From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
Primary
Systemic
Amyloidosis:
Multivariate
in 168
By Robert
One
hundred
sixty-eight
amyloidosis
(AL)
diagnosis
was
patients
for
only.
Utilizing
wise
multivariate
influence
that
A
with
peripheral
factors
LTHOUGI-I
as
myeloma
amyloidosis
a century,
there
light
were
has
the
been
patients
els
major
linear,
consist
are
nonbranching
of the variable
arranged
portion
in a 3-pleated
generally
resist
amyloid
deposits
Except
aggregated
for
of a monoclonal
sheet
proteolytic
that
multiple
formation,
digestion,
The
fibrils
light
chain,
are
and
myeloma,
fifth of the patients
with primary
amyloidosis
have no evidence
of preceding
or coexisting
(AL),
In two
series
of patients
MATERIALS
Mayo
Clinic
amyloidosis
from
AND
records
reporting
1, 1970,
to Dec
Jan
a
the data were abstracted
on sheets
laboratory
data were obtained
from
month
of
the
histologic
senile
with
(AL),
amyloidosis
histologic
suitable
Mayo
diagnosis
secondary
amyloidosis
multiple
of
amyloidosis
were
myeloma
were
(AL)
diagnosis
were
records
All
with
Patients
because
localized,
with
and
All
within
I
parameters
familial,
amyloidosis
dfferentiation
method
subsequent
on this
influence
Supported
in
Submitted
©
reprint
St SW,
1986
22.
or
and
basis
survival.
All
and Internal
Medicine
and the
and Epidemiology.
Mayo Clinic
Minn.
Research
Public
Grant
Health
accepted
to Dr Robert
MN
& Stratton,
0006-4971/86/6707--0034$03.00/0
220
1 985;
requests
Rochester,
by Grune
by
of Health,
April
Address
First
part
Institutes
55905.
Inc.
March
CA-16385
Service,
from
the
and the Toor
identified
(Table
amyloid
Mayo
or for at least
methods
in
clinical
I year
were used
after
the
used
to summarize
Survival
technique.4
The
to determine
the
curves
were
proportional-
for the first year after
Clinic.
200
patients
with
with
multiple
40
1). Amyloidosis
deposits
procedures
electron
positive
microscopy.
rectal
biopsy.
nerve
was
in tissue
variables
that
diagnosis
and
Some
liver
extended
more
basis
amyloid
fibrils
with
positive
in 83%
to 100%
of specimens
was noted
in 42% of the patients;
the
contributed
significantly
to the prediction
Among
those
who lost weight,
the loss
40.9 kg (5 to 90 lb), with a median
of 9.1
patients
was
on the
percent
of the patients
had a
of the kidney,
small intestine,
kg (20 Ib). Fatigue
was common,
168 patients.
Purpura
was found
The
diagnosed
Seventy
Biopsies
were
Loss of weight
amount
of the loss
of early
survival.
ranged
from 2.3 to
primary
systemic
myeloma)
were
by the use of appropriate
or of demonstrating
staining
had more
palpable
than
than
one symptom.
in one-third
10 cm
in 55% of the
gross bleeding
being found
in 1 5% and
below
of the
the
right
patients
costal
but
margin
in
only two. The spleen was palpable
in only 4% and was modest
in size; none extended
>3 cm below
the left costal
margin.
Macroglossia,
present
patients
in one-fourth
the
constituted
major
was
syndromes
(5.3%)
at
diagnosed
had
of
the
disease.
infrequent.
present
was
occasion-
of the patients,
manifestation
the
are
time
listed
a malabsorption
primary
in
systemic
Table
syndrome.
2.
Nine
Symptoms
of nephrotic
approximately
syndrome
and congestive
heart
failure
existed
1 to 3 months
before the diagnosis
of amyloi-
dosis,
symptoms
while
tunnel
syndrome
before
1. /986.
A. Kyle.
is important
to prospective
parameters.
sixty-eight
of finding
The
National
Fund.
first
years.
years.5
amyloidosis
From the Division ofHematology
Department
of Medical
Statistics
and Mayo Foundation,
Rochester,
was
(including
Lymphadenopathy
not
death
separately
hundred
myeloma
did
the
Inc.
up until
of Cox
survival
ally
amyloidosis
& Stratton.
followed
difficult
inasmuch
as these
conditions
represent
the same
fundamental
process. In a recent report,3 the presence or absence of
with
for
to
mod-
subsequent
on survival
randomized
Standard
univariate
statistical
the distribution
of each
of the
estimated
by the Kaplan-Meier
in 9%.
is often
in patients
in the
groups
for
for
used
of amyloidosis.
and sural
studied.
of
reviewed,
for keypunching.
Clinic
amyloidosis.
or
excluded.
included
were
One
were measured
in all patients. The data for multiple
visits were
recorded
on separate
sheets,
and a longitudinal
view was obtained.
Patients
patients
amyloidosis
responsi-
amyloidosis
1980,
variables
were
variables
high-risk
separately
most
RESULTS
METHODS
31,
models
to the
the
survival
the
diagnosis
of amyloid
was
survival
and the lack of an
of prognostic
factors
in primary
us to undertake
this study.
analysis
prompted
All
primary
with
survival
after histologic
1 year.’2 This short
of these
by Grune
for
ble for the amyloidosis.
the median
approximately
These
and
and
orthostatic
were
affecting
according
of patients
influenced
patients
disease
1 year.
myeloma.
protein
adversely
moderate-,
influence
hazards
insoluble,
constitute
serum
diagnosis
a 1986
and destroy
normal
tissues.
which
is seen in about one-
replace
low-,
diagnosis
of prognostic
fibrils.
Factors
trials.
after
factors.
Amyloid,
a substance
that appears
to be homogeneous and amorphous
under the light microscope,
consists of
rigid,
multiple
monoclonal
patients
stratification
for more
recognized
creatinine.
surviving
after
The
factors
year
and
variables
into
year
hepato-
Prognostic
O’Fallon
Serum
categorize
revealed
first
no analysis
has been
50
a step-
chain,
the
important
simultaneous
of diagnosis
during
for
to
in
Michael
hypotension.
neuropathy
the
urine
survival
failure
and W.
diagnosis.
after
4 months
model
evaluate
failure,
multiple
affecting
than
from
heart
to
risk
heart
and
systemic
for
Cases
R. Greipp,
survival
proportional-hazards
of putative
megaly.
primary
congestive
fashion
congestive
adversely
ranged
presenting
the
Philip
Median
and
with
those
with
identified.
1 2 months
presenting
months
patients
were
A. Kyle,
Analysis
and
amyloidosis
orthostatic
patient’s
of peripheral
were
present
neuropathy
for
was diagnosed.
hypotension
Congestive
frequently
or
approximately
developed
carpal
a year
heart
failure
during
the
illness.
Laboratory
ing, the initial
studies.
median
Anemia
hemoglobin
was not a prominent
findvalue being 12.7 g/dL.
Of
Blood, Vol 68, No
1 (July), 1986:
pp 220-224
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
AMYLOIDOSIS
(AL):
PROGNOSIS
1 . Age and Sex
Table
221
Distribution
Systemic
of 1 68 Patients
Amyloidosis
With
Primary
I0
9
(AL)
8
>
6
Total
>
Age
Males
(yr)
<40
Females
2
No.
0
%
5
U)
2
4
0
1
3
>-
40-49
11
6
17
10
50-59
29
15
44
26
60-69
30
25
55
33
70-79
31
13
44
26
80
0
6
Total
Median,
64
109
59
(65%)
(35%)
6
.0
(6
.0
0
2
4
168
100
0
Years
Fig 1 .
temic
the
1 8 patients
myeloma,
with
8 had
level
an initial
renal
<
(> 500,000/mm3)
initially
in 55%
Twenty-six
percent
an initial
level
2.0
>
and
I 2% of the females
sis revealed
a monoclonal
ly, 26% of the patients
the serum
(Bence
predominated
1.3 g/dL).
of the
normal
Jones
Lambda
light
urine
patients
and
revealed
an
a globulin
albumin
peak
urine
specimen
the
showed
patients
found
light
their
studies.
1 % to 99%,
than
in 89%
a median
light
Table
In
chain
2.
in
illness.
Colchicine
patients
of
of
the
protein
was
of the patients.
cell
counts
Roentgenograms
Syndromes
at Time
did
after
diagnosis
of primary
ranged
may
of Dia gnosis
Eighty-four
alkylating
agent
given
any
receive
died
have
by
were
found
percent
some
to
time
13
therapy.
of cardiac
of
patients.
(Fig
1 ). All
year,
and,
Nineteen
Cardiac
involvement
disease.
Median
syndromes.
1 patient
survival
of amyloidosis
were
patients
Only
died
followed
of
was
up, if alive,
the
for at least
patients
4 months
for
failure
with
to
50
months
the
both)
(or
with
various
presenting
with
for
those
(Table
3).
carpal
tunnel
neuropathy
only
presenting
for those
was
due
of
syndrome
to eventual
syndromes
congestive
only
presenting
Death
patients
or
static
hypotension
more
than
of Primary
at
3 years
2 of them
presentation.
after
the
are now
Syst emic
known
Amyloidosis
No
.
Amyloidosis
38
23
3.5
0-12
After
.
of the
Nine
diagnosis
to have
with a nephrotic
failure
or ortho54 survived
of amyloidosis,
died,
and
I of malignant
(AL)
.
Range
54
32
1.5
46
27
23
28
of Amyloidosis
Total
No.
%
19
57
34
0-36
6
60
36
9.2
0-227
1
47
28
14
6.2
0-39
9
32
19
17
12.8
0-58
1
29
17
Congestive
Nephrotic
syndrome
Carpal
tunnel
syndrome
Orthostatic
hypotension
Peripheral
neuropathy
Some
patients
had
m ore
than one condition.
of
organs.
D,agnos,s
heartfailure
with
presentperipheral
involvement
Seventeen
of the 54 patients
presenting
syndrome
also had either congestive
heart
Median
I
last follow-up,
79% had died. In contrast,
median
survival
from diagnosis
of amyloidosis
from
peripheral
%
168
1 2 months
as of the
death
No.
the
their
during
melanoma.
the diagnosis
after
Month Before
Diagnosis
of
Amyloidosis
ofdeath.
lesions
myeloma.
malignancy-malignant
Survival
only
were
At
Before
Diagnosis
of
Condition
sys-
for 40% of the deaths,
but the percentage
was
higher
because
many
patients
who died of “amyloi-
of another
other
Osteolytic
multiple
was
not
neuropathy
75%
two-thirds
plasma
of 9%.
an
ing
concentrated
X. A monoclonal
marrow
cause
heart
70%.
adequately
disease.
were
or urine
Bone
with
an
and
ranged
of the
overt
received
the estimated
urinalysis)
of concen-
in two-thirds
a monoclonal
chains
in the serum
Other
from
during
the
patients,
band
in more
of
Immunoelectrophoresis
Therapy
to
Urine protein
findings.
Proteinuria
(routine
was found in 80% of the patients.
Electrophoresis
trated
chains
in 31 cases).
K
patients.
patients
patients
in
of the
all had
in 62%
dosis”
band or spike
it was usually
of
Immunoelectrophore-
proteinemia).
of survival
(AL).
in 1 5 patients;
accounted
probably
patients
serum
serum protein
in 69%. Unexpectedhad a free monoclonal
light chain
in 83 and
(A
half
or a
pattern.
A localized
and when present,
size (median,
had
mg/dL.
than
Probability
amyloidosis
normal
was evifemales.
in 7%. Renal
insufficiency
of the males and 59% of the
protein
electrophoretic
was found in 74 patients,
modest
diagnosis
multiple
gastrointestinal
cause.
Leukopenia
was
in 1%, and thrombocy-
Serum
protein
findings.
More
had
either
hypogammaglobulinemia
only
8 had
I had
of the males
creatinine
g/dL,
I0
insufficiency,
bleeding,
and
1 had no apparent
found
in only 1%, thrombocytopenia
tosis
dent
after
years.
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
KYLE
222
Table
3.
Survival
by Presenting
Symptoms
Systemic
Primary
of 168
Amyloidosis
Patients
Patients
group
Hierarchical
Orthostatic
hypotension
tunnel
Peripheral
Patients
either
may
have
4
syndrome
were
Congestive
only
in the
listed
congestive
heart
had the carpal
first
failure
tunnel
Multiple
37
16
Monoclonal
28
23
I of suicide.
and
more
I 2 years
than
they
with
occurred
congestive
heart
failure
patient
diagnosis.
but
continues
Only
at presentation
with
Because
on dialysis
3 patients
survived
who had
more
2
than
the assumption
of propor-
tional-hazards
functions
was
not satisfied
over the entire
follow-up
period but did hold separately
within the first year
subsequently,
used separately
and
was
evaluate
dentally,
the proportional-hazards
for these two periods
influence
of the variables
of our patients
were dead
the
half
Analysis
of
survival
ables-congestive
(ULC),
heart
hepatomegaly,
highly
significant
(Table
4). Four
during
the
failure
(CHF),
of combinations
of the
variables
that
fashion
into
on entry,
were
were
entered
CHF
MCS (monoclonal
(P
the
serum
step-wise
concern
for
in
some
4.
Effect
During
chain
loss
(amount)
Electrophoretic
of albumin
Elevated
creatinine
Sex
Myeloma
continue
data
0.97
protein
and
(MCS)
0.0064
0.58
0.0
106
0.65
0.0
126
-0.87
0.0008
possibility
However,
5)
.0023
predicted
interact
variables
survival
of patients
the
of the first
cannot
with
the question
of such
manner.
The model
influence
of the
five
variables
among
by
them, and therefore
model
are based
on the
the
variables,
and
even when data are sparse.
The coefficients
of the variables
predictions
in this
the joint
distnibu-
are
model
possible,
suggest
a diagnosis
of CHF
is highly
detrimental
to survival,
presence
of ULC somewhat
less detrimental,
the presence
HEP and MM about equal and even less detrimental,
and
presence
of MCS
actually
be
combinations
“protective.”
This
model
that
the
of
the
was used
to create
a gradient
defined according
of risk, and three classes of patients
were
to this gradient.
These
classes, referred
to
as low,
and
moderate,
Patients
with
HEP,
MM,
ULC.
HEP,
MM,
ULC
MCS
and
CHF.
all factors
except
one or more
MM,
high risk,
or MCS
no factors
(2) Moderate
or MCS and
(3) High risk:
CHF
of HEP,
are
(I )
low risk:
and one of
risk: Patients
with one of
two of HEP,
MM,
ULC
or
Patients
with CHF
alone or
or CHF
MM,
defined
as
or MCS
alone
with
ULC
or without
or two
MCS
or more
with
of HEP,
ULC.
When
definitions,
the
I 68 patients
were classified
there were 60 patients
in the
in the low-risk
group,
Kaplan-Meier
estimates
according
high-risk
and 48 in the moderate-risk
of the survival
curves
to these
group,
70
group.
for these
The
three
.0037
serum
.0370
protein
Urinary
summarizing
of the individual
tion
five
on
small
to address
in a satisfactory
no interactions
influences
of these
influence
the numbers
of variables
is too
potential
interactions
(Table
some
their
effects
the
for.
P (log-rank)
.0022
Monoclonal
in
after
accounted
First Year
creatinine
.0002
that
other
0.05)
<
been
Curves
Serum
Myeloma
(P
had
light
chain
.0540
.0 108
serum
IIONTHS
(>2.0
<0.0001
an additional
Hemoglobin
.0001
.0055
and
limited
Variable
1
P values
hepatomegaly
After
pattern
in urine
to
as having
(log-rank)
.000
three
0.0001),
=
Varia bles on Survival
heart
light
first
their
of the
patients,
identified
P
Hepatomegaly
Weight
of
(P
in a
simultaneous
0.009).
allowed
Year
failure
Urinary
was
implications
of Indi vidual
First
=
employed
and
ULC
0.05).
<
The
model,
(P
(P
the
variables.
the
protein)
process
subsets
Variable
Congestive
vanchain
significant
was then
0.0001),
<
the
were
myeloma
Table
Four
light
to evaluate
influence
multiple
year.
urinary
first
were
model
multivariate
available
Coinci-
amount
of weight
loss-had
a
on survival
during
the first year
variables
(albuminuria,
elevated
serum
step-wise
without
on survival.
at 1 year.
and
creatinine,
sex, and myeloma)
The proportional-hazards
When
method
of Cox
in an attempt
to
influence
other
P Value
1 .43
(MM)
survival
each
assumes
ofsurvival.
(CHF)
(ULC)
variables
The
some
neuropathy.
years.
Analysis
to Survival
Systemic
(AL)
(HEP)
serum
on
three
syndrome
hypotension.
or peripheral
effect
in. Thus,
a nephrotic
or orthostatic
One
after
chain
Related
of Primary
Coefficient
failure
myeloma
denied.
melanoma
Diagnosis
AL
50
group
syndrome
light
12
as presenting
heart
Hepatomegaly
17
11
placed
of the 37 patients
had
38
neuropathy
Five Variables
After
Variable
12
syndrome
Carpal
none
(mo)
168
failure
Involving
Year
First
Amyloidosis
Urine
heart
A Model
Survival
groups
Congestive
Nephrotic
5.
During
Median
Total
Table
With
(AL)
ET
mg/dL)
SINCE
DIAGNOSIS
.0270
.0320
.0420
Fig
2.
moderate-,
sis (AL).
Kaplan-Meier
and high-risk
estimates
patients
of the
with
survival
primary
curves
systemic
for
low-.
amyloido-
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
AMYLOIDOSIS
classes
(AL): PROGNOSIS
are illustrated
in Fig
cantly
different
(P
a clear classification
ing
<
to likelihood
amyloidosis.
Analysis
223
2. The
three
curves
are signifi-
0.0001,
log-rank
test) and demonstrate
of the patients
into three groups accord-
of
surviving
1 year
after
a diagnosis
U
R
of
survival
after
1 year.
The
proportional-
hazards
model
was also used to identify
variables
value at diagnosis
influenced
the rate of subsequent
ity
among
(Table
the 84 patients
Hemoglobin
4).
presence
of
influence
on survival
who survived
1 year
level,
creatinine
serum
myeloma
multiple
of borderline
(P
have
0.005),
<
a
with
after
V
N
diagnosis
level,
highly
MCS
V
whose
mortaland
significant
and ULC
YEARS SINCE DIAGNOSIS
being
significance.
As before,
step-wise
the
model
proportional-hazards
fashion
to evaluate
influence
of several
variables
the influence
of a variable
variables
has been taken into
on survival
after
the
account.
multivaniate
was
used
in a
the simultaneous
and/or
influence
to evaluate
of other
myeloma,
the serum
orthostatic
hypotension,
and monoclonal
protein
(Table
6). Although
no interactions
were found
significant,
them.
the
As before
sample
size
(in reference
limits
our
to year
I
ability
median
in
to
is used
to
factors
or
(3) high
factors
or serum
OH
alone
serum
risk:
creatinine
<2.0
Serum
creatinine
creatinine
or two
Of the 84 patients
these
(P
<
who
MCS,
survived
32
in
the estimated
three
0.0001,
and either
groups.
log-rank
MM
the diagnosis
the
high-risk
group.
curves
(Kaplan-Meier)
curves
death
with
Figure
with
3
for
series
median
survival
Hewlett7
Table
comprising
6.
was
the
median
survival
Survival
After
Variables
Affecting
of Hemoglobin
Variable
Iess.”6
First
(MM)
Orthostatic
hypotension
Monoclonal
serum
protein
(OH)
(MCS)
with
heart
The
also
myeloma
had
the first
year.
contrast
to
of
only
the
effect
of this
more
than
I
year
for
Utilization
of the proportional-hazards
wise multivariate
fashion
revealed
that
of Primary
Systemic
with
P
Value
0.000 1
1 .07
0.0014
1 .75
0.0007
1 .04
0.0065
the high-risk
more
creatinine
severe
systemic
levels,
during
the
protein
but only
phenomenon
in
is
allowed
the
group
low-
or
myeloma,
in a stepfirst year,
had
died
and
orthostatic
serum protein
in the urine were
affecting
survival.
Patients
in
had a median
the first year (total,
that the significant
model
after the
amyloidosis
multiple
the first year (total,
22 months),
als in the low- and moderate-risk
after
sized
failure.
The
and multiple
groups.
hypotension,
and monoclonal
the most important
variables
0.2 1
was
the first
variables
those
with
serum
the
the patients
into low risk, moderate
risk, or
first
year after
diagnosis.
Patients
in the
had a median
survival
of 3.5 months,
in
of patients
that
during
heart
chain,
of these
moderate-risk
patients
of
in our series
on survival
explanation
usually
In fact,
40%
of a monoclonal
effect on survival
Utilization
be
peripheral
of
for survival
and
Following
should
with
deaths
congestive
urinary
light
adverse
An
to
in those
It
I 68 patients
factor
The
presence
a “protective”
available.
of primary
for
the
risk
an
and
patients
to 50 months
Daniels
Year
26
amyloidosis
neuropathy.
presenting
of
major
first
I 2 months.
appeared
to have
Clinic,
the
of
failure
accounted
who died.
median
survival
The
for
diagnosis
peripheral
the patients
involvement
patients
more
with
the
Pruzanski
1976,
months
or the carpal
tunnel
syndrome
who died
subsequent
cardiac
or renal involvement.
us to categorize
high
risk the
high-risk
group
(AL)
Coefficient
creatinine
myeloma
in Cases
cases
Mayo
or
that
Multiple
the
months
Amyloidosis
Serum
500
from
14.7
reported
the Elimination
almost
(AL)
amyloidosis
series,8
series of 168 patients
presenting
ranged
from 4 months
in those
congestive
out that
neuropathy
did so from
during
DISCUSSION
In three
current
syndromes
only
not readily
systemic
the
In
of 28
from
year
was the presence
presence
of hepatomegaly,
significantly
differ
in another
who had died.
survival
among
associated
cardiac
survival
amyloidosis
median
pointed
or
38 in the moder-
survival
The
test).
MM
or
no risk
or MCS
while
14 months.3
a mean
primary
I 2 months.
after
group,
with
presenting
OH.
1 year
in the low-risk
of amyloid,
14 were
ate-risk
group,
and
illustrates
>2.0
of MM,
or more
and either
>6.5
and
was
reported
presenting
moderate,
and high
risk. These
classes
are ( I ) low risk:
Serum
creatinine
2.0
and
no risk factors
(MM,
OH,
MCS);
(2) moderate
risk: Serum
creatinine
2.0 to 6.5 and no
MCS;
was 5 months,
survival
Katz9
The
establish
a gradient
of risk, and three
classes
of patients
are
defined
on the basis of the values
of the four variables
at the
time
of the diagnosis
of amyloid
and referred
to as low,
risk
amyloidosis
no patients
with primary
amyloidosis
(AL)
survived
than
1 2 months
after diagnosis.
In a series of 32 patients
primary
systemic
amyloidosis
with or without
myeloma,
to detect
the model
),
Fig 3.
Kaplan-Meier
estimates
of the survival
curves for low-.
moderate-.
and high-risk
patients
with primary
systemic
amyloidosis (AL) who survived
1 year after diagnosis.
primary
In the modeling
process, hemoglobin
and serum creatinine
levels appeared
to be surrogates
of each other,
and the final
model
(P < 0.0001)
included
serum
creatinine,
multiple
be
S
of
survival
of I 0 months
after
whereas
the median
survivgroups exceeded
28 months
40 months).
It should
be emphavariables
influencing
survival
dun-
From www.bloodjournal.org by guest on June 14, 2017. For personal use only.
KYLE
224
ing
the
first
year
diagnosis-congestive
after
light chain,
negligible
This
study
permits
a more
heart
failure,
and loss of weight-had
after the first year.
hepatomegaly,
role in affecting
survival
urinary
accurate
assessment
stratification
a
of patients
to prospective
clinical
trials.
of survival
at the time of diagnosis
of primary
systemic
amyloidosis.
influence
of these variables
on survival
is important
randomized
ET AL
ACKNOWLEDGMENT
The
in the
We are indebted to Rebecca
ming, and statistical
analysis.
A. Pierce
for data
retrieval,
program-
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1986 68: 220-224
Primary systemic amyloidosis: multivariate analysis for prognostic factors
in 168 cases
RA Kyle, PR Greipp and WM O'Fallon
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