Taewoong Choi

Despite the exciting advancement of novel therapies, chronic graft-versus-host disease (cGVHD) remains the most common cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HCT). Frontline treatment of cGVHD involves systemic steroids, which are associated with significant morbidities. We previously found that inhibition of spleen tyrosine kinase (SYK) with fostamatinib preferentially eradicated aberrantly activated B cells in both ex vivo studies of cGVHD patient B cells, as well as in vivo mouse studies. These and other preclinical studies implicated hyper-reactive B-cell receptor signaling and increased SYK expression in the pathogenesis of cGVHD and compelled this first in-human allogeneic HCT clinical trial. We investigated the safety and efficacy of the oral SYK inhibitor, fostamatinib, for both the prevention and treatment of cGVHD. The primary objective was to evaluate the safety of fostamatinib and determine its maximum tolerated dose in the post-HCT setting. Secondary objectives included assessing the efficacy of fostamatinib in preventing and treating cGVHD, as well as examining alterations in B-cell compartments with treatment. This was a single-institution phase I clinical trial that evaluated the use of fostamatinib in allogeneic HCT patients before the development of cGVHD or at the time of steroid-refractory cGVHD (SR-cGVHD). Patients received fostamatinib at one of three dose levels using a continual reassessment algorithm to determine the maximum tolerated dose. Multiparameter flow cytometry was used to evaluate changes in B cell subpopulations over the first year of treatment with fostamatinib. Nineteen patients were enrolled in this phase I trial, with 5 in the prophylaxis arm and 14 in the therapeutic arm. One patient (5%) required discontinuation of therapy for a dose-limiting toxicity. At a median follow-up of over 3 years, no patients had cancer relapse while on fostamatinib treatment, and recurrent malignancy was observed in 1 patient 2 years after the end of therapy. In the prophylaxis arm, 1 of 5 patients (20%) developed cGVHD while on fostamatinib. In the therapeutic arm, the overall response rate was 77%, with a complete response rate of 31%. The median duration of response was 19.3 months and the 12-month failure-free survival was 69% (95% confidence interval, 48-100). Patients were able to reduce their steroid dose by a median of 80%, with 73% remaining on a lower dose at 1 year compared to baseline. There was an early reduction in the proportion of IgD-CD38hi plasmablast-like cells with fostamatinib treatment, particularly in those SR-cGVHD patients who had an eventual response. B-cell reconstitution was not significantly impacted by fostamatinib therapy after allogeneic HCT. Fostamatinib featured a favorable safety profile in the post-HCT setting. Our data suggests an early efficacy signal that was associated with effects on expected cell targets in both the prophylaxis and treatment of cGVHD, providing rationale for a phase II investigation.

<jats:title>Abstract</jats:title> <jats:p /> <jats:p>Introduction: NKTR-255, an investigational novel polymer-conjugated recombinant human interleukin (IL)-15 agonist, maintains the full spectrum of IL-15 biology and provides sustained pharmacodynamic (PD) responses without the need for daily dosing. NKTR-255 engages IL-15Rα and IL-2/IL-15Rβγ leading to natural killer (NK) and CD8 + T-cell expansion, proliferation, and activation. In preclinical studies, NKTR-255 enhanced antibody-dependent cellular cytotoxicity (ADCC) of each of daratumumab, rituximab, trastuzumab, and cetuximab, resulting in synergistic anticancer activity. This ongoing Phase 1 trial (NCT04136756) evaluates the safety, tolerability, and pharmacokinetic (PK)/PD of NKTR-255 in patients with hematologic malignancies, including determination of the recommended Phase 2 dose (RP2D).</jats:p> <jats:p>Methods: Heavily pretreated patients with relapsed/refractory multiple myeloma (MM) or non-Hodgkin lymphoma (NHL) received escalating doses of NKTR-255 intravenously every 3 weeks. Patients were observed following the first NKTR-255 dose for dose-limiting toxicity. Preliminary PK and PD analyses were conducted. NKTR-255-mediated activation of the immune system was assessed by flow cytometry and plasma cytokine analysis. Fold change was calculated as treatment with NKTR-255 over baseline (baseline = 1).</jats:p> <jats:p>Results: As of June 8, 2021, 14 patients were enrolled, ranging in age from 49 to 80 years; 71% male. Eight (57%) had MM and 6 (43%) had NHL. Two (25%) of 8 patients with MM and 2 (33%) of 6 patients with NHL had received prior chimeric antigen receptor T-cell (CAR-T) therapy. The 14 patients were dosed at 4 levels: (1.5 µg/kg: 3 patients; 3.0 µg/kg: 4 patients; 4.5 µg/kg: 4 patients; 6.0 µg/kg: 3 patients). Among the 11 response-evaluable patients, 7 patients (64%) reported disease stabilization (4/5 [80%] MM patients; 3/6 [50%] NHL patients). Treatment-related adverse events occurring in ≥30% of patients were pyrexia (12/14; 86%), chills (10/14; 71%), nausea (8/14; 57%), headache (6/14; 43%), infusion-related reaction (5/14; 36%), and fatigue (5/14; 36%). Most adverse events were transient and resolved spontaneously, or by using standard treatment protocols. No dose-limiting toxicities were observed, and no patients discontinued NKTR-255 due to adverse events. NKTR-255- induced dose dependent, transient changes in inflammatory cytokines, including interferon-γ, monocyte chemoattractant protein-1 and IL-6 peaked at 3 to 6 hours post-infusion and resolved to baseline levels by 24 to 48 hours, supporting the safety profile of NKTR-255. Preliminary PK analyses showed target mediate disposition at the lowest dose level (1.5 µg/kg) and linear PK toward higher dose levels (&amp;gt;3.0 µg/kg). The average half-life of NKTR-255 was ~39 hours. No accumulation was observed following repeat dosing. There was a dose-dependent expansion in cell numbers of NK and CD8+ T cells in the peripheral blood of patients, with peak fold-changes of ~8-fold and ~2-fold respectively, within the first 2 cycles of NKTR-255 treatment at the 6.0 µg/kg dose. Consistent with NKTR-255 mechanism of action, minimal induction of Tregs was observed at all dose levels tested. Moreover, NK and CD8 + T cells demonstrated proliferative ability, which was maintained across multiple treatment cycles at all dose levels.</jats:p> <jats:p>Conclusions: In this heavily pretreated relapsed/refractory patient population with hematologic malignancies, NKTR-255 was biologically active, and demonstrated sustained increases in NK and CD8 + T cells. NKTR-255 was well tolerated with minimal treatment-related toxicities and transient upregulation and rapid decline of cytokines to baseline levels. RP2D for NKTR-255 monotherapy has not yet been reached; and dose escalation is ongoing at 9.0 µg/kg. NKTR-255 is currently being evaluated in multiple clinical studies in both hematologic malignancies and solid tumors as a monotherapy and in combination with agents that induce ADCC.</jats:p> <jats:p>Ethics approval: The study was approved by the institutional review board of each participating site.</jats:p> <jats:p>Trial registration: ClinicalTrials.gov NCT04136756</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Shah: Sanofi: Consultancy; Precision Biosciences: Research Funding; Nektar: Research Funding; Karyopharm: Consultancy; Indapta Therapeutics: Consultancy; CareDx: Consultancy; Kite: Consultancy; BMS/Celgene: Research Funding; Bluebird Bio: Research Funding; Amgen: Consultancy; CSL Behring: Consultancy; GSK: Consultancy; Janssen: Research Funding; Oncopeptides: Consultancy; Sutro Biopharma: Research Funding; Poseida: Research Funding; Teneobio: Research Funding. Budde: Merck, Inc: Research Funding; Amgen: Research Funding; Astra Zeneca: Research Funding; Mustang Bio: Research Funding; Novartis: Consultancy; Gilead: Consultancy; Roche: Consultancy; Beigene: Consultancy. Hofmeister: Sanofi: Other: National PI for CST; PI or co-PI IST; BMS/Celgene: Other: National PI for CST; PI or co-PI IST; Local PI of CST; Nektar Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: Local PI of CST; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Oncolytics: Other: National PI for CST; PI or co-PI IST; Takeda: Other: Local PI of CST; Genzyme: Membership on an entity's Board of Directors or advisory committees; Myeloma360: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; BioAscend: Other: CME speaker; Philips Gilmore: Other: CME speaker; Non-pharma speaker for education, research, marketing; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Non-CME speaker; BlueBird Bio: Other: Non-CME speaker; Aptitude Health: Other: Non-pharma speaker for education, research, marketing; Verascity: Other: Non-pharma speaker for education, research, marketing; TRM Oncology: Other: Non-pharma speaker for education, research, marketing; DAVA Oncology: Other: Non-pharma speaker for education, research, marketing; Medscape: Other: Non-pharma speaker for education, research, marketing; Ohio State University: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: IP rights, Patents &amp; Royalties. Cowan: Bristol Myers Squibb: Research Funding; GSK: Consultancy; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Cellectar: Consultancy; Harpoon: Research Funding; Secura Bio: Consultancy; Nektar: Research Funding; Sanofi Aventis: Consultancy, Research Funding. Perales: Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Cidara: Honoraria; Equilium: Honoraria; Incyte: Honoraria, Other; Karyopharm: Honoraria; Kite/Gilead: Honoraria, Other; Medigene: Honoraria; Merck: Honoraria; Miltenyi Biotec: Honoraria, Other; MorphoSys: Honoraria; Nektar Therapeutics: Honoraria, Other; NexImmune: Honoraria; Novartis: Honoraria, Other; Omeros: Honoraria; Sellas Life Sciences: Honoraria; Servier: Honoraria; Takeda: Honoraria. Choi: Janssen Biotech: Speakers Bureau. Saeed: MorphoSys AG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Consultancy, Other: research investigator; Other-TG therapeutics: Consultancy, Other: investigator; Kite Pharma: Consultancy, Other: investigator; MEI Pharma Inc: Consultancy, Other: investigator; Celgene Corporation: Consultancy, Other: investigator; Janssen Pharmaceutica Products, LP: Consultancy, Other: investigator; sano-aventis U.S.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Company: Consultancy; Other-Epizyme, Inc.: Consultancy; Other-Secura Bio, Inc.: Consultancy; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chavez: AbbVie: Consultancy; Adaptive: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; BeiGene: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Epizyme: Speakers Bureau; Karyopharm: Consultancy; Kite/Gilead: Consultancy; Merck: Research Funding; MorphoSys: Speakers Bureau; Novartis: Consultancy. Ye: Alexion, AstraZeneca Rare Disease: Other: Study investigator. Cairo: Jazz Pharmaceutical: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; Servier: Speakers Bureau; Sobi: Speakers Bureau; Omeros: Membership on an entity's Board of Directors or advisory committees; Nektar: Membership on an entity's Board of Directors or advisory committees. Rizzieri: Celltron/Teva: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: presentation to FDA for biosimilar review ; Mustang: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Other: personal fee; Gilead: Other: personal fee; Incyte: Other: personal fee; Amgen: Other: personal fee; Kite: Other: personal fee; AROG: Other; Pharmacyclics: Other. Lee: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Dixit: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Nieves: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zhao: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Wang: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Kai: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Marcondes: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Tagliaferri: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zalevsky: Nektar Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Patel: Pfizer: Consultancy; Janssen: Consultancy, Research Funding; BMS Celgene: Consultancy, Research Funding; Oncopeptides: Consultancy.</jats:p> </jats:sec>

Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative treatment for both malignant and nonmalignant hematologic diseases; however, reported rates of treatment-related mortality approach 30%. Outcomes are worse in patients who begin HCT with functional impairments. To detect such impairments, a geriatric assessment (GA) is recommended in adults age ≥65 years. Younger HCT candidates also may be impaired because of chemotherapy regimens pre-HCT. Therefore, we hypothesized that GA can be beneficial for adult patients of all ages and subsequently created a clinical pretransplantation optimization program to assess all HCT candidates using a modified GA. One-hundred fifty-seven patients were evaluated in 4 functional domains- physical, cognitive, nutritional, and psychological-at 2 time points prior to HCT-new patient evaluation (NPE) and sign-off (SO)-between October 2017 and January 2020. At NPE, 80.9% of the patients had at least 1 domain with a functional impairment, and physical (P = .006), cognitive (P = .04), and psychological (P = .04) impairments were associated with an increased likelihood of not proceeding to HCT. In addition, patients age 18 to 39 years were more likely than older patients to have a physical function impairment (P = .001). Between NPE and SO, 51.9% of the patients had resolution of 1 or more impairments, and nutritional impairment at SO was predictive of worse overall survival (P = .01). Our study shows that GA can identify functional impairments in patients of all ages. Early identification of impairments could facilitate referrals to supportive care and resolution of impairments prior to HCT, suggesting that GA could be recommended for HCT candidates of all ages.

Recent studies have revealed the possible association between serum cholesterol levels and hematologic malignancy (HM). However, limited information is available about how reproductive factors interact with this association. Therefore, we investigated the roles of serum cholesterol in the risk of HM according to the menopausal status. We finally identified 1,189,806 premenopausal and 1,621,604 postmenopausal women who underwent a national health screening program in 2009 using data from the Korean National Health Insurance Service database. Overall, 5449 (0.19%) developed HM. Among postmenopausal women, the inverse associations were observed between total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) levels, and the risk of overall HM. In premenopausal women, the highest quartile of HDL-C was associated with a reduced risk of HM compared with the lowest quartile of HDL-C consistent with results in postmenopausal women (adjusted hazard ratio [aHR] 0.80, 95% confidence interval [CI] [0.68-0.95]), whereas the highest quartile of triglyceride (TG) showed an increased risk of HM compared to the lowest quartile of TG, (aHR 1.22, 95% CI [1.02,1.44]) only in premenopausal women. Our finding suggests that lipid profiles are differently associated with HM risk by menopausal status.