- Email: [email protected]
prednisone versus colchicine
Primary Systemic Amyloidosis Comparison of MelphalarVPrednisone versus Colchicine
ROBERT A. KYLE, M.D. PHILIP R. GREIPP, M.D. JOHN P. GARTON, M.D. MORIE A. GERTZ, M.D. Rochester,
This is the first prospectively randomized study of the use of melphalan/prednisone and colchlclne In the treatment of primary systemic amyloidosis. One hundred one patlents were stratlfled according to their dominant clinical manifestation. Forty-nine patients inltlally received melphalan/prednisone and eight subsequently had colchlclne added to their regimen. Fifty-two patients lnltially received colchlclne and 35 subsequently required melphalan/prednlsone because of progressive disease. There was no difference in survival when the two groups were analyzed in aggregate (melphalan/prednlsone, 25.2 months versus colchlcine, 18 months; p = 0.23). When the survival of patients receiving only one regimen was analyzed or when survival was analyzed from the time of entry Into the study to the time of death or progression of disease, significant diierences (p -CO.001 and p
Minnesota
From the Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. This work was supported in part by Research Grant CA-16835 from the National Institutes of Health, Public Health Service, Bethesda, Maryland, and by the Toor Myeloma Research Fund, West Palm Beach, Florida. Requests for reprints should be addressed to Dr. Robert A. Kyle, Mayo Clinic, 200 First Street S.W., Rochester, Minnesota 55905. Manuscript accepted February 5, 1985.
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Primary systemic amyloidosis is an uncommon disease characterized by deposition of a fibrillar protein, often in vital organs (particularly the heart and kidney), resulting in organ dysfunction and death. The median survival was 14.7 months for 132 patients described from the Mayo Clinic in 1975 [l] and 12 months for 229 patients described from the same institution in 1983 [2]. Satisfactory treatment for primary amyloidosis does not exist. In 1964, Osserman and colleagues [3] emphasized the association of Bence Jones protein with amyloidosis and reported that these amyloid light chains tend to bind to certain normal tissues. Glenner and colleagues [4] in 1971 and Terry et al [5] in 1973 demonstrated that the amyloid fibrils in a patient with primary amyloidosis [6] were virtually identical to the variable portion of the monoclonal light chain (Bence Jones protein). Because monoclonal light chains are synthesized by plasma cells and increased numbers of plasma cells are commonly found on bone marrow examination in primary amyloidosis [7], it is reasonable to attempt treatment with alkylating agents that are effective against diseases characterized by proliferation of neoplastic plasma cells [8]. Melphalan, an alkylating agent, has been reported as beneficially influencing primary amyloidosis [9-2 11. In a prospective randomized study of 55 patients with primary amyloidosis comparing melphalan/prednisone therapy with placebo, Kyle and Greipp [21] demonstrated some benefit to patients with the nephrotic syndrome who were treated with melphalan/prednisone, but were unable to detect a significant difference in survival.
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Colchicine may be helpful in the treatment of amyloidosis. Amyloidosis occurs in more than one fourth of patients with familial Mediterranean fever and is a major cause of death [22]. Colchicine decreases the episodes of familial Mediterranean fever [23,24] and has been reported to inhibit casein-induced amyloidosis in mice [25,26]. Urinary protein excretion decreased significantly in six patients with familial Mediterranean fever and proteinuria who were treated with colchicine [27]. In 1976, Nimoityn et al [28] described a patient with familial Mediterranean fever in whom abdominal pain and proteinuria decreased with colchicine therapy. Suppressor T cell activity and chemotaxis are decreased in untreated familial Mediterranean fever, but these abnormalities are reversed with colchicine therapy [29]. Colchicine blocks the synthesis and secretion of serum arnyloid A protein from the hepatocytes of mice [30,31]. On the basis of a comparison with historical control subjects, survival of patients with primary amyloidosis increased with the daily use of colchicine [32]. No prospective study has compared melphalan/prednisone and colchicine therapies. We report our experience in a prospective randomized study comparing these agents. PATIENTS
AND METHODS
Patients. A complete history was obtained and physical examination performed in each patient. Special attention was given to the presence or absence and the degree of hepatomegaly, macroglossia, skin involvement, and any other observable lesions. Amyloidosis was confirmed by biopsy in every patient. Routine hematologic and chemical parameters were measured. lmmunoelectrophoresis or immunofixation was performed [33]. All patients had clinical or laboratory evidence of systemic amyloidosis. Excluded from the study were patients with secondary, familial, or localized amyloidosis; patients with overt symptomatic multiple myeloma or diarrhea; patients who had received alkylating agents or colchicine; and patients with brittle diabetes, severe hypertension, or an active peptic ulcer that would prevent the use of prednisone as indicated in the protocol. Written informed consent was obtained from each patient. Randomization. Each patient was assigned to one of four groups, depending on the patient’s major clinical feature: (1) nephrotic syndrome or renal failure, (2) congestive heart failure, (3) peripheral neuropathy, and (4) other. Patients who had more than one of these features were assigned to the group whose characteristics were most prominent in the patient. Medications. By means of a dynamic randomization scheme that assured a balance in the four clinical groups, the patients were assigned to receive (1) melphalan (0.15 mg/kg) in two divided doses daily and prednisone (0.8 mg/kg) in four divided doses daily for the same seven-day period or (2) colchicine (0.6 mg twice a day). Patients receiving melphalan and prednisone were advised to follow a bland diet and to take antacids, 1 ounce
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TABLE I
Group
SYSTEMIC
AMYLOIDOSIS-KYLE
Stratification of 101 Patients Systemic Amyloidosis
ET AL
with Primary
Melphalan/ Prednisone
Colchicine
Number
23
23
46
45
8
9
17
17
7
a
15
15
Nephrotic syndrome
Total Percent
Congestive heart failure Peripheral neuropathy Others’
11
12
23
23
Total
49
52
101
100
* Hepatomegaly (five), macroglossia (four), purpura or other skin lesion (three), abdominal pain (three), myopathy (two), cranial neuropathies (two), pronounced loss of weight, jaw claudication, joint pains, and proteinuria (one each).
four times daily during the week of therapy. Leukocyte and platelet counts were determined every three weeks initially, and melphalanlprednisone therapy was repeated every six weeks. The dose of melphalan was increased by 2 mg daily for each six-week course until mid-cycle leukopenia or thrombocytopenia occurred. If severe leukopenia or thrombocytopenia occurred, the dose of melphalan was reduced accordingly. The colchicine dose was increased by 0.6 mg daily each week until abdominal cramps or diarrhea developed. The use of colchicine was then discontinued and was resumed in the highest dosage that did not produce side effects. Patients continued to receive therapy for at least six months, unless significant toxicity developed. If there was progressive disease or lack of benefit from therapy, melphalan/prednisone or colchicine was added to the original therapeutic regimen. RESULTS One hundred one patients were entered in the study. Forty-nine were randomly assigned to receive melphalan/ prednisone therapy and 52 were randomly assigned to receive the colchicine regimen (Table I).
Initial Comparison of Melphalan/Prednii tine Groups. No important differences
and Cokhi-
were found bein the history and results of initial
tween the two groups physical examination (Table II). The serum monoclonal light chains were of the lambda class in 75 percent of the colchicine group and 82 percent of the melphalan/prednisone group with a monoclonal protein (Table Ill); normally, lambda light chains are found in two thirds of patients with primary amyloidosis with a monoclonal protein [2] and in only one third of patients with multiple myeloma. Free monoclonal light chains were found in the serum in 13 percent of the colchicine group and in 16 percent of the melphalan/ prednisone group. A urinary monoclonal lambda light chain was recognized in 42 percent of the colchicine group and in 61 percent of the melphalan/prednisone
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TABLE II
AMYLOIDOSIS-KYLE
ET AL
Initial Findings in 101 Cases of Primary Systemic Amyloidosis
Number of patients Age (years)* Males (percent) Females (percent) Weight loss Percent of patients Amount (pounds)* Hepatomegaly (percent) Macroglossia (percent) Hemoglobin (g/dl)* Creatinine (mg/dl)’ Percent >2.0 Alkaline phosphatase (IU)‘? Serum albumin (g/W* Plasma cells in bone marrow (percent)* Serum monoclonal protein present (percent) Serum monoclonal protein (g/dl)’ Urine monoclonal protein present (percent) Urine monoclonal protein (g/24 hours)’ Median. t Normal less than
TABLE
Melphalan/ Prednisone
Colchicine
Total Group
49 64 60 40
52 62 57 43
101 63 58 42
33 20 31
46 20 37
40 20 34
8
17
13
14.0 1.1 12 164
13.5 1.15 19 174
13.9 1.1 15 187
IgG kappa IgG lambda IgA kappa IgA lambda IgM kappa IgM lambda IgD lambda Kappa only Lambda only Negative
3.0
3.1
5
5
5
67
54
60
76
0.38
1.2 71
0.30
Rectum Kidney Carpal ligament Liver Small intestine Bone marrow Sural nerve
1.1 73
0.31
250.
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8 23 2 6 0 1 1 2 15 42
100
Tissue Diagnoses Amyloidosls
in Primary
100
Systemic
Percentage of Biopsy Specimens Showing Amyloidosis
group. A monoclonal protein was found in the serum or urine in 81 percent of the colchicine group and in 90 percent of the melphalan/prednisone group. The prothrombin time was increased (more than 12 seconds) in only four patients. The factor X level was reduced in three patients. The serum carotene level was reduced (less than 48 pg/dl) in only one patient. The serum vitamin B12 value was less than 200 rig/liter in 12 patients, but none had evidence of pernicious anemia. Echocardiography (M-mode and two-dimensional) was performed in 53 patients. Results of echocardiography revealed abnormalities consistent with amyloid infiltration in 60 percent. Results were similar in both treatment groups. Histologic diagnosis of arnyloidosis was made in all patients (Table IV). Of 76 rectal biopsy specimens, 74 percent demonstrated amyloid. All 24 renal biopsy specimens showed amyloid. Forty-one percent of the bone marrow biopsy specimens showed amyloid. Two patients had negative results of carpal ligament biopsy-in one,
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Total
6 15 4 6 0 2 0 2 13 52
100
Site 1.1
in Primary
of Patients Colchlclne
10 31 0 6 0 0 2 2 16 33
Total
TABLE IV 3.1
Serum lmmunoelectrophoresls Systemic Amvloidosls Percentage MelphalanlPrednisone
l
710
III
Tests Performed
MelphalarV Prednisone
Colchiclne
Total Group
76 24 5
75 100 100
72 100 50
74 100 60
11 3
100 100
72 100
82 100
91 10
43 80
39 100
41 90
paraffin blocks from the biopsy performed elsewhere could not be obtained, and in the other, carpal ligament biopsy was performed after chemotherapy. Two patients had a negative liver biopsy result-in one of these, the original paraffin blocks taken at the patient’s home hospital had been discarded. Results of sural nerve biopsy were negative in one patient with peripheral neuropathy, despite examination of 150 sections of the nerve. Results of Therapy. The peripheral neuropathy became worse in all 15 patients. Patients with congestive heart failure did not seem to be benefited objectively, although survival of these patients was longer for the melphalan/ prednisone group than for the colchicine group (p = 0.02, Figure 1). One patient who presented with overt congestive heart failure has continued to do well with melphalan/prednisone therapy at 46-month follow-up. However, serial echocardiography has revealed objective evidence of increased amyloid infiltration. Another patient had improvement of congestive heart failure and less deposition on echocardiography. Hepatomegaly devel-
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oped during therapy in nine patients in the melphalan/ prednisone group and in 10 in the colchicine group. Serum alkaline phosphatase activity increased more than 50 percent in two patients in the melphalan/prednisone group and in 11 receiving colchicine. Serum alkaline phosphatase levels decreased in five patients receiving melphalan/prednisone and in only one receiving colchitine therapy. The effect of therapy on hemoglobin level, serum creatinine level, and bone marrow is shown in Table V. Serum creatinine levels increased more than 0.5 mg/dl in 18 patients receiving melphalan/prednisone therapy and in 19 receiving colchicine therapy. There was a more than 50 percent increase in serum creatinine levels in 17 patients in each group. Five patients receiving melphalan/prednisone and six receiving colchicine required hemodialysis. In patients receiving melphalan/prednisone therapy, serum monoclonal protein decreased or disappeared in almost one third, and urinary monoclonal protein was reduced or disappeared in more than half. Protein reduction did not occur with the colchicine regimen (Table VI). Three of 35 patients had more than 50 percent reduction or disappearance of serum monoclonal protein at six months; seven of 24 had more than 50 percent reduction or disappearance at 12 months. Two of nine had more than 50 percent reduction or disappearance of urinary monoclonal protein at six months; four of nine had more than 50 percent reduction or disappearance at 12 months. There was no statistically significant difference in survival at six or 12 months between patients with reduction or disappearance of serum monoclonal protein and those without monoclonal protein reduction. Proteinuria decreased more than 50 percent in six of 28 patients at six months and in nine of 2 1 at 12 months. There was no statistically significant difference in survival at six or 12 months between patients with reduction and those without it. Duration and Amount of Therapy. Patients receiving melphalan/prednisone underwent a one-week course of therapy every six weeks for 12 months (median) (range one to 60). The number of one-week courses of melphalan/prednisone ranged from one to 30. The median daily dose of melphalan was 9.8 mg, with a range of 6 to 20 mg daily. The median total dose of melphalan was 840 mg, with a range of 42 to 2,205 mg. Colchicine was taken for less than one month to 56 months (median 12). The daily dose of colchicine ranged from less than 0.6 mg to 3.0 mg, with a median dose of 1.5 mg. Toxicity. By design, leukopenia (leukocyte count less than 3,000/mm3) occurred in almost half of the patients receiving melphalan/prednisone. In nine, the leukocyte count decreased to less than 1 ,500/mm3. No patient had sepsis related to the leukopenia. Thrombocytopenia occurred in slightly more than half of the patients receiving
December
SYSTEMIC
1
AMYLOIDOSIS-KYLE
2 t
3
ET AL
4
(years)
Figure 1. Probability of survival of patients with primary amyloidosis and congestive heart failure treated with meC pha/an/prednisone (MJ or colchicine (CT). p = 0.02 (logrank).
melphalan/prednisone, and the counts decreased to less than 50,000/mm3 in 12. There was no serious bleeding related to the thrombocytopenia. By design, diarrhea, abdominal cramps, or nausea and vomiting occurred temporarily in every patient who received colchicine. With a single daily colchicine tablet, an occasional patient had gastrointestinal symptoms. One patient had renal failure after diarrhea developed during colchicine therapy. Cause of Death. Cardiac manifestations were the most frequent causes of death in both groups. Some patients who were reported to have died suddenly probably had cardiac arrhythmia as the terminal event. Four patients died of acute nonlymphocytic leukemia. They had received melphalan/prednisone from 23 to 39 months (median 33) and a median dose of 950 mg (range 350 to 1,3 16). Three of the four had been given colchicine-two for almost four years. Two patients had a preleukemic phase characterized by pancytopenia. One patient had unexpected episodes of cytopenia from modest doses of melphalan and had received only 350 mg of the drug during the 29 months of chemotherapy. Survival (Figures 1 to 7). The median survival for the 101 patients was 22 months. The median survival was 25.2 months for patients receivint&melphalan/prednisone therapy and 18 months for those receiving colchicine therapy (p = 0.23) (Figure 5).
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’ Number
of patients
with Primary
8 3 0 0 28
7 4 1 1 52
Peripheral Neuropathy Melphalan/ Prednisone Colchicine
in Patients
involved.
Therapy
Number of patients Decrease of 12 gldl in hemoglobin‘ Increase of 10.5 mg/dl in creatinine’ Decrease in marrow plasma cells’ Median survival (months) Developed (during follow-up)* Congestive heart failure Carpal tunnel syndrome Orthostatic hypotension Peripheral neuropathy Malabsorption Nephrotic syndrome
TABLE V
11.5
0
0
2
8
Congestive Melphalan/ Prednisone
Systemic
Colchicine
Heart Failure
Amyloidosis
44
0
4
5
11
MelphalarV Prednisone
Other
18
0
1
4
12
Colchicine
8 10 5 0 1
4 10 4 0 0
25
3
18
2
2
11
11
9
18
2
19
24
52
49 28
Colchicine
Total Melphalan/ Prednisone
8
26
2
15
15
23
Colchicine
Syndrome
7
17
2
13
17
23
Nephrolic Melphalan/ Prednisone
PRIMARY
TABLE VI
Effects of Therapy on Monoclonal in Primary Systemic Amyloidosis
SYSTEMIC
AMYLOIDOSIS-KYLE
ET AL
Protein .w
-__I monoclonal protein Number of patients >50 percent decrease Disappeared Urine monoclonal Number of patients >50 percent decrease Disappeared
Melphalanl Prednisone
Colchlcine
Melphalanl Prednisone after Colchicine Failure
33
36
19
5
0
0
7
0
4
37
37
23
9
0
7
11
0
6
if ..,0
.8
Serum
protein
I
I
I
I
1
2
3
4
5
t (years) igure 3. Probability of survival of patients with prima; amyloidosis and “other” conditions treated with melpha/an/prednisone (MJ or colchicine (c). p = 0.58 (logrank).
1
1.0
0
Group
1
2
3
t (years)
C (n-8)
4
1
5
December
4
3
5
t (years)
.~~i
Figure 2. Probability of survival of patients with primary amyloidosis and peripheral neuropathy treated with me/phalanlprednisone (M) or colchicine (c). p = 0.79 (logrank).
2
Figure 4. Probability of survival of patients with primary amyloidosis and nephrotic syndrome treated with melphalanlprednisone (m or colchicine (C). p = 0.98 (logrank).
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AMYLOIDOSIS-KYLE
ET AL
m Group
Group
I
M (n=49)
C (n=52)
Group
I
I
I
I
I
I
1
2
3
4
5
1
t (years)
2
3
t (years)
Figure 5. Probability of survival of patients amyloidosis treated with melphalan/prednisone chicine (C). p = 0.23 (log-rank).
with primary (M) or col-
C
(1~52) 4
J
Figure 7. Probability of survival of patients with primary amyloidosis treated with melphalan/prednisone (MJ or co& chicine (c) from beginning of therapy to either death or until disease progression required change of therapy. p = 0.000 7 (log-rank).
If survival analysis were limited to patients who had received only a single regimen, the median survival was significantly longer (p = 0.00 1) for the melphalan/prednisone group (n = 41) (16 months) than for the colchicine group (n = 17) (three months) (Figure 6). Survival was also calculated from the time of study randomization to the time of death or until progression of disease necessitated adding the other therapeutic regimen. The “progression-free” median survival was 16 months for the melphalan/prednisone group and six months for the colchicine group (p = 0.0001) (Figure 7).
.8
.6
COMMENTS
Group
Treatment for primary systemic amyloidosis is not satisfactory. In a double-blind study [21] involving 55 patients with primary amyloidosis, those given melphalan/prednisone therapy were able to continue undergoing treatment longer and received larger doses than did patients in the placebo group, before the code was broken because of progressive disease. In that study, among 24 patients with the nephrotic syndrome, proteinuria virtually disappeared in two and urinary excretion of protein was reduced by 50 percent in eight others given melphalan/prednisone therapy.
C (n= 17)
I
1
I
I
4
1
2
3
4
5
t (years) Figure 6. Probability of survival of patients with primary amyloidosis treated with a single regimen of either melphalan/prednisone (M) or colchicine (C). p = 0.00 I (log-rank).
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Seven patients with the nephrotic syndrome and histologically proved primary amyloidosis have been reported to benefit from chemotherapy [g-14]. In all seven, the proteinuria had been reduced and the edema disappeared. Improvement occurred in all seven within one year after therapy was initiated. Four of the seven patients underwent pretreatment renal biopsy, but kidney tissue was not obtained in any patient after improvement. Initially, the liver was enlarged in four patients, and it subsequently decreased to normal size in all four. Four other patients with histologically proved amyloidosis without the nephrotic syndrome have also benefited from chemotherapy [ 17-201. Spontaneous remissions of the nephrotic syndrome have been noted in two patients with amyloidosis [34]. However, one of the patients had had pulmonary tuberculosis, and the other had had pulmonary tuberculosis and chronic ulcerative colitis; secondary amyloidosis could not be excluded. In 1982, Kyle et al [ 161 reported on two patients with primary amylokfosis and the nephrotic syndrome in whom the administration of melphalan and prednisone was associated with resolution of the nephrotic syndrome. In both patients, the serum albumin level returned to normal, proteinuria decreased to near-normal, edema resolved, the monoclonal protein in the serum and urine disappeared, renal function remained stable, and hepatomegaly disappeared. In both, however, amyloid deposition was greater in follow-up renal tissue than in the initial specimen. Since that report, an additional similar case has been seen. The results of therapy in amyloidosis are difficult to document because the amount of amyloid in a patient cannot be measured accurately. In animals, the redistribution of amyloid deposits from the spleen and liver to the kidneys increases the problem of evaluation [35]. At present, investigators are limited to evaluation of organ function and measurement of the monoclonal protein in the serum and urine. A simple method is needed for measuring the amount of amyloid in a patient. In our series, the nephrotic syndrome was the most common presenting manifestation of primary amyloidosis and was seen in almost half of the patients. Comparison of the initial physical findings and laboratory data revealed
SYSTEMIC
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ET AL
no important differences between the melphalan/prednisone and the colchicine groups. Light chains of the lambda type predominated in each group. The size of the monoclonal protein in both the serum and urine was modest and essentially equal in the two treatment regimens. Urinary protein decreased more than 50 percent in 21 of the 39 patients with the nephrotic syndrome who received melphalan/prednisone, whereas none in the colchicine group evidenced such a reduction before the addition of melphalan/prednisone. The serum creatinine level remained stable in 10 of the 21 patients. Colchicine was well tolerated, except for the expected gastrointestinal symptoms. Leukopenia and thrombocytopenia did not constitute a serious problem. However, in four patients receiving melphalan/prednisone, acute nonlymphocytic leukemia developed, presumably from the alkylating agent. The difference in survival between the total melphalan/prednisone and colchicine groups was not significant. However, survival was significantly better (p = 0.02) in patients with amyloid and congestive heart failure who were treated with melphalan/prednisone, despiie the small numbers. Survival was significantly longer for the patients treated with melphalan/prednisone when analysis was lim ited to those receiving only a single regimen or when survival was calculated from the time of randomization to the time of death or until progression of the disease necessitated the addition of the other therapeutic regimen. This suggests that melphalan/prednisone is potentially superior to colchicine. This superiority is also supported by the fact that in 35 cases, melphalan/pr&isone was added to colchicine, whereas colchicine was ad&d to melphalan/ prednisone in only eight cases. However, colchicine may not have been added to the melphalan/prednisone regimen because of the presence of gastrointestinal symptoms from amyloidosis or because of bias on the part of the investigators. In this study, a crossover design was included because it was considered difficult to withhold another potentially beneficial agent in the presence of progressive amyloidosis. The results of this study suggest that melphalan/prednisone is superior to colchicine, but to confirm this, the agents must be compared in a prospective randomized fashion without a provision for crossover.
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Kyle RA, Bayrd ED: Amyloklosis: review of 236 cases. Meditine (Baltimore) 1975; 54: 271-299. Kyle RA, Greipp PR: Amyloidosis (AL): clinical and laboratory features in 229 cases. Mayo Clin Proc 1983; 58: 665-683. Osserman EF, Takatsuki K, Talal N: Multiple myeloma I. The pathogenesis of “amyloidosis.” Semin Hematol 1964; 1: 3-85. Glenner GG, Terry W, Harada M, lsersky C, Page D: Amyloid
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fibril proteins: proof of homology with immunoglobulin light chains by sequence analyses. Science 1971; 172: 1150-1151. Terry WD, Page DL, Kimura S, lsobe T, Osserman EF. Glenner GG: Structural identity of Bence Jones and amyloid fibril proteins in a patient with plasma cell dyscrasia and amyloidosis. J Clin Invest 1973; 52: 1276-1281. Cohen AS, Wegelius 0: Classification of amyloid:
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1979-1980. Arthritis Rheum 1980; 23: 644-645. Kyle RA, Bayrd ED: “Primary” systemic amyloidosis and myeloma: discussion of relationship and review of 81 cases. Arch Intern Med 1961; 107: 344-353. Costa G, Engle RL Jr, Schilling A, et al: Melphalan and prednisone: an effective combination for the treatment of multiple myeloma. Am J Med 1973; 54: 589-599. Cohen HJ. Lessin LS. Hallal J, Burkholder P: Resolution of primary amyloidosis during chemotherapy: studies in a patient with nephrotic syndrome. Ann Intern Med 1975; 82: 466-473. Jones NF, Hilton PJ, Tighe JR, Hobbs JR: Treatment of “primary” renal amyloidosis with melphalan. Lancet 1972; II: 616-619. Horne MK Ill: Improvement in amyloidosis (letter). Ann Intern Med 1975; 83: 281-282. Schwartz RS, Cohen JR, Schrier SL: Therapy of primary amyloidosis with melphalan and prednisone. Arch Intern Med 1979; 139: 1144-1147. Buxbaum JN, Hurley ME, Chuba J, Spiro T: Amyloidosis of the AL type: clinical, morphologic and biochemical aspects of the response to therapy with alkylating agents and prednisone. Am J Med 1979; 67: 887-878. Emmerich B, Kircher A, Fink U, Schmid L, Rostetter J: Primare Amyloidose mit nephrotischem Syndrom: 5jahriger Verlauf unter kombinierter Chemotherapie. Klin Wochenschr 1980; 58: 1207-1213. Kyle RA, Pierre RV, Bayrd ED: Primary amyloidosis and acute leukemia associated with melphalan therapy. Blood 1974; 44: 333-337. Kyle RA, Wagoner RD, Holley KE: Primary systemic amyloidosis: resolution of the nephrotic syndrome with melphalan and prednisone. Arch Intern Med 1982, 142: 1445-1447. Mehta AD: Regression of amyloidosis in multiple myeloma. Br J Clin Pratt 1978; 32: 358-359, 36 1. Bradstock K, Clancy R, Uther J, Basten A, Richards J: The successful treatment of primary amyloidosis with intermittent chemotherapy. Aust NZ J Med 1978; 8: 176- 179. Corkery J, Bern MM, Tullis JL: Resolution of amyloidosis and plasma-cell dyscrasia with combination chemotherapy (letter). Lancet 1978; II: 425-426. Farhangi M, Thakur VM, Durham JB: Objective response in amylotdosis treated with intermittent chemotherapy. South Med J 1984; 77: 775-776.
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Kyle RA, Greipp PR: Primary systemic amvloidosis: comoarison of melphalan and prednisone versus placebo. Blood 1978; 52: 818-827. Sohar E, Gafni J, Pras M, Heller H: Familial Mediterranean fever: a survey of 470 cases and review of the literature. Am J Med 1967; 43: 227-253. Goldfinger SE: Colchicine for familial Mediterranean fever (letter). N Engl J Med 1972; 287: 1302. Reimann HA: Colchicine for periodic peritonitis. JAMA 1975; 23 1: 64-66. Shirahama T, Cohen AS: Blockage of amyloid induction by colchicine in an animal model. J Exp Med 1974; 140: 1102-1107. Kedar (Keizman) I, Ravid M, Sohar E. Gafni J: Colchicine inhibition of casein-induced amyloidosis in mice. Isr J Med Sci 1974; 10: 787-789. Zemer D, Pras M, Sohar E, Gafni J: Colchicine in familial Mediterranean fever (letter). N Engl J Med 1976; 294: 170-171. Nimoityn P, Lasker N, Soriano RZ: Detection of urinary amyloid in familial Mediterranean fever. Br Med J 1976; 2: 284. Melamed I, Shemer Y, Zakuth V, Tzehoval E. Pras M. Soirer Z: The immune system in familial Mediterranean fever. Clin Exp lmmunol 1983; 53: 659-682. Selinger MJ, McAdam KPWJ, Kaplan MM, Sipe JD, Vogel SN, Rosenstreich DL: Monokine-induced synthesis of serum amyloid A protein by hepatocytes. Nature 1980; 285: 498-500. 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. Rubinow A, Cohen AS, Kayne H, Libbey CA: Colchicine therapy in primary amyloidosis. A preliminary report (abstr). Arthritis Rheum 1981; 24: S124. Kyle RA: Classification and diagnosis of monoclonal gammopathies, section B, 2nd ed. In: Rose NR, Friedman H, eds. Manual of clinical immunology. Washington: American Society of Microbiology, 1980; 135-150. Michael J, Jones NF: Spontaneous remissions of neohrotic syndrome in renal amyloidosis. Br Med J 1978; 1: 1592-1593. Shirahama T, Cohen AS: Redistribution of amyloid deposits. Am J Pathol 1980; 99: 539-550.
22.
23. 24. 25.
26.
27.
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31.
32.
33.
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35.
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ROBERT A. KYLE, M.D. PHILIP R. GREIPP, M.D. JOHN P. GARTON, M.D. MORIE A. GERTZ, M.D. Rochester,
This is the first prospectively randomized study of the use of melphalan/prednisone and colchlclne In the treatment of primary systemic amyloidosis. One hundred one patlents were stratlfled according to their dominant clinical manifestation. Forty-nine patients inltlally received melphalan/prednisone and eight subsequently had colchlclne added to their regimen. Fifty-two patients lnltially received colchlclne and 35 subsequently required melphalan/prednlsone because of progressive disease. There was no difference in survival when the two groups were analyzed in aggregate (melphalan/prednlsone, 25.2 months versus colchlcine, 18 months; p = 0.23). When the survival of patients receiving only one regimen was analyzed or when survival was analyzed from the time of entry Into the study to the time of death or progression of disease, significant diierences (p -CO.001 and p
Minnesota
From the Division of Hematology and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota. This work was supported in part by Research Grant CA-16835 from the National Institutes of Health, Public Health Service, Bethesda, Maryland, and by the Toor Myeloma Research Fund, West Palm Beach, Florida. Requests for reprints should be addressed to Dr. Robert A. Kyle, Mayo Clinic, 200 First Street S.W., Rochester, Minnesota 55905. Manuscript accepted February 5, 1985.
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Primary systemic amyloidosis is an uncommon disease characterized by deposition of a fibrillar protein, often in vital organs (particularly the heart and kidney), resulting in organ dysfunction and death. The median survival was 14.7 months for 132 patients described from the Mayo Clinic in 1975 [l] and 12 months for 229 patients described from the same institution in 1983 [2]. Satisfactory treatment for primary amyloidosis does not exist. In 1964, Osserman and colleagues [3] emphasized the association of Bence Jones protein with amyloidosis and reported that these amyloid light chains tend to bind to certain normal tissues. Glenner and colleagues [4] in 1971 and Terry et al [5] in 1973 demonstrated that the amyloid fibrils in a patient with primary amyloidosis [6] were virtually identical to the variable portion of the monoclonal light chain (Bence Jones protein). Because monoclonal light chains are synthesized by plasma cells and increased numbers of plasma cells are commonly found on bone marrow examination in primary amyloidosis [7], it is reasonable to attempt treatment with alkylating agents that are effective against diseases characterized by proliferation of neoplastic plasma cells [8]. Melphalan, an alkylating agent, has been reported as beneficially influencing primary amyloidosis [9-2 11. In a prospective randomized study of 55 patients with primary amyloidosis comparing melphalan/prednisone therapy with placebo, Kyle and Greipp [21] demonstrated some benefit to patients with the nephrotic syndrome who were treated with melphalan/prednisone, but were unable to detect a significant difference in survival.
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Colchicine may be helpful in the treatment of amyloidosis. Amyloidosis occurs in more than one fourth of patients with familial Mediterranean fever and is a major cause of death [22]. Colchicine decreases the episodes of familial Mediterranean fever [23,24] and has been reported to inhibit casein-induced amyloidosis in mice [25,26]. Urinary protein excretion decreased significantly in six patients with familial Mediterranean fever and proteinuria who were treated with colchicine [27]. In 1976, Nimoityn et al [28] described a patient with familial Mediterranean fever in whom abdominal pain and proteinuria decreased with colchicine therapy. Suppressor T cell activity and chemotaxis are decreased in untreated familial Mediterranean fever, but these abnormalities are reversed with colchicine therapy [29]. Colchicine blocks the synthesis and secretion of serum arnyloid A protein from the hepatocytes of mice [30,31]. On the basis of a comparison with historical control subjects, survival of patients with primary amyloidosis increased with the daily use of colchicine [32]. No prospective study has compared melphalan/prednisone and colchicine therapies. We report our experience in a prospective randomized study comparing these agents. PATIENTS
AND METHODS
Patients. A complete history was obtained and physical examination performed in each patient. Special attention was given to the presence or absence and the degree of hepatomegaly, macroglossia, skin involvement, and any other observable lesions. Amyloidosis was confirmed by biopsy in every patient. Routine hematologic and chemical parameters were measured. lmmunoelectrophoresis or immunofixation was performed [33]. All patients had clinical or laboratory evidence of systemic amyloidosis. Excluded from the study were patients with secondary, familial, or localized amyloidosis; patients with overt symptomatic multiple myeloma or diarrhea; patients who had received alkylating agents or colchicine; and patients with brittle diabetes, severe hypertension, or an active peptic ulcer that would prevent the use of prednisone as indicated in the protocol. Written informed consent was obtained from each patient. Randomization. Each patient was assigned to one of four groups, depending on the patient’s major clinical feature: (1) nephrotic syndrome or renal failure, (2) congestive heart failure, (3) peripheral neuropathy, and (4) other. Patients who had more than one of these features were assigned to the group whose characteristics were most prominent in the patient. Medications. By means of a dynamic randomization scheme that assured a balance in the four clinical groups, the patients were assigned to receive (1) melphalan (0.15 mg/kg) in two divided doses daily and prednisone (0.8 mg/kg) in four divided doses daily for the same seven-day period or (2) colchicine (0.6 mg twice a day). Patients receiving melphalan and prednisone were advised to follow a bland diet and to take antacids, 1 ounce
December
TABLE I
Group
SYSTEMIC
AMYLOIDOSIS-KYLE
Stratification of 101 Patients Systemic Amyloidosis
ET AL
with Primary
Melphalan/ Prednisone
Colchicine
Number
23
23
46
45
8
9
17
17
7
a
15
15
Nephrotic syndrome
Total Percent
Congestive heart failure Peripheral neuropathy Others’
11
12
23
23
Total
49
52
101
100
* Hepatomegaly (five), macroglossia (four), purpura or other skin lesion (three), abdominal pain (three), myopathy (two), cranial neuropathies (two), pronounced loss of weight, jaw claudication, joint pains, and proteinuria (one each).
four times daily during the week of therapy. Leukocyte and platelet counts were determined every three weeks initially, and melphalanlprednisone therapy was repeated every six weeks. The dose of melphalan was increased by 2 mg daily for each six-week course until mid-cycle leukopenia or thrombocytopenia occurred. If severe leukopenia or thrombocytopenia occurred, the dose of melphalan was reduced accordingly. The colchicine dose was increased by 0.6 mg daily each week until abdominal cramps or diarrhea developed. The use of colchicine was then discontinued and was resumed in the highest dosage that did not produce side effects. Patients continued to receive therapy for at least six months, unless significant toxicity developed. If there was progressive disease or lack of benefit from therapy, melphalan/prednisone or colchicine was added to the original therapeutic regimen. RESULTS One hundred one patients were entered in the study. Forty-nine were randomly assigned to receive melphalan/ prednisone therapy and 52 were randomly assigned to receive the colchicine regimen (Table I).
Initial Comparison of Melphalan/Prednii tine Groups. No important differences
and Cokhi-
were found bein the history and results of initial
tween the two groups physical examination (Table II). The serum monoclonal light chains were of the lambda class in 75 percent of the colchicine group and 82 percent of the melphalan/prednisone group with a monoclonal protein (Table Ill); normally, lambda light chains are found in two thirds of patients with primary amyloidosis with a monoclonal protein [2] and in only one third of patients with multiple myeloma. Free monoclonal light chains were found in the serum in 13 percent of the colchicine group and in 16 percent of the melphalan/ prednisone group. A urinary monoclonal lambda light chain was recognized in 42 percent of the colchicine group and in 61 percent of the melphalan/prednisone
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SYSTEMIC
TABLE II
AMYLOIDOSIS-KYLE
ET AL
Initial Findings in 101 Cases of Primary Systemic Amyloidosis
Number of patients Age (years)* Males (percent) Females (percent) Weight loss Percent of patients Amount (pounds)* Hepatomegaly (percent) Macroglossia (percent) Hemoglobin (g/dl)* Creatinine (mg/dl)’ Percent >2.0 Alkaline phosphatase (IU)‘? Serum albumin (g/W* Plasma cells in bone marrow (percent)* Serum monoclonal protein present (percent) Serum monoclonal protein (g/dl)’ Urine monoclonal protein present (percent) Urine monoclonal protein (g/24 hours)’ Median. t Normal less than
TABLE
Melphalan/ Prednisone
Colchicine
Total Group
49 64 60 40
52 62 57 43
101 63 58 42
33 20 31
46 20 37
40 20 34
8
17
13
14.0 1.1 12 164
13.5 1.15 19 174
13.9 1.1 15 187
IgG kappa IgG lambda IgA kappa IgA lambda IgM kappa IgM lambda IgD lambda Kappa only Lambda only Negative
3.0
3.1
5
5
5
67
54
60
76
0.38
1.2 71
0.30
Rectum Kidney Carpal ligament Liver Small intestine Bone marrow Sural nerve
1.1 73
0.31
250.
1985
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8 23 2 6 0 1 1 2 15 42
100
Tissue Diagnoses Amyloidosls
in Primary
100
Systemic
Percentage of Biopsy Specimens Showing Amyloidosis
group. A monoclonal protein was found in the serum or urine in 81 percent of the colchicine group and in 90 percent of the melphalan/prednisone group. The prothrombin time was increased (more than 12 seconds) in only four patients. The factor X level was reduced in three patients. The serum carotene level was reduced (less than 48 pg/dl) in only one patient. The serum vitamin B12 value was less than 200 rig/liter in 12 patients, but none had evidence of pernicious anemia. Echocardiography (M-mode and two-dimensional) was performed in 53 patients. Results of echocardiography revealed abnormalities consistent with amyloid infiltration in 60 percent. Results were similar in both treatment groups. Histologic diagnosis of arnyloidosis was made in all patients (Table IV). Of 76 rectal biopsy specimens, 74 percent demonstrated amyloid. All 24 renal biopsy specimens showed amyloid. Forty-one percent of the bone marrow biopsy specimens showed amyloid. Two patients had negative results of carpal ligament biopsy-in one,
December
Total
6 15 4 6 0 2 0 2 13 52
100
Site 1.1
in Primary
of Patients Colchlclne
10 31 0 6 0 0 2 2 16 33
Total
TABLE IV 3.1
Serum lmmunoelectrophoresls Systemic Amvloidosls Percentage MelphalanlPrednisone
l
710
III
Tests Performed
MelphalarV Prednisone
Colchiclne
Total Group
76 24 5
75 100 100
72 100 50
74 100 60
11 3
100 100
72 100
82 100
91 10
43 80
39 100
41 90
paraffin blocks from the biopsy performed elsewhere could not be obtained, and in the other, carpal ligament biopsy was performed after chemotherapy. Two patients had a negative liver biopsy result-in one of these, the original paraffin blocks taken at the patient’s home hospital had been discarded. Results of sural nerve biopsy were negative in one patient with peripheral neuropathy, despite examination of 150 sections of the nerve. Results of Therapy. The peripheral neuropathy became worse in all 15 patients. Patients with congestive heart failure did not seem to be benefited objectively, although survival of these patients was longer for the melphalan/ prednisone group than for the colchicine group (p = 0.02, Figure 1). One patient who presented with overt congestive heart failure has continued to do well with melphalan/prednisone therapy at 46-month follow-up. However, serial echocardiography has revealed objective evidence of increased amyloid infiltration. Another patient had improvement of congestive heart failure and less deposition on echocardiography. Hepatomegaly devel-
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oped during therapy in nine patients in the melphalan/ prednisone group and in 10 in the colchicine group. Serum alkaline phosphatase activity increased more than 50 percent in two patients in the melphalan/prednisone group and in 11 receiving colchicine. Serum alkaline phosphatase levels decreased in five patients receiving melphalan/prednisone and in only one receiving colchitine therapy. The effect of therapy on hemoglobin level, serum creatinine level, and bone marrow is shown in Table V. Serum creatinine levels increased more than 0.5 mg/dl in 18 patients receiving melphalan/prednisone therapy and in 19 receiving colchicine therapy. There was a more than 50 percent increase in serum creatinine levels in 17 patients in each group. Five patients receiving melphalan/prednisone and six receiving colchicine required hemodialysis. In patients receiving melphalan/prednisone therapy, serum monoclonal protein decreased or disappeared in almost one third, and urinary monoclonal protein was reduced or disappeared in more than half. Protein reduction did not occur with the colchicine regimen (Table VI). Three of 35 patients had more than 50 percent reduction or disappearance of serum monoclonal protein at six months; seven of 24 had more than 50 percent reduction or disappearance at 12 months. Two of nine had more than 50 percent reduction or disappearance of urinary monoclonal protein at six months; four of nine had more than 50 percent reduction or disappearance at 12 months. There was no statistically significant difference in survival at six or 12 months between patients with reduction or disappearance of serum monoclonal protein and those without monoclonal protein reduction. Proteinuria decreased more than 50 percent in six of 28 patients at six months and in nine of 2 1 at 12 months. There was no statistically significant difference in survival at six or 12 months between patients with reduction and those without it. Duration and Amount of Therapy. Patients receiving melphalan/prednisone underwent a one-week course of therapy every six weeks for 12 months (median) (range one to 60). The number of one-week courses of melphalan/prednisone ranged from one to 30. The median daily dose of melphalan was 9.8 mg, with a range of 6 to 20 mg daily. The median total dose of melphalan was 840 mg, with a range of 42 to 2,205 mg. Colchicine was taken for less than one month to 56 months (median 12). The daily dose of colchicine ranged from less than 0.6 mg to 3.0 mg, with a median dose of 1.5 mg. Toxicity. By design, leukopenia (leukocyte count less than 3,000/mm3) occurred in almost half of the patients receiving melphalan/prednisone. In nine, the leukocyte count decreased to less than 1 ,500/mm3. No patient had sepsis related to the leukopenia. Thrombocytopenia occurred in slightly more than half of the patients receiving
December
SYSTEMIC
1
AMYLOIDOSIS-KYLE
2 t
3
ET AL
4
(years)
Figure 1. Probability of survival of patients with primary amyloidosis and congestive heart failure treated with meC pha/an/prednisone (MJ or colchicine (CT). p = 0.02 (logrank).
melphalan/prednisone, and the counts decreased to less than 50,000/mm3 in 12. There was no serious bleeding related to the thrombocytopenia. By design, diarrhea, abdominal cramps, or nausea and vomiting occurred temporarily in every patient who received colchicine. With a single daily colchicine tablet, an occasional patient had gastrointestinal symptoms. One patient had renal failure after diarrhea developed during colchicine therapy. Cause of Death. Cardiac manifestations were the most frequent causes of death in both groups. Some patients who were reported to have died suddenly probably had cardiac arrhythmia as the terminal event. Four patients died of acute nonlymphocytic leukemia. They had received melphalan/prednisone from 23 to 39 months (median 33) and a median dose of 950 mg (range 350 to 1,3 16). Three of the four had been given colchicine-two for almost four years. Two patients had a preleukemic phase characterized by pancytopenia. One patient had unexpected episodes of cytopenia from modest doses of melphalan and had received only 350 mg of the drug during the 29 months of chemotherapy. Survival (Figures 1 to 7). The median survival for the 101 patients was 22 months. The median survival was 25.2 months for patients receivint&melphalan/prednisone therapy and 18 months for those receiving colchicine therapy (p = 0.23) (Figure 5).
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’ Number
of patients
with Primary
8 3 0 0 28
7 4 1 1 52
Peripheral Neuropathy Melphalan/ Prednisone Colchicine
in Patients
involved.
Therapy
Number of patients Decrease of 12 gldl in hemoglobin‘ Increase of 10.5 mg/dl in creatinine’ Decrease in marrow plasma cells’ Median survival (months) Developed (during follow-up)* Congestive heart failure Carpal tunnel syndrome Orthostatic hypotension Peripheral neuropathy Malabsorption Nephrotic syndrome
TABLE V
11.5
0
0
2
8
Congestive Melphalan/ Prednisone
Systemic
Colchicine
Heart Failure
Amyloidosis
44
0
4
5
11
MelphalarV Prednisone
Other
18
0
1
4
12
Colchicine
8 10 5 0 1
4 10 4 0 0
25
3
18
2
2
11
11
9
18
2
19
24
52
49 28
Colchicine
Total Melphalan/ Prednisone
8
26
2
15
15
23
Colchicine
Syndrome
7
17
2
13
17
23
Nephrolic Melphalan/ Prednisone
PRIMARY
TABLE VI
Effects of Therapy on Monoclonal in Primary Systemic Amyloidosis
SYSTEMIC
AMYLOIDOSIS-KYLE
ET AL
Protein .w
-__I monoclonal protein Number of patients >50 percent decrease Disappeared Urine monoclonal Number of patients >50 percent decrease Disappeared
Melphalanl Prednisone
Colchlcine
Melphalanl Prednisone after Colchicine Failure
33
36
19
5
0
0
7
0
4
37
37
23
9
0
7
11
0
6
if ..,0
.8
Serum
protein
I
I
I
I
1
2
3
4
5
t (years) igure 3. Probability of survival of patients with prima; amyloidosis and “other” conditions treated with melpha/an/prednisone (MJ or colchicine (c). p = 0.58 (logrank).
1
1.0
0
Group
1
2
3
t (years)
C (n-8)
4
1
5
December
4
3
5
t (years)
.~~i
Figure 2. Probability of survival of patients with primary amyloidosis and peripheral neuropathy treated with me/phalanlprednisone (M) or colchicine (c). p = 0.79 (logrank).
2
Figure 4. Probability of survival of patients with primary amyloidosis and nephrotic syndrome treated with melphalanlprednisone (m or colchicine (C). p = 0.98 (logrank).
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SYSTEMIC
AMYLOIDOSIS-KYLE
ET AL
m Group
Group
I
M (n=49)
C (n=52)
Group
I
I
I
I
I
I
1
2
3
4
5
1
t (years)
2
3
t (years)
Figure 5. Probability of survival of patients amyloidosis treated with melphalan/prednisone chicine (C). p = 0.23 (log-rank).
with primary (M) or col-
C
(1~52) 4
J
Figure 7. Probability of survival of patients with primary amyloidosis treated with melphalan/prednisone (MJ or co& chicine (c) from beginning of therapy to either death or until disease progression required change of therapy. p = 0.000 7 (log-rank).
If survival analysis were limited to patients who had received only a single regimen, the median survival was significantly longer (p = 0.00 1) for the melphalan/prednisone group (n = 41) (16 months) than for the colchicine group (n = 17) (three months) (Figure 6). Survival was also calculated from the time of study randomization to the time of death or until progression of disease necessitated adding the other therapeutic regimen. The “progression-free” median survival was 16 months for the melphalan/prednisone group and six months for the colchicine group (p = 0.0001) (Figure 7).
.8
.6
COMMENTS
Group
Treatment for primary systemic amyloidosis is not satisfactory. In a double-blind study [21] involving 55 patients with primary amyloidosis, those given melphalan/prednisone therapy were able to continue undergoing treatment longer and received larger doses than did patients in the placebo group, before the code was broken because of progressive disease. In that study, among 24 patients with the nephrotic syndrome, proteinuria virtually disappeared in two and urinary excretion of protein was reduced by 50 percent in eight others given melphalan/prednisone therapy.
C (n= 17)
I
1
I
I
4
1
2
3
4
5
t (years) Figure 6. Probability of survival of patients with primary amyloidosis treated with a single regimen of either melphalan/prednisone (M) or colchicine (C). p = 0.00 I (log-rank).
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Seven patients with the nephrotic syndrome and histologically proved primary amyloidosis have been reported to benefit from chemotherapy [g-14]. In all seven, the proteinuria had been reduced and the edema disappeared. Improvement occurred in all seven within one year after therapy was initiated. Four of the seven patients underwent pretreatment renal biopsy, but kidney tissue was not obtained in any patient after improvement. Initially, the liver was enlarged in four patients, and it subsequently decreased to normal size in all four. Four other patients with histologically proved amyloidosis without the nephrotic syndrome have also benefited from chemotherapy [ 17-201. Spontaneous remissions of the nephrotic syndrome have been noted in two patients with amyloidosis [34]. However, one of the patients had had pulmonary tuberculosis, and the other had had pulmonary tuberculosis and chronic ulcerative colitis; secondary amyloidosis could not be excluded. In 1982, Kyle et al [ 161 reported on two patients with primary amylokfosis and the nephrotic syndrome in whom the administration of melphalan and prednisone was associated with resolution of the nephrotic syndrome. In both patients, the serum albumin level returned to normal, proteinuria decreased to near-normal, edema resolved, the monoclonal protein in the serum and urine disappeared, renal function remained stable, and hepatomegaly disappeared. In both, however, amyloid deposition was greater in follow-up renal tissue than in the initial specimen. Since that report, an additional similar case has been seen. The results of therapy in amyloidosis are difficult to document because the amount of amyloid in a patient cannot be measured accurately. In animals, the redistribution of amyloid deposits from the spleen and liver to the kidneys increases the problem of evaluation [35]. At present, investigators are limited to evaluation of organ function and measurement of the monoclonal protein in the serum and urine. A simple method is needed for measuring the amount of amyloid in a patient. In our series, the nephrotic syndrome was the most common presenting manifestation of primary amyloidosis and was seen in almost half of the patients. Comparison of the initial physical findings and laboratory data revealed
SYSTEMIC
AMYLOIDOSIS-KYLE
ET AL
no important differences between the melphalan/prednisone and the colchicine groups. Light chains of the lambda type predominated in each group. The size of the monoclonal protein in both the serum and urine was modest and essentially equal in the two treatment regimens. Urinary protein decreased more than 50 percent in 21 of the 39 patients with the nephrotic syndrome who received melphalan/prednisone, whereas none in the colchicine group evidenced such a reduction before the addition of melphalan/prednisone. The serum creatinine level remained stable in 10 of the 21 patients. Colchicine was well tolerated, except for the expected gastrointestinal symptoms. Leukopenia and thrombocytopenia did not constitute a serious problem. However, in four patients receiving melphalan/prednisone, acute nonlymphocytic leukemia developed, presumably from the alkylating agent. The difference in survival between the total melphalan/prednisone and colchicine groups was not significant. However, survival was significantly better (p = 0.02) in patients with amyloid and congestive heart failure who were treated with melphalan/prednisone, despiie the small numbers. Survival was significantly longer for the patients treated with melphalan/prednisone when analysis was lim ited to those receiving only a single regimen or when survival was calculated from the time of randomization to the time of death or until progression of the disease necessitated the addition of the other therapeutic regimen. This suggests that melphalan/prednisone is potentially superior to colchicine. This superiority is also supported by the fact that in 35 cases, melphalan/pr&isone was added to colchicine, whereas colchicine was ad&d to melphalan/ prednisone in only eight cases. However, colchicine may not have been added to the melphalan/prednisone regimen because of the presence of gastrointestinal symptoms from amyloidosis or because of bias on the part of the investigators. In this study, a crossover design was included because it was considered difficult to withhold another potentially beneficial agent in the presence of progressive amyloidosis. The results of this study suggest that melphalan/prednisone is superior to colchicine, but to confirm this, the agents must be compared in a prospective randomized fashion without a provision for crossover.
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4.
Kyle RA, Bayrd ED: Amyloklosis: review of 236 cases. Meditine (Baltimore) 1975; 54: 271-299. Kyle RA, Greipp PR: Amyloidosis (AL): clinical and laboratory features in 229 cases. Mayo Clin Proc 1983; 58: 665-683. Osserman EF, Takatsuki K, Talal N: Multiple myeloma I. The pathogenesis of “amyloidosis.” Semin Hematol 1964; 1: 3-85. Glenner GG, Terry W, Harada M, lsersky C, Page D: Amyloid
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fibril proteins: proof of homology with immunoglobulin light chains by sequence analyses. Science 1971; 172: 1150-1151. Terry WD, Page DL, Kimura S, lsobe T, Osserman EF. Glenner GG: Structural identity of Bence Jones and amyloid fibril proteins in a patient with plasma cell dyscrasia and amyloidosis. J Clin Invest 1973; 52: 1276-1281. Cohen AS, Wegelius 0: Classification of amyloid:
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1979-1980. Arthritis Rheum 1980; 23: 644-645. Kyle RA, Bayrd ED: “Primary” systemic amyloidosis and myeloma: discussion of relationship and review of 81 cases. Arch Intern Med 1961; 107: 344-353. Costa G, Engle RL Jr, Schilling A, et al: Melphalan and prednisone: an effective combination for the treatment of multiple myeloma. Am J Med 1973; 54: 589-599. Cohen HJ. Lessin LS. Hallal J, Burkholder P: Resolution of primary amyloidosis during chemotherapy: studies in a patient with nephrotic syndrome. Ann Intern Med 1975; 82: 466-473. Jones NF, Hilton PJ, Tighe JR, Hobbs JR: Treatment of “primary” renal amyloidosis with melphalan. Lancet 1972; II: 616-619. Horne MK Ill: Improvement in amyloidosis (letter). Ann Intern Med 1975; 83: 281-282. Schwartz RS, Cohen JR, Schrier SL: Therapy of primary amyloidosis with melphalan and prednisone. Arch Intern Med 1979; 139: 1144-1147. Buxbaum JN, Hurley ME, Chuba J, Spiro T: Amyloidosis of the AL type: clinical, morphologic and biochemical aspects of the response to therapy with alkylating agents and prednisone. Am J Med 1979; 67: 887-878. Emmerich B, Kircher A, Fink U, Schmid L, Rostetter J: Primare Amyloidose mit nephrotischem Syndrom: 5jahriger Verlauf unter kombinierter Chemotherapie. Klin Wochenschr 1980; 58: 1207-1213. Kyle RA, Pierre RV, Bayrd ED: Primary amyloidosis and acute leukemia associated with melphalan therapy. Blood 1974; 44: 333-337. Kyle RA, Wagoner RD, Holley KE: Primary systemic amyloidosis: resolution of the nephrotic syndrome with melphalan and prednisone. Arch Intern Med 1982, 142: 1445-1447. Mehta AD: Regression of amyloidosis in multiple myeloma. Br J Clin Pratt 1978; 32: 358-359, 36 1. Bradstock K, Clancy R, Uther J, Basten A, Richards J: The successful treatment of primary amyloidosis with intermittent chemotherapy. Aust NZ J Med 1978; 8: 176- 179. Corkery J, Bern MM, Tullis JL: Resolution of amyloidosis and plasma-cell dyscrasia with combination chemotherapy (letter). Lancet 1978; II: 425-426. Farhangi M, Thakur VM, Durham JB: Objective response in amylotdosis treated with intermittent chemotherapy. South Med J 1984; 77: 775-776.
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Kyle RA, Greipp PR: Primary systemic amvloidosis: comoarison of melphalan and prednisone versus placebo. Blood 1978; 52: 818-827. Sohar E, Gafni J, Pras M, Heller H: Familial Mediterranean fever: a survey of 470 cases and review of the literature. Am J Med 1967; 43: 227-253. Goldfinger SE: Colchicine for familial Mediterranean fever (letter). N Engl J Med 1972; 287: 1302. Reimann HA: Colchicine for periodic peritonitis. JAMA 1975; 23 1: 64-66. Shirahama T, Cohen AS: Blockage of amyloid induction by colchicine in an animal model. J Exp Med 1974; 140: 1102-1107. Kedar (Keizman) I, Ravid M, Sohar E. Gafni J: Colchicine inhibition of casein-induced amyloidosis in mice. Isr J Med Sci 1974; 10: 787-789. Zemer D, Pras M, Sohar E, Gafni J: Colchicine in familial Mediterranean fever (letter). N Engl J Med 1976; 294: 170-171. Nimoityn P, Lasker N, Soriano RZ: Detection of urinary amyloid in familial Mediterranean fever. Br Med J 1976; 2: 284. Melamed I, Shemer Y, Zakuth V, Tzehoval E. Pras M. Soirer Z: The immune system in familial Mediterranean fever. Clin Exp lmmunol 1983; 53: 659-682. Selinger MJ, McAdam KPWJ, Kaplan MM, Sipe JD, Vogel SN, Rosenstreich DL: Monokine-induced synthesis of serum amyloid A protein by hepatocytes. Nature 1980; 285: 498-500. 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. Rubinow A, Cohen AS, Kayne H, Libbey CA: Colchicine therapy in primary amyloidosis. A preliminary report (abstr). Arthritis Rheum 1981; 24: S124. Kyle RA: Classification and diagnosis of monoclonal gammopathies, section B, 2nd ed. In: Rose NR, Friedman H, eds. Manual of clinical immunology. Washington: American Society of Microbiology, 1980; 135-150. Michael J, Jones NF: Spontaneous remissions of neohrotic syndrome in renal amyloidosis. Br Med J 1978; 1: 1592-1593. Shirahama T, Cohen AS: Redistribution of amyloid deposits. Am J Pathol 1980; 99: 539-550.
22.
23. 24. 25.
26.
27.
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35.
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