scholarly journals Harnessing Extracellular Vesicles from Red Blood Cells for Targeted Delivery of Therapeutic Peptides and RNAs for Leukemia Treatment

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3980-3980
Author(s):  
Migara Kavishka Jayasinghe ◽  
Marco Pirisinu ◽  
Huan Chen ◽  
Yuqi Yang ◽  
Boya Peng ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Board Of Directors ◽  
Targeted Delivery ◽  
Blood Cells ◽  
Stock Options ◽  
Clinical Applications ◽  
Leukemia Cells ◽  
Advisory Committees ◽  
Leukemia Treatment ◽  
Therapeutic Peptides

Abstract Extracellular vesicles (EVs) are emerging as a new class of natural drug carriers with intrinsic ability to deliver bioactive cargo at high efficiency and low toxicity. However, clinical applications of EVs are limited by the production scale and the delivery specificity. We have recently established a new platform for purification and surface modification of EVs from red blood cells (RBCs) that are scalable and versatile for targeted delivery of small-molecule drugs and RNA therapeutics (Usman et al, Nat. Com. 2019 and Pham et al, J. Extracell. Vesicles 2021). Here, we describe a new development of the method for conjugation of RBC-EVs to obtain a higher targeting efficiency. We conjugate RBC-EVs, not only with peptides and nanobodies, but also with monoclonal antibodies, by coupling peptide conjugated EVs with streptavidin-bound biotinylated antibodies. Our data demonstrate that the conjugation is stable and does not affect the physicochemical characteristics of EVs. Conjugation of EVs with a cyclic peptide targeting CXCR4 or a monoclonal antibody targeting CD33 promotes specific binding and uptake of the conjugated EVs by leukemia cells expressing the corresponding receptors. We further use CXCR4-targeting RBC-EVs to specifically deliver the pro-apoptotic peptide KLA to CXCR4-expressing leukemia cells. Delivery of KLA using CXCR4-targeting EVs significantly suppresses leukemia burden and increases survival in a leukemia xenografted mouse model. Antibody-conjugated RBC-EVs are used to deliver RNA antisense oligonucleotides to knockdown FLT3 and miR-125b in cell lines and in patient-derived xenograft models of leukemia. Finally, we demonstrate that peptide/antibody conjugated RBC-EVs are biocompatible and nonimmunogenic. Our study provides a new platform for targeted delivery of therapeutic peptides and RNAs that is highly efficient, stable, versatile and biocompatible for potential clinical applications in leukemia treatment. Migara Kavishka Jayasinghe, Marco Pirisinu, Huan Chen, and Yuqi Yang contributed equally to this work as first authors. Disclosures Jayasinghe: Carmine Therapeutics: Patents & Royalties. Shi: Carmine Therapeutics: Consultancy, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Le: Carmine Therapeutics: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

scholarly journals Transfusion Practices Among Hematology/Oncology Healthcare Professionals

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2552-2552
Author(s):  
Majd T Ghanim ◽  
Jennifer H Voeks ◽  
Julie Kanter
Keyword(s):  
Red Blood Cells ◽  
Board Of Directors ◽  
Blood Cells ◽  
Research Funding ◽  
Evidence Based ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Pediatric Hematology ◽  
Oncology Providers ◽  
Platelet Transfusions

Abstract Introduction/Background: There are no evidence-based guidelines for optimal transfusion practices for patients undergoing chemotherapy and stem cell transplant. There are minimal low-quality studies regarding transfusion thresholds as well as the efficacy of pre-transfusion medications (to reduce febrile non-hemolytic transfusion reactions) for these patients. To pursue a prospective quality improvement study, it is important to know the current transfusion standards used by practitioners regarding: 1) transfusion thresholds for platelets and red blood cells and 2) routine use of pre medications prior to transfusions. Additional research questions included differences in the above standards by region or by pediatrics vs. adult providers. Study Design and Methods: Expedited IRB approval was obtained. We conducted a REDCap survey from 3/1/18-4/12/18 targeting hematology oncology providers of both pediatric and adult providers. The survey was emailed through multiple databases with members form several countries that included both adult and pediatric hematology/oncology practitioners. Results: One hundred and nineteen hematology/oncology practitioners completed the survey: 94 attending physicians, 19 fellows and 6 nurse practitioners. Most respondents practiced in United States (90 %, 107/119), the rest practiced in Canada, India, Italy and Iran. The majority of participants were pediatric hematology/oncology providers (84 %, 100/119). Of the remaining providers 10 treated only adults and 9 treated both adults and children. The vast majority (97%, 115/119) of participants did not utilize a standard policy for premedication prior to red blood cell transfusions. Similarly, 95 % (111/117) or participants made individual decisions on premedication with platelet transfusions rather than using an institutional policy. When asked about the threshold to transfuse blood products, 71% (75/105) of those who treated patients undergoing chemotherapy said they would transfuse red blood cells when patients had a hemoglobin of</= 7 g/dL, and 79% (82/104) would transfuse platelets when patients had a platelet count <10 K/mL. Practitioners treating bone marrow transplant (BMT) patients had more variability and used higher transfusion thresholds. Fifty-two percent (33/64) of them would transfuse red blood cells for patients undergoing BMT with a higher threshold of hemoglobin of 8 g/dL while only 36% used the lower threshold of 7 g/dL. Similarly, for platelet transfusions for patients undergoing BMT, 47% (31/66) would use a 20K/mL threshold, and 45% would transfuse platelets at a threshold of 10 K/mL. Conclusion: There is currently no routine practice of utilizing pre-medications prior to transfusions of red blood cells or platelets. Instead, practitioners surveyed indicated a preference for individualizing the use of pre-medications only if patients had a previous transfusion reaction. As the use of these medications is not evidence-based, additional studies are needed to determine their efficacy. Transfusion thresholds are relatively consistent among providers with the majority aiming for more liberal thresholds in patients undergoing chemotherapy and more conservative for those undergoing BMT. More studies are needed to evaluate the risks and benefits of using different transfusion thresholds. Disclosures Kanter: Sancilio: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Research Funding; Apopharma: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding.

Evaluation Of The Appropriateness Of Frozen Plasma Usage In The Era Of Prothrombin Complex Concentrates: A Retrospective Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3664-3664
Author(s):  
Andrew W. Shih ◽  
Mark A. Crowther ◽  
Neal Manning ◽  
Shuoyan Ning ◽  
Emma Kolesar
Keyword(s):  
Red Blood Cells ◽  
Board Of Directors ◽  
Blood Cells ◽  
Research Funding ◽  
Chart Review ◽  
Weighted Kappa ◽  
Care Hospital ◽  
Prothrombin Complex Concentrates ◽  
Advisory Committees ◽  
Frozen Plasma

Abstract Introduction Although frozen plasma (FP) transfusion is ubiquitous in clinical practice there is growing evidence that calls into question its administration outside a few selected clinical disorders. Indications for FP have been further reduced by the introduction of prothrombin complex concentrates (PCCs), which are now recommended for reversal of coagulopathies due to vitamin K antagonists (VKA). Audits consistently demonstrate that FP is administered to patients who do not have a specific indication for its use; in some cases “inappropriate” FP use exceeds “appropriate” FP use. This audit sought to determine if the introduction of PCCs has changed patterns of practice and the appropriateness of FP use. Methods After ethics review we performed a quality assurance retrospective chart audit at a single tertiary care hospital of consecutive patients receiving FP over a 3 month period. Baseline characteristics were obtained for each of these patients via chart review. Each episode of FP use over a 24 hour period was adjudicated independently by two Hematology fellows and determined to be appropriate, inconsistent (with guidelines) yet appropriate, or inappropriate in accordance to Canadian and AABB guidelines. Episodes where a consensus could not be reached were adjudicated independently by a consultant hematologist. Specific criteria for “appropriateness” were developed based on the chart review; for example, transfusion of more than 5 units of packed red blood cells in a 2:1 ratio or greater with FP was considered inconsistent yet appropriate. Bleeding was defined as a decrease in hemoglobin of 2 g/dL over 24 hours, a transfusion of 2 units of red blood cells without a rise in hemoglobin, or bleeding in an enclosed space. Reversal of oral VKAs with FP was always deemed inappropriate. FP usage during the study period was also compared to 3-month periods from previous years. Results Over the study period, 111 episodes and 466 units of frozen plasma use were recorded. Comparisons to the three month period between January to March of previous years are shown in Figure 1. Interobserver agreement was good between the two Hematology fellows (weighted kappa=0.736) and very good with the fellows to the consensus adjudication (weighted kappa=0.824 and 0.810). After exclusion of FP use for plasmapheresis (always considered appropriate), 33/89 (37.1%), 16/89 (18.0%), and 40/89 (44.9%) episodes were deemed to be appropriate, inconsistent yet appropriate, or inappropriate, respectively. The most common reasons for inappropriate use were the absence of bleeding with an increased INR or VKA reversal. Results are presented in further detail in Table 1. FP transfusion occurred in the ICU 74.8% of the time. Conclusion Our study is the first to audit FP transfusions in the post-PCC era. FP usage remains inappropriately high. FP transfusion to patients who are not bleeding or having procedures despite INR prolongation and the use of FP to reverse VKA are the main reasons for inappropriate FP usage. The majority of FP usage occurred in the ICU. Targeted interventions to reduce FP usage in the future should include both educational and administrative programs, with a focus on the ICU. Clearer evidence on the role of FP in massive transfusions may also reduce FP usage. Disclosures: Crowther: Pfizer: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Merck: Consultancy; Leo Pharma: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; CSL Behring: Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Baxter: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Asahi Kasai: Membership on an entity’s Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Viropharma: Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Increased Adhesiveness of Red Blood Cells from Sickle Cell Trait Carriers after Exposure to Daunirubicin Breast Cancer Chemotherapeutic Agent

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Jing Zhang ◽  
Matthew Hadfield ◽  
Helen Swede ◽  
Biree Andemariam ◽  
George Lykotrafitis
Keyword(s):  
Breast Cancer ◽  
African American ◽  
Adverse Events ◽  
Red Blood Cells ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Blood Cells ◽  
Systemic Treatment ◽  
Sickle Cell Trait ◽  
Advisory Committees

Introduction: African-Americans (AA) with breast cancer continue to experience worse morbidity and mortality than white patients. In addition to barriers to care, an active area of investigation has been the etiology of the increased risk adverse events (AEs) related to chemotherapy. An emerging question is if sickle cell trait (i.e., heterozygotes for hemoglobin beta gene), present in an estimated 1 in 12 of the AA population, confers increased susceptibility to chemotherapy-related complications. We posit that conditions of high physiological stress might be manifest during systemic treatment with toxic agents resulting in alterations of red blood cells (RBCs). Using an experimental biomechanical model system, we hypothesized that RBCs from SCT carriers would be prone to increased adhesiveness after exposure to a common systemic anti-cancer agent used in breast cancer. Increased adhesiveness of RBCs can be a precipitating factor of blocked vasculature and subsequent sickling crises, potentially leading to AEs during treatment. Methods: Our study testedex vivoRBCs from two groups of healthy female participants: 20 African-American sickle cell trait carriers (AA-SCT); and 15 white subjects with wild-type hemoglobin (W-WT). Isolated RBCs were treated with scaled Daunorubicin (DNR) doses. The unbinding forces between αvβ3 ligands and intercellular adhesion molecule-4 (ICAM-4) receptors are reported using the frequency distribution, which states the percentage of events whose unbinding forces are within each width of the bin. We then compared the median values of the forces measured in experiments without and with treatment for each drug. The collective frequency (CF%) is related to the population of active ICAM-4 receptors and is defined as the percentage of all unbinding events divided by the total number of measurements, which is 32 × 32 =1024 for each cell multiplied by the number of tested cells for each blood sample. Results: For AA-SCT RBCs, pre-treatment baseline CF of active ICAM-4 receptors was 4.88 ± 0.87%, which was significantly increased after administration of DNR (13.13 ± 2.30%, p&lt;0.0001). In contrast, treatment of W-WT RBCs held the CF of active ICAM-4 receptors at a comparable level as untreated RBCs (9.54 ± 1.48%; 7.47 ± 1.07%, p=0.50, respectively). Conclusion: Our findings could support hypotheses for adhesion-related RBC clumping among AAs with SCT during systemic treatment with anti-neoplastic agents, and, putatively, resultant AEs. Given past studies showing African-American women with breast cancer have higher rates of self-withdrawal from treatment, further exploration with additional systemic agents are warranted. Our novel study is limited by a small sample size as well lack of potential confounding factors in analyses. Future studies are planned with additional agent(s) and AAs without SCT. Should it be confirmed that SCT carrier status predicts RBC alterations during systemic treatment for breast cancer, and are linked to subsequent adverse events, it could lead to precision treatment planning. Disclosures Andemariam: Novartis:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Hemanext:Membership on an entity's Board of Directors or advisory committees;Global Blood Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees;Vertex:Honoraria;Imara:Research Funding;Emmaus:Membership on an entity's Board of Directors or advisory committees;bluebird bio:Consultancy, Membership on an entity's Board of Directors or advisory committees;NovoNordisk:Consultancy, Membership on an entity's Board of Directors or advisory committees;CRISPR/Vertex:Consultancy, Membership on an entity's Board of Directors or advisory committees;CHNCT:Consultancy;Accordant:Membership on an entity's Board of Directors or advisory committees;Guidepoint:Honoraria;Sanofi Genzyme:Consultancy, Membership on an entity's Board of Directors or advisory committees;Terumo BCT:Consultancy, Membership on an entity's Board of Directors or advisory committees;Roche:Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Cyclerion:Consultancy, Membership on an entity's Board of Directors or advisory committees;Pfizer:Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Bleeding Complications in Patients with Cancer and COVID 19- Analysis from the COVID 19and Cancer Consortium (CCC19) Registry

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4997-4997
Author(s):  
Surbhi Shah ◽  
Shuchi Gulati ◽  
Ang Li ◽  
Julie Fu ◽  
Vaibhav Kumar ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Tumor Board ◽  
Bleeding Complications ◽  
Advisory Committees ◽  
Icu Admission ◽  
Patients With Cancer ◽  
Privately Held

Abstract Background : Patients (pts) with COVID-19 are reported to have increased risk of venous thromboembolism yet bleeding has been an under recognized complication. Rates of bleeding remain unexamined in all patients especially in pts with cancer and COVID-19. Aim: To estimate the incidence of bleeding complication in patients with cancer and COVID 19 Methods: The CCC19 international registry (NCT04354701) aims to investigate complications of COVID-19 in pts with cancer. Our aim was to investigate the frequency of bleeding in hospitalized adult pts with cancer andCOVID-19, enrolled between March 16, 2020 and Feb 8, 2021. The incidence of bleeding complications was captured as defined by CCC19 and included both major and non major bleeding . Associated baseline clinic-pathologic prognostic factors and outcomes such as need for mechanical ventilation, intensive care unit (ICU) admission and mortality rates were assessed Results :3849 pts met analysis inclusion criteria. Bleeding was reported in 276 (7%) pts with median age of 70years; incidence was 6.6 % in females and 7.6 % in males, 6.5% in non-Hispanic white pts, 8.2 % in non-Hispanic Black pts, and 7.8 % in Hispanic pts. 74% had solid cancer and 29% had hematologic malignancies, 33% had received anti-cancer therapy in preceding 30 days, and 8% had surgery within 4weeks. In pts taking antiplatelet or anticoagulant medications at baseline, 7.2% developed bleeding. Need for mechanical ventilation, ICU admission, 30-day mortality, and total mortality were significantly higher in those with bleeding complications compared to those without, p&lt;0.05 Conclusion : We describe the incidence of bleeding in a large cohort of pts with cancer and COVID-19. Bleeding events were observed in those with adverse outcomes including mechanical ventilation, ICU admission, and high mortality; the overall mortality of 43% in patients with bleeding complications is especially notable. This important complication may reflect underlying COVID-19 pathophysiology as well as iatrogenic causes. Figure 1 Figure 1. Disclosures Kumar: Diagnostica Stago: Honoraria. Zon: AMAGMA AND RLZ: Consultancy, Current holder of individual stocks in a privately-held company. Byeff: Pfizer, BMS, Takeda,Teva, Merck, United health: Consultancy, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Nagaraj: Novartis: Research Funding. Hwang: astrazaneca,Merck,bayer, Genentech: Consultancy, Research Funding. McKay: Myovant: Consultancy; Bayer: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calithera: Membership on an entity's Board of Directors or advisory committees; Tempus: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tempus: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dendreon: Consultancy; Caris: Other: Serves as a molecular tumor board ; Vividion: Consultancy; Sorrento Therapeutics: Consultancy; Bayer: Research Funding. Warner: Westat, Hemonc.org: Consultancy, Current holder of stock options in a privately-held company. Connors: Pfizer: Honoraria; CSL Behring: Research Funding; Alnylam: Consultancy; Bristol-Myers Squibb: Honoraria; takeda: Honoraria; Abbott: Consultancy. Rosovsky: Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Ponatinib In Heavily Pretreated Patients With Chronic Phase Chronic Myeloid Leukemia (CP-CML): Management Of Adverse Events (AEs)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1496-1496 ◽  
Author(s):  
Philipp D. Le Coutre ◽  
Dong-Wook Kim ◽  
Javier Pinilla-Ibarz ◽  
Ronald Paquette ◽  
Charles Chuah ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Stock Options ◽  
Research Funding ◽  
Peripheral Vascular ◽  
Vascular Events ◽  
Advisory Committees ◽  
Dose Modification ◽  
Advisory Boards ◽  
Initial Onset ◽  
Grade 3

Abstract Background Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) with activity against native and mutant BCR-ABL. The efficacy and safety of ponatinib (45 mg once daily) in pts with CP-CML were evaluated in the phase 2 PACE trial. Objectives To review the management of treatment-related AEs (TRAEs) that emerged during therapy with ponatinib in the PACE trial. Methods A total of 270 CP-CML pts (267 in efficacy population) resistant or intolerant to dasatinib or nilotinib or with the T315I mutation were enrolled in this ongoing, phase 2, international, open-label clinical trial. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 mos. Safety monitoring included collection of AEs, and the following variables were evaluated: incidence, severity, time to onset, duration, and management. Select TRAEs are discussed. Data as of 01 Apr 2013 are reported, with a median follow-up of 20 (0.1–28) mos. Minimum follow-up for pts remaining on study was 18 mos. Results Median age was 60 (18-94) yrs; median time from diagnosis to first dose was 7 (0.5-27) yrs; 93% had ≥2 prior TKIs, 60% ≥3. Ponatinib demonstrated significant activity in CP-CML pts: 56% MCyR, 46% CCyR, and 36% MMR. At the time of analysis, 60% of pts remained on study. The most frequent reasons for discontinuation were AEs (14%) and progression (8%). The most common hematologic TRAE was thrombocytopenia (41% any grade, 32% grade 3/4). The incidence by time to initial onset is shown below (Figure). Pts experienced thrombocytopenia for a median total duration of 166 days (64% of whom had >1 event) and typically required dose modification: 13% drug withdrawn, 40% dose reduced, 29% dose interrupted only, 17% no dose modification. Among pts with thrombocytopenia, 27% required a platelet transfusion. Thirteen percent of CP-CML pts experienced treatment-related neutropenia and thrombocytopenia. The most common nonhematologic TRAE was rash (39% any grade, 4% grade 3/4), which includes erythematous, macular, and papular rash. Pts experienced rash for a median total duration of 65 days (46% of whom had >1 event) and most did not require dose modification: 0% drug withdrawn, 15% dose reduced, 11% dose interrupted only, 73% no dose modification. One additional pt discontinued due to grade 2 treatment-related exfoliative rash. Pancreatitis was observed (7% any grade, 6% grade 3/4). Median duration was 5 days. Pts were typically managed with dose modification: 5% drug withdrawn, 58% dose reduced, 32% dose interrupted only, 5% no dose modification. Treatment-emergent cardiovascular events were observed in 8% of pts and treatment-emergent cerebrovascular or peripheral vascular events in 11%. Cardiovascular events were considered treatment-related in 4%; cerebrovascular or peripheral vascular events were also considered treatment-related in 4%. The median time to initial onset was 9 mos for cardiovascular and 11 mos for cerebrovascular or peripheral vascular events. The median duration was 6 and 97 days, respectively. Management of pts with cardiovascular AEs: 20% drug withdrawn, 10% dose reduced, 40% dose interrupted only, 30% no dose modification. Management of pts with cerebrovascular or peripheral vascular AEs: 8% drug withdrawn; 8% dose reduced; 17% dose interrupted only; 67% no dose modification. Conclusions Ponatinib has robust antileukemic activity in heavily pretreated CP-CML pts (93% of whom received ≥2 prior TKIs). Treatment-related thrombocytopenia and pancreatitis generally occurred early in therapy and were manageable with dose modification. Treatment-related rash generally occurred early in therapy, was mild-to-moderate in severity, managed without the need for dose modification, and rarely led to discontinuation. Management of treatment-related arterial thrombotic events varied; pts with predisposing cardiovascular risk factors should be monitored closely and managed accordingly. ClinicalTrials.gov ID: NCT01207440 aIncidence = (number of pts with initial onset during time interval) / (number of pts dosed during time interval [N] excluding those who previously experienced the event) X 100 Disclosures: Le Coutre: Novartis: Research Funding; Novartis, BMS, Pfizer: Honoraria. Kim:BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Pinilla-Ibarz:Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. Paquette:Ariad, BMS, Novartis: Consultancy; Ariad, BMS, Novartis: Honoraria; Ariad, BMS, Novartis: Speakers Bureau. Chuah:Novartis, BMS: Honoraria. Nicolini:Novartis, ARIAD, Teva: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, Teva, Pfizer, ARIAD: Honoraria; Novartis, BMS, TEva: Speakers Bureau; Novartis, ARIAD, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Apperley:Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees. DeAngelo:Ariad, Novartis, BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Muller:Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria. Gambacorti-Passerini:Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Yanase:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc. Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus:Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:ARIAD: Honoraria. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.

scholarly journals Obinutuzumab Short Duration Infusion Is Preferred By Healthcare Providers and Has Minimal Impact on Patient-Reported Symptoms Among Patients with Untreated, Advanced Follicular Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1345-1345
Author(s):  
Peter Trask ◽  
Jaisson Bortolini ◽  
Shinya Rai ◽  
Antonio Salar ◽  
Miguel Canales ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Stock Options ◽  
Advisory Committees ◽  
Bulky Disease ◽  
Time Savings ◽  
Low Levels ◽  
Grade 3 ◽  
Privately Held

Abstract Background: Patients with follicular lymphoma (FL) who are on initial treatment, report low levels of symptoms and a higher quality of life index in contrast to patients who have relapsed (Pettengell et al. Ann Oncol 2008). In the immunochemotherapy era, effective and safe treatments should create minimal treatment-related symptoms, regardless of the underlying patient characteristics. In the GALLIUM study (NCT01332968), patients treated with obinutuzumab (G)-chemotherapy followed by G maintenance reported low levels of symptoms (Davies et al. Ann Hematol 2020). Short duration infusions (SDI) of treatments for patients with untreated, advanced FL may yield substantial time savings for patients, and free up healthcare resources. The GAZELLE study (NCT03817853) is a prospective open label, multicenter, single arm, Phase IV study, which evaluated the safety of G administered as a 90-minute (min) SDI infusion from Cycle 2 (C2) onwards in patients with previously untreated advanced FL. G SDI appears to be safe, with no Grade 3 infusion-related reactions (IRRs) reported in C2, and only one Grade 3 IRR reported in subsequent cycles (Canales et al. ASCO 2021). In this analysis, we report symptom levels and provider preference during G SDI administration. Methods: During the first cycle, patients received the first three infusions of G (1000mg) administered at the standard infusion rate on Days 1, 8, and 15. Patients who did not experience any Grade ≥3 IRRs during the first cycle received G as a SDI from C2 onwards. The M.D. Anderson Symptom Inventory (MDASI: range 0 [not present) to 10 [worst]) was used to assess the severity of disease/treatment-related symptoms, and how symptoms interfere with aspects of the patient's daily living. It was completed on Day 1 of C1-6, at the end of induction, during maintenance, at the end of maintenance, and at the end of the study. Additional MDASI analyses were conducted based on patient risk groups (bulky disease, Ann Arbor staging, Eastern Cooperative Oncology Group performance score, B-symptoms, Follicular Lymphoma International Prognostic Index). At any time point after C4 Day 1, study investigators (physicians and nurses) completed an evaluation composed of questions addressing their site's experience with regards to time saved, convenience and infusion preference after administration of SDI and standard infusion of G, across all patients enrolled in the study. Results: 110/113 patients received at least one SDI of G, as per protocol. Median age was 62 years, (range: 28-86 years) and 62% of patients had stage IV FL, 51% presented with B-symptoms at baseline, 45% with bulky disease and 45% were classified as high-risk FLIPI. Median baseline MDASI severity and interference scores were 0 or 1 for most symptoms. Interference scores did not meaningfully change over the course of treatment. Median MDASI scores (baseline or change over treatment), also did not differ by risk subgroups. Over 60% of providers reported that SDI of G would save at least 2 hours in infusion time per visit, with &gt;65% saying it was much more convenient versus regular infusion. SDI was preferred by &gt;95% of providers for reasons attributed to time savings and patient comfort. Conclusions: Untreated, advanced FL patients had no or mild symptom severity and interference at baseline regardless of risk group. These low levels were maintained during G SDI administration. Additionally, SDI administration was preferred by providers for the time it saved, convenience, and comfort for patients, suggesting that G SDI administration can be a beneficial treatment option for untreated, advanced FL patients by minimizing patient treatment burden with no impact on health-related quality of life. Disclosures Trask: Genentech: Current Employment; Genentech/Roche: Current equity holder in publicly-traded company. Bortolini: Novartis: Speakers Bureau. Rai: Janssen Pharmaceutical: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau. Salar: Abbvie: Research Funding; Beigene: Consultancy; BMS/Celgene: Consultancy, Speakers Bureau; EusaPharma: Consultancy; Janssen: Consultancy, Speakers Bureau; Hospital del Mar: Current Employment. Canales: Eusa Pharma: Consultancy, Honoraria; iQone: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Incyte: Consultancy; Novartis: Consultancy, Honoraria; Sanofi: Consultancy; Sandoz: Honoraria, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau. Klingbiel: F.Hoffmann-La Roche Ltd: Current Employment, Current holder of individual stocks in a privately-held company. Parreira: Hoffmann la Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Ended employment in the past 24 months, Honoraria. Deraet: Hoffmann La Roche: Current Employment, Current holder of individual stocks in a privately-held company. Vorozheikina: IQVIA: Current Employment. Hübel: Celgene: Consultancy; Servier: Consultancy, Speakers Bureau; EUSA: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Buchholz: Scripps Health Care System: Current Employment; Roche (Navify software): Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nucleix LLC: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Ultimate Opinions in Medicine LLC: Honoraria; Empyrean medical systems: Membership on an entity's Board of Directors or advisory committees; Mirada: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Combined Genetic Lesions in TP53 and CDKN2A/CDKN2B Drive B Cell Receptor-Dependent/Costimulatory Signal-Independent Proliferation in Richter Syndrome

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 5-6
Author(s):  
Supriya Chakraborty ◽  
Claudio Martines ◽  
Fabiola Porro ◽  
Ilaria Fortunati ◽  
Alice Bonato ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Board Of Directors ◽  
Combined Treatment ◽  
Cell Receptor ◽  
Leukemia Cells ◽  
Wild Type ◽  
Advisory Committees ◽  
Richter Syndrome

B cell receptor (BCR) signals play a critical role in the pathogenesis of chronic lymphocytic leukemia (CLL), but their role in regulating CLL cell proliferation has still not been firmly established. Unlike normal B cells, CLL cells do not proliferate in vitro upon engagement of the BCR, suggesting that CLL cell proliferation is regulated by other signals from the microenvironment, such as those provided by Toll-like receptor (TLR) ligands or T cells. However, the rapid reduction in the percentage of proliferating CLL cells in patients treated with a BTK or SYK inhibitor suggests that the BCR may be more directly involved, at least in a subset of cases. To further address this issue, we investigated the expression of cell cycle regulatory proteins in human and Eμ-TCL1-derived murine CLL cells stimulated with immobilized anti-IgM or cognate antigen, respectively. In both cases, BCR stimulation induced the expression of the positive cell cycle regulators MYC, CCND1, CCND2 and CDK4, consistent with G1 cell cycle entry, but also induced the expression of the negative regulators CDKN1A, CDKN2A and CDKN2B, which block cell cycle progression. Since combined deficiency of these negative regulators occurs in approximately one quarter of Richter syndrome cases because of deletion of the CDKN2A/CDKN2B locus and inactivating genetic lesions of the CDKN1A regulator TP53, we introduced these defects by CRISPR/Cas9 in autoreactive murine Eμ-TCL1 leukemia cells and investigated the effects on leukemia behavior. Adoptive transfer experiments showed that combined targeting of TP53, CDKN2A and CDKN2B results in accelerated leukemia growth and morphological changes consistent with Richter's transformation, including more diffuse infiltration, larger and more pleomorphic cells, and a higher proliferation rate. Moreover, in vitro experiments showed that cells with combined TP53/CDKN2A/2B deficiency had acquired the capacity for spontaneous proliferation, in contrast to control, TP53- or CDKN2A/2B-targeted cells which died after a couple of weeks in culture. Nucleotide sequencing of the TP53/CDKN2A/2B-targeted cells showed complete disappearance of the wild type alleles, suggesting that biallelic loss of all three genes is required for spontaneous growth in vitro. Combined disruption of TP53, CDKN2A and CDKN2B in two other autoreactive Eμ-TCL1 leukemias yielded the same results. To determine whether the spontaneous in vitro proliferation is dependent on BCR signals, the TP53/CDKN2A/2B-deficient cells were transfected with Cas9 ribonucleoprotein complexes targeting the IgM heavy chain constant region (IGHM) gene or were treated with the BCR inhibitors ibrutinib, idelalisib and fostamatinib. Disruption of the IGHM gene or treatment with a BCR inhibitor resulted in almost complete block of proliferation. In contrast, knockdown of the TLR-adaptor protein MyD88 had no effect. Considering that T cells were not present in the culture conditions, these experiments establish that proliferation of Eμ-TCL1 leukemia cells with biallelic TP53/CDKN2A/2B disruption is BCR-dependent but independent of costimulatory signals. To validate these findings in a human setting, we performed experiments with two recently established Richter syndrome patient-derived xenografts, one with biallelic inactivation/deletion of TP53, CDKN2A and CDKN2B (RS9737), and one with wild type TP53, CDKN2A and CDKN2B (RS1316). BrdU incorporation experiments showed that only RS9737 cells proliferate in vitro following BCR stimulation, whereas both RS9737 and RS1316 cells proliferate following stimulation with CpG + IL-15 or CD40L + IL-4 + IL-21. Finally, we tested the activity of combined treatment with a BCR inhibitor and the CDK4/6 inhibitor palbociclib against the murine and human TP53/CDKN2A/2B-deficient Richter syndrome models. Combined treatment showed synergistic activity in vitro and significantly prolonged mouse survival in vivo compared to single agent treatment (n = 10 mice/group, P&lt;0.001). In conclusion, these data provide evidence that BCR signals are directly involved in regulating CLL cell proliferation and suggest that frequently co-occurring genetic lesions in TP53 and CDKN2A/2B contribute to Richter transformation by allowing for BCR dependent/costimulatory signal independent proliferation, which can be therapeutically targeted with a BCR and CDK4/6 inhibitor combination. Disclosures Deaglio: Verastem: Research Funding; Heidelberg Pharma: Research Funding. Laurenti:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees. Efremov:Janssen-Cilag International: Speakers Bureau.

scholarly journals Bitter Taste Receptors System Is Expressed and Functional in Both HSCs and Leukemic Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2560-2560
Author(s):  
Valentina Salvestrini ◽  
Valentina Pensato ◽  
Marilena Ciciarello ◽  
Giorgia Simonetti ◽  
Dorian Forte ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Lines ◽  
Research Funding ◽  
Bitter Taste ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
High Dose ◽  
Taste Receptors ◽  
Advisory Committees ◽  
Hematopoietic Stem

Abstract Acute Myeloid Leukemia (AML) is a clonal disease sprouting from a rare population of leukemic stem cells. Over the past years, increasing interest is gaining the contribution that cell-extrinsic factors have in AML generation and maintenance. In this context, the ability of leukemia cells to detect changes in the microenvironment is important in responsiveness to environmental fluctuations. Bitter taste receptors (T2Rs) are typical G-protein coupled receptors and are normally found on the surface of the tongue. Recent studies showed that T2Rs are widely expressed in various parts of human anatomy and have been shown to be involved in physiology of respiratory system, gastrointestinal tract and endocrine system. thus suggesting a wider function in "sensing microenvironment". We recently reported that AML cell lines OCI-AML3, THP-1, and AML primary cells expressed fully functional T2Rs subtypes. Gene expression profile analysis showed that after T2Rs activation, leukemic cell lines underwent down-regulation of genes involved in positive regulation of cell proliferation, migration, and cell-cycle. Whereas genes involved in cell adhesion and DNA repair were up-regulated. Functional assays supported these results (Blood 2017 130:3949). In the present work, we further investigated the role of T2Rs in BM microenvironment by extending the analysis to AML primary samples and to normal hematopoietic stem cells (HSCs). Similarly to AML cell lines, T2Rs activation with high dose of agonist induced a reduction of cell viability associated to apoptosis induction, while non-toxic doses reduced cell migration and clonogenic capacity. In addition, T2Rs stimulation with agonist makes AML cell lines more prone to oxidative and metabolic stress. Leukemia cells displayed a quiescent phenotype in response to T2Rs activation suggesting that mitochondrial activity is significantly limited by T2Rs agonist treatment. Since no data are available on the presence and the function of T2Rs on normal hematopoietic stem cell counterpart, we characterized T2Rs expression on CD34+ cell isolated from healthy donor. CD34+ cells express several T2Rs subtype without significant differences compare to AML cells. Their activation with high dose of agonist reduced HSCs viability inducing apoptosis, while non-cytotoxic doses reduced clonogenic capacity and promoted migration. Given the effect of T2Rs activation on crucial AML cell function, we tested the therapeutical potential of T2R agonist with and without conventional chemioterapic agent. Interestingly we observed that T2Rs agonist have a synergistic effect with cytarabine, reducing leukemia cell viability when combined with ARA-C compared to their use as single compound. The combination allowed to reach a high toxicity using lower doses of chemotherapic agent. Overall our results indicate that T2Rs receptor system is expressed and functional in both leukemic cells and HSCs. In particular, in AML cells T2Rs activation is associated with quiescence induction and prevention of migration. T2Rs stimulation modulates HSCs function but their role need to be further deepen. These data may suggest a role for microenvironment "bitter" molecules in regulating normal and leukemic hematopoiesis. Disclosures Cavo: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Identification of Biomarkers That Are Associated with Clinical Complications of Hemoglobin SC Disease and Sickle Cell Anemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 962-962
Author(s):  
Minke A.E. Rab ◽  
Celeste K. Kanne ◽  
Mitchel C. Berrevoets ◽  
Jennifer Bos ◽  
Brigitte A. van Oirschot ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Sickle Cell ◽  
Blood Viscosity ◽  
Whole Blood ◽  
Blood Cells ◽  
Research Funding ◽  
Advisory Committees ◽  
Whole Blood Viscosity ◽  
Clinical Complications ◽  
Hemoglobin Sc Disease

Abstract Introduction: Sickle cell disease (SCD) is an umbrella term used to describe inherited anemias that originate from a mutation in HBB, the gene coding for β-globin, that causes the formation of the abnormal hemoglobin S (HbS). The two most common genotypes are HbSS, termed sickle cell anemia (SCA) and HbSC, termed hemoglobin SC disease. Due to the higher prevalence and more severe clinical symptoms in SCA, attention is focused on this latter group of patients. Patients with HbSC disease who report significant SCD related symptoms are treated largely the same as SCA patients, despite differences in disease pathophysiology. Objective: To evaluate rheological differences in red blood cells (RBC) and whole blood from individuals with SCA and HbSC, and examine for associations with clinical complications. Methods: We analyzed an adult (n=30) and pediatric cohort (n=226) of SCA and HbSC individuals. Blood samples were evaluated for percent dense red blood cells (% DRBC), whole blood viscosity, and several ektacytometry-derived parameters, such as the cell membrane stability test, osmotic gradient ektacytometry and Point of Sickling (PoS): an oxygen gradient ektacytometry-derived biomarker that depicts the oxygen tension at which sickling is initiated. Subsequently, we assessed in the pediatric cohort (189 SCA and 37 HbSC individuals) if PoS, dense RBCs or blood viscosity are associated with clinical complications. Results: In particular (micro)dense RBCs (Figure 1A and B), blood viscosity (Figure 1C) and point of sickling (PoS, Figure 1D-F), are notably different in HbSC disease compared to SCA. In SCA, PoS was associated with occurrence of acute chest syndrome (ACS, for every 10mmHg increase OR 1.84, p&lt;0.0001, adjusted OR 1.67, p=0.002), but no such association was found in children with HbSC. In contrast, we found an association of blood viscosity and ACS (OR 9.3, p=0.012; adjusted OR 13.5, p=0.015) in HbSC children, while we found no such association in SCA. No significant association of micro dense RBCs was found in SCA or HbSC children. Conclusion: We found that associations between PoS and ACS found in SCA were not found in HbSC. Instead, in HbSC ACS was associated with higher whole blood viscosity. We therefore conclude that sickling is a key factor in the pathophysiology of SCA, whereas in HbSC disease blood viscosity might play a crucial role in development of certain complications like ACS. This study suggests that complications in SCA and HbSC disease are driven by different aspects of blood abnormalities, and may warrant a distinct treatment approach. Figure 1 Figure 1. Disclosures Rab: Axcella Health: Research Funding; Agios Pharmaceuticals: Research Funding. Schutgens: Shire/Takeda: Research Funding; Pfizer: Research Funding; OctaPharma: Research Funding; Novo Nordisk: Research Funding; CSL Behring: Research Funding; Bayer: Research Funding. Wijk: Axcella health: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Beers: Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; RR Mechatronics: Research Funding; Pfizer: Research Funding. Sheehan: Beam Therapeutics: Research Funding; Novartis: Research Funding; Forma Therapeutics: Research Funding.

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