organ transplantation in al amyloidosis...median overall survival on dialysis gertz et al. arch...

Organ transplantation in AL Amyloidosis

Andrea Havasi, MDBoston University

Renal Section

Disclosure of Conflict of Interest

I do not have a relationship with a for-profit and/or a not-for-profit organization to disclose

Renal Involvement in AL amyloidosis

• Over 70-78% of patients present with renal involvement

• Up to 40% require renal replacement therapy (RRT)

Gertz MA et al. Kidney Int. 2002. Gertz MA et al. Nephrol Dial Transplant. 2009. Havasi A et al. Am J Hematol. 2016.Palladini G et al. Blood. 2014.Sidiqi MH et al. Bone Marrow Transplant. 2019

Overall survival from diagnosis

Kyle RA et al. N Engl J Med 1997.

Gertz MA et al. Nephrol Dial Transplant. 2009.

Havasi A et al. Am J Hematol. 2016.

Palladini G et al. Blood. 2014.

Sidiqi MH et al. Bone Marrow Transplant. 2019

1990’s

• 12-18 months

Today

• HDM/SCT BU cohort with renal involvement: 8.2 years

• HDM/SCT Mayo cohort with or without renal involvement: 11.2 years

• All patients Pavia cohort: 3.9 years

• All patients Heidelberg cohort: 4.5 years

More patients with ESRD

Median overall survival on dialysis

Gertz et al. Arch Intern Med. 1992.

Havasi A et al. Am J Hematol. 2016.

Palladini G et al. Blood. 2014.

Sidiqi MH et al. Bone Marrow Transplant. 2019.

Batalini F at al. Biol Blood Marrow Transplant. 2018.

1990’s

• 8.2 months

Today

• 24-39 months; regardless of treatment modality

After starting dialysis mortality is mainly driven by

ESRD!!

(but OS 5.8 years if ESRD was reached before

HDM/SCT; 6% became dialysis-independent after

achieving CR and 33% had kidney transplantation)

Renal transplantation in AL amyloidosis??

• Concerns about recurrence in the graft

• Lack of data regarding overall survival and renal transplant outcomes

• No clear guidelines regarding renal transplant eligibility

Limited referral or acceptance

for renal transplantation

49 AL amyloidosis pts

Boston University

Amyloidosis Center

1987-2017

Median follow up

7.2 years

(0-19)

Angel-Korman A et al. KI. 2019.

Clinical features at diagnosis

Feature Median (range)

Age (years) 53.7 (26.4-73.8)

Gender Male: 82%

Race White 98%

Light chain clonalityLambda 61%

Kappa 37%

Creatinine 2 mg/dL (0.4-12)

eGFR 36 mL/min/1.73m2 (2-117)

Proteinuria 7.2 g/24 hr (0.1-42)

Organ involvementRenal only 20%, Cardiac 33%,

≥3 organs 43%

OS from diagnosis 15.4 years (1-20.7)

Renal transplant characteristics

Feature Median (range)

Age at renal transplantation60.1 years (30.7-73.2)

ESRD statuspre-emptive 18%

post RRT 82%

Transplant type

Living donor 65%

Deceased donor 20%

Unknown 15%

Time from diagnosis to ESRD 1.5 years (0-10.3)

Time from diagnosis to renal

transplantation4 years (-5.7-12)

Time from ESRD to renal

transplantation1.9 years (0.2-11.3)

Time from hematologic response to

renal transplantation

2.4 years (0.4-10.4)

Number of transplants per decade


Overall survival after renal

transplant improved over the last

decade

OS from diagnosis OS from transplant


Graft survival and recurrence rate

after renal transplant improved over

the last decade

Graft survival Recurrence in the graft


Renal transplant outcomes –Overall survival


USRDS

(cadaveric/

living)

(All

etiologies)

Our

cohort

(AL

only)

UK

National

amyloidosi

s center

2010

(AL only)

Mayo

clinic 2011

(AL only)

All types of

amyloid

patients

USRDS

2017

>65 yrs

(cadaveric/

living)

(All

etiologies)

DM

(cadaveric

/living)

(All

etiologies)

Number

of

patients

49 22 19 576

Overall

Survival

(years

from

renal Tx)

Media

nN/A

10.5

(1-20.3)

6.5

(0.2-13.3)

Not

reached5.8 N/A N/A

1 yr 97%/98.7% 96% 95% N/A 91% 94.2%/96% 96%/97%

3 yrs N/A 91% N/A N/A N/A 86%/89.5% 89%/93%

5 yrs 86%/93% 86% 67% N/A 70% 74%/82% 83%/87%

Renal transplant outcomes –Overall survival

Adapted from Angel-Korman A et al. KI. 2019.

USRDS

(cadaveric/

living)

(All

etiologies)

Our

cohort

(AL

only)

UK

National

amyloidosi

s center

2010

(AL only)

Mayo

clinic 2011

(AL only)

All types of

amyloid

patients

USRDS

2017

>65 yrs

(cadaveric/

living)

(All

etiologies)

DM

(cadaveric

/living)

(All

etiologies)

Number

of

patients

49 22 19 576

Overall

Survival

(years

from

renal Tx)

Media

nN/A

10.5

(1-20.3)

6.5

(0.2-13.3)

Not

reached5.8 N/A N/A

1 yr 97%/98.7% 96% 95% N/A 91% 94.2%/96% 96%/97%

3 yrs N/A 91% N/A N/A N/A 86%/89.5% 89%/93%

5 yrs 86%/93% 86% 67% N/A 70% 74%/82% 83%/87%

Renal transplant outcomes –Graft survival

USRDS

(cadaveric/

living)

(All etiologies)

Our

cohort

(AL

only)

UK National

amyloidosis

center 2010

(AL only)

Mayo clinic

2011

(AL only)

All types of

amyloid

patients

USRDS

2017

>65 yrs

(cadaveric

/living)

(All

etiologies)

DM

(cadaveric

/living)

(All

etiologies)

Number

of

patients

49 22 19 576

Median

Graft

Survival

(years)

9.1

6.9

(0.5-

18.8)

5.8Not

reached4.8

1 yrs 93.4%/97.2% 94% N/A (74%) N/A N/A/94% 92%/96%

3 yrs N/A 89% N/A N/A N/A N/A/87% 83%/88.5%

5 yrs 72.4%/84.6% 81% N/A (53%) N/A N/A/78% 73%/81.5%


Eligibility criteria for renal

transplantation?

Overall survival from diagnosis:CR/VGPR vs PR/NR

Median OS:

17.9 y vs 9.7 y


Overall survival from renal transplant:

CR/VGPR vs PR/NR

Median OS:

11.7 y vs 7 y


Graft survival:CR/VGPR vs PR/NR

Median time to

graft loss:

10.4 y vs 5.5 y


Recurrence of amyloid in the graft

• 14 pts (29%) had recurrent amyloidosis in the graft

• Median time from renal transplantation to

recurrence: 3.7 years (range 1.1-11.9)

• 20 pts received treatment for hematologic relapse:

graft survival was not different from the pts without

relapse (6.9 vs 8.3 years, p=0.35)

• 4 pts lost the graft due to amyloidosis

• 10 pts were successfully treated

• 6 pts HDM/SCT >>> VGPR or CR


Lower recurrence in the graft in CR/VGPR

Time from renal transplantation to recurrence in the graft: CR/VGPR vs

PR/NR


Cause of death # of pts

Progressive amyloidosis 10/23

Renal failure 2

Treatment related 2

Sepsis 2

Heart failure (non-AL) 1

Surgical complication (unrelated) 1

CVA 1

Unknown 4

Cause of death in kidney transplant recipients


No difference in OS and graft survival

• HDM/SCT vs. chemotherapy (39 vs 10 pts)

• Hematologic relapse vs no relapse (20 vs 29 pts)

• HDM/SCT before vs after renal transplantation (33

vs 6 pts)

• Living vs. cadaveric

• Pre-emptive

• Number of organs involved

• Cardiac involvement at the time of diagnosis

• κ vs λ

What does not seem to change renal

transplant outcome?

• Standard therapies

• No change in regimen while getting treatment for

AL amyloidosis

• During SCT: mycophenolate on hold

• Only 4 acute rejections

Immunosuppressive regimens

• 4 y (range -5.7-12) from diagnosis

• 1.9 y (range 0.2-11.3) from ESRD

• 2.4 y (range 0.4-10.4) from hematological response

Why?

• The time it requires to go through the transplant

evaluation (both recipient and donor, if available)

• Wait time on the cadaveric transplant list

• Patients’ preference regarding the timing of

transplantation

Timing of renal transplantation

Wait 6-12 months post hematologic response

to document the durability of response and to

recover from therapy related toxicities

Timing of renal transplantation

Our recommendation

Limitations

• Small sample size

• Mostly white (98%) perhaps representing under-diagnosis of amyloidosis in other races or ethnicities

• Retrospective study

• The choice of treatment, the timing of treatment and renal transplantation were physician and patient dependent >>>>> selection bias

Heart transplantation in AL

amyloidosis

• Mayo Clinic; 1992-2011; 23 pts; median age 53

• OS: 3.5 years (95%CI: 1.2-8.2)

• OS in CR (=7 pts) in response to chemoth or

HDM/SCT: 10.8 years

• Survival is better in pts with limited extra-cardiac

involvement

• 5-year survival 43% vs 85% for non-amyloid

• Eight patients had rejection at a median of 1.8

months post OHT (range 0.4 to 4.9 mo)

What did we learn from heart transplants?

Grogan M at al. World J Transplant. 2016.

Gray Gilstrap L at al. J Heart Lung Transplant. 2014.

Grogan M at al. World J Transplant. 2016.

Cause of death # of pts

Progressive amyloidosis 12/20

Complications of HDM/SCT 3

Post-transplant lymphoproliferative disorder 2

Acute rejection 1

Cardiac vasculopathy 1

Metastatic melanoma 1

Myelodysplastic syndrome 1

Unknown 1

Cause of death in heart transplant recipients

• MGH/BU; 2000-2011

• 18 pts

• median age 56

• OHT followed by HDM/SCT

• OS similar to non-amyloid, restrictive (p = 0.34),

non-amyloid dilated (p = 0.34), or all non-amyloid

cardiomyopathy patients (p = 0.22) in the SRTR

database


Dey BR at al. Transplantation. 2010.

Disease-free survival of heart

transplant recipients

0

0.2

0.4

0.6

0.8

1

0 20 40 60 80 100

■MGH/BU♦Hosenpud

Dis

ease

-fre

e S

urv

ival

P=0.04

Hosenpud JD at al. Circulation 1991.

Dey BR at al. Transplantation. 2010.

• Survival is better in pts with limited extra-cardiac

involvement, s/p HDM/SCT and CR

• More rejection episodes


• Kidney transplantation can have a good outcome in carefully selected AL amyloidosis patients

• Recurrence of disease can still be managed without leading to graft loss

• Peri-transplant and post-transplant management require a multidisciplinary approach involving nephrologists, transplant surgeons and hematologists with experience in the treatment of this rare disease

Summary

Summary

We recommend consideration of renal

transplantation for those patients who

achieved CR or VGPR

• Should dialysis-dependent pts without extra-renal

amyloidosis receive chemotherapy while on dialysis

for the sole purpose of achieving a clonal response

to allow listing or undergo renal transplantation

followed by chemotherapy/SCT to prevent ongoing

amyloid deposition and disease recurrence in the

graft?

• Renal transplantation while being actively treated?

• Larger cohort?

Further questions

ACKNOLEDGMENTS

• The McCaleb Award from the Amyloidosis Center, Boston University School of Medicine, Alan and Sandra Gerry Amyloid Research Laboratory

• NIH/NIDDK/K08

• The Renal Section, Boston Medical Center

www.bu.edu/amyloid [email protected]; [email protected]

Thank you!

http://www.bu.edu/amyloid

mailto:[email protected]

organ transplantation in al amyloidosis...median overall survival on dialysis gertz et al. arch...

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