were venetoclax/HMA naïve had a CR/CRi 83.3% (5/6 patients). The response rates for each cohort are summarized in Table 2. Three of the five patients with CR/CRi (60%) achieved MRD negativity by flow cytometry. Four patients who achieved CR/CRi proceeded to allogeneic HCT after therapy. Median OS of the cohort was 5.4 months (1.8-14) and median OS was not reached in patients with CR/CRi. Conclusions: The addition of pevonedistat to venetoclax and azacitidine backbone is safe and well tolerated in patients with RR-AML. Dose escalation yielded encouraging efficacy in venetoclax/HMA naïve RR-AML patients. The study is currently in the dose expansion phase. Details on correlative studies examining mechanisms of therapeutic efficacy and resistance will be reported in the main meeting. Figure 1 Figure 1. Disclosures Guru Murthy: Cardinal health: Honoraria; TG Therapeutics: Other: Advisory board meeting; DAVA Oncology: Honoraria; CancerExpertNow: Honoraria; Qessential: Honoraria; Techspert: Consultancy; Curio Sciences: Honoraria; Guidepoint: Consultancy. Abedin: AltruBio: Research Funding; Helsinn: Research Funding; Amgen: Honoraria; Pfizer: Research Funding; Agios: Honoraria; Actinium: Research Funding; Astellas Pharma Inc.: Research Funding. Litzow: Jazz: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Atallah: Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau; Amgen: Consultancy.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-149351

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 23, No. 31 ( 2005-11-01), p. 8124-8125

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2005.03.2458

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2005

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 19-21

Abstract: Introduction: CRS is a potentially life-threatening toxicity observed following T cell-redirecting therapies. CRS is associated with elevated cytokines, including IL6, IFNγ, TNFα, IL2 and GM-CSF. Glucocorticosteroids (GC) and the IL6 receptor blocking antibody tocilizumab (TCZ) can reduce CRS severity; however, CRS may still occur and limit the therapeutic window of novel immunotherapeutic agents. Disruption of cytokine signaling via Janus kinase (JAK) pathway interference may represent a complementary approach to blocking CRS. Ruxolitinib (RUX), an oral JAK1/2 inhibitor approved for the treatment of myelofibrosis and polycythemia vera, interferes with signaling of several cytokines, including IFNγ and IL6, via blockade of the JAK/STAT pathway. We hypothesized that RUX may reduce the frequency and severity of CRS in R/R AML patients (pts) undergoing treatment with flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific DART® molecule. Methods: Relapse/refractory (including primary induction failure, early relapse and late relapse) AML pts were included in this study. RUX pts were treated at a single site, Washington University, St. Louis, MO. RUX was dosed at 10 mg or 20mg BID days -1 through 14. Comparator (non-RUX) pts (n=23) were treated at other clinical sites. FLZ was administered at 500 ng/kg/day continuously in 28-day cycles following multi-step lead-in dosing in week 1 of cycle 1. CRS was graded per Lee criteria1. Results: As of July 1st, 2020, 10 R/R AML pts, median age 65 (range 40-82) years, have been enrolled and treated in the RUX cohort (6 at 10mg, 4 at 20 mg of RUX). All pts had non-favorable risk by ELN 2017 criteria (8 adverse and 2 intermediate); 1 (10.0%) pt had secondary AML; pt characteristics in the RUX and non-RUX cohorts were balanced, except for median baseline BM blasts which was higher in non-RUX pts: 15% (range 5-72) vs (40% (range 7-84), RUX and non-RUX pts respectively. Cytokine analysis showed statistically significant (p & lt;0.05) lower levels of IL4, IL12p70, IL13, IL15, IL17A, IFNα2, but higher levels of GM-CSF were measured in RUX vs non-RUX pts, specifically during co-administration with FLZ (Fig. 1). However, incidence and severity of CRS events were similar. In the RUX cohort, 9 (90%) pts experienced mild to moderate (grade ≤ 2; 48.6% of events were grade 1) CRS events whereas no grade ≥ 3 CRS were reported; in the non-RUX cohort, 23 (100%) pts experienced mild to moderate (grade ≤ 2; 73.1% of events were grade 1) CRS events, 1 (4.3%) grade ≥ 3 CRS was reported. Most CRS events occurred in the first 2 weeks of FLZ administration (75% and 92%, respectively). No differences in duration of CRS events were noted. However, more CRS-directed treatment was used in the RUX cohort. Five (50%) pts received a total of 12 doses of TCZ, 1 (10%) pt received GC and 1 (10%) pts received vasopressors in the RUX cohort. In the non-RUX cohort, 5 (21.7%) pts received 8 doses of TCZ, 3 (13.0%) pts received GC and 1 (3.7%) pt received vasopressors. Dose intensity (DI) at FLZ dose of 500 ng/kg/day was comparable, with median DI of 97.6% and 98.0% in RUX and non-RUX cohorts, respectively. Time to first response (TTFR; BM & lt; 5% blasts) and time on treatment (ToT) were similar between both groups. Median TTFR was 1 cycle for both groups (range 1-2 cycles), and median ToT was 1.4 (range 0.9-5.1) and 1.8 (range 1.3-5.1) months, for RUX and non-RUX pts, respectively. Complete response rate (BM & lt; 5% blasts) was similar: 4 (40%) in RUX pts, and 8 (34.8%) in non-RUX pts; 2 RUX (50%) and 5 non-RUX (62.5%) responders transitioned to stem cell transplant. Conclusion: Prophylactic RUX produced a clear difference in cytokine profiles but no discernable improvement in clinical CRS or response rates in FLZ treated patients. A larger study may be required to determine the prophylactic role of RUX in CRS. References: 1. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124(2): 188-195. doi: 10.1182/blood-2014-05-552729 Disclosures Uy: Pfizer: Consultancy; Agios: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Astellas Pharma: Honoraria. Aldoss:abbvie: Consultancy, Research Funding; kite: Consultancy; agios: Honoraria; autolus limited: Consultancy; JAZZ: Honoraria, Speakers Bureau; Amgen: Consultancy; Agios: Consultancy. Arellano:Cephalon Oncology: Research Funding; Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Research Funding. Foster:Daiichi Sankyo: Consultancy; Bellicum Pharmaceuticals: Research Funding; Macrogenics: Consultancy, Research Funding. Ravandi:Celgene: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding. Advani:Takeda: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding; Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; OBI: Research Funding. Wieduwilt:Macrogeneics: Research Funding; Amgen: Research Funding; Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Emadi:Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; KinaRx: Other: co-founder and scientific advisor; Servier: Membership on an entity's Board of Directors or advisory committees. Michaelis:Jazz Pharmaceuticals: Research Funding. Stiff:Macrogenics: Research Funding; Kite, a Gilead Company: Research Funding; Delta-Fly: Research Funding; Unum: Research Funding; Atara: Research Funding; Gamida Cell: Research Funding; Amgen: Research Funding. Wermke:MacroGenics: Honoraria. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Muth:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Collins:MacroGenics: Current equity holder in publicly-traded company, Other: I currently work as a contractor for MacroGenics; IQVIA: Other: I have worked as a contractor for IQVIA in the past, within the past 24 months.. Guo:Macrogenics: Current Employment. Tran:MacroGenics: Current Employment. Kaminker:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Patel:MacroGenics: Current Employment. Bakkacha:MacroGenics: Current Employment. Jacobs:MacroGenics: Current Employment. Seiler:MacroGenics: Current Employment. Rutella:MacroGenics Inc.: Research Funding; Kura Oncology: Research Funding; NanoString Technologies Inc.: Research Funding. Walter:Aptevo Therapeutics: Research Funding. Bonvini:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Davidson-Moncada:Macrogenics: Current Employment. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-134612

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Leukemia & Lymphoma, Informa UK Limited, Vol. 64, No. 2 ( 2023-01-28), p. 473-477

Type of Medium: Online Resource

ISSN: 1042-8194 , 1029-2403

URL: Article

DOI: 10.1080/10428194.2022.2148212

Language: English

Publisher: Informa UK Limited

Publication Date: 2023

detail.hit.zdb_id: 2030637-4

In: Leukemia & Lymphoma, Informa UK Limited, Vol. 64, No. 1 ( 2023-01-02), p. 250-252

Type of Medium: Online Resource

ISSN: 1042-8194 , 1029-2403

URL: Article

DOI: 10.1080/10428194.2022.2131416

Language: English

Publisher: Informa UK Limited

Publication Date: 2023

detail.hit.zdb_id: 2030637-4

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 16-18

Abstract: Introduction. Approximately 40% of patients (pts) with newly diagnosed AML either fail to achieve complete remission with intensive induction therapy or experience disease recurrence after a short remission (CR1 & lt;6 months). While these primary induction failure (PIF) and early relapse (ER) pts are treated collectively with late relapse (LR) pts (CR1 & gt;6 months), the probability of response for PIF/ER pts is particularly poor (~12%) with median expected overall survival of ~3.5 month and no approved therapy for this specific population. We have recently shown that increased immune infiltration of the tumor microenvironment (TME) is associated with induction failure and poor prognosis; conversely, an infiltrated TME predisposes for immunotherapy response1. We provide an update of the first-in-human study of flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific DART® molecule currently in clinical development for PIF/ER AML pts. Methods. In this phase of the study, PIF is defined as being refractory to induction with: ≥1 high-intensity cytarabine-based chemotherapy (CTx) cycles, or ≥2 but ≤4 Bcl-2 inhibitor-based combinations, or gemtuzumab ozogamicin only. ER is defined as relapse following CR1 & lt; 6 months. Pts who receive up to one prior salvage attempt are included. Pts whose AML recurred following HSCT are excluded. The recommended Phase 2 dose (RP2D) of FLZ is 500 ng/kg/day administered as a continuous infusion in 28-day cycles following a step-up ('priming') lead-in dose during Cycle 1 Week 1. Disease status is assessed by modified IWG criteria. Duration of response is measured from initial response to relapse or death. Results. As of July 1, 2020, 38 PIF/ER (as defined above) AML patients have been treated at the RP2D (median age 63yrs [range 28-81]; 31.6% [12] pts female). Most pts (63.2%, 24/38) were PIF and the large majority (94.7%, 36/38) had non-favorable risk by ELN 2017 criteria (25 pts adverse, 11 pts intermediate); 34.2% (13/38) had secondary AML. For ER pts, median duration of CR1 was 2.9 months (range: 0.7-4.0 months). Cytokine release syndrome (CRS) was the most frequently reported treatment related adverse event (TRAE), with all pts experiencing mild-to-moderate (grade ≤ 2) CRS. No grade ≥ 3 CRS events have been reported in this cohort. Most CRS events (51.5%) occurred in the first week of treatment during step-up dosing. The incidence of CRS progressively decreased during dosing at RP2D (34.8% in week 2, 4.5% in week 3, and 6.1% in week 4), allowing outpatient treatment in most cases. Neurologic AEs have been infrequent, with the most prominent event being grade 1 or grade 2 headache in 23.7% (9/38) treated at the RP2D. Two pts experienced grade 3 confusion of short duration (1-2 days) that was fully reversible. Over half (57.9%) of pts had evidence of antileukemic activity (reduction in blast count) with a median decrease of 92.7% in BM blasts (Fig. 1). The overall complete response rate (CRR, & lt;5% bone marrow blast) was 42.1% (16/38; 7 CR, 4 CRh, 4 CRi, and 1 MLFS), with 68.8% (11/16) subsequently undergoing stem cell transplant. PIF pts showed a CRR of 45.8% (11/24; 5 CR, 3 CRh, and 3 CRi); CRR for ER pts was 35.7% (5/14; 2 CR, 1 CRh, 1CRi and 1 MLFS). Median time to first response was 1 cycle (range: 1-3 cycles). Sixty-nine percent (11/16) of responders normalized PB counts while on FLZ. Transfusion independence was achieved in 35.7% (10/28) of pts for whom data were available. Preliminary, median duration of response (mDOR) was 3.1 months (range 0.4-30.0 months) with many pts (29%, 11/38) still ongoing. With a median follow up time of 10.8 months, median overall survival (mOS) was 4.5 months (95% confidence interval [CI]: 2.9, 8.8). In pts that responded (CRR) the mOS was 7.7 months (95% confidence interval [CI] : 2.9, NA). Overall 6 and 12-month survival rates are 41 % (22.1%, 59.0%) and 24 % (6.1%, 42.5%), respectively. Conclusion: FLZ demonstrated encouraging activity in pts with PIF/ER AML, a population with poor prognosis and high unmet medical need, with 42.1% achieving CRR and over half of those receiving a stem cell transplant. Treatment is tolerable with a minimum 8 day inpatient treatment. The study is currently enrolling patients [NCT02152956] 1 Vadakekolathu J, Minden MD, Hood T, Church SE, Reeder S, Altmann H et al. Immune landscapes predict chemotherapy resistance and immunotherapy response in acute myeloid leukemia. Sci Trans Med 2020. Disclosures Aldoss: abbvie: Consultancy, Research Funding; agios: Honoraria; kite: Consultancy; autolus limited: Consultancy; JAZZ: Honoraria, Speakers Bureau; Amgen: Consultancy; Agios: Consultancy. Uy:Genentech: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Astellas Pharma: Honoraria. Emadi:Amgen: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor; Servier: Membership on an entity's Board of Directors or advisory committees. Walter:Aptevo Therapeutics: Research Funding. Foster:Daiichi Sankyo: Consultancy; Bellicum Pharmaceuticals: Research Funding; Macrogenics: Consultancy, Research Funding. Arellano:Hanmi: Research Funding; Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cephalon Oncology: Research Funding. Wieduwilt:Amgen: Research Funding; Macrogeneics: Research Funding; Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Michaelis:Jazz Pharmaceuticals: Research Funding. Stiff:Kite, a Gilead Company: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Delta-Fly: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Advani:Novartis: Consultancy, Other: advisory board; Pfizer: Honoraria, Research Funding; Takeda: Research Funding; OBI: Research Funding; Kite: Other: Advisory board/ honoraria; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Immunogen: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Wermke:MacroGenics: Honoraria. Erba:AbbVie, Daiichi Sankyo, Forma, ImmunoGen, Jazz Pharmaceuticals, MacroGenics, Novartis, PTC: Research Funding; Glycomimetics: Other: member of Scientific Steering Committee; Celgene: Other: chair of the Scientific Steering Committee; Covance (AbbVie): Other: chair of the Independent Review Committee; AbbVie, Agios, Celgene, Incyte, Jazz Pharmaceuticals, and Novartis: Speakers Bureau; AbbVie, Agios, Amgen, Astellas, Celgene, Daiichi Sankyo, Glycomimetics, ImmunoGen, Incyte, Jazz Pharmaceuticals, MacroGenics, Novartis, and Pfizer: Consultancy. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Ravandi:Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Orsenix: Consultancy, Honoraria, Research Funding. Muth:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Collins:IQVIA: Other: I have worked as a contractor for IQVIA in the past, within the past 24 months.; MacroGenics: Current equity holder in publicly-traded company, Other: I currently work as a contractor for MacroGenics. Guo:Macrogenics: Current Employment. Tran:MacroGenics: Current Employment. Kaminker:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Patel:MacroGenics: Current Employment. Bakkacha:MacroGenics: Current Employment. Jacobs:MacroGenics: Current Employment. Seiler:MacroGenics: Current Employment. Rutella:Kura Oncology: Research Funding; MacroGenics Inc.: Research Funding; NanoString Technologies Inc.: Research Funding. Bonvini:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Davidson-Moncada:Macrogenics: Current Employment. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-134576

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 220-220

Abstract: Background: Therapeutic resistance and treatment tolerance vary greatly in patients with AML, likely due to the advanced age and genetic diversity in pharmacokinetics of those affected. Undoubtedly, tools to accurately predict outcomes of individual therapies for patients could inform decision-making and improve response rates. To this end, several scoring systems have been developed aimed at identifying patients at high risk of poor outcome after intensive chemotherapy. Similar tools for use after non-intensive therapies are currently not available. As such therapies are increasingly effective and more widely utilized we sought to develop tools to predict early death and survival for patients treated with non-intensive therapies. Patients and Methods: We developed prediction models for all-cause death by day 28, 42, 56, and 100 from enrollment using data from 796 patients enrolled on MRC/NCRI trial LI-1, which we then validated in a cohort of 540 patients treated on SWOG trials S0432, S0703, and S1612. Treatments included: Low dose Ara-C (LDAC) alone, sapacitabine alone and LDAC in combination with vosaroxin, tosedostat or ganetespib (MRC/NCRI); Azacytidine (AZA) alone, tipifarnib alone, and AZA in combination with mylotarg, midostaurin, and nivolumab (SWOG). The following covariates were available in the MRC/NCRI and SWOG cohorts to build multivariable logistic regression models (quantitative unless specified otherwise): age, performance status (PS; 0-1 vs. 2-4), secondary AML (vs. de novo AML or high-risk myelodysplastic syndrome), white blood cell and platelet counts, and percentage of bone marrow blasts - all assessed at enrollment. The regression coefficients from the model fit in the MRC/NCRI cohort were used to derive a score and applied to each patient in the SWOG cohort. The models' prognostic accuracies were assessed using the area under the receiver operating characteristic curve (AUC). For the MRC/NCRI cohort, additional covariates were available: cytogenetic risk (per Grimwade 2011), FLT3-ITD, and NPM1 mutation and patient-reported outcomes using the QLQ-C30 instrument. Logistic regression models with these covariates were fit and optimism-corrected AUC estimated to assess prognostic performance for early death. Results: Both patient cohorts were largely composed of older individuals (median age of 75 [range: 60-91] for MRC/NCRI and 77 [60-94] for SWOG, respectively. A substantial subset in each had a PS of 2-4 (MRC/NCRI: 20%; SWOG: 37%) and/or secondary AML (MRC/NCRI: 26%; SWOG: 41%). Overall, the ability to predict early death either by day 28, 42, 56, or 100 was limited in the MRC/NCRI cohort. Subscales of the QLQ-C30 had univariate AUC=0.67, the highest among all covariates evaluated. Multivariable models with just clinical covariates had optimism-corrected AUCs ranging from 0.63-0.65; adding cytogenetic risk and FLT3-ITD and NPM1 mutation status led optimism-corrected AUCs ranging from 0.64-0.66; addition of two QLQ-C30 subscales (fatigue and appetite loss) led to optimism-corrected AUCs ranging from 0.66-0.69. The SWOG cohort did not collect QLQ-C30 or mutational data on all patients and only the clinical multivariable models could be evaluated. The models had a similar performance in the SWOG cohort with AUCs ranging from 0.65-0.68. Conclusion: Our ability to predict early death in older patients treated with lower intensity AML therapies is limited with routinely available clinical variables. Inclusion of cytogenetic risk, FLT3-ITD, and NPM1 mutation status minimally improved the prognostic accuracy as did some of the QLQ-C30 subscales. Our data highlight the difficulties in predicting outcomes with non-intensive AML therapy with routinely available baseline clinical information. Improving the clinical utility of these models may require more complete characterization of patient comorbidities (including frailty index, cognitive function, renal and hepatic function, comorbidity scores) or additional PRO measures since some QLQ-C30 subscales had the strongest univariate signals. Support: NIH/NCI grants CA180888 and CA180819; Blood Cancer UK grant 13041 and Cardiff University. Figure 1 Figure 1. Disclosures Assouline: Novartis: Honoraria, Research Funding; Amgen: Current equity holder in publicly-traded company, Research Funding; Gilead: Speakers Bureau; Johnson & Johnson: Current equity holder in publicly-traded company; Jewish General Hospital, Montreal, Quebec: Current Employment; Eli Lilly: Research Funding; Roche/Genentech: Research Funding; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Erba: AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee; AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding. Walter: Jazz: Research Funding; Pfizer: Consultancy, Research Funding; Selvita: Research Funding; Amphivena: Consultancy, Other: ownership interests; Agios: Consultancy; Astellas: Consultancy; BMS: Consultancy; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Macrogenics: Consultancy, Research Funding; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Othus: Daiichi Sankyo: Consultancy; Celgene: Other: Data safety monitoring board; Merck: Consultancy; Biosight: Consultancy; Glycomimetics: Other: Data safety monitoring board.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-151597

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7