AND My presentation does include discussion of off-label or investigational use (empiric therapy)

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Managing Sensitized Patients Pre-Heart Transplantation Patricia P.

Chang, MD MHS Associate Professor of Medicine Director, UNC Heart Failure & Transplant Program Chapel Hill, NC, USA I have no financial

AND My presentation does include discussion of off-label or investigational use (empiric therapy) Learning objectives At the end of this

1 Managing Sensitized Patients Pre-Heart Transplantation Patricia P. Chang, MD MHS Associate Professor of Medicine Director, UNC Heart Failure & Transplant Program Patricia P. Chang, MD MHS Associate Professor of Medicine Director, UNC Heart Failure & Transplant Program Chapel Hill, NC, USA I have no financial relationships with commercial interests to disclose. AND My presentation does include discussion of off-label or investigational use (empiric therapy) Learning objectives At the end of this activity, the learner will be able to 1. Describe potential management strategies for sensitized patients awaiting heart transplant 2. Identify specific desensitization therapies of sensitized patients awaiting heart transplant 3. Describe outcomes of sensitized patients who undergo heart transplant w/ or w/o adjunctive therapy 1

Similar findings when limited to propensity-matched sensitized pts PRA reduction 20% vs <20%: Adj HR 0.88 (0.80-0.96), p=0.

2 Sensitized Patients Higher risk for rejection and worse survival +DSA associated with AMR and ACR N=175 N=19 N=6 Reinsmoen NL et al, Transplantation 2014;97: Sensitized Patients UNOS (N=27102 HTX, ) Shaffer JM et al, J Thorac CV Surg 2013;145: Similar findings when limited to propensity-matched sensitized pts PRA reduction 20% vs <20%: Adj HR 0.88 ( ), p=0.006 (esp after adjusting for peak PRA) Limitations: PRA did not differentiate HLA classes, few VAD pts,?rx Shaffer JM et al, J Thorac CV Surg 2013;145:

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Year of Transplant 2016 * LVAD, RVAD, TAH, ECMO JHLT.

3 Sensitized Patients At risk for more sensitizing events pre-transplant (esp. LVAD patients) Adult Heart Transplants % of Patients Bridged with Mechanical Circulatory Support* (Transplants: January 2000 December 2014) % of Patients Year of Transplant 2016 * LVAD, RVAD, TAH, ECMO JHLT Oct; 35(10): LVAD Patients risk for highly sensi zed Blood flows through VAD constantly Frequent transfusions (peri-op, GI bleeds) Should they be treated differently? Yes: they get more therapy pre and peri-op No Maybe: e.g., Yes but not if they are infected Threshold to treat vs not treat? E.g., to decrease ab to decrease waiting time (monthly IVIG+/-Plasmapheresis, Cyclophosphamide) John R et al, Circulation 1999;100(suppl2):II-229 3

4 LVAD pts (UNOS) N=1544 ( ): effect of VADs (HM XVE, HMII) on PRA and outcomes 63% PRA 0% 16% PRA>25% 14% Class I, 7% Class II High PRA did not mortality or rejection High PRA Class II PGD Amaoutakis GJ et al, J ThoracCV Surg 2011;142(5): How Sensitized? Assessed preoperatively by cpra cpra cutoff to desensitize or not desensitization therapy? Frequency of cpramonitoring, +/-desensitization therapy? Threshold to list unacceptable HLA Ags? Reassessed perioperativelywith crossmatch (XM) results Threshold to continue or start adjunctive therapy Reassessed postoperatively with DSA testing Pre-Transplant Assessment & Monitoring HLA antibody screening Solid phase assays Single antigen testing MFI cutoffs for determining cpra Frequency of HLA Ab screening* Initial evaluation then every 3-6 months 2 weeks after a sensitizing event (e.g., transfusion) 1-2 weeks after desensitizing therapy How does cpra >0% change frequency of screening? Additional assays/techniques C1q or C4d testing when HLA specific Abs defined EDTA, heat inactivation, dilution to minimize interfering factors (complement, prozone) * Kobashigawa J et al, JHLT 2009;28:

Rituximab 2,6,7 Itescu S et al, Circ 2002 4 Patel J et al, JHLT 2011 and JHLT 2015 * 5 John R et al, Circ 1999 Plasmapheresis 1,2,4 6 Weeks P et al, JHLT 2016 Cyclophosphamide 3 Bortezomib 4

5 Pre-Transplant Management When to desensitize? cpracutoff? Individualized based on center s experience/practice Most published studies: cpra >10-50% Many potential pre-txregimens (individual or in combo IVIG 1,2,5,7 1 Leech SH et al, Clin Transplant 2006 * 3 Rituximab 2,6,7 Itescu S et al, Circ Patel J et al, JHLT 2011 and JHLT 2015 * 5 John R et al, Circ 1999 Plasmapheresis 1,2,4 6 Weeks P et al, JHLT 2016 Cyclophosphamide 3 Bortezomib 4 Carfilzomib 6 2 Kobashigawa JA et al, Clin Transplant Schumacher KR et al, JHLT 2011 and JHLT 2012 Desensitization Therapies Chih S, Patel J, JHLT 2016:35:962 Definition of Success? PRA 0%! (rare) PRA post-rx < PRA pre-rx Patient does well-post-htx (patient- and centerdependent) Definition of Failure? ( Patient not eligible for HTx, bad outcome) 5

6 Desensitization Therapies Data is based on single-center studies, observational (no RCT), most w/o control group, adults >> pediatric 1 Goal: successful HTX and post-txsurvival Sample size: 1 to Results: cpradecreases; successfully transplanted; but similar long-term outcomes compared to historical controls (e.g., 5-year survival and CAV 2 ) 1 Schumacher KR et al, JHLT 2011 and JHLT Kobashigawa JA et al, Clin Transplant 2011 Getting Ready for Transplant Threshold to list unacceptable antigens vs not (to increase donor pool) Center-dependent Prospective XM must be done Virtual XM Laboratory XM pre-tx if possible Retrospective XM must be done if no Prospective XM Within hours of HTx Donor T and B cells should be used for Lab XM, and distinguish IgG vs IgM Perioperative Assessment & Management Perioperative XM (prospective vs retrospective) XM is negative Do nothing Do something (e.g., Plasmapheresis on way to OR or intraoperative) XM is positive Hard to do nothing (vs reject the donor) 6

7 Perioperative/Postoperative Therapy Induction therapy (Cytolytic/ATG, IL2-receptor antagonist/basiliximab) 1,2,3,5,8,10 Plasmapheresis (or Immunoadsorption) /- IVIG 1,2,5,8,9,11 Rituximab 10,11 Alemtuzumab 7 1 Bucin D et al, Transplantation Daly KP et al, Pediatr Transplant Holt DB et al, JHLT 2007 Cyclophosphamide 3 4 Jackups R et al, J Clin Apheresis Kobashigawa JA et al, Clin Transplant Larson DF, J Extra Corpor Technol 1999 Bortezomib 8 8 Patel J et al, JHLT Pisani et al, JHLT 1999 Photopheresis 3 10 Pollock-BarZiv SM, Circulation Richmond ME et al, Pediatr Transplant Patel J et al, JHLT 2015 (abstract) Eculizumab 12 7 Lick SD et al, JHLT 2008 and Ann Thorac Surg 2011 (LVAD pts) (5/12 studies in pediatric population) Desensitization Therapies Chih S, Patel J, JHLT 2016:35:962 Treatment Options Rx Pre-Tx Intra-Op Post-Op Plasmapheresis (or immunoadsoption) IVIG + + Rituximab + + Induction Rx (ATG or Basiliximab) Cyclophosphamide + + Alemtuzumab + + Bortezomib + Carfilzomib + Photopheresis + Eculizumab

8 Future Therapies? RCT CTOT-13 failed to enroll ( ): Bortezimib + PP DUET (Dr. JigneshPatel): Eculizumab(sensitized pts, PRA 70%) & AMR CTOT-11 (Dr. Randy Starling): Rituximab (nonsensitized pts) & CAV Future therapies (learning from KTX) C1 esterase inhibitor (C1-INH) IdeS(Strep pyogenes proteolytic enzyme) What is the best strategy (debate) Desensitize (negative XM) Preemptive Rx (positive XM) Summary Quality of Data is overall low-moderate Case-series of treated pts Center-dependent strategies Multiple therapies Sensitized patient considered to have worse outcomes Peri/post-transplant monitoring important Post-test question: 1. Which of the following desensitization therapies has the most supportive evidence for its use in sensitized patients awaiting heart transplant a) Alemtuzemab b) Bortezimib c) Plasmapheresis d) Rituximab 8

Solid Organ Transplant

Solid Organ Transplant Lee R. Goldberg, MD, MPH, FACC Associate Professor of Medicine Medical Director, Heart Failure and CardiacTransplant Program University of Pennsylvania Disclosures Thoratec Consulting