therapeutic plasma exchange facilitates successful solid ......2005/05/16 · antibody-mediated...

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Therapeutic Plasma Exchange Facilitates Successful Solid Organ Transplantation HLA Desensitization and Antibody Mediated Rejection Theresa Kinard, MD Mayo Clinic, Arizona


Disclosures • No conflicts of interest to disclose relevant to

this presentation

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


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


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.”


Major Histocompatibility Complex • Adaptive immunity • Human Leukocyte Antigen (HLA)= human MHC

Class Expression Genes

I All nucleated cells A, B, C

II Antigen presenting cells DP, DQ, DR


Human Leukocyte Antigens • Principle target of the transplantation immune

response

https://upload.wikimedia.org/wikipedia/commons/d/d4/MHC_expression.svg


Patient with end organ failure

A B Bw C DRB1 DRB3/4/5 DQB1 DQA1 DPB1

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

Pre-Transplant

HLA type


Patient- Unsensitized A B Bw C DRB1 DRB3/

4/5 DQB1 DQA1 DPB1

11 35 6 4 11 52 7 05 17:01 31 49 4 7 12 52 7 05 88:01


1 8 6 5 17 52 2 03 04:01 2 44 4 7 4 53 7 05 04:01

Donor

Virtual XM Negative

HLA antibodies Class I: negative Class II: negative


Patient- Sensitized A B Bw C DRB1 DRB3/

4/5 DQB1 DQA1 DPB1

11 35 6 4 11 52 7 05 17:01 31 49 4 7 12 52 7 05 88:01


1 8 6 5 17 52 2 03 04:01 2 44 4 7 4 53 7 05 04:01

HLA antibodies Class I: A3, A24, C12 Class II: DR51

Virtual XM Negative

Donor


Patient- Sensitized with DSAs A B Bw C DRB1 DRB3/

4/5 DQB1 DQA1 DPB1

11 35 6 4 11 52 7 05 17:01 31 49 4 7 12 52 7 05 88:01


1 8 6 5 17 52 2 03 04:01 2 44 4 7 4 53 7 05 04:01

Recipient HLA antibodies Class I: A3, A24, B44, C12, Class II: DR51, DR17, DR53

Virtual XM Positive

Donor


Sensitization

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


Desensitization Goals

• Antibody removal • Therapeutic plasma exchange • Immunoabsorption

• Immunomodulation • IVIG

• Reduce antibody product • Rituximab • Bortezomib


Desensitization Therapies

Therapy Dose Frequency

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

IVIG • 0.1 mg/kg – 3g/kg • 20-150g

• Every 2 weeks • Monthly

Rituximab • 500 mg – 1g • 375 mg/m2

• Weekly x4 • Every 2 weeks • 2 doses

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


Desensitization Treatment Targets

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

APC T

cell B

cell Plasma

cell

IVIG

Rituximab Bortezomib TPE Steroids, other


Renal Transplant Desensitization Experience

Patient Survival (%)

Group 1 year 3 years 5 years 8 years

Desensitized + Transplanted 90.6 85.7 80.6 80.6

Hemodialysis or Transplanted 93.1 77.0 65.6 49.1

Hemodialysis only 91.1 67.2 51.5 30.5

• Montgomery et al. (2011)


Established Desensitization Programs

Program Patient Survival

Graft Survival

Acute Rejection

Johns Hopkins University

1-1.5 PV TPE Q.O.D. + IVIG 100 mg/kg

95% 3 years

81% 3 years 62%

Cedars-Sinai Medical Center

IVIG 2g/kg +/- rituximab

97% 5 years

87% 5 years 36%

IVIG- Intravenous Immunoglobulin, PV- Plasma volume, Q.O.D.- every other day, TPE- Therapeutic Plasma Exchange


Heart Transplant Desensitization Experience

Consensus conference (2009) • 45% >50% reduction in circulating antibodies • 73% transplanted

Author Treatment Outcomes

Kobashigawa, et al. (2011)

TPE daily x5 +/- IVIG (2g/kg) +/- rituximab

Similar 5 year survival as historical control; Mean PRA 70% 30%

Patel, et al. (2011)

1.5PV TPE x8 + bortezomib

Mean PRA 63% 35%


Lung Desensitization Experience • Tinckam et al. (2015)

• Intraoperative (3PV) and post operative (1PV) TPE x5

• Postoperative IVIG (1g/kg) and ATG

Graft Survival (%) Group 30 day 1 year 5 years DSA+ 96 89

73% PRA + 99 88 Unsensitized 96 86

ATG- Antithymocyte Globulin, DSA- Donor Specific Antibody, IVIG- Intravenous Immunoglobulin, PRA- Panel Reactive Antibody, PV- Plasma volume


Desensitization using TPE for Solid Organ Transplant

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


ASFA HLA Desensitization Guidelines

Organ Category Recommendation Grade

Cardiac - Positive XM due to DSA III 2C Lung -- -- Renal - Living donor - Positive XM due to DSA

I 1B

Renal - High PRA, deceased donor III 2C

XM- Crossmatch


Life after transplant: Acute Antibody Mediated Rejection

Plasma cell

Endothelial cell

• Immediate stimulation of the immune response


Once transplanted…

• Donor Specific Antibodies • Anti-HLA • Non-anti-HLA

• Rejection- increase risk for: • Subsequent rejection • Chronic rejection • Graft loss


Transplanted Patients who Received Desensitization

• ↑Acute rejection • ↑ Subclinical AMR leading to chronic graft rejection

• ↓Graft survival


Immunosuppression

• 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 Mediated Rejection Treatments • Immunomodulation

• IVIG

• Antibody Removal • TPE • IA

• B cell:

• Rituximab

• Plasma cells • Bortezomib

• Complement

• Eculizumab

• Adjustments to basal immunosuppresion


Antibody Mediated Rejection Treatment Targets

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

APC T

cell B

cell Plasma

cell Endothelial cell

IVIG

Steroids, ATG, other

Rituximab Bortezomib TPE

Eculizumab

complement


Kidney Transplant AMR Treatment

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


Kidney Transplant AMR Reports

Author Treatment Outcome

Montgomery et al. (2000)

1PV TPE Q.O.D. 100mg/kg IVIG Until clinical improvement or decreased DSA

10 patients; all successfully rescued

Gubensek et al. (2013)

1-1.5 PV TPE Q.O.D. (avg 10) 100mg/kg CMV Ig

19/23 (83%) rescued; 1 year graft survival 62%; 1 year patient survival 95%

Lefaucher et al. (2009)

A) IVIG(2g/kg) x4 versus B) 1PV TPE daily x4 + IVIG + rituximab x2

B) better graft survival, lower DSA, no dialysis

IVIG- Intravenous Immunoglobulin, CMV- Cytomegalovirus, DSA- Donor Specific Antibody, PV- Plasma Volume, TPE- Therapeutic Plasma Exchange, Q.O.D.- every other day


American Heart Association Scientific Statement • Primary Therapy:

• TPE • Corticosteroids • IVIG • Anti-lymphocyte antibodies

• Secondary therapy • Rituximab • Bortezomib • Eculizimab


Heart Transplant AMR Reports

Author Therapy Outcome Grauhan

et al. (2001)

A) CS + cytolytic AB B) CS +cytolytic AB +

TPE (x1-5)

TPE improved hemodynamics and survival (6/6 patients versus 2/7

patients)

Creso-Leiro (2005) CS + >7 daily TPE

11/12 recovery of allograft function with good long term

survival

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

51% 5 year survival

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


Lung Transplant AMR Reports

Author Treatment Outcome

Rummler et al. (2010)

1.3PV TPE daily, at least x3 days

5/7 heart and 2/2 heart/lung patients recovered with good graft function

Astor et al. (2005)

CS, then 1-1.5PV TPE daily x5 for refractory cases

18/23 patient who were refractory to CS responded to TPE

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


Therapeutic Plasma Exchange for the Treatment of AMR

• Cornerstone of AMR treatment • Successful management of AMR requires therapies to suppress antibody production

• Safe and effective • May prevent graft failure


ASFA Antibody Mediated Rejection TPE Guidelines

Organ Category Recommendation Grade

Cardiac III 2C Lung III 2C Renal I 1B


Therapeutic Plasma Exchange: Challenges for Solid Organ Transplantation

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

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjb94fc4b7MAhWjs4MKHf76DVMQjRwIBw&url=http://mylvad.com/content/heartware%C2%AE-lvad&bvm=bv.121070826,d.amc&psig=AFQjCNGFR7m9J4hd2ycxk9IBzkLmL0rukg&ust=1462394371702002

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjXq43v4b7MAhUBn4MKHWHmD30QjRwIBw&url=http://www.perfusion.com/services/clinical/perfusion-services/ecmo/&bvm=bv.121070826,d.amc&psig=AFQjCNGJJLSpDLo2JmkSau16nrZcqOMeBQ&ust=1462394405404618


Transplants in 2015


Current Waiting List


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


Thank you • Marcelo Pando, Ph.D. • Andres Jaramillo, Ph.D • Vonni Desmarteau, C.H.S. • Kevin Leslie, M.D. • Matthew Zarka, M.D. • Jill Adamski, M.D., Ph.D.


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therapeutic plasma exchange facilitates successful solid ......2005/05/16 · antibody-mediated...

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