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REVIEW ARTICLE
From the Hematology Service, Department of Medicine,
Memorial Sloan-Kettering Cancer Center, New York, NY; and the Division
of Hematology, Mayo Clinic, Rochester, MN.
High-dose melphalan with autologous blood stem cell transplantation
(SCT) can reverse the disease process in selected patients with primary
systemic amyloidosis (AL); however, SCT for AL remains controversial
because of the treatment-related mortality in patients with cardiac and
multisystem organ involvement. In this review, we briefly discuss
recent advances in AL, such as the free light-chain assay and the role
of immunoglobulin light-chain variable region germline genes in the
disease, and then we discuss the current status of SCT for AL with
emphases on patient selection, approaches to stem cell
mobilization, and peri-SCT management. It is clear that patients with
AL who have advanced amyloid cardiomyopathy or more than 2 major
viscera involved with disease are poor candidates for SCT. Therefore,
the importance of patient selection cannot be overemphasized, and
patients with 1 or 2 involved organs or with early cardiac involvement
are usually appropriate candidates for SCT. Because the toxicity of
melphalan is dose-related and survival with AL may be
age-related, patient age and the extent of organ involvement can
provide a basis for patient stratification. We discuss such a
risk-adapted approach to melphalan dosing in detail and conclude with a
brief overview of current research using SCT to treat patients with AL.
(Blood. 2002;99:4276-4282) Primary systemic amyloidosis (AL) is a protein
conformation disorder and a clonal plasma cell dyscrasia.1
Systemic disease results from amorphous extracellular deposits of
material, composed in part of immunoglobulin light- or heavy-chain
fragments, in key viscera such as the kidneys, heart, and liver and in
the peripheral nervous system.2 Various presentations are
observed at diagnosis, the most common of which is nephrotic-range
proteinuria with or without renal insufficiency, congestive
cardiomyopathy, unexplained hepatomegaly, and sensorimotor and
autonomic peripheral neuropathy.2,3 As systemic deposits
of amyloid accumulate, they disrupt organ function and ultimately lead
to the death of the patient.3,4 The disorder has an
incidence of 8 per million persons per year, and it is one fifth as
common as multiple myeloma but more devastating because the median
survival of patients seen within 1 month of diagnosis is 13.2 months.5 Moreover, for those with congestive heart failure
the median survival is 4 months, and less than 5% of all AL patients
survive 10 years or more from the time of
diagnosis.6,7
Limited progress had been made in reversing the pathology of AL until
the mid-1990s, when patients underwent dose-intensive intravenous
melphalan therapy and autologous hematopoietic stem cell
transplantation (SCT).8-10 As the production of deposits is halted and amyloid resorbed, the performance status and the quality
of life of AL patients can improve.11-13 However,
transplantation-related mortality was high in the early studies because
the viscera of AL patients were compromised by deposits of amyloid. AL
patients commonly have renal, cardiac, hepatic, gastrointestinal, or
neuropathic problems that make them distinct from other SCT
candidates.11,12 That is, most patients who undergo
autologous transplantation have hematologic malignancies but no
visceral organ dysfunction, whereas most patients with AL who undergo
SCT have precisely the opposite findings. Therefore, refinement
of patient selection and improvement of peri-transplantation clinical
management have become priorities.12,14 In this review we
describe relevant recent advances in AL and summarize the data on SCT
for AL to improve current practice and to stimulate further clinical
research. We also suggest a risk-adapted approach to patient selection
and melphalan dosing with the expectation of reducing
transplantation-related mortality, and we offer it as a basis for
future research efforts.
AL is not a neoplasm per se. The monoclonal protein does not
increase over time, as it often does in multiple myeloma, and the
percentage of bone marrow plasma cells is comparatively low Recent diagnostic advances have also included the development of
specific antisera that can identify the type of amyloid deposited in
tissues and the development of new methods for sequencing amyloid proteins.17,18 Given the limited amount of sample
available from diagnostic needle biopsies, it is often difficult to
isolate and purify amyloid for direct sequencing. A new micro-method to isolate and purify the amyloid fibrils exists.18 The
technique involves extraction of the amyloid with purification by
polyacrylamide gel electrophoresis followed by electroblotting and
elution of amyloid protein-related bands and then reverse-phase
high-performance liquid chromatography. It is possible with this
technique to obtain sufficient material to establish the chemical and
molecular composition of fibrillar deposits.18
With respect to the immunoglobulin genetics that underlie AL, clonal
plasma cells are more frequently All patients with AL carry a poor prognosis. Therefore, all
patients who have a systemic clinical amyloidosis syndrome (with the
exceptions of purpura, focal soft tissue amyloid, or carpal tunnel
syndrome only) should be considered candidates for SCT. Patients who
have incidental amyloid deposits detected in a bone marrow performed
for multiple myeloma should not be considered as having a systemic
amyloid syndrome unless they have symptoms referable to viscera
involved with amyloid. Because the monoclonal protein in AL does not
increase over time as it does in multiple myeloma, it is not
appropriate to observe patients for a change in the level of the M
protein before considering SCT.24 Moreover, the
distinction between AL with and without myeloma is usually based on a
cut off of bone marrow plasma cells. Nearly 40% of patients with AL
have more than 10% plasma cells in their bone marrow. However, if
these patients are monitored over time, few if any will go on to
acquire lytic bone disease, light-chain nephropathy, or soft tissue
plasmacytomas.24 It is appropriate to treat AL patients
with a high percentage of bone marrow plasma cells (eg, more than 20%)
the same as patients with AL and a lower percentage of plasma cells in
the bone marrow. There are no data to support a benefit from
cytoreduction before SCT. Indeed, evidence from a recently reported
randomized prospective clinical trial indicates that the delay
associated with pre-SCT cytoreduction is likely to allow disease
progression.25 Therefore, we usually elect to go directly
to SCT in AL patients.
The toxicities of SCT for AL have been appreciated at all centers that
have attempted to treat AL patients with SCT. The average 100-day
mortality of SCT in 4 single-center clinical trials was 21%, and in 2 multicenter trials it was 39%, which is unacceptably high and requires
attention (Table 1).10,26-30
In addition, deaths have been reported during stem cell mobilization
(with growth factor alone) and during stem cell component infusion,
highlighting AL SCT patients as unusually prone to adverse
events.10,28,29 Traditional selection criteria for
autologous transplantation were designed to exclude patients with
significant visceral dysfunction to minimize the morbidity and
mortality of SCT and to allow standardized patient screening to conduct
clinical research.31 Nevertheless, in most clinical trials
in Table 1, standard criteria for autologous SCT were used to determine
eligibility for transplantation. (One notable exception is the
intermediate-dose melphalan trial reported in Comenzo et
al28). Despite the use of such screening criteria, the
transplantation-related mortality of patients with AL was 4 to 8 times
higher than that currently reported for patients with multiple myeloma
(which in our centers is much less than 5%).
The extent of amyloid organ involvement before SCT clearly accounts for
much transplantation-related mortality, as demonstrated by 2 early
trials that used similar patient assessment and selection criteria and
similar transplantation conditioning regimens.10,27 Of 43 patients who underwent transplantation, those with 2 or fewer organ
systems involved had significantly superior 100-day survival rates
(81%; 25 of 31) compared with those who had more than 2 systems
involved (33%; 4 of 12; P < .01, Fisher exact test). Similar outcomes have been reported in several multicenter
studies.26,30 Causes of death included cardiac
arrhythmias, intractable hypotension, multiorgan failure, and
gastrointestinal bleeding. Gastrointestinal bleeding, particularly
unusual after autologous transplantation for hematologic malignancies,
is frequently seen in patients with AL.10,26,30,32,33
In 66 patients who underwent transplantation at the Mayo Clinic for AL,
the treatment-related mortality observed was 14%.34 In a
multivariate analysis of survival, the 2 key predictors were the serum
creatinine level at the time of transplantation and the number of
visceral organs involved. The 30-month actuarial survival of patients
transplanted is 72%; however, if more than 2 organs are involved at
the time of transplantation, the actuarial survival is less than 20%.
Not only does serum creatinine predict for an adverse survival with
typical high-dose chemotherapy (ie, 140 mg/m2 melphalan and
total body irradiation, or 200 mg/m2 melphalan), it also
predicts for the development of renal failure during the
transplantation procedure itself. The median creatinine level for 9 patients who required dialysis during transplantation was 1.7 mg/dL.
Seven of the 9 patients subsequently died. Patients whose serum
creatinine levels exceed 1.5 mg/dL or whose creatinine clearance is
less than 51 mL/min are candidates for reduced-dose therapy in
the risk-adapted model we propose (intermediate-risk patients).34
The presence of cardiac amyloid also contributes significantly to
peri-transplantation mortality.29 Noninvasive criteria used to evaluate patients for cardiac involvement with AL may underestimate the incidence of cardiac deposition
disease.35,36 In our experience, the peri-transplantation
mortality rate in patients with cardiac amyloid and clinical congestive
heart failure or a history of arrhythmias, syncope, or recurrent
pleural effusions approaches 100%. In the British multicenter series,
3 of 7 cardiac patients underwent heart transplantation before
SCT and survived SCT without complication.26 This
therapeutic approach remains in search of a North American clinical
trial.37 In a retrospective overview of 6 years'
experience with SCT for AL, Sanchorawala et al10,28,38,39
at Boston Medical Center aggregate the outcomes of a series of clinical
trials using a range of melphalan doses. They do not evaluate post-SCT
survival as a function of number of major viscera involved and, though
they allude to the use of a range of melphalan doses, they do not
describe their approach to melphalan dosing in detail. Nevertheless,
they succinctly describe the association between dominant cardiac
amyloid, peri-transplantation mortality, and reduced overall survival.
Seventy percent of AL patients who experienced early mortality had
amyloid cardiomyopathy; the median survival of cardiac patients was
2 years, whereas that of patients with other dominant organ involvement
was more than 4 years. Of the 205 patients who began SCT during the
6-year period, 115 (56%) survived for at least 1 year after SCT,
nearly half of whom had complete hematologic responses (undetectability
of M proteins by immunofixation and absence of clonal plasma
cells).39 Furthermore, it is clear from their data and
analysis, and from that of others, that no other modality of therapy is
as effective in achieving complete hematologic responses and reversal
of amyloid-related organ dysfunction in two thirds of surviving
patients (Table 1).10,14,26,27,30,39 Indeed, amyloid P
component radionuclide scans have demonstrated resorption of AL
deposits subsequent to the reduction or elimination of the clonal
plasma cell disorder that is their root cause.26
Given the strict selection criteria for SCT, however, it is reasonable
to think that the survival of a group of SCT-eligible patients with AL
would exceed the 13 months reported for all AL patients. To address
this issue, the amyloid database of the Mayo Clinic was queried by
Gertz et al11 for patients who would in theory be eligible
for SCT. Selection criteria included symptomatic disease, absence of
multiple myeloma, age younger than 70 years, ventricular septal
thickness less than 15 mm, cardiac ejection fraction greater than 55%,
creatinine concentration less than 2 mg/dL, alkaline phosphatase value
less than 3 times normal, and direct bilirubin value less than 2 mg/dL.
Of the 1288 patients seen from 1983 to 1997, 234 (18%) met these
criteria With an eye on such risk-adapted stratification, it is useful to
compare this archival analysis with the results of a phase 2 trial in
which 30 patients with AL (17 men and 13 women; median age, 62 years;
range, 43-71 years) who were ineligible by standard criteria for SCT
were treated with an intermediate dose of intravenous melphalan and
stem cells.28 Although the incidence of significant morbidity with stem cell mobilization and collection was 17% and the
peri-transplantation mortality rate was 20%, 17% of patients achieved
complete hematologic responses and 40% of patients had stabilized or
improved amyloid-related organ involvement, including 3 of 9 symptomatic cardiac patients who lived for more than 2 years after SCT.
Median survival had not been reached at a median follow-up of 2 years.
The lesson to be drawn from the comparison of this trial with the Mayo
Clinic archival data is that though increasing age may be associated
with shorter survival in good risk patients, a risk-adapted approach to
the treatment of AL patients with intravenous melphalan might usefully
accommodate the biology of the disease and improve tolerance to
therapy. This could allow a much greater number of patients to receive
SCT as the primary management of AL, a point borne out to some degree by the aggregate data from Boston Medical Center.39
Given the impaired visceral reserve, vasculopathy, and
coagulopathies associated with AL, it was predictable that
regimen-related toxicity would be more severe in patients with AL who
underwent SCT. It was not expected, however, that there would be
significant toxicity associated with stem cell mobilization and
collection.10 Deaths have been reported during the
mobilization of patients with symptomatic cardiac amyloid or
multisystem disease, at centers using moderate doses of
cyclophosphamide (eg, 2.5 g/m2) or hematopoietic growth
factors alone.10,29 During stem cell mobilization with
granulocyte-colony-stimulating factor (G-CSF; 16 µg/kg per day for 5 days), we and others on rare occasions observed a sometimes fatal
though unexplained syndrome associated with progressive hypoxia and
hypotension unresponsive to supportive measures; it can occur in
patients without cardiac involvement and may be caused by a combination
of the effects of G-CSF, activated platelets returned during
leukapheresis, pulmonary shunting, cytokines, or mediators of septic
hemodynamics such as HMG-1.41,42
To minimize the risk for such toxicities, we recommend that G-CSF
dosing for mobilization be given twice a day in lower doses (eg, 6 µg/kg every 12 hours) with collection beginning on the fifth day 2 to
4 hours after the morning dose of G-CSF.43 During mobilization and leukapheresis, patients with severe nephrotic syndrome
who have hypoalbuminemia and are salt avid may become edematous and
require diuresis and albumin infusions, whereas patients with renal and
cardiac involvement may rarely experience complications such as rapidly
accumulating pleural effusions and flash pulmonary edema. In addition,
to minimize hypocalcemia and citrate toxicity in neuropathic and
cardiac patients, it may help to use heparin anticoagulation during
leukapheresis. The complication rate is approximately 15% in AL
patients during mobilization and leukapheresis, and collections may
have to be interrupted because of worsening edema or
hypoxia.9,28
In the early SCT trials, the ability to mobilize
CD34+ cells in patients who had previously received more
than 200 mg oral melphalan was significantly lower than in patients who
had previously received less or no melphalan.10,27 There
were no significant differences with respect to the number of
CD34+ cells collected on individual days or in total in
patients receiving G-CSF alone for mobilization.10 In
patients randomized to receive G-CSF (10 µg/kg per day) or serial
GM-CSF then G-CSF, similar numbers of CD34+ cells were
collected in both groups.28 In all these trials, two
thirds of patients had amyloid identified in the bone marrow, and AL
deposits did not obviously impair stem cell mobilization. Currently,
G-CSF mobilization can be considered the standard approach in this
population. Because of the clinical advantages associated with prompt
myeloid and thrombopoietic recovery, we recommend that the optimal dose
of CD34+ cells in AL patients who undergo SCT be at least
5 × 106 CD34+ cells/kg.
In all reported trials, complete engraftment following infusion of
unmanipulated stem cell components was typical for the CD34 doses used,
with median neutrophil and platelet recoveries occurring within 10 and
13 days, respectively, demonstrating that AL deposits did not interfere
with engraftment. Contamination with clonotypic immunoglobulin-positive
plasma cells has been demonstrated in the collected apheresis products
from patients with amyloidosis undergoing leukapheresis after growth
factor priming.38,40 CD34-selected cells were used
in a clinical trial in which selection was performed from
G-CSF-mobilized blood stem cells.38,44 Using the Isolex
device (Nexell, Irvine, CA), median yield and purity were 42% and
85%, respectively, and median CD34+ cell dose per kilogram
was 4.1 × 106. Four of 15 patients (27%) did not
achieve the required dose of CD34-selected cells per kilogram (more
than 2 × 106) following 2 column purification
procedures; these patients (median age, 62 years; range, 56-70 years)
required either additional stem cell collections or a bone marrow
harvest to support high-dose therapy. Of note, in patients receiving
CD34-selected stem cells, myeloid recovery was as rapid as that seen
with unselected cells, but lymphoid recovery was significantly delayed
and opportunistic infections were observed in several
patients.38,44 In a phase 3 trial, CD34 selection, though
capable of reducing clonotypic cells in the apheresis product, has not
resulted in improved disease-free or overall survival in multiple
myeloma. It is therefore unlikely to provide benefit in patients with
amyloidosis.45
The frequency and grade of regimen-related toxicities are to some
degree a function of the dose of intravenous melphalan, as indicated by
a comparison of toxicities from cohorts treated at either 200 or
100 mg/m2 (Table 2). Of
particular note, the gastrointestinal toxicity with 200 mg/m2 melphalan is striking, as are the higher rates of
edema and bleeding. Gastrointestinal bleeding has been a significant
cause of early mortality with SCT. Involvement of the gastrointestinal
tract with AL may be focal or diffuse.8 Macroglossia
occurs in approximately 10% of patients and can be massive, producing
an inability to breathe, eat, or drink normally. Achalasia,
hematemesis, gastroparesis, and pseudo-obstruction are among the many
other manifestations of gastrointestinal amyloid. If amyloid
extensively infiltrates the submucosa of the stomach or lower
intestinal tract, the potential for severe mucositis with hemorrhage
must be anticipated, whereas neuropathic compromise of the enteric
plexus often results in atony, persistent posttransplantation nausea,
and need for prolonged nutritional support. The potential for airway
compromise exists in patients with macroglossia and dysphagia,
particularly when mucositis develops and the risk for thrombocytopenic
bleeding exists.
For these reasons, pretransplantation planning becomes essential. Patient evaluation should include a detailed review of gastrointestinal signs and symptoms, serial stool guaiacs, endoscopic studies to define disease when indicated by symptoms or other findings, and a complete assessment of coagulation status. In general, proton-pump inhibitors such as omeprazole should be used for prophylaxis, and, because dose-intensive intravenous melphalan can cause delayed emesis, an antiemetic regimen may be particularly useful beginning the day after stem cell infusion and consisting of 2 to 4 mg dexamethasone twice a day, 0.5 to 1.0 mg lorazepam 2 or 3 times a day, and 5 mg prochlorperazine 2 or 3 times a day. If breakthrough nausea and vomiting occur, daily granisetron may be used in place of prochlorperazine. This regimen is usually continued from days 1 through 7. Major gastrointestinal bleeds can present atypically as new-onset atrial fibrillation or supraventricular tachycardia or as hemodynamic instability. In SCT patients with known GI amyloid, the hematocrit should be maintained at 30% or greater and platelets at 50 000/µL or greater if stool guaiacs are positive. Because splenic rupture can also occur acutely in SCT patients with AL during stem cell mobilization or the early transplantation period, vague or atypical left-sided abdominal or shoulder pain should raise a concern about splenic hemorrhage and lead to consideration of imaging the abdomen. Splenic rupture occurring during this period has been successfully managed surgically. Other viscera, such as the esophagus or small bowel, can also perforate and present life-threatening challenges.32 Of note, we have used corticosteroids at the time of stem cell infusion in patients with renal amyloidosis to reduce the risk for dimethyl sulfoxide-induced compromise of renal function and, because we have observed capillary leak syndrome in patients with amyloidosis, we have also used steroids to prevent alveolar hemorrhage at the time of engraftment.42 The management of intravascular volume and hypotension is a critical aspect of the care of AL patients who undergo SCT. Nephrotic syndrome causes salt avidity and hypoalbuminemia, often leading to significant edema. The risk for over-diuresis, however, may be greater than the risk for allowing some peripheral edema in patients with clinical euvolemia. Nevertheless, intravenous fluids administered should be sodium-free whenever possible, and maintaining a diuresis concurrently with melphalan administration and stem cell infusion is reasonable. Even mild intravascular volume depletion may exacerbate nausea and emesis; therefore, limited hydration and a limited period of diuresis are recommended. Because a major factor causing pulmonary and peripheral edema is hypoalbuminemia, albumin infusions should be used throughout the treatment period to maintain a serum level greater than 2.0 g/dL. Volume depletion, bleeding, sepsis, and hypoadrenalism, followed by worsening autonomic neuropathy, are the most likely causes of hypotension after SCT. Rapid intravenous infusion of magnesium supplements can also cause vasodilation and hypotension. Use of morphine or fentanyl to treat mucositis can affect blood pressure and urine output and can complicate acyclovir prophylaxis. Acyclovir toxicity will increase (particularly central nervous system toxicity) in patients with reduced renal perfusion and urine output. Midodrine and fludrocortisone are useful agents to treat orthostasis, but they do not work reliably in transplantation.39 It is reasonable to omit post-SCT G-CSF administration in patients with severe nephrotic syndrome because of the fluid retention associated with its use. At the time of neutrophil recovery or myeloid engraftment, it is not uncommon for patients to experience orthostasis requiring more aggressive hydration. In patients with dominant cardiac amyloid with minimal symptoms,
preserved left ventricular function usually assures diuretic responsiveness. Maintenance of normal electrolyte levels in cardiac patients under diuresis is an obvious requirement. The mortality associated with cardiac amyloid in SCT is attributed to sudden cardiac
death and to cardiopulmonary failure resulting in hypotension and
hypoxia. Patients rarely, if ever, survive after ventricular arrhythmias or symptomatic bradycardia episodes begin to occur peri-SCT
despite the addition of appropriate medications and the use of advanced
life-support measures. Hemodynamically stable tachycardias, on the
other hand, occur with some frequency and are usually well tolerated;
use of
Patients with AL who have more than 2 major involved organs or who have advanced cardiomyopathy are at high risk for dying within the peri-transplantation period and, therefore, are poor risk candidates for SCT using high-dose regimens. At the same time, patients with involvement of 1 or 2 organs and those with uncomplicated cardiac disease are good candidates for SCT on clinical trials. We recommend that the dose of intravenous melphalan be attenuated based on age and organ involvement. We call this a risk-adapted approach, based on the dose-related differences in toxicity observed in clinical trials (at 100 and 200 mg/m2 of intravenous melphalan) and on the age-related differences in survival observed in the retrospective data from the Mayo Clinic amyloid database. A suggested risk-adapted schema is described in Figure
1. Patients with 1 or 2 involved organs
without dominant cardiac amyloid are considered good risks and would
receive either 200 or 140 mg/m2 intravenous melphalan based
on age. Patients younger than 71 years with 1 or 2 involved organs and
uncomplicated cardiac amyloid are considered intermediate risks and
would receive either 140 or 100 mg/m2 based on age. It may
be reasonable to provide more intensive therapy for patients in this
category, as some have done, in a monitored setting. Good-risk patients
should meet standard criteria for autologous SCT (see above). Patients
with involvement by more than 2 organs or with advanced cardiomyopathy
are considered poor risk (ie, not SCT candidates) and would be treated
with investigational therapies or oral melphalan and prednisone. There
will be patients whose disease does not fit these simple categories;
for example, patients with only renal amyloid and a creatinine
clearance less than 51 mL/min. Such patients are at higher than average
risk for renal failure with SCT.34 Therefore, good risk AL
patients who have 1 or 2 involved organs and no cardiac involvement may occasionally have impaired renal function and be at risk for becoming dialysis dependent after SCT at 200 mg/m2 melphalan.
Dose-reductions to 140 or 100 mg/m2 (depending on age) are
reasonable in such patients. In addition, patients with dominant
hepatic disease, massive hepatomegaly, waning hepatic synthetic
function, and elevated bilirubin require special consideration before
commitment to SCT because of the risk for acute hepatic failure and
peri-SCT death.46
It is apparent that continued efforts to treat AL with SCT will depend on clinical trials designed to make SCT result in less morbidity or to answer specific questions of interest. The risk-adapted approach we suggest may expand the pool of AL patients as SCT candidates but would also, we hope, reduce the morbidity associated with SCT for AL patients. A multicenter phase 3 trial by a French myeloma intergroup is under way. AL patients are randomized to receive high-dose melphalan with SCT or oral melphalan and dexamethasone. Phase 2 tandem transplantation trials are also under way at several American centers, and a phase 2 ECOG trial has been completed but is yet to be reported. Although these trials did not use a risk-adapted approach, further insight may be gained from them with respect to the application of SCT to AL. Of particular interest is the stratified randomized phase 2 trial
recently reported in which AL patients received either SCT as initial
therapy (arm 1) or 2 cycles of oral melphalan and prednisone and then
SCT (arm 2).25 Overall survival was the primary endpoint. Although patients were stratified by dominant organ involvement for
randomization, patients were not stratified based on number of organs
involved or age. One hundred patients within 1 year of diagnosis
(median age, 56 years; range, 37-80 years; male-female ratio, 1.8:1)
were enrolled. Fifty-two patients were randomized to arm 1 and 48 to
arm 2, and there were no differences in age or sex between the arms.
The dominant symptomatic organ involved was renal in 56% of patients
in both arms. A substantial proportion of patients also had evidence of
cardiac involvement: 34 patients in arm 1 (65%) and 23 patients in arm
2 (48%). Of the 52 patients in arm 1, 9 (17%) did not proceed to SCT
because of disease progression/death (n = 1), complications or death
during stem cell mobilization (n = 4) or patient withdrawal
(n = 4). Of the 48 patients in arm 2, 16 (33%) did not proceed to
SCT because of progression of disease/death before SCT (n = 8),
complications or death during stem cell mobilization (n = 6) or
patient withdrawal (n = 2). With 12 to 58 months of follow-up, median
survival has not been reached for either treatment arm by Kaplan-Meier.
However, survival of patients 1 year after randomization was
significantly higher for arm 1 (70%) than for arm 2 (58%)
(P = .04). For patients with cardiac involvement, median
survival was significantly longer for arm 1 (19.6 months) than for arm
2 (5.3 months) (P = .02). Overall, 35% of patients undergoing SCT in both arms had complete hematologic responses. Responses of the amyloid-related organ disease are still under evaluation. However, the overall incidence of disease progression, death, or severe complications with mobilization was 19% New approaches to AL may emerge from current efforts. For example, a transgenic mouse model has been developed carrying the human interleukin-6 gene with increased concentrations of the precursor secondary amyloid protein SAA.46 These mice develop renal and hepatosplenic amyloidosis at 3 months of age and have a clinical course remarkably similar to that of human AA. The availability of in vivo experimental models of AA provides a means to assess the therapeutic efficacy of new agents developed to prevent fibrillogenesis in amyloid-associated disease.47 In addition, a murine model of AL has been developed, clinically manifest as subcutaneous amyloidomas.48 When these AL-bearing animals receive injections of anti-light-chain monoclonal antibodies with specificity for an amyloid-related epitope, regression has been documented with the resolution of amyloid tumoral masses. This in vivo demonstration that amyloid deposits of immunoglobulin origin can be lysed by passive administration of an amyloid-reactive antibody has the potential for important clinical benefit to patients with AL.48 It is hoped that the antifibrillar and the serotherapeutic approaches to AL will be in clinical trials within this decade. We are also encouraged by the testing of novel biologic agents, such as amifostine and keratinocyte growth factor, that may reduce gastrointestinal toxicity in SCT. Hypotheses of a translational nature that are worth examining in future trials include asking whether immunoglobulin VL germline gene use has prognostic significance because germline gene use contributes to the organ tropism of AL and whether hematopoietic stem cells trans-differentiate to contribute to post-SCT tissue-specific recovery in patients with cardiac amyloid. We anticipate that the willingness of patients with AL to participate in clinical research will increase the likelihood of acquiring a better understanding of the mechanisms of AL disease and of amyloid resorption and organ recovery.
Stem cell transplantation for primary systemic amyloidosis is applicable to a minority of patients, such as those with limited organ disease and no significant cardiac involvement. Response rates with SCT appear to be higher than those seen in patients treated with traditional melphalan and prednisone. Morbidity and mortality are clearly higher than in patients with multiple myeloma or other hematologic malignancies undergoing autologous SCT. There is an unusually high rate of significant gastrointestinal tract hemorrhage, and cardiac complications including arrhythmias are prevalent. SCT for AL will remain controversial until there is either a multicenter phase 3 trial comparing it to standard therapy in newly diagnosed patients or a multicenter phase 2 trial using a risk-adapted approach showing reduced treatment-related mortality. We anticipate that improved patient selection and peri-transplantation management and adoption of a risk-adapted approach to melphalan dosing based on organ involvement and age will accelerate the acquisition of the expertise needed for the conduct of multicenter SCT trials and will enhance the impetus for early diagnosis and timely treatment of AL.
We thank Stephen Nimer for a critical reading of this manuscript and our colleagues at Memorial Sloan-Kettering, Mayo Clinic and in the amyloidosis community for many helpful discussions.
Submitted September 25, 2001; accepted February 1, 2002.
Reprints: Raymond L. Comenzo, Hematology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021; e-mail: comenzor{at}mskcc.org.
1. Kyle RA, Gertz MA. Primary systemic amyloidosis: clinical and laboratory features in 474 cases. Semin Hematol. 1995;32:45-59[Medline] [Order article via Infotrieve].
2.
Falk RH, Comenzo RL, Skinner M.
The systemic amyloidoses: current approaches to diagnosis and treatment.
N Engl J Med.
1997;337:898-909 3. Gertz MA, Kyle RA. Amyloidosis: prognosis and treatment. Semin Arthritis Rheum. 1994;24:124-138[CrossRef][Medline] [Order article via Infotrieve]. 4. Gillmore JD, Hawkins PN, Pepys MB. Amyloidosis: a review of recent diagnostic and therapeutic developments. Br J Haematol. 1997;99:245-256[CrossRef][Medline] [Order article via Infotrieve].
5.
Kyle R, Gertz M, Greipp P, et al.
A trial of three regimens for primary amyloidosis: colchicine alone, melphalan and prednisolone, and melphalan, prednisolone and colchicine.
N Engl J Med.
1997;336:1202-1207 6. Skinner M, Anderson JJ, Simms R, et al. Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine alone. Am J Med. 1996;100:290-298[CrossRef][Medline] [Order article via Infotrieve].
7.
Kyle RA, Gertz MA, Greipp PR, et al.
Long-term survival (10 years or more) in 30 patients with primary amyloidosis.
Blood.
1999;93:1062-1066 8. Merlini G. Treatment of primary amyloidosis. Semin Hematol. 1995;32:60-79[Medline] [Order article via Infotrieve]. 9. Comenzo RL. Autologous hematopoietic cell transplantation for AL amyloidosis. In: Forman SJ,Blume KG,Thomas ED, eds. Hematopoietic Cell Transplantation. 2nd edition. New York, NY: Blackwell; 1999:1014-1028.
10.
Comenzo RL, Vosburgh E, Falk RH, et al.
Dose-intensive melphalan with blood stem-cell support for the treatment of AL amyloidosis: survival and responses in 25 patients.
Blood.
1998;91:3662-3670 11. Gertz MA, Lacy MQ, Dispenzieri A. Myeloablative chemotherapy with stem cell rescue for the treatment of primary systemic amyloidosis: a status report. Bone Marrow Transplant. 2000;25:465-470[CrossRef][Medline] [Order article via Infotrieve]. 12. Kyle RA. High-dose therapy in multiple myeloma and primary amyloidosis: an overview. Semin Oncol. 1999;26:74-83[Medline] [Order article via Infotrieve]. 13. Sezer O, Schmid P, Shweigert M, et al. Rapid reversal of nephrotic syndrome due to primary systemic AL amyloidosis after VAD and subsequent high-dose chemotherapy with autologous stem cell support. Bone Marrow Transplant. 1999;23:967-969[CrossRef][Medline] [Order article via Infotrieve]. 14. Comenzo RL. Hematopoietic cell transplantation for primary systemic amyloidosis: what have we learned. Leuk Lymphoma. 2000;37:245-258[Medline] [Order article via Infotrieve].
15.
Bradwell A, Carr-Smith HD, Mead GP, et al.
Highly sensitive automated immunoassay for immunoglobulin free light chains in serum and urine.
Clin Chem.
2001;47:673-680
16.
Drayon M, Tang LX, Drew R, et al.
Serum-free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma.
Blood.
2001;97:2900-2902
17.
Murphy CL, Eulitz M, Hrncic R, et al.
Chemical typing of amyloid protein contained in formalin-fixed paraffin-embedded biopsy specimens.
Am J Clin Pathol.
2001;116:135-142 18. Kaplan B, Murphy CL, Ratner V, et al. Micro-method to isolate and purify amyloid proteins for chemical characterization. Amyloid. 2001;8:22-29[Medline] [Order article via Infotrieve].
19.
Solomon A, Frangione B, Franklin EC.
Preferential association of the V 20. Comenzo RL, Wally J, Kica G, et al. Clonal immunoglobulin light chain variable region germline gene use in AL amyloidosis: association with dominant amyloid-related organ involvement and survival after stem cell transplantation. Br J Haematol. 1999;106:744-751[CrossRef][Medline] [Order article via Infotrieve].
21.
Comenzo RL, Zhang Y, Martinez C, Osman K, Herrera G.
The tropism of organ involvement in primary systemic amyloidosis: contributions of Ig VL germline gene use and plasma cell burden.
Blood.
2001;98:714-720 22. Perfetti V, Colli Vignarelli M, Casarini S, Ascari E, Merlini G. Biological features of the clone involved in primary amyloidosis (AL). Leukemia. 2001;15:195-202[CrossRef][Medline] [Order article via Infotrieve]. 23. Abraham RS, Price-Troska DL, Gertz MA, Kyle RA, Fonseca R. Association of rearranged light chain variable region genes with organ tropism and light chain associated (AL) amyloidosis [abstract]. Blood. 2001;98:151. 24. Rajkumar SV, Gertz MA, Kyle RA. Primary systemic amyloidosis with delayed progression to multiple myeloma. Cancer. 1998;82:1501-1505[CrossRef][Medline] [Order article via Infotrieve]. 25. Sanchorawala V, Wright DG, Seldin DC, et al. High-dose intravenous melphalan and autologous stem cell transplantation as initial therapy or following two cycles of oral chemotherapy for the treatment of AL amyloidosis: results of a prospective randomized trial [abstract]. Blood. 2001;98:815. 26. Gillmore JD, Apperley JF, Craddock C, et al. High dose melphalan and stem cell rescue for AL amyloidosis. In: Kyle RA,Gertz MA, eds. Amyloid and Amyloidosis. Pearl River, NY: Parthenon Publishing; 1999:102-104. 27. Gertz MA, Lacy MQ, Gastineau DA, et al. Blood stem cell transplantation as therapy for primary systemic amyloidosis (AL). Bone Marrow Transplant. 2000;26:963-969[CrossRef][Medline] [Order article via Infotrieve]. 28. Comenzo RL, Sanchorawala V, Fisher C, et al. Intermediate-dose intravenous melphalan and blood stem cells mobilized with sequential GM+G-CFS or G-CSF alone to treat AL (amyloid light chain) amyloidosis. Br J Haematol. 1999;104:553-559[CrossRef][Medline] [Order article via Infotrieve]. 29. Saba N, Sutton D, Ross H, et al. High treatment-related mortality in cardiac amyloid patients undergoing autologous stem cell transplant. Bone Marrow Transplant. 1999;24:853-855[CrossRef][Medline] [Order article via Infotrieve]. 30. Moreau P, Leblond V, Baurquelot P, et al. Prognostic factors of survival and response after high-dose therapy and autologous stem cell transplantation in systemic AL amyloidosis: a report on 21 patients. Br J Haematol. 1998;101:766-769[CrossRef][Medline] [Order article via Infotrieve]. 31. Harousseau JL, Attal M, Divine M, et al. Comparison of autologous bone marrow transplantation and peripheral blood stem cell transplantation after first remission induction treatment in multiple myeloma. Bone Marrow Transplant. 1995;15:963-969[Medline] [Order article via Infotrieve]. 32. Schulenburg A, Kalhs P, Oberhuber G, et al. Gastrointestinal perforation early after peripheral blood stem cell transplantation for AL amyloidosis. Bone Marrow Transplant. 1998;22:293-295[CrossRef][Medline] [Order article via Infotrieve]. 33. Kumar S, Dispenzieri A, Lacy MQ, Litzow MR, Gertz MA. High incidence of gastrointestinal tract bleeding after autologous stem cell transplant for primary systemic amyloidosis. Bone Marrow Transplant. 2001;28:381-385[CrossRef][Medline] [Order article via Infotrieve]. 34. Gertz MA, Lacy MQ, Dispenzieri A, et al. Stem cell transplantation for management of primary amyloidosis [abstract]. Blood. 2001;98:816. 35. Gertz MA, Grogan M, Kyle RA, Tajik AJ. Endomyocardial biopsy-proven light chain amyloidosis (AL) without echocardiographic features of infiltrative cardiomyopathy. Am J Cardiol. 1997;80:93-95[CrossRef][Medline] [Order article via Infotrieve]. 36. Clesham GJ, Vigushin DM, Hawkins PN, et al. Echocardiographic assessment of cardiac involvement in systemic AL amyloidosis in relation to whole body amyloid load measured by serum amyloid P component (SAP) clearance. Am J Cardiol. 1997;80:1104-1108[CrossRef][Medline] [Order article via Infotrieve]. 37. Pelosi F, Capehart J, Roberts WC. Effectiveness of cardiac transplantation for primary (AL) cardiac amyloidosis. Am J Cardiol. 1997;79:532-535[CrossRef][Medline] [Order article via Infotrieve]. 38. Comenzo RL, Michelle D, LeBlanc M, et al. Mobilized CD34+ cells selected as autografts in patients with primary light-chain amyloidosis: rationale and application. Transfusion. 1998;38:60-69[CrossRef][Medline] [Order article via Infotrieve]. 39. Sanchorawala V, Wright DG, Seldin DC, et al. An overview of the use of high-dose melphalan with autologous stem cell transplantation for the treatment of AL amyloidosis. Bone Marrow Transplant. 2001;28:637-642[CrossRef][Medline] [Order article via Infotrieve]. 40. Perfetti V, Ubbiali P, Magni M, et al. Cells with clonal light chains are present in peripheral blood at diagnosis and in apheretic stem cell harvests of primary amyloidosis. Bone Marrow Transplant. 1999;23:323-327[CrossRef][Medline] [Order article via Infotrieve].
41.
Wang H, Bloom O, Zhang M, et al.
HMG-1 as a late mediator of endotoxin lethality in mice.
Science.
1999;285:248-251 42. Gertz MA, Lacy MQ, Bjornsson J, Litzow MR. Fatal pulmonary toxicity related to the administration of granulocyte-colony stimulating factor in amyloidosis: a report and review of growth factor-induced pulmonary toxicity. J Hematother Stem Cell Res. 2000;9:635-643[CrossRef][Medline] [Order article via Infotrieve]. 43. Arbona C, Prosper F, Benet I, et al. Comparison between once a day vs twice a day G-CSF for mobilization of peripheral blood progenitor cells (PBPC) in normal donors for allogeneic PBPC transplantation. Bone Marrow Transplant. 1998;22:39-45[CrossRef][Medline] [Order article via Infotrieve]. 44. Akpek G, Vosburgh E, Michelle D, et al. High-dose melphalan with CD34+ blood stem cell transplantation in patients with AL amyloidosis: a feasible approach. In: Kyle RA,Gertz MA, eds. Amyloid and Amyloidosis. Pearl River, NY: Parthenon Publishing; 1999:175-177.
45.
Stewart AK, Vescio R, Schiller G, et al.
Purging of autologous peripheral-blood stem cells using CD34 selection does not improve overall or progression-free survival after high-dose chemotherapy for multiple myeloma: results of a multicenter randomized controlled trial.
J Clin Oncol.
2001;19:3771-3779 46. Gertz MA, Kyle RA. Hepatic amyloidosis: clinical appraisal in 77 patients. Hepatology. 1997;25:118-121[CrossRef][Medline] [Order article via Infotrieve].
47.
Solomon A, Weiss DT, Schell M, et al.
Transgenic mouse model of AA amyloidosis.
Am J Pathol.
1999;154:1267-1272
48.
Hrncic R, Wall J, Wolfenbarger DA, et al.
Antibody-mediated resolution of light chain-associated amyloid deposits.
Am J Pathol.
2000;157:1239-1246   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
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Top
Abstract
Introduction
60% of AL
patients have 10% or fewer clonal marrow plasma cells, a percentage
that remains stable over time.
than 
(3:1), and the
immunoglobulin light-chain variable region genes expressed by AL clones
include several that are less frequently expressed in the normal
repertoire, indicating that germline-encoded features may contribute to
the propensity of certain subtypes of light chains to form
amyloid.
genes were more likely to have dominant cardiac and multisystem disease.
blockade simply for control of sinus tachycardia should not
be routine. Whether prophylactic antiarrhythmic agents or devices can
decrease mortality remains to be investigated.
