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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 10 (May 15), 1998:
pp. 3662-3670
Dose-Intensive Melphalan With Blood Stem-Cell Support for the
Treatment of AL (Amyloid Light-Chain) Amyloidosis:
Survival and Responses in 25 Patients
By
Raymond L. Comenzo,
Evan Vosburgh,
Rodney H. Falk,
Vaishali Sanchorawala,
Johann Reisinger,
Simon Dubrey,
Laura M. Dember,
John L. Berk,
Gorgun Akpek,
Michael LaValley,
Carl O'Hara, Charles F. Arkin,
Daniel G. Wright, and
Martha Skinner
From the Amyloid Treatment and Research Program, Boston University
School of Medicine (BUSM); the Transfusion Medicine Program, Department
of Pathology and Laboratory Medicine and the Section of
Hematology-Oncology of the Department of Medicine; the Arthritis,
Cardiology, Renal, and Pulmonary Sections of the Department of
Medicine; and the Stem-cell Transplant Program, Boston Medical Center,
Boston, MA.
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ABSTRACT |
AL (amyloid light-chain) amyloidosis is an uncommon
plasma cell disorder in which depositions of amyloid light-chain
protein cause progressive organ failure and death in a median of 13 months. Autologous stem-cell transplantation is effective therapy for multiple myeloma and therefore, we evaluated its efficacy for AL
amyloidosis. Patients with adequate cardiac, pulmonary, and renal
function had stem cells mobilized with granulocyte-colony stimulating
factor and were treated with dose-intensive intravenous melphalan (200 mg/m2). Response to therapy was determined by survival and
improvement of performance status, complete response or persistence of
the clonal plasma cell disorder, and change in the function of organs involved with amyloid at baseline. We enrolled 25 patients with a
median age of 48 years (range, 29-60), all of whom had biopsy-proven amyloidosis with clonal plasma cell disorders. Twenty-two (88%) were
Southwest Oncology Group performance status 1 or 2 within a year of
diagnosis, and 16 (64%) had received no prior therapy. Predominant
amyloid-related organ involvement was cardiac (n = 8), renal (n = 7), hepatic (n = 6), neuropathic (n = 3), and lymphatic (n = 1).
Fifteen patients had one or two organ systems involved, whereas 10 had
three or more involved. With a median follow-up of 24 months (12-38),
17 of 25 patients (68%) are alive, and the median survival has not
been reached. Thirteen of 21 patients (62%) evaluated 3 months
posttransplant had complete responses of their clonal plasma cell
disorders. Currently, two thirds of the surviving patients (11 of 17)
have experienced improvements of amyloid-related organ involvement in
all systems, whereas 4 of 17 have stable disease. The improvement in
the median performance status of the 17 survivors at follow-up (0 [range, 0-3]) is statistically significant versus
baseline (2 [range, 1-3]; P < .01). Significant negative
prognostic factors with respect to overall survival include amyloid
involvement of more than two major organ systems and predominant cardiac involvement. Three patients have experienced relapses of the
clonal plasma cell disorder at 12 and 24 months. Dose-intensive therapy
should currently be considered as the preferred therapy for patients
with AL amyloidosis who meet functional criteria for autologous
transplantation.
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INTRODUCTION |
THE MEDIAN SURVIVAL of patients with AL
(amyloid light-chain) amyloidosis is only 13 months from
diagnosis.1 Because this uncommon aggressive disease is
characterized by the deposition of immunoglobulin light chains produced
by clonal plasma cells, attempts at therapy have been based on the use
of alkylating agents active against multiple myeloma. Several
randomized prospective clinical trials have shown that treatment with
oral melphalan and prednisone results in objective responses and
prolonged survival (medians of 16 to 18 months).2,3 In the
most recent of these trials, patients who experienced reductions in
their serum or urine monoclonal proteins (M-proteins) had significantly
prolonged survival versus nonresponders, although only 20% of patients
treated with melphalan and prednisone on that trial were reported to
respond in such a manner.4
Given the results with intermittent oral melphalan and prednisone, we
considered it reasonable to investigate the use of dose-intensive intravenous melphalan to treat this disorder.5,6 Recently we described an initial experience of five patients with AL treated with dose-intensive melphalan and blood stem cells.7 One
year post-therapy, these patients were found to have improvements in performance status and amyloid-related organ involvement, and three of
them had complete hematologic responses with respect to their plasma
cell disorders. We now report on our experience with autologous
transplantation in those five and an additional 20 patients with AL.
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MATERIALS AND METHODS |
Patients
Between January 1, 1994 and September 31, 1996, 25 patients who had
biopsy-proven amyloidosis in association with a clonal plasma cell
proliferative disorder and were 18 to 61 years of age were enrolled in
a phase-II clinical study whereby they were to receive dose-intensive
intravenous melphalan (200 mg/m2) followed by blood stem
cell autograft, provided they had adequate cardiac, pulmonary, hepatic,
and renal function as previously described.7
Patients with familial, secondary, senile cardiac, or other forms of
amyloidosis were not included in this study.8,9 The first
15 patients enrolled to receive unselected blood stem cells, and the
next 10 enrolled to receive CD34-selected blood stem cells (Isolex 300;
Baxter Biotech, Deer Park, IL).10
Blood stem cells were mobilized with granulocyte-colony stimulating
factor (G-CSF; 10 to 16 µg/kg; Filgrastim; Amgen, Thousand Oaks, CA),
collected, and evaluated as previously described.11 Dose-intensive melphalan was administered intravenously over 2 days
(days  4 and 3), 100 mg/m2/d, and stem cells
were infused 72 hours later (day 0). Patients received antibiotic
prophylaxis with an oral quinoline and acyclovir beginning
on day 3 after stem-cell infusion. Hematopoietic recovery was
determined by daily blood counts and defined as days from stem-cell
infusion to recovery of neutrophils >0.5 × 109/L
for 2 consecutive days and of platelets >20 × 109/L
for 2 days with independence from platelet transfusion. Toxicities were
recorded and graded according to Southwest Oncology Group (SWOG)
criteria. At the time of study entry, at follow-up 3 months after
therapy, and annually thereafter, each patient was evaluated for
performance status, for status of the clonal plasma cell proliferative disorder, and for extent, predominance, and response of amyloid-related organ involvement.
Plasma Cell Proliferative Disorder
Presence of a clonal plasma cell disorder was assessed by serum and
urine immunofixation electrophoresis (SIFE and UIFE; Paragon, Baxter,
Deerfield, IL) and by bone marrow biopsy with  2-cm core samples. The
percentage of plasma cells in the bone marrow biopsy was estimated and
clonality identified with standard immunohistochemical staining for
light-chain isotypes (clonal dominance being a  to  ratio greater than 3 or less than 1). Amyloid depositions in marrow
biopsy specimens stained with Congo red were graded as 0 (none
detected), 1 (in blood vessels only), 2 (in blood vessels and in focal
interstitial deposits in  2 high-power fields), and 3 (in prominent
interstitial deposits in >2 high-power fields).
After therapy, a patient's plasma cell proliferative disorder was
categorized as having completely responded or persisted. A complete
hematologic response to therapy was defined both as the absence of
detectable M-protein in SIFE and UIFE and by a bone marrow biopsy
specimen containing less than 5% plasma cells with polyclonal staining
(ie, without clonal dominance of or ). Persistent disease was
defined as the persistence of an M-protein by SIFE or UIFE or of clonal
dominance. In a patient with a previously confirmed complete
hematologic response, relapse was defined as the detection of the
pretherapy M-protein by SIFE or UIFE or as the reversion to the prior
K or clonal dominance on bone marrow biopsy.
Amyloid-Related Organ Involvement
At study entry the extent of amyloid-related organ involvement was
evaluated in each patient. Organ system involvement was determined as
previously described, and each patient's predominant organ involvement
was determined based on clinical consensus.2 On follow-up
evaluation, amyloid-related organ involvement was assessed as improved,
stable, or worsened.
Cardiac involvement was defined as the presence of a mean left
ventricular wall thickness on echocardiogram >11 mm in the absence of
a history of hypertension or valvular heart disease, or as the presence
of unexplained low voltage (<0.5 mV) on the electrocardiogram.12 Clinical status was based on history,
physical examination, and New York Heart Association (NYHA) heart
failure class. Patients who were NYHA class 1 with evidence of cardiac amyloid by echocardiogram or electrocardiogram were categorized as
having asymptomatic cardiac involvement. Patients who were NYHA class 2 or higher with evidence of cardiac involvement were categorized as
having predominant cardiac involvement (amyloid cardiomyopathy).
An improvement or response to therapy for patients with cardiac
involvement was defined as a decrease of 2 mm in mean left ventricular wall thickness in patients with baseline wall thickness >11 mm or a decrease in two classes in NYHA class (ie, from 3 to 1).
Stable disease was defined as no evidence of clinical response and no
progressive disease by clinical, electrocardiographic, and
echocardiographic evaluation. Progression of cardiac involvement post-therapy was defined by worsening clinical signs or symptoms, worsening NYHA class (ie, from 1 to 3), or by an increase of 2 mm in
mean left ventricular wall thickness in a patient with baseline wall
thickness 11 mm.
Renal involvement was defined as proteinuria >0.5 g/d. An improvement
or response to therapy was defined as a 50% decrease in daily
proteinuria without progressive renal insufficiency. Hepatic
involvement was defined as hepatomegaly with an alkaline phosphatase
>200 U/L. Improvement was defined as a decrease in liver span of 2
cm with a concomitant decrease of alkaline phosphatase by 50%.
Neuropathic involvement was defined based on clinical history,
autonomic dysfunction with orthostasis, gastric atony by gastric
emptying scan, and abnormal sensory and/or motor findings on
neurological examination. Improvement was defined as normalization of
orthostatic vital signs and symptoms and resolution of gastric atony
and of abnormal findings on neurological examination. Stabilization or
worsening of renal, hepatic, and neuropathic involvement was defined by
consensus based on clinical evaluation and appropriate noninvasive
tests.
Statistics
Medians, ranges, means, and standard deviations (SD) were calculated,
and regression analyses and other test statistics were performed with
Minitab (Minitab, State College, PA) or with SAS (SAS
Institute, Cary, NC).13
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RESULTS |
Patients
Between January 1, 1994 and October 1, 1996, 25 patients were enrolled
and gave written informed consent as approved by our Institutional
Review Board. The majority of patients were performance status 1 or 2, within a year of diagnosis, and minimally pretreated with oral
melphalan and prednisone (Table 1).
Fourteen had an M-protein in serum and urine, whereas 9 had an
M-protein in urine only; 5 had and 18 M-proteins. With respect
to marrow plasmacytosis, 7 had 5%, 14 had 5% to 10%, and 3 had
>10% plasma cells on biopsy. The distribution of dominant
amyloid-related organ involvement included cardiac (8), renal (7),
hepatic (6), neuropathic (3), and lymphatic (1). With respect to
multisystem involvement, 15 had one or two systems involved and 10 had
three or more systems involved (Table 2).
Survival and Performance Status
As of October 1, 1997, with a median follow-up of 24 months (12 to 38),
68% (17 of 25) of the patients were alive (Table 2 and
Fig 1A). Eighty-seven percent of patients
(13 of 15) with two or less major organ systems involved survived, as
opposed to only 40% (4 of 10) surviving among those with more than two involved systems (P < .05, one-tailed Fisher's exact test).
Eighty-two percent of patients without predominant cardiac involvement
at baseline (14 of 17) were alive in follow-up compared with 38% of
patients with predominant cardiac involvement (3 of 8; Table 2 and Fig
1B; P < .05). Overall survival of patients with a baseline performance status of 1 was 80% (8 of 10), whereas that of patients with a baseline performance status of 2 or 3 was 60% (9 of 15; P = .402). With respect to the 17 patients surviving a year or more in follow-up, the difference between their median performance status before therapy (2 [range, 1 to 3]) and at follow-up (0 [range, 0 to 3]) was statistically significant (P < .05, Wilcoxon rank sum).
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| Fig 1.
Overall survival and survival by category of organ
involvement. With median follow-up of 24 months (12 to 38), 17 of 25 patients (68%) survived, and the median survival has not yet been
reached as depicted in (A) a Kaplan-Meier plot showing the 95%
confidence interval (CI; proportional survival 0.65, 95% CI 0.48 to
0.88). (B) Survival by predominant organ involvement is shown. Total and mean times of follow-up for the three cohorts are 149 and 21.3 months (renal, n = 7), 225 and 22.5 months (other, n = 10), and 101 and 12.6 months (cardiac, n = 8). Patients without predominant cardiac involvement had better overall survival than cardiac patients (one-tailed Fisher's exact test, P < .05).
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Two patients died before receiving chemotherapy (patients 1 and 25).
Both had rapidly progressive amyloidosis and died after stem-cell
collection but before being treated. One with predominant hepatic
involvement died of massive gastrointestinal bleeding a month after
collection, and the other with predominant cardiac involvement and a
history of syncope died of hypoxia, hypotension, and cardiopulmonary
failure within 24 hours of completing stem-cell collection.
Twenty-three patients received dose-intensive melphalan treatment.
There were no deaths within 30 days of transplant. However, there were
three deaths within 100 days of transplant, one in a patient with
massive lymphatic involvement who died of cardiorespiratory failure,
and two in patients with predominant cardiac involvement who
experienced sudden cardiac events despite amiodarone therapy and an
implanted cardiac defibrillator; hence, the 100-day posttransplant mortality was 13% (3 of 23), whereas, on an intention-to-treat basis,
the overall early (<3 month) mortality associated with attempted
therapy was 20% (5 of 25). Two more cardiac patients have died in
follow-up, one at 5 months posttransplant of apparent sepsis and the
other at 20 months posttransplant of secondary acute myelogenous
leukemia. Additionally, at 20 months posttransplant, a patient with
predominant hepatic involvement died in his sleep.
Responses of the Plasma Cell Disorders
At 3 months posttransplant, 62% of patients (13 of 21) experienced
complete hematologic responses of their clonal plasma cell disorders.
Eight patients without a serum M-protein (ie, with Bence-Jones protein
and/or marrow isotype dominance) had complete hematologic
responses, whereas 5 of 13 with serum M-proteins completely responded,
resulting in a significant difference (P = .015, two-tailed Fisher's exact test). All patients with a isotype (4 of 4)
responded completely; in contrast, only 9 of 17 with a isotype did
so (P = .26). Three patients, all with predominant renal
involvement and isotype disease, have relapsed: two (patients 11 and 24) at 12 and one (patient 13) at 24 months. Two had findings of
recurrent serum M-proteins and the third of a recurrent urine
M-protein. All three showed recurrent marrow isotype dominance with
less than 5% total plasma cells staining for . Their
amyloid-related organ involvement had not progressed at the time of
relapse.
Responses of Amyloid Disease
Cardiac.
Eight patients had predominant cardiac involvement. Three had a history
of syncope and all died: one postleukapheresis before receiving
chemotherapy (see above), and two suddenly within 3 months after
treatment. One year post-treatment, three of four surviving patients
with predominant cardiac involvement experienced an improvement in
their performance status to level 0, whereas the fourth experienced a
deterioration in performance status caused by a leg ulcer and
complications of hip replacement surgery, both sequelae of prolonged
steroid use. One patient (patient 3), who had endomyocardial biopsy,
echocardiographic, and clinical evidence of disease at baseline,
experienced a >2-mm reduction of mean left ventricular wall
thickness. Another patient (patient 18) improved two NYHA classes and
is now class 1 without a diuretic requirement.
The follow-up data on eight patients with asymptomatic cardiac
involvement and other predominant organ involvement are shown in
Table 3. None of the six patients who
experienced a complete hematologic response have progressed to
symptomatic amyloid cardiomyopathy. Two patients with complete
hematologic responses experienced reductions of their mean ventricular
wall thickness of 2 and 4 mm, respectively, consistent with a cardiac
response to therapy. One patient with persistent plasma cell disease
and baseline low-voltage on the electrocardiogram experienced
progression of cardiac amyloid with an increase of 3 mm of mean wall
thickness to a mean thickness of 12 mm.
Renal.
Fourteen patients with renal involvement, including 7 with predominant
renal involvement, were treated and survived in follow-up as shown in
Table 4. Three of 7 with predominant renal
involvement and 6 of 7 with nonpredominant renal involvement improved
in response to therapy. Three patients have stable disease and 2 have
worsened disease, 1 caused in part by treatment-related toxicity
(patient 23) with a creatinine increase from 0.9 to 4.9 mg/dL by day
15. The overall response rate for renal involvement then was 64% (9 of
14), and the median pretreatment and posttreatment levels of daily
proteinuria in the 9 responders were significantly different (pretreatment, 6,030 mg [range, 645 to 23,595]; posttreatment, 1,573 [range, 102 to 7,560]; P < .01, Wilcoxon rank sum).
Posttreatment albumin levels in the responders were also significantly
improved over baseline (P < .01), whereas creatinine levels
were not significantly altered (P = .183).
Hepatic.
Improvements have been observed in four of five patients with
predominant and one of two with nonpredominant hepatic involvement, including elimination of symptoms and reduction in craniocaudal liver
span from over 20 cm to normal size (<14 cm) usually accompanied by a
>50% reduction in alkaline phosphatase levels (patient 5 is scored
as improved; she had symptomatic hepatomegaly with a baseline alkaline
phosphatase of 184 U/L and experienced a significant reduction in liver
span, elimination of symptoms, and normalization of alkaline
phosphatase; Table 4). The two remaining patients (8 and 14) were
scored as having stable disease, although patient 8 had a reduction in
liver span of >2 cm without a change in alkaline phosphatase level.
The overall response rate for hepatic involvement then was 71% (5 of
7), and the median pretreatment and posttreatment levels of alkaline
phosphatase in the five responders approached statistical significance
(P = .059). In addition, correction of blood smear
abnormalities at 1 year posttreatment was noted in four responding
patients with the loss of Howell-Jolly bodies and target cells and with
normalization of red blood cell morphology indicative of improved
hepatosplenic function (the fifth responder, patient 10, had an
emergent splenectomy 6 months posttransplant).
Neuropathic.
As reported previously, there were improvements in patients with
predominant neuropathic involvement.7,14 Two of the three patients with predominant neuropathic involvement have had complete resolution of their autonomic and peripheral polyneuropathies, including resolution of orthostasis and gastric atony measured by a
gastric emptying scan. In addition, patients 17 and 18 who had
neuropathic involvement (orthostasis) experienced complete resolution
of signs and symptoms. Therefore, the overall response rate for
neurological involvement was 80% (4 of 5). Resolution of neuropathy
has not been previously reported with oral chemotherapy and supports
the concept that a reversible metabolic derangement may be the
pathophysiological mechanism that underlies the polyneuropathy in this
disease.15,16
Treatment and Toxicities
Twenty-two patients were treated with 200 mg/m2 melphalan; patient 15 with predominant
cardiac involvement was treated with a reduced dose (100 mg/m2) because cardiac function worsened shortly before
treatment. Data regarding toxicities of therapy and extent of
transfusion requirements are summarized in
Table 5. Patients were hospitalized for a
median of 20 days (range, 15 to 42).
Infectious Complications
There were no deaths caused by sepsis. With respect to infectious
complications, six patients had fever with positive blood cultures:
Streptococcus viridans (n = 3), coagulase-negative
Staphylococcus (n = 1), Candida kruseii (n = 1), and a
species of Penicillium (n = 1). The latter two infections
occurred in patients who received CD34-selected stem cells and were
also diagnosed with Pneumocystis carinii pneumonia. Both
patients were hyposplenic; one had replacement of her lymph nodes with
amyloid and bilateral genitourinary fungal bezoars that were
undiagnosed before therapy.10,17 The other was severely
hypogammaglobulinemic at baseline (IgG <100 mg/dL). Both responded to
antibiotics, although the patient with C kruseii died of
cardiopulmonary failure on day 99 after completing antifungal therapy
and had no evidence of infection postmortem. Whether T-cell-depleted CD34-selected autografts carry an increased risk of infection in
certain categories of patients remains an open question.18
Renal and Hepatic Toxicities
One of seven patients (patient 23) with predominant renal involvement
experienced the only episode of significant treatment-related renal
toxicity. One of five patients with predominant hepatic involvement
(patient 17) experienced jaundice and an increase in bilirubin to 18 mg/dL, which was attributed to drug toxicities (opiates,
trimethoprim-sulfamethoxazole) and suspected veno-occlusive disease.
The patient improved promptly and bilirubin returned to normal by the
time of follow-up at 3 months.
Delayed Platelet Engraftment
Three patients had delayed platelet reconstitution. All other patients
engrafted for platelets within 17 days. These three late engrafters had
significant toxicities of therapy. Patient 8 who had received no prior
oral melphalan engrafted on day 65 after experiencing grade-4
mucositis, grade-3 pulmonary edema, and grade-4 sepsis. Patient 11, who
had received 320 mg of prior oral melphalan, engrafted on day 52 after
experiencing grade-3 peripheral edema and grade-3 gastrointestinal
bleeding. Both patients had evidence of splenic dysfunction
(Howell-Jolly bodies).
Secondary Leukemia
The third patient who experienced delayed platelet engraftment (patient
14), in addition to receiving the largest amount of prior oral
melphalan of the 23 patients (672 mg), had grade-3 mucositis and
grade-3 pulmonary edema. Eighteen months posttransplant, this patient,
a 61-year-old woman, developed acute myelogenous leukemia with a
complex karyotype including deletion of chromosome 7. She died 2 months
later, 20 months after treatment.
Stem-Cell Autografts and Transfusion Requirements
All patients were mobilized with G-CSF, usually 16 µg/kg
subcutaneously daily for 4 to 5 days, with stem-cell
collections beginning on day 4. A median of 8.9 × 106
CD34+ cells/kg were collected (range 2.9 to 25.4) in two to
three aphereses. The numbers of mobilized circulating baseline
CD34+ cells in patients who had previously received more
than 200 mg of oral melphalan pulse therapy were significantly less
than in patients who had previously received less or no melphalan (mean ± SD; 48 ± 25 versus 78 ± 63 × 106/L;
P = .028, two-tailed t-test). However, there were no
significant differences between these groups with respect to
CD34+ cells collected on individual days or in toto.
The numbers of CD34+ cells collected by leukapheresis on
days 4 and 5 failed to correlate by regression analysis with patient age or gender, the baseline leukocyte count, the presence of
Howell-Jolly bodies, or the number of blood volumes processed during
leukapheresis. However, the number of peripheral CD34+
cells circulating at baseline before leukapheresis was a weak but
significant predictor of the number of CD34+ cells
collected on day 4 (R2 = .316, P < .01), and the
day-5 collection was correlated with the number of CD34+
cells collected on day 4 (R2 = .435, P < .01).
Neutrophil and platelet engraftment occurred in medians of 10 (8 to 17)
and 14 days (8 to 65), respectively. There were no differences in
neutrophil or platelet engraftment based on CD34+ cell dose
or the use of unselected or CD34-selected cells, although differences
in lymphocyte recovery were documented.10 With respect to
transfusion of red blood cells and platelets in this transplant population, one that had a 39% incidence of bleeding complications, simple regression analysis was performed with baseline patient characteristics and graded toxicities of therapy to determine if there
were significant correlations between any of those variables and
transfusion requirements. There were significant correlations between
marrow amyloid grade and units of red blood cells transfused and
between the grade of peripheral edema and number of platelet transfusions (Fig 2).
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| Fig 2.
Correlates of red blood cell and platelet transfusion
requirements. Transfusion requirements were of interest in patients with AL undergoing dose-intensive therapy because of the association between AL, coagulation abnormalities, and vascular pathology. (A)
Patients with higher marrow amyloid grades required more red blood cell
transfusion support, a correlation identified initially by simple
regression analysis (R2 = .46, P < .01). (B)
Patients with higher grades of edema during the myelosuppressive
period, caused by combinations of salt avidity, hypoalbuminemia,
autonomic dysfunction, sepsis, or low cardiac output, required more
platelet transfusions, perhaps because of increased vascular injury.
This correlation was also identified initially by simple regression
analysis (R2 = .31, P < .01). Peripheral edema
was graded clinically by SWOG criteria. Values are medians and ranges.
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DISCUSSION |
Dose-intensive melphalan with blood stem-cell support for patients with
AL amyloidosis represents an important therapeutic advance in the
treatment of this rapidly fatal disease.19-22 Currently, with a median of 24 months follow-up (12 to 38), 68% (17 of 25) of
patients are alive and the median survival has not been reached (Fig
1A). Amyloid involvement of more than two major organ systems or
presence of symptomatic cardiac involvement are significant negative
prognostic factors with respect to overall survival. Eighty seven
percent of patients (13 of 15) with up to two major organ systems
involved have survived, as opposed to only 40% (4 of 10) surviving
among those with more than two involved systems. Eighty-two percent of
patients without symptomatic amyloid cardiomyopathy at baseline (14 of
17) were alive in follow-up compared with 38% of patients with
symptomatic amyloid cardiomyopathy (3 of 8; Fig 1B). Conversely,
involvement of no more than two major organ systems and absence of
predominant cardiac involvement appear to be important positive
prognostic factors. With respect to the 17 patients surviving a year or
more in follow-up, the improvement in their performance status is
statistically significant compared with baseline.
Complete hematologic responses were seen in 60% of surviving patients,
most frequently in those without a serum M-protein or with a monoclonal
protein of the isotype. The achievement of significant
cytoreductive responses, as suggested by the frequency of complete
responses, is likely to be responsible for the improvements observed in
survival, performance status, and organ function. The degree to which
such improvements are caused by cessation of amyloid deposition,
resorption of existing amyloid depositions, or both, is unclear.
Moreover, response of amyloid-related organ involvement and relapse of
the plasma cell proliferative disorder can occur, suggesting a possible
role for molecular methods that can identify the presence of minimal
residual disease to ascertain prognosis and plan additional therapy if
warranted.10 The rate of amyloid progression and clinical
deterioration after hematologic relapse is also unclear at this time.
Amyloid cardiomyopathy, a fatal condition with a median untreated
survival of less than 6 months from onset of symptoms, is rarely
responsive to oral chemotherapy.23 It is encouraging that
38% (3 of 8) of patients with predominant cardiac involvement treated
with dose-intensive therapy remain alive more than a year after
treatment and that two have experienced significant improvements in
performance status 1 year posttransplant. Of equal significance is the
fact that no surviving patient with baseline asymptomatic cardiac
involvement and a complete hematologic response has developed symptomatic amyloid cardiomyopathy. Indeed, two of these patients have
shown a decrease in mean ventricular wall thickness of 2 mm.
Nonetheless, patients with predominant cardiac involvement, particularly those with more than two organ systems involved, are
clearly high-risk candidates for dose-intensive therapy and stem-cell
transplant, with an early (<3 months) treatment-related mortality of
38% (3 of 8). However, for those with predominant cardiac and minimal
other organ involvement who are NYHA class 3, consideration of
eligibility for cardiac transplant (and subsequent stem-cell
transplant) is clearly indicated.
Response rates in patients with predominant renal and hepatic
involvement are also striking, particularly with respect to the
reduction of proteinuria in the former and correction of red blood cell
morphologic abnormalities in the latter. Loss of Howell-Jolly bodies on
the peripheral blood smear is indicative of a return of splenic
function and normalization of the lipid profile associated with hepatic
and renal dysfunction. Moreover, the responses described in patients
with predominant neuropathic involvement have not been described
previously to occur after any other form of therapy.24
These data, with respect to survival, hematologic responses, and
improvements in amyloid-related organ involvement, are dramatically different from those reported with oral chemotherapy. Because 18 of the
patients (72%) studied were 3 to 12 months from diagnosis and a third
of them had received some prior oral therapy, concerns regarding
selection bias are reasonable. Patients with rapidly progressive AL
often die within 3 months of diagnosis; therefore, the role of
dose-intensive therapy in newly diagnosed untreated patients is a
matter for further clinical study. Moreover, there may be a role for
cytoreductive therapy with oral melphalan and prednisone, or other
regimens, as a prelude to dose-intensive therapy. Both of these matters
are currently being evaluated in a randomized clinical trial at our
center.
With respect to stem-cell mobilization and hematologic recovery after
autografting, it is clear that stem-cell mobilization with G-CSF is an
effective method of stem-cell procurement. The overall quality of
mobilization in AL patients, the majority of whom were not heavily
pretreated, is similar to that observed in normal donors, and
neutrophil and platelet recoveries did not appear to be significantly
affected by amyloid marrow deposits.25 However, the
increased red blood cell transfusion requirement in patients with
higher amyloid marrow grades suggests that interstitial marrow
depositions may slow erythropoietic recovery because of impaired
production or increased destruction of red blood cells, or both. The
apparent association between peripheral edema and the platelet
transfusion requirement is equally intriguing (Fig 2). Possible
explanations include either increased peripheral use or destruction
(caused by vascular injury), decreased activity of thrombopoietin
(caused by a leak into the interstitial space) causing decreased
production, or both. These considerations are clinically relevant in
view of the 39% incidence of bleeding, particularly gastrointestinal
bleeding, that occurred in these patients during therapy. It was not
unusual, for example, for patients to bleed from sites of previous
tissue biopsies (eg, the rectum). Bleeding episodes may well be tied to
the known abnormalities of coagulation and vascular integrity
associated with AL.1,3,26
Our findings lead us to conclude that patients with performance status
0 to 2 who have predominant cardiac, renal, hepatic, or neuropathic
involvement with one other organ system involved are highly likely to
survive dose-intensive therapy and to benefit from it. Although the
risks of renal and hepatic toxicity cannot be minimized, our data
indicate that they are not contraindications to the use of this
therapeutic approach. Patients with predominantly neuropathic
involvement and performance status 3 caused by neuropathy are also
highly likely to survive and to benefit from dose-intensive therapy
despite their poor nutritional and functional status.
It would be reasonable to conclude that, because the results of this
treatment are substantially better than those obtained with oral
chemotherapy, patients are likely to experience prolonged disease-free
survival. Because of the frequency with which patients improve and
plasma cell proliferative disorders respond, we believe that
dose-intensive therapy should be considered standard therapy for
patients with AL who meet functional criteria for autologous stem-cell
transplantation. Clearly, patients with predominant cardiac involvement
and performance status 3 who are ineligible for cardiac transplant
should not be treated with dose-intensive melphalan; however, effective
diuretic therapy may result in sufficient improvement for some,
allowing them to become candidates for less intensive regimens of
intravenous melphalan (eg, 100 or 140 mg/m2).
Less than one third of the patients we treated had received more than
200 mg of prior oral melphalan, and no patient had evidence of
myelodysplasia on bone marrow biopsy specimens or peripheral blood
smears. However, patients who have received extended therapy with oral
melphalan or have evidence of myelodysplasia subsequent to oral
melphalan therapy may not be optimal candidates for stem-cell mobilization and transplantation, and in such cases appreciation and
discussion of the risk of chemotherapy-induced leukemia are appropriate.
In summary, a new and frequently effective therapy, dose-intensive
melphalan with blood stem-cell support, has been identified for a
hitherto almost uniformly fatal systemic disease. The efficacy of this
therapy is likely associated with obtaining a significant or complete
response of the plasma cell proliferative disorder.27 Furthermore, the existence of this therapy creates an impetus for
physicians to diagnose AL early despite its multifaceted presentations and to consider treatment promptly in view of its inexorable
progression. This would appear to make the critical issue not whether
but to whom and when dose-intensive therapy should be
offered.4,28,29 However, a caveat applies with respect to
the security of the diagnosis of AL, because patients with secondary or
familial variants of systemic amyloidosis are never candidates for
dose-intensive melphalan. Therefore, the issue of diagnostic confidence
in problematic cases becomes equally critical.8,30,31
| |
FOOTNOTES |
Submitted October 14, 1997;
accepted January 12, 1998.
Supported by grants from the Food and Drug Administration
(FD-R-001346-01) (R.L.C.), the Arthritis Foundation (R.L.C.), the Amyloid Research Fund, the Sue Sellors Finley Cardiac Amyloid Research
Fund, and the Stem-cell Laboratory Fund of BUSM and the Boston Medical
Center.
Address reprint requests to Raymond L. Comenzo, MD, Director,
Transfusion Medicine Program, H-303, Boston Medical Center, Boston, MA
02118.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
We thank the staff of the Boston Medical Center blood bank and clinical
laboratories; the Hematology-Oncology nurses in the Center for Cancer
and Blood Disorders and on Atrium 7E, particularly Diane Sarnacki, RN;
and members of the staff of the Clinical Trials Office, the Boston
University School of Public Health, and the Amyloid Program, including
Kathleen Finn, RN, Steven Evans, Salli Fennessey, and Ceit McCaleb.
| |
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Abstract
Introduction
Abstract
