Transplantation for Light Chain (AL) and

Transthyreitin (TTR) Amyloidosis

Marc J. Semigran MD

Medical Director Heart Failure and Cardiac Transplantation

Massachusetts General Hospital

Associate Professor of Medicine

Harvard Medical School

Introduction

• Patients with cardiac amyloidosis due to either light chain

(AL) or transthyretin (ATTR) deposition presenting with

moderate or greater heart failure have a median survival of

6-8 months.

• Orthotopic heart transplant (OHT), followed by autologous

stem cell transplantation (ASCT) for AL amyloidosis and

often by orthotopic liver transplant (OLT) for ATTR

amyloidosis, have proven successful in small studies.

• Rapid progression of cardiac amyloidosis, particularly AL, as

well as the limited number of donor hearts, mandates that

we understand patient characteristics and treatments that

will lead to the best possible clinical outcomes. This can

provide insight into the timing of referral.

Introduction

Therefore, ten transplant centers in the US and Europe

agreed to pool their patient data for analysis:

Massachusetts General Hosp, NY Presbyterian Med. Ctr.

Houston Methodist Hosp. Stanford U. Med. Ctr.

University of Padova Newark-Beth Israel Med. Ctr.

Boston U Med. Ctr. Cedars-Sinai Med. Ctr.

Cleveland Clinic UC: San Francisco

Methods

• Patients with AL and ATTR amyloidosis undergoing serial

OHT/ASCT (for AL), or either isolated OHT or OHT/OLT (for

ATTR) between 1998-2014 were identified at each of 10

collaborating institutions in the US & Europe.

• Demographic and clinical characteristics, including measures

of both cardiac and extracardiac manifestations of

amyloidosis were entered into the Research Electronic Data

Capture (REDCap) online clinical data registry.

• For patients with AL amyloidosis, clinical characteristics for

patients waitlisted for transplantation who died prior to

receiving a donor organ and those who survived to OHT

were compared.

Methods

• Survival after OHT in AL and ATTR amyloidosis patients

was compared with a contemporaneous age-matched

population of patients with restrictive cardiomyopathy

reported to the Scientific Registry of Transplant Recipients

(SRTR).

• Univariate and multivariate analysis, using Cox regression,

were used to identify predictors of waitlist mortality in AL

amyloidosis patients, and post transplant survival in AL and

ATTR patients.

AL amyloidosis

(n=86)

ATTR

amyloidosis

(n=26) p-value

Age (years) 55 ± 8 61 ± 7 0.001

NYHA (II, III, IV) 4%, 57%, 39% 24%, 48%, 28% 0.017

LVED diameter (cm) 4.0 ± 0.6 4.4 ± 0.6 0.005

Posterior wall thickness (cm) 1.5 (0.4) 1.8 (0.4) < 0.001

Septal wall thickness (cm) 1.5 (0.4) 2.0 (0.8) < 0.001

LVEF (%) 40 ± 13 32 ± 14 < 0.001

Time from diagnosis to OHT evaluation

(days) 338 ±521 913 ± 726

< 0.001

Study Population at the Time of OHT Evaluation

OHT (n=56)

Listed for OHT (n=86)

OHT + ASCT

(n=42)

Died before OHT (n=27)

Reasons:

-Multisystem organ failure (6)

-Cardiac arrest (11)

-Progressive CHF (6)

-Severe sepsis (3)

-Other/unknown (1)

Reasons:

-Multisystem organ failure (2)

-Severe gastrointestinal

hemorrhage and sepsis (1)

-Respiratory failure/ sepsis (1)

Awaiting

Donor (n=3)

Died before

ASCT (n=4)

Died after

ASCT (n=15) Alive at follow-

up (n=27)

Alive, no ASCT

(n=10) -awaiting ASCT (2)

-received chemo (4)

AL Amyloidosis

Reasons:

-Multisystem organ failure with recurrent amyloid (3)

-Multisystem organ failure (2)

-Recurrent amyloid/heart failure (1)

-Severe sepsis (3)

-Cardiac arrest (2)

-Severe diarrhea (1)

-Acute on chronic respiratory failure (1)

-Unknown (2)

Median time from placement on the transplant

waitlist to:

Transplant 25 (41) days

Death 37 (60) days

Characteristics of patients with AL amyloidosis at time

of evaluation stratified by survival to transplant

Died before OHT (n=27) OHT (n=56) p-value

Age (years) 55 ± 9 55 ± 7 0.76

Weight (kg) 84 ± 19 75 ± 13 0.01

Gender, male 18, 67% 29, 52% 0.24

Race, white 18, 67% 46, 82% 0.16

BMI (kg/m2) 26 (6) 26 (4) 0.32

Blood type (A, O, B, AB) 38%, 50%, 8%,4% 45%, 40%, 11%, 4% 0.87

Time from diagnosis to evaluation for OHT (days) 96 (116) 107 (314) 0.08

Time from evaluation to waitlisting for OHT (days) 14 (21) 15 (26) 0.24

New York Heart Association Class (II, III, IV) 0%, 54%, 46% 4%, 61%, 35% 0.58

AICD 5, 19% 4, 7% 0.14

PPM 3, 11% 2, 4% 0.32

data expressed as mean ± standard deviation, median (IQR), or # patients, %.

BMI, body mass index; AICD, automatic internal cardiac defibrillator; PPM, primary pacemaker.

Hemodynamic characteristics at evaluation

stratified by survival to transplant

Died before OHT

(n=27) OHT (n=56) p-value

Mean Arterial Pressure (mmHg) 75 (14) 79 (16) 0.43

Cardiac Index (L/min/m2) 1.7 (0.6) 1.9 (0.5) 0.09

Stroke Volume Index (mL/m2/beat) 22 ± 7 23 ± 6 0.26

Right Atrial Pressure (mmHg) 15 ± 5 12 ± 6 0.05

Pulmonary artery systolic pressure (mmHg) 39 ± 11 42 ± 12 0.38

Pulmonary capillary wedge pressure (mmHg) 21 ± 7 21 ± 7 0.76

Pulmonary vascular resistance (dyne-sec/cm5) 128 (182) 166 (133) 0.29

Left ventricle end diastolic diameter (cm) 4.0 ± 0.6 4.1 ± 0.6 0.62

Posterior wall thickness (cm) 1.6 ± 0.2 1.5 ± 0.3 0.11

Septal wall thickness (cm) 1.6 ± 0.3 1.4 ± 0.3 0.03

Left ventricle ejection fraction (%) 35 ± 12 43 ± 13 0.01

NT-proBNP (pg/mL) 12189 (14997) [n=7] 4947 (7690) [n=14] 0.33

BNP (pg/mL) 3006 (1935) [n=6] 734 (882) [n=24] 0.01

Ventriclar assist device* 6, 22% 4, 7% 0.07

Intra-aortic balloon pump* 10, 37% 12, 21% 0.29

data expressed as mean ± standard deviation, median (IQR), or # patients, %. [n=#pts with data available]

*determined at the time of either transplant or death

Extra-cardiac Amyloid Manifestations at OHT Evaluation

Died before OHT

(n=27) OHT (n=56) p-value

Renal

Biopsy proven (pts+/pts biopsied) 2 / 4 12 / 12 0.05

eGFR (mL/min/1.73m2)Δ 51 (45) 66 (34) 0.06

24hr proteinuria (mg/day) 349 (608) [n=21] 348 (669) [n=40] 0.95

Gastrointestinal

Biopsy proven (pts+/pts biopsied) 19 / 19 25 / 27 0.50

Modified BMI (BMI x albumin) 940 (282) 939 (259) 0.89

Pulmonary

FEV1/FVC (% predicted) 95 (15) [n=18] 86 (16) [n=37] 0.04

DLCO/VA (% predicted) 84 ± 16 [n=9] 84 ± 15 [n=22] 0.95

Hepatic

Total bilirubin (mg/dL) 1.0 (1.0) 0.9 (0.6) 0.37

Alkaline phosphatase (U/L) 101 (84) 107 (66) 0.89

Nervous system

Peripheral neuropathy 4, 15% 7, 13% 1.00

Autonomic neuropathy 4, 15% 0 0.01

data expressed as mean ± standard deviation, median (IQR), or # patients, %. [n= # patients with

given study] Δestimated by MDRD equation.

Hematologic Characteristics at Evaluation for

OHT

Died before OHT

(n=27) OHT (n=56) p-value

% plasma cells in bone marrow 12 (7) 8 (4) 0.02

FLC ratio (lower/higher) 0.041 (0.095)* 0.096 (0.295)Δ 0.11

FLC difference (higher-lower, mg/L) 247 (303)* 96 (207)Δ 0.02

Typing (% lambda) 96% 73% 0.05

data expressed as median (IQR) or # patients

*data available for 18 patients; Δ data available for 44 patients

Predictors of waitlist mortality

A. Univariate analysis, using Cox regression

Covariate

Relative risk of death on

the waitlist 95% CI p-value

LVEF (per %) 0.9610 0.9328 to 0.9907 0.01

Time from diagnosis to eval (per month) 0.9583 0.9187 to 0.9996 0.05

FLC Ratio (per 0.1) 0.6368 0.3948 to 1.0272 0.06

Plasma cells in bone marrow (per %) 1.0709 0.9972 to 1.1499 0.06

B. Multivariate analysis, using Cox Regression: adjusting for age, gender, LVEF, plasma cells in

bone marrow

Covariate

Relative risk of death on

the waitlist 95% CI p-value

FLC Ratio (per 0.1) 0.3049 0.0938 to 0.9904 0.05

A lower FLC ratio at the time of waitlisting was

associated with increased risk of death on the waitlist.

Survival After OHT/ACT for AL Amyloidosis

SRTR restrictive

cardiomyopathy

AL amyloidosis

Time (years)

Su

rviv

al

1.0

0.50

0.25

0

0.75

0 2 4 6

p=0.90

1y=85%

5y=60%

Survival After OHT Alone for AL Amyloidosis

0

20

40

60

80

100

0 1 2 3 4 5

% S

urv

ival

Years post transplantation

Cardiac amyloid

(N=10)

ISHLT registry (N=5633)

Hosenpud et al, Circulation 1991;Suppl III:338-43

15

• No clinical characteristics assessed at the time of evaluation

for OHT were found to predict survival after transplant in AL

amyloidosis patients

• Of patients not treated with chemotherapy prior to OHT

(n=38), the cardiac recurrence rate was 29%.

• Of patients receiving chemotherapy prior to OHT (n=18),

none had recurrence of amyloid in the allograft heart post-

transplant (p=0.01).

Predictors of survival after OHT

OHT only (n=16)

Listed for OHT (n=26)

Died (n=2) Alive at

follow-up

(n=14)

Died before

OHT (n=1)

Awaiting

OHT (n=2)

Reason:

-MSOF

Reasons:

-Sepsis (1)

-Respiratory failure (1)

OHT + OLT (n=7) -sequential (4)

-concurrent (3)

Died (n=4)

Reasons:

-Sepsis (2)

-MSOF (1)

-Recurrent Amyloid (1)

Alive at

follow-up

(n=3)

ATTR Amyloidosis

Mutation

V122I 13

Thr60Ala 2

Other (Val30Met, Ser23Asn, Thr59Lys) 3

Wildtype 3

Unknown 5

Median time from placement on the transplant

waitlist to:

Transplant 186 (47) days

Survival post OHT for ATTR amyloidosis patients

ATTR amyloidosis

SRTR restrictive

cardiomyopathy

1.0

0.75

0.50

0.25

0

Su

rviv

al

Time (years)

2 0 4 6

p=0.08

Summary

1. The rapid progression of AL cardiac amyloidosis is shown by

the significant mortality of patients while awaiting OHT.

2. For AL amyloidosis, those that died while waiting for a donor

heart had higher weight, lower LVEF, and more advanced

hematologic parameters than those that survived to OHT.

3. Cardiac recurrence of amyloid post-transplant occurred in

19% of patients undergoing OHT. No patients treated with

chemotherapy prior to OHT had cardiac recurrence.

4. Survival after heart transplant for either AL or ATTR amyloid

patients is no different than contemporaneous age-matched

groups from the SRTR.

Conclusion

• Orthotopic heart transplant, followed by ASCT for AL and often OLT for ATTR, are appropriate options in the treatment of patients presenting with advanced heart failure due to cardiac amyloidosis. Cardiologists need to diagnose and treat or refer these patients.

• Decreased survival on the transplant waitlist suggests that high-risk AL patients with greater LV wall thickness, depressed LVEF, lower FLC ratio, and λ subtype should be rapidly referred and evaluated for OHT/ASCT.

THANKS!

Alvarez-Munoz J Patel J

Baran D Sarswat N

Cordero A Selby, V

Estep JD Seldin D

Feltrin G Stone JR

Hanna M Tabtabai S

Maurer M Witteles R

Niehaus E, Zucker M

21

AL

Amyloidosis

ATTR

Amyloidosis

Restrictive

Cardiomyopathy*

N 86 26 206

Age (years) 55 ± 8 61 ± 7 55 ± 6

Weight (kg) 77 ± 15 86 ± 23 79 ± 6

Gender, male 48 (56%) 14 (54%) 128 (62%)

Race, white 67 (78%) 12 (46%)

BMI (kg/m2) 26 ± 5 28 ± 8 24 ± 3.0

Time from listing to OHT or death

(days) 57± 72 186 ± 329

Study Population at the Time of OHT Evaluation

*Data obtained at time of transplant

Su

rviv

al

Survival after transplantation

Post-op RRT (n=8)

No post-op RRT (n=46)

Post-op RRT= renal replacement therapy initiated during index transplant hospitalization

Time from OHT to last follow-up/death (years)

5 2 3 4 1 0

0

0.25

0.50

0.75

1.0

Survival post OHT for patients requiring post-op RRT

Log-rank test: p<0.0001