clinical outcomes of perioperative desensitization in

CLINICAL OUTCOMES OF PERIOPERATIVE DESENSITIZATION IN ORTHOTOPIC HEART TRANSPLANT

RECIPIENTS

Michael E. Plazak, PharmD; Stormi E. Gale, PharmD; Brent N. Reed, PharmD; Sara Hammad, PharmD; Van-Khue Ton, MD, PhD; David J. Kaczorowski, MD; Bharath Ravichandran, PharmD

Table of Contents

Figure S1. Rabbit Anti-Thymocyte Globulin Induction Pathway .................................................... 2

Figure S2. Alemtuzumab Induction Pathway .................................................................................. 3

Figure S3. Standard Immunosuppression Pathway ........................................................................ 4

Figure S4. Freedom from Acute Rejection at 12 months ............................................................... 5

Figure S5. Freedom from Antibody-Mediated Rejection and Acute Cellular Rejection at 12 Months ............................................................................................................................................ 6

Figure S6. Freedom from ISHLT CAV1 at 12 Months ...................................................................... 7

Figure S7. Freedom from Use of Granulocyte-Colony Stimulating (G-CSF) Factor at 12 Months .. 8

Figure S8. Glomerular Filtration Rate Over 12 Months .................................................................. 9

Figure S9. White Blood Cell Count Over 12 Months ..................................................................... 10

Figure S10. Serum Tacrolimus Troughs Over 12 Months ............................................................. 11

Figure S11. Corticosteroid Dosing Over 12 Months ..................................................................... 12

Table S1. Maintenance Immunosuppression Pathways ............................................................... 13

Table S2. Desensitization Maintenance Immunosuppression Pathway ....................................... 14

Table S3. Infectious Disease Prophylaxis ...................................................................................... 15

Table S4. Infectious and Malignancy Outcomes at 12 Months .................................................... 16

Table S5. Opportunistic Infection Prophylaxis .............................................................................. 17

Table S6. Laboratory Data ............................................................................................................. 18

Table S7. Surgical Data .................................................................................................................. 21

2

Figure S1. Rabbit Anti-Thymocyte Globulin Induction Pathway

POD OR 0 1 2 3 4

Methylprednisolone 500 mg

IV

250 mg

IV

125 mg

IV

125 mg

IV

rATG 1.5 mg/kg

IBW

1.5 mg/kg

IBW

1.5 mg/kg

IBW

1.5 mg/kg

IBW

Prednisone 20 mg

PO

20 mg

PO

Tacrolimus* 8-10

ng/mL

8-10

ng/mL

8-10

ng/mL

8-10

ng/mL

8-10

ng/mL

MMF or equivalent 2000 mg

PO

2000 mg

PO

2000 mg

PO

2000 mg

PO

2000 mg

PO

Abbreviations: IV - intravenous, PO - by mouth, POD - post-operative day, rATG - rabbit anti-thymocyte

globulin, MMF – mycophenolate mofetil

*Goal tacrolimus trough and initiation date may be adjusted based on patient-specific characteristics, or

therapy may be held for 24-48 hours if induction is being used to delay calcineurin inhibitor initiation

3

Figure S2. Alemtuzumab Induction Pathway

POD OR 0 1 2 3 4 5


IV

500 mg

IV

Alemtuzumab 30 mg

IV

30 mg

IV

Prednisone 10 mg

PO

Tacrolimus* 8-10

ng/mL

8-10

ng/mL

8-10

ng/mL

8-10

ng/mL

8-10

ng/mL

8-10

ng/mL

MMF or equivalent 2000 mg

PO

2000 mg

PO

2000 mg

PO

2000 mg

PO

2000 mg

PO

2000 mg

PO

Abbreviations: IV - intravenous, PO - by mouth, POD - post-operative day, MMF – mycophenolate

mofetil

*Goal tacrolimus trough and initiation date may be adjusted based on patient-specific characteristics, or

therapy may be held for 24-48 hours if induction is being used to delay calcineurin inhibitor initiation

4

Figure S3. Standard Immunosuppression Pathway

POD OR 0 1 2 3 4 5 6 7


IV

125 mg

IV x 3

80 mg

IV

70 mg

IV

60 mg

IV

50 mg

IV

40 mg

IV

30 mg

IV

Prednisone 20 mg

PO

Tacrolimus 10-15

ng/mL

10-15

ng/mL

10-15

ng/mL

10-15

ng/mL

10-15

ng/mL

10-15

ng/mL

10-15

ng/mL

10-15

ng/mL

MMF or equivalent 2000

mg PO

2000

mg PO

2000

mg PO

2000

mg PO

2000

mg PO

2000

mg PO

2000

mg PO

2000

mg PO

Abbreviations: IV - intravenous, PO - by mouth, POD - post-operative day, MMF – mycophenolate

mofetil

5

Figure S4. Freedom from Acute Rejection at 12 months

Figure S4A. Freedom from any acute rejection at 12 months. Figure S4B. Freedom from ISHLT grade ≥ 2R

ACR or grade 2 pAMR at 12 months.

0 60 120 180 240 300 3600

20

40

60

80

100

Time from transplant (days)

Fre

ed

om

fro

mre

ject

ion

(%)

No Induction

Induction

Desensitization

p=0.01 by log-rank testHR, 0.36; 95% CI, 0.08-1.51; p=0.16 for Desensitization vs. No InductionHR, 0.93; 95% CI, 0.21-4.18; p=0.92 for Desensitization vs. Induction

0 60 120 180 240 300 3600

20

40

60

80

100


Fre

ed

om

fro

mse

vere

reje

ctio

n(%

)

No Induction

Induction

Desensitization


S4A.

S4B.

6

Figure S5. Freedom from Antibody-Mediated Rejection and Acute Cellular Rejection at 12 Months

Figure S5A. Freedom from ISHLT grade ≥ 2 pAMR. Figure S5B. Freedom from ISHLT grade ≥ 2R ACR

0 60 120 180 240 300 3600

20

40

60

80

100

Tim e from transplant (days)

Fre

ed

om

fro

mse

vere

AM

R(%

)

No Induction

Induction

Desensitization

p=0.49 by log-rank test

HR and 95% CI could not be calculated; p=0.62 for Desensitization vs. No Induction*

HR and 95% CI could not be calculated; p=0.78 for Desensitization vs. Induction*

0 60 120 180 240 300 3600

20

40

60

80

100


Fre

ed

om

fro

mse

vere

AC

R(%

)

No Induction

Induction

Desensitization

p=0.08 by log-rank testHR, 1.01; 95% CI, 0.12-8.62; p=0.99 for Desensitization vs. No Induction

HR and 95% CI could not be calculated; p=0.75 for Desensitization vs. Induction*

S5A.

S5B.

7

Figure S6. Freedom from ISHLT CAV1 at 12 Months

0 60 120 180 240 300 360

0

20

40

60

80

100


Free

do

mfr

om

ISH

LTC

AV

1(%

)

No Induction

Induction

Desensitization


8

Figure S7. Freedom from Use of Granulocyte-Colony Stimulating (G-CSF) Factor at 12 Months

0 60 120 180 240 300 3600

20

40

60

80

100


Fre

ed

om

fro

mG

-CSF

Use

(%)

No Induction

Induction

Desensitization

p=0.40 by log-rank testHR, 0.66; 95% CI, 0.08-5.33; p=0.69 for Desensitization vs. No InducationHR, 0.39; 95% CI, 0.05-3.03; p=0.37 for Desensitization vs. Induction

9

Figure S8. Glomerular Filtration Rate Over 12 Months

40

50

60

70

80

90


Glo

me

rula

rfi

ltra

tio

nra

te(m

L/m

in)

No Induction

Induction

Desensitization

7 30 90 180 365

*

10

Figure S9. White Blood Cell Count Over 12 Months

* p<0.05 for comparison of no induction cohort to induction cohort

‡ p<0.05 for comparison of no induction cohort to desensitization cohort

0

2

4

6

8

10

12

14


Wh

ite

blo

od

cell

cou

nt

(K/m

m3 )

No Induction

Induction

Desensitization

‡

*

7 30 90 180 365

*

11

Figure S10. Serum Tacrolimus Troughs Over 12 Months


† p<0.05 for comparison of induction cohort to desensitization cohort


0

2

4

6

8

10

12

14


Tacr

oli

mu

str

ou

ghco

nce

ntr

atio

n(n

g/m

L)

No Induction

Induction

Desensitization

7 30 90 180 365

*

‡

†

*

*

*

12

Figure S11. Corticosteroid Dosing Over 12 Months




0

10

20

30

40

50


Co

rtic

ost

ero

idd

ose

(mg/

day

)

No Induction

Induction

Desensitization

7 30 90 180 365

*

†

‡

*

†

*

13

Table S1. Maintenance Immunosuppression Pathways

Time Tacrolimus goal (ng/mL) Mycophenolate mofetil Prednisone

Standard Induction Standard Induction Standard Induction

1 – 3 months

10–15 8–10

1000 mg BID 500-1000 mg BID 15 mg

0–10 mg 3 – 6 months

8–12 1000 mg BID

10 mg

6 – 12 months

8–12 0–5 mg

Abbreviations: BID - twice daily

14

Table S2. Desensitization Maintenance Immunosuppression Pathway

Time Tacrolimus goal (ng/mL) Mycophenolate mofetil Prednisone

1 – 3 months

10–15 1000 mg BID 15 mg

3 – 6 months

8–12 1000 mg BID 10 mg

6 – 12 months

8–12 1000 mg BID 0-5 mg

Abbreviations: BID - twice daily

15

Table S3. Infectious Disease Prophylaxis

Indication Criteria Medication Dose Duration

Antibacterial Pending donor

cultures Ceftriaxone 2 g IV q24h

48 hours after

chest closure

Antifungal All patients Vancomycin 10-15 mg/kg IV

q12h-24h

48 hours after

chest closure

Antiviral

CMV R+ or D-/R- Valganciclovir 900 mg daily 6 months

CMV D+/R- Valganciclovir 900 mg daily Up to 12 months

Pneumocystis

jirovecii and

Toxoplasma

gondii

Preferred Sulfamethoxazole/

trimethoprim 400-80 mg daily 6 months or until

prednisone < 10

mg/day Sulfa-allergic Dapsone 100 mg daily

G6PD deficiency Atovaquone 1500 mg daily

Toxoplasma gondii*

Pyrimethamine/

Leucovorin

50 mg weekly/

25 mg weekly Consider lifelong

Abbreviations: CMV - cytomegalovirus, D - donor, R - recipient, G6PD - glucose-6-phosphate

dehydrogenase, IV - intravenous, q - every.

*If not on preferred regimen

16

Table S4. Infectious and Malignancy Outcomes at 12 Months

Desensitization

(n=10) No Induction

(n=48) Induction

(n=46) p-value

Infectious complication 1 (10.0) 8 (16.7) 14 (30.4) 0.17

Type of infection

C. difficile 0 (0.0) 5 (10.4) 3 (6.5) 0.49

CMV viremia 1 (10.0) 4 (8.3) 10 (21.7) 0.17

Fungal 0 (0.0) 3 (6.3) 2 (4.3) 0.69

Atypical 0 (0.0) 0 (0.0) 1 (2.2) 0.53

Donor-derived 1 (10.0) 1 (2.1) 2 (4.3) 0.48

Malignancy 0 (0.0) 2 (4.2) 1 (2.2) 0.72

G-CSF Use 1 (10.0) 7 (14.6) 11 (23.9) 0.39

Abbreviations: CMV – cytomegalovirus, G-CSF – granulocyte colony-stimulating factor

17

Table S5. Opportunistic Infection Prophylaxis

Desensitization

(n=10)

No Induction

(n=48)

Induction

(n=46) p-value

PJP Prophylaxis – n (%)

Day 7* 2 (20.0) 19 (39.6) 8 (17.4) 0.02

Month 1 7 (70.0) 43 (89.6) 35 (76.1) 0.14

Month 3* 9 (90.0) 43 (89.6) 30 (65.2) 0.002

Month 6* 7 (70.0) 36 (75.0) 20 (43.4) 0.003

CMV Prophylaxis – n (%)

Day 7 9 (90.0) 45 (93.8) 44 (95.7) 0.73

Month 1 10 (100.0) 48 (100.0) 43 (93.5) 0.14

Month 3* 9 (90.0) 44 (91.7) 36 (78.3) 0.04

Month 6 6 (60.0) 39 (81.3) 29 (63.0) 0.09

Abbreviations: CMV - cytomegalovirus, PJP - Pneumocystis jirovecii

* p<0.05 for comparison of no-induction cohort to induction cohort

18

Table S6. Laboratory Data

Desensitization

(n=10)

No Induction

(n=48)

Induction

(n=46) p-value

Hemoglobin A1c

Baseline 5.8 (5.6-6.4) 5.6 (5.2-6.3) 5.9 (5.4-6.7) 0.32

12 months* 6.4 (5.4-8.9) 5.7 (5.3-6.1) 6 (5.6-6.9) 0.02

Total cholesterol

(mg/dL)

Baseline 115 (111-124) 130.5 (112.3-161.8) 146.5 (110.3-165.8) 0.20

12 months 145.5 (113-187.5) 148 (123-168.5) 158 (136-190) 0.18

Triglycerides

(mg/dL)

Baseline 127 (50.5-171.5) 109.5 (69-138.8) 95 (62-141.5) 0.61

12 months 127.5 (76.3-197.5) 104.5 (81.5-152.5) 102 (77-159) 0.87

High-density lipoprotein

(mg/dL)

Baseline 46 (29-57.5) 40 (30.5-49.5) 37.5 (29-61.8) 0.83

12 months 50 (37-68.3) 43.5 (36.8-56) 47 (39-56.5) 0.73

Low-density lipoprotein

(mg/dL)

Baseline† 48 (46-59) 66 (48-85.5) 77.5 (57-96.8) 0.04

12 months 75 (50.3-80.5) 74.5 (57-88.8) 87 (67-109.5) 0.06

19

Serum creatinine

(mg/dL)

Baseline* 1.48 (1.04-1.81) 1.00 (0.85-1.23) 1.35 (0.96-1.81) 0.002

Day 7 1.11 (1.03-1.40) 1.05 (0.87-1.31) 1.1 (0.87-1.44) 0.49

Month 1 1.41 (0.99-1.9) 1.14 (0.94-1.42) 1.38 (1-1.82) 0.06

Month 3 1.51 (1.06-1.8) 1.3 (1.05-1.46) 1.37 (1.15-1.67) 0.67

Month 6 1.49 (1.24-1.87) 1.33 (1.07-1.64) 1.45 (1.15-1.75) 0.29

Month 12 1.35 (1.20-1.76) 1.41 (1.2-1.67) 1.52 (1.30-1.88) 0.38

Glomerular filtration

rate (mL/min)

Baseline* 57.4 (39.3-88.4) 85.7 (61.9-107) 58.3 (43.6-92.3) 0.007

Day 7 74.1 (62.5-81.1) 75.6 (60-106.4) 76.7 (55.4-97.1) 0.67

Month 1 61.6 (43.7-78) 69.2 (56.2-88.9) 60 (40.3-83.7) 0.10

Month 3 59.3 (44.5-83.1) 60.6 (51-75.2) 63.4 (45.5-79.6) 0.90

Month 6 50 (38.1-67.9) 62.2 (44-82.2) 55 (43.8-73.1) 0.33

Month 12 55.9 (40-73.5) 59.5 (43.3-67.9) 49.7 (40.7-70.2) 0.68

White blood cell count

(K/mm3)

Baseline 6.7 (4.9-12.4) 8.3 (5.8-13.4) 7.4 (6.2-10.8) 0.63

Day 7*‡ 9.7 (6.9-12.5) 13.2 (10.9-16.1) 9.8 (7.6-13.2) 0.0002

Month 1* 6.5 (5-9.9) 7.9 (6.6-9.9) 5.6 (4-7.4) 0.0002

Month 3 5.8 (3.6-7.1) 4.7 (3.7-7.7) 4.3 (3.2-5.9) 0.23

Month 6 4.2 (2.8-6.4) 4.5 (3.7-6) 4 (3.4-5.4) 0.35

Month 12 4.9 (3.6-9.3) 5.4 (3.9-6.8) 4.7 (4-5.9) 0.61

20

Platelet count (K/mm3)

Baseline 213 (149-257) 153 (133.3-205.5) 180 (127.5-232.3) 0.16

Day 7†‡ 72 (61.5-113.5) 150.5 (118.5-204) 129 (102-177.8) 0.001

Month 1 292 (217.5-406.5) 281 (235-339.3) 277.5 (212.5-335.8) 0.76

Month 3 217 (156.5-287.5) 207 (153-248) 223 (185-257) 0.27

Month 6 197 (153.5-240.5) 194 (164-237) 202 (162.8-229.3) 0.96

Month 12 206 (137-257) 179 (163-217) 197.5 (151.5-248.8) 0.86

* p<0.05 for comparison of no-induction cohort to induction cohort

† p<0.05 for comparison of desensitization cohort to induction cohort

‡ p<0.05 for comparison of desensitization cohort to no-induction cohort

21

Table S7. Surgical Data

No Induction

(n=48)

Induction

(n=46)

Desensitization

(n=10)

p-value

Surgery time (minutes) 567.5 (524.5-625) 556 (518-671) 499.5 (456.8-762.3 0.52

CPB time (minutes) 184 (150.5-206.5) 190 (157-226.3) 181 (142-235.5) 0.74

Cross clamp time

(minutes)

100 (82.5-123) 99 (87.5-136) 98 (78.8-112.3) 0.78

OR red blood cell

transfusions (units)

3 (2-6) 5 (1-7.3) 4 (1-10.5) 0.67

OR platelet transfusions

(units)

2 (1-2) 2 (1-3) 2.5 (1-3.3) 0.21

OR fresh frozen plasma


6 (3-7) 4 (3.5-8) 11 (0-17) 0.14

OR cryoprecipitate


2 (2-4) 2 (0.8-4) 4 (2-6.3) 0.19

Total day 7 red blood cell


4 (2-8) 6 (2-10) 6 (2-12) 0.46

Total day 7 platelet


2 (1-3) 3 (2-4) 3.5 (1.8-8) 0.12

Total day 7 fresh frozen

plasma†‡ (units)

7 (4-8) 5.5 (3-8) 19 (8.3-24.8) 0.02

22

Total day 7

cryoprecipitate


2 (2-4) 2 (1-4.3) 4 (3.5-7) 0.13

Abbreviations: CPB – cardiopulmonary bypass time; OR – operating room



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