ORIGINAL ARTICLE
HSCT FOR PRIMARY SYSTEMIC AMYLOIDOSIS
High-Dose Therapy and Autologous Hematopoietic Stem Cell
Transplantation for Patients With Primary Systemic Amyloidosis:
A Center for International Blood and Marrow Transplant Research Study
DAVID H. VESOLE, MD, PHD; WALESKA S. PÉREZ, MPH; MARWAN AKASHEH, MD; CHRISTIAN BOUDREAU, PHD;
DONNA E. REECE, MD; AND CHRISTOPHER N. BREDESON, MD, MSC, FOR THE PLASMA CELL DISORDERS
WORKING COMMITTEE OF THE CENTER FOR INTERNATIONAL BLOOD AND MARROW TRANSPLANT RESEARCH
OBJECTIVE: To determine the outcome of high-dose therapy with
autologous hematopoietic stem cell transplantation (HSCT) in pa-
tients with primary systemic amyloidosis reported to the Center for
International Blood and Marrow Transplant Research (CIBMTR).
PATIENTS AND METHODS: A total of 107 recipients of autologous
HSCT for amyloidosis from 48 transplantation centers were re-
ported to the CIBMTR between 1995 and 2001. Hematologic and
organ responses were assessed at 100 days and 1 year. Trans-
plantation-related mortality (TRM) was assessed at day 30 after
HSCT. A multivariate analysis assessed factors that influenced
overall survival.
RESULTS: Improvement at day 100 was seen in 1 or more amyloid-
osis-affected sites (bone marrow, kidney, liver, and/or heart) in
28 (36%) of 77 patients; the 1-year responses included complete
response (16%), partial response (16%), stable disease (31%),
and disease progression (10%). With a median follow-up of 30
months, the 1- and 3-year survival rates were 66% (95% confi-
dence interval [CI], 56%-75%) and 56% (95% CI, 45%-66%), re-
spectively. The day 30 TRM was 18% (95% CI, 11%-26%). In the
multivariate analysis, only the year of transplantation (patients
who most recently underwent transplantation) was associated
with post-HSCT survival (P=.02).
CONCLUSION: In this multi-institutional CIBMTR study, the 3-year
survival rate was comparable to single-center results, with patients
who more recently underwent transplantation faring better. Of note,
the TRM was higher than that reported by single centers, which
may reflect differences in patient selection and/or experience in
treating this challenging disease. We hope that a better under-
standing of the recently recognized prognostic factors and more
stringent patient selection will result in lower TRM and improved
survival.
Mayo Clin Proc. 2006;81(7):880-888
CI = confidence interval; CIBMTR = Center for International Blood and
Marrow Transplant Research; HSCT = hematopoietic stem cell trans-
plantation; KPS = Karnofsky performance score; TRM = transplantation-
related mortality
P rimary systemic amyloidosis is an uncommon plasma
cell dyscrasia, with approximately 2500 cases diag-
nosed yearly in North America. In this disease, monoclonal
immunoglobulin light chains are produced by malignant
plasma cells, resulting in amyloid fibril deposition in vital
organs, leading to progressive, fatal multisystem failure.
The median survival for treated patients is approximately
18 months compared with 12 months for untreated patients;
the median survival for patients with symptomatic cardiac
involvement is only 6 months.1,2
880 Mayo Clin Proc. • July 2006;81(7):880-888
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
Conventional therapy for primary systemic amyloidosis
has historically been with melphalan and prednisone.3 Re-
sponse rates are observed in 20% to
35% of patients, which results in a For editorial
modest increase in survival. More re- comment,
cently, dexamethasone, dexamethasone see page 874
combined with interferon, thalidomide-
or anthracycline-based regimens, and other novel therapies
have been studied with comparable response rates.4-9
With the favorable outcomes observed with high-dose
chemotherapy and autologous hematopoietic stem cell
transplantation (HSCT) in multiple myeloma, pilot trials to
test this approach in primary systemic amyloidosis were
pursued.10-15 These pilot trials, which predominantly used
From the St. Vincent’s Comprehensive Cancer Center, New York, NY (D.H.V.);
Center for International Blood and Marrow Transplant Research, Medical
College of Wisconsin, Milwaukee (W.S.P.); King Hussein Medical Center,
Amman, Jordan (M.A.); Department of Statistics and Actuarial Science, Uni-
versity of Waterloo, Waterloo, Ontario (C.B.); Princess Margaret Hospital,
Toronto, Ontario (D.E.R.); Manitoba Blood and Marrow Transplant Program
and CancerCare, Manitoba, Winnipeg (C.N.B.). Other members of the Plasma
Cell Disorders Working Committee of the Center for International Blood and
Marrow Transplant Research are listed at the end of the article.
This study was supported by Public Health Service grant U24-CA76518 from
the National Cancer Institute, National Institute of Allergy and Infectious
Diseases, and National Heart, Lung, and Blood Institute; Office of Naval
Research; Health Resources Services Administration; and American Associa-
tion of Blood Banks, Aetna; AIG Medical Excess; American Red Cross; Amgen
Inc; anonymous donation to the Medical College of Wisconsin; AnorMED Inc;
Berlex Laboratories Inc; Biogen IDEC Inc; Blue Cross and Blue Shield Associa-
tion; BRT Laboratories Inc; Celgene Corp; Cell Therapeutics Inc; CelMed
Biosciences; Cubist Pharmaceuticals; Dynal Biotech LLC; Edwards Life-
sciences RMI; Endo Pharmaceuticals Inc; Enzon Pharmaceuticals Inc; ESP
Pharma; Fujisawa Healthcare Inc; Gambro BCT Inc; Genzyme Corporation;
GlaxoSmithKline Inc; Histogenetics Inc; Human Genome Sciences; ILEX On-
cology Inc; Kirin Brewery Company; Ligand Pharmaceuticals Inc; Merck &
Company; Millennium Pharmaceuticals; Miller Pharmacal Group; Milliman
USA Inc; Miltenyi Biotec; National Center for Biotechnology Information;
National Leukemia Research Association; National Marrow Donor Program;
NeoRx Corporation; Novartis Pharmaceuticals Inc; Novo Nordisk Pharmaceuti-
cals; Ortho Biotech Inc; Osiris Therapeutics Inc; Pall Medical; Pfizer Inc;
Pharmion Corp; QOL Medical; Roche Laboratories; StemCyte Inc; Stemco
Biomedical; StemSoft Software Inc; SuperGen Inc; Sysmex; The Marrow
Foundation; THERAKOS, a Johnson & Johnson Co; University of Colorado Cord
Blood Bank; Valeant Pharmaceuticals; ViaCell Inc; ViraCor Laboratories; WB
Saunders Mosby Churchill; and Wellpoint Health Network.
Individual reprints of this article are not available. Address correspondence to
Christopher N. Bredeson, MD, MSc, CancerCare Manitoba, 675 McDermot
Ave, Winnipeg, Manitoba, R3M 3H8, Canada (e-mail: christopher.bredeson
@cancercare.mb.ca).
© 2006 Mayo Foundation for Medical Education and Research
• www.mayoclinicproceedings.com

high-dose melphalan, again based on the experience in
multiple myeloma, showed encouraging results: the hema-
tologic response rate was approximately 60%; organ re-
sponse rates were also observed but at a lower rate. Unfor-
tunately, these early pilot trials were associated with a high
transplantation-related mortality (TRM) of 15% to 25%. In
patients with AL cardiomyopathy, mortality approached
65%.10,12 More recently, clinical trials conducted with more
stringent patient selection criteria have reported a lower
TRM of 10% to 15%.16-23
Since primary systemic amyloidosis is a rare entity,
only a few academic programs have a specific focus on
the treatment of this disease. In the United States, the
primary research centers are the Mayo Clinic in Roches-
ter, Minn, and Boston University in Boston, Mass. Most
patients with primary systemic amyloidosis, however, are
treated outside these 2 centers. Although the outcomes of
HSCT in primary systemic amyloidosis at the Mayo
Clinic and Boston University are impressive, it is impor-
tant to determine whether comparable outcomes can be
reproduced in the general academic community. To this
end, in 2001, the Center for International Blood and Mar-
row Transplant Research (CIBMTR) initiated a study of
autologous HSCT outcomes in patients with primary sys-
temic amyloidosis.
PATIENTS AND METHODS
DATA SOURCES
The CIBMTR is a research affiliation of the International
Bone Marrow Transplant Registry, the Autologous Blood
and Marrow Transplant Registry, and the National Marrow
Donor Program that comprises a voluntary working group
of more than 450 transplantation centers worldwide that
contribute detailed data on consecutive allogeneic and au-
tologous HSCTs to a Statistical Center at the Health Policy
Institute of the Medical College of Wisconsin in Milwau-
kee or the National Marrow Donor Program Coordinating
Center in Minneapolis, Minn. Participating centers are re-
quired to report all transplantations consecutively; compli-
ance is monitored by on-site audits. Patients are followed
up longitudinally, with yearly follow-up. Computerized
checks for errors, physicians’ review of submitted data, and
on-site audits of participating centers ensure data quality.
Observational studies conducted by the CIBMTR are per-
formed with a waiver of informed consent and in compli-
ance with Health Insurance Portability and Accountability
Act regulations as determined by the institutional review
board and the privacy officer of the Medical College of
Wisconsin.
The CIBMTR collects data at 2 levels: registration and
research. Registration data include disease type, age, sex,
Mayo Clin Proc. • July 2006;81(7):880-888
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HSCT FOR PRIMARY SYSTEMIC AMYLOIDOSIS
pretransplantation disease stage and chemotherapy respon-
siveness, date of diagnosis, graft type (bone marrow– and/
or blood-derived stem cells), high-dose conditioning regi-
men, posttransplantation disease progression and sur-
vival, development of a new malignancy, and cause of
death. Requests for data on progression or death for regis-
tered patients are made at 6-month intervals. All CIBMTR
teams contribute registration data. Research data are col-
lected on a subset of registered patients selected by using a
weighted randomization scheme and include detailed dis-
ease and pretransplantation and posttransplantation clin-
ical information.
PATIENTS
Three hundred four patients were registered as having un-
dergone autologous HSCT for primary systemic amyloid-
osis between 1995 and 2001. Of these 304 patients, com-
prehensive patient, disease, and transplant characteristics
were available for 107 patients (35%). All patients in-
cluded in the study were determined to have amyloidosis
based on tissue biopsy findings. The definitions of organ
involvement are as follows: renal, positive biopsy result or
total urinary protein excretion greater than 3.5 g/24 h;
hepatic, positive liver biopsy result or hepatomegaly (liver
>12 cm); and cardiac, positive cardiac biopsy result, inter-
ventricular septal wall thickness greater than 15 mm, left
ventricular ejection fraction of 40% or less, or New York
Heart Association cardiac dysfunction class II to IV. The
number of transplantations per center were as follows:
25 centers performed 1 transplantation only, 8 centers
performed 2 transplantations, 7 centers performed 3 trans-
plantations, 2 centers performed 5 transplantations, and 1
center performed 15 transplantations. No patients from
Boston University or the Mayo Clinic were included in
this study. Patient, disease, and transplant characteristics
and overall survival of those with or without comprehen-
sive data were similar. Eligible cases came from 48 re-
porting centers. Median follow-up of survivors was 30
months (range, 3-82 months).
END POINTS
At the time of this analysis, there were no universally
accepted response criteria for amyloidosis. The response
criteria for this study were defined as follows. A partial
hematologic response was defined as a more than 50%
decrease in urine and/or serum paraprotein levels, and a
complete hematologic remission was defined as a negative
urine and/or serum protein electrophoresis result. An organ
response was defined as either improvement or lack of
improvement in 3 organ systems: renal, hepatic, and car-
diac. The determination of improvement was determined
by the reporting center and not based on specified objective
• www.mayoclinicproceedings.com 881
HSCT FOR PRIMARY SYSTEMIC AMYLOIDOSIS
criteria. Recently, a uniform system was proposed at the
10th International Amyloidosis Symposium in April 2004.
These criteria were subsequently presented at the Decem-
ber 2004 American Society of Hematology meeting.24 Be-
cause of limitations inherent in the collection of registry
data, it is not possible to retrospectively apply these criteria
to the existing data set. Transplantation-related mortality
was defined as all causes of death within 30 days after
transplantation.
STATISTICAL ANALYSES
Estimates of overall survival were calculated using the
Kaplan-Meier estimator, with SE estimated by the Green-
wood formula. Ninety-five percent confidence intervals
(CIs) were calculated using log-transformed intervals. Po-
tential prognostic factors for survival were evaluated in a
multivariate analysis using Cox proportional hazards re-
gression.25 The variables considered in the multivariate
analysis were age at transplantation, sex, Karnofsky perfor-
mance status (KPS) before transplantation (≤80% vs
>80%), prior chemotherapy (no treatment vs melphalan
with or without other therapy vs other chemotherapy vs
other single agent), lines of therapy (≤1 vs >1), organ
involvement at anytime before transplantation (≤1 vs >1
organ), cardiac involvement at anytime before transplanta-
tion (no vs yes), time from diagnosis to transplantation,
conditioning regimen (melphalan alone vs others), and year
of transplantation (1995-1997 vs 1998-1999 vs 2000-
2001). All computations were made using the procedure
PHREG in the statistical package SAS, version 8 (SAS
Institute Inc, Cary, NC). Forward stepwise variable selec-
tion at a .10 significance level was used to identify
covariates associated with the main outcome. In the model,
the assumption of proportional hazards was tested for each
variable using a time-dependent covariate and graphic
methods. All variables considered in the multivariate
analysis satisfied the proportionality assumption. The final
multivariate model was built using a forward stepwise
model selection approach. Factors significant at a P=.05
level were kept in the final model. Examination for center
effects used a random effects or frailty model.26 We found
no evidence of correlation between center and any of the
outcomes. All P values are 2-sided.
RESULTS
PATIENT CHARACTERISTICS
The median patient age was 55 years (range, 31-71 years),
with a male-female ratio of 60:40. All patients had a bi-
opsy-confirmed diagnosis of primary systemic amyloid-
osis. The paraprotein isotypes were IgG (36 [35%] of 102
patients), IgA (10 [10%] of 102 patients), light chain only
882 Mayo Clin Proc. • July 2006;81(7):880-888
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
(45 [44%] of 102 patients), other (2 [2%] of 102 patients),
and none (9 [9%] of 102 patients). A pretransplantation
KPS less than 80 was reported in 23 (23%) of 101 patients;
42 (42%) of 101 patients had a KPS equal to 80, and 36
(36%) had a KPS of 90 or 100 (Table 1).
ORGAN INVOLVEMENT
The kidney was the most commonly reported involved
organ, with urinary protein levels that exceeded 200 mg/24 h
observed in 57 (93%) of 61 evaluated patients. Forty-four
(72%) of 61 evaluated patients had nephrotic syndrome
range proteinuria (protein >3 g/24h) and 37 (41%) of 90
had hypoalbuminemia. Approximately one third had an
elevated serum creatinine level; 31 (29%) of 106 had creat-
inine levels greater than 2 mg/dL. Although not part of our
definition of hepatic involvement, approximately one third
(35/99) had elevated serum alkaline phosphatase levels
greater than 1.5 times the institutional upper limit of nor-
mal, a marker that has been reported as consistent with
hepatic involvement. Peripheral neuropathy was reported
in one fourth of the patients. Cardiac involvement was
documented by biopsy in 28 (26%) of 106 patients; subjec-
tive symptoms were reported in 34 (45%) of 76 patients
(New York Heart Association class ≥II).
Most patients had only single organ involvement,
whereas 35 (33%) of 107 had 2 or more organs involved;
however, 16 (15%) of 107 did not have organ (heart, kid-
ney, liver) involvement as per the definition given in the
“Patients and Methods” section. Some of these patients had
evidence suggestive of early involvement, such as a urinary
protein level less than 3.5 g/24 h or an alkaline phosphatase
level more than 1.5 times normal but no hepatomegaly and
no liver biopsy.
PRIOR THERAPY
Approximately one third of patients had received no
therapy before HSCT. Of those patients who received prior
therapies, melphalan-based regimens were the most com-
monly used. Three fourths of the patients were minimally
treated: 37 (35%) of 105 with no prior therapy and 42
(40%) of 105 with one prior treatment regimen. One fourth
of the patients had 2 or more lines of prior therapy. The
median time from diagnosis to transplantation was 6
months (range, 1-178 months), and the time from first
treatment to transplantation was within 6 months in 76
(75%) of 102 patients. Seventeen (17%) of 102 patients had
6 to 12 months of prior therapy, and only 9 (9%) of 102 had
more than 1 year of prior treatment.
PREPARATIVE REGIMENS
As has been observed in other primary systemic amyloid-
osis transplantation studies, most transplantation centers
• www.mayoclinicproceedings.com
 HSCT FOR PRIMARY SYSTEMIC AMYLOIDOSIS

TABLE 1. Characteristics of Patients With Amyloidosis Before Autologous Transplantation

No. (%) of No. (%) of

Characteristics evaluable patients* Characteristics evaluable patients*
Total No. of centers 48 Prior chemotherapy
Total No. of patients 107 No treatment 37 (35)
Median age of patients (y) (range) 55 (31-71) Melphalan with or without other treatment 27 (25)
Male 64 (60) Other chemotherapy 30 (28)
Pretransplantation Karnofsky score (n=101) Other single agent‡ 13 (12)
<80 23 (23) Lines of therapy (n=105)
80 42 (42) 0 37 (35)
>80 36 (36) 1 42 (40)
Median serum monoclonal immunoglobulin, 2 13 (12)
g/dL (range) (n=31) 0.3 (0-6) 3 11 (11)
Cardiac ejection fraction ≤40% (n=81) 3 (4) 4 2 (2)
Interventricular septal thickness >15 mm Median time from diagnosis to transplantation
(n=40) 6 (15) (mo) (range) 6 (1-178)
New York Heart Association class Time from first treatment to transplantation
(n=76) (n=102)
I 42 (55) No treatment 37 (36)
II 25 (33) <6 mo 39 (38)
III 8 (11) 6-12 mo 17 (17)
IV 1 (1) >12 mo 9 (9)
Protein excretion >200 mg/24h (n=61) 57 (93) Conditioning regimen
Alkaline phosphatase greater than the upper Melphalan alone 89 (83)
limit of normal (n=99) 47 (47) Total-body irradiation containing 8 (7)
Creatinine >2 mg/dL (n=106) 31 (29) Others§ 10 (9)
Albumin <2.5 g/dL (n=90) 37 (41) Dose of melphalan (mg/m2) (n=82)
Nephrotic syndrome (n=61) 44 (72) <129 12 (15)
Percentage of plasma cells in 130-189 32 (39)
bone marrow (aspirate) (range) (n=44) 3 (0-29) ≥190 38 (46)
Percentage of plasma cells in bone marrow Double transplantation 6 (6)
(biopsy) (range) (n=25) 5 (0-30) Planned double transplantation 8 (7)
Organ involvement Year of transplantation
0 16 (15) 1995 2 (2)
1 56 (52) 1996 1 (1)
2 27 (25) 1997 14 (13)
3 8 (8) 1998 17 (16)
Cardiac involvement (n=106)† 28 (26) 1999 29 (27)
Liver involvement (n=104) 29 (28) 2000 24 (22)
Renal involvement (n=97) 77 (79) 2001 20 (19)
Total No. of CD34+ cells infused (× 107/kg) Purging 7 (7)
(n=98) 4 (0.02-76) Median follow-up of survivors (range) (mo) 30 (3-82)
*The sample size is 107 unless otherwise indicated.
†Cardiac involvement was defined as follows: positive cardiac biopsy result or interventricular septal wall thickness >15 mm or left ventricular ejection
fraction of ≤40% or New York Heart Association class II, III, or IV.
‡Other single agents included thalidomide, colchicine, or corticosteroids.
§Other conditioning regimens included melphalan and corticosteroids (6); melphalan, total lymphoid irradiation, and cyclophosphamide (1); melphalan,
thiotepa, and busulfan (1); melphalan and ifosfamide (1); and melphalan and etoposide (1).

used single-agent melphalan as the preparative regimen: 89
(83%) of 107 patients received melphalan alone, 8 (7%) of
107 patients received total-body irradiation–containing
regimens, and 10 (9%) of 107 patients received other regi-
mens. Most patients (70 [85%] of 82) received melphalan
(≥130 mg/m2). Six patients were enrolled in tandem autolo-
gous transplantation protocols; 3 additional patients under-
went tandem transplantations.
RESPONSE
Responses at day 100 were seen in at least one organ
system (hematologic, renal, hepatic, and/or cardiac) in 28
(36%) of the 77 patients with organ-specific data available.
Since response to therapy in patients with primary systemic
amyloidosis may occur during a prolonged period, some-
times exceeding a year, response was evaluated 1 year after
HSCT.15 With regard to hematologic response, 34 (32%) of
107 patients had an objective response to transplantation
equally divided between complete response (17 [16%]) and
partial response (17 [16%]); 33 (31%) had stable disease,
and 11 (10%) had progressive disease. The TRM was 27%
(29/107 patients). Five of the 6 patients who had enrolled in
a tandem transplantation protocol completed both trans-
plantations. Three additional patients subsequently under-
went tandem transplantations. The 1-year responses for
these 9 patients were as follows: 3 with partial responses, 3

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HSCT FOR PRIMARY SYSTEMIC AMYLOIDOSIS

100

80

Survival probability (%)

95% Pointwise confidence interval

60

40
95% Pointwise confidence interval

20

0
0 1 2 3 4
Time (y)

FIGURE 1. Probability of survival after autotransplantations for amyloidosis.

with stable disease, 1 with progressive disease, and 2 CAUSES OF DEATH

deaths from transplantation-related causes. Renal, hepatic, Nineteen patients (18%; 95% CI, 11%-26%) died of infec-
or cardiac responses were also reported at 1 year after tion or organ failure within 30 days of transplantation. Car-
transplantation. For renal involvement, of 32 evaluated diac failure was the most commonly reported organ-specific
patients, 15, 11, and 6 were reported to have improved, cause of death, occurring in 7 (37%) of 19 patients: 3 deaths
stable disease, or progressed, respectively. For hepatic in- occurred in patients with known cardiac involvement before
volvement, of 19 evaluated patients, 11, 4, and 4 were transplantation, and 4 deaths occurred in patients without
reported to have improved, stable disease, or progressed, known cardiac involvement before transplantation. An addi-
respectively. Cardiac involvement was reported as im- tional 26 patients died beyond 30 days after transplantation
proved, stable, or progressed in 7, 4, and 4 of 15 assessed due to disease progression (n=18) or other causes (n=8). Of
patients, respectively. these, 3 deaths from transplantation-related toxic effects
(acute respiratory distress syndrome, interstitial pneumoni-
OVERALL SURVIVAL tis, and infection) occurred between day 30 and day 100 after
Overall survival after transplantation is shown in Figure 1. transplantation.
The 1-year survival rate was 66% (95% CI, 56%-75%) and
the 3-year survival rate was 56% (95% CI, 45%-66%) for TABLE 2. Univariate Analysis of Transplantation Outcomes
Among Patients Receiving Autotransplants for Amyloidosis by
the 107 patients. One-year survival rates in patients based Organ Involvement at Anytime Before Transplantation*
on pretransplantation organ involvement (cardiac, renal,
Overall survival (95% CI)
hepatic) were 72% (95% CI, 61%-82%) if 0 or 1 organ was
At 1 y At 3 y P value
involved and 54% (95% CI, 38%-70%) if 2 or more organs
were involved (Table 2; P=.11). The median overall sur- Overall 66 (56-75) 56 (45-66)
Organ involvement anytime
vival for all patients was 47.2 months. Survival was similar before treatment .11
whether there was reported cardiac involvement or not ≤1 organ (n=72) 72 (61-82) 60 (47-73)
(56% [95% CI, 37%-74%] vs 69% [95% CI, 58%-79%]; >1 organ (n=35) 54 (38-70) 46 (29-64)
Cardiac involvement
P=.50). We compared overall survival in patients who anytime before treatment .50
underwent transplantation in 2000-2001 with overall sur- No (n=78) 69 (58-79) 56 (43-69)
vival in patients who underwent transplantation in 1995- Yes (n=28) 56 (37-74) 51 (32-70)
Liver involvement anytime
1999. Both 1-year (77% vs 58%) and 3-year (74% vs 48%) before treatment .07
survival rates were superior in the patients who more re- No (n=75) 71 (60-81) 62 (50-74)
cently underwent transplantation (P=.04) (Figure 2). Patient, Yes (n=29) 59 (41-76) 46 (27-65)
Renal involvement anytime
disease, and treatment characteristics of the patients in the 2 before treatment .32
groups based on year of transplantation were similar. Im- No (n=20) 64 (42-84) 36 (14-62)
provement of transplantation results over time was con- Yes (n=77) 63 (52-74) 59 (48-70)
firmed in the multivariate analysis of prognostic factors. *CI = confidence interval.

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For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

100
80
Survival probability (%)
60
40
20
P=.04
0
0 1
FIGURE 2. Probability of survival after autotransplantations for amyloidosis by year of
transplantation.
PROGNOSTIC FACTORS
In univariate analysis, neither the number of organs in-
volved nor the presence or absence of any 1 of the 3 organ
systems evaluated (renal, hepatic, and cardiac) was pre-
dictive of overall survival (Table 2). In multivariate
analyses, the year of transplantation was the only statis-
tically significant predictor of survival among patient-,
disease-, or transplant-related variables (P=.02). Using
1995-1997 as the referent, the relative risks of death by
year of transplantation were 0.54 (95% CI, 0.27-1.10;
P=.09) for 1998-1999 and 0.32 (95% CI, 0.14-0.73;
P=.007) for 2000-2001. In a pairwise comparison of
2000-2001 and 1998-1999, the relative risk of death was
0.59 (95% CI, 0.28-1.22; P=.15).
DISCUSSION
Primary systemic amyloidosis is an uncommon plasma cell
dyscrasia. The median survival for treated patients is ap-
proximately 18 months.1,2 Marginal improvement has oc-
curred in the treatment of this disease during the past 20
years: melphalan and/or corticosteroid-based regimens re-
main the mainstay of treatment.1-3,5-7 Some newer agents,
such as thalidomide, which have proven efficacy in multiple
myeloma, are still in pilot trials in primary systemic amy-
loidosis.8,9 In myeloma, these agents are reasonably well
tolerated. However, most studies report that adverse effects
from thalidomide are greater than those observed in my-
eloma. Whether lower doses, which are better tolerated, are
sufficient for disease control in primary systemic amyloid-
osis is unclear. The use of monoclonal antibodies is provoca-
tive but is still in the early stages of clinical development.27
During the past 10 years, evidence has been mounting
that high-dose therapy with autologous HSCT is effica-
Mayo Clin Proc.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
HSCT FOR PRIMARY SYSTEMIC AMYLOIDOSIS
2000-2001 (n=44)
1995-1999 (n=63)
2 3
Time (y)
cious in controlling the malignant plasma cell clone present
in patients with primary systemic amyloidosis.16-23 Reduc-
tion and/or elimination of the offending light chain para-
protein production and subsequent tissue infiltration may
allow for improvement in end-organ function.28-30 This ulti-
mately translates to improve quality of life to a level that is
not achieved with conventional therapy.31
The initial efforts in high-dose therapy with HSCT in
primary systemic amyloidosis were associated with high
TRM, particularly for patients with cardiac amyloidosis
and those with 2 or more organs involved.10-12 The favor-
able results observed in these pilot studies have been con-
sidered by some to reflect in part patient selection bias.14,17
However, a case-control study has demonstrated the supe-
riority of HSCT to conventional therapy.32 A trial compar-
ing HSCT to conventional therapy is currently being evalu-
ated in a French phase 3 study.
The current study reports the outcomes in 107 patients
with primary systemic amyloidosis undergoing HSCT
from 48 centers, with only 3 centers contributing 5 or more
patients. Because of the nature of a registry analysis, pa-
tient details and the response criteria are less stringent than
those reported by single institutions or cooperative groups.
The recent approval of uniform response criteria by the
attendees of the 10th International Amyloidosis Sympo-
sium will provide consistent guidelines and assist in
analysis of future studies, but these could not be retro-
spectively applied for this analysis.24 Despite the lack of
more stringent response criteria in this study, the 3-year
overall observed survival is comparable to other reports
from single institutions and cooperative groups (Table 3).
The CIBMTR TRM at 30 days was higher (18%) than that
reported by single institutions and cooperative groups. This
finding may be explained by the absence of standardized
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HSCT FOR PRIMARY SYSTEMIC AMYLOIDOSIS

TABLE 3. Review of Reported Hematopoietic Stem Cell Transplantation

for Primary Systemic Amyloidosis*
No. of TRM OS
Study patients (%) (%) Prognostic factors
CIBMTR 107 18 at 30 d 56 at 3 y None
Boston, Mass16 205 13 at100 d 60 at 3 y ≥2 organs; cardiac
Mayo Clinic22 171 12 at 100 d 21.5 mo if ≥2 ≥2 organs/<2 organs
organs involved
Not reached if <2
organs involved
ECOG19 30 10 at 30 d 62 at 3 y Not analyzed
Moreau et al11 21 43 at 30 d 57 at >4 y 2 organs (11% vs 92%)
Mollee et al17 20 35 at 100 d 56 at 3 y BP, poor PS
Blum et al20 13 15 at 100 d 47 at 2 y Cardiac
*BP = blood pressure; CIBMTR = Center for International Blood and Marrow Transplant Research;
ECOG = Eastern Cooperative Oncology Group; OS = overall survival; PS = performance status;
TRM = treatment-related mortality.

eligibility criteria and treatment regimens from the various
transplantation centers that may allow for higher-risk pa-
tients. Alternatively, the higher mortality may be a factor of
inexperience in caring for these patients who often have
multisystem compromise in contrast to patients with mul-
tiple myeloma, although no center-specific effect was
identified in multivariate analysis. Even at transplantation
centers experienced in the care of patients with primary
systemic amyloidosis, the TRM for such patients undergo-
ing HSCT approaches 10% to 15% compared with 1% to
2% for those with multiple myeloma. However, in multi-
variate analysis, patients who have more recently under-
gone transplantation had a superior outcome. This finding
may reflect improved patient selection and/or increased
experience in caring for patients with primary systemic
amyloidosis along with improvements in supportive care
during the past 10 years.
In contrast to most other reports, neither cardiac in-
volvement nor multiple organ involvement was predictive
of overall survival in the current study. This may be a
feature of the sample size in this study. However, of note,
the Mayo Clinic experience did not observe a relationship
between cardiac involvement by conventional assessment
and overall survival.15 This finding may also reflect the
nature of studies conducted using an observational data-
base that reports activities of member centers without
dictating practices. Specifically, not all patients were sys-
tematically evaluated in the same manner for organ in-
volvement before or after transplantation, and some pa-
tients may potentially have had organ involvement that was
not characterized by the transplantation program.
To improve transplantation outcomes in primary sys-
temic amyloidosis, it is necessary to address disease-related
and treatment-related factors. Regarding disease-related fac-
tors, we now have a better understanding of primary sys-
temic amyloidosis–associated prognostic factors: pro–brain
natriuretic peptide, cardiac troponin, β2-microglobulin, and
the number of organs involved.21-23,33 This information
should be incorporated into the development of treatment
strategies with more stringent patient selection criteria
and risk-directed therapy.16,18,22 Ultimately, this should
result in lower TRM and improved survival. Future stud-
ies should incorporate these biologic prognostic factors
and evaluate their value in HSCT. To maximize the
knowledge gained from performing transplantations in
patients with primary systemic amyloidosis and to use
that information to design future prospective trials or to
make treatment decisions for patients not eligible for clin-
ical trials, centers must commit to systematically evaluat-
ing patients with primary systemic amyloidosis before and
after transplantation for potential prognostic factors and
organ involvement in such a way that the data can be
pooled for analysis between centers. Ideally, centers
should share their experience by reporting their data to
national and multinational cooperative transplantation reg-
istries, such as the European Group for Blood and Marrow
Transplantation and the CIBMTR because they provide a
different perspective from that of the disease-focused ex-
pert center.
Transplantation outcomes should improve with better
patient selection based on prognostic factors and poten-
tially the use of comorbidity scores, as has been introduced
in allogeneic transplantation studies.34 Morbidity and mor-
tality may also be improved through the use of a more
tolerable transplantation regimen, such as a lower dose of
melphalan. Unfortunately, lowering the dose of melphalan
to reduce toxic effects has resulted in less pronounced
response rates in some studies22 but marginally so in other
studies.16 Another approach would be to administer
melphalan in combination with a cytoprotectant agent such
as amifostine or keratinocyte growth factor (palifermin). In
myeloma, it has been demonstrated that amifostine as a

886 Mayo Clin Proc. • July 2006;81(7):880-888 • www.mayoclinicproceedings.com

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

cytoprotectant agent allowed for administration of single-
agent melphalan to 280 mg/m2.35 In this regard, the Eastern
Cooperative Oncology Group has initiated a phase 1/2
study of dose-escalating melphalan with amifostine as a
cytoprotectant. Palifermin was recently shown to reduce
mucositis in patients undergoing radiation-based autolo-
gous HSCT.36 Furthermore, if the transplantation-related
morbidity and mortality can be adequately reduced, it may
be possible to safely administer multiple cycles of dose-
intensive therapy with HSCT,37,38 as has been shown to be
effective in multiple myeloma.39
Finally, although the median overall survival with
HSCT for primary systemic amyloidosis approaches 4
years in our study and 5 years in other studies, there does
not appear to be a plateau of survival curves.15,16 The obser-
vation that a graft-vs-myeloma effect afforded by allo-
reactive T lymphocytes can result in long-term disease
control in some patients with myeloma undergoing alloge-
neic transplantation40,41 may be predictive of a similar out-
come in patients with primary systemic amyloidosis. The
use of allogeneic transplantation for primary systemic
amyloidosis, particularly with reduced-intensity condition-
ing regimens, has just started to be evaluated in pilot stud-
ies.42,43 These transplantations should be performed only
within well-designed clinical trials at centers with expertise
in the management of transplantation-related complica-
tions, such as graft-vs-host disease. All patients with pri-
mary systemic amyloidosis should be considered for clini-
cal trials and may benefit by referral for evaluation to
programs that specialize in the study and care of these
patients.
CONCLUSION
In this multi-institutional CIBMTR study, the 3-year sur-
vival was comparable to single-center results, with patients
who had more recently undergone transplantations faring
better. Of note, the TRM was higher than that reported by
single centers, which may reflect differences in patient
selection and/or experience in treating this challenging dis-
ease. We hope that a better understanding of the recently
recognized prognostic factors and more stringent patient
selection will result in lower TRM and improved survival.
Other Members of the Working Committee. A. Bashey, MD,
PhD, BMT Group of Georgia, Atlanta; M. W. Brunvand, MD,
Rocky Mountain Cancer Center, Denver, Colo; A. Dispenzieri,
MD, Mayo Clinic College of Medicine, Rochester, Minn; C. O.
Freytes, MD, University of Texas Health Science Center, San
Antonio; R. P. Gale, MD, PhD, Ziopharm Oncology, Los Ange-
les, Calif; J. Gibson, MD, MBBS, PhD, Royal Prince Alfred
Hospital, Campertown, Australia; S. A. Giralt, MD, M.D. Ander-
Mayo Clin Proc. • July 2006;81(7):880-888
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
HSCT FOR PRIMARY SYSTEMIC AMYLOIDOSIS
son Cancer Center, Houston, Tex; H. K. Holland, MD, BMT
Group of Georgia, Atlanta; R. A. Kyle, MD, Mayo Clinic College
of Medicine, Rochester, Minn; H. M. Lazarus, MD, University
Hospitals of Cleveland, Cleveland, Ohio; P. L. McCarthy, MD,
Roswell Park Cancer Institute, Buffalo, NY; G. A. Milone, MD,
Fundaleu, Buenos Aires, Argentina; G. Schiller, MD, University
of California School of Medicine, Los Angeles; D. Siegel, MD,
PhD, Hackensack University Medical Center, Hackensack, NJ; P.
H. Wiernik, MD, OLM Comprehensive Cancer Center, Bronx,
NY.
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