Learning Objectives 3/6/2017

Transcription

1 Prevention of Antibody Development Post Transplantation Results from the CTOT-11 Trial () Randall C Starling MD MPH FACC FAHA FESC FHFSA Professor of Medicine Kaufman Center for Heart Failure Department of Cardiovascular Medicine Heart & Vascular Institute Cleveland Clinic Lerner College of Medicine Randall C Starling MD MPH Professor of Medicine Kaufman Center for Heart Failure Heart and Vascular Institute Cleveland Clinic Cleveland Ohio USA No Disclosures My presentation doesinclude discussion of off-label or investigational use. (rituximab use in a clinical trial) Learning Objectives Describe the implications of use of rituximab as an induction agent in heart transplantation Describe the ability of rituximab to impact the formation of donor specific antibody after cardiac transplantation 1

2 Outline Cardiac transplant HLA, DSA CTOT 5, 18 CTOT 11, heart tx De novo AB Luminex MFI De novo associated With survival Reinsmoen NL Transplantation 214;97: heart tx 6 DSA at tx 19 de novo DSA 175 never DSA Non HLA ATR-1 FREEDOM AMR & CMR 2

3 95 heart tx Luminex assay Serial measures Worse Survival Late de novo Ho EK Human Immunology 72 (211) 5 Primary: death, retransplant BPAR, CAV Induction 43% Anti-HLA 24% 12% class 1 DSA 14% 3% de novo MFI> CTOT-18 Primary Endpoint 3

4 CTOT 18 Preliminary data* % not meeting the Composite Endpt AntiHLA Pos at M12 AntiHLA Neg at M12 p=.87 *to be presented ISHLT April 217 J Stehlik et al Day following completion of CTOT-5 CTOT-11 Trial Aim to study effectiveness of rituximab as induction therapy Multi-center prospective randomized controlled trial Unsensitized cardiac transplant recipients; PRA<% Subjects are then randomized (1:1) to receive rituximab or placebo as induction Presented ATC 216 Boston MA Induction In Cardiac Transplantation Is Associated With Accelerated Coronary Artery Vasculopathy: CTOT11 study results Randall C Starling, Jon Kobashigawa, Josef Stehlik, Michael Givertz, Robin Pierson, Sean Pinney, Joren Madsen, Steven Nissen, Indira Guleria, Yvonne Morrison, Brian Armstrong, David Ikle, Nancy Bridges, Mohamed H Sayegh, Anil Chandraker. 4

5 Study Center Participants BRIGHAM AND WOMEN S HOSPITAL (MAPB) TUFTS MEDICAL CENTER (MANM) Michael Givertz, M.D. David DeNofrio, MD CEDARS SINAI HEART INSTITUTE (CACS) UNIVERSITY OF MARYLAND (MDUM) Jon Kobashigawa, M.D. Erika Feller, M.D. CLEVELAND CLINIC FOUNDATION (OHCC) UNIVERSITY OF PENNSYLVANIA (PAUP) Randall C. Starling, M.D., MPH Lee Goldberg, M.D. VA PALO ALTO UCSF (CASF) Michael Pham, MD Teresa DeMarco, M.D. INTERMOUNTAIN MEDICAL CENTER (UTLD) UNIVERSITY OF UTAH (UTMC) A.G. Kfoury, M.D., FACC Josef Stehlik, M.D. MASSACHUSETTS GENERAL HOSPITAL (MAMG) UNIVERSITY OF WISCONSIN (WIUW) Joren C. Madsen, M.D. Maryl Johnson, M.D. MEDICAL CITY DALLAS HOSPITAL (TXHD) DREXEL UNIVERSITY COLLEGE OF MEDICINE Judson Hunt, M.D. Howard Eisen, MD MEDICAL UNIVERSITY SOUTH CAROLINA (SCMU) THE METHODIST HOSPITAL (TXMH) Adrian Van Bakel, MD Arvind Bhimaraj, MD MOUNT SINAI SCHOOL OF MEDICINE (NYMS) UNIVERSITY OF CALIFORNIA LOS ANGELES (CAUC) Sean Pinney, M.D. Gregg Fonarow, MD/ Mario Deng, MD MINNEAPOLIS HEART INSTITUTE (MNAN) UNIVERSITY OF MINNESOTA (MNUM) David Feldman, M.D. Monica Colvin-Adams, MD NORTHWESTERN UNIVERSITY (ILNM) COLUMBIA UNIVERSITY MEDICAL CENTER (NYCP) Robert Gordon, M.D. Donna Mancini, MD STANFORD UNIVERSITY (CASU) ALLEGHENY GENERAL HOSPITAL Kiran Khush, MD, MAS, FACC Srinivas Murali, MD Background and Apriori Hypothesis B cells are important in the development of coronary allograft vasculopathy (CAV) by acting as APCs for T cell activation through alloantibody production Use of anti-cd2 Ab as induction therapy will abrogate CAV in cardiac transplant recipients RCS1 RCS2 CTOT-11 Study Design Multi-center prospective randomized controlled trial Non-sensitized cardiac transplant recipients Subjects randomized (1:1) to receive rituximab or placebo as induction Randomization stratified by site and block randomized Primary endpoint Coronary Artery Vasculopathy (CAV) progression assessed by IVUS during year 1 post transplant 5

6 Slide 14 RCS1 RCS2 spell out coronary artery vasculopathy; appearing for the first time RANDALL C STARLING, 6/14/216 spell out percent atheroma volume RANDALL C STARLING, 6/14/216

7 Percent Atheroma Volume (PAV) Based on pilot data in a contemporary transplant population from the Cleveland Clinic Foundation (n=93), the PAV increased by 3.11%(SD=5.196) over one year. Data from CTOT-5 cohort of 54 ptsshowed a change in PAV in the 1 st year of 2.46±4.21% This is a large rate of progression as Nissen and colleagues have observed a change in PAV over one year in non-transplant subjects of ~1%. Nissen SE et al. JAMA 28; 299 (13): Primary Endpoint Primary Endpoint The nominal change from baseline to 1 year in percent atheroma volume (PAV) measured by IVUS in a target coronary artery Percent atheroma volume (PAV)reflects the summation of disease burden, expressed as a proportion of the total vessel wall dimensions. PAV is a more sensitive and robust measure of disease burden, with less measurement variability.* We hypothesized that the nominal change in PAV at one year will be reducedby 1.5% in subjects treated with rituximab compared to placebo. * Intravascular Ultrasound-Derived Measures of Coronary Atherosclerotic Plaque Burden and Clinical Outcome Stephen J. Nicholls, et al J Am Coll Cardiol 2;55: IVUS Procedure IVUS at week 4-8 post-transplant (baseline), and month 12. The IVUS imaging analyzed at the Core Laboratory (Cleveland Clinic). Arterial side branch landmarks used to match baseline and month 12 IVUS interrogated segments. Images will be collected at one-millimeter intervals throughout the matched segment. A typical IVUS pullback exam includes a 4-5mm segment of coronary artery. Every one-millimeter cross section is analyzed to obtain lumen and media-adventitial areas. Volumes are calculated using Simpson s rule. The left anterior descending artery is the preferred artery for imaging when feasible. AUTOMATED PULL BACK MATCHED SITE 4-5 MM SEGMENT 6

8 Study Design Study Arm: 1 gram IV day & 14 Control Arm: Maintenance Therapy: Tacrolimus/MMF/Steroid taper Inclusion Criteria Men or women recipients of first heart transplant years of age PRA % by Luminex (defined as unsensitized ) MFI 2 GFR >= 4 ml/min at the time of enrollment CTOT Enrolled *Trial closed before conclusion of target enrollment n=3 241 Transplanted 163 * Randomized Discontinued Pre-Transplant: 121 Discontinued Pre-Randomization: (53) primary endpoint analysis N=89 N=74 Completed Study 84 Completed Study 68 Discontinued Therapy 9 Discontinued Therapy 4 Terminated Study 5 Terminated Study 6 Discontinued Therapy 2 Discontinued Therapy 2 Baseline IVUS Baseline IVUS Total Collected 78 Total Collected 62 Acceptable for Evaluation 65 Acceptable for Evaluation 5 Month 12 IVUS Month 12 IVUS Total Collected 63 Total Collected 49 Acceptable for Evaluation 49 Acceptable for Evaluation 37 Baseline and M12 Paired, Evaluable IVUS 49 Baseline and M12 Paired, Evaluable IVUS 37 7

9 Baseline Characteristics (89) (74) Total Txed (163) Donor Age (Yrs) Male (%) Race (%) Death Head Trauma (%) Recip Age (Yrs) High Cholesterol Smoking (%) Wt (Kg) BMI Ischemic Time (Hrs) Primary Endpoint Result Change in PAV at M p=.19 * Paired IVUS measures were available at baseline and 1 year in 86 subjects (49 RIT, 37 PLAC). Mean (±SD) increase in PAV at 12 mos 6.8 ±8.2% vs 1.9 ±4.4% Hypothesized a 1.5% reduction with rituximab * Subjects who received induction therapy with rituximab had an average change in percent atheroma volume that was 4.79% higher (p=.19) than those who received placebo induction, when adjusted for baseline PAV. (89) (74) p value Total Txed (163) Death (1 Yr) 3(3.4) 5 (6.8).47 8 (4.9) Re-Tx PTLD Local Treated Rejection 22 (24.7) 24 (32.4) (28.2) C4d + 11 (12.4) (13.5) (12.9) Daysto Local Treated Rejection Central Rejection ACR 2R Outcomes 9 ±4 121 ± ± (14.6) 15 (2.3) (17.2) CNI 89 () 74 () 163 () Steroid 89 () 74 ) 163 () MPA 89 () 74 () 163 () mtor 5 (5.6) 3 (4.1) 8 (4.9) 8

10 Percentage Subjects with Anti HLA Abs detected at 12 months CTOT MFI cutoff Class I ClassII Class I & II Anti-HLA Abs DSA at V12 % of Subjects Positive for Abs p=.75 p= n=28 3 n=18 n=23 2 n=12 n=11 n=7 Anti-HLA Class I Class II N=8 N=65 N=82 N=65 N=8 N=65 % of Subjects Positive for Abs n= n=8 n=2 n=5 n=9 n=3 DSA Class I Class II N=8 N=65 N=82 N=65 N=8 N=65 4 DSA Data DSA* Change in PAV at M

11 Summary & Conclusions Use of as induction therapy in nonsensitized cardiac transplant recipients increased CAV at 12 months. was not associated with increased rejection nor development of anti HLA Ab. Long-term follow up is required to understand the effects on graft function and patient survival; CTOT 23 Acknowledgements RHO NIAID CTOT staff Thank You Randall C Starling MD MPH starlir@ccf.org