CLINICAL AND TRANSLATIONAL RESEARCH
Cardiac Transplantation Followed by Dose-Intensive
Melphalan and Autologous Stem-Cell Transplantation
for Light Chain Amyloidosis and Heart Failure
Bimalangshu R. Dey,1Stephen S. Chung,1Thomas R. Spitzer,1Hui Zheng,2Thomas E. MacGillivray,3
David C. Seldin,4Steven McAfee,1Karen Ballen,1Eyal Attar,1Thomas Wang,5Jordan Shin,5
Christopher Newton-Cheh,5Stephanie Moore,5Vaishali Sanchorawala,4Martha Skinner,4
Joren C. Madsen,3and Marc J. Semigran5,6
Background. Patients with light chain (AL) amyloidosis who present with severe heart failure due to cardiac involvement
rarely survive more than 6 months. Survival after cardiac transplantation is markedly reduced due to the progression of
Methods. We developed a treatment strategy of cardiac transplant followed by ASCT. Twenty-six patients were eval-
received an ASCT.
Results. Six of seven evaluable patients achieved a complete hematologic remission, and one achieved a partial remis-
sion. At a median follow-up of 56 months from cardiac transplant, five of seven patients are alive without recurrent
amyloidosis. Their survival is comparable with 17,389 patients who received heart transplants for nonamyloid heart
disease: 64% in nonamyloid vs. 60% in amyloid patients at 7 years (P?0.83). Seven of eight transplanted patients have
had no evidence of amyloid in their cardiac allograft.
Conclusions. This demonstrates that cardiac transplantation followed by ASCT is feasible in selected patients with AL
amyloidosis and heart failure, and that such a strategy may lead to improved overall survival.
Keywords: Amyloid, Cardiac amyloidosis, Stem-cell transplantation.
(Transplantation 2010;90: 905–911)
ystemic AL amyloidosis is a plasma cell dyscrasia (PCD)
marked by the progressive systemic deposition of mono-
to organ failure and death (18). Conventional chemotherapy
median survival to only 18 to 24 months (1–4). The overall
survival of these patients has been improved by the use of
high-dose chemotherapy and autologous stem-cell trans-
plantation (ASCT), leading to a median survival of 4.6 years
(5–7). Patients with AL amyloidosis who present with severe
heart failure due to cardiac amyloidosis have particularly
poor prognosis, with a median survival of only 6 months and
a 100% mortality at 2 years (1, 3, 8–10). In addition, patients
tially higher ASCT-related mortality with survival outcomes
inferior to those without cardiac involvement (5, 11) and,
therefore, are currently precluded from undergoing ASCT at
There are no conflicts of interest for the authors to disclose.
1Hematology/Oncology, Massachusetts General Hospital, Boston, MA.
2Biostatistics Center, Massachusetts General Hospital, Boston, MA.
3Cardiac Surgery, Massachusetts General Hospital, Boston, MA.
4Stem Cell Transplantation and Amyloid Treatment and Research Pro-
grams, Department of Medicine, Boston University School of Medicine
and Boston Medical Center, Boston, MA.
5Cardiology, Massachusetts General Hospital, Boston, MA.
6Address correspondence to: Marc J. Semigran, M.D., Bigelow 800, Massa-
chusetts General Hospital, Fruit St., Boston, MA 02114.
Dey participated in writing and editing of manuscript, collection of and
analysis of data, direct care of patients undergoing bone marrow trans-
plantation; Chung participated in writing and editing of manuscript,
collection and analysis of data; Spitzer participated in direct care of pa-
tients undergoing bone marrow transplantation; Zheng participated in
statistical analysis of data; MacGillivray and Madsen participated in di-
rect care of patients undergoing orthotopic heart transplantation; Seldin
participated in initial diagnosis of and direct care of patients who pre-
sented to Boston Medical Center; McAfee, Ballen and Attar participated
in direct care of patients undergoing bone marrow transplantation;
Wang, Shin, Newton-Cheh, and Moore participated in direct care and
management of heart failure in our patients; Sanchorawala and Skinner
to Boston Medical Center; and Semigran participated in writing and
editing of manuscript and the revision, collection and analysis of data,
direct care and management of heart failure in our patients.
Received 4 January 2010. Revision requested 14 January 2010.
Accepted 7 July 2010.
Copyright © 2010 by Lippincott Williams & Wilkins
Transplantation • Volume 90, Number 8, October 27, 2010www.transplantjournal.com | 905
In 1988, cardiac transplantation began to be used to
treat AL amyloidosis patients with overt heart failure (12).
was markedly reduced because of progressive amyloid depo-
sition causing severe organ dysfunction, often involving the
cardiac allograft (12–15). Hosenpud et al. (13) reported a
4-year survival rate of 39% in these cardiac transplant recip-
ients, with significant systemic progression of amyloidosis in
plantation as a therapeutic option for these patients. More
reported a 5-year survival of 38% in recipients with AL amy-
loidosis compared with 67% in recipients with heart failure
due to nonamyloid causes (14). Based on these discouraging
outcomes and the shortage of donor organs, amyloid heart
heart transplantation (OHT).
osis who received high-dose melphalan followed by ASCT
vival without progressive amyloid deposition, if amyloid pa-
tients undergoing cardiac transplantation were subsequently
diac transplantation followed by ASCT has been shown to be
feasible with an apparent improvement in survival in care-
fully selected patients with AL amyloidosis presenting with
severe heart failure (17, 18).
In 2000, we developed a treatment strategy for patients
with systemic AL amyloidosis and heart failure consisting of
cardiac transplantation followed by ASCT, with the goal of
this study, we report the outcomes of 26 patients with AL
amyloidosis complicated by severe heart failure referred to
the Massachusetts General Hospital for sequential cardiac
transplantation and dose-intensive melphalan and ASCT.
MATERIALS AND METHODS
versity School of Medicine/Boston Medical Center Amyloid Treatment and
heart failure despite medical therapy. Institutional Review Board approval
was obtained to analyze the outcomes of these patients. High-dose chemo-
therapy/ASCT without a prior OHT was contraindicated in all patients be-
cause of severe involvement of the heart by amyloidosis. All patients had the
tions, and bone marrow biopsies. Cardiac amyloidosis was confirmed by
endomyocardial biopsy and Congo red staining. Immunohistochemistry of
type of light chains present, lambda versus kappa. The diagnosis of heart
failure was confirmed by right heart catheterization showing increased ven-
tricular filling pressures, a depressed cardiac index, or both. All patients
underwent coronary angiography to exclude significant epicardial coronary
artery disease. In addition to the routine cardiac transplant evaluation stud-
osis, including upper and lower gastrointestinal endoscopies with biopsies.
Patients with hepatic dysfunction or renal dysfunction (defined as serum
creatinine ?2.0, serum alanine/aspartate aminotransferase ? twice the up-
(right atrial pressure ? 8 mm Hg, cardiac index ?2.4 L/min m2) underwent
liver biopsy, kidney biopsy, or both. Patients who met defining criteria for
multiple myeloma (presence of an M-protein in serum or urine, 10% or
more clonal bone marrow plasma cells, and related tissue or organ damage
including hypercalcemia, renal injury, anemia, or lytic bone lesions) were
excluded from further consideration for transplantation. In addition, pa-
tients with severe coagulopathy, hepatosplenomegaly, or medication non-
compliance were also excluded.
Patients considered eligible for sequential transplantation were listed as
recipients with the Organ Procurement and Transplantation Network
(OPTN). Inotropic or mechanical support was used as needed, and waiting
tocol. All patients were discharged from the hospital receiving a calcineurin
level of 200–300 ng/mL or tacrolimus 0.15–0.30 mg/kg per day with a target
whole blood trough level of 5–15 ng/mL), mycophenolate mofetil (1.0–2.0
g/day), and prednisone (0.4–0.5 mg/kg per day). Follow-up of transplant
2 weeks for 8 weeks, then once monthly for 6 months, then once every 2
months for 6–12 months, and then once every 6 months), with tapering of
the prednisone dose in the absence of clinically significant rejection.
Plasma-Cell–Targeted Therapy Before ASCT
loidosis. Only three patients received some form of therapy before OHT:
patients 2 and 4 each received one course of melphalan and prednisone
4 days) and patient 8 received dexamethasone 10 mg daily for 4 days every
week over a course of 3 months before OHT.
Autologous Stem-Cell Transplantation
less than or equal to 10 mg/day and they were otherwise clinically stable.
Mycophenolate therapy was gradually tapered off, and 2 to 3 weeks later
subcutaneously twice daily for 4 days, with apheresis beginning on the 5th
day. The intended total target cell dose was more than or equal to 2?106
CD34? cells/kg body weight. Patients were then evaluated based on our
institutional ASCT eligibility criteria. High-dose melphalan was adminis-
infusions (day 0) were performed 48 hr after the second dose of melphalan.
Supportive care was provided based on our institutional guidelines.
Follow-Up of Recipients of Cardiac and
sies. All endomyocardial biopsy specimens were stained with hematoxylin-
eosin to assess for allograft rejection, and with Congo red to assess for the
light was used to confirm the presence of amyloid protein. Specimens with
positive Congo red staining then underwent indirect immunoflorescence
staining for the presence of amyloid protein. One-year after OHT, and an-
nually thereafter, patients underwent echocardiography, right and left heart
catheterization with endomyocardial biopsy, and coronary angiography. Se-
rum protein electrophoresis and urine protein electrophoresis with im-
munofixation, as well as serum free light chains, were determined at 3, 6, 9,
and 12 months after ASCT, and then annually. Bone marrow biopsy was
performed (as feasible) between 3 and 12 months after ASCT, then as clini-
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Transplantation • Volume 90, Number 8, October 27, 2010
Analysis of Clinical Outcomes
allograft rejection are available for all patients in the study population and for
17,389 patients undergoing cardiac transplantation for diagnoses other than
amyloidosis as registered in the International Society for Heart and Lung
Transplantation (ISHLT) database during this time period. Information re-
garding patient and allograft survival in a cohort of 10 AL amyloidosis pa-
comparison by Dr. Jeffrey Hosenpud.
survival rates are estimated using Kaplan-Meier method. Comparisons of
survival between two groups of patients were made using the log-rank and
Wilcoxon tests. Statistical significance is determined by a P value less than
0.05. We used SAS Version 9 for statistical analyses.
with systemic amyloidosis unable to undergo ASCT due to
severe heart failure presented to the Massachusetts General
Hospital Heart Failure Center for further evaluation. On
completion of the evaluation, 18 patients were listed with the
OPTN as potential heart recipients; eight patients were ex-
(Fig. 1). Nine of the transplant candidates subsequently un-
derwent OHT, whereas nine eligible patients died prior to
transplantation (DPT) due to the lack of a cardiac donor. Of
the nine patients who underwent cardiac transplantation,
eight patients underwent ASCT. Because of poor perfor-
mance status for a prolonged period of time after OHT, one
patient did not proceed to ASCT and shortly thereafter died
from progressive amyloidosis.
The characteristics of the patients listed for transplan-
were found to have coronary artery disease and underwent
percutaneous intervention before their transplant, whereas
no patients in the DPT were found to have coronary artery
disease. All patients were NYHA functional class III or IV.
Patients who underwent successful cardiac transplantation
had a longer period of time from the onset of symptoms to
diagnosis (14 vs. 7 months, P?0.05), but a similar duration
showed a left ventricular (LV) ejection fraction of less than
50% in all patients except one in each group. All patients had
abnormal LV wall thickness (?11 mm) in the presence of a
normal LV internal dimension (?54 mm). Seven patients in
had kappa AL amyloidosis; this was a similar distribution to
that seen in the DPT group. Monoclonal plasma cells com-
prised 5% to 10% of marrow cellularity in both groups, with
no significant difference between the OHT and DPT groups.
Extracardiac solid organ involvement by amyloidosis was
Not OHT candidate
Listed for OHT
Severe coagulopathy (1)
Medication noncompliance (1)
Multiple myeloma (2)
Failed stem cell transplant (1)
Refused transplantation (1)
Advanced stage amyloidosis (2)
PEA Arrest (2)
GI Hemorrhage (1)
Progression to myeloma (1)
*Patient #9 did not
receive ASCT due to
prolonged poor PS after
OHT and died from
OHT, orthotopic heart transplant; ASCT, autologous hema-
topoietic stem-cell transplant; GI, gastrointestinal.
sequential heart and ASCT candidates
Characteristics of patients listed as potential
Age, median (range) (yr)
Symptom onset to diagnosis,
Diagnosis to conclusion of
OHT evaluation (mo)
NYHA class III, IV at
Type of light chain
LV wall thickness (mm)
LV end-diastolic internal
Male 7, female 2
Male 5, female 4
5.4 (2.4–10) 6.2 (1–14)
3, 62, 7
? 7, ? 2
? 7, ? 2
2, positive for
3, positive for
8, positive for
9, positive for
Abnormal liver function
2, positive for
1, positive for
ASCT, autologous stem-cell transplantation; OHT, orthotopic heart trans-
plantation; LVEF, left ventricular ejection fraction; LV, left ventricular; LVAD,
left ventricular assist devices; BiVAD, biventricular assist device; IABP, intraaortic
© 2010 Lippincott Williams & Wilkins
Dey et al.
present in all patients. At the time of evaluation, significant
of the DPT patients. OHT patients had, on average, less pro-
ilar between the two groups (Table 1). Renal biopsies were
performed in two patients in the OHT group and in three
patients in the DPT group. Evidence of amyloid deposition
was seen in all five of these patients.
All patients underwent esophagogastroduodenoscopy
and colonoscopy with biopsy as part of their evaluation, and
emptying studies. In one of these patients, severe malnutri-
tion developed, leading to removal from the donor waiting
list. Two patients in the OHT group and one in the DPT
group underwent liver biopsies for persistently abnormal
serum transaminases and bilirubin, all three with biopsies
positive for amyloid deposition. However, right atrial
pressure was also increased in all these patients, and their
abnormal hepatic function tests all resolved after cardiac
Circulatory Support Before Transplantation
While awaiting cardiac transplantation, all patients re-
quired mechanical circulatory support (Table 1) or intrave-
nous inotropic support. At the time of transplantation, three
two with left ventricular assist devices and one with a biven-
tricular assist device. The other six OHT patients received
dobutamine, with two patients also requiring milrinone to
maintain adequate cardiac output. The one patient in the
DPT group who died with biventricular assist device support
developed refractory hypercalcemia due to progression to
multiple myeloma and renal failure.
OHT was performed in all patients using the bicaval
anastomotic technique. Because of significant renal impair-
ment, patient 4 received a kidney allograft along with the
cardiac allograft. Two patients required early re-exploration
for bleeding within the first 48 hr postoperatively. OHT pa-
tients required intensive care for a median of 8.5 days (range,
after surgery. Three OHT patients received cytolytic induc-
tion therapy due to the development of transient renal dys-
function; two with monoclonal murine anti-CD3 antibodies
and one with antithymocyte globulin. All patients were dis-
charged on a calcineurin inhibitor, mycophenolate mofetil,
and prednisone. Patient 6 was hospitalized for congestive
heart failure within a month of his OHT and a biopsy dem-
onstrated myocardial necrosis consistent with ischemic in-
jury, without signs of rejection. Echocardiogram showed an
motion abnormalities, and subsequent coronary angiogra-
descending coronary artery. Despite urgent coronary inter-
loon pump and subsequently received a second OHT.
Autologous Stem-Cell Transplantation
The median time interval between heart transplanta-
tion and stem-cell transplantation was 7.0 months. In one
patient, ASCT was delayed until 11 months after OHT be-
immunosuppression. Stem-cell procurement in all patients
was successful after mobilization with granulocyte colony-
kg; range 2.3–3.97?106/kg). G-CSF was tolerated well by all
except patient 5 who developed “fluid retention syndrome”
during leukapheresis, manifested by significant weight gain,
pleural effusions, and lower extremity edema which were all
successfully treated with diuretics. Neutrophil and platelet
engraftment (absolute neutrophil count ?0.5?109/L, plate-
let count ?20?109/L) was achieved approximately 12 days
after stem-cell infusion in all patients except patient 7, who
died from overwhelming Escherichia coli sepsis 8 days after
ASCT. Three patients who were cytomegalovirus seropositive
before OHT had reactivation of infection after stem-cell trans-
plantation as indicated by a positive cytomegalovirus antigen-
emia assay. All three were successfully treated with ganciclovir
Disease characteristics and response to treatment in
seven evaluable patients who received OHT followed by
ASCT are summarized in Table 2. At day ?100 post-ASCT,
six of the seven patients (85%) achieved a complete hemato-
logic remission (CR) and one patient (patient 5) achieved a
partial remission. Two of the six patients (patients 3 and 4)
who achieved CR later developed evidence of PCD at 18 and
52 months, respectively, after ASCT, with the other four pa-
tients remaining in hematologic CR.
Follow-up information is available for all eight of the
OHT/ASCT patients at a median of 56 months (range, 12–
101 months post-OHT). Transplant-related mortality has
been 12.5% and overall mortality has been 37.5%, with one
patient dying from overwhelming sepsis within a month of
ASCT, one from progressive amyloidosis 35 months after
OHT, and one from sudden cardiac death 45 months after
disease-free survival by Kaplan-Meier estimate was not
with a good functional status (NYHA class I) and no signs of
recurrent amyloidosis, 49 to 101 months from the time of
cardiac transplantation. These five patients remain on thera-
peutic doses of cyclosporine or tacrolimus, mycophenolate
mofetil, and low-dose prednisone (5–10 mg/day). Four pa-
tients have no evidence of recurrent PCD.
evidenced by increased plasma light-chain concentrations,
increased marrow plasmacytosis, and clinical signs of amy-
loidosis. Patient 3 had an increase in plasma light chain con-
centration and relapse of marrow plasmacytosis 18 months
after stem-cell transplantation. This patient also developed
allograft coronary vasculopathy, but endomyocardial biopsy
908 | www.transplantjournal.com
Transplantation • Volume 90, Number 8, October 27, 2010
was negative for amyloid. She died suddenly 45 months after
OHT. Patient 5, who achieved only a partial remission after
her bone marrow 12 months after ASCT, along with a slowly
increasing serum paraproteinemia and lambda-free light-
chain concentration. She later presented with clinical evi-
dence of systemic amyloidosis and did not respond to thalid-
omide and dexamethasone. Amyloid deposition was
identified on a subsequent endomyocardial biopsy, and the
patient eventually died from progressive cardiac, liver, and
Outcomes after sequential OHT and ASCT
1 61/M39 NoCR NoNo Negative Alive and well
Alive and well
2 58/M 108 Yes (MP)CR No No Negative
3 55/F5 11 No CRYes (18)? ecchymosis
4 67/M87Yes (MP)CR Yes (50)NegativeAlive and well
5 38/F84NoPRYes (11)Yes, hepatomegaly,
6 45/M67NoCRNoNegative Alive and well
Alive and well
7 54/M146No CRNoNoNegative
aMedian 7 mo.
bMedian 7 mo.
MP, melphalan and prednisone; Dex, dexamethasone; CR, complete remission; PR, partial remission; OHT, orthotopic heart transplantation; ASCT,
autologous stem-cell transplantation.
0 10 2030 4050 60 70 8090
OHT for non-amyloid (ISHLT)
OHT+ASCT for cardiac amyloidosis (MGH Data)
were censored at the last time they were known to be alive. Comparisons of survival between two groups of patients were
made using the log-rank and Wilcoxon tests. OHT, orthotopic heart transplant; ASCT, autologous hematopoietic stem-cell
transplant; ISHLT, International Society for Heart and Lung Transplantation.
Kaplan-Meier overall survival estimates, according to treatment. Open circles represent patients whose data
© 2010 Lippincott Williams & Wilkins
Dey et al.
clonal gammopathy and a monoclonal plasmacytosis in the
bone marrow at 52 months after ASCT, but he has had no
was negative for amyloid. Serial endomyocardial biopsies after
Five of our eight patients who underwent sequential
OHT/ASCT are alive with a good functional status (NYHA
class I) at a median follow-up of 56 months (range, 7–101
months). None have evidence of recurrent amyloidosis, with
four remaining in complete hematologic remission. The ac-
tuarial survival of these patients (Fig. 2) is 60% at 7 years,
which is not significantly different from the outcomes of
17,389 patients collected in the database of the ISHLT who
underwent OHT for nonamyloid heart disease during the
all survival of 39% at 4 years in 10 patients with AL amyloid-
osis who received a cardiac transplant without ASCT (13).
patients with AL cardiac amyloidosis. Two died from pro-
gressive amyloidosis and three are alive, including one who
high-dose corticosteroids (17). Lacy et al. from the Mayo
Clinic have also published a series of 11 patients undergoing
sequential OHT/ASCT. They reported a 5-year overall sur-
Two patients died from transplant-related toxicity and three
arial disease-free survival (without recurrent amyloidosis) in
possible improvement may include patient selection (less-
severe systemic amyloidosis) and improvements in support-
ive care post-ASCT.
Although these small series included only carefully se-
lected patients, the results indicate that good outcomes are
achievable in patients with severe cardiac AL amyloidosis af-
a significant step forward from the outcomes of the 10 pa-
tients in Hosenpud’s study who received OHT without sub-
sequent ASCT, the majority of whom developed progressive
amyloidosis involving major organs and recurrent amyloid
deposition in their cardiac allografts.
The PCD relapsed in three of our seven evaluable pa-
tients 12 to 52 months after ASCT, but only one patient (pa-
fluid retention during the stem-cell mobilization and after
ASCT, and she eventually died from progressive amyloidosis
complicated by multiorgan failure. Of note, patients with
have a particularly poor prognosis (19). Interestingly, amy-
loid deposition in the transplanted heart of this patient was
believed to have had little, if any, clinical significance; there
was no echocardiographic evidence of amyloid cardiomyopa-
Lacy et al. showed amyloid deposition in the cardiac allograft,
although none of them had symptoms, echocardiographic evi-
dence, or biochemical evidence of cardiac amyloidosis (18). A
similar observation was reported by Hosenpud et al. where the
majority of patients undergoing OHT without subsequent
and had recurrent amyloid deposition in the allograft, but car-
diac amyloidosis had no apparent clinical significance (13). In
contrast, Gilmore showed that relapse of the PCD after ASCT
cardiac amyloidosis and rise in serum NT-pro-BNP (17). Al-
though conclusions are limited by the small sample size in our
amyloidosis in the transplanted heart despite the presence of
clear disease progression in other organs might be due to an
respect to the “allogeneic” heart. It is possible that, in time,
additional patients will demonstrate clinical manifestations
of cardiac amyloidosis if light chain production is not ade-
heart failure have an extraordinarily poor prognosis on com-
pleting their cardiac transplant evaluation. Of 26 patients
evaluated, 18 patients were carefully selected and listed with
the OPTN for OHT/ASCT, but only half survived to OHT.
0204060 80 100
free survival estimates, according to
transplant followed by hematopoietic
stem-cell transplant for cardiac amy-
loidosis; Hosenpud, orthotopic heart
transplant alone for cardiac amyloid-
osis. Comparisons of survival between
two groups of patients were made us-
ing the log-rank and Wilcoxon tests.
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Transplantation • Volume 90, Number 8, October 27, 2010
Nine patients died while waiting for OHT (DPT group) due Download full-text
osis, and one patient had progression to multiple myeloma.
With regard to patient characteristics, there were no signifi-
OHT/ASCT and the patients who did not (DPT). However,
ment in their clinical outcomes after OHT/ASCT, and this
increases the possible need for a change in cardiac donor
allocation. The earlier application of plasma-cell-targeted
therapeutic approaches with newer agents, such as bort-
ezomib and lenalidomide (16, 20), which are effective and
better tolerated than conventional chemotherapeutics, be-
ginning at the time of the evaluation process may be ben-
eficial, and improve patients’ chances for receiving an
OHT. A similar approach may also be considered for pa-
tients who are not ready for ASCT after OHT since a pro-
longed time without treatment may allow progression of
the amyloidosis and therefore both impair the candidacy
of these patients for ASCT and increase their transplant-
Our observation of a similar survival in patients with
amyloid heart disease undergoing sequential heart and
stem-cell transplant to those in the ISHLT registry under-
going heart transplant for other diagnoses is subject to
several limitations. Survival after cardiac transplantation
has continued to improve in patients with advanced heart
failure due to causes other than amyloidosis. We have ob-
served recurrent plasma-cell disease in several of our pa-
tients after sequential heart and stem-cell transplantation
that may limit their future survival. Thus, it is possible that
survival in the two groups of patients beyond the time
described may differ.
In conclusion, the tandem approach of OHT followed
by high-dose melphalan and ASCT is a feasible strategy and
can improve the survival of carefully selected patients with
A multidisciplinary approach dedicated to early diagnosis,
timodality PCD-specific strategy incorporating both high-
after OHT, and after ASCT) is currently underway at the
MGH to address AL amyloidosis patients who present with
severe cardiac amyloidosis.
Amyloid research at Boston University School of Medi-
cine/Boston Medical Center was supported by grants from the
National Institutes of Health (P01 HL68705), the Gerry Foun-
dation, and the Amyloid Research Fund at Boston University.
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