Therapeutic Plasma Exchange Facilitates Successful Solid Organ Transplantation HLA Desensitization and Antibody Mediated Rejection

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Theresa Kinard, MD Mayo Clinic, Arizona

Discussion of Off Label Use • IVIG • Rituximab • Bortezomib • Eculizimab

©2016 MFMER | slide-2 Goals • What are the barriers to solid organ transplantation and maintaining graft function? • How can patients be optimized prior to transplantation? • How are patients managed during graft failures? • What role does apheresis have in preparing a patient for transplantation and the complications which may arise?

The Interesting History of Solid Organ Transplantation

1906 Mathieu Jaboulay

1912 Alexis Carrel

“Should an organ, extirpated from an animal and replanted into its owner by a certain technique, continue to functionate normally, and should it cease to functionate normally when transplanted into another animal by the same technique, the physiologic disturbance could not be considered as brought about by the organ but would be due to the influence of the host, that is, the biologic factors.”

Class Expression Genes I All nucleated cells A, B, C Antigen presenting II DP, DQ, DR cells

Patient with end organ failure HLA type

DRB3/ A B Bw C DRB1 DQB1 DQA1 DPB1 4/5 11 35 6 4 11 52 7 05 17:01 31 49 4 7 12 52 7 05 88:01

HLA antibodies screen Class I: negative Class II: negative

©2016 MFMER | slide-8 Patient- Unsensitized DRB3/ A B Bw C DRB1 DQB1 DQA1 DPB1 4/5 11 35 6 4 11 52 7 05 17:01 31 49 4 7 12 52 7 05 88:01 HLA antibodies Virtual XM Class I: negative Negative Class II: negative

Donor DRB3/ A B Bw C DRB1 DQB1 DQA1 DPB1 4/5 1 8 6 5 17 52 2 03 04:01 2 44 4 7 4 53 7 05 04:01

©2016 MFMER | slide-9 Patient- Sensitized DRB3/ A B Bw C DRB1 DQB1 DQA1 DPB1 4/5 11 35 6 4 11 52 7 05 17:01 31 49 4 7 12 52 7 05 88:01 HLA antibodies Virtual XM Class I: A3, A24, C12 Negative Class II: DR51

Donor DRB3/ A B Bw C DRB1 DQB1 DQA1 DPB1 4/5 1 8 6 5 17 52 2 03 04:01 2 44 4 7 4 53 7 05 04:01

Recipient HLA antibodies Virtual XM Class I: A3, A24, B44, C12, Positive Class II: DR51, DR17, DR53 Donor DRB3/ A B Bw C DRB1 DQB1 DQA1 DPB1 4/5 1 8 6 5 17 52 2 03 04:01 2 44 4 7 4 53 7 05 04:01

Limit donor pool Increase wait list time Increase risk of rejection Development of vasculopathy Graft loss

• Antibody removal • Therapeutic plasma exchange • Immunoabsorption • Immunomodulation • IVIG • Reduce antibody product • Rituximab • Bortezomib

Therapy Dose Frequency

• 2-3/week until transplant • 1- 1.5 PV TPE • 5 daily

• 0.1 mg/kg – 3g/kg • Every 2 weeks IVIG • 20-150g • Monthly

• Weekly x4 • 500 mg – 1g • Every 2 weeks Rituximab • 375 mg/m2 • 2 doses

IVIG- Intravenous Immunoglobulin, PV- Plasma Volume, TPE- Therapeutic Plasma Exchange

T B Plasma APC cell cell cell

Steroids, Rituximab Bortezomib TPE other

Djamali, A., Kaufman, D. B., Ellis, T. M., Zhong, W., Matas, A. and Samaniego, M. (2014), Diagnosis and Management of Antibody-Mediated Rejection: Current Status and Novel Approaches. American Journal of Transplantation, 14: 255–271. doi: 10.1111/ajt.12589 ©2016 MFMER | slide-15 Renal Transplant Desensitization Experience

Patient Survival (%)

Group 1 year 3 years 5 years 8 years

Desensitized + 90.6 85.7 80.6 80.6 Transplanted

Hemodialysis or 93.1 77.0 65.6 49.1 Transplanted

Hemodialysis only 91.1 67.2 51.5 30.5

• Montgomery et al. (2011) ©2016 MFMER | slide-16 Established Desensitization Programs Patient Graft Acute Program Survival Survival Rejection Johns Hopkins 95% 81% University 62% 1-1.5 PV TPE Q.O.D. 3 years 3 years + IVIG 100 mg/kg Cedars-Sinai Medical Center 97% 87% IVIG 2g/kg 36% +/- rituximab 5 years 5 years

IVIG- Intravenous Immunoglobulin, PV- Plasma volume, Q.O.D.- every other day, TPE- Therapeutic Plasma Exchange ©2016 MFMER | slide-17 Heart Transplant Desensitization Experience Consensus conference (2009) • 45% >50% reduction in circulating antibodies • 73% transplanted

Author Treatment Outcomes Kobashigawa, TPE daily x5 Similar 5 year survival et al. (2011) +/- IVIG (2g/kg) as historical control; +/- rituximab Mean PRA 70%  30% Patel, et al. 1.5PV TPE x8 Mean PRA 63%  35% (2011) + bortezomib

Graft Survival (%) Group 30 day 1 year 5 years DSA+ 96 89 PRA + 99 88 73% Unsensitized 96 86

ATG- Antithymocyte Globulin, DSA- Donor Specific Antibody, IVIG- Intravenous

• Safe and effective • Combination therapy is better • Collaboration across specialties • Cost savings • Living donors, paired donation programs

Recommendation Category Organ Grade Cardiac - Positive XM due to DSA III 2C Lung -- -- Renal - Living donor I 1B - Positive XM due to DSA Renal - High PRA, deceased donor III 2C

Plasma cell

Endothelial cell

• Donor Specific Antibodies • Anti-HLA • Non-anti-HLA • Rejection- increase risk for: • Subsequent rejection • Chronic rejection • Graft loss

• Nonspecific immunosuppressive agents are needed to prevent rejection, even when HLA matched donors are used

• No methods will suppress the host’s immune response to foreign antigens and at the same time maintain other immune responses

• Antibody Removal • Complement • TPE • Eculizumab • IA • Adjustments to basal • B cell: immunosuppresion • Rituximab

IVIG Eculizumab

complement

T B Plasma APC cell cell cell Endothelial cell

Steroids, Rituximab Bortezomib ATG, other TPE

• KDIGO Transplant Work Group (2009) • TPE • IVIG • Rituximab • Lymphocyte depleting antibody

Author Treatment Outcome

1PV TPE Q.O.D. Montgomery 100mg/kg IVIG 10 patients; all et al. (2000) Until clinical improvement or successfully rescued decreased DSA 19/23 (83%) rescued; Gubensek 1-1.5 PV TPE Q.O.D. (avg 10) 1 year graft survival et al. (2013) 100mg/kg CMV Ig 62%; 1 year patient survival 95% A) IVIG(2g/kg) x4 versus Lefaucher B) better graft survival, B) 1PV TPE daily x4 + IVIG + et al. (2009) lower DSA, no dialysis rituximab x2 IVIG- Intravenous Immunoglobulin, CMV- Cytomegalovirus, DSA- Donor Specific Antibody, PV- Plasma Volume, TPE- Therapeutic Plasma Exchange, Q.O.D.- every other day ©2016 MFMER | slide-29 American Heart Association Scientific Statement • Primary Therapy: • TPE • Corticosteroids • IVIG • Anti-lymphocyte antibodies • Secondary therapy • Rituximab • Bortezomib • Eculizimab

Author Therapy Outcome A) CS + cytolytic AB TPE improved hemodynamics and Grauhan B) CS +cytolytic AB + survival (6/6 patients versus 2/7 et al. (2001) TPE (x1-5) patients)

11/12 recovery of allograft Creso-Leiro CS + >7 daily TPE function with good long term (2005) survival

Wang et al. 75% 1 year survival CS + 5 daily 2PV TPE (2006) 51% 5 year survival

AB- Antibody, CS- corticosteroids, PV- Plasma Volume, TPE- Therapeutic Plasma Exchange

Author Treatment Outcome 5/7 heart and 2/2 Rummler 1.3PV TPE daily, at least heart/lung patients et al. (2010) x3 days recovered with good graft function 18/23 patient who CS, then 1-1.5PV TPE Astor were refractory to daily x5 for refractory et al. (2005) CS responded to cases TPE

IVIG- Intravenous Immunoglobulin, PV- Plasma Volume, TPE- Therapeutic Plasma Exchange

• Cornerstone of AMR treatment • Successful management of AMR requires therapies to suppress antibody production • Safe and effective • May prevent graft failure

Recommendation Category Organ Grade Cardiac III 2C Lung III 2C Renal I 1B

• Multiple medical complications • Managing adverse effects of TPE • Coordination with other therapies • Competing instruments or devices

©2016 MFMER | slide-37 Desensitization and AMR Treatment Summary • Need large, prospective trials • Combination therapies are better than any single treatment • TPE is safe and effective for all phases of transplant care • Be flexible and adaptable to the clinical situation

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