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

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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Unfractionated Heparin Use in Children: Clinical Outcomes in a Pediatric Cohort Managed Using an Anti-Factor Xa Based Nomogram

Blood ◽

10.1182/blood.v130.suppl_1.701.701 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 701-701

Author(s):

Surbhi Saini ◽

Katherine L Harsh ◽

Joseph R Stanek ◽

Sarah O'Brien ◽

Amy L. Dunn ◽

...

Keyword(s):

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Bleeding Risk ◽

Advisory Board ◽

Minor Bleeding ◽

Direct Oral Anticoagulant ◽

Bleeding Events ◽

Advisory Committees ◽

Educational Grant

Abstract Background: Given its short half-life and immediate, complete reversibility with protamine sulfate, unfractionated heparin (UFH) remains the anticoagulant of choice for critically-ill children. The American College of Chest Physicians recommends that a therapeutic activated partial thromboplastin time (APTT) range in children on treatment doses of UFH should reflect an anti-FXa level of 0.35-0.7 IU/mL. A previous study from our institution showed moderate correlation between APTT and anti-FXa, prompting an institution-wide change to an anti-FXa based nomogram. Per the new nomogram, APTT and anti-FXa levels were simultaneously collected at pre-specified time points, though dose titrations were made on anti-FXa levels alone. In this study, we present our 20-month experience using this nomogram. Objectives: To assess the utility of anti-FXa based UFH dosing guidelines in children over a 20-month period (September 2015-May 2017). Methods: Permission for this study was obtained from the Institutional Review Board. Data was abstracted for all pediatric patients (age<21 yrs.) receiving therapeutic dosing of UFH (≥18 u/kg/hr) at Nationwide Children's Hospital (NCH) over the study period. Patients receiving UFH for <24 hrs, patients with mechanical circuits (ECMO and ventricular assist devices), and patients receiving concomitant anti-platelet therapy were excluded. Data were analyzed using descriptive statistics and comparisons were made using non-parametric methods. Correlations were assessed using the Bland-Altman method for repeated measures. Results: Over a 20-month period, 176 patients received UFH therapy at NCH. Of these, 95 patients met our pre-specified inclusion criteria. These 95 patients had 1102 simultaneous APTT and anti-FXa measurements performed. Baseline demographic information is described in Table 1. Mean duration of UFH therapy was 5.2 days (range: 1-45 days). Median UFH dose required to reach therapeutic anti-FXa goal was 22 units/kg/hr (range: 18-55 units/kg/hr), and was significantly higher in infants (<1yr of age) compared to older children (33.9 u/kg and 20 u/kg respectively; p<0.0001). Median time to achieve therapeutic anti-Xa was 10 hours (range: 2-96 hours), and was significantly shorter in patients who received a bolus (n=44) compared to those who did not (5 hrs and 12 hrs respectively; p=0.03). Five patients never achieved therapeutic anti-FXa levels. In patients with thrombo-embolism (n=75), 65 had end-of-therapy imaging (complete response: 36; partial or no response: 29). Time to achieve therapeutic anti-FXa was not predictive of radiological response (p=0.27). Moderate linear correlation between the APTT and anti-FXa (r = 0.74; 95% CI = 0.71-0.77) (Figure 1) was noted for the entire cohort. Eleven (10.6%) major and non-major bleeding events and 10 (10.5%) minor bleeding events were noted. When comparing coagulation parameters of patients with major and non-major bleeding to those with no-bleeding and minor bleeding age, indication for anticoagulation, peak anti-FXa, peak APTT, lowest platelet count and fibrinogen were not predictive of bleeding. Critically high APTT (>250 sec) was noted on 43 occasions in 21 unique patients and not associated with an increased risk of major and non-major bleeds (p=0.07). Conclusions: UFH monitoring is challenging in children. Time to achieve therapeutic anticoagulation and bleeding risk in our cohort is consistent with previous publications. Contrary to previous publications, extreme elevation of APTT was not associated with increased bleeding risk. Disclosures O'Brien: Pfizer: Consultancy, Other: study of direct oral anticoagulant in treatment of pediatric VTE; 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; Bristol Myers Squibb: Other: study of direct oral anticoagulant in prevention of pediatric VTE, Research Funding; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: advisory board - VWD diagnosis and management. Dunn: Alnylam: Other: Unrestricted educational grant; Bayer: Consultancy, Other: Unrestricted educational grant; Kedrion: Other: Unrestricted educational grant; NovoNordisk: Other: Unrestricted educational grant; Octapharma: Other: Unrestricted educational grant; Shire: Consultancy, Other: Unrestricted educational grant, Research Funding; Biogen: Other: Unrestricted educational grant, Research Funding; CSL Behring: Consultancy, Other: Unrestricted educational grant; World Federation of Hemophilia USA: Membership on an entity's Board of Directors or advisory committees. Kumar: Bayer: Consultancy; CSL Behring: Consultancy.

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Thrombotic and Bleeding Outcomes Following Perioperative Interruption of Direct Oral Anticoagulants and Vitamin K Antagonists in Patients with Non-Valvular Atrial Fibrillation - a Comparative Analysis

Blood ◽

10.1182/blood-2018-99-111698 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1234-1234

Author(s):

Joseph R. Shaw ◽

Tinghua Zhang ◽

Gregoire Le Gal ◽

James Douketis ◽

Marc Carrier

Keyword(s):

Major Bleeding ◽

Research Funding ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Risk ◽

Advisory Board ◽

Bleeding Events ◽

Chads2 Score ◽

High Bleeding Risk

Abstract Background: Atrial fibrillation (AF) is a common disorder that will affect up to 5.6 million patients in the U.S. by 2050. Both direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs), typically warfarin, are used for stroke prevention in AF and such patients frequently undergo invasive procedures requiring anticoagulant interruption. Temporary interruption of anticoagulants can be associated with significant morbidity and mortality in the form of thromboembolic and bleeding complications. DOACs have a short half-life and fast onset of action, thereby facilitating their perioperative management as compared to VKAs. Despite important differences in perioperative management and pharmacokinetics between DOACs and VKAs, there is a paucity of data comparing perioperative outcomes in DOAC and VKA-treated patients. Methods: We undertook a single-center, retrospective chart review that compared consecutive DOAC- or warfarin-treated patients with AF who underwent perioperative anticoagulant interruption for invasive procedures between January 2017 and March 2018. Perioperative warfarin interruption was done as per CHEST guidelines (Douketis et al. Chest 141,2 Suppl). Perioperative bridging with low-molecular-weight heparin was only used for patients with CHADS2 scores of 5-6 or in patients with stroke within the past 6 months. Perioperative interruption of DOACs was done as per Thrombosis Canada guidelines, with anticoagulation held for 3 half-lives prior to low bleeding risk procedures and 5 half-lives for high bleeding risk procedures. Primary outcomes included the 30-day post-operative thromboembolic and major bleeding rates. Secondary outcomes included the 30-day clinically relevant non-major bleeding (CRNMB) andl mortality rates. Major bleeding and CRNMB were defined according to ISTH definitions. Procedural bleeding risk was defined as per Schulman et al (Circulation 2015; 132(3)). Outcome events were independently adjudicated by two investigators. Outcomes from patients on DOACs and VKAs were compared. Demographic data was analyzed on a per-patient basis, p-values were calculated using independent T-Test, Chi-Square/Fisher's Exact Test where appropriate. Outcome data was analyzed on a per-interruption basis. P-values for unadjusted and adjusted comparisons were calculated using generalized estimating equations (GEE) to account for correlation between multiple procedures on the same patients. Results: 325 DOAC patients and 199 warfarin patients underwent 351 and 221 periprocedural interruptions, respectively. Warfarin patients had a significantly higher mean age, CHADS2 score, and proportion with renal dysfunction (Table 1). There was no statistically significant difference in 30-day post-operative rates of thromboembolism, CRNMB, and overall mortality, but warfarin patients had a significantly higher rate of major bleeding (Table 2). This latter result remained statistically significant following multivariate logistic regression correction for age, CHADS2 score and level of renal dysfunction. All bleeding events occurred post-procedure, with major bleeding events occurring from post-operative day 1 to post-operative day 25. None of the warfarin patients with major bleeding received perioperative bridging; the mean international normalized ratio (INR) at the time of major bleeding was 3.3. Most major bleeding events (7/8) in the VKA arm were surgical, with a single non-surgical major-bleed (spontaneous ICH on post-operative day 15 following urological surgery). Conclusions: The perioperative interruption of warfarin was associated with a higher 30-day rate of major bleeding as compared with DOAC interruption. Re-initiation of warfarin should be done judiciously following high bleeding risk procedures, and close INR monitoring may be warranted. Disclosures Shaw: Portola Pharmaceuticals: Research Funding. Douketis:Janssen: Consultancy; Pfizer: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; Portola: Other: Advisory Board; The Medicines Company: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Biotie: Other: Advisory Board; Bayer: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; BMS: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board. Carrier:Bayer: Honoraria; Pfizer: Honoraria; BMS: Honoraria, Research Funding; Leo Pharma: Research Funding.

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Maintaining Perioperative Hemostasis in Patients with Severe Hemophilia A and Inhibitors Receiving Emicizumab Prophylaxis

Blood ◽

10.1182/blood-2018-99-115089 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 635-635 ◽

Cited By ~ 7

Author(s):

Karen L. Zimowski ◽

Glaivy M. Batsuli ◽

Mark T. Reding ◽

Jatin Rana ◽

Michael U. Callaghan ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Perioperative Management ◽

Hemophilia A ◽

Advisory Board ◽

Severe Hemophilia ◽

Invasive Procedures ◽

Advisory Committees ◽

Perioperative Bleeding ◽

Bypassing Agents

Abstract Introduction: Patients with severe hemophilia A and anti-factor VIII (fVIII) antibodies (inhibitors) are at risk of significant bleeding during invasive procedures. Prior to the introduction of the bispecific humanized antibody, emicizumab, the standard of care for preventing perioperative bleeding in these patients consisted of repeated doses of bypassing agents such as recombinant activated factor VII (rfVIIa) and activated prothrombin complex concentrates (aPCCs) or high-doses of fVIII products. This practice often prolonged hospital admission and was associated with increased patient-care costs. Prophylaxis with emicizumab has significantly reduced bleeding symptoms in patients with hemophilia A and inhibitors. However, questions regarding the appropriate management of acute bleeding episodes and invasive procedures in patients receiving this novel therapy remain unanswered. Additionally, there are concerns about the hemostatic efficacy and safety of fVIII products and bypassing agents necessary for the management of perioperative bleeding and breakthrough bleeds in patients with inhibitors treated with emicizumab. In this case series, we report on the perioperative management and outcomes of patients receiving emicizumab prophylaxis who underwent invasive procedures. Methods: Patients between the ages of 1 - 60 years old with severe hemophilia A (fVIII activity <1%) with a history of low or high titer inhibitors on emicizumab prophylaxis treated at the Emory Pediatric Hemophilia Treatment Center, the Center for Bleeding and Clotting Disorders at the University of Minnesota Medical Center, the Michigan State University Center for Bleeding and Clotting Disorders, and the Children's Hospital of Michigan/Wayne State University were included in this analysis. All patients were continued on their emicizumab prophylaxis throughout the perioperative period. Due to the potential risk of thrombosis and thrombotic microangiopathy with aPCCs, these agents were avoided and rfVIIa was the preferred bypassing agent. Either recombinant (r) fVIII or plasma-derived (pd) fVIII were used in patients that had known response to high-dose fVIII. Perioperative treatment regimens, bleeding symptoms, and complications were monitored. Results: Seven patients underwent invasive procedures while on emicizumab prophylaxis and an additional two patients had minor procedures performed that required observation alone. These patients have historical peak inhibitor titers, defined as the highest inhibitor titer prior to starting emicizumab ranging from 2.0 - 4,792 BU/mL. Their inhibitor titers prior to the procedure ranged from 0 - 193.3 BU/mL. All patients initiated emicizumab prophylaxis at a median of 12 weeks prior to their procedures (range: 2 - 28 weeks). All 4 of the pediatric patients requiring invasive procedures underwent central venous access device (CVAD) - related procedures. The 3 adult patients requiring invasive procedures underwent removal of an infected penile prosthesis, a complex dental extraction consisting of 4 extractions and 1 alveoloplasty, and a right elbow synovectomy with radial head excision. Six patients were admitted to the inpatient hematology service for observation for a median of 48 hours (range: 24 - 168 hours) following their procedures. No patient required readmission after hospital discharge. All patients experienced minimal blood loss perioperatively, and none required transfusions of blood products. The patient undergoing CVAD removal developed a hematoma at the prior port site noted 1 week post-procedure that responded to rfVIIa 90 mcg/kg once daily for 2 days. A second patient had mild surgical site bleeding 1 week post-procedure, which responded to one dose of rfVIIa (90 mcg/kg). No other patient had bleeding complications, and no patient experienced thrombosis or thrombotic microangiopathy. The perioperative management plans are outlined in Table 1. Conclusions: This is the largest case series outside of the HAVEN series detailing the perioperative management of severe hemophilia A patients with a history of low or high titer inhibitors receiving emicizumab prophylaxis. During these invasive procedures, these patients required decreased dosing of fVIII products or bypassing agents and experienced minimal complications. Minor procedures were able to be completed with observation alone. Disclosures Zimowski: National Hemophilia Association/Shire: Other: Funding for clinical fellowship in Hemostasis/Thrombosis. Batsuli:Bayer: Other: Advisory Board; Genentech: Other: Advisory Board; Octapharma: Other: Advisory Board. Reding:Genentech: Other: Advisory Board. Callaghan:Global Blood Therepeutics: Employment; Amgen: Employment; Octapharma: Honoraria; Novo Nordisk: Employment, Membership on an entity's Board of Directors or advisory committees; Alnylam Pharmaceuticals: Equity Ownership; Hema Pharmaceuticals: Honoraria; Roche/Genentech: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Honoraria; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria; Sancilio Pharmaceuticals Company: Employment; Pfizer: Employment, Honoraria, Research Funding. Meeks:HEMA Biologics: Other: Advisory Board; Genentech: Other: Advisory Board; Catalyst Biosciences: Other: Advisory Board; CSL Behring: Other: Advisory Board; Bayer: Other: Advisory Board; Bioverativ: Other: Advisory Board; Shire: Other: Advisory Board; Pfizer: Research Funding. Sidonio:Uniqure: Other: Advisory Board; Novo Nordisk: Other: Advisory Board; Genentech: Other: Advisory Board, Research Funding; Kedrion: Research Funding; Shire: Other: Advisory Board, Research Funding; Octapharma: Other: Advisory Board; Biomarin: Other: Advisory Board; Bioverativ: Other: Advisory Board, Research Funding; Grifols: Other: Advisory Board, Research Funding; CSL Behring: Other: Advisory Board.

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Periprocedural Interruption of Anticoagulation in Patients with Cancer-Associated VTE: An Analysis of Thrombotic and Bleeding Outcomes

Blood ◽

10.1182/blood-2018-99-117715 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1235-1235

Author(s):

Joseph R. Shaw ◽

James Douketis ◽

Gregoire Le Gal ◽

Marc Carrier

Keyword(s):

Major Bleeding ◽

Patient Population ◽

Research Funding ◽

Bleeding Risk ◽

Advisory Board ◽

Bleeding Complications ◽

Invasive Procedures ◽

Patients With Cancer ◽

High Bleeding Risk ◽

Active Cancer

Abstract Background: Approximately 10-20% of patients with venous thromboembolic events (VTE) have underlying malignancy. VTE is considered the second leading cause of death in patients with cancer, and patients with cancer-associated VTE are at higher risk of anticoagulant-related bleeding. Although patients with cancer often undergo diagnostic or therapeutic invasive procedures, there is a paucity of data on adverse outcomes following the periprocedural interruption of anticoagulation in this patient population. Methods: We did a single-center, retrospective chart review of consecutive patients with cancer-associated VTE who had periprocedural interruption of anticoagulation for invasive procedures between November 2015 and March 2018. Perioperative interruption of warfarin/low-molecular-weight heparin was done as per CHEST guidelines (Douketis et al. Chest 141(2 Suppl). Heparin bridging anticoagulation was used only for patients with recent (< 3 months) VTE. Perioperative interruption of direct oral anticoagulants (DOACs) was done as per Thrombosis Canada guidelines, with anticoagulation held for 3 half-lives prior to low bleeding risk procedures and 5 half-lives for high bleeding risk procedures. Active cancer was defined as per the HOKUSAI VTE CANCER trial (Raskob et al. NEJM 378(7)). Primary outcomes were 30-day post-operative rates of VTE and major bleeding. Secondary outcomes were 30-day post-operative rates of clinically relevant non-major bleeding (CRNMB) and mortality. Major bleeding and CRNMB were defined according to ISTH definitions. Data are reported on a per-interruption basis. Herein, we present an interim analysis of results. Results: To date, 82 perioperative interruptions are included, of whom 69.5% were receiving a DOAC. Mean age of the cohort was 65.8 years, 62.2% were male, 92.6% had active cancer and 41.5% had metastatic cancer. Thrombocytopenia (platelet count < 100 x 106/L) was present in 12.2% of interruptions. Procedures were stratified as high bleeding risk in 65.9% of cases. The 30-day rates of thromboembolism and major bleeding were both 3.70 % (95% confidence interval [CI] 1.25 to 10.2%), as was the 30-day rate of CRNMB. There were no deaths during the 30-day follow-up period. Conclusions: The periprocedural interruption of anticoagulation in patients with cancer-associated VTE appears to be associated with high rates of post-operative thrombotic and bleeding complications. Prospective studies are required to better quantify the risks of periprocedural anticoagulation interruption in this patient population. Disclosures Shaw: Portola Pharmaceuticals: Research Funding. Douketis:BMS: Other: Advisory Board; Janssen: Consultancy; Bayer: Other: Advisory Board; Pfizer: Other: Advisory Board; Daiichi-Sankyo: Other: Advisory Board; Portola: Other: Advisory Board; Astra-Zeneca: Other: Advisory Board; Sanofi: Consultancy, Other: Advisory Board; Biotie: Other: Advisory Board; Boehringer-Ingelheim: Consultancy, Other: Advisory Board, Research Funding; The Medicines Company: Other: Advisory Board. Carrier:Pfizer: Honoraria; Bayer: Honoraria; BMS: Honoraria, Research Funding; Leo Pharma: Research Funding.

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Rivaroxaban for Treatment of Suspected or Confirmed Heparin-Induced Thrombocytopenia Study

Blood ◽

10.1182/blood.v126.23.3468.3468 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3468-3468 ◽

Cited By ~ 2

Author(s):

Lori Ann Linkins ◽

Theodore E. Warkentin ◽

Menaka Pai ◽

Sudeep Shivakumar ◽

Rizwan Manji ◽

...

Keyword(s):

Sample Size ◽

Board Of Directors ◽

Major Bleeding ◽

Research Funding ◽

Serotonin Release ◽

Advisory Committees ◽

Platelet Recovery ◽

Heparin Induced Thrombocytopenia ◽

Arterial Thromboembolism ◽

Routine Coagulation

Abstract Rivaroxaban is an ideal potential alternative for treatment of heparin-induced thrombocytopenia because it is administered orally by fixed dosing, requires no routine coagulation monitoring and has been proven effective in the treatment of venous and arterial thromboembolism in other settings. The Rivaroxaban for HIT Study prospectively evaluated the efficacy and safety of patients with suspected or confirmed HIT who were treated with rivaroxaban [NCT01598168 - investigator sponsored study funded by Bayer] Methods: Canadian multicenter, single-arm, prospective cohort study of patients with confirmed or suspected HIT (4Ts score ≥4) treated with rivaroxaban 15 mg bid until the diagnosis was supported or refuted using the local HIT assay. Participants with HIT (positive local assay result) received rivaroxaban 15 mg bid until platelet recovery (or until Day 21 if the patient had acute thrombosis; HITT) then stepped down to rivaroxaban 20 mg daily until Day 30. Central testing with the serotonin-release assay (SRA) was performed (not in real-time at all centres). HIT positive was defined as a 4Ts score ≥4 plus serotonin release ≥50%. The primary outcome measure was the incidence of new symptomatic, objectively-confirmed venous and arterial thromboembolism in the combined cohort of patients with suspected and confirmed HIT at 30 days. Secondary objectives included incidence of symptomatic thromboembolism while on treatment with rivaroxaban (combined cohort) and the following outcomes among SRA-positive participants while on treatment with rivaroxaban: incidence of venous and arterial thromboembolism, incidence of major bleeding, and time to platelet recovery. Sample size of 200 participants (10 to 30 with SRA-confirmed HIT) was based on feasibility and an anticipated thrombotic event rate in the study population (combined cohort) of 6.5% at 30 days (5% in HIT negative; 11% in HIT positive while on rivaroxaban). Results: 22 participants (12 HIT positive) were enrolled between January 2013 and July 2015. The study was terminated early due to poor recruitment, but after enrolling the minimum expected number of HIT positive participants. Of the 12 HIT positive participants (SRA, mean release 95%), 3(25%) had HITT at time of study entry and 6 had received at least one dose of fondaparinux prior to study enrolment. Half of the HIT positive participants were enrolled in study after the SRA result had already been reported as positive. After 371 days of exposure to rivaroxaban (combined cohort), 1 HIT positive participant had possible symptomatic recurrent VTE (4.5%, 95% CI: 0 to 23.5%), 1 HIT positive participant had major bleeding (9 days after rivaroxaban was held) and there were 4 deaths (cancer 2, sepsis 1, end-stage COPD 1). The single episode of possible recurrent VTE was extension of previously documented apheresis catheter-related arm DVT in a HIT positive participant who presented on Day 7 with worsening arm pain. A repeat ultrasound showed extension of DVT; however a baseline scan had not been performed at time of study entry. Interestingly, the same participant failed treatment with fondaparinux prior to study enrolment (development of erythematous plaques at injection sites and failure of platelets to rise). His apheresis catheter was removed on Day 8, rivaroxaban was continued and complete resolution of his symptoms as well as platelet recovery was achieved. One HIT positive participant presented with evidence of bilateral lower limb arterial ischemia (HIT-related acute arterial thrombosis on documented chronic peripheral vascular disease) at the time of study enrolment. Despite achieving platelet recovery, he underwent bilateral below knee amputation on Day 16. Out of the 12 HIT positive participants, 11 achieved platelet recovery with mean time to recovery 9 days. The single participant who did not achieve platelet recovery received only 2 doses of rivaroxaban before it was held due to a transient rise in liver enzymes. Rivaroxaban was never restarted because he bled while receiving fondaparinux as an alternative. Conclusions: Rivaroxaban appears to be effective for treating patients with confirmed HIT, although lack of a comparator and a small sample size are limitations of our findings. The advantages of rivaroxaban over other agents currently used to treat HIT such as ease of administration, lack of routine coagulation monitoring and low cost make it an attractive option. Disclosures Linkins: Pfizer: Honoraria; Bayer: Honoraria, Research Funding. Off Label Use: rivaroxaban has not been approved for treatment of heparin-induced thrombocytopenia. Warkentin:W.L. Gore: Consultancy, Research Funding; Instrumentation Laboratory: Consultancy, Honoraria; Pfizer: Consultancy. Pai:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS-Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Shivakumar:Bayer: Honoraria. Wells:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS-Pfizer: Research Funding. Wu:Pfizer Canada: Membership on an entity's Board of Directors or advisory committees; Leopharma: Membership on an entity's Board of Directors or advisory committees.

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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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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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