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Survival of patients with primary (AL) amyloidosis
Survival of Patients with Primary (AL) Amyloidosis Colchicine-Treated Cases from 1976 to 1983 Compared with Cases Seen in Previous Years (1961 to 1973) 1
ALAN S. COHEN, M.D. ALAN RUBINOW, M.D. JENNIFER J. ANDERSON, Ph.D. MARTHA SKINNER, M.D. JOHN H. MASON, M.A. CARYN LIBBEY, M.D. HERBERT KAYNE, Ph.D.
Primary amyloidosis has a variable course, but is generally associated with a short life expectancy. To date, no specific therapy has been available. Fifty-three patients with AL amyloidosis seen between 1976 and 1963 were treated with colchicine, and their clinical course and survival were compared with that in 29 other patients seen between 1961 and 1973. Of the variables measured, the treatment, the patient’s sex, and the time interval from diagnosis to referral or treatment were significantly associated with length of survival, Median-survival for the colchicine-treated patients was 17 months, compared with six months for the non-colchicine-treated patients. A surprising fkrdirig was the longer life span in female patients (median eight months versus four and a half months in the non-colchicine-treated gr&p,‘and 25.5 months versus 10 months in the colchicine-treated group). The study suggests that colchicine has improved the life expectancy in AL amyloidosis. Although it is not a specific therapy, it may be a reasonable form of adjunctive treatment in this complex disorder.
Boston, Massachusetts
From the Thorndike Memorial Laboratory and the Department of Medicine, Boston City Hospital, the Arthritis Center, Department of Medicine, Boston University School of Medicine, and Boston University School of Public Health, Boston, Massachusetts. This work was supported by grants from the United States Public Health Service, National Institute of Arthritis, Metabolic and Digestive and Kidney Diseases (AM-04599 and AM-07014), Multipurpose Arthritis Center, National Institutes of Health (AM-20613), the General Clinical Research Centers Branch of the Division of Research Resources, National Institutes of Health @R-533), and the Arthritis Foundation, and was presented in part at the Fourth International Symposium on Amyloidosis, November 14, 1984, Harriman, New York. Requests for reprints should be addressed to Dr. Alan S. Cohen, Department of Medicine, Boston City Hospital, Thorndike Building 314, 818 Harrison Avenue, Boston, Massachusetts 02 118. Manuscript submitted October 6, 1986, and accepted December 30, 1986.
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No specific treatment has been found for any variety of amyloidosis [ 11. Eradication of the predisposing disease may slow the progression of reactive or secondary (AA) amyloidosis, but only sporadic reports have appeared with suitable serial biopsy evidence of resorption [2-51. “Remissions” have occurred both spontaneously and after treatment of an inflammatory or infectious disease leading to secondary amyloidosis. Primary (AL) amyloidosis, currently the more commonly seen form of the disorder, has a variable outcome but is generally associated with a short life expectancy [6,7]. Since primary amyloid is composed of light chains and since kappa and lambda light chains are produced by plasma cells, melphalan/prednisone regimens have sporadically been utilized. In 1978, the results of a prospective randomized study comparing a placebo and a melphalan/prednisone regimen showed no significant difference in survival between the two groups [8]. Recently, in another prospective randomized trial, Kyle and co-workers [9] reported that melphalan/prednisone was superior to colchicine when the data were analyzed from time of entry into the study to time of death or progression of disease, but not when the data were analyzed in the aggregate. Colchicine, which effectively prevents acute febrile episodes in patients with familial Mediterranean fever, a condition that predisposes to amyloidosis, has been shown to block amyloid production in the mouse model of secondary amyloidosis [ 10,l I]. In addition, reports from Israel indicated that amyloidosis no longer developed in colchicine-treated patients with familial Mediterranean fever, and suggested improvement in some patients with this form of AA amyloid [ 12- 141. How might colchi-
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tine influence outcome in primary amyloidosis? Colchitine is known to affect mitosis, to disrupt microtubule organization, and to.potentially interfere with microtubule cell function [ 151. Due to the presumed participation of the macrophage in the pathogenesis of AA amyloidosis and the concept that in AL amyloid, the immunoglobulin is processed (catabolized) by the macrophage prior to tissue deposition [ 161, it seems reasonable to suspect that colchicine might alter or delay fibril formation or deposition in AL amyloid. More recent data also suggest that, at least in acquired amyloidosis, the mechanism of action of colchitine may involve reduced protein synthesis rather than blockage of secretion of newly synthesized protein [17,18]. The steady influx of patients with amyloidosis who were referred to us provided a unique opportunity to conduct a therapeutic study with colchicine, a relatively innocuous agent. .Our original protocol was a double-blind, randomized controlled study in which patients would be treated with colchicine or placebo. Although reasonably conceived, this study was abandoned as a result of the outright refusal of the majority of patients (with a potentially fatal disease) to accept placebo, a similar unwillingness on the part of referring physicians to allow their patients with amyloid to enter a placebo study, and the discovery that, whichever protocol we used, referring physicians still treated their patients with colchicine (in four of the first six cases). Such practical and ethical objections to random drug allocations in potentially fatal conditions and the alternative use of historical control subjects have been discussed [19-261. On the basis of this literature and our own experience with randomization, an open study in which all patients were to be offered colchicine, with entrance data carefully gathered and compared with our previous experience, appeared to be the realistic alternative. In the present study, therefore, the survival of the colchicinetested group was compared with the survival of previous patients we had seen when no drug therapy was available and only supportive measures were used.
PATIENTS AND METHODS Patient Groups. Between August 1961 and April 1983, 112 patients with primary amyloidosis were seen at our Clinical Research Center. The diagnosis was made in 34 patients between August 1961 and the end of 1973, before colchicine was available as a therapy, in 15 patients during 1974 and 1975 (nine of whom survived long enough to eventually receive colchicine therapy in 1976 or later), and in 63 patients between early 1976 and March 1983, for whom colchicine therapy was available. Group A, the “untreated” control subjects, was drawn from the earliest cohort, and Group B, the colchicine-treated patients, was drawn from those in whom the diagnosis was made in 1976 or later. Evaluation and Treatment. Initial detailed clinical evalua-
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tion and classification were carried out in the Thorndike Memorial Laboratory Clinical Research Center. All patients provided complete histories and underwent physical examination. Evaluation included the measurable clinical parameters (congestive heart failure, nephrotic syndrome, hepatomegaly, splenomegaly, and macroglossia), routine and speand liver cial laboratory tests (e.g., renal, pulmonary, function studies), and routine and special blood chemical determinations. One major clinical feature was listed for each patient, i.e., renal insufficiency, cardiovascular abnormalities, peripheral neuropathy, liver disease, or other. Note was made of all treatment that the patients had been given, especially whether they had ever, even for a short period, been receiving immunosuppressive agents, such as melphalan and prednisone, chlorambucil, or any other drugs. For all patients, previous biopsy results were reviewed and either rectal or subcutaneous fat [27] plus skin biopsy specimens were obtained. The presence of amyloid was determined histopathologically by the demonstration of Congo red-positive deposits that showed green birefringence on polarization microscopy [28]. Studies included a search for urinary and plasma monoclonal components and kappa or lambda light chains, bone marrow aspiration or biopsy, and skeletal survey. If a diagnosis of multiple myeloma was made (lytic bone lesions and sheets of immature plasma cells in the bone marrow), the patient was excluded from this series. Patients with familial amyloid polyneuropathy (A prealbumin) or with reactive (AA) amyloid secondary to chronic infectious or inflammatory disease were also excluded. All patients referred between June 1976 and April 1983 were treated with colchicine 0.5 mg tablets (one to two tablets per day depending upon tolerance). Patients were requested to complete compliance forms and return them on a regular basis and to return to the Clinical Research Center for thorough re-evaluations in one to two years. They also underwent periodic examinations performed by local physicians. Criteria for Inclusion in Analysis. There were 34 untreated patients in Group A, and 63 patients who were seen subsequently were included in Group B. The 15 patients in whom the diagnosis was made in 1974 and 1975 were excluded from analysis to eliminate treatment assignment bias arising during this crossover period when colchicine was first made available to patients referred to the Thorndike Memorial Laboratory Clinical Research Center. Patients were included in the study only if they survived at least three months from the time of their first symptom, or at least one month from the date of the diagnosis, or, for the colchicinetreated patients, one month from the start of colchicine therapy. A total of five patients were excluded on this basis, two from Group A and three from Group B. As the outcome of interest was the time from diagnosis to death, we also did not inolude in the analysis any patients for whom the interval from diagnosis until referral or the start of treatment exceeded one year. In the treatment group, any colchicine effect would have been overestimated due to ascribing the entire survival interval to a colchicine effect. Ten patients were excluded for this reason, three from Group A with the
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TABLE
AMYLOIDOSIS
I
TREATED
Baseline
WITH
COLCHICINE-COHEN
Comparison
ET AL
of Study Groups Group A 1961-1973 (n = 29)
Total (n = 82) Age (years)” Sex (percent female) Months from first symptom to diagnosis* Months from diagnosis to referral/start treatment* Clinical variables (at referral) Creatinine level (mg/dl)* 24-hour protein (g)” Postural hypotension (percent)t Congestive heart failure (percent) Major clinical feature (percent) Renal insufficiency Cardiovascular abnormalities Peripheral neuropathy Liver disease Immunosuppressive treatment (percent) Any Adeouate * Mean f standard deviation. t Data were available for only
17 patients
in Group
56.9
of
f 10.3 44 15.0 f 16.4 2.7 f 2.7
follow-up
date
for
seven
of the
more
2.4 f 3.2 5.2 f 4.8 24 34
43 22 2 26 22 6 A and 50 patients
recent
Group
in Group
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f 8.5 38 13.3 f 13.9 3.1 f 2.5
1.5 f 6.4 f
1.0 6.5
0.123 0.164 0.269 0.091
6 6
0.269 0.378 0.063 0.001
45 21 3 24
42 23 2 26
0.818 0.999 0.999 0.999
24
21 6
0.783 0.999
B.
RESULTS
Patients in Groups A and B were similar in age, percent female, time interval from first symptom to diagnosis, and time interval from diagnosis until referral or treatment (Table I). However, the Group A patients were more apt to have had congestive heart failure by the time of their referral (34 percent versus 6 percent of Group B patients, p
B
Volume
58.3
P Value
the two groups, varied with the year of diagnosis, or displayed an association with survival. The results are expressed in terms of adjusted relative risk, which is the proportional increase in risk associated with the presence of a factor (such as colchicine treatment), or with a change of one unit in a scalar variable (such as the time interval between diagnosis and referral or treatment). The correlation of baseline variables with membership in Group A or B was evaluated using chi-square” for categoric variables and t tests for continuous variables. Equality of variance in the two groups was assessed by the F test. Association of the study variables with time period of diagnosis or months of survival was analyzed using Pearson correlation coefficients, or, for binary variables, the appropriate t test. The primary cause of death, from postmortem examination and from clinical records, was determined whenever possible.
patients). Cox proportional-hazards regression model with backward elimination was used to compare risk of death for the patients in the two groups [30,31]. Covariates initially included were all of the parameters that differed between
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f 12.7 55 18.0 f 20.2 2.1 f 2.9
1.7 f 1.8 6.1 f 6.1 10 16
intervals from diagnosis to referral ranging from three to five years, and seven patients from Group B with treatment delays ranging from 13 months to nearly three years. Thus, Group A consisted of 29 patients and Group B consisted of 53 patients. Statistical Analysis. Baseline factors studied included age, sex, 24-hour urine protein, serum creatinine, presence of postural hypotension, evidence of congestive heart failure, both at the time of diagnosis and on referral, and the use of immunosuppressive drugs, as well as time intervals from symptoms to diagnosis and from diagnosis to treatment. If the serum creatinine value was greater than 1.5 mg/dl, the patient was considered to have renal insufficiency. Postural hypotension was diagnosed by a drop of more than 20 mm Hg in the systolic blood pressure on standing. Criteria for determination of congestive heart failure were taken from the Framingham Heart Study [29]. If at least two of the major criteria were satisfied, the patient was considered to have congestive heart failure. The possibility of time trends in the patients’ baseline factors was explored by relating these variables to the time period of each patient’s diagnosis. The first period was 1961 to 1969, coded 1, the second 1970 to 1971, coded 2, and each subsequent two-year interval defined a further time period, concluding with the eighth, 1982 to 1983, coded 8. The first time period was longer because of the smaller number of patients with diagnoses made in these earlier years. The outcome measure analyzed was the number of months of survival from diagnosis until death (or until the last
54.2
Group B 1976-1983 (n = 53)
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some of these clinical variables, with creatinine levels and the probabilities of postural hypotension and congestive heart failure at referral improving over time (Table II). This suggests that some of the patients in whom the diagnosis was made in the earlier years were sicker than the patients in whom the diagnosis was made later, possibly because of delays in the diagnoses of amyloid disease. On the other hand, there were no apparent time trends in the presence of various clinical features or use of immunosuppressive drug treatment. Female gender, absence of postural hypotension, and the number of months from diagnosis to treatment correlated with lengthening survival (Table II). None of the remaining variables considered, including months from symptoms to diagnosis and age, displayed significant association with patient survival in these bivariate analyses. In order to make an unbiased survival time comparison of Group A and Group B patients, all variables that differed between the two groups, exhibited a trend over time, or were associated with length of survival were included as covariates in the proportional-hazards regression model. These covariates were the patient’s sex, number of months from diagnosis to treatment, each of the referral variables (creatinine level, presence of postural hypotension, 24-hour protein, and presence of congestive heart failure), as well as the year of diagnosis. In this full model, only the treatment group (colchicine or non-colchicine), the patient’s sex, and the time interval from diagnosis to referral or treatment were significant. This last variable can be thought of as a clinical summary variable, since the less sick a patient appears at the time of diagnosis, the longer the time interval between diagnosis and referral or treatment is likely to be. The adjusted relative risks derived from a Cox regression model that includes only the significant variables are shown in Table Ill. After adjustment for the two covariates, the relative risk of death associated with colchicine treatment was 0.35 (p
AMYLOIDOSIS
TABLE
II
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Association of Study Variables of Diagnosis and with Survival
ET AL
with Period Tiiire
Time Period of Diagnosis
Survival
(p value)*
(p value)?
from symptoms to diagnosis Months from diagnosis to referral/treatment
0.10
0.65
0.33
0.03
(+)
Age Sex (female gender) Referral variables Creatinine Protein Postural hypotension Congestive heart failure Clinical features Renal insufficiency Cardiovascular abnormalities Peripheral neuropathy Liver disease lmmunosuppresive treatment Any Adequate
0.10 0.11
0.70 0.04
(-k)
Study Variable Months
0.01 0.89 0.01 0.01
(-)
0.51 0.50 0.01 (-) 0.49
(-) (-)
0.26 0.56 0.97 0.65
0.41 0.83 0.96 0.10
0.44 0.60
0.46 0.71
The first time period is 1961 to 1968, the second is 1970 to 1971, and each subsequent two-year interval is another time period, concluding with the eighth, 1982 to 1983. + Number of months from diagnosis to death, or in the case of seven colchicine-treated patients, until the date of last follow-up. NOTE: For those associations that are significant (p <0.05), the direction of the association is indicated in parentheses (i.e., iindicates a positive association: as one variable increases, so does the other; and - indicates a negative association). l
TABLE Ill
Survival Analysis Using ProportionalHazards Regression 95 Percent
Contributing
Factor
Colchicine treatment Female gender Time from diagnosis to treatment or referral (per month increase)
Adjusted Relative Risk 0.35 0.49 0.89
Confidence Interval 0.21, 0.33, 0.81,
p Value
0.59 0.78 0.98
0.001 0.003 0.018
each sex in the two patient groups are plotted (Figure 2), both the effect of colchicine and the consistent differences in survival by sex are seen. Median survival for male patients in Group A was four and a half months, Compared with eight months for female patients in this group. Median survival times for male and female patients in Group B were 10 months and 25.5 months, respectively. Median survival times in months for each time period under study are shown in Table IV. Patients in the first
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Figure 1. Probability of survival of pa Cents with primary amyloidosis treated with colchicine (Group s) or not treated (Group A), adjusted for sex and for time interval from diagnosis to treatment/ referral.
t-
1.0
0.8
T
L,:. 11.: /‘7:: F:b-1 :.... 11 3 ~:
0.2
0.0
I 1
!
I
2
3
I
4 YEARS
I
/
I
5
6
7
three time periods did not receive colchicine, whereas patients in the last four time periods did receive colchitine. The median survival time by sex for each time period is also included in this table. The overall consistency of the effects of colchicine treatment and of sex of the patient is apparent in this table despite considerable variability between medians of the very small groups. In an additional proportional-hazards regression analysis, sepa-
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FIgwe 2. Probability of survival of male and female patients with primary amyloidosis treated with colchicine (Group E?) or not treated (Group A), adjusted for time interval from diagnosis to treatment/referral.
rate trend variables for the time periods with and without colchicine treatment were included. These were in addition to the treatment, sex, and interval from diagnosis to treatment or referral variables retained previously (as in Table Ill). Neither of the trend variables was significant, nor did their presence reduce the effect of colchicine treatment found in the earlier analysis. This, together with the lack of effect of the diagnosis year variable in the
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TABLE
original proportional-hazards regression model, indicates that the colchicine effect is not explainable as a secular trend. Median survival times given in Table IV for the periods 1978 to 1979 and 1982 to 1983 are underestimates, because there were patients in these time periods who were still alive at the date of last contact (four from 1978 to 1979 and three from 1982 to 1983). Of these seven patients, five (71 percent) were female. This is a higher percentage than would be expected (chi-square = 4.42, p <0.05), since only 16 (36 percent) of the 44 patients with a diagnosis of primary amyloid made during the last three time periods were female. The major cause of death for patients in Group A and Group B was cardiac, accounting for 34 percent of the deaths in the former group and 44 percent of those in the latter series (Table V). The percentage of deaths due to renal liver, pulmonary, or cerebrovascular disease or gastrointestinal bleeding was approximately the same in both groups. None of these causes of death significantly differentiated the two patient groups. The precise cause of death could not be determined or was not available in three (10 percent) of the Group A patients and in three (7 percent) of the Group B patients. Further examination of cardiac mortality shows sudden death to be responsible for 60 percent of total deaths in each of the patient groups. Intractable congestive heart failure was the cause for the remainder of the Group A cardiac deaths and for all but one of the cardiac deaths in Group B.
IV
TREATED
Median Sex
WITH
Survival
COLCHICINE-COHEN
Time by Time Period and
Number of Patients
Time Period (years of diagnosis) Non-Colchicine-Treated 1961-1968 1970-1971 1972-1973 Total Colchicine-Treated 1976-1977 1978-1979 1980-1981 1982-1983 Total
ET AL
Survival Time (months) All Patients Male Female
10 7 12
6.5 9.0 6.0
5.5 4.0 6.0
8.0 10.0 6.0
29
6.0
5.0
8.0
9 19 14 11
22.0 18.0 9.0 10.0
18.0 14.5” 5.0 10.0
32.0 37.07 26.0 17.0x
53
17.0
10.0
25.5
* Two censored survival times (79 months and 63 months) (i.e., patients still alive at time of last contact). + Two censored survival times (71 months and 83 months). 1 Three censored survival times (three months, 25 months, and 27 months).
TABLE V
Cardiac Sudden death Congestive heart failure Myocardial infarction Renal Pulmonary Liver Gastrointestinal hemorrhage Cerebrovascular Other? Unknown
COMMENTS
Evaluation of the treatment of a chronic disease whose natural history is not well defined poses great problems. Clearly, a prospective double-blind study with randomized control subjects should be carried out whenever possible. Such a study was our original intent. Due to the reasons mentioned, especially the lack of cooperation of patients and of participating physicians, this plan was abandoned. Although the use of historical control subjects is controversial and filled with the possibility of bias [21-251, it has been pointed out that “many of the most thoroughly accepted current drugs including morphine, digitalis, aspirin, insulin, penicillin, and ccrticosteroids were established on the basis of historical controls without concurrent comparisons” [32]. The strategy of obtaining an observational data bank based on the prospective data collected on unselected patients with continuous surveillance for outcome has been discussed [24], as well as the potential errors that can occur. It is a well-known fact that with the use of historical control subjects, even with stringent selection criteria and adjustment for prognostic factors, biases in patient’s selection may weigh the outcome in favor of new therapies. It has been suggested that reconsideration
June
Cause of Death in Primary
Amyloidosis
Group A 1961-1973 (n = 29)
Group B 1976-1983 (n = 46)”
10 (34%) 6 4 0 9(31%) 4 (14%) 1(3%) 1(3%) 1(3%) 0 (0%) 3 (10%)
20 (44%) 12 7 14 (30%) 3(7%) 2 (4%) 1(2%) 2 (4%) 1(2%) 3 (7%)
* Seven patients still living at last contact. 7 Fat embolism during hip surgery.
of the significance level of 0.05 would be helpful. In the study reported herein, a significance level of less than 0.00 1 was attained, thus increasing our confidence in the conclusion that colchicine is an effective treatment. The possibility exists that, as information about amyloidosis improves, it will be shown that simple supportive treatment and avoidance of medications that adversely affect amyloid have favorably influenced outcome in this series regardless of the added treatment. This, however, was not borne out in our exploration of possible time trends. This study presents one of the few significant experiences with the long-term follow-up of primary amyloid, evaluates the prognostic effect of various (heart, kidney, liver) types of system involvement, and gives a modern
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view of the life history and causes of death in primary (AL) amyloidosis. The very magnitude of difference of survival of those treated with colchicine compared with those not so treated suggests that this disparity cannot be explained entirely either by differences in severity of disease, or by improved overall survival in later years for all patients with amyloid. As mentioned earlier, certain cases were eliminated from consideration in our survival analysis in order to avoid bias favoring the colchicine-treated group. The fact that the remaining group difference is so considerable, and also that no upward trend was noted in survival time within the two series, argues for a real drug effect exhibited by these data. Although colchicine appeared to decrease the rate of disease progression, data on clinical variables over time were not available, since time of death was the endpoint. Our overall survival results (median 17 months in Group B, six months in Group A) may not be strictly comparable with those reported in several other modern series. In the 1960 to 1972 series of 193 patients in Rochester, Minnesota, median survival after histologic diagnosis of AL amyloid (non-myeloma) was 14.7 months [33]. The median survival in their 1970 to 1980 series of 182 patients with AL amyloid but without myeloma was 13 months [34]. Their most recent series reported a 25.2-month survival of melphalan/prednisone-treated patients and an 18-month survival of patients receiving colchicine (p = 0.23) [9]. We have excluded some of the longest surviving patients from our analysis because of considerable delay between diagnosis and treatment/ referral, and our purpose was to have an unbiased treatment comparison. If these patients are included for the purpose of comparing survival with that in other series, our Group A median survival increases from six to seven months, versus an increase from 17 to 18 months in Group B. The difference between the early Boston and Rochester series can also be explained in part by the use of current techniques that allow precise biochemical identification of amyloid type. Since our study was performed recently and tissue was available in all patients, a careful immunohistochemical evaluation was carried out in each case. By this technique, we were able to eliminate patients that had secondary (AA) or hereditary (prealbumin) forms of amyloid that clinically mimicked AL amyloid and would usually be associated with a longer survival. Such an analysis was not possible at the time of the aforementioned series with which we compared our data. The literature clearly demonstrates no known universally accepted treatment of systemic amyloidosis [I]. Interventions most evaluated concern the treatment of secondary (AA) amyloid and more recently hereditary (familial amyloid polyneuropathy or prealbumin) amyloidosis. These latter two forms have not been considered herein. Animal models, even those first suggesting the beneficial effect of colchicine [ 10,11], have also been
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related to AA amyloid, for there are no known animal models of primary (AL) amyloidosis. Agents that have been considered in the treatment of generalized primary (AL) amyloid include steroids, vitamin C, penicillamine, dimethylsulfoxide, and colchicine [35]. Prior to 1974, no therapy was known to affect outcome. Since primary amyloid is a plasma cell dyscrasia consisting of light chain deposits of various types, it is not surprising that patients have been and are still treated with a variety of immunosuppressive drugs, including chlorambucil, azathioprine, and cyclophosphamide, or combination regimens such as those used in the treatment of multiple myeloma, a disorder complicated by AL amyloid in 10 to 20 percent of cases. It is important to understand that although subsets of primary (AL) amyloid may exist, they are not well defined, and that the disorder is distinct from myeloma (AL) amyloid in the absence of clear-cut malignant or immature plasma cells in the bone marrow. Indeed, in the several instances in which it has been determined, the outcome in primary amyloid and myeloma amyloid has been distinctly different. For example, in the series of 193 patients described between 1960 and 1972, median survival after histologic diagnosis of primary amyloid was 14.7 months as compared with four months for those with myeloma amyloid [33]. In the subsequent decade (1970 to 1980) at the same institution, median survival was 13 months for the 182 patients with primary amyloid and five months for the 47 patients with myeloma amyloid [34]. The recent study of Kyle et al [9] comparing melphalan/prednisone to colchicine is clearly an important advance. The authors conservatively noted that their two groups showed no significant aggregate survival differences, but that on analysis of only one regimen, i.e., colchicine or melphalan/prednisone, survival from time of study entry to death or disease progression did demonstrate significant differences. The crossover aspect of the study also complicates the interpretation of their data. Of note is the rare case with biopsy-proved decrease or absence of previously present amyloid lesions after a course of melphalan/prednisone [36]. A surprising finding of great interest in our study was the apparent protective effect of being female. This was further supported by an examination of cases excluded from the analysis. All patients not included because of too rapid disease progression were male. The majority of patients excluded because of referral or treatment delay exceeding one year proved to be female (two of three of those excluded up through diagnosis in 1973, five of seven of those excluded with diagnosis made in 1976 or later). Of these, the patients with a diagnosis made before 1974 received colchicine because they survived until the drug became generally available. Those with disease diagnosed after 1975 whose treatment was delayed may not have had disease progression rapid enough to warrant
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early therapy. In any event, all three situations (rapid death, longevity, and apparent slowly progressing disease) indicate that female patients do generally better than male patients with primary (AL) amyloidosis. In the present study, whether Group A or Group B patients were considered, cardiovascular disease was the leading cause of death (33 percent and 44 percent in Groups A and B, respectively) followed by renal disease (31 percent and 30 percent), with liver and pulmonary disease together accounting for 17 percent of the deaths in Group A and 11 percent in Group B. These results are comparable with those in the other large modern series reported in 1983 [34]. In that group of 142 patients who died with AL amyloid but without myeloma, 40 percent of the deaths were from cardiac disorders, 2 1 percent from “amyloidosis” (presumably the terminal event listed on the death certificate), 11 percent from renal disease, followed by infection (4 percent), strokes (3 percent), other malignancy (1 percent), miscellaneous (6 percent), and unknown (14 percent). In a smaller series of 20 patients, a group selected as autopsy subjects, the incidence of cardiac-related death was 50 percent, the incidence of deaths due to renal disease was 35 percent, and the incidence of gastrointestinal-related death was 10 percent [37]. In an older series, cardiac, renal, and hepatic deaths [38] were said to be dominant; about that same time, our previous analysis found that renal disease predominated in 28 deaths (only six patients had primary amyloidosis) [7]. In retrospect, it is clear that in those six patients with primary amyloid, sudden deaths due to cardiovascular disease were prevalent even then. In the current study, sudden death (probably due to arrhythmias) was the major cause (60 percent) of death due to cardiac disorders. Thirty-seven percent and 3 percent (due to amyloid in one case) of the remaining cardiac deaths were caused by congestive heart failure
AMYLOIDOSIS
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ET AL
and myocardial infarction, respectively. These autopsy data emphasize the importance of cardiovascular mortality and enhance the significance of recent clinical noninvasive studies demonstrating its widespread occurrence, complex and variable nature, and the potential for better diagnosis and treatment of amyloid of the heart. [39-431. Immunosuppressive treatment was used sporadically in both Groups A and l3. In some patients, classified as having had “any” immunosuppressive therapy, minimal doses and/or duration of a variety of regimens (steroids, chlorambucil, melphalan) were utilized. In others, at least two courses of agents such as melphalan and/or prednisone were administered. In neither instance was a significant difference noted in usage between the groups, nor did treatment with immunosuppressive drugs have an impact on survival. This clearly does not imply that an adequate controlled trial of immunosuppressive agents was present, merely that the outcomes in these series were apparently unaffected by such medication. The natural history of primary (AL) amyloid disease, the prognostic factors, and the causes of death are now better understood. This study strongly suggests, but does not prove, that colchicine treatment and modern supportive therapy are associated with improved prognosis in this systemic form of amyloid. There is nothing to suggest that colchicine is a specific therapy. However, since it is virtually non-toxic in the dosage given, even over a great many years, and since life expectancy in the disease has improved parallel with the drug’s use, we believe that colchicine is a reasonable form of adjunctive treatment in this complex disorder. It is indeed likely that with the data at hand, prospective double-blind drug protocols can be devised for new and more promising agents, using colchitine as a control form of supportive therapy and melphalan/prednisone as an alternative mode.
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6. 7.
8.
Cohen AS: Amyloidosis. N Engl J Med 1967; 277: 522-530, 574-583, 628-638. Lowenstein J, Gallo G: Remission of the nephrotic syndrome in renal amyloidosis. N Engl J Med 1970; 282: 128-132. Triger DR, Joekes AM: Renal amyloidosis-a 14 year study. Q J Med 1973; 42: 15-40. Dikman SH, Kahn T, Gribetz D, Chung J: Resolution of renal amyloidosis. Am J Med 1977; 63: 430-433. Michael J, Jones NF: Spontaneous remissions of nephrotic syndrome in renal amyloidosis. Br Med J 1978; 17: 1592-1593. Kyle RA: Amyloidosis. Clin Hematol 1982; 11: 151-180. Brandt K, Cathcart ES, Cohen AS: A clinical analysis of the course and prognosis of 42 patients with amyloidosis. Am J Med 1968; 44: 955-969. Kyle RA, Greipp RR: Primary systemic amyloidosis: comparison of melphalan and prednisone versus placebo. Blood 1978; 52: 818-827.
9.
10.
11.
12.
13. 14.
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Kyle RA, Greipp PR, Garton JP, Gertz MA: Primary systemic amyloidosis. Comparison of melphalan/prednisone versus colchicine. Am J Med 1985; 79: 708-716. Kedar I, Ravid M, Sohar E, et al: Colchicine inhibition of casein-induced amyloidosis in mice. Isr J Med Sci 1974; 10: 787-789. Shirahama T, Cohen AS: Blockage of amyloid induction by colchicine in animal model. J Exp Med 1974; 140: 1102-l 107. Zemer D, Pras M, Shemer Y, Sohar E, Gafni J: Daily prophylactic colchicine in familial Mediterranean fever: In: Glenner GG, Costa P, Freitas F, eds. Amvloid and amvloidosis. Amsterdam: Excerpta Medica, 1986; 584-586. Zemer D, Pras M, Sohar E: Colchicine in familial Mediterranean fever. N Engl J Med 1976; 294: 170-171. Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J: Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med 1986;
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1.5. 16.
17.
18.
19. 20. 21.
22.
23.
24.
25. 26. 27.
28.
29.
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314: 1001-1005. Malkinson FD: Colchicine. New uses of an old, old drug. Arch Dermatol 1982; 118: 453-457. Cohen AS, Shirahama T, Sipe JD, Skinner M: Amyloid proteins, precursors, mediator and enhancer. Lab Invest * 1983; 48: 1-4. Tatsuta E, Sipe JD, Shirahama T, Skinner M, Cohen AS: Colchicine inhibition of serum amyloid protein SAA and SAP synthesis in primary mouse liver cell cultures. Arthritis Rheum 1984; 27: 349-352. Brandwein SR, Sipe JD, Skinner M, Cohen AS: Effect of colchicine on experimental amyloidosis in two CBA/J mouse models. Lab Invest 1985; 52: 319-325. Gehan EA, Freireich EJ: Non-randomized controls in cancer clinical trials. N Engl J Med 1974; 290: 198-203. Weinstein MC: Allocation of subjects in medical experiments. N Engl J Med 1974; 291: 1278-1285. Moses LE: The series of consecutive cases as a device for assessing outcomes of intervention. N Engl J Med 1984; 311: 705710. Bailer JC III, Louis TA, Lavori PW, Polansky M: Studies without internal controls. N Engl J Med 1984; 311: 156-162. Sacks H, Chalmers TC, Smith H Jr: Randomized versus historical controls for clinical trials. Am J Med 1982; 72: 233-239. Starmer CF, Lee KL: A data-based approach to assessing clinical interventions in the staging of chronic disease. Cancer Treat Rep 1982; 6: 1077-l 082. Gehan EA: Design of controlled clinical trials: use of historical controls. Cancer Treat Rep 1982; 66: 1089-1093. Schafer A: The ethics of the randomized clinical trial. N Engl J Med 1982; 307: 719-724. Libbey CA, Skinner M, Cohen AS: The abdominal fat tissue aspirate for the diagnosis of systemic amyloidosis. Arch Intern Med 1983; 143: 1549-1552. Cohen AS, Skinner M: The diagnosis of amyloidosis. In: Cohen AS, ed. Laboratory diagnostic procedures in the rheumatic diseases, 3rd ed. Tampa, Florida: Grune and Stratton, 1985; 377-399. McKee PA, Castelli WP, McNamara P, Kannel WB: The natural history of congestive heart failure: the Framing-
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32. 33. 34.
35.
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38. 39.
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ham study. N Engl J Med 1971; 285: 1141-1146. Cox DR: Regression models and life tables. J R Stat Sot Br 1972; 34: 187-220. Harrell FE: The PHGLM procedure. In: SAS Institute. SUGI supplemental library users guide. Cary, North Carolina, 1983; 267-294. Feinstein AR: Clinical biostatistics. St. Louis: CV Mosby, 1977; 106. Kyle RA, Baird ED: Amyloidosis: review of 236 cases. Medicine 1975; 54: 271-299. Kyle RA, Greipp PR: Amyloidosis (AL). Clinical and laboratory features in 229 cases. Mayo Clin Proc 1983; 58: 665-683, Cohen AS, Rubinow A: Amyloidosis. In: Baumgarten A, Richards FF, eds. CRC handbook series in clinical laboratory science. Section F, Immunology, volume 1, part 1. West Palm Beach, Florida: CRC Press, 1978; 21 l-225. Gertz MA, Kyle RA: Response of primary hepatic amyloidosis to melphalan and prednisone: a case report and review of the literature. Mayo Clin Proc 1986; 61: 218-223. Wright JR, Calkins E: Clinical-pathological differentiation of common amyloid syndromes. Medicine 1981; 60: 429-448. Barth WF, Wilkerson JT, Waldmann TA, Decker JL: Primary amyloidosis. Am J Med 1969: 47: 259-273. Falk RH, Cohen AS, Hood WB Jr: The sensitivity of technetium-99m-pyrophosphate scintigraphy for the diagnosis of cardiac amyloidosis. Am J Cardiol 1983; 51: 826-830. Falk RH, Schick E, Boinary R, Rubinow A, Cohen AS: Sensitivity and specificity of “granular sparkling” on 2-D echocardiography for the diagnosis of cardiac amyloidosis (abstr). Circulation 1983; 68 (part 2): 163. Falk RH, Rubinow A, Cohen AS: Cardiac arrhythmias in systemic amyloidosis: correlation with echocardiographic abnormalities. J Am Coll Cardiol 1984; 3: 107-l 13. Rubinow A, Skinner M, Cohen AS: Digoxin sensitivity in amyloid cardiomyopathy. Circulation 1981; 63: 1285-1288. Gertz MA, Falk RH, Skinner M, Cohen AS, Kyle RA: Worsening of congestive heart failure in amyloid heart disease treated by calcium channel-blocking agents. Am J Cardiol 1985; 55: 1645.
ALAN S. COHEN, M.D. ALAN RUBINOW, M.D. JENNIFER J. ANDERSON, Ph.D. MARTHA SKINNER, M.D. JOHN H. MASON, M.A. CARYN LIBBEY, M.D. HERBERT KAYNE, Ph.D.
Primary amyloidosis has a variable course, but is generally associated with a short life expectancy. To date, no specific therapy has been available. Fifty-three patients with AL amyloidosis seen between 1976 and 1963 were treated with colchicine, and their clinical course and survival were compared with that in 29 other patients seen between 1961 and 1973. Of the variables measured, the treatment, the patient’s sex, and the time interval from diagnosis to referral or treatment were significantly associated with length of survival, Median-survival for the colchicine-treated patients was 17 months, compared with six months for the non-colchicine-treated patients. A surprising fkrdirig was the longer life span in female patients (median eight months versus four and a half months in the non-colchicine-treated gr&p,‘and 25.5 months versus 10 months in the colchicine-treated group). The study suggests that colchicine has improved the life expectancy in AL amyloidosis. Although it is not a specific therapy, it may be a reasonable form of adjunctive treatment in this complex disorder.
Boston, Massachusetts
From the Thorndike Memorial Laboratory and the Department of Medicine, Boston City Hospital, the Arthritis Center, Department of Medicine, Boston University School of Medicine, and Boston University School of Public Health, Boston, Massachusetts. This work was supported by grants from the United States Public Health Service, National Institute of Arthritis, Metabolic and Digestive and Kidney Diseases (AM-04599 and AM-07014), Multipurpose Arthritis Center, National Institutes of Health (AM-20613), the General Clinical Research Centers Branch of the Division of Research Resources, National Institutes of Health @R-533), and the Arthritis Foundation, and was presented in part at the Fourth International Symposium on Amyloidosis, November 14, 1984, Harriman, New York. Requests for reprints should be addressed to Dr. Alan S. Cohen, Department of Medicine, Boston City Hospital, Thorndike Building 314, 818 Harrison Avenue, Boston, Massachusetts 02 118. Manuscript submitted October 6, 1986, and accepted December 30, 1986.
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No specific treatment has been found for any variety of amyloidosis [ 11. Eradication of the predisposing disease may slow the progression of reactive or secondary (AA) amyloidosis, but only sporadic reports have appeared with suitable serial biopsy evidence of resorption [2-51. “Remissions” have occurred both spontaneously and after treatment of an inflammatory or infectious disease leading to secondary amyloidosis. Primary (AL) amyloidosis, currently the more commonly seen form of the disorder, has a variable outcome but is generally associated with a short life expectancy [6,7]. Since primary amyloid is composed of light chains and since kappa and lambda light chains are produced by plasma cells, melphalan/prednisone regimens have sporadically been utilized. In 1978, the results of a prospective randomized study comparing a placebo and a melphalan/prednisone regimen showed no significant difference in survival between the two groups [8]. Recently, in another prospective randomized trial, Kyle and co-workers [9] reported that melphalan/prednisone was superior to colchicine when the data were analyzed from time of entry into the study to time of death or progression of disease, but not when the data were analyzed in the aggregate. Colchicine, which effectively prevents acute febrile episodes in patients with familial Mediterranean fever, a condition that predisposes to amyloidosis, has been shown to block amyloid production in the mouse model of secondary amyloidosis [ 10,l I]. In addition, reports from Israel indicated that amyloidosis no longer developed in colchicine-treated patients with familial Mediterranean fever, and suggested improvement in some patients with this form of AA amyloid [ 12- 141. How might colchi-
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tine influence outcome in primary amyloidosis? Colchitine is known to affect mitosis, to disrupt microtubule organization, and to.potentially interfere with microtubule cell function [ 151. Due to the presumed participation of the macrophage in the pathogenesis of AA amyloidosis and the concept that in AL amyloid, the immunoglobulin is processed (catabolized) by the macrophage prior to tissue deposition [ 161, it seems reasonable to suspect that colchicine might alter or delay fibril formation or deposition in AL amyloid. More recent data also suggest that, at least in acquired amyloidosis, the mechanism of action of colchitine may involve reduced protein synthesis rather than blockage of secretion of newly synthesized protein [17,18]. The steady influx of patients with amyloidosis who were referred to us provided a unique opportunity to conduct a therapeutic study with colchicine, a relatively innocuous agent. .Our original protocol was a double-blind, randomized controlled study in which patients would be treated with colchicine or placebo. Although reasonably conceived, this study was abandoned as a result of the outright refusal of the majority of patients (with a potentially fatal disease) to accept placebo, a similar unwillingness on the part of referring physicians to allow their patients with amyloid to enter a placebo study, and the discovery that, whichever protocol we used, referring physicians still treated their patients with colchicine (in four of the first six cases). Such practical and ethical objections to random drug allocations in potentially fatal conditions and the alternative use of historical control subjects have been discussed [19-261. On the basis of this literature and our own experience with randomization, an open study in which all patients were to be offered colchicine, with entrance data carefully gathered and compared with our previous experience, appeared to be the realistic alternative. In the present study, therefore, the survival of the colchicinetested group was compared with the survival of previous patients we had seen when no drug therapy was available and only supportive measures were used.
PATIENTS AND METHODS Patient Groups. Between August 1961 and April 1983, 112 patients with primary amyloidosis were seen at our Clinical Research Center. The diagnosis was made in 34 patients between August 1961 and the end of 1973, before colchicine was available as a therapy, in 15 patients during 1974 and 1975 (nine of whom survived long enough to eventually receive colchicine therapy in 1976 or later), and in 63 patients between early 1976 and March 1983, for whom colchicine therapy was available. Group A, the “untreated” control subjects, was drawn from the earliest cohort, and Group B, the colchicine-treated patients, was drawn from those in whom the diagnosis was made in 1976 or later. Evaluation and Treatment. Initial detailed clinical evalua-
AMYLOIDOSIS
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ET AL
tion and classification were carried out in the Thorndike Memorial Laboratory Clinical Research Center. All patients provided complete histories and underwent physical examination. Evaluation included the measurable clinical parameters (congestive heart failure, nephrotic syndrome, hepatomegaly, splenomegaly, and macroglossia), routine and speand liver cial laboratory tests (e.g., renal, pulmonary, function studies), and routine and special blood chemical determinations. One major clinical feature was listed for each patient, i.e., renal insufficiency, cardiovascular abnormalities, peripheral neuropathy, liver disease, or other. Note was made of all treatment that the patients had been given, especially whether they had ever, even for a short period, been receiving immunosuppressive agents, such as melphalan and prednisone, chlorambucil, or any other drugs. For all patients, previous biopsy results were reviewed and either rectal or subcutaneous fat [27] plus skin biopsy specimens were obtained. The presence of amyloid was determined histopathologically by the demonstration of Congo red-positive deposits that showed green birefringence on polarization microscopy [28]. Studies included a search for urinary and plasma monoclonal components and kappa or lambda light chains, bone marrow aspiration or biopsy, and skeletal survey. If a diagnosis of multiple myeloma was made (lytic bone lesions and sheets of immature plasma cells in the bone marrow), the patient was excluded from this series. Patients with familial amyloid polyneuropathy (A prealbumin) or with reactive (AA) amyloid secondary to chronic infectious or inflammatory disease were also excluded. All patients referred between June 1976 and April 1983 were treated with colchicine 0.5 mg tablets (one to two tablets per day depending upon tolerance). Patients were requested to complete compliance forms and return them on a regular basis and to return to the Clinical Research Center for thorough re-evaluations in one to two years. They also underwent periodic examinations performed by local physicians. Criteria for Inclusion in Analysis. There were 34 untreated patients in Group A, and 63 patients who were seen subsequently were included in Group B. The 15 patients in whom the diagnosis was made in 1974 and 1975 were excluded from analysis to eliminate treatment assignment bias arising during this crossover period when colchicine was first made available to patients referred to the Thorndike Memorial Laboratory Clinical Research Center. Patients were included in the study only if they survived at least three months from the time of their first symptom, or at least one month from the date of the diagnosis, or, for the colchicinetreated patients, one month from the start of colchicine therapy. A total of five patients were excluded on this basis, two from Group A and three from Group B. As the outcome of interest was the time from diagnosis to death, we also did not inolude in the analysis any patients for whom the interval from diagnosis until referral or the start of treatment exceeded one year. In the treatment group, any colchicine effect would have been overestimated due to ascribing the entire survival interval to a colchicine effect. Ten patients were excluded for this reason, three from Group A with the
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TABLE
AMYLOIDOSIS
I
TREATED
Baseline
WITH
COLCHICINE-COHEN
Comparison
ET AL
of Study Groups Group A 1961-1973 (n = 29)
Total (n = 82) Age (years)” Sex (percent female) Months from first symptom to diagnosis* Months from diagnosis to referral/start treatment* Clinical variables (at referral) Creatinine level (mg/dl)* 24-hour protein (g)” Postural hypotension (percent)t Congestive heart failure (percent) Major clinical feature (percent) Renal insufficiency Cardiovascular abnormalities Peripheral neuropathy Liver disease Immunosuppressive treatment (percent) Any Adeouate * Mean f standard deviation. t Data were available for only
17 patients
in Group
56.9
of
f 10.3 44 15.0 f 16.4 2.7 f 2.7
follow-up
date
for
seven
of the
more
2.4 f 3.2 5.2 f 4.8 24 34
43 22 2 26 22 6 A and 50 patients
recent
Group
in Group
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f 8.5 38 13.3 f 13.9 3.1 f 2.5
1.5 f 6.4 f
1.0 6.5
0.123 0.164 0.269 0.091
6 6
0.269 0.378 0.063 0.001
45 21 3 24
42 23 2 26
0.818 0.999 0.999 0.999
24
21 6
0.783 0.999
B.
RESULTS
Patients in Groups A and B were similar in age, percent female, time interval from first symptom to diagnosis, and time interval from diagnosis until referral or treatment (Table I). However, the Group A patients were more apt to have had congestive heart failure by the time of their referral (34 percent versus 6 percent of Group B patients, p
B
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58.3
P Value
the two groups, varied with the year of diagnosis, or displayed an association with survival. The results are expressed in terms of adjusted relative risk, which is the proportional increase in risk associated with the presence of a factor (such as colchicine treatment), or with a change of one unit in a scalar variable (such as the time interval between diagnosis and referral or treatment). The correlation of baseline variables with membership in Group A or B was evaluated using chi-square” for categoric variables and t tests for continuous variables. Equality of variance in the two groups was assessed by the F test. Association of the study variables with time period of diagnosis or months of survival was analyzed using Pearson correlation coefficients, or, for binary variables, the appropriate t test. The primary cause of death, from postmortem examination and from clinical records, was determined whenever possible.
patients). Cox proportional-hazards regression model with backward elimination was used to compare risk of death for the patients in the two groups [30,31]. Covariates initially included were all of the parameters that differed between
1184
f 12.7 55 18.0 f 20.2 2.1 f 2.9
1.7 f 1.8 6.1 f 6.1 10 16
intervals from diagnosis to referral ranging from three to five years, and seven patients from Group B with treatment delays ranging from 13 months to nearly three years. Thus, Group A consisted of 29 patients and Group B consisted of 53 patients. Statistical Analysis. Baseline factors studied included age, sex, 24-hour urine protein, serum creatinine, presence of postural hypotension, evidence of congestive heart failure, both at the time of diagnosis and on referral, and the use of immunosuppressive drugs, as well as time intervals from symptoms to diagnosis and from diagnosis to treatment. If the serum creatinine value was greater than 1.5 mg/dl, the patient was considered to have renal insufficiency. Postural hypotension was diagnosed by a drop of more than 20 mm Hg in the systolic blood pressure on standing. Criteria for determination of congestive heart failure were taken from the Framingham Heart Study [29]. If at least two of the major criteria were satisfied, the patient was considered to have congestive heart failure. The possibility of time trends in the patients’ baseline factors was explored by relating these variables to the time period of each patient’s diagnosis. The first period was 1961 to 1969, coded 1, the second 1970 to 1971, coded 2, and each subsequent two-year interval defined a further time period, concluding with the eighth, 1982 to 1983, coded 8. The first time period was longer because of the smaller number of patients with diagnoses made in these earlier years. The outcome measure analyzed was the number of months of survival from diagnosis until death (or until the last
54.2
Group B 1976-1983 (n = 53)
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some of these clinical variables, with creatinine levels and the probabilities of postural hypotension and congestive heart failure at referral improving over time (Table II). This suggests that some of the patients in whom the diagnosis was made in the earlier years were sicker than the patients in whom the diagnosis was made later, possibly because of delays in the diagnoses of amyloid disease. On the other hand, there were no apparent time trends in the presence of various clinical features or use of immunosuppressive drug treatment. Female gender, absence of postural hypotension, and the number of months from diagnosis to treatment correlated with lengthening survival (Table II). None of the remaining variables considered, including months from symptoms to diagnosis and age, displayed significant association with patient survival in these bivariate analyses. In order to make an unbiased survival time comparison of Group A and Group B patients, all variables that differed between the two groups, exhibited a trend over time, or were associated with length of survival were included as covariates in the proportional-hazards regression model. These covariates were the patient’s sex, number of months from diagnosis to treatment, each of the referral variables (creatinine level, presence of postural hypotension, 24-hour protein, and presence of congestive heart failure), as well as the year of diagnosis. In this full model, only the treatment group (colchicine or non-colchicine), the patient’s sex, and the time interval from diagnosis to referral or treatment were significant. This last variable can be thought of as a clinical summary variable, since the less sick a patient appears at the time of diagnosis, the longer the time interval between diagnosis and referral or treatment is likely to be. The adjusted relative risks derived from a Cox regression model that includes only the significant variables are shown in Table Ill. After adjustment for the two covariates, the relative risk of death associated with colchicine treatment was 0.35 (p
AMYLOIDOSIS
TABLE
II
TREATED
WITH
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Association of Study Variables of Diagnosis and with Survival
ET AL
with Period Tiiire
Time Period of Diagnosis
Survival
(p value)*
(p value)?
from symptoms to diagnosis Months from diagnosis to referral/treatment
0.10
0.65
0.33
0.03
(+)
Age Sex (female gender) Referral variables Creatinine Protein Postural hypotension Congestive heart failure Clinical features Renal insufficiency Cardiovascular abnormalities Peripheral neuropathy Liver disease lmmunosuppresive treatment Any Adequate
0.10 0.11
0.70 0.04
(-k)
Study Variable Months
0.01 0.89 0.01 0.01
(-)
0.51 0.50 0.01 (-) 0.49
(-) (-)
0.26 0.56 0.97 0.65
0.41 0.83 0.96 0.10
0.44 0.60
0.46 0.71
The first time period is 1961 to 1968, the second is 1970 to 1971, and each subsequent two-year interval is another time period, concluding with the eighth, 1982 to 1983. + Number of months from diagnosis to death, or in the case of seven colchicine-treated patients, until the date of last follow-up. NOTE: For those associations that are significant (p <0.05), the direction of the association is indicated in parentheses (i.e., iindicates a positive association: as one variable increases, so does the other; and - indicates a negative association). l
TABLE Ill
Survival Analysis Using ProportionalHazards Regression 95 Percent
Contributing
Factor
Colchicine treatment Female gender Time from diagnosis to treatment or referral (per month increase)
Adjusted Relative Risk 0.35 0.49 0.89
Confidence Interval 0.21, 0.33, 0.81,
p Value
0.59 0.78 0.98
0.001 0.003 0.018
each sex in the two patient groups are plotted (Figure 2), both the effect of colchicine and the consistent differences in survival by sex are seen. Median survival for male patients in Group A was four and a half months, Compared with eight months for female patients in this group. Median survival times for male and female patients in Group B were 10 months and 25.5 months, respectively. Median survival times in months for each time period under study are shown in Table IV. Patients in the first
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Figure 1. Probability of survival of pa Cents with primary amyloidosis treated with colchicine (Group s) or not treated (Group A), adjusted for sex and for time interval from diagnosis to treatment/ referral.
t-
1.0
0.8
T
L,:. 11.: /‘7:: F:b-1 :.... 11 3 ~:
0.2
0.0
I 1
!
I
2
3
I
4 YEARS
I
/
I
5
6
7
three time periods did not receive colchicine, whereas patients in the last four time periods did receive colchitine. The median survival time by sex for each time period is also included in this table. The overall consistency of the effects of colchicine treatment and of sex of the patient is apparent in this table despite considerable variability between medians of the very small groups. In an additional proportional-hazards regression analysis, sepa-
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FIgwe 2. Probability of survival of male and female patients with primary amyloidosis treated with colchicine (Group E?) or not treated (Group A), adjusted for time interval from diagnosis to treatment/referral.
rate trend variables for the time periods with and without colchicine treatment were included. These were in addition to the treatment, sex, and interval from diagnosis to treatment or referral variables retained previously (as in Table Ill). Neither of the trend variables was significant, nor did their presence reduce the effect of colchicine treatment found in the earlier analysis. This, together with the lack of effect of the diagnosis year variable in the
82
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AMYLOIDOSIS
TABLE
original proportional-hazards regression model, indicates that the colchicine effect is not explainable as a secular trend. Median survival times given in Table IV for the periods 1978 to 1979 and 1982 to 1983 are underestimates, because there were patients in these time periods who were still alive at the date of last contact (four from 1978 to 1979 and three from 1982 to 1983). Of these seven patients, five (71 percent) were female. This is a higher percentage than would be expected (chi-square = 4.42, p <0.05), since only 16 (36 percent) of the 44 patients with a diagnosis of primary amyloid made during the last three time periods were female. The major cause of death for patients in Group A and Group B was cardiac, accounting for 34 percent of the deaths in the former group and 44 percent of those in the latter series (Table V). The percentage of deaths due to renal liver, pulmonary, or cerebrovascular disease or gastrointestinal bleeding was approximately the same in both groups. None of these causes of death significantly differentiated the two patient groups. The precise cause of death could not be determined or was not available in three (10 percent) of the Group A patients and in three (7 percent) of the Group B patients. Further examination of cardiac mortality shows sudden death to be responsible for 60 percent of total deaths in each of the patient groups. Intractable congestive heart failure was the cause for the remainder of the Group A cardiac deaths and for all but one of the cardiac deaths in Group B.
IV
TREATED
Median Sex
WITH
Survival
COLCHICINE-COHEN
Time by Time Period and
Number of Patients
Time Period (years of diagnosis) Non-Colchicine-Treated 1961-1968 1970-1971 1972-1973 Total Colchicine-Treated 1976-1977 1978-1979 1980-1981 1982-1983 Total
ET AL
Survival Time (months) All Patients Male Female
10 7 12
6.5 9.0 6.0
5.5 4.0 6.0
8.0 10.0 6.0
29
6.0
5.0
8.0
9 19 14 11
22.0 18.0 9.0 10.0
18.0 14.5” 5.0 10.0
32.0 37.07 26.0 17.0x
53
17.0
10.0
25.5
* Two censored survival times (79 months and 63 months) (i.e., patients still alive at time of last contact). + Two censored survival times (71 months and 83 months). 1 Three censored survival times (three months, 25 months, and 27 months).
TABLE V
Cardiac Sudden death Congestive heart failure Myocardial infarction Renal Pulmonary Liver Gastrointestinal hemorrhage Cerebrovascular Other? Unknown
COMMENTS
Evaluation of the treatment of a chronic disease whose natural history is not well defined poses great problems. Clearly, a prospective double-blind study with randomized control subjects should be carried out whenever possible. Such a study was our original intent. Due to the reasons mentioned, especially the lack of cooperation of patients and of participating physicians, this plan was abandoned. Although the use of historical control subjects is controversial and filled with the possibility of bias [21-251, it has been pointed out that “many of the most thoroughly accepted current drugs including morphine, digitalis, aspirin, insulin, penicillin, and ccrticosteroids were established on the basis of historical controls without concurrent comparisons” [32]. The strategy of obtaining an observational data bank based on the prospective data collected on unselected patients with continuous surveillance for outcome has been discussed [24], as well as the potential errors that can occur. It is a well-known fact that with the use of historical control subjects, even with stringent selection criteria and adjustment for prognostic factors, biases in patient’s selection may weigh the outcome in favor of new therapies. It has been suggested that reconsideration
June
Cause of Death in Primary
Amyloidosis
Group A 1961-1973 (n = 29)
Group B 1976-1983 (n = 46)”
10 (34%) 6 4 0 9(31%) 4 (14%) 1(3%) 1(3%) 1(3%) 0 (0%) 3 (10%)
20 (44%) 12 7 14 (30%) 3(7%) 2 (4%) 1(2%) 2 (4%) 1(2%) 3 (7%)
* Seven patients still living at last contact. 7 Fat embolism during hip surgery.
of the significance level of 0.05 would be helpful. In the study reported herein, a significance level of less than 0.00 1 was attained, thus increasing our confidence in the conclusion that colchicine is an effective treatment. The possibility exists that, as information about amyloidosis improves, it will be shown that simple supportive treatment and avoidance of medications that adversely affect amyloid have favorably influenced outcome in this series regardless of the added treatment. This, however, was not borne out in our exploration of possible time trends. This study presents one of the few significant experiences with the long-term follow-up of primary amyloid, evaluates the prognostic effect of various (heart, kidney, liver) types of system involvement, and gives a modern
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view of the life history and causes of death in primary (AL) amyloidosis. The very magnitude of difference of survival of those treated with colchicine compared with those not so treated suggests that this disparity cannot be explained entirely either by differences in severity of disease, or by improved overall survival in later years for all patients with amyloid. As mentioned earlier, certain cases were eliminated from consideration in our survival analysis in order to avoid bias favoring the colchicine-treated group. The fact that the remaining group difference is so considerable, and also that no upward trend was noted in survival time within the two series, argues for a real drug effect exhibited by these data. Although colchicine appeared to decrease the rate of disease progression, data on clinical variables over time were not available, since time of death was the endpoint. Our overall survival results (median 17 months in Group B, six months in Group A) may not be strictly comparable with those reported in several other modern series. In the 1960 to 1972 series of 193 patients in Rochester, Minnesota, median survival after histologic diagnosis of AL amyloid (non-myeloma) was 14.7 months [33]. The median survival in their 1970 to 1980 series of 182 patients with AL amyloid but without myeloma was 13 months [34]. Their most recent series reported a 25.2-month survival of melphalan/prednisone-treated patients and an 18-month survival of patients receiving colchicine (p = 0.23) [9]. We have excluded some of the longest surviving patients from our analysis because of considerable delay between diagnosis and treatment/ referral, and our purpose was to have an unbiased treatment comparison. If these patients are included for the purpose of comparing survival with that in other series, our Group A median survival increases from six to seven months, versus an increase from 17 to 18 months in Group B. The difference between the early Boston and Rochester series can also be explained in part by the use of current techniques that allow precise biochemical identification of amyloid type. Since our study was performed recently and tissue was available in all patients, a careful immunohistochemical evaluation was carried out in each case. By this technique, we were able to eliminate patients that had secondary (AA) or hereditary (prealbumin) forms of amyloid that clinically mimicked AL amyloid and would usually be associated with a longer survival. Such an analysis was not possible at the time of the aforementioned series with which we compared our data. The literature clearly demonstrates no known universally accepted treatment of systemic amyloidosis [I]. Interventions most evaluated concern the treatment of secondary (AA) amyloid and more recently hereditary (familial amyloid polyneuropathy or prealbumin) amyloidosis. These latter two forms have not been considered herein. Animal models, even those first suggesting the beneficial effect of colchicine [ 10,11], have also been
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related to AA amyloid, for there are no known animal models of primary (AL) amyloidosis. Agents that have been considered in the treatment of generalized primary (AL) amyloid include steroids, vitamin C, penicillamine, dimethylsulfoxide, and colchicine [35]. Prior to 1974, no therapy was known to affect outcome. Since primary amyloid is a plasma cell dyscrasia consisting of light chain deposits of various types, it is not surprising that patients have been and are still treated with a variety of immunosuppressive drugs, including chlorambucil, azathioprine, and cyclophosphamide, or combination regimens such as those used in the treatment of multiple myeloma, a disorder complicated by AL amyloid in 10 to 20 percent of cases. It is important to understand that although subsets of primary (AL) amyloid may exist, they are not well defined, and that the disorder is distinct from myeloma (AL) amyloid in the absence of clear-cut malignant or immature plasma cells in the bone marrow. Indeed, in the several instances in which it has been determined, the outcome in primary amyloid and myeloma amyloid has been distinctly different. For example, in the series of 193 patients described between 1960 and 1972, median survival after histologic diagnosis of primary amyloid was 14.7 months as compared with four months for those with myeloma amyloid [33]. In the subsequent decade (1970 to 1980) at the same institution, median survival was 13 months for the 182 patients with primary amyloid and five months for the 47 patients with myeloma amyloid [34]. The recent study of Kyle et al [9] comparing melphalan/prednisone to colchicine is clearly an important advance. The authors conservatively noted that their two groups showed no significant aggregate survival differences, but that on analysis of only one regimen, i.e., colchicine or melphalan/prednisone, survival from time of study entry to death or disease progression did demonstrate significant differences. The crossover aspect of the study also complicates the interpretation of their data. Of note is the rare case with biopsy-proved decrease or absence of previously present amyloid lesions after a course of melphalan/prednisone [36]. A surprising finding of great interest in our study was the apparent protective effect of being female. This was further supported by an examination of cases excluded from the analysis. All patients not included because of too rapid disease progression were male. The majority of patients excluded because of referral or treatment delay exceeding one year proved to be female (two of three of those excluded up through diagnosis in 1973, five of seven of those excluded with diagnosis made in 1976 or later). Of these, the patients with a diagnosis made before 1974 received colchicine because they survived until the drug became generally available. Those with disease diagnosed after 1975 whose treatment was delayed may not have had disease progression rapid enough to warrant
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early therapy. In any event, all three situations (rapid death, longevity, and apparent slowly progressing disease) indicate that female patients do generally better than male patients with primary (AL) amyloidosis. In the present study, whether Group A or Group B patients were considered, cardiovascular disease was the leading cause of death (33 percent and 44 percent in Groups A and B, respectively) followed by renal disease (31 percent and 30 percent), with liver and pulmonary disease together accounting for 17 percent of the deaths in Group A and 11 percent in Group B. These results are comparable with those in the other large modern series reported in 1983 [34]. In that group of 142 patients who died with AL amyloid but without myeloma, 40 percent of the deaths were from cardiac disorders, 2 1 percent from “amyloidosis” (presumably the terminal event listed on the death certificate), 11 percent from renal disease, followed by infection (4 percent), strokes (3 percent), other malignancy (1 percent), miscellaneous (6 percent), and unknown (14 percent). In a smaller series of 20 patients, a group selected as autopsy subjects, the incidence of cardiac-related death was 50 percent, the incidence of deaths due to renal disease was 35 percent, and the incidence of gastrointestinal-related death was 10 percent [37]. In an older series, cardiac, renal, and hepatic deaths [38] were said to be dominant; about that same time, our previous analysis found that renal disease predominated in 28 deaths (only six patients had primary amyloidosis) [7]. In retrospect, it is clear that in those six patients with primary amyloid, sudden deaths due to cardiovascular disease were prevalent even then. In the current study, sudden death (probably due to arrhythmias) was the major cause (60 percent) of death due to cardiac disorders. Thirty-seven percent and 3 percent (due to amyloid in one case) of the remaining cardiac deaths were caused by congestive heart failure
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and myocardial infarction, respectively. These autopsy data emphasize the importance of cardiovascular mortality and enhance the significance of recent clinical noninvasive studies demonstrating its widespread occurrence, complex and variable nature, and the potential for better diagnosis and treatment of amyloid of the heart. [39-431. Immunosuppressive treatment was used sporadically in both Groups A and l3. In some patients, classified as having had “any” immunosuppressive therapy, minimal doses and/or duration of a variety of regimens (steroids, chlorambucil, melphalan) were utilized. In others, at least two courses of agents such as melphalan and/or prednisone were administered. In neither instance was a significant difference noted in usage between the groups, nor did treatment with immunosuppressive drugs have an impact on survival. This clearly does not imply that an adequate controlled trial of immunosuppressive agents was present, merely that the outcomes in these series were apparently unaffected by such medication. The natural history of primary (AL) amyloid disease, the prognostic factors, and the causes of death are now better understood. This study strongly suggests, but does not prove, that colchicine treatment and modern supportive therapy are associated with improved prognosis in this systemic form of amyloid. There is nothing to suggest that colchicine is a specific therapy. However, since it is virtually non-toxic in the dosage given, even over a great many years, and since life expectancy in the disease has improved parallel with the drug’s use, we believe that colchicine is a reasonable form of adjunctive treatment in this complex disorder. It is indeed likely that with the data at hand, prospective double-blind drug protocols can be devised for new and more promising agents, using colchitine as a control form of supportive therapy and melphalan/prednisone as an alternative mode.
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