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Randall C Starling MD MPH FACC FAHA FESC FHFSAProfessor of Medicine

Kaufman Center for Heart Failure

Department of Cardiovascular MedicineHeart & Vascular Institute

Cleveland Clinic Lerner College of Medicine

Prevention of Antibody Development Post Transplantation

Results from the CTOT-11 Trial (Rituximab)

Randall C Starling MD MPH

Professor of Medicine

Kaufman Center for Heart Failure

Heart and Vascular Institute

Cleveland Clinic

Cleveland Ohio USA

No Disclosures

My presentation does include discussion of off-label or investigational use.

(rituximab use in a clinical trial)

Learning Objectives

• Describe the implications of use of rituximab

as an induction agent in heart transplantation

• Describe the ability of rituximab to impact the

formation of donor specific antibody after

cardiac transplantation

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Outline

• Cardiac transplant HLA, DSA

• CTOT 05, 18

• CTOT 11, 23

243 heart tx

De novo AB

Luminex MFI 1000

De novo associated

With survival

200 heart tx

6 DSA at tx

19 de novo DSA

175 never DSA

Non HLA ATR-1

FREEDOM AMR & CMR

Reinsmoen NL Transplantation 2014;97: 595-601

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950 heart tx

Luminex assay

Serial measures Worse

Survival

Late de novo

Ho EK Human Immunology 72 (2011) 5–10

Anti-HLA 24% 12% class 1

Primary: death, retransplant

BPAR, CAV

Induction 43%

DSA 14% 3% de novo

MFI>1000

CTOT-18

Primary Endpoint

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CTOT 18Preliminary data*

Day following completion of CTOT-05

% n

ot

meeti

ng

th

e C

om

po

sit

e E

nd

pt

0 500 1000 1500 2000 25000

10

20

30

40

50

60

70

80

90

100

AntiHLA Pos at M12AntiHLA Neg at M12

p=0.8700

*to be presented ISHLT April 2017

J Stehlik et al

CTOT-11 Trial

• Aim to study effectiveness of rituximab as induction therapy

• Multi-center prospective randomized controlled trial

• Unsensitized cardiac transplant recipients; PRA<10%

• Subjects are then randomized (1:1) to receive rituximab or placebo as induction

Rituximab Induction In Cardiac Transplantation Is

Associated With Accelerated Coronary Artery

Vasculopathy: CTOT11 study results

Randall C Starling, Jon Kobashigawa, Josef Stehlik, Michael Givertz, Robin Pierson, Sean

Pinney, Joren Madsen, Steven Nissen, Indira Guleria, Yvonne Morrison, Brian Armstrong,

David Ikle, Nancy Bridges, Mohamed H Sayegh, Anil Chandraker.

Presented ATC 2016 Boston MA

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Study Center ParticipantsTUFTS MEDICAL CENTER (MANM)

David DeNofrio, MD

UNIVERSITY OF MARYLAND (MDUM)

Erika Feller, M.D.

UNIVERSITY OF PENNSYLVANIA (PAUP)

Lee Goldberg, M.D.

UCSF (CASF)

Teresa DeMarco, M.D.

UNIVERSITY OF UTAH (UTMC)

Josef Stehlik, M.D.

UNIVERSITY OF WISCONSIN (WIUW)

Maryl Johnson, M.D.

DREXEL UNIVERSITY COLLEGE OF MEDICINE

Howard Eisen, MD

THE METHODIST HOSPITAL (TXMH)

Arvind Bhimaraj, MD

UNIVERSITY OF CALIFORNIA LOS ANGELES (CAUC)

Gregg Fonarow, MD/ Mario Deng, MD

UNIVERSITY OF MINNESOTA (MNUM)

Monica Colvin-Adams, MD

COLUMBIA UNIVERSITY MEDICAL CENTER (NYCP)

Donna Mancini, MD

ALLEGHENY GENERAL HOSPITAL

Srinivas Murali, MD

BRIGHAM AND WOMEN’S HOSPITAL (MAPB)

Michael Givertz, M.D.

CEDARS SINAI HEART INSTITUTE (CACS)

Jon Kobashigawa, M.D.

CLEVELAND CLINIC FOUNDATION (OHCC)

Randall C. Starling, M.D., MPH

VA PALO ALTO

Michael Pham, MD

INTERMOUNTAIN MEDICAL CENTER (UTLD)

A.G. Kfoury, M.D., FACC

MASSACHUSETTS GENERAL HOSPITAL (MAMG)

Joren C. Madsen, M.D.

MEDICAL CITY DALLAS HOSPITAL (TXHD)

Judson Hunt, M.D.

MEDICAL UNIVERSITY SOUTH CAROLINA (SCMU)

Adrian Van Bakel, MD

MOUNT SINAI SCHOOL OF MEDICINE (NYMS)

Sean Pinney, M.D.

MINNEAPOLIS HEART INSTITUTE (MNAN)

David Feldman, M.D.

NORTHWESTERN UNIVERSITY (ILNM)

Robert Gordon, M.D.

STANFORD UNIVERSITY (CASU)

Kiran Khush, MD, MAS, FACC

Background and Apriori Hypothesis

• B cells are important in the development of

coronary allograft vasculopathy (CAV) by acting as

APCs for T cell activation through alloantibody

production

• Use of anti-CD20 Ab as induction therapy will

abrogate CAV in cardiac transplant recipients

RCS1

RCS2

CTOT-11 Study Design

• Multi-center prospective randomized controlled trial

• Non-sensitized cardiac transplant recipients

• Subjects randomized (1:1) to receive rituximab or placebo as induction

• Randomization stratified by site and block randomized

• Primary endpoint –

– Coronary Artery Vasculopathy (CAV) progression

assessed by IVUS during year 1 post transplant

Slide 14

RCS1 spell out coronary artery vasculopathy; appearing for the first timeRANDALL C STARLING, 6/14/2016

RCS2 spell out percent atheroma volume RANDALL C STARLING, 6/14/2016

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Percent Atheroma Volume (PAV)

• Based on pilot data in a contemporary transplant

population from the Cleveland Clinic Foundation

(n=93), the PAV increased by 3.11% (SD=5.196) over

one year.

• Data from CTOT-05 cohort of 54 pts showed a change

in PAV in the 1st year of 2.46 ± 4.21%

• This is a large rate of progression as Nissen and

colleagues have observed a change in PAV over one

year in non-transplant subjects of ~1%.

Nissen SE et al. JAMA 2008; 299 (13): 1561-1573.

Primary EndpointPrimary Endpoint

– The nominal change from baseline to 1 year in percent atheroma

volume (PAV) measured by IVUS in a target coronary artery

• Percent atheroma volume (PAV) reflects the summation

of disease burden, expressed as a proportion of the total

vessel wall dimensions.

• PAV is a more sensitive and robust measure of disease

burden, with less measurement variability.*

• We hypothesized that the nominal change in PAV at one

year will be reduced by 1.5% in subjects treated with

rituximab compared to placebo.* Intravascular Ultrasound-Derived Measures of Coronary Atherosclerotic Plaque Burden and Clinical

Outcome Stephen J. Nicholls, et al J Am Coll Cardiol 2010;55:2399–407

IVUS Procedure• IVUS at week 4-8 post-transplant (baseline), and month 12.

• The IVUS imaging analyzed at the Core Laboratory (Cleveland Clinic).

• Arterial side branch landmarks used to match baseline and month 12 IVUS interrogated segments.

• Images will be collected at one-millimeter intervals throughout the matched segment.

• A typical IVUS pullback exam includes a 40-50mm segment of coronary artery.

• Every one-millimeter cross section is analyzed to obtain lumen and media-adventitial areas. Volumes are

calculated using Simpson’s rule.

• The left anterior descending artery is the preferred artery for imaging when feasible.

AUTOMATED

PULL BACK MATCHED

SITE

40-50 MM

SEGMENT

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Study Design

Study Arm: Rituximab 1 gram IV day 0 & 14

Control Arm: Placebo

Maintenance Therapy: Tacrolimus/MMF/Steroid taper

Inclusion Criteria

• Men or women recipients of first heart

transplant

• 18-75 years of age

• PRA ≤10% by Luminex (defined as

“unsensitized”)

• MFI ≤ 2000

• GFR >= 40 ml/min at the time of enrollment

362

Enrolled

Placebo

N=74

Completed Study

Discontinued Therapy

68

4

Terminated Study

Discontinued Therapy

6

2

Baseline IVUS

Total Collected

Acceptable for Evaluation

62

50

Month 12 IVUS

Total Collected

Acceptable for Evaluation

49

37

Baseline and M12 Paired, Evaluable IVUS 37

Rituximab

N=89

Completed Study

Discontinued Therapy

84

9

Terminated Study

Discontinued Therapy

5

2

Baseline IVUS

Total Collected

Acceptable for Evaluation

78

65

Month 12 IVUS

Total Collected

Acceptable for Evaluation

63

49

Baseline and M12 Paired, Evaluable IVUS 49

Discontinued Pre-Transplant:

121

241

Transplanted

163 *

Randomized

Discontinued Pre-Randomization: 78

*Trial closed before conclusion

of target enrollment n=300 86 (53) primary endpoint analysis

CTOT 11

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Rituximab

(89)

Placebo

(74)

Total Txed

(163)

Donor Age (Yrs) 33.7 33.5 33.6

Male (%) 70.8 73 71.8

Race (%) 70.8 82.4 76.1

Death – Head

Trauma (%)

43.8 39.2 41.7

Recip Age (Yrs) 54.6 54.8 54.7

High Cholesterol 28.1 32.4 30.1

Smoking (%) 50.6 60.8 55.2

Wt (Kg) 86.3 87.2 86.7

BMI 28.9 28.4 28.4

Ischemic Time (Hrs) 3.02 3.23 3.12

Baseline Characteristics

Ch

an

ge in

PA

V a

t M

12

Rituximab Placebo-10

0

10

20

30

40

p=0.0019

Paired IVUS measures were available at

baseline and 1 year in 86 subjects

(49 RIT, 37 PLAC).

Mean (±SD) increase in PAV at 12 mos

6.8 ± 8.2% Rituximab

vs

1.9 ± 4.4% Placebo

Primary Endpoint Result

*

* Subjects who received induction therapy with rituximab had an average change in

percent atheroma volume that was 4.79% higher (p=0.0019) than those who received

placebo induction, when adjusted for baseline PAV.

Hypothesized a 1.5% reduction

with rituximab

Rituximab

(89)

Placebo

(74)

p

value

Total Txed

(163)

Death (1 Yr) 3 (3.4) 5 (6.8) 0.47 8 (4.9)

Re-Tx 0 0 0

PTLD 0 0 0

Local Treated

Rejection22 (24.7) 24 (32.4) 0.276 46 (28.2)

C4d + 11 (12.4) 10 (13.5) 0.827 21 (12.9)

Days to Local

Treated

Rejection

90 ± 104 121 ± 118 0.351 106 ± 111

Central

Rejection

ACR≥2R

13 (14.6) 15 (20.3) 0.307 28 (17.2)

CNI 89 (100) 74 (100) 163 (100)

Steroid 89 (100) 74 100) 163 (100)

MPA 89 (100) 74 (100) 163 (100)

mTOR 5 (5.6) 3 (4.1) 8 (4.9)

Outcomes

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0

10

20

30

40

50

60

500 1000 1500

Pe

rce

nta

ge

Subjects with Anti HLA Abs

detected at 12 months CTOT-11

Class I

ClassII

Class I & II

MFI cutoff

Anti-HLA Abs DSA at V12

% o

f S

ub

jec

ts P

osit

ive f

or

Ab

s

Anti-HLA Class I Class II0

10

20

30

40

50

60

70

80

90

100

Rituximab Placebo

N=80 N=65 N=82 N=65 N=80 N=65

n=28

n=18

n=7

n=12

n=23

n=11

p=0.075 p=0.095

% o

f S

ub

jects

Po

sit

ive f

or

Ab

s

DSA Class I Class II0

10

20

30

40

50

60

70

80

90

100

Rituximab Placebo

N=80 N=65 N=82 N=65 N=80 N=65

n=10 n=8

n=2n=5

n=9

n=3

DSA Data

Ch

an

ge in

PA

V a

t M

12

Rituximab Placebo-10

0

10

20

30

40

DSA*

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Summary & Conclusions

• Use of Rituximab as induction therapy in non-

sensitized cardiac transplant recipients increased

CAV at 12 months.

• Rituximab was not associated with increased

rejection nor development of anti HLA Ab.

• Long-term follow up is required to understand the

effects on graft function and patient survival; CTOT 23

Acknowledgements

RHO

NIAID CTOT staff

Thank You

Randall C Starling MD MPH

starlir@ccf.org

216.536.5231