Heart Transplant: Induction Therapy

1. Heart Transplant:Induction Therapy Robert Thompson Intermountain Medical Center 09/19/13

2. Learning Objectives Discuss current heart transplant guidelines Explain components of induction and maintenance therapies Determine when induction therapy should be used Get acquainted with a new investigational clinical trial for a monoclonal antibody induction agent

3. Patient Case

4. History of Present Illness TP is 67 yo male with a history of CABG in November 2011 CABG was unsuccessful and a HeartMate II was placed The patient was deemed to be a good candidate for heart transplant and was listed as status 1B

5. History of Present Illness On August 22nd the patient was diagnosed with an infection at his driveline exit site. Cultures grew Klebsiella and Levaquin was started TP denied fevers, cough, chest pain, but did report increased sweats Transplant status was changed to 1Ab Status post ICD History of atrial fibrillation

6. Social History TP is married and lives with his wife. He is retired and denies use of tobacco, EtOH, or illicit drugs

7. Home Medications Celexa® 20 mg PO daily Gabapentin 300 mg PO qhs Omeprazole 40 mg PO bid Warfarin 4 mg PO daily APAP 650 mg PO tid Vit. C 1000 mg PO daily Aspirin 325 mg PO daily Vit. D3 2000 units PO daily OsCal® 1 tablet PO bid

8. Physical Exam: 9/7/13 Vitals: BP – 115/115 RR – 23 O2 – 99% room air HR: 69 Temp: 36.9

9. 138 101 16 110 Labs: 9/7/13 0.68 26 4.1 • Ca: 9.0 • Mg: 2.1 11.5 5.9 219 36.5

10. TP receives a new heart on 9/8/13

11. Guidelines The ISHLT guidelines recommend the following for induction: Routine use of immunosuppressive induction in all patients has not been shown to be superior to immunosuppressive regimens that do not use such therapy (B) Immunosuppressive induction with anti-thymocyte globulin (ATG) may be beneficial in patients at high risk for acute rejection (C) High risk is defined as: Previous transplant; high PRA; black/hispanic; deceased donor; poor HLA match Constanzo MR, et al. ISHLT 2010

12. Thymoglobulin® (rabbit) • MOA: Induces T-cell clearance and alters T-cell activation and cytotoxic activities. Decreased T-cells reduces rejection rates • Must be administered via a central line and filtering is required • Monitoring for anaphylaxis and flu like symptoms should occur during infusion Clinical Pharm 2009

13. Immunosuppression Therapy Induction for heart transplant is accomplished through high dose corticosteroids and Cellcept® - Pre-operative: Solu Medrol® 500 mg IVP X1 - Post-operative: Solu Medrol® 125mg IVP X1 upon return Solu Medrol® 250 mg IVD X1 over 16 hours SoluMedrol® 100 mg IVP X1 Prednisone taper

14. Cardiac Allograft Vasculopathy One of the major factors that limits longevity in heart transplant patients Thought to stem from injury to the allograft causing a chronic inflammatory state T-cells and B-cells are both components of the immune response that leads to CAV Constanzo MR, et al. ISHLT 2010

15. Thymoglobulin® for CAV? • There is a single center study that has been listed with clinicaltrials.gov since 2010. However, it has not yet begun enrolling patients • This study plans to test the hypothesis that T-cell suppression will lower the rates of CAV • In a study reported by Bonaros et al. in 2006 Thymoglobulin® reduced chronic rejection by 80% (p=0.031). This study included all solid organ transplants and cannot be extrapolated to the cardiac population Bonaros et al. 2006

16. CTOT-11(Prevention of CAV Using Rituximab Therapy In Cardiac Transplantation) An investigational study to test if decreasing B-cells using rituximab will help prevent CAV Randomized, double-blind; multi-centered; placebo controlled; efficacy study guidelines.gov

17. CTOT-11 Inclusion: 18 – 75 years old; male or female Candidate for their 1st heart transplant PRA < 10% Exclusion: Any history of organ transplant Intention to use any induction agents Previous use of rituximab guidelines.gov

18. CTOT-11 Intervention: 1000 mg rituximab IV or placebo Conventional immunosuppression TAC, MMF, and steroid taper Primary outcome: Nominal change after 1 year in percent of lipid containing plaque, measured by intravascular ultrasound guidelines.gov

19. Induction Regimen For TP The patient elected to enroll in CTOT-11 Rituximab 1000 mg IV was administered over 2 hours on 9/10/13 TP tolerated the infusion and will receive the next dose on 9/24/13 He was started on corticosteroid, MMF, and tacrolimus immunosuppression maintenance

20. References Constanzo MR, Dipchand A, Starling R, et al. The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients. J Heart Lung Transplantation [Internet]. 2010 Jun[cited 2013 Sep 16];29(8):914-56. Available from: http://www.ishlt.org/publications/guidelines.asp de Jonge N, Kirkels JH, Balk AHMM, et al. Guidelines for heart transplantation. Netherlands Heart Journal [Internet]. 2008 Mar[cited 2013 Sep 17];16(3):79-87. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2266869/ Clinical Pharmacology [Internet]. Tampa, (FL): Gold Standard, Inc. rituximab;[Updated 2011 Apr 20;Cited 2013 Sep 16]; [about 3 screens]. Available from: http://www.clinicalpharmacology.com Registration and login required. Clinical Pharmacology [Internet]. Tampa, (FL): Gold Standard, Inc. Thymoglobulin;[Updated 2009 Sep 28;Cited 2013 Sep 16]; [about 2 screens]. Available from: http://www.clinicalpharmacology.com Registration and login required. Bonaros N, Dunkler D, Kocher A, et al. Ten-year followup of a prospective, randomized trial of BT563/bb10 versus anti-thymocyte globulin as induction therapy after heart transplantation. J Heart Lung Transplant 2006 Sep;25(9):1154-63 Starling R, Sayegh M, Chandraker A. Prevention of Cardiac Allograft Vasculopathy Using Rituximab Therapy in Cardiac Transplantation. National Heart, Lung, and Blood Institute. Available from: http://clinicaltrials.gov/ct2/show/NCT01278745?term=CTOT-11&rank=1