scholarly journals Feasibility of Delivering Pediatric-to-Adult Transition Education during Annual Comprehensive Clinic Appointments and Patient-Reported Outcomes: A Quality Improvement Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2993-2993
Author(s):  
Emily Wheat ◽  
Bryn M Dunham ◽  
Whitney Tedeschi ◽  
Kim Richfield ◽  
Nancy MS Spomer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Quality Improvement ◽  
Board Of Directors ◽  
Multidisciplinary Team ◽  
Bleeding Disorder ◽  
Advisory Committees ◽  
Knowledge And Skills ◽  
Trial Investigator ◽  
Transition Education ◽  
Specific Education

Abstract Individuals with bleeding disorder diagnoses require developmentally sensitive care across the lifespan, particularly as they gain knowledge and skills necessary to successfully tackle their illness-specific needs as independent adults (Breakey et al., 2010). The current study describes one phase of a larger quality improvement (QI) initiative aimed at improving transition from pediatric to adult care (TAC) at one US Hemophilia and Thrombosis Center (HTC). Our aim was to assess the feasibility of delivering transition specific education to youth-caregiver dyads during youth annual multidisciplinary clinic appointments. Youth-caregiver dyads were selected given previous research revealing that both patients and their parents express worries about related to TAC (Geerts et al., 2008). Education included discussion of the knowledge and skills necessary for autonomous management of one's bleeding disorder (e.g., illness basics, treatment, communication, and healthy living). During an 8-month period, 101 youth-caregiver dyads were approached. Patients were between the ages of 12 and 25 (M age = 17.66, SD = 3.45). Approximately half of patients were diagnosed with hemophilia A (53.5%) and 16.8% were female. Of the 101 patients approached, 90 completed the transition education discussion. On average, these discussions took 12.80 minutes (SD = 8.49) and ranged from 5 to 50 minutes. Social work delivered the bulk of these discussions (78.7%) and spent an average of 10.61 minutes (SD = 5.76) with youth and caregivers. While the intention was to deliver transition education to youth-caregiver dyads, this only occurred in 37 discussions. Other discussions included the patient only (n = 31), caregiver only (n = 20), or had missing data (n = 1). In instances when a youth-caregiver dyad was approached, but a discussion did not take place, barriers to completing the discussion were identified. "Provider" was listed most frequently (n = 5) as a barrier (e.g., youth sent home by medical team prior to transition discussion occurring; miscommunication between members of multidisciplinary team; low staffing of those trained to deliver transition discussion). Even in instances when a transition discussion did take place, barriers to having the discussion were identified. "Patient" barriers were the most frequently listed (n = 13), followed by barriers related to "Time" (n = 11), and barriers related to "Clinic" (n = 3). At the end of the transition discussion, youth and/or caregivers were encouraged to identify a goal for improving their skills or knowledge in one of the four areas discussed during their appointment. Of those having transition discussions, 72 created a transition goal. The majority of participants reported goals related to Treatment (e.g., infusion skills; n = 36) followed by goals related to Communication (n = 18), Healthy Living (n = 11), and Bleeding Disorder Basics (n = 7). There was a statistically significant difference in the type of goal of expressed by youth and/or caregivers when the patient was 17 years old or younger vs those older than 18, X 2 (3, N = 72) = 9.49, p = 0.024. Generally, more youth reported goals related to Treatment (e.g., infusion skills) than predicted by chance in both age groups. Patients or patient caregivers were contacted via phone between 5 and 14 months following their transition discussion. Approximately 1/3 of the patients who completed transition discussion, responded and provided ratings on progress toward meeting their transition goal. Ratings (M = 4.24, SD = 2.63) were made on a Likert-type scale ranging from 1 (no progress made) to 10 (maximum progress made). The information gleaned from this QI initiative revealed that delivery of transition-specific education within the CU-HTC annual multidisciplinary appointments is feasible and in some cases, served as the impetus necessary for accomplishing transition-specific goals. The results from this initiative have been instrumental in subsequent transition-related efforts related to: (a) fostering full engagement across the multidisciplinary team in TAC efforts utilizing HEMO-Milestones Tool (Croteau et al., 2016); (b) adopting specific materials developed to assess TAC in individuals with bleeding disorder diagnoses (i.e., American Society of Hematology Hemophilia Transition Readiness Assessment); and (c) reducing time between patient goal-setting and follow-up from the HTC. Disclosures Wang: Novo Nordisk: Consultancy, Other: Clinical trial investigator; Bioverativ: Consultancy, Other: Clinical trial investigator; Bayer: Consultancy, Other: Clinical trial investigator; Octapharma: Other; uniQure: Consultancy, Other: Clinical trial investigator; Pfizer/Spark: Other: clinical trial investigator; Genentech: Consultancy, Other: Clinical trial investigator; BioMarin: Consultancy, Other: Clinical trial investigator; CSL Behring: Consultancy, Other: Clinical trial investigator; Takeda: Consultancy, Other: Clinical trial investigator; Hema Biologics: Consultancy, Other: Clinical trial investigator. Buckner: CSL Behring: Honoraria; Tremeau Pharmaceuticals: Consultancy, Honoraria; Genetech: Honoraria; Bayer: Honoraria; Spark: Honoraria; Sanofi: Honoraria; Novo Nordisk: Honoraria; Pfizer: Honoraria; BioMarin: Consultancy, Honoraria; Takeda: Honoraria; American Thrombosis: Membership on an entity's Board of Directors or advisory committees; Hemostasis Network: Membership on an entity's Board of Directors or advisory committees; uniQure: Consultancy, Honoraria.

scholarly journals Unexpected Toxicities When Nivolumab Was Given after Allogeneic Stem Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1956-1956
Author(s):  
Amy Wang ◽  
Justin Kline ◽  
Wendy Stock ◽  
Satyajit Kosuri ◽  
Andrew S. Artz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Stem Cell ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Research Funding ◽  
Checkpoint Inhibitors ◽  
Advisory Committees ◽  
Relapsed Disease

Background:Treatment options are limited for patients (pts) with hematologic malignancies who relapse after allogeneic stem cell transplantation (allo-SCT). We hypothesized that checkpoint inhibitors may offer a novel approach for maintaining remission after allo-SCT. Data from pre-clinical studies have suggested a potential role for PD-1/PD-L1 inhibitors in acute myeloid leukemia (AML) (Zhang et al., Blood 2009), so it is possible that immunomodulation with checkpoint inhibitors could stimulate the donor anti-leukemia immune response and prevent disease relapse. However, the safety of checkpoint blockade early after allografting remains to be established. Methods:We conducted a pilot study to assess the tolerability and efficacy of Nivolumab, a PD-1 inhibitor, as maintenance therapy after allo-SCT (NCT02985554). Pts were eligible if they were post allo-SCT without evidence of relapse or active graft-vs-host disease (GVHD) or history of prior greater than stage I skin acute GVHD. Nivolumab was to be administered intravenously at 1mg/kg every 2 weeks for 4 doses followed by dosing every 12 weeks. Treatment started 4 weeks after routine immunosuppression was discontinued until 2 years after the transplant. The primary objective was to determine the tolerability of Nivolumab on this schedule. Secondary objectives were evaluation of adverse events, relapse, and overall survival. Results:Four pts were enrolled from December 2017 through November 2018. (Table 1)All pts experienced immune-related adverse events (irAE) from Nivolumab, and 2 (50%) pts experienced serious adverse events. (Table 2)One pt developed grade (G) 4 neutropenia soon after the first dose. (Figure 1)The absolute neutrophil count nadired at 20 cells/µL, at which point pegfilgrastim was administered. An interim bone marrow biopsy (BMBx) confirmed no evidence of relapsed disease. Full neutrophil recovery occurred approximately 3 months after the initial dose, and no subsequent toxicities occurred. Another pt developed G3 autoimmune encephalopathy concurrently with G2 transaminitis and G2 thrombocytopenia after one dose of Nivolumab. (Figure 2)Intravenous methylprednisolone (1mg/kg daily for 3 days) and immunoglobulin (2g/kg in 4 divided doses) were administered, followed by a 7-week steroid taper with full resolution of symptoms. Relapsed disease was ruled out by a BMBx. A third pt developed G2 skin rash approximately 10 days after the first dose of Nivolumab. Skin biopsy demonstrated drug hypersensitivity reaction vs GVHD, and the pt was treated with a 3-week prednisone course (starting at 1mg/kg followed by a taper). A mild flare recurred 2 weeks later, which was treated with topical steroids only. However, Nivolumab was not resumed. The fourth pt developed G2 elevated TSH approximately 2 months into therapy and after 4 doses of Nivolumab. Thyroid hormone replacement was initiated with subsequent symptom improvement and normalization of TSH over a 4-month period. As a result of these unexpected severe toxicities, the study was closed to further enrollment, and further Nivolumab administration ceased. Thus far, one pt (#1) relapsed after a total remission duration of 530 days; the remission duration after starting Nivolumab was 318 days. One pt has mild chronic skin GVHD. All 4 patients remain alive with a median overall survival of 2.3 years (range, 1.9-4.7). Conclusions:Even at low doses, the use of Nivolumab as maintenance therapy in the post allo-SCT setting was not tolerable at the current dosing and schedule due to an unexpected number of high grade irAEs. Additional studies of dose and timing after allo-SCT are needed to improve safety and tolerability, in conjunction with correlative studies to better understand the immunomodulatory processes in the post-transplant setting. Disclosures Kline: Merck: Honoraria; Merck: Research Funding. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Artz:Miltenyi: Research Funding. Larson:Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials; Celgene: Consultancy. Riedell:Novartis: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Speakers Bureau; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau. Bishop:CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Juno: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Liu:Arog: Other: PI of clinical trial; BMS: Research Funding; Agios: Honoraria; Novartis: Other: PI of clinical trial; Karyopharm: Research Funding. OffLabel Disclosure: Nivolumab used as maintenance therapy in the post-transplant setting

Long Term Treatment and Prevention Of Recurrent VTE In Cancer Patients: Results Of The Canadian Proact Survey

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5581-5581
Author(s):  
Normand Blais ◽  
Charles A. Butts ◽  
Mark A. Crowther ◽  
Nanette Cox-Kennett ◽  
Josée Martineau
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Research Funding ◽  
Term Treatment ◽  
Advisory Committees ◽  
Extended Treatment ◽  
Treatment And Prevention ◽  
Long Term Treatment ◽  
Recurrent Vte

Abstract Introduction Cancer associated thrombosis (CAT) is the second leading cause of death in cancer patients after death from cancer. Despite multiple available guidelines for CAT management, there remains variability in treatment practices. In order to gain insight on this variability in Canada, a survey was conducted to identify the perceived importance of managing CAT, identify differences in the pharmacological management of CAT, highlight the main barriers to optimal extended treatment and prevention of recurrent venous thromboembolism (VTE), outline challenges associated with long term treatment adherence, and identify predictors of patient non-adherence. Methods A survey was designed targeting physicians involved in the management of CAT. The questionnaire included queries on physician practice, 37 items related to beliefs and attitudes about extended treatment for prevention of recurrence of VTE, and a 30-item patient-specific profile. Results Responses were obtained from 21 professionals from four Canadian provinces (Nova Scotia, Quebec, Ontario, and Alberta); 76% were hematologists and/or oncologists, 14% were internists and 10% were pharmacists. Community and academic centers were well represented. Specific management profiles were obtained for 131 patients. Most care givers felt that VTE recurrence was an important issue deserving extended therapy for most patients. Although more than 90% believed bleeding and recurrent VTE risk should influence the length of treatment, only 62% believe that VTE recurrence risk should modify the type of treatment and 52% were concerned of the risk of bleeding with long term therapy (≥6 months). 71% of respondents believed patients’ lack of awareness of the risk of recurrent VTE reduces adherence to anticoagulant therapy for extended treatment of VTE. Although 100% of respondents detailed giving verbal patient counseling, only 19% provided written information to patients. 95% stated they assessed compliance verbally; less than 20% used more objective measures (pharmacy records, laboratory monitoring). Participants admitted to using results of clinical trials (95%) more than clinical guidelines (48%) as most felt that the published guidelines contained conflicting recommendations. The main drivers of treatment choice were clinical evidence, efficacy, and personal experience. No respondents indicated they preferred to use oral anticoagulants for extended therapy of CAT and 43% believed that LMWHs should not be used interchangeably. Most (95%) stated they follow-up with patients directly to reassess therapy after 3-6 months of treatment. The patient profile information showed the median age of patients was 62 years and 60% were female. Lung cancer, colon cancer, breast cancer, and lymphoma were the most common tumor sites and accounted for 50% of described cases. Cases of deep vein thrombosis (DVT) and pulmonary embolism (PE) were evenly represented and 82% were symptomatic. Most events were temporally related to cancer therapy (69%), presence of a central venous catheter (18%), and recent surgery (17%). Less than 5% of these cases presented with a contraindication to anticoagulation therapy (severe thrombocytopenia, active bleeding) at CAT diagnosis. Most patients were treated in the outpatient setting. Nonetheless, hospitalization was required in 33% of cases with an average patient stay of 10.8 days. Hospitalized patients were preferentially treated with LMWH (84%) and usually stayed on the same regimen upon discharge (8.3 ± 6.4 months). Long term treatment was largely managed with LMWHs (most frequently dalteparin – 80% of all treated patients) while few were managed with vitamin K antagonists (6%) or novel direct antithrombotics (2%). Anticoagulant therapy for outpatients was prescribed for 9.0 ± 7.7 months after the most recent VTE episode. Conclusion In Canada, CAT is believed to be an important complication of cancer. Extended therapy is indicated for most patients with CAT.  Although bleeding risk is perceived as an important reason to modify therapy, contraindications to LMWHs were rare in the reported cases. Uptake of outpatient therapy of CAT is widespread in this country, yet hospitalization is still frequently required at diagnosis and is associated with prolonged inpatient stays. Even if non-adherence to antithrombotic therapy was believed to be rare among patients with CAT, this was rarely rigorously monitored. Disclosures: Blais: Pfizer: Consultancy; Sanofi: Consultancy; Leo: Consultancy. Butts:Pfizer: Consultancy, Honoraria, Speakers Bureau. 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. Cox-Kennett:Pfizer: honorarium as a speaker Other. Martineau:Pfizer: honorarium as a speaker Other; Boehringer: honorarium as a speaker, honorarium as a speaker Other; Bayer: honorarium as a speaker, honorarium as a speaker Other; Sanofi: honorarium as a speaker and participated in clinical trial, honorarium as a speaker and participated in clinical trial Other; BMS: honorarium as a speaker Other.

Anti-Myeloma Activity of a Novel Free Radical Inducer Rrx-001

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4712-4712 ◽  
Author(s):  
Deepika Sharma Das ◽  
Ze Tian ◽  
Arghya Ray ◽  
Durgadevi Ravillah ◽  
Yan Song ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Clinical Trial ◽  
Drug Resistance ◽  
Board Of Directors ◽  
Tumor Cells ◽  
Cell Lines ◽  
Advisory Committees ◽  
Healthy Donors

Abstract Background and Rationale: Multiple Myeloma (MM) remains incurable despite the advent of novel drugs, highlighting the need for further identification of factors mediating disease progression and resistance. The bone marrow (BM) microenvironment confers growth, survival, and drug resistance in MM cells. Studies to date suggest an important role of BM hypoxia (low oxygenation) in MM cell survival, drug resistance, migration, and metastasis. Therapies targeting the MM cell in its BM milieu under hypoxic conditions may therefore achieve responses in patients resistant to various therapies. Recent studies led to the development of a novel aerospace-industry derived Phase 2 molecule RRx-001 with epigenetic and NO-donating properties. RRx-001 generates reactive oxygen and nitrogen species (RONS), which induces oxidative stress in tumor cells. Importantly, RRx-001 is also a potent vascular disrupting agent, which further provides rationale for utilizing RRx-001 as a therapeutic agent since tumor-associated angiogenesis is a characteristic of MM. A Phase I clinical trial has shown RRx-001 to have antitumor activity in heavily pretreated cancer patients and to be safe and well tolerated with no dose-limiting toxicities (Reid et al. J Clin Oncol 32:5s, 2014 suppl; abstr 2578). Here we examined the anti-MM activity of RRx-001 using in vitro and in vivo models of MM. Materials and methods: MM cell lines, patient MM cells, and peripheral blood mononuclear cells (PBMCs) from normal healthy donors were utilized to assess the anti-MM activity of RRx-001 alone or in combination with other agents. Drug sensitivity, cell viability, apoptosis, and migration assays were performed using WST, MTT, Annexin V staining, and transwell Inserts, respectively. Synergistic/additive anti-MM activity was assessed by isobologram analysisusing “CalcuSyn” software program. Signal transduction pathways were evaluated using immunoblotting. ROS release, nitric oxide generation, and mitochondrial membrane potential was measured as previously described (Chauhan et al., Blood, 2004, 104:2458). In vitro angiogenesis was assessed using matrigel capillary-like tube structure formation assays. DNMT1 activity was measured in protein lysates using EpiQuik DNMT1 assay kit. 5-methyl cytosine levels were analyzed in gDNA samples using methylflash methylated DNA quantification kit from Enzo life sciences; USA. For xenograft mouse model, CB-17 SCID-mice were subcutaneously inoculated with MM.1S cells as previously described (Chauhan et al., Blood, 2010, 115:834). Statistical significance of data was determined using a Student’st test. RRx-001 was obtained from RadioRx Inc., CA, USA; bortezomib, SAHA, and pomalidomide were purchased from Selleck chemicals, USA. Results: Treatment of MM cell lines (MM.1S, MM.1R, RPMI-8226, OPM2, H929, Dox-40 ARP-1, KMS-11, ANBL6.WT, ANBL6.BR, and LR5) and primary patient cells for 24h significantly decreased their viability (IC50 range 1.25nM to 2.5nM) (p < 0.001; n=3) without markedly affecting PBMCs from normal healthy donors, suggesting specific anti-MM activity and a favorable therapeutic index for RRx-001. Tumor cells from 3 of 5 patients were obtained from patients whose disease was progressing while on bortezomib, dexamethasone, and lenalidomide therapies. Moreover, RRx-001 inhibits proliferation of MM cells even in the presence of BM stromal cells. Mechanistic studies show that RRx-001-triggered apoptosis is associated with 1) induction of DNA damage response signaling via ATM/p53/gH2AX axis; 2) activation of caspases mediating both intrinsic and extrinsic apoptotic pathways; 3) increase in oxidative stress through release of ROS and generation of NO; and 4) decrease in DNA methyltransferase (DNMT1) enzymatic activity and global methylation levels. Furthermore, RRx-001 blocked migration of MM cells and angiogenesis. In vivo studies using subcutaneous human MM xenograft models show that RRx-001 is well tolerated and inhibits tumor growth. Finally, combining RRx-001 with bortezomib, SAHA, or pomalidomide induces synergistic anti-MM activity and overcomes drug resistance. Conclusion: Our preclinical studies showing efficacy of RRx-001 in MM disease models provide the framework for clinical trial of RRx-001, either alone or in combination, to improve outcome in relapsed and refractory MM patients. Disclosures Richardson: Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Oronsky:RadioRx Inc, : Employment. Scicinski:RadioRx Inc,: Employment. Chauhan:Triphase Accelerator: Consultancy. Anderson:Celgene: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Gilead: Consultancy; Sanofi Aventis: Consultancy; BMS: Consultancy; Oncopep/Acetylon: Equity Ownership.

Multiple Myeloma (MM): Impact of Immunoglobulin Isotype on the Speed of Response

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4191-4191 ◽  
Author(s):  
Helene Caillon ◽  
Michel Attal ◽  
Philippe Moreau ◽  
Thomas Dejoie
Keyword(s):  
Clinical Trial ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Advisory Committees ◽  
Speed Of Response ◽  
Measurable Disease ◽  
Multiple Myelomas ◽  
The Impact ◽  
Monoclonal Components

Abstract Background: Detection and/or measurement of monoclonal components by serum protein electrophoresis (SPE) is essential for evaluation of response in multiple myeloma according to the International Myeloma Working Group (IMWG) criteria. Patient peak on SPE has a single presentation due to the extreme heterogeneity of monoclonal components based on isotype of immunoglobulin (Ig), charge, polymerization, viscosity, precipitation … Regarding the Ig isotype, distribution of myelomas has been known for a long time with about 55 % of IgG myelomas, 25 % of IgA myelomas, and 15% of light chain multiple myelomas (LCMM). Therefore differences in terms of various physical and chemical characteristics are observed according to isotype such as half-lives (IgG : 7-21 days ; IgA : 6 days ; only a few hours for light chains of Ig). Considering both differences about frequency and clearance according to Ig isotype, we addressed the question of the impact of isotype on the speed of response in multiple myeloma. Objective: The aim of this study was to assess if the different isotypes of monoclonal components involved in multiple myeloma have an impact on the velocity and the depth of response. Design and methods: Data from two recent clinical trials conducted by IFM were analysed. The first analysis was based on patients enrolled in the IFM DFCI 2009 clinical trial who benefited of each of the three MRD points planned in this trial (after induction and autograft for one arm, pre-maintenance and post-maintenance). Patients were categorized on the isotype of the monoclonal component involved : IgG, IgA or IgD intact immunoglobulin multiple myelomas (IIMM) with serum measurable disease according to IMWG criteria (i.e. serum monoclonal peak ≥ 10 g/L), LCMM, and IIMM without any serum measurable disease (i.e. serum monoclonal peak < 10 g/L).The percentage of patients who achieved at least a very good partial response (VGPR) was evaluated globally as well as for each category defined. The same analysis was carried out for the IFM 2013-04 clinical trial with one response assessment, after four induction cycles. Results: Concerning IFM DFCI 2009 trial, 398 patients evaluated on the three MRD points could be included in this analysis, divided into 185 and 213 in each arm of treatment. Within the total enrolment, two types of response kinetics could be distinguished : for IgA, IgD IIMM, IIMM without serum measurable disease and LCMM, the gain of response between post-induction +/- autograft and post-maintenance is on average 11,1 points (6,7 - 15) when IgG myelomas presented a difference of VGPR percentage of 27,9 points. The same observation could be made for each arm of treatment : 16,6 and 5,8 points of VGPR percentage gained in each arm for the "faster response" group as defined previously, whereas 33,3 and 23,3 points were gained for IgG myelomas. Apart from this difference of kinetics, we notably observed that IgG myelomas never reached VGPR rates obtained with other isotype myelomas. About IFM 2013-04 trial, 264 patients could be evaluated in our analysis after four cycles of VTD (131) or VCD (133) for induction. 98,0% of IgA myelomas achieved at least VGPR after induction (96,3% for VTD arm and 100% for VCD arm) whereas only 50,6% for IgG myelomas (57,3% and 43,2%) and 68,3% for LCMM (46,7% for VTD arm and 80,8 for VCD arm). Conclusion: This study shows that time of evaluation is a key factor regarding the different speed of response for each isotype of Ig. IgA myelomas and LCMM have a faster response than IgG myelomas. IgG myelomas have a lower biochemical response than other isotype myelomas. Consequently, for an accurate interpretation of data in clinical trials, patients should be equally distributed in each arm of treatment according to their isotype. Ideally, to be compared, clinical trials should always have the same isotype distribution, especially when an early evaluation is performed such as after induction. Disclosures Attal: jansen: Honoraria; celgene: Membership on an entity's Board of Directors or advisory committees. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees.

Ultra-Deep Targeted Sequencing Does Not Identify MM Patients with Different Prognosis: Results from a Randomized Phase II Clinical Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2078-2078
Author(s):  
Yanira Ruiz-Heredia ◽  
Joaquín Martínez-López ◽  
Jose Carlos Martínez-Ávila ◽  
Beatriz Sanchez-Vega ◽  
Inmaculada Rapado ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Allele Frequency ◽  
Plasma Cells ◽  
Read Depth ◽  
Cox Proportional Hazard Model ◽  
Proportional Hazard ◽  
Proportional Hazard Model ◽  
Advisory Committees ◽  
Cox Proportional Hazard

Abstract Next-generation sequencing (NGS) has revealed new insight into the complexity of clonal and subclonal architecture of multiple myeloma (MM). The introduction of targeted studies allows the detection of mutations with very low allele frequencies at affordable price. However, there is few information about the prognostic impact of this mutational profile in series of homogeneously treated MM patients. In this study, we analyzed the most frequently mutated genes in MM from patients included in a randomized clinical trial applying the highest read depth to date. We performed a correlation study between our results and cytogenetics aberrations and clinical outcomes. We used Ampliseq Library Kit 2.0 to target 77 genes (M3Pv2.0 panel) related to critical pathophysiological pathways, associated to drug resistance or targetable with molecular drugs in MM. We sequenced DNA (15ng) from CD138+ purified plasma cells from 80 MM patients at diagnosis included in GEM2010MAS65 clinical trial. We sequenced at an average read depth of 1500X and using Ion Proton sequencer (Thermo Fisher, USA, PaloAlto, CA). We used Ion Reporter software applying in-house modifications in call variants process. We also sequenced DNA from CD138 negative population in 30% of patients in order to filter out potential artifacts and stablish conditions for excluding germline variants. We first fitted a cox-proportional hazard model to predict survival and a second approach using a penalized regression LASSO. We identified 137 gene mutations in the 80 patients analyzed, 54 mutations were predicted pathogenic by Shif and Poliphen and 65 have been described in COSMIC database. 85% of patients harbored at least 1 mutation. The most frequently mutated genes were KRAS (16%), DIS3 (15%), NRAS (13%), BRAF (6%), and TP53 (5%), accounting for the 54% of the total number of mutations. The most frequently mutated pathways were RAS and NFKB in 34% and 28% of patients respectively. Mutational allele frequency for KRAS, BRAF and TP53 was, in all cases, lower than 50% while DIS3 showed mutations in a broad range (from 2 to 85%). Only one patient presented one mutation in NRAS at 73 % of allele frequency. For patients with more than one mutation, two different scenarios have been found. Some patients showed several genes mutated in a similar allele frequency values. On the contrary, a complex subclonal structure was confirmed in 3 patients, with mutations at very different clonal frequency. CD138 negative fraction was sequenced to confirm that these mutations were exclusive of plasma cells. The first of them had two mutations in DIS3 at 8 and 53% of allele frequency, second in KRAS and DIS3 at 13 and 63% respectively and the third in NRAS and IFNGR2 at 5 and 37% respectively. We found no differences in the survival based on pathway, mutational allele frequency or number of mutations. We also investigated pairwise associations between events and we not found significant correlations (Figure 1). Cox-proportional hazard model only showed a negative impact in survival of patients with TP53 mutations. This ultra-deep targeted sequencing strategy is able to detect mutations in most of patients, at very low allele frequency and using a minimal amount of DNA. Despite of its huge capacity to detect mutations, we have not identified new prognostic factors in MM patients treated with highly efficient therapies. However, this study again confirms the complexity of the genomic landscape of MM and the great heterogeneity between patients. The role of theses mutations at relapse as well as in the subsequent treatment effectiveness remains unknown and should be preferably investigated in larger cohorts of homogeneously treated MM patients. Figure 1 Figure 1. Disclosures Martínez-López: Novartis: Honoraria, Speakers Bureau. Oriol:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:celgene: Consultancy.

A Phase I Study of Selinexor in Combination with Daunorubicin and Cytarabine in Patients with Newly Diagnosed Poor-Risk Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4040-4040 ◽  
Author(s):  
Kendra L. Sweet ◽  
Rami S. Komrokji ◽  
Eric Padron ◽  
Christopher L Cubitt ◽  
Leyla Khavarian ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Febrile Neutropenia ◽  
Phase I ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Poor Risk

Abstract Background: Induction chemotherapy for older adults with poor-risk AML has remained largely unchanged over the past 40 years, with complete remission (CR) rates ranging from 20-50%. Five-year overall survival (OS) ranges from 2-15%, illustrating the need for novel treatment strategies. Selinexor is an oral selective inhibitor of nuclear export (SINE) that has shown promising single agent activity in AML (NCT01607892). By inhibiting the primary export protein, XPO1, selinexor localizes tumor suppressor proteins to the nucleus leading to their activation. Furthermore, selinexor inhibits DNA damage repair, rationalizing its use in combination with DNA damaging agents. Preclinical data from our institution suggest Selinexor synergizes with daunorubicin when used in CD34+ AML cells. Here we report early results from a phase I clinical trial with selinexor plus cytarabine and daunorubicin in patients (pts) with newly diagnosed, poor-risk AML. Methods: This is a single institution phase I clinical trial with a 3+3 design and an expansion phase at the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). The primary endpoint was to determine the MTD/RP2D of selinexor. Secondary endpoints included rate of CR/CRi, overall survival (OS), relapse free survival (RFS) and toxicity assessment. Eligible pts had a diagnosis of previously untreated AML (non-M3), with poor-risk features based on karyotype, mutational profile, secondary AML (sAML) arising from an antecedent hematologic disorder (AHD) or prior chemotherapy, or age ≥60 years. Prior treatment for an AHD was allowed. Induction included daunorubicin 60 mg/m2/day on days 1-3 and cytarabine 100 mg/m2/day CIVI days 1-7 (7+3) with two dose cohorts of selinexor: 60 mg and 80 mg PO. Selinexor was given on days 1, 3, 8, 10, 15 and 17. Re-induction with 5+2 plus selinexor was allowed if indicated. Once in CR, pts received 1-2 cycles of consolidation with 5+2 plus selinexor followed by maintenance selinexor on days 1 and 8 of a 21 day cycle for up 12 months. Selinexor was given at the same dose for all phases of the study. Pts could proceed to hematopoietic stem cell transplant (HCT) at any time after achieving CR. Results: 21 pts (14 (67%) M / 7 (33%) F) were enrolled from June 2015 to June 2016. Median age was 68 years (range 37-77); 18 (86%) were age ≥60 and 9 (43%) were age ≥70. Nineteen (90%) pts were considered poor-risk (unrelated to age), and two (10%) were eligible due to age ≥60 only. Each cohort enrolled 4 pts, and 13 pts were enrolled in the expansion. One pt in each cohort was replaced before completing the 28-day DLT period; one withdrew consent and the second died on day 23 from acute renal failure related to antibiotics. At data cutoff, 18 pts were included in the safety and efficacy assessment. Three additional patients have not completed induction. The early death rate (≤60 days) was 4.8%. No DLTs occurred in the dose-escalation cohorts. The MTD of selinexor was not reached and the RP2D was 80 mg twice weekly. The most common grade 3/4 non-hematologic, treatment emergent AEs in all pts were febrile neutropenia (56%), diarrhea (22%), hyponatremia (22%) and sepsis (17%). Nine patients (50%) achieved CR/CRi. Of the 14 pts treated at the RP2D (selinexor 80 mg), 6 (43%) achieved CR/CRi. In the entire cohort, the median age of the responders was 69 (61-77) and 4 (44%) were age ≥70. Seven (78%) were considered high-risk. Four (44%) had sAML. Two (22%) required a second induction. The median time to response was 47 days (range 28-77) At a median follow up of 8.7 months in the 9 responding pts, 7 (78%) remain in remission. Overall, 4 pts (44%) underwent HCT, and 1 (11%) relapsed just prior to HCT. Conclusion: Results from this phase I trial suggest that selinexor 80mg PO twice weekly can be safely administered in combination with induction chemotherapy using cytarabine and daunorubicin to pts with poor-risk AML, including older pts. The most prominent AEs were febrile neutropenia, diarrhea and hyponatremia. Response rates are encouraging and many elderly pts proceeded to transplant, suggesting this regimen warrants further investigation in this challenging population. Disclosures Sweet: Karyopharm: Honoraria, Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Pfizer: Speakers Bureau. Komrokji:Novartis: Consultancy, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sullivan:Karyopharm: Research Funding. Shah:Incyte: Research Funding; Rosetta Genomics: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; Bayer: Honoraria; Pfizer: Honoraria.

A Phase 1/2 Study of the Second Generation Selective Inhibitor of Nuclear Export (SINE) Compound, KPT-8602, in Patients with Relapsed Refractory Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4509-4509 ◽  
Author(s):  
R. Frank Cornell ◽  
Adriana C Rossi ◽  
Rachid Baz ◽  
Craig C Hofmeister ◽  
Chaim Shustik ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Nuclear Export ◽  
Research Funding ◽  
Low Dose ◽  
Phase 1 ◽  
Single Agent ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction - Inhibition of Exportin 1 (XPO1) is a novel treatment approach for multiple myeloma (MM). XPO1 mediates the nuclear export of cell-cycle regulators and tumor suppressor proteins leading to their functional inactivation. In addition, XPO1 promotes the export and translation of the mRNA of key oncoproteins (e.g. c-MYC, BCL-2, Cyclin D). XPO1 overexpression occurs in solid and hematological malignancies, including MM and is essential for MM cell survival. Selinexor, the first oral SINE compound, has shown promising anti-MM activity in phase 1 studies but has been associated with gastrointestinal and constitutional toxicities including nausea, anorexia and fatigue. KPT-8602 is a second generation oral SINE compound with similar in vitro potency to selinexor, however, has substantially reduced brain penetration compared with selinexor, and demonstrated markedly improved tolerability with minimal anorexia and weight loss in preclinical toxicology studies. In murine models of MM, KPT-8602 can be dosed daily (QDx5) with minimal anorexia and weight loss. We have therefore initiated a phase 1/2 first-in-human clinical trial. Methods - This phase 1/2 clinical trial was designed to evaluate KPT-8602 as a single agent and in combination with low dose dexamethasone (dex) in patients (pts) with relapsed / refractory MM (RRMM). KPT-8602 is dosed orally (QDx5) for a 28-day cycle with a starting dose of 5 mg. Low dose dex (20 mg, twice weekly) is allowed after cycle 1 if at least a minimal response (MR) is not observed. The primary objective is to evaluate the safety and tolerability including dose-limiting toxicity (DLT), determine the maximum tolerated dose (MTD), the recommended Phase 2 dose (RP2D), and evidence for anti-MM activity for KPT-8602 single agent and in combination with dex. The pharmacokinetic (PK) and pharmacodynamic (PDn; XPO1 mRNA) profile of KPT-8602 will also be determined. PDn predictive biomarker analysis and ex vivo drug response assays are underway using tumor cells from bone marrow aspirates before treatment, during and at relapse. These analyses include cell death pathway assays by flow and nuclear/cytoplasmic localization of XPO1, NF-ƙB, IƙBα, IKKα, NRIF and p53 by imaging flow and IHC. Results - As of 01-Aug-2016, 6 pts 2 M/4 F, (median of 6 prior treatment regimens, median age of 71) with RRMM have been enrolled. Common related grade 1/2 adverse events (AEs) include thrombocytopenia (3 pts), nausea (2 pts) and diarrhea (2 pts). Grade 3 AEs include neutropenia (1 pt) and dehydration (1 pt). No grade 4 or 5 AEs have been reported. No DLTs have been observed and the MTD has not been reached. 5 pts were evaluable for responses (1 pt pending evaluation): 1 partial response, 1 minimal response, and 3 stable disease; no pts have progressed on therapy with the longest on for >5 months. The PK properties following oral administration showed that 5 mg of KPT-8602 was rapidly absorbed (mean tmax= 1 hr, mean Cmax= 30.6 ng/mL). The mean AUCinf was calculated to be 141 ng•hr/mL. After tmax, KPT-8602 declined at an estimated mean t½ of 4 hr. At the same dose level, XPO1 mRNA expression was the highest (~2.5 fold) at 8 hr post dose. Conclusions - Oral KPT-8602 is well tolerated in heavily pretreated pts with RRMM. Gastrointestinal and constitutional toxicities observed with twice weekly selinexor have not been observed with 5x/week KPT-8602, including in pts on study for >4 months. PK was predictable and in line with selinexor. These early results show encouraging disease control with pts remaining on therapy. Enrollment is on-going. Disclosures Rossi: Takeda: Speakers Bureau; Janssen: Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Baz:Takeda/Millennium: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Signal Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Novartis: Research Funding. Hofmeister:Karyopharm Therapeutics: Research Funding; Arno Therapeutics, Inc.: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees. Shustik:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: 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; Amgen: 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. Richter:Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Jannsen: Speakers Bureau. Chen:Janssen: Honoraria, Research Funding; Takeda: Research Funding; Celgene: Honoraria, Research Funding. Vogl:Takeda: Consultancy, Research Funding; Celgene: Consultancy; GSK: Research Funding; Calithera: Research Funding; Teva: Consultancy; Karyopharm: Consultancy; Acetylon: Research Funding; Constellation: Research Funding. Shacham:Karyopharm Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Baloglu:Karyopharm Therapeutics: Employment, Equity Ownership. Senapedis:Karyopharm Therapeutics: Employment, Equity Ownership. Ellis:Karyopharm Therapeutics: Employment, Equity Ownership. Friedlander:Karyopharm Therapeutics: Employment. Choe-Juliak:Karyopharm Therapeutics: Employment. Sullivan:Karyopharm Therapeutics: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Major Bleeding Complications Among Patients Treated with Ibrutinib and Concomitant Antiplatelet, Anticoagulant, or Supplemental Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4387-4387 ◽  
Author(s):  
Aaron Pavlik ◽  
Hallie Barr ◽  
Emily Dotson ◽  
John C. Byrd ◽  
Kristie A. Blum ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Major Bleeding ◽  
Research Funding ◽  
Bleeding Event ◽  
Antiplatelet Agents ◽  
Bleeding Complications ◽  
Bleeding Events ◽  
Advisory Committees ◽  
Major Bleeding Events

Abstract Background: Ibrutinib, an orally bioavailable small molecular inhibitor of Bruton's tyrosine kinase (BTK), is an approved therapy for chronic lymphocytic leukemia (CLL), relapsed mantle cell lymphoma (MCL) and Waldenstrӧm's macroglobulinemia (WM). Beyond B lymphocytes, BTK signaling is important for collagen-mediated platelet activation, and BTK inhibition has been associated with primary hemostatic bleeding events (Levade et al Blood 2014). Although serious bleeding events have been uncommon (1-5%) in clinical trial populations, there is limited data describing the potential for increased serious bleeding incidence when ibrutinib is co-administered with other agents affecting the clotting cascade or platelet function. Methods: We conducted a retrospective cohort study to evaluate the incidence of major bleeding in patients receiving ibrutinib concomitantly with antiplatelet agents (non-steroidal anti-inflammatory agents, ADP inhibitors), anticoagulants (heparins, warfarin, novel oral anticoagulants), or supplements with potential anticoagulant activity (vitamin E and fish oil). Major bleeding events were identified using criteria developed by the International Society on Thrombosis and Haemostasis (Schulman et al J Thromb Haemost 2005). Patients 18-89 years of age and treated with ibrutinib for CLL, MCL, or WM between March 1, 2010 and March 1, 2015 were included. The primary endpoint of this study was the incidence of major bleeding events, but we also sought to identify risk factors associated with the development of major bleeding, focusing on potential drug interactions. Based on the historic prevalence of major bleeding in ibrutinib clinical studies, we calculated that at least 20 major bleeding events would need to be identified in order to perform blinded multinomial regression on the collected data of an estimated 400 patients. Results: 437 eligible patients were included in the analysis. Patients were overwhelmingly male (71.4%) and white (94.8%), with a mean age of 67.1 years (range: 29-89). 53.1% received ibrutinib as participants of a clinical trial, and the remainder received standard-of-care ibrutinib treatment. The table (upper panel) summarizes use of concomitant antihemostatic agents by presence or absence of major bleeding events. Characteristics of the major bleeding events are further detailed in the lower panel. The most commonly observed concomitant antihemostatic medication was aspirin, with 147 patients (33.6%) being exposed to aspirin within the study period. Fourteen instances of major bleeding were observed, corresponding to an overall incidence of 3.2%. These major bleeding events all occurred in CLL patients receiving ibrutinib at the standard dose of 420 mg daily. Two patients had platelet counts less than 50 k/µL at time of the bleeding event. One-half of the major bleeding events were observed in the absence of an antihemostatic medication, and 2 of the observed major bleeding events resulted in death (1 received concomitant warfarin). Fourteen patients (3.3%) in the group without major bleeding were on anticoagulation, 4 being warfarin. The most common sites of major bleeding were gastrointestinal (50%), intracranial (14.3%) and thoracic (14.3%). While most patients developing major bleeding permanently discontinued ibrutinib (57.1%), approximately one third of the patients who developed major bleeding subsequently resumed ibrutinib following resolution of the bleeding event. Subsequently, these patients did not experience a recurrent major bleeding event. The rate of major bleeding did not meet power to detect statistical differences in bleeding events when comparing concomitant therapy, Conclusions: Our observed incidence of major bleeding is consistent with previous controlled clinical trials, suggesting similar safety profile when ibrutinib is used outside of a controlled setting. Major bleeding events were uncommon despite the frequent co-administration of antiplatelet agents. However, because we modified practice early to avoid therapeutic anticoagulation during ibrutinib therapy whenever possible, the number of patients receiving such drugs in combination was small and precludes inferences regarding safety. Table Table. Disclosures Blum: Pharmacyclics: Research Funding. Awan:Innate Pharma: Research Funding; Pharmacyclics: Consultancy; Novartis Oncology: Consultancy. Woyach:Acerta: Research Funding; Karyopharm: Research Funding; Morphosys: Research Funding. Christian:Pharmacyclics: Research Funding; Janssen: Research Funding. Jones:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Identification of Qualitative Platelet Disorders in Adolescent Women with Heavy Menstrual Bleeding

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4922-4922
Author(s):  
Kristina M. Haley ◽  
Susan Lattimore ◽  
Cara McDavitt ◽  
Ayesha Khader ◽  
Colin Boehnlein ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Board Of Directors ◽  
Platelet Function ◽  
Research Funding ◽  
Blood Platelet ◽  
Bleeding Disorder ◽  
Advisory Committees ◽  
Adolescent Women ◽  
Platelet Disorder ◽  
Platelet Function Assays

Abstract Introduction: Nearly 40% of adolescent women experience heavy menstrual bleeding (HMB), and identifiable bleeding disorders are diagnosed in only 20-60% of these patients. We suspect that qualitative platelet disorders contribute to HMB, but are under-diagnosed. A pilot study was conducted to evaluate platelet function in adolescent women with HMB employing four novel, small-volume, whole blood platelet function assays. In addition, primary and secondary hemostasis, bleeding phenotype, and quality of life were assessed. Methods: Patients referred to the Young Women's Hematology Clinic at Oregon Health & Science University for evaluation of HMB were offered participation in the study. Participants underwent standard review of their medical and family history and physical exam. Standard lab evaluation included CBC, PT, PTT, fibrinogen, thrombin time, Von Willebrand Panel, PFA-100, and iron studies with platelet aggregation or phenotyping performed if clinically indicated. Using less than 0.5 mL of whole blood, platelet function was assessed with four novel platelet function assays: assessment of platelet activation, secretion, and aggregation was assessed by flow cytometry analysis, while platelet adhesion and aggregation was assessed under shear in a capillary tube. Quality of life (QOL) was assessed using the PedsQL tool. Bleeding phenotype was assessed with the ISTH Bleeding Assessment Tool (ISTH BAT). Menorrhagia was assessed with the Pictorial Bleeding Assessment Chart (PBAC), the Philipp Tool and the clinical history. Results: Nine participants have enrolled on study to date, with 2 completing the 3-month visit. The median age of the cohort was 16 years (14-18 years). Eight out of nine categorized their period as heavy, 6 also had epistaxis, and 7 reported excessive bruising. The median ISTH BAT score was 4 (3-7). Of the 7 patients who had a Philipp Score obtained, 5 were positive. Median PBAC score was 161 (64-196). Median ferritin was 13 ng/mL (4-65 ng/mL). Median QOL psychosocial score was 70 (68.36-88.25), comparable to that of pediatric patients with cancer. Of the 9 participants, 6 had platelet aggregation and phenotyping. Four participants did not receive a bleeding disorder diagnosis, 1 was diagnosed with Type 1 VWD, 1 was diagnosed with bleeding disorder, NOS, and 1 was diagnosed with Ehlers Danlos Syndrome. Two participants were diagnosed with a qualitative platelet disorder (QPD): one based on platelet aggregation and one based on thromboelastography. The four novel platelet function assays confirmed platelet function abnormalities in the participants diagnosed with QPD's (Figure 1&2). Impaired platelet response to agonist stimulation was also observed in participants with non-platelet disorder bleeding disorder diagnoses and in participants without a bleeding disorder diagnosis. Conclusions: In this pilot study, the etiology of HMB in adolescent women was evaluated with four novel platelet assays in addition to standard assays of hemostasis. A bleeding disorder diagnosis was not made with standard evaluations in 4 out of 9 participants. The novel assays detected platelet abnormalities not observed using currently available clinical labs, and confirmed the presence of abnormal platelet function in participants with abnormal platelet function testing. These assays require significantly less blood volume than currently available assays and expand investigation of platelet function to platelet adhesion and platelet interactions in whole and flowing blood. Further work is needed to determine the sensitivity and specificity of the novel assays in detecting platelet dysfunction. Continued investigation into the impact of HMB on the adolescent female population is needed. Disclosures Haley: CSL Behring: Honoraria; Baxalta: Membership on an entity's Board of Directors or advisory committees. Recht:Biogen: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Biogen: Research Funding; Genentech: Research Funding; Novo Nordisk: Research Funding; Baxalta: Research Funding; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Sickle-Cell Disease in Greece: Patient Reported Outcomes Related to Clinical Complications, Treatment Choices and Attitudes, Beliefs and Trends Affecting Potential Participation in Clinical Trials - a Greek National Multicentric Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4838-4838
Author(s):  
Sophia Delicou ◽  
Michael D. Diamantidis ◽  
Konstantinos Manganas ◽  
Eftychios Eftychiadis ◽  
Despoina Pantelidou ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Educational Status ◽  
Current Treatment ◽  
Advisory Committees ◽  
Chi Square ◽  
Clinical Complications

Background: Sickle cell disease (SCD) is an autosomal recessive disorder caused by a point mutation in the β-globin chain of hemoglobin that forms hemoglobin S. It is clinically characterized by complicated episodes of veno-occlusive crises (VOC), emergency room (ER) visits and uncomplicated inpatient admissions. Aim: We investigated the clinical complications and treatment choices of a large cohort of Greek SCD patients, representative of the whole country. Most importantly, this study aimed to assess patients' attitudes and beliefs regarding their enrollment in clinical trials testing new drugs. We examined the factors influencing such a participation. Patients and Methods: A total of 254 patients from 10 Thalassemia and Sickle Cell Departments across Greece (110 men/144 women), aged 18 - over 65, 210 (82.7%) with β-thalassemia/sickle cell trait and 44 (17.3%) with homozygous SCD participated in the study. The participants had variable educational and socioeconomic background. They all answered an anonymous self-report questionnaire during their medical evaluations between November 2018 and May 2019, including their demographic and clinical characteristics, their current treatment and their opinion regarding a possible participation in a clinical trial for SCD. Descriptive statistical analysis using calculated scale variables and Chi-square test were performed. Results: All participants completed the survey. During the previous year, 64 patients (25.3%) had no admissions for VOC, 128 (50.6%) had 1-5, whereas 21 (8.3%) had 5-10 and 40 (15.8%) more than 10. Except for acute pain crises, the most frequent complications were chronic pain (59%), liver/spleen dysfunction (32.4%), infectious episodes (29.5%), iron overload (23.8%) and pulmonary hypertension (20.1%). In addition to hematological care, patients seeked medical attention from expert physicians for disease complications; 77.6% of the patients reported that they yearly visited a cardiologist, 42.4% an ophthalmologist, 31.9% an orthopedic, 28.4% a pneumonologist, 28.9% a hepatologist, 12.6% an urologist, 14% a nephrologist, 11.9% an infectious disease doctor, 10.1% a pain management specialist and 8.1% a neurologist. The therapeutic approaches included daily folic acid supplementation (86.1%), vaccines (68.3%), hydroxyurea (66.3%), antibiotics (57.1%), simple pain moderators (52.4%), opioids (48.8%) and iron chelators (30.2%). Previous experience in clinical trials was reported by only 17 patients (6.9%). Regarding the patients' attitudes towards a probable clinical trial, 41.3% were positive to try new therapies, 28.3% negative and 30.4% neutral. 67.2% were satisfied with their current treatment, without excluding a potential participation in clinical trials; such treatment satisfaction correlated significantly with older age, lower income and secondary hemochromatosis under chelation treatment (p<0.05). 40% reported that they had been waiting for years for a new treatment, but 43.2% strongly denied becoming an experimental mouse model, whereas 47.3% mentioned that they would trust their doctors' advice correlating positively with male gender and higher income (p<0.05). Lower educational status, prior intake of hydroxyurea and residence/origin in the capital in contrast to the countryside (chi-square, p<0.05) significantly correlated with a potential clinical trial participation. Internet and television information motivated patients to seek more details from their doctor. Concerning the factors rated as the most important for a potential participation in a clinical trial, 7 out of 10 patients of our cohort considered of utmost equal importance the effectiveness of a probable treatment and the relative toxicity. Conclusions: Most SCD patients have chronic complications and visit specialized physicians. Since the participation of larger number of patients in clinical trials is essential for the application of novel drugs, the most important factors of our cohort are the effectiveness of a probable treatment and the relative toxicity, along with the trust to the doctor. These factors are crucial, influencing patients' decision. Even though a proportion of our patients remain skeptical towards clinical trials, an increasing number is willing to participate, which correlates positively with residence in the capital, lower educational status and prior intake of hydroxyurea. Disclosures Kattamis: Apopharma: Honoraria; Vertex: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ionis: Membership on an entity's Board of Directors or advisory committees; ViFOR: Membership on an entity's Board of Directors or advisory committees; Novartis Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Symeonidis:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: 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, Research Funding; Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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