Diagnosis and Management of Paget-Schroetter Syndrome in Children: An Institutional Experience

Abstract Background: Paget-Schroetter Syndrome (PSS), also known as venous thoracic outlet syndrome or effort-induced upper extremity deep vein thrombosis, is a rare condition that occurs secondary to impingement of the subclavian vein by the overlying cervical ribs, long transverse processes of the cervical spine, musculo-fascial bands, or clavicular or first rib abnormalities. PSS often affects otherwise healthy and athletic individuals with a history of repetitive overhead activities. Given the paucity of published pediatric data, making evidence-based recommendations on appropriate therapeutic strategies is challenging. Objective: The principal objective of this single-institution study was to review the presentation, management, and outcomes of pediatric patients treated for PSS at Nationwide Children's Hospital (NCH) over a six-year period (January 1, 2010 to December 31, 2016). Methods: The study was approved by the Institutional Review Board at NCH. The Electronic Data Warehouse was used to identify patients diagnosed with PSS during the 6-year study period using modified ICD-9-CM codes. Eligible subjects were defined as children under the age of 21 who presented with an unprovoked upper extremity deep vein thrombosis (DVT) and had evidence of compression of the subclavian vein at the level on the thoracic outlet on dynamic imaging. Baseline demographic data, diagnostic and therapeutic details, and available follow-up information was abstracted from patient charts. Eligible subjects were also mailed a previously validated pediatric post-thrombotic syndrome (PTS) self-report instrument and a self-report health-related quality of life (HRQoL) instrument (PedsQL 4.0). All data were summarized and presented using descriptive statistics. Comparisons were made using nonparametric statistical methods. Results: The study cohort consisted of 21 subjects (11 female). Median age at DVT diagnosis was 16.3 (range 13.7-18.2) years. Subjects presented to NCH a median of 2 (range 0-34) days after symptom onset. Eighteen subjects (86%) reported repetitive exercise or overuse activity prior to diagnosis. Twelve subjects (57%) had evidence of congenital/acquired thrombophilia (Table 1). All subjects were treated with anticoagulation for a median duration of 3.2 (range 1.4-8.6) months. Nine subjects (43%) were also treated with catheter-directed and/or pharmaco-mechanical thrombolysis, and six of these subjects additionally underwent balloon angioplasty. All 21 subjects underwent decompressive surgery (first or cervical rib resection) a median of 7.7 (range 2-63.2) weeks after symptom onset. Four subjects (19%) experienced surgical complications, including minor bleeding/hematoma formation (3), pneumothorax (3), and winged scapula (1). Only 2/14 subjects diagnosed before 2014 underwent thrombolytic therapy, whereas all (7/7) subjects diagnosed after 2014 underwent thrombolysis. The subjects who did not undergo thrombolysis were not significantly different from those who did, except for the presence of a thrombophilia (p=0.02). Of the twelve subjects who did not undergo thrombolysis, eleven (92%) had complete/partial resolution of their DVT and one (8%) had no resolution on most recent imaging. Of the nine subjects who received thrombolysis, 100% had complete/partial resolution of their DVT on most recent imaging. We are currently analyzing data on PTS and HRQoL. Discussion: Herein, we report one of the largest pediatric cohorts of PSS. All subjects received anticoagulation and underwent decompressive surgery. Additionally, 9/21 subjects underwent catheter-directed and/or pharmaco-mechanical thrombolysis. 20/21 subjects had complete/partial resolution of the DVT on most recent imaging. Our single-institution study suggests that high rates of thrombus resolution may be achieved in children with PSS with anticoagulation and decompressive surgery, with or without thrombolytic therapy. Larger, prospective studies are needed to confirm our findings and further examine the relationship between treatment and outcomes. Disclosures O'Brien: Bristol Myers Squibb: Other: study of direct oral anticoagulant in prevention of pediatric VTE, Research Funding; Glaxo Smith Kline: Other: DSMB for Arixtra Study in Pediatric VTE; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: advisory board - von Willebrand Disease diagnosis & management; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: advisory board - VWD diagnosis and management; Pfizer: Consultancy, Other: study of direct oral anticoagulant in treatment of pediatric VTE. Kumar: CSL Behring: Consultancy; Bayer: Consultancy.

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Optimal Timing for Removal of an Upper Extremity Central Catheter When Associated with a Deep Vein Thrombosis: A Venous Thromboembolism Network US Multicenter Retrospective Cohort Study

Blood ◽

10.1182/blood-2019-124139 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 325-325

Author(s):

Damon E. Houghton ◽

Henny Heisler H. Billett ◽

Manila Gaddh ◽

Oluwatomiloba Onadeko ◽

Gemlyn George ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Board Of Directors ◽

Upper Extremity ◽

Catheter Removal ◽

Pulmonary Emboli ◽

Continuous Variables ◽

Advisory Committees ◽

No Removal ◽

Vein Thrombosis ◽

Deep Vein

Background: Standard treatment for catheter-associated upper extremity deep vein thrombosis (UEDVT) is anticoagulation. If catheter removal is otherwise indicated, it is unknown if catheter removal close to the time of initiation of anticoagulation is associated with a higher incidence of pulmonary embolization. Methods: A multicenter retrospective cohort study was performed at 8 participating institutions through the Venous thromboEmbolism Network US (VENUS). ICD-9/10 codes were used to identify patients with hematologic malignancies and upper extremity deep vein thrombosis (UEDVT) from 1/1/2010 through 12/31/2016. Identified patients underwent medical record review to verify diagnostic codes and determine if a catheter was associated with the upper extremity DVT and assess for outcomes. Patients were excluded if the UEDVT was not catheter provoked or if there were associated lower extremity DVT and/or pulmonary emboli. The anticoagulant start and finish date as well as the timing of the catheter removal, total follow up, and death were recorded. Patients started on anticoagulation at the time of their diagnosis were divided into two groups: 1) anticoagulation with delayed (> 48 hrs) or no catheter removal and 2) anticoagulation with early catheter removal (< 48 hrs). Outcomes were also assessed in patients with no anticoagulation initiation but catheter removal as the only treatment. The primary outcome was clinically identified pulmonary emboli within 7 days and the secondary outcome was pulmonary emboli or death from any cause within 7 days. Baseline characteristics were compared between groups using Χ2 for categorical variables, 2-tailed t-tests for continuous variables, and Wilcoxon rank-sum for nonparametric continuous variables. Fisher's exact test was used to evaluate the primary and secondary outcomes. Results: 663 patients with hematologic malignancies and isolated catheter-associated UEDVT underwent chart review. 512 patients were treated with anticoagulation of which 312 underwent early catheter removal while 200 had delayed or no catheter removal (Figure 1). 151 patients received no anticoagulation and 119 underwent catheter removal alone as the treatment for the DVT. Among patients who were treated with anticoagulation, the mean age was 52.6 years and 44% were male; age and sex did not differ between patients with early vs. delayed or no catheter removal (Table 1). Type of hematologic malignancy, type of central catheter, and DVT location were significantly different between groups. Patients with PICC lines were more likely to have early catheter removal (71% vs. 49%). The median platelet count was not significantly different among patients treated with anticoagulation, but was lower in patients treated with catheter removal only. Most patients were initially treated with low molecular weight heparins (LMWH) and anticoagulation treatment did not differ between groups. Pulmonary emboli within 7 days occurred in 2 patients (0.64%) with early catheter removal compared to 1 patient (0.5%) with delayed or no removal (p=1.0). Pulmonary emboli or any cause death within 7 days occurred in 3 patients (1.0%) with early removal compared to 3 patients (1.5%) with delayed or no removal (p=0.68). In patients treated with catheter removal only (no anticoagulation), there were no pulmonary emboli within 7 days and 3 deaths. All 3 patients with pulmonary emboli within 7 days had PICC lines and leukemia/MDS and the sites of most proximal DVT involvement were brachiocephalic veins (2 patients) and subclavian vein (1 patient). Conclusions: In patients with hematological malignancy and catheter-associated UEDVT, removal of catheters within 48 hours was not associated with increased risk of pulmonary emboli compared to delayed or no removal. Disclosures Billett: Albert Einstein College of Medicine: Patents & Royalties: Patent application pending for NETs AI software. Gaddh:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Hema Biologics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC: Membership on an entity's Board of Directors or advisory committees. Oo:Medical Education Speakers Network: Honoraria; Janssen and Janssen: Other: Research: site co-investigator . Jaglal:NOVARTIS: Consultancy. Streiff:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Portola: Consultancy, Honoraria; Roche: Research Funding. Baumann Kreuziger:Vaccine Injury Compensation Program: Consultancy; CSL Behring: Consultancy.

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MASS-FIX for the Diagnosis of Plasma Cell Disorders: A Single Institution Experience of 4118 Patients

Blood ◽

10.1182/blood-2020-138829 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 48-49

Author(s):

Patrick Mellors ◽

Surendra Dasari ◽

Mindy Kohlhagen ◽

Bonnie Kaye Arendt ◽

Morie A. Gertz ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Light Chain ◽

Mayo Clinic ◽

Research Funding ◽

Advisory Board ◽

Single Institution ◽

Advisory Committees ◽

Monoclonal Protein ◽

Monoclonal Proteins

Introduction: Since 2018, immunoenrichment-based matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), termed MASS-FIX, has replaced immunofixation for the detection and isotyping of serum monoclonal proteins at Mayo Clinic. MASS-FIX has advantages including increased sensitivity, specificity, and the ability to distinguish therapeutic monoclonal antibodies. Herein, we report the laboratory characteristics and distribution of diagnoses of patients tested clinically at Mayo Clinic. Methods: MASS-FIX was performed on patient samples as previously described (Kohlhagen et. al. Clin Chem Lab 2020). Demographics and laboratory data, including quantitative M-spike, serum free light chains (FLC), and quantitative immunoglobulins at the time of MASS-FIX were recorded. For patients with multiple samples during the study period, only the initial MASS-FIX was evaluated. We identified 9195 unique patients with MASS-FIX performed between 7/24/2018 and 3/6/2020. Seven-thousand nine hundred and forty-six patients provided consent for study enrollment, and 7689 had data available on index diagnosis. Given considerable variability in the interpretation of diagnostic criteria for light chain (LC) MGUS, patients with this diagnosis (1360, 18%) were excluded. Patients were considered to have negative results (2211 in total) on MASS-FIX if: 1) no monoclonal protein was identified (1081, 49%); 2) the interpretation was "cannot rule out monoclonal protein" (945, 43%); 3) multiple, nonspecific spectral peaks were identified consistent with immune reconstitution (29, 1%); or 4) the only monoclonal protein identified was consistent with a therapeutic monoclonal antibody (156, 7%). Results: The final cohort consisted of 4118 patients with a positive MASS-FIX and 2211 patients with a negative MASS-FIX, all in the setting of underlying PCDs. Figure 1 illustrates the numbers and percentages of patients who are MASS-FIX positive versus MASS-FIX negative by diagnosis. MGUS and multiple myeloma (MM) were the most common diagnoses overall, and both were more common in the MASS-FIX positive cohort. More than 90% of patients with Waldenstrom's macroglobulinemia (WM), smoldering WM, smoldering MM, and cold agglutinin disease were positive by MASS-FIX. For MASS-FIX positive patients, IgG isotype was identified in 2575 patients (63%), IgA in 703 (17%) and IgM in 710 (17%). Bence Jones proteinemia was identified in 283 patients (7%) with lambda restriction being the most common (57%). 3625 patients (88%) had a monoclonal pattern, 228 patients (6%) had a bi-clonal pattern, and 7 (<1%) had a tri-clonal pattern. The majority of patients (58%) were kappa LC restricted by MASS-FIX, 222 (5%) had N-glycosylated LC, and 2 patients (<1%) had a heavy chain with no light chain. Conclusions: This single institution experience illustrates the practicality of MASS-FIX in detecting and following monoclonal proteins for a wide range of PCDs in a tertiary center. In this cohort, the percentage of patients who were MASS-FIX positive varied by diagnosis, reflecting cross sectional sampling of patients throughout their disease course. Disclosures Gertz: Research to Practice: Other; Springer Publishing: Patents & Royalties; Aurora Bio: Other; Johnson and Johnson: Speakers Bureau; Sanofi: Other; Amgen: Other: personal fee; Appellis: Other: personal fee; Annexon: Other: personal fee; Spectrum: Other: personal fee, Research Funding; Janssen: Other: personal fee; Prothena: Other: personal fee; Alnylam: Other: personal fee; Ionis/Akcea: Other: personal fee; Proclara: Other; DAVA oncology: Speakers Bureau; Celgene: Other; Teva: Speakers Bureau; Abbvie: Other; Physicians Education Resource: Other: personal fee; Medscape: Other: personal fee, Speakers Bureau. Kumar:AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Carsgen: Other, Research Funding; Karyopharm: Consultancy; Merck: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Genecentrix: Consultancy; Adaptive Biotechnologies: Consultancy; Novartis: Research Funding; MedImmune: Research Funding; Sanofi: Research Funding; Tenebio: Other, Research Funding; Cellectar: Other; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments. Kapoor:Sanofi: Consultancy, Research Funding; Amgen: Research Funding; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Cellectar: Consultancy; Janssen: Research Funding; Celgene: Honoraria. Dingli:Karyopharm Therapeutics: Research Funding; Bristol Myers Squibb: Research Funding; Rigel: Consultancy; Alexion: Consultancy; Sanofi-Genzyme: Consultancy; Janssen: Consultancy; Apellis: Consultancy; Millenium: Consultancy. Lin:Merck: Research Funding; Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Gamida Cells: Consultancy; Takeda: Research Funding; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vineti: Consultancy. Murray:The Binding Site: Patents & Royalties: Patent Use of Mass Spec to identify monoclonal proteins licensed to The Binding Site. Dispenzieri:Alnylam, Intellia, Janssen, Takeda, Pfizer, Prothena, Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Prognostic Factors for Developing Thrombosis in Polycytemia Vera: A Retrospective Analysis of 331 Patients with Long-Term Follow-up Highlights the Importance of White Blood Cells Levels

Blood ◽

10.1182/blood-2020-139431 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 48-49

Author(s):

Samantha Ferrari ◽

Chiara Pagani ◽

Mariella D'Adda ◽

Nicola Bianchetti ◽

Annamaria Pelizzari ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

High Risk ◽

Board Of Directors ◽

Advisory Board ◽

Advisory Committees ◽

Risk Status ◽

History Of ◽

Wbc Count

Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm characterized by erythrocytosis, constitutively active mutations in JAK2 and an increased susceptibility to thrombotic events (TEs). There is still controversy about the role of increased hematocrit and of other variables including elevated white blood cell count as risk factors for the occurrence of TEs. A better definition of the relative prognostic importance of hematologic parameters would help us to better tailor the therapeutic approach to PV patients (pts), which is currently mainly based on the use of acetilsalycilic acid (ASA), venesection and hydroxyurea . The aim of our study was to analyze if any clinical or laboratory variables were significantly associated to the occurrence of TEs both at PV diagnosis and during the course of the disease in a large series of PV pts uniformly followed at a single Center over a period of 29.5 years from January 1986 to June 2019. Clinical and laboratory data were obtained from the time of diagnosis until death, progression to acute leukemia or last follow-up. Hematocrit (Hct), hemoglobin (Hb), white blood cell (WBC) and platelet (PLT) levels were recorded for each patient at least every 6 months. Among a total of 331 pts, the median age was 65 years (range 30-92 years), and 56% were male. "High risk" features (age ≥ 60 years and/or history of prior thrombosis) were present in 221 pts (66.7%). The incidence of cardiovascular risk factors was: hypertension 64%, diabetes 15%, hyperlipidemia 28%, history of active or remote smoking 41%. Patients on ASA were 279 (84%), 19 (6%) were on oral anticoagulation, while 27 (8%) were on ASA+oral anticoagulant. At PV diagnosis 54 pts (16%) presented with thrombosis, arterial in 32 (59%) and venous in 22 (41%). A previous TE was recorded in 57 pts (17%): in 43 (75%) arterial, in 12 (22%) venous and in 2 (3%) mixed (arterial+venous). Previous thrombosis was the only variable significantly associated with the presence of a TE at PV diagnosis (P=0.02). After PV diagnosis, with a median follow-up of 81 months (range 1-374 months), 63 pts (19%) experienced a TE and 11 of them a further episode, for a total of 74 TEs. The incidence rate (pts/year) of TEs was 2.7%. Forty-two events were arterial (57%), 31 were venous (42%) and 1 (1%) was mixed. It was the first TE for 37 pts. Cerebrovascular accidents and deep-venous thrombosis were the most frequent arterial and venous TEs both at PV diagnosis and throughout the disease course, with a relative incidence of 50% and 32% respectively. The table compares the characteristics of patients who did or did not develop a TE after PV diagnosis. At univariate analysis, PV high risk status, a previous TE and hyperlipidemia at PV diagnosis were significantly associated with a subsequent TE. Among hematologic variables an elevated WBC count at the time of thrombosis, but not Hct or PLT levels, was highly significantly associated with the development of a TE. At multivariate analysis, WBC count ≥10.4 x 10^9/L and hyperlipidemia maintained their independent prognostic value, while high risk status and a previous TE lost their prognostic significance. Both at univariate and multivariate analysis, hyperlipidemia at diagnosis (P=0.009 and P=0.002) and high WBC count at thrombosis (P=0.001 and P=<0.0001) predicted for arterial thromboses, while only a history of prior thrombosis (P=0.03) predicted for venous ones. In conclusion, our analysis confirms that elevated WBC count at the moment of the event more than increased hematocrit is associated to the development of thrombosis in PV pts. We also found that hyperlipidemia was an independent risk factor for arterial thrombosis, calling for an accurate management of increased lipid levels. Whether a reduction of the WBC count during the course of PV may reduce the frequency of TE remains to be demonstrated by prospective studies. Table Disclosures D'Adda: Novartis: Other: Advisory board; Incyte: Other: Advisory board; Pfizer: Other: Advisory board. Rossi:Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Alexion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study: A Perioperative Management Plan for Patients with Atrial Fibrillation Who Are Receiving a Direct Oral Anticoagulant

Blood ◽

10.1182/blood-2018-120770 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. LBA-5-LBA-5 ◽

Cited By ~ 2

Author(s):

James Douketis ◽

Alex C. Spyropoulos ◽

Joanne M Duncan ◽

Marc Carrier ◽

Gregoire Le Gal ◽

...

Keyword(s):

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Perioperative Management ◽

Elective Surgery ◽

Bleeding Risk ◽

Advisory Board ◽

Advisory Committees ◽

Arterial Thromboembolism ◽

High Bleeding Risk

Abstract Introduction: The perioperative management of patients who are taking a direct oral anticoagulant (DOAC) for atrial fibrillation (AF) and require an elective surgery/procedure is uncertain. No studies have addressed the timing of perioperative DOAC interruption and resumption, and if perioperative heparin bridging and coagulation function testing are needed. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) Study hypothesized that a simple, standardized perioperative management strategy, based on DOAC-specific interruption and resumption intervals, that foregoes perioperative heparin bridging and coagulation function testing, is safe for patient care, with associated low rates of major bleeding (1%) and arterial thromboembolism (0.5%). We postulated that this management yields a high proportion of patients (>90%) with a minimal to no DOAC level at surgery/procedure. Methods: PAUSE is a prospective study with 3 parallel DOAC cohorts of patients with AF taking apixaban, dabigatran or rivaroxaban and requiring anticoagulant interruption for an elective surgery/procedure. Patients were managed using a standardized protocol based on DOAC pharmacokinetic properties, procedure-associated bleeding risk (Appendix 1) and creatinine clearance (CrCl). DOACs were interrupted for 1 day before and after surgery for a low bleed risk surgery and 2 days before and after a high bleed surgery; longer interruption was done in patients on dabigatran with a CrCl<50 mL/min (Figure 1). A blood sample was obtained just before the procedure to measure residual DOAC levels (Appendix 2). Heparin bridging and preoperative coagulation testing were not used to manage patients. Patient follow-up occurred weekly for 30 days post-procedure for the primary clinical outcomes of major bleeding and arterial thromboembolism (Appendix 3). The incidence (95% confidence interval [CI]) of clinical outcomes was determined for each DOAC cohort using an intention-to-treat (ITT) analysis (interrupted at least 1 DOAC dose) and per-protocol analysis (adhering to DOAC interruption and resumption protocol). Results: We enrolled 3007 patients from 23 sites in Canada, the U.S. and Europe (Appendix 4). The patient characteristics were (Figure 2): mean age 72.5 years; 66.1% male; 33.5% high bleeding risk surgery/procedure, with 1257 patients in the apixaban cohort, 668 in the dabigatran cohort and 1082 in the rivaroxaban cohort (Table 1). DOAC interruption and resumption intervals are shown in Table 2. The 30-day postoperative rate (95% CI) of major bleeding was 1.35% (0-2.00) in the apixaban cohort, 0.90% (0-1.73) in the dabigatran cohort and 1.85% (0-2.65) in the rivaroxaban cohort; the rate (95% CI) of arterial thromboembolism was 0.16% (0-0.48) in the apixaban cohort, 0.6% (0-1.33) in the dabigatran cohort and 0.37% (0-0.82) in the rivaroxaban cohort (Table 3). There were 2541 (84.5%) patients with preoperative DOAC levels measured: a level <50 ng/ml occurred in 90.5% of patients in the apixaban cohort, in 95.1% of the dabigatran cohort and in 96.8% of the rivaroxaban cohort. Of 1007 patients having a high bleeding risk procedure, 832 (82.6%) had DOAC levels measured: 98.8% had a level <50 ng/mL (Table 4). Rates of major bleeding and arterial thromboembolism in the per protocol analysis were comparable to those of the ITT analysis (Table 5). Conclusions: In patients with AF who were taking a DOAC (apixaban, dabigatran, rivaroxaban) and required anticoagulant interruption for an elective surgery/procedure, using a standardized DOAC-specific perioperative management strategy was safe for patient care, with associated low rates of perioperative MB (<2%) and ATE (<1%). Further, a high proportion of patients (>90% overall; 98.8% at high bleeding risk) had a minimal or no residual DOAC level at the time of the surgery/procedure. PAUSE is the largest study, to date, that addresses how to manage the common problem of perioperative DOAC management. It is likely to have a practice-changing impact and will inform future practice guidelines in perioperative care. Study Funding: CIHR (313156) and the H&S Foundation of Canada (G-14-0006136). Aniara-Hyphen Biomed (assays). Acknowledgments: We thank Drs. Walter Ageno, David Garcia, Lehana Thabane, Wendt Lim, Lori Linkins, William Ristevski, and Demetrios J. Sahlas. Also, Kayla Lucier, Grace Wang, Tara McDougall, and HRLMP and CRLB. Supported by CanVector and REDCap. Disclosures Douketis: Bayer: Other: Advisory Board; Janssen: Consultancy; BMS: Other: Advisory Board; Biotie: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; The Medicines Company: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Portola: Other: Advisory Board; Pfizer: Other: Advisory Board. Spyropoulos:Janssen Scientific Affairs, LLC: Consultancy. Carrier:Bayer: Honoraria; Leo Pharma: Research Funding; Pfizer: Honoraria; BMS: Honoraria, Research Funding. Vanassche:Bayer: Consultancy; Boehringer Ingelheim: Consultancy; BMS/Pfizer: Consultancy. Verhamme:Bayer: Honoraria, Research Funding; Medtronic: Honoraria; Portola: Honoraria; Boehringer Ingelheim: Honoraria; Leo Pharma: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Shivakumar:Pfizer: Honoraria; Servier: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria. Gross:Pfizer: Honoraria; Bayer: Honoraria; LEO Pharma: Honoraria; Servier: Honoraria. Lee:Pfizer: Consultancy, Research Funding; BMS: Research Funding; Servier: Honoraria; LEO Pharma: Consultancy, Research Funding; Bayer: Consultancy, Honoraria. Le Templier:BMS-pfizer: Honoraria. Wu:Leo Pharma: Honoraria; Pfizer: Honoraria; BMS-Pfizer: Honoraria. Coppens:Bayer: Honoraria, Other: Non-financial support, Research Funding; CSL Behring: Honoraria, Other: non-financial support, Research Funding; Uniqure BV: Research Funding. Arnold:Bristol Myers Squibb: Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding. Caprini:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Recovery Force: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizor: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Membership on an entity's Board of Directors or advisory committees. Summer:Octapharma: Honoraria. Schulman:Daiichi-Sankyo: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Boehringer-Ingelheim: Honoraria, Research Funding.

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Preclinical Evaluation of Gilteritinib on NPM1-ALK Driven Anaplastic Large Cell Lymphoma Cells

Blood ◽

10.1182/blood-2019-130633 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2865-2865

Author(s):

Sudhakiranmayi Kuravi ◽

Janice Cheng ◽

Kishore Polireddy ◽

Gabrielle Fangman ◽

Roy A Jensen ◽

...

Keyword(s):

Tyrosine Kinase ◽

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Large Cell ◽

Advisory Board ◽

Advisory Committees ◽

Apoptotic Protein ◽

Large Cell Lymphoma ◽

Alk Positive

Anaplastic large cell lymphoma (ALCL) is an aggressive type of non-Hodgkin's lymphoma (NHL) comprising 2-8% of adult and 10-20% of pediatric and adolescent NHL. More than three-fourths of anaplastic lymphoma kinase (ALK)-positive ALCL express (nucleophosmin1) NPM1-ALK fusion gene as a result of t(2;5) chromosomal translocation. The self-dimerization of fusion kinase NPM1-ALK mediates constitutive activation of the chimeric tyrosine kinase activity leading to downstream signaling pathways responsible for lymphoma cell proliferation and survival. The current standard treatment regimen for ALK+ ALCL is CHOP (cyclophosphamide, hydroxy doxorubicin, vincristine, prednisone) chemotherapy. Oftentimes, resistance and failure of remission occur with CHOP therapy, making it a suboptimal treatment regimen for many patients. Therefore, an alternative therapeutic approach is warranted to better address the needs of the ALK+ ALCL population. Gilteritinib is a recently FDA approved tyrosine kinase inhibitor for the treatment of FMS-like tyrosine kinase (FLT3) mutation-positive acute myeloid leukemia. Along with inhibition of FLT3, gilteritinib also inhibits other tyrosine kinases such as AXL and ALK. In this study, for the first time, we demonstrated gilteritinib mediated growth inhibitory effects on NPM1-ALK driven ALCL cells. We have used a total of five cell lines in our study: NPM1-ALK endogenously expressing human ALCL cell lines (SUDHL-1, SUP-M2, SR-786, and DEL), and our laboratory generated ectopically overexpressing Ba/F3-FG-NPM1-ALK, a murine cell line. Gilteritinib treatment (5-20 nM) inhibited NPM1-ALK fusion kinase phosphorylation, which resulted in downregulation of downstream survival signaling pathways including AKT, ERK1/2, and STAT3 leading to induced apoptosis and decreased clonogenic survival. Gilteritinib mediated apoptosis was associated with caspase 3/9 and poly (ADP-ribose) polymerase cleavage with increased pro-apoptotic protein BAD and decreased anti-apoptotic protein MCL-1. Increased expression of c-Myc is associated with ALK-positive ALCL and gilteritinib treatment decreased c-Myc levels in a dose dependent manner. Cell cycle analysis demonstrated gilteritinib treatment induced cell cycle arrest at the G0/G1 phase with a concomitant decrease in G2/M and S phases. In summary, our preclinical results suggest gilteritinib has therapeutic potential for the treatment of ALCL cells expressing NPM1-ALK and other ALK /ALK-fusion driven hematologic or solid malignancies. Disclosures Lin: Jazz Pharmaceuticals: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ganguly:Daiichi Sankyo: Research Funding; Seattle Genetics: Speakers Bureau; Janssen: Honoraria, Other: Advisory Board; Kite Pharma: Honoraria, Other: Advisory Board. McGuirk:ArticulateScience LLC: Other: Assistance with manuscript preparation; Juno Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bellicum Pharmaceuticals: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding; Pluristem Ltd: Research Funding; Gamida Cell: Research Funding; Kite Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Multicenter Analysis of Treatment and Outcomes for Patient with TP53 Mutated AML in the Era of Novel Therapies; Significant Impact of Allogeneic Stem Cell Transplantation on Survival

Blood ◽

10.1182/blood-2021-147639 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 797-797

Author(s):

Talha Badar ◽

Mark R. Litzow ◽

Rory M. Shallis ◽

Jan Philipp Bewersdorf ◽

Antoine Saliba ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Advisory Board ◽

Novel Therapies ◽

Advisory Committees ◽

Tp53 Mutations

Abstract Background: TP53 mutations occur in 10-20% of patients with AML, constitute high-risk disease as per ELN criteria, and confer poorer prognosis. Venetoclax combination therapies and CPX-351 were recently approved for AML treatment and lead to improved outcomes in subsets of high-risk AML, however the most effective approach for treatment of TP53-mutated (m) AML remains unclear. In this study we explored the clinical outcome of TP53m AML patients treated over the last 8 years as novel therapies have been introduced to our therapeutic armamentarium. Methods: We conducted a multicenter observational study in collaboration with 4 U.S. academic centers and analyzed clinical characteristics and outcome of 174 TP53m AML patients diagnosed between March 2013 and February 2021. Mutation analysis was performed on bone marrow specimens using 42, 49, 199, or 400 gene targeted next generation sequencing (NGS) panels. Patients with an initial diagnosis of AML were divided into 4 groups (GP) based on the progressive use of novel therapies in clinical trials and their approvals as AML induction therapy during different time periods: 2013-2017 (GP1, n= 37), 2018-2019 (GP2, n= 53), 2019-2020 (GP3, n= 48) and 2020-2021 (GP4, n= 36) to analyze difference in outcome. Results: Baseline characteristics were not significantly different across different GP, as shown in Table 1. Median age of patients was 68 (range [R], 18-83), 65 (R, 29-88), 69 (R, 37-90) and 70 (R, 51-97) years in GP1-4, respectively (p=0.40). The percentage of patients with de novo AML/secondary AML/therapy-related AML in GP1-4 was 40/40/20, 36/29/24, 37.5/37.5/25 and 28/52/20, respectively (p=0.82). The proportion of patients with complex cytogenetics (CG) was 92%, 89%, 96% and 94% in GP1-4, respectively (p=0.54). The median TP53m variant allele frequency (VAF) was 48% (range [R], 5-94), 42% (R, 5-91), 45% (R, 10-94) and 60% (R, 8-82) in GP1-4, respectively (p=0.38). Four (11%), 13 (24.5%), 10 (21%) and 9 (25%) patients had multiple TP53 mutations in GP1-4, respectively (p=0.33). The proportion of patients who received 3+7 (30%, 16%, 6% & 8%; p=0.01), HMA only (11%, 18%, 2% & 8%; p=0.06), venetoclax-based (2.5%, 12%, 48%, & 61%; p <0.01) and CPX-351 induction (16%, 40%, 28% & 5%; p<0.001) were varied in GP1-4, respectively. The rate of CR/CRi was 22%, 26%, 28% and 18% in GP1-4, respectively (p=0.63). Treatment related mortality during induction was observed in 3%, 7%, 10% and 17% of patients in GP1-4, respectively (p=0.18). Overall, 28 (16%) patients received allogeneic hematopoietic stem cell transplantation (alloHCT) after induction/consolidation: 22%, 15%, 17% and 11% in GP1-4, respectively (p=0.67). In subset analysis, there was no difference in the rate of CR/CRi with venetoclax-based regimens vs. others (39% vs 61%, p=0.18) or with CPX-351 vs. others (25% vs 75%, p=0.84). The median progression-free survival was 7.7, 7.0, 5.1 and 6.6 months in GP1-4, respectively (p=0.60, Fig 1A). The median overall survival (OS) was 9.4, 6.1, 4.0 and 8.0 months in GP1-4, respectively (p=0.29, Fig 1B). In univariate analysis for OS, achievement of CR/CRi (p<0.001) and alloHCT in CR1 (p<0.001) associated with favorable outcome, whereas complex CG (p=0.01) and primary refractory disease (p<0.001) associated with poor outcome. Multiple TP53 mutations (p=0.73), concurrent ASXL1m (p=0.86), extra-medullary disease (p=0.92), ≥ 3 non-TP53m mutations (p=0.72), TP53m VAF ≥ 40% vs. < 40% (p=0.25), induction with CPX-351 vs. others (p=0.59) or venetoclax-based regimen vs. others (p=0.14) did not show significance for favorable or poor OS in univariate analysis. In multivariable analysis, alloHCT in CR1 (hazard ratio [HR]=0.28, 95% CI: 0.15-0.53; p=0.001) retained an association with favorable OS and complex CG (HR 4.23, 95%CI: 1.79-10.0; p=0.001) retained an association with dismal OS. Conclusion: We present the largest experience with TP53m AML patients analyzed by NGS. Although outcomes were almost universally dismal, alloHCT appears to improve the long-term survival in a subset of these patients. Effective therapies are warranted to successfully bridge patients to alloHCT and to prolong survival for transplant ineligible patients. Figure 1 Figure 1. Disclosures Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Litzow: Omeros: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Shallis: Curis: Divested equity in a private or publicly-traded company in the past 24 months. Goldberg: Celularity: Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aprea: Research Funding; Arog: Research Funding; DAVA Oncology: Honoraria; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Prelude Therapeutics: Research Funding; Aptose: Consultancy, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah: BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Amgen: Consultancy; Abbvie: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Foran: revolution medicine: Honoraria; gamida: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; takeda: Research Funding; kura: Research Funding; h3bioscience: Research Funding; OncLive: Honoraria; servier: Honoraria; aptose: Research Funding; actinium: Research Funding; abbvie: Research Funding; trillium: Research Funding; sanofi aventis: Honoraria; certara: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding.

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Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Blood ◽

10.1182/blood-2019-123637 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1589-1589

Author(s):

Fabian Frontzek ◽

Marita Ziepert ◽

Maike Nickelsen ◽

Bettina Altmann ◽

Bertram Glass ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

High Dose ◽

Advisory Committees ◽

Scientific Advisory Board ◽

Scientific Advisory

Introduction: The R-MegaCHOEP trial showed that dose-escalation of conventional chemotherapy necessitating autologous stem cell transplantation (ASCT) does not confer a survival benefit for younger patients (pts) with high-risk aggressive B-cell lymphoma in the Rituximab era (Schmitz et al., Lancet Oncology 2012; 13, 1250-1259). To describe efficacy and toxicity over time and document the long-term risks of relapse and secondary malignancy we present the 10-year follow-up of this study. Methods: In the randomized, prospective phase 3 trial R-MegaCHOEP younger pts aged 18-60 years with newly diagnosed, high-risk (aaIPI 2-3) aggressive B-cell lymphoma were assigned to 8 cycles of CHOEP (cyclophosphamide, doxorubcine, vincristine, etoposide, prednisone) or 4 cycles of dose-escalated high-dose therapy (HDT) necessitating repetitive ASCT both combined with Rituximab. Both arms were stratified according to aaIPI, bulky disease, and center. Primary endpoint was event-free survival (EFS). All analyses were calculated for the intention-to-treat population. This follow-up report includes molecular data based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) for MYC (IHC: 31/92 positive [40-100%], FISH: 14/103 positive), BCL2 (IHC: 65/89 positive [50-100%], FISH: 23/111 positive) and BCL6 (IHC: 52/86 positive [30-100%], FISH: 34/110 positive) and data on cell of origin (COO) classification according to the Lymph2CX assay (GCB: 53/88; ABC: 24/88; unclassified: 11/88). Results: 130 pts had been assigned to R-CHOEP and 132 to R-MegaCHOEP. DLBCL was the most common lymphoma subtype (~80%). 73% of pts scored an aaIPI of 2 and 27% an aaIPI of 3. 60% of pts had an initial lymphoma bulk and in 40% more than 1 extranodal site was involved. After a median observation time of 111 months, EFS at 10 years was 57% (95% CI 47-67%) in the R-CHOEP vs. 51% in the R-MegaCHOEP arm (42-61%) (hazard ratio 1.3, 95% CI 0.9-1.8, p=0.228), overall survival (OS) after 10 years was 72% (63-81%) vs. 66% (57-76%) respectively (p=0.249). With regard to molecular characterization, we were unable to detect a significant benefit for HDT/ASCT in any subgroup analyzed. In total, 16% of pts (30 pts) relapsed after having achieved a complete remission (CR). 23% of all relapses (7 pts) showed an indolent histology (follicular lymphoma grade 1-3a) and 6 of these pts survived long-term. In contrast, of 23 pts (77%) relapsing with aggressive DLBCL or unknown histology 18 pts died due to lymphoma or related therapy. The majority of relapses occurred during the first 3 years after randomization (median time: 22 months) while after 5 years we detected relapses only in 5 pts (3% of all 190 pts prior CR). 11% of pts were initially progressive (28 pts) among whom 71% (20 pts) died rapidly due to lymphoma. Interestingly, the remaining 29% (8 pts) showed a long-term survival after salvage therapy (+/- ASCT); only 1 pt received allogeneic transplantation. The frequency of secondary malignancies was very similar in both treatment arms (9% vs. 8%) despite the very high dose of etoposide (total 4g/m2)in the R-MegaCHOEP arm. We observed 2 cases of AML and 1 case of MDS per arm. In total 70 pts (28%) have died: 30 pts due to lymphoma (12%), 22 pts therapy-related (11 pts due to salvage therapy) (9%), 8 pts of secondary neoplasia (3%), 5 pts due to concomitant disease (2%) and 5 pts for unknown reasons. Conclusions: This 10-year long-term follow-up of the R-MegaCHOEP trial confirms the very encouraging outcome of young high-risk pts following conventional chemotherapy with R-CHOEP. High-dose therapy did not improve outcome in any subgroup analysis including molecular high-risk groups. Relapse rate was generally low. Pts with aggressive relapse showed a very poor long-term outcome while pts with indolent histology at relapse survived long-term. Secondary malignancies occurred; however, they were rare with no excess leukemias/MDS following treatment with very high doses of etoposide and other cytotoxic agents. Supported by Deutsche Krebshilfe. Figure Disclosures Nickelsen: Roche Pharma AG: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant; Janssen: Membership on an entity's Board of Directors or advisory committees. Hänel:Amgen: Honoraria; Celgene: Other: advisory board; Novartis: Honoraria; Takeda: Other: advisory board; Roche: Honoraria. Truemper:Nordic Nanovector: Consultancy; Roche: Research Funding; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Takeda: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding. Held:Roche: Consultancy, Other: Travel support, Research Funding; Amgen: Research Funding; Acrotech: Research Funding; MSD: Consultancy; Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding. Dreyling:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: scientific advisory board, Research Funding, Speakers Bureau; Bayer: Consultancy, Other: scientific advisory board, Speakers Bureau; Celgene: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Research Funding; Gilead: Consultancy, Other: scientific advisory board, Speakers Bureau; Novartis: Other: scientific advisory board; Sandoz: Other: scientific advisory board; Janssen: Consultancy, Other: scientific advisory board, Research Funding, Speakers Bureau; Acerta: Other: scientific advisory board. Viardot:Kite/Gilead: 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; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosenwald:MorphoSys: Consultancy. Lenz:Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding; Agios: Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Employment, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy. Schmitz:Novartis: Honoraria; Gilead: Honoraria; Celgene: Equity Ownership; Riemser: Consultancy, Honoraria.

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Identification of Two CAR T-Cell Populations Associated with Complete Response or Progressive Disease in Adult Lymphoma Patients Treated with Axi-Cel

Blood ◽

10.1182/blood-2019-130815 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 779-779 ◽

Cited By ~ 2

Author(s):

Zinaida Good ◽

Jay Y. Spiegel ◽

Bita Sahaf ◽

Meena B. Malipatlolla ◽

Matthew J. Frank ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Advisory Committees ◽

Car T Cells ◽

Scientific Advisory Board ◽

Car T ◽

Scientific Advisory

Axicabtagene ciloleucel (Axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for the treatment of relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). Long-term analysis of the ZUMA-1 phase 1-2 clinical trial showed that ~40% of Axi-cel patients remained progression-free at 2 years (Locke et al., Lancet Oncology 2019). Those patients who achieved a complete response (CR) at 6 months generally remained progression-free long-term. The biological basis for achieving a durable CR in patients receiving Axi-cel remains poorly understood. Here, we sought to identify CAR T-cell intrinsic features associated with CR at 6 months in DLBCL patients receiving commercial Axi-cel at our institution. Using mass cytometry, we assessed expression of 33 surface or intracellular proteins relevant to T-cell function on blood collected before CAR T cell infusion, on day 7 (peak expansion), and on day 21 (late expansion) post-infusion. To identify cell features that distinguish patients with durable CR (n = 11) from those who developed progressive disease (PD, n = 14) by 6 months following Axi-cel infusion, we performed differential abundance analysis of multiparametric protein expression on CAR T cells. This unsupervised analysis identified populations on day 7 associated with persistent CR or PD at 6 months. Using 10-fold cross-validation, we next fitted a least absolute shrinkage and selection operator (lasso) model that identified two clusters of CD4+ CAR T cells on day 7 as potentially predictive of clinical outcome. The first cluster identified by our model was associated with CR at 6 months and had high expression of CD45RO, CD57, PD1, and T-bet transcription factor. Analysis of protein co-expression in this cluster enabled us to define a simple gating scheme based on high expression of CD57 and T-bet, which captured a population of CD4+ CAR T cells on day 7 with greater expansion in patients experiencing a durable CR (mean±s.e.m. CR: 26.13%±2.59%, PD: 10.99%±2.53%, P = 0.0014). In contrast, the second cluster was associated with PD at 6 months and had high expression of CD25, TIGIT, and Helios transcription factor with no CD57. A CD57-negative Helios-positive gate captured a population of CD4+ CAR T cells was enriched on day 7 in patients who experienced progression (CR: 9.75%±2.70%, PD: 20.93%±3.70%, P = 0.016). Co-expression of CD4, CD25, and Helios on these CAR T cells highlights their similarity to regulatory T cells, which could provide a basis for their detrimental effects. In this exploratory analysis of 25 patients treated with Axi-cel, we identified two populations of CD4+ CAR T cells on day 7 that were highly associated with clinical outcome at 6 months. Ongoing analyses are underway to fully characterize this dataset, to explore the biological activity of the populations identified, and to assess the presence of other populations that may be associated with CAR-T expansion or neurotoxicity. This work demonstrates how multidimensional correlative studies can enhance our understanding of CAR T-cell biology and uncover populations associated with clinical outcome in CAR T cell therapies. This work was supported by the Parker Institute for Cancer Immunotherapy. Figure Disclosures Muffly: Pfizer: Consultancy; Adaptive: Research Funding; KITE: Consultancy. Miklos:Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; AlloGene: Membership on an entity's Board of Directors or advisory committees; Precision Bioscience: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotech: Membership on an entity's Board of Directors or advisory committees; Becton Dickinson: Research Funding; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees. Mackall:Vor: Other: Scientific Advisory Board; Roche: Other: Scientific Advisory Board; Adaptimmune LLC: Other: Scientific Advisory Board; Glaxo-Smith-Kline: Other: Scientific Advisory Board; Allogene: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Obsidian: Research Funding; Lyell: Consultancy, Equity Ownership, Other: Founder, Research Funding; Nektar: Other: Scientific Advisory Board; PACT: Other: Scientific Advisory Board; Bryologyx: Other: Scientific Advisory Board.

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Sickle Stroke Screen: A Patient-Centered Educational Initiative for Children with Sickle Cell Anemia in the Displace Consortium

Blood ◽

10.1182/blood-2020-141963 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 43-44

Author(s):

Alyssa M Schlenz ◽

Shannon Phillips ◽

Martina Mueller ◽

Cathy L Melvin ◽

Robert J Adams ◽

...

Keyword(s):

Needs Assessment ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Stroke Prevention ◽

Stroke Risk ◽

Advisory Board ◽

Educational Initiative ◽

Advisory Committees ◽

Board Membership

Introduction: The NHLBI funded Dissemination and Implementation of Stroke Prevention Looking at the Care Environment (DISPLACE) study was designed to improve implementation of stroke prevention guidelines in children with sickle cell anemia (SCA), particularly implementation of transcranial Doppler (TCD) ultrasound for identifying individuals at risk of stroke. The study consists of 3 phases: 1) evaluating current stroke risk screening practices, 2) exploring barriers and facilitators to guideline implementation (needs assessment), and 3) designing and implementing interventions to improve stroke risk screening. A key barrier identified through qualitative methods during the needs assessment was a gap in education, including an overall lack of understanding among patients and caregivers of the purpose of TCD screening. This abstract describes the process of developing one of the interventions for phase 3, a rebranding and educational initiative. Methods: During the needs assessment, 27 key informant interviews and 173 complete surveys were conducted with individuals with SCA and their caregivers. Transcripts from the interviews and survey responses were reviewed to better understand the extent of educational gaps described by families as well as to guide initial rebranding prototypes. Prototypes were developed by the study team, including a new name and logo for TCD as well as an infographic. An interview guide was then created to obtain feedback on the prototypes from individuals with SCA and/or the parent or primary caregiver from two sites in the consortium. Cue cards with prototypes were included with prompts for the "think aloud" method to be applied during interviews. Cue cards were presented first with prototypes for the new name in black font on a white background to solicit feedback on the wording alone. Then, cue cards included various layouts, fonts, and graphics with the prototype names for in-depth feedback on the logo appearance. Finally, participants were asked questions pertaining to the infographic. Results: Twenty interviews were conducted with individuals with SCA and/or the parent/caregiver at two DISPLACE sites. Almost all participants (95%) made the connection between the wording prototypes and TCD without prompting. Many participants expressed that the word "stroke" in both options was "scary," and sometimes chose the option that was "less scary to them." However, many participants also felt that the word "stroke" was necessary to explain the reason for the procedure and would prompt families to ask about the screening as opposed to making them more fearful. The majority of participants (60%) chose "Sickle Stroke Screen" over "Stroke Risk Screen." Participants reported preferring this wording because it is specific to SCA, was easier to remember and represented a less "scary" option. The most commonly preferred logo is presented in Figure 1. Participant reasons for selecting this option were: it is easier to read; they preferred the stacked layout; it is less spread out; they liked the bold letters; it is more eye catching; and it includes the words "sickle cell" in the logo. When asked about preferences for an infographic, the majority described including a picture of a brain. Nearly all participants believed a reassuring message was needed to balance out the fear of the word "stroke." The message, "knowledge is power" provided this balance and resonated with nearly all participants (95%). Figure 2 presents the infographic developed based on participant feedback. Conclusions: Results from this educational rebranding effort highlight the importance of understanding patient and family educational gaps and incorporating their perspective and feedback into educational campaigns. The new logo and infographic were integrated into an educational pamphlet, informative posters and other material designed by the DISPLACE site principal investigators. Part 3 of the study is underway including implementation of the educational initiative at the DISPLACE sites. The new terminology and logo have also been broadly distributed throughout the US through community-based organizations to other patients, families, and stakeholders. Disclosures Kanter: AGIOS: Membership on an entity's Board of Directors or advisory committees; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; Wells Fargo: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; GLG: Honoraria; BEAM: Membership on an entity's Board of Directors or advisory committees.

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Clonal Tracking By Whole Genome Sequencing Permits Comprehensive Mapping of the Genomic Landscape in Pre- and Post-Gene Therapy Sickle Cell Patients

Blood ◽

10.1182/blood-2021-152262 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 559-559

Author(s):

Alyssa H. Cull ◽

Michael Spencer Chapman ◽

Marioara Ciuculescu ◽

Emily Mitchell ◽

Myriam Armant ◽

...

Keyword(s):

Gene Therapy ◽

Stem Cell ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Phylogenetic Trees ◽

Insertion Site ◽

Advisory Board ◽

Advisory Committees ◽

Genomic Landscape

Abstract Recent advances in clonal stem cell tracking strategies have enabled interrogation of unperturbed human hematopoiesis. Whole genome sequencing (WGS) can be used to map the clonal dynamics of hematopoietic stem and progenitor cells (HSPCs) by employing spontaneous somatic mutations as unique clonal tags (Lee-Six et al., Nature, 2018). These tags allow for retrospective analysis of individual stem cell clones and the construction of phylogenetic trees mapping out stem cell relatedness, with mutations being acquired in a near-linear fashion over the course of an individual's life. The unprecedented level of information obtained in these studies is particularly well-suited to understanding genomic changes in gene therapy trials aimed at curing diseases such as sickle cell disease (SCD). In addition to mapping relatedness between stem cells, sequencing data can be used to better define mutational signatures for HSPC clones that have been successfully gene-modified as well as those that lack an integrated copy of the therapeutic vector. Given this method's ability to identify low frequency mutations in individual HSPC clones, mutations with extremely low variant allele frequencies can be detected much more readily than through traditional bulk sequencing approaches, something that is particularly relevant given recent safety concerns in some SCD gene therapy trials. In this study, we have mapped the clonal dynamics of HSPCs obtained from pre- and post-gene therapy samples from 4 SCD patients who have undergone autologous gene therapy performed using a BCL11A shmiR lentivirus vector (NCT 03282656, 12-36 months follow-up). HSPCs from mobilized peripheral blood (pre-gene therapy), bone marrow aspirates (both pre- and post-gene therapy) or unmobilized peripheral blood (post-gene therapy) were expanded as single clones and 1508 individual colonies were then sequenced using WGS to an average sequencing depth of 12.3x. Initial results indicate that the mean mutation burden per cell in a pre-gene therapy sample is elevated for some patients compared to what would be expected based on patient age in similar studies. In pre-gene therapy samples, the structure of the phylogenetic trees appeared to be highly polyclonal, indicating that there were no significant clonal expansion events prior to gene therapy. In one patient where we undertook extensive profiling, approximately 15-20 excess mutations per HSPC were observed across the entire genome 24 months after transplantation, presumably acquired as a consequence of gene therapy and/or reconstitution post-transplantation, which is equivalent to approximately one year of normal ageing without a transplantation intervention. However, no clonal expansions or driver mutations were identified at this 24 month follow-up timepoint, suggesting that no strong selective advantage or pre-leukemic events were present prior to or following the gene therapy protocol. Extending this approach to a wider range and larger number of patients will allow for comprehensive mapping of the genomic landscape and clonal evolution of stem cells in sickle cell patients and will also set the stage for improved assessment of safety and potential leukemia-initiating events in the context of gene therapy. Disclosures Esrick: bluebird bio: Consultancy. Williams: bluebird bio: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Analysis Advisory Board, Patents & Royalties: BCH licensed certain IP relevant to hemoglobinopathies to bluebird bio. The current license includes the potential for future royalty/milestone income. Bluebird has indicated they will not pursue this as a clinical program and BCH is negotiating return of, Research Funding; BioMarin: Membership on an entity's Board of Directors or advisory committees, Other: Insertion Site Advisory Board; Beam Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Emerging Therapy Solutions: Membership on an entity's Board of Directors or advisory committees, Other: Chief Scientific Chair; Geneception: Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; Alerion Biosciences: Other: Co-founder (now licensed to Avro Bio, potential for future milestones/royalties); Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee, Novartis ETB115E2201 (eltrombopag in aplastic anemia). Advisory fees donated to NAPAAC.; Orchard Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other: Membership on a safety advisory board (SAB): SAB position ended 05/20/2021. Co-founder , Patents & Royalties: Potential for future royalty/milestone income, X-SCID. Provided GMP vector for clinical trial, Research Funding. Campbell: Mu Genomics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Kent: STRM.bio: Research Funding.

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