scholarly journals Rare Cases of Infusion-Related Reactions (IRRs) Presenting As Pain Events during or after Crizanlizumab Infusion in Patients (Pts) with Sickle Cell Disease (SCD): A Systematic Evaluation of Post-Marketing (PM) Reports

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3112-3112
Author(s):  
Julie Kanter ◽  
Amit Shah ◽  
Vikas Joshi ◽  
Harshit Mehta ◽  
Michael Levine ◽  
...  
Keyword(s):  
Back Pain ◽  
Chest Pain ◽  
Board Of Directors ◽  
Reporting Rate ◽  
Systematic Evaluation ◽  
Biologic Agent ◽  
Acute Chest Syndrome ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Data Limitations

Abstract Background: Vaso-occlusive crises (VOCs) are the hallmark of SCD. VOCs and silent vaso-occlusion can lead to complications (eg acute chest syndrome, hepatic/renal dysfunction, chronic pain, multi-organ failure) and premature death. Crizanlizumab, an anti-P-selectin monoclonal antibody (mAb), is authorized in >40 countries to prevent/reduce VOCs in SCD pts aged ≥16 yrs. IRRs are defined as any signs/symptoms (S/S) experienced by pts during/within 24 hrs of infusion of a pharmacologic/biologic agent. IRRs are quite common with mAbs (frequency 1.6‒99%; Rombouts et al Anticancer Res 2020). S/S of IRRs vary; pain events, such as headache, back pain, myalgia, chest pain and joint pain, have been described as S/S of IRRs. Although pain events are known adverse drug reactions in the crizanlizumab label (eg arthralgia, myalgia, pain at various locations), due to data limitations and confounding manifestations of SCD, pain events occurring during/within 24 hrs of crizanlizumab infusion in SUSTAIN were not identified as potential IRRs (Ataga et al N Engl J Med 2017). For pts receiving crizanlizumab, IRR-related pain events may differ in location, severity and/or nature from a pt's usual SCD/VOC pain. Aim: To review data on IRRs presenting as pain events in SCD pts treated with crizanlizumab via reports received by Novartis since approval in Nov 2019. Methods: Data sources included PM reports from providers (spontaneous) and reports from the managed access/pt orientation program. To obtain the reports (which could include ≥1 event), a cumulative custom search of the Novartis safety database was performed up to Jun 2021, using ~111 MedDRA terms associated with potential S/S of IRRs presenting as pain events. IRRs must have occurred during/within 24 hrs of the most recent crizanlizumab infusion, and pain could differ from a pt's usual SCD/VOC, with/without other S/S. IRR incidence was measured by the reporting rate (RR). Reports were not gathered via a uniform data collection system, so there are limitations, including potential underreporting, incompletely documented cases, or bias towards reporting severe events. Results: IRRs presenting as pain events were experienced by 28 pts (Table 1); the most common S/S were back pain, pain in extremity, arthralgia, musculoskeletal chest pain and headache. RR was 1.67 cases per 100 pt-yrs (95% CI 1.11‒2.42). Most pts (n=24) initially experienced IRR at the 1st or 2nd infusion, and the majority recovered within 3 days. IRR recurred on subsequent infusion(s) in 6 pts. Of the 28 pts, 20 (71%) were hospitalized for further treatment, including analgesics, antihistamines, IV fluids and/or steroids. Nine pts (32%) reported SCD complications after IRR (Table 2). Crizanlizumab was discontinued in 23 pts (82%) after their most recent IRR occurrence, including all pts who experienced secondary SCD complications. Discussion: Comprehensive investigation identified 28 pts with reported IRRs presenting as pain events that had a potential causal relationship with crizanlizumab infusion based on temporality. All pts recovered or are recovering, except 1 who had SCD complications and refused blood transfusions for personal reasons. Most pts had initial IRR at the 1st or 2nd infusion and discontinued crizanlizumab after initial IRR; 6 experienced recurrent IRRs on subsequent infusion(s). Resolution time was prolonged for pts who reported known SCD complications following IRR. Causal association of complications following IRR was confounded by the underlying disease and use of steroids to treat IRRs. Systemic corticosteroid exposure in SCD pts has been associated with pain and other complications, from severe VOCs to hemorrhagic stroke and death. No data are available regarding whether the 28 pts had an active VOC or other SCD complications prior to receiving crizanlizumab. Conclusions: Although rare, based on review of PM data, healthcare professionals should be aware of the possibility of IRRs presenting as pain events during or after any crizanlizumab infusion. Crizanlizumab labels have been/are being updated by Novartis to provide information on monitoring for S/S of IRRs presenting as pain events, and guidance on management/prevention of subsequent IRRs, including a statement recommending caution when using corticosteroids in SCD pts. Given the limited data regarding IRRs and predictability of complications, Novartis is committed to further understanding these events. Figure 1 Figure 1. Disclosures Kanter: Fulcrum Therapeutics, Inc.: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Forma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beam: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Graphite Bio: Consultancy; GuidePoint Global: Honoraria; Fulcrum Tx: Consultancy. Shah: Johnson & Johnson: Current equity holder in publicly-traded company; Novartis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Joshi: Novartis Healthcare Private Limited: Current Employment. Mehta: Novartis Healthcare Pvt. Ltd.: Current Employment. Levine: Biontech: Current equity holder in publicly-traded company; Novartis: Current Employment, Current equity holder in publicly-traded company. Arunagiri: Novartis Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Paulose: Novartis Pharmaceuticals Corporation: Current Employment. Donohue: Novartis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Scalera: Novartis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Manwani: Novartis: Consultancy.

scholarly journals Preliminary Results of a Phase II Study to Determine the Safety of Defibrotide in Children and Adolescents with Sickle Cell Disease-Associated Acute Chest Syndrome (IND 127812)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 8-9
Author(s):  
Jordan Milner ◽  
Deborah Friedman ◽  
Marise D'Souza ◽  
Krishnan Sankaran ◽  
Liana Klejmont ◽  
...  
Keyword(s):  
Chest Pain ◽  
Pulmonary Function ◽  
Board Of Directors ◽  
Research Funding ◽  
Pulmonary Infiltrate ◽  
Acute Chest Syndrome ◽  
Cell Disease ◽  
Advisory Committees ◽  
The Us

Background: Sickle cell disease (SCD) is a vasculopathy resulting in recurrent vaso-occlusive crises leading to endothelial dysfunction, chronic end-organ damage, poor quality of life, early mortality and the major curative therapy to date is allogeneic stem cell transplantation (AlloSCT) (Talano/Cairo, EJH, 2015). Acute chest syndrome (ACS) can result in pulmonary hypertension and is the leading cause of morbidity and mortality in patients with SCD (Gladwin et al, NEJM, 2008). ACS accounts for 25% of deaths (Vichinsky et al, Blood, 1997). Clinical definition of ACS is chest pain, fever, cough, dyspnea, and new pulmonary infiltrate on chest radiography. Defibrotide was approved in the US for the treatment of severe sinusoidal obstructive syndrome (SOS) with renal or pulmonary dysfunction following HSCT (Cairo et al, BJH, 2020). Defibrotide primarily targets endothelium in microvascular beds and has anti-inflammatory and anti-coagulant activity, which can treat the underlying pathophysiology of ACS (Falanga et al, Leukemia, 2003 and Scallia et al, Clin Pharm, 1996 and Pescador et al, Vasc Pharm, 2013). Objective: To determine the safety and toxicity of defibrotide in children, adolescents, and young adults with SCD-associated ACS. Design/Methods: Patients with SCD aged 2 to 40 years meeting ACS criteria (at least two of the following: fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on chest imaging, decreased oxygen saturation with or without supplemental oxygen requirements) and eligibility were enrolled within 72 hours of diagnosis after consent was obtained (NCT03805581). Baseline studies comprised of chest radiograph, CT chest angiogram, echocardiography with TRJ velocity and brachial artery reactivity, pulmonary function tests, and biomarkers (IFN-a and -g, TNF-a, IL-6, 8, and 10, sCD163, TSP-1, secretory phospholipase A(2), sVCAM-1, sTNFR1, Ang2, sTei-2, PAI-1, sICAM-1, sP-and sE-selectin, sPECAM-1, VEGF-A, C, D and sVEGFR1 and 2). Defibrotide was administered at 6.25mg/kg IV q6 hours and continued for 7 days or until time of discharge, whichever occurred earlier and patients were followed until day +30 following defibrotide. Dose limiting toxicities include Grade III/IV infusion/allergic reaction or hemorrhage probably or directly related to defibrotide. Results: We have enrolled thirteen patients aged 3 to 18 years with a gender ratio (M/F) of 4/9. Patients' genotypes are as follows: hemoglobin SS disease in nine patients, hemoglobin SC disease in two patients, and hemoglobin Sb0/+ thalassemia in two patients. Presenting symptoms included fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on imaging, and hypoxia.Eight patients completed seven days of treatment, one patient received 6 days of treatment, three patients were discharged after three days of treatment, and one patient withdrew due to recurrent fevers unrelated to defibrotide. All but one patient had resolution of fevers prior to end of treatment. Patients required an average of 1.15 days of oxygen support, with one patient requiring high flow nasal cannula, and no patients required mechanical ventilation. There were no adverse events possibly, probably, or directly related to defibrotide. There was no evidence of hemorrhage in any patient despite four patients receiving concomitant ketorolac or ibuprofen. Of the eleven patients who had pulmonary infiltrates on imaging, eight were evaluated on day +30, two had complete resolution of infiltrate, five had improvements, and one had no change. Seven patients did not follow-up for echocardiography or pulmonary function testing and two of those patients were unable to be evaluated at day +30 due to COVID-19. Discussion: The preliminary data suggest defibrotide is safe and well tolerated in patients with SCD-related ACS. All patients at diagnosis have had baseline studies, which included biomarkers; however, only eight of the thirteen patients have completed all required observations due to poor compliance. After four patients were enrolled and three failed to follow-up, changes to appointment schedules were made with detailed information on all follow-ups. Efforts at improving compliance post therapy are ongoing. Further accrual is needed to determine clinical significance of improvements in cardiac and/or pulmonary function. This study was funded in part by a grant from Jazz Pharmaceuticals. Disclosures Cooke: Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cairo:Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Technology Inc/Miltenyi Biotec: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Miltenyi: Research Funding. OffLabel Disclosure: Defibrotide is utilized in patients with acute chest syndrome to decrease the amount of time they are hospitalized and to assist in alleviating symptoms. Defibrotide is approved in the US for sinusoidal obstructive syndrome with renal or pulmonary dysfunction.

Combinatorial Antigen Targeting Strategy for Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Pinar Ataca Atilla ◽  
Mary K McKenna ◽  
Norihiro Watanabe ◽  
Maksim Mamonkin ◽  
Malcolm K. Brenner ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Tumor Control ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Introduction: Efforts to safely and effectively treat acute myeloid leukemia (AML) by targeting a single leukemia associated antigen with chimeric antigen receptor T (CAR T) cells have had limited success. We determined whether combinatorial expression of chimeric antigen receptors directed to two different AML associated antigens would augment tumor eradication and prevent relapse in targets with heterogeneous expression of myeloid antigens. Methods: We generated CD123 and CD33 targeting CARs; each containing a 4-1BBz or CD28z endodomain. We analyzed the anti-tumor activity of T cells expressing each CAR alone or in co-transduction with a CLL-1 CAR with CD28z endodomain and CD8 hinge previously optimized for use in our open CAR-T cell trial for AML (NCT04219163). We analyzed CAR-T cell phenotype, expansion and transduction efficacy by flow cytometry and assessed function by in vitro and in vivo activity against AML cell lines expressing high, intermediate or low levels of the target antigens (Molm 13= CD123 high, CD33 high, CLL-1 intermediate, KG1a= CD123 low, CD33 low, CLL-1 low and HL60= CD123 low, CD33 intermediate, CLL-1 intermediate/high) For in vivo studies we used NOD.SCID IL-2Rg-/-3/GM/SF (NSGS) mice with established leukemia, determining antitumor activity by bioluminescence imaging. Results: We obtained high levels of gene transfer and expression with both single (CD33.4-1BBʓ, CD123.4-1BBʓ, CD33.CD28ʓ, CD123.CD28ʓ, CLL-1 CAR) and double transduction CD33/CD123.4-1BBʓ or CD33/CD123.CD28ʓ) although single-transductants had marginally higher total CAR expression of 70%-80% versus 60-70% after co-transduction. Constructs containing CD28 co-stimulatory domain exhibited rapid expansion with elevated peak levels compared to 41BB co-stim domain irrespective of the CAR specificity. (p<0.001) (Fig 1a). In 72h co-culture assays, we found consistently improved anti-tumor activity by CAR Ts expressing CLL-1 in combination either with CD33 or with CD123 compared to T cells expressing CLL-1 CAR alone. The benefit of dual expression was most evident when the target cell line expressed low levels of one or both target antigens (e.g. KG1a) (Fig 1b) (P<0.001). No antigen escape was detected in residual tumor. Mechanistically, dual expression was associated with higher pCD3ʓ levels compared to single CAR T cells on exposure to any given tumor (Fig 1c). Increased pCD3ʓ levels were in turn associated with augmented CAR-T degranulation (assessed by CD107a expression) in both CD4 and CD8 T cell populations and with increased TNFα and IFNɣ production (p<0.001 Fig 1d). In vivo, combinatorial targeting with CD123/CD33.CD28ʓ and CLL-1 CAR T cells improved tumor control and animal survival in lines (KG1a, MOLM13 and HL60) expressing diverse levels of the target antigens (Fig 2). Conclusion: Combinatorial targeting of T cells with CD33 or CD123.CD28z CARs and CLL-1-CAR improves CAR T cell activation associated with superior recruitment/phosphorylation of CD3ʓ, producing enhanced effector function and tumor control. The events that lead to increased pCD3ʓ after antigen engagement in the dual transduced cells may in part be due to an overall increase in CAR expression but may also reflect superior CAR recruitment after antigen engagement. We are now comparing the formation, structure, and stability of immune synapses in single and dual targeting CARs for AML. Disclosures Brenner: Walking Fish: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Tumstone: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Founder; Maker Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Other: Founder; Memmgen: Membership on an entity's Board of Directors or advisory committees; Allogene: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Atilla:Bluebird Bio: Membership on an entity's Board of Directors or advisory committees; Tumstone: Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: founder; Marker Therapeuticsa: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties; Allogene: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Walking Fish: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Memgen: Membership on an entity's Board of Directors or advisory committees; KUUR: Membership on an entity's Board of Directors or advisory committees.

Evolving Unmet Need in Patients Refractory to Lenalidomide: Overview of the Clinical Trials in Relapsed/Refractory Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Maria-Victoria Mateos ◽  
Rohan Medhekar ◽  
Istvan Majer ◽  
Mehmet Turgut
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Literature Review ◽  
Board Of Directors ◽  
Unmet Need ◽  
Publicly Traded ◽  
First Line ◽  
Advisory Committees ◽  
Line Of Therapy

Introduction: The majority of newly diagnosed multiple myeloma (NDMM) patients are currently treated with lenalidomide-based regimens as their first line of therapy. This trend is likely to continue in the coming years. Typically, lenalidomide is administered until disease progression and has significantly contributed to better outcomes in these patients. However, most patients relapse, and prognosis worsens with each relapse. The choice of optimal treatment for patients who relapse while receiving lenalidomide as first line of therapy is unclear. Moreau et al (Blood Cancer J. 9, 38 [2019]) concluded that there is limited data on approved combinations for treating these patients and are restricted by the low number of lenalidomide-refractory patients enrolled in the pivotal trials. Results from the ongoing clinical trials of the combination of carfilzomib and anti-CD38 antibodies were not available at the time of the Moreau et al publication. The aim of this targeted literature review was to include this new data and to summarize currently available evidence on progression-free survival (PFS) for the treatment of RRMM patients who progressed on lenalidomide-based regimens. Methods: A targeted literature review was conducted to identify registrational clinical trials in patients with RRMM reporting PFS outcomes. PubMed, congress proceedings, and product labels were searched between Jan 2014 to July 2020. In addition to PFS, demographic, disease characteristics and treatment history were extracted for the trial populations to contextualize potential variations in study outcomes. The regimens studied in these trials were classified as lenalidomide-based, proteasome inhibitor (PI)-based and pomalidomide-based. Number of prior lines of therapy, prior exposure and refractoriness to lenalidomide and bortezomib were reported. Results: Twelve registrational trials were identified based on the search criteria (Table 1). Most pivotal trials assessing lenalidomide-based regimens (POLLUX, ELOQUENT-II, TOURMALINE-MM1) except the ASPIRE trial excluded patients who were refractory to lenalidomide. Trials evaluating PI-based regimens (e.g., CANDOR) or pomalidomide-based regimens (e.g., OPTIMISMM) included these patients, with more recent studies enrolling a larger proportion. Percentage of lenalidomide-exposed (and lenalidomide refractory) ranged from 40% (32%) in CANDOR to 98% (90%) in ELOQUENT III. These studies also enrolled a larger proportion of patients who were bortezomib-exposed, although most of these patients were at first relapse, with the exception of ELOQUENT III and ICARIA where most patients were at third relapse. Among lenalidomide-refractory patients, the median-PFS (mPFS) observed for the pomalidomide-based regimens ranged from 9.5 to 10.1 months and that observed for PI-based regimens ranged from 4.9 to 25.7 months. PFS in the lenalidomide-refractory subgroup was considerably shorter than in the ITT population. The mPFS for patients receiving carfilzomib/daratumumab/dexamethasone (KDd; CANDOR) and isatuximab/carfilzomib/dexamethasone (IsaKd; IKEMA) was not reached at median follow-up of 16.9 and 20.7 months respectively. While the mPFS for (KDd) for lenalidomide-refractory patients in CANDOR trial was not yet reached at median follow up of 16.9 months; the mPFS of 25.7 months for KDd in the MMY-1001 trial appears to be the longest among the assessed regimens. Conclusion: Patients refractory to lenalidomide have shorter PFS and represent a population with high unmet need. This targeted literature review suggests that the PI-based KDd regimen provides longer PFS compared to other lenalidomide-sparing regimens in lenalidomide-refractory populations. Heterogeneity across trial populations may limit the comparability of these treatments. Disclosures Mateos: Regeneron: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaMar-Zeltia: Consultancy; GlaxoSmithKline: Consultancy. Medhekar:Amgen Inc.: Current Employment, Current equity holder in publicly-traded company. Majer:Amgen (Europe) GmbH: Current Employment, Current equity holder in publicly-traded company.

scholarly journals Predictors of Maternal Morbidity Among Participants Enrolled in the Sickle Cell Disease Implementation Consortium Registry

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-3
Author(s):  
Rita V Masese ◽  
Dominique Bulgin ◽  
Liliana Preiss ◽  
Mitchell Knisely ◽  
Eleanor Stevenson ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Transfusion Requirement ◽  
The United States ◽  
Acute Chest Syndrome ◽  
Maternal Outcomes ◽  
Maternal Complications ◽  
Advisory Committees ◽  
Increased Risk

Introduction Pregnancy in sickle cell disease (SCD) is associated with an exacerbation of SCD-related complications and an increased risk of maternal complications. The increased risk is partly due to physiologic adaptations in pregnancy, which include increased metabolic demands and a hypercoagulable state. The maternal death rate for SCD is 629 per 100,000 deliveries, compared to 12 per 100,000 deliveries in black women and 6 per 100,000 deliveries in the general population (Raider et al., 2016). Studies on maternal and perinatal outcomes of patients with SCD present inconsistent and conflicting results. Some studies have reported an increase in maternal complications such as pre-eclampsia, acute chest syndrome and thromboembolic events, while other studies have reported no significant risk in adverse maternal outcomes. The inconsistent findings reported in prior studies may be attributed to small sample sizes and single-centered sites. Our study aims to determine the prevalence and predictors of maternal morbidity among participants enrolled in the SCD Implementation Consortium (SCDIC) registry, which is the largest, most geographically diverse SCD participant sample in the United States. Methods This cross-sectional study included women enrolled in the SCDIC registry who had at least one pregnancy event. The SCDIC is composed of eight academic SCD centers across the United States and one data-coordinating center. Participants were enrolled in the SCDIC registry if they were 18 to 45 years of age and had a confirmed diagnosis of SCD. Enrolled participants completed a series of surveys that collected sociodemographic information, SCD and pregnancy history and data abstractions of participants' medical records was completed. Medical complications queried during pregnancy included: vaso-occlusive episodes, acute chest syndrome, blood transfusion requirement, preeclampsia, maternal diabetes and deep venous thrombosis. Descriptive analysis of sociodemographic, clinical and maternal characteristics was conducted. Bivariate analysis was performed using Chi-Square test, Mann-Whitney U test, t-test, and logistic regressions, as appropriate. A p-value of ≤ 0.05 was considered statistically significant for all analysis. Results The study sample included 743 women who had at least one pregnancy event, and a total of 1066 live births. Almost all women (96.3%) were African American, with a median age of 21 years (inter-quartile range of 19 to 23 years) at first birth. The majority had Hb SS SCD genotype (69.5%; 513 of the 738 with SCD genotype data). Of all reported pregnancies, participants did not use hydroxyurea during conception (78%), and pregnancy (84.5%). Only 2.7 % of the women reported using fertility drugs or assisted reproductive procedures. Seventy five percent of the pregnancies that ended in live births had maternal complications. The leading complications were vaso-occlusive episodes (61.2%), pregnancy requiring blood transfusion(s) (33.2%), preeclampsia (15.4%), deep venous thrombosis (5.6%) and acute chest syndrome (7.7%). When the pregnancies were stratified by SCD genotype, women with Hb SS had a higher occurrence of acute chest syndrome (63.4% vs. 26.7%), transfusion requirement (70.8% vs. 21%) and preeclampsia (66.7% vs 22.4%). In the univariate logistic regressions, multiparous women, with a history of adverse maternal outcomes in a previous pregnancy, had higher odds of vaso-occlusive episodes (OR: 3.42; 95% CI: 2.42-4.94) acute chest syndrome (OR:4.99; 95% CI:2.56- 9.48), transfusion requirement (OR:3.86; 95% CI:2.64- 5.69), and pre-eclampsia (OR:3.36; 95% CI:2.05-5.45). Conclusion In this large multicenter registry, we found pregnant women with SCD have significant maternal complications. Early antenatal care by healthcare providers knowledgeable about risk factors for adverse maternal outcomes in SCD is essential improve maternal and fetal outcomes and reduce the maternal death rate for SCD. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria. Treadwell:Global Blood Therapeutics: Consultancy; UpToDate: Honoraria. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Guidepoint Global: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy. Glassberg:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Eli Lilly and Company: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau.

scholarly journals Effect of Moderate and Severe Hemophilia a on Daily Life in Children and Their Caregivers: A CHESS Paediatrics Study Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-45
Author(s):  
Kate Khair ◽  
Francis Nissen ◽  
Mariabeth Silkey ◽  
Tom Burke ◽  
Aijing Shang ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Disease Burden ◽  
Hemophilia A ◽  
Daily Life ◽  
Social Activity ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Lost Work ◽  
Hours Of Work

Introduction: Hemophilia A (HA) is a congenital bleeding disorder, caused by a deficiency in clotting factor VIII (FVIII) and characterized by uncontrolled bleeding and progressive joint damage. This analysis assesses the impact of disease burden on the daily life of children with hemophilia A (CwHA) and their caregivers, addressing a deficit of current research on this topic. Methods: The Cost of Haemophilia in Europe: a Socioeconomic Survey in a Paediatric Population (CHESS Paediatrics) is a retrospective, burden-of-illness study in children with moderate and severe HA (defined by endogenous FVIII [IU/dL] relative to normal; moderate, 1-5%; severe, <1%) across France, Germany, Italy, Spain and the UK. CwHA were recruited and stratified by both age group (0-5 years:6-11 years:12-17 years=1:1:1) and disease severity (severe:moderate=approximately 2:1, prioritizing children with severe HA [CwSHA]). Data for this analysis were captured from physicians, children, and their caregivers. Physicians completed online case report forms for treated children, and the child and/or their caregivers completed a paper-based questionnaire utilizing 5-point Likert scales. For CwHA aged 0-7, the questionnaire was completed by the caregiver, while for CwHA aged 8-17, children and caregivers completed different sections. Hours of care provided by the caregiver and work lost by the caregiver were reported as median values due to non-normal data distribution. Informed consent was obtained for all participants. Upon review, the study was approved by the University of Chester ethical committee. Results: Data from child/caregiver questionnaires were available for 196 CwHA (moderate, 25.5%; severe, 74.5%); the majority of these children, as expected, were receiving prophylaxis (72.4%), and did not have FVIII inhibitors (89.8%; Table 1). There was a direct impact of disease burden on CwHA, particularly with regard to physical and social activities (Figure 1). Overall, it was agreed or strongly agreed by the child or caregiver that 48.0% and 57.5% of children with moderate HA (CwMHA) and CwSHA respectively, have reduced physical activity due to HA, and 46.0% and 57.5%, respectively, have reduced social activity due to HA. A total of 36.0% and 61.0% of CwMHA and CwSHA, respectively, had adapted their treatment in anticipation of physical or social activity (Table 1). Furthermore, 34.0% of CwMHA and 55.4% of CwSHA were frustrated due to their disease, and many (CwMHA, 36.0%; CwSHA, 50.7%) felt that they had missed opportunities (Figure 1). For 66.0% of CwMHA and 76.0% of CwSHA, it was reported that their daily life was compromised due to their HA. Caregivers provided a median (interquartile range [IQR]) of 19.0 (10.0-59.5) and 12.0 (5.0-20.0) hours a week of care for the hemophilia-related needs of their CwMHA (n=30) or CwSHA (n=105), respectively. Of those who responded, 17.4% (n=4/23) and 25.0% (n=20/80) of caregivers to CwMHA or CwSHA, respectively, stated they have lost work due to their caregiving duty. This was more than twice as common for caregivers in families with multiple CwHA (42.9%, n=9/21 responses) compared with those in families with one CwHA (18.5%, n=15/81 responses). Median (IQR) hours of work per week estimated to be lost were 20.0 (17.0-22.0) for caregivers of CwMHA (n=4) and 12.5 (4.50-20.0) for caregivers of CwSHA (n=20). Conclusions: In conclusion, both children and caregivers make sacrifices in their daily lives due to HA; many CwHA reported reduced physical and social activities, fewer opportunities and feelings of frustration due to their HA. Caregivers reported spending a significant number of hours caring for their child and some reported losing work due to their caring responsibilities. However, some outcomes may be limited by the small number of respondents and narrow response options, particularly those regarding the caregiver burden. Responses on the hours of work lost may be subject to selection bias, as caregivers who have lost work may be more likely to respond to this question. Additionally, as this question is targeted at caregivers in employment, it is unknown if some caregivers have left employment due to their caregiving responsibilities. According to this analysis, children/caregivers are frequently required to adapt the child's treatment before the child engages in activities. Overall, the burden of disease was similar in children with moderate and severe HA. Disclosures Khair: Takeda: Honoraria, Speakers Bureau; Bayer: Consultancy, Honoraria, Speakers Bureau; Biomarin: Consultancy; HCD Economics: Consultancy; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medikhair: Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Research Funding, Speakers Bureau; CSL Behring: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Haemnet: Membership on an entity's Board of Directors or advisory committees. Nissen:GSK: Research Funding; Novartis: Research Funding; Actelion: Consultancy; F. Hoffmann-La Roche Ltd: Current Employment. Silkey:Aerotek AG: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Burke:HCD Economics: Current Employment; University of Chester: Current Employment; F. Hoffmann-La Roche Ltd: Consultancy. Shang:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Aizenas:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Meier:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. O'Hara:HCD Economics: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Consultancy. Noone:Research Investigator PROBE: Research Funding; Healthcare Decision Consultants: Membership on an entity's Board of Directors or advisory committees; European Haemophilia Consortium: Membership on an entity's Board of Directors or advisory committees.

scholarly journals To Treat or Not to Treat? Understanding Treatment Patterns in Patients with Lower-Risk Myelofibrosis at the Time of Enrollment in the MOST Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 49-51
Author(s):  
Rami S. Komrokji ◽  
Brady L. Stein ◽  
Robyn M. Scherber ◽  
Patricia Kalafut ◽  
Haobo Ren ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Lower Risk ◽  
Research Funding ◽  
Symptom Burden ◽  
Risk Groups ◽  
Treatment Patterns ◽  
Low Risk ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Therapy Initiation

Background: Myelofibrosis (MF) is a chronic Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) characterized by extramedullary hematopoiesis, bone marrow fibrosis, splenomegaly, constitutional symptoms, and diminished quality of life. Treatment decisions may involve a variety of factors including prognosis and symptomatology. Data regarding real-world disease and demographic factors that contribute to therapy initiation and choice in pts with lower risk MF are limited. This analysis of data from the ongoing Myelofibrosis and Essential Thrombocythemia Observational STudy (MOST; NCT02953704) assessed whether these factors differ for lower risk pts who were treated vs untreated at enrollment. Methods: MOST is a longitudinal, noninterventional, prospective, observational study in pts with MF or essential thrombocythemia enrolled at clinical practices within the US. Pts included in the analysis (≥18 y), had low risk MF by the Dynamic International Prognostic Scoring System (DIPSS; Blood. 2010;115:1703), or intermediate-1 (INT-1) risk by age >65 y alone. Pt data were entered into an electronic case report form during usual-care visits over a planned 36-month observation period. Pt-reported symptom burden was assessed using the MPN-Symptom Assessment Form (MPN-SAF); Total Symptom Score (TSS) was calculated (0 [absent] to 100 [worst imaginable]; J Clin Oncol. 2012;30:4098). Data were analyzed with basic descriptive and inferential statistics. Results: Of 233 pts with MF enrolled at 124 sites between 11/29/2016 and 03/29/2019, 205 were included in this analysis; 28 were excluded for being INT-1 risk for reasons other than age. Of the 205 pts, 85 (41.5%) were low- and 120 (58.5%) were INT-1 risk; 56.5% (48/85) and 59.2% (71/120), respectively, were being treated at enrollment. Pt characteristics are listed in Table 1A. Fewer low- vs INT-1 risk pts were JAK2 V617F or MPL positive, and more were CALR positive. The proportion of pts with palpable splenomegaly was similar for treated low- and INT-1 risk pts. In low risk pts, the proportion of pts with palpable splenomegaly was higher in untreated vs treated pts; whereas, in INT-1 risk pts, the opposite was observed (ie, lower proportion in untreated vs treated pts). Blood counts were generally similar across cohorts, except median leukocytes were lower for low risk treated pts and platelet counts were elevated in low- vs INT-1 risk pts. The proportion of pts with comorbidities was similar across cohorts, except for fewer cardiovascular comorbidities in low- vs INT-1 risk pts. Mean TSS was lower in low- vs INT-1 risk pts, but the proportion of pts with TSS ≥20 was greater in treated vs untreated pts in both low- and INT-1 risk groups. Fatigue was the most severe pt-reported symptom in all cohorts. Differences in mean TSS and individual symptom scores between risk groups were not significant (P > 0.05), except itching was worse among INT-1 risk pts (P=0.03). Physician-reported signs and symptoms were generally more frequent for untreated vs treated pts, irrespective of risk (all P > 0.05). Most low risk (69.4%) and INT-1 risk pts (61.2%) who were currently untreated at enrollment had not received any prior MF-directed treatment (Table 1B); the most common prior treatment among currently untreated pts was hydroxyurea (HU) in both risk groups. Of currently treated pts, HU was the most common MF-directed monotherapy at enrollment in low-risk pts, and ruxolitinib was most common in INT-1 risk pts. No low risk pts and few INT-1 risk pts were currently receiving >1 MF-directed therapy at enrollment. Conclusion: These real-world data from pts with MF enrolled in MOST show that a substantial proportion of both low- and INT-1 risk pts who had received treatment before enrollment were not being treated at the time of enrollment. Although watch-and-wait is a therapeutic option, the finding that many of these lower risk pts had in fact received prior therapies suggests an unmet need for effective and tolerable second-line treatment options. Treated pts had greater pt-reported symptom burden vs untreated pts, which suggests that high symptom burden may contribute to the decision for treatment. Prospective studies are needed to evaluate symptom burden change with therapy initiation. In this regard, future analyses of data from MOST are planned to assess the longitudinal evolution of the clinical characteristics, treatment patterns, and management of pts with MF. Disclosures Komrokji: Geron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Acceleron: Honoraria. Stein:Incyte: Research Funding; Kartos: Other: educational content presented; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmaessentia: Membership on an entity's Board of Directors or advisory committees. Scherber:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Kalafut:Incyte: Current Employment, Current equity holder in publicly-traded company. Ren:Incyte: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; CTI Biopharma Corp: Research Funding; NS Pharma: Research Funding; ItalPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Protagonist Therapeutics: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; Promedior: Research Funding.

scholarly journals Outcomes with Interferon in Essential Thrombocythemia: A Systematic Review and Meta-Analysis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3147-3147
Author(s):  
Moazzam Shahzad ◽  
Mamoon Ahmed ◽  
Sakina Abbas ◽  
Muhammad Arslan ◽  
Tooba Kashif ◽  
...  
Keyword(s):  
Systematic Review ◽  
Board Of Directors ◽  
Interferon Alpha ◽  
Essential Thrombocythemia ◽  
Research Funding ◽  
Meta Analysis ◽  
Molecular Response ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Hematological Response

Abstract Introduction Essential thrombocythemia (ET) is a BCR-ABL negative myeloproliferative disorder characterized by high burden of symptoms, thrombocytosis, increased risk of thrombosis and bleeding, and risk of progression to Myelofibrosis. Interferon alpha (IFN-α) is a potent immunomodulation agent proposed to be capable of inducing complete hematological remission in patients with myeloproliferative disorders. Many INF- α have been studied for treatment of patients with ET. We present a systematic review and meta-analysis assessing the efficacy of IFN-α therapy in patients with ET. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, and Clinical trials.gov using MeSH terms and keywords for " Thrombocythemia, Essential " AND " Interferons " in April 2021. We did not place any time constraints. Our search produced a total of 825 records and duplicates were removed. After screening and removing irrelevant and review articles, we included 21 original articles reporting IFN-α as the only treatment for ET in adult patients. The data were collected for baseline characteristics of the participants and efficacy and safety of the intervention. Quality evaluation was done using the NIH quality assessment tool. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with 95% Confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the R programming language (version 4.16-2). Results A total of 388 patients from 21 articles were evaluated. The median age of participants was 54 (35-62) years and 31% (n=64/205) were males. The type of IFN used were Interferon-alpha in 4 studies, pegylated (PEG)IFN-α-2a in 2 studies, IFN-α-2b in 6 studies, recombinant IFN-α-2C in 3 studies, recombinant IFN-y in 1 study, PEG-IFN-2b in 1 study, recombinant IFN-2b in 2 studies, and PEG-IFN in 1 study. The pooled overall hematological response (OHR) was 86.4% (95% Cl 0.67-0.98, I 2= 65%, p=0.02, n=73) with complete hematological response (CHR) of 70.6% (95% Cl 0.54-0.84, I 2=34%, p=0.21, n=65) and partial hematological response (PHR) of 13% (95% Cl 0.02-0.27, I 2=42%, p=0.16, n=65). The pooled overall molecular response (OMR) was 84% (95% Cl 0.72-0.93, I 2=13%, p=<0.01, n=81) with complete molecular response (CMR) of 64.2% (95% Cl 0.41-0.84, I 2=68%, p=<0.01, n=81) and partial molecular response (PMR) of 35% (95% Cl 0.16-0.56, I 2=33%, p=0.01, n=43). Side effects reported were nausea, allergic reactions, liver dysfunction, dose dependent mild myalgia, fever, malaise, itching, persistent fever, headache, and flu like symptoms. Conclusion Interferon alpha, in different formulations shows consistent and high activity in patients with essential thrombocythemia. It resulted in clinical responses, as well as molecular responses. Side effect profiles were consistent among different reports and were reasonable tolerated. There is a large body of evidence supporting actively and safety of this approach in a diverse ET patient population. Figure 1 Figure 1. Disclosures McGuirk: Gamida Cell: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Astelllas Pharma: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Bellicum Pharmaceuticals: Research Funding; Fresenius Biotech: Research Funding; Novartis: Research Funding; EcoR1 Capital: Consultancy; Pluristem Therapeutics: Research Funding. Yacoub: Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company.

scholarly journals A Phase I Trial of the Antibody-Cytokine Fusion Protein F16IL2 in Combination with Anti-CD33 Immunotherapy for Posttransplant AML Relapse

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2345-2345
Author(s):  
Andrew F. Berdel ◽  
Christoph Rollig ◽  
Martin Wermke ◽  
Linus Angenendt ◽  
Leo Ruhnke ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Nk Cells ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Human Antibody ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Dose Levels

Abstract Introduction Natural killer (NK) cells are key effectors in cancer immunosurveillance and posttransplant immunity, but shortage of environmental growth factors and deficient recognition of malignant cells may limit their anticancer efficacy. We hypothesized that the antibody-mediated anchoring of interleukin-2 (IL-2) to the leukemia-modified extracellular matrix (ECM) would increase NK cell abundance and activity to potentiate antibody-dependent cellular cytotoxicity (ADCC) against acute myeloid leukemia (AML) blasts. In this novel-novel combination dose-escalation phase 1 trial, we enrolled patients with AML relapse after allogeneic hematopoietic stem cell transplantation (HSCT) to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of F16IL2, an antibody-cytokine fusion protein composed of the human antibody fragment scFv(F16) in diabody format and two molecules of human IL-2, in combination with the Fc-optimized, ADCC-mediating anti-CD33 monoclonal antibody BI 836858. F16 specifically targets the A1 domain of the ECM protein tenascin C (TnC), which is spliced into the TnC molecule during active angiogenesis and tissue remodeling while it is virtually absent in normal tissues. Methods F16IL2 (10 - 20 Mio IU IV) was administered on days 1, 8, 15 and 22 of 28-day cycles, followed by administration of BI 836858 (10 - 40 mg IV) two days after each F16IL2 infusion. Dose escalation was performed over 4 dose levels (DL). Cohort 1 (10 Mio IU F16IL2 and 10 mg BI 836858, n = 5), cohort 2 (10 Mio IU F16IL2 and 20 mg BI 836858, n = 3), cohort 3 (20 Mio IU F16IL2 and 20 mg BI 836858, n = 4), cohort 4 (20 Mio IU F16IL2 and 40 mg BI 836858, n = 3). Safety and tolerability, pharmacodynamics and -kinetics, clinical efficacy and immune effector cell dynamics were investigated. This trial was registered at EudraCT as #2015-004763-37. Results Between December 2016 and March 2020, 15 patients with a median age of 50 years (range, 20 - 68) were enrolled and treated across 4 dose levels. Six patients (40%) had received two or more prior HSCT. The most frequent drug-related AEs (F16IL2 or BI 836858 or combination) were pyrexia (n = 13, 87%), chills (n = 12, 80%) and infusion-related reactions (n = 9, 60%), consistent with the expected toxicity profile of cytokine-armed or naked mAbs. These events were generally manageable, transient and of grade ≤ 2. One dose-limiting toxicity occurred at each of DL 3 (pulmonary edema) and 4 (acute GVHD). No patient died within the first 30 days of treatment initiation. Whereas no formal maximum tolerated dose (MTD) was reached, the maximum tested dose of 20 Mio IU F16IL2 and 40 mg BI 836858 was considered the recommended dose (RD). Three objective responses (1 CR, 1 CRi, 1 PR in extramedullary AML) were observed among 7 patients treated at the two higher DL, whereas no responses occurred at the two starting DL. Median OS among all 15 patients was 4.8 months (1.5 - 12.9), with a 6- and 12-month OS of 40% and 27%, respectively. Among those 7 patients whose AML was at least temporarily controlled with study treatment (CR/CRi, PR, SD), 12-month OS was 67% vs. 0% in non-responders. Combination therapy stimulated the expansion and activation of NK cells in bone marrow and peripheral blood. Conclusions To the best of our knowledge, this is the first study demonstrating that the strategy of potentiating ADCC with tumor-targeted immunocytokines is feasible in humans. In the difficult-to-treat situation of posttransplant AML relapse, responses were observed at higher DL, even in patients with extramedullary disease. The antibody-mediated targeted delivery of IL-2 to the ECM combined with anti-CD33 immunotherapy represents an innovative experimental approach associated with acceptable safety and encouraging biologic and clinical activity in posttransplant AML relapse. Disclosures Wermke: Novartis, Roche, Pfizer, BMS: Consultancy, Honoraria, Research Funding. Hemmerle: Philogen S.p.A.: Current Employment. Schäfers: Philogen S.p.A.: Research Funding. Rossig: BMS and Celgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; AdBoards by Amgen: Honoraria. Stelljes: Pfizer: Consultancy, Research Funding, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Rueter: Boehringer Ingelheim Pharma GmbH & Co. KG: Current Employment. Neri: Philogen S.p.A.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Multiple patents on vascular targeting; ETH Zurich: Patents & Royalties: CD117xCD3 TEA. Berdel: Philogen S.p.A.: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schliemann: Roche: Consultancy; Philogen S.p.A.: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Other: travel grants; Boehringer-Ingelheim: Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; AstraZeneca: Consultancy; Abbvie: Consultancy, Other: travel grants.

scholarly journals Efficacy and Safety of Voxelotor in Adolescents and Adults with Sickle Cell Disease: HOPE Trial 72-Week Analysis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-19
Author(s):  
Jo Howard ◽  
Kenneth I. Ataga ◽  
R. Clark Brown ◽  
Maureen Achebe ◽  
Videlis Nduba ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Board Of Directors ◽  
Research Funding ◽  
Efficacy And Safety ◽  
Cell Disease ◽  
Publicly Traded ◽  
Advisory Committees ◽  
Time Points ◽  
Indirect Bilirubin ◽  
Safety Signals

Background: Sickle cell disease (SCD) is a lifelong, inherited disorder characterized by mutations in the hemoglobin (Hb) subunit β gene that leads to the production of sickle hemoglobin (HbS). When HbS is deoxygenated, polymerization leads to red blood cell sickling and damage, resulting in hemolysis, chronic anemia, and episodic vaso-occlusive crises (VOCs). Patients with SCD are at an increased risk of developing long-term complications, including stroke, leg ulcers, and other end-organ damage. Lower Hb levels highly correlate with increased morbidity and early mortality in SCD. Voxelotor (Oxbryta®) is an oral, once-daily HbS polymerization inhibitor indicated for the treatment of SCD in adults and adolescent patients ≥12 years of age. The 24-week analysis of the HOPE trial demonstrated that treatment with voxelotor 1500 mg resulted in a significantly greater proportion of patients achieving a >1 g/dL Hb increase compared with placebo (51.1% vs 6.5%, P<0.001), which was associated with concordant improvements in hematological markers of hemolysis (indirect bilirubin and reticulocyte percentage). Here we report the evaluation of efficacy and safety of voxelotor 1500 mg at 72 weeks, the conclusion of the placebo-controlled HOPE trial. Methods: In the randomized, double-blinded, placebo-controlled, phase 3 HOPE trial, adults and adolescents (aged 12-65 years) with SCD were randomized to receive voxelotor (1500 mg or 900 mg) or placebo. Included patients had an Hb level of 5.5 to 10.5 g/dL at enrollment and 1 to 10 vaso-occlusive crises in the 12 months prior to screening. Concurrent hydroxyurea was allowed if the dose had been stable for ≥90 days at enrollment. Changes from baseline in Hb and hemolysis markers (absolute and percentage reticulocyte, indirect bilirubin levels, and lactate dehydrogenase levels) and safety were assessed at week 72. Results: 89% (95% CI, 82.4% to 95.4%) of patients receiving voxelotor 1500 mg achieved a Hb increase of >1 g/dL at 1 or more time points during the 72-week treatment period compared with 25% (95% CI, 16.2% to 33.8%) of those receiving placebo (P<0.001). The mean change in Hb from baseline at week 72 was 1.0 g/dL in patients treated with voxelotor 1500 mg compared with 0.0 g/dL in patients receiving placebo (Figure 1; P<0.001). Mean change from baseline to average Hb throughout the 72-week duration was 1.26 g/dL in patients treated with voxelotor 1500 mg. Consistent with the week 24 analysis, significant improvements in markers of hemolysis (assessed by difference in adjusted mean percent change versus placebo) were seen in indirect bilirubin (-26.6% [95% CI, -40.2% to -12.9%]) and reticulocyte percentage (-18.6% [95% CI, -33.9% to -3.3%]) in the voxelotor 1500 mg group relative to placebo, with favorable trends of reduction in other markers, such as absolute reticulocyte count (-5.8% [95% CI, -23.4% to 11.9%] and lactate dehydrogenase (-4.8% [95% CI, -13.8% to 4.1%]). The overall incidence rate of VOCs was numerically lower in the 1500 mg arm compared with placebo, but was not statistically significant. Rates of non-SCD and SCD-related treatment-emergent adverse events were similar between the treatment groups, with no new safety signals noted through week 72. Conclusions: Voxelotor 1500 mg resulted in durable improvements in Hb levels and markers of hemolysis out to 72 weeks of treatment, with approximately 90% of patients achieving an increase in Hb >1 g/dL at 1 or more time points during the study. Treatment with voxelotor remained well tolerated, with no new safety signals detected with longer-term follow-up. These results support the sustained and chronic use of voxelotor to reduce anemia and hemolysis, thereby potentially mitigating the associated morbidity and mortality of SCD. Disclosures Howard: Imara, Inc., Novartis, Resonance Health: Honoraria; Agios, Forma Therapeutics, Inc., Global Blood Therapeutics, Imara, Inc., Novo Nordisk, Novartis: Membership on an entity's Board of Directors or advisory committees. Ataga:Editas Medicine: Honoraria; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire/Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Forma Therapeutics: Consultancy; Modus Therapeutics: Honoraria; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees. Achebe:Global Blood Therapeutics: Consultancy. Hassab:Global Blood Therapeutics: Research Funding. Agodoa:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Tonda:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gray:Global Blood Therapeutics: Current Employment, Current equity holder in publicly-traded company. Lehrer-Graiwer:Global Blood Therapeutics: Other: Former employee and former equity holder. Vichinsky:Pfizer: Research Funding; Agios: Research Funding; Global Blood Therapeutics: Consultancy.

scholarly journals Gabarap Loss Mediates Immune Escape in High Risk Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 891-891
Author(s):  
Annamaria Gulla ◽  
Eugenio Morelli ◽  
Mehmet K. Samur ◽  
Cirino Botta ◽  
Megan Johnstone ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Clinical Outcome ◽  
Board Of Directors ◽  
Research Funding ◽  
Immune Escape ◽  
Publicly Traded ◽  
Advisory Committees

Abstract Immune therapies including CAR T cells and bispecific T cell engagers are demonstrating remarkable efficacy in relapsed refractory myeloma (MM). In this context, we have recently shown that proteasome inhibitor bortezomib (BTZ) results in immunogenic cell death (ICD) and in a viral mimicry state in MM cells, allowing for immune recognition of tumor cells. Induction of a robust anti-MM immune response after BTZ was confirmed both in vitro and in vivo: treatment of 5TGM1 MM cells with BTZ induced tumor regression associated with memory immune response, confirmed by ELISPOT of mouse splenocytes. We have confirmed the obligate role of calreticulin (CALR) exposure in phagocytosis and the ICD process, since BTZ-induced ICD is impaired in CALR KO MM cells both in vitro and in vivo. We further showed that the therapeutic efficacy of BTZ in patients was correlated with ICD induction: BTZ-induced ICD signature was positively correlated with OS (p=0.01) in patients enrolled in the IFM/DFCI 2009 study. Together, these studies indicate that ICD is associated with long-term response after BTZ treatment. In this work, we reasoned that genomic or transcriptomic alterations associated with shorter survival of MM patients after BTZ treatment may impair activation of the ICD pathway. To this aim, we performed a transcriptomic analysis of purified CD138+ cells from 360 newly diagnosed, clinically-annotated MM patients enrolled in the IFM/DFCI 2009 study. By focusing on genes involved in the ICD process, we found that low levels of GABA Type A Receptor-Associated Protein (GABARAP) were associated with inferior clinical outcome (EFS, p=0.0055). GABARAP gene locus is located on chr17p13.1, a region deleted in high risk (HR) MM with unfavorable prognosis. Remarkably, we found that correlation of low GABARAP levels with shorter EFS was significant (p=0.018) even after excluding MM patients with del17p; and GABARAP is therefore an independent predictor of clinical outcome. GABARAP is a regulator of autophagy and vesicular trafficking, and a putative CALR binding partner. Interestingly, among a panel of MM cell lines (n=6), BTZ treatment failed to induce exposure of CALR and MM cell phagocytosis by DCs in KMS11 cells, which carry a monoallelic deletion of GABARAP. This effect was rescued by stable overexpression of GABARAP. Moreover, CRISPR/Cas9-mediated KO of GABARAP in 3 ICD-sensitive cell lines (AMO1, H929, 5TGM1) abrogated CALR exposure and ICD induction by BTZ. GABARAP add-back by stable overexpression in KO clones restored both CALR exposure and induction of ICD, confirming GABARAP on-target activity. Similarly, pre-treatment of GABARAP KO cells with recombinant CALR restored MM phagocytosis, further confirming that GABARAP impairs ICD via inhibition of CALR exposure. Based on these findings, we hypothesized that GABARAP loss may alter the ICD pathway via CALR trapping, resulting in the ICD resistant phenotype observed in GABARAP null and del17p cells. To this end, we explored the impact of GABARAP KO on the CALR protein interactome, in the presence or absence of BTZ. Importantly, GABARAP KO produced a significant increase of CALR binding to stanniocalcin 1 (STC1), a phagocytosis checkpoint that mediates the mitochondrial trapping of CALR, thereby minimizing its exposure upon ICD. Consistently, GABARAP KO also affected CALR interactome in BTZ-treated cells, which was significantly enriched in mitochondrial proteins. Importantly, co-IP experiments confirmed GABARAP interaction with STC1. These data indicate a molecular scenario whereby GABARAP interacts with STC1 to avoid STC1-mediated trapping of CALR, allowing for the induction of ICD after treatment with ICD inducers; on the other hand, this mechanism is compromised in GABARAP null or del17p cells, and the STC1-CALR complex remains trapped in the mitochondria, resulting in ICD resistance. To functionally validate our findings in the context of the immune microenvironment, we performed mass Cytometry after T cell co-culture with DCs primed by both WT and GABARAP KO AMO1 clones. And we confirmed that treatment of GABARAP KO clones with BTZ failed to activate an efficient T cell response. In conclusion, our work identifies a unique mechanism of immune escape which may contribute to the poor clinical outcome observed in del17p HR MM patients. It further suggests that novel therapies to restore GABARAP may allow for the induction of ICD and improved patient outcome in MM. Disclosures Bianchi: Jacob D. Fuchsberg Law Firm: Consultancy; MJH: Honoraria; Karyopharm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Richardson: AstraZeneca: Consultancy; Regeneron: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; GlaxoSmithKline: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Chauhan: C4 Therapeutics: Current equity holder in publicly-traded company; Stemline Therapeutics, Inc: Consultancy. Munshi: Legend: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Oncopep: Consultancy, Current equity holder in publicly-traded company, Other: scientific founder, Patents & Royalties; Abbvie: Consultancy; Takeda: Consultancy; Adaptive Biotechnology: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy. Anderson: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Scientific Founder of Oncopep and C4 Therapeutics: Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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