Marcelo Cypel MD MSc FRCSCCanada Research Chair in Lung TransplantationSurgical Director ECLS Lung Program UHNAssociate Professor of Surgery Division of Thoracic SurgeryDepartment of SurgeryUniversity of Toronto

The Toronto Experience & Current Status

Disclosure

• Founding Partner:• Perfusix Canada Inc.

• Perfusix USA Inc. (Lung Bioengineering /UT)

• XOR Labs Toronto Inc.

• XVIVO Perfusion – Research support and clinical trial• United Therapeutics – Consultant • Xenios/Fresenius – Research support and investor in XOR• Gilead Sciences – Research Support

Van Raemdonck et al. Transplant Int 2014 Mar 15. doi: 10.1111/tri.12317

Commercial Devices for Ex Vivo Lung Perfusion

TORONTO EVLP

Perfusion : 40% CO, LAP 5mmHg, PAP 10-12mmHgVentilation: 7cc/kg, 7BPM, PEEP 5, FiO2 = 21%

Cypel/Keshavjee J Heart Lung Transplant 2008; 27(12):1319-25.

5

Concept Development & Study Design

Equipment Troubleshooting

1st Animal Experiment

Human Trial Design:Researchers,Ethics board, patients

1st Human Transplant

Completion of Trial and Health Canada Application

Approved for clinical use

Reimbursement

2005

20072008

20102012

2012

20052006

Toronto EVLP Timeline of Development

1st Patient transplanted with Toronto EVLP system

Health Canada• FDA (Aug 2014)

OHTAC MOH

6April 14th 2011, vol. 364, no. 15, pp. 1431-1440.

Early outcomes were similar in the 2 groups

NEJM, April 14th 2011

EVLP for high risk donor lungs is safe

8

Yeung, J. JHLT 2016

0 1 2 3 4 5 6 7 8 9 10

0

10

20

30

40

50

60

70

80

90

100

Time (Years)

Surv

ival

pro

babi

lity

(%)

Number at riskEVLP: No

133 100 73 51 34 23 14 12 5 2 0EVLP: Yes

133 89 55 40 26 14 10 0 0 0 0

EVLPNoYes

133 EVLPs vs. 133 matched controls

Early Outcomes

9

Category No EVLP (n=133) EVLP (n=133) p

Hospital LOS (Median, IQR) 23 (16.5-43) 21 (16-34) 0.21

ICU LOS (Median, IQR) 4 (2-14.5) 4 (2-10.5) 0.83

ISHLT PGD at 72h 0.02

0 82 (61.7%) 92 (69.2%)1 8 (6.0%) 18 (13.5%)2 30 (22.6%) 14 (10.5%)3 12 (9.0%) 9 (6.8%)

Yeung. J, JHLT 2016

Indications for EVLP at TGH(n=397 cases)

1) High-risk BDD: 55%2) Standard DCD: 11%3) High-risk DCD: 29%4) Logistics or retrieval by another team: 5%

Results EVLP by indications: AATS Annual Meeting 2018

Clinical EVLP Experience at TGH = 397 cases

Total utilization rate= 69%

EVLP & Lung Transplant Activity / Year 1983 - 2017

0

20

40

60

80

100

120

140

160

180

83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 '07

'08

'09

'10

'11

'12

'13

'14

'15 16 17

No

of T

x /

yr

Year

EVLP-LTXLTx only

Total EVLP performed to-date(N=252)

Toronto Lung Transplant Program Annual Growth 1991- 2017

27 27 25 2432 30 31 33 38

5042

59 5464 68

87

100

86

102

84

102104

133

115

128

145

170

0

50

100

150

200

91 92 93 94 95 96 97 98 99 '00

'01

'02

'03

'04

'05

'06

'07

'08

'09

'10

'11

'12

'13

'14

'15

'16 17

Num

ber o

f LTx

YearLTx/Year

2006-2011Plateau

mean 93.52000-2006~100% increase

ECD era

2012-201670% increase

EVLP era

14

Operative (30d) Mortality Rate(Avg 3% past 5 yr)

0%

25%

50%

75%

100%

1983

1984

1985

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

2014

2015

2016

2017

Rate %: # death within 30-d post-op / # Tx within Calendar year

•DCD

•Extending Lung Preservation

•Implementation Process

EVLP

•DCD

•Extending Lung Preservation

•Implementation Process

EVLP

• SRTR data: DNDD utilization rate in USA is 21%• DCDD utilization rate in USA is 2.1%• DCDD rate in Canada and Australia and Europe 28%

DCD Lung Transplantation: Standard of Care

15-30% of transplants from DCDs

Cypel at al. J Heart Lung Transplant 2015 Oct;34(10):1278-82

Should All DCD Lungs be Treated with EVLP? Avoid surprises…

DCD, rapid arrest after WLST, “no concerns” straight to transplant

Machuca TN, et al. Am J Transplant. 2015;15:993-1002

•DCD

•Extending Lung Preservation

•Implementation Process

EVLP

Combining Cold and Warm Preservation in Large Animal Model can substantially prolong preservation time

Hsin et al. J Heart Lung Transplant 2016 Jan;35(1):130-6.

Towards Elective Lung Transplantation: Outcome of Transplantation of Lungs Preserved More Than 12h

90-day Mortality

P re s e rv a t io n T im e (H o u rs )

Ca

se

s

1 2 1 4 1 6 1 8 2 0 2 2

M e d ia n

Yeung J, Krueger, Yasufuku K, de Perrot M, Pierre A, Waddell T, Singer L, Keshavjee S, Cypel M. Nov 17, 2016

p=0.6

TGH Practice

•We routinely transplant lungs over 12h preservation time•Patients can remain at home – further distances•Don’t need to call in patient until donor assessment is complete (even more important in DCD as 40-50% don’t arrest)

•No need to rush in difficult cases worrying about ischemic time•More transplants can occur in the daytime – teams can sleep better performance, lower costs, allow program volume escalation without team burnout

Dr. X

Dr. MC

•DCD

•Extending Lung Preservation

•Implementation Process

EVLP

Transplant Center - Centric Model

Organ Repair Hub Model

Toronto Lung TransplantEVLP Process

Donor offers in Canada

Donor offers in US

UHN Organ repair center

Lung Bioengineering

(Maryland)

TGH transplant

Early days of EVLP at TGH

31

Concept Development & Study Design

Equipment Troubleshooting

1st Animal Experiment

Human Trial Design:Researchers,Ethics board, patients

1st Human Transplant

Completion of Trial and Health Canada Application

Approved for clinical use

Reimbursement

2005

20072008

20102012

2012

20052006

Staff surgeon- fellows- OPS

OPS • 3 EVLP teams (pairs): 1 full time OPS + 1 research fellow doing lab EVLP projects.

OPS Call Schedule has first and second call

34

Conclusions

• ~ 30-40% of our lung transplant activities come from EVLP lungs

• EVLP is a very effective method to test quality and improve function in DCDs and NDDs

• Combining cold static preservation and EVLP allows us to bring lung transplantation to a semi-elective procedure.