Download Dose-Intensive Melphalan With Blood Stem Cell

From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
Dose-Intensive Melphalan With Blood Stem Cell Support for the Treatment
of AL Amyloidosis: One-Year Follow-up in Five Patients
By Raymond L. Comenzo, Evan Vosburgh, Robert W. Simms, Peter Bergethon, Diane Sarnacki, Kathleen Finn,
Simon Dubrey, Douglas V. Faller, Daniel G. Wright, Rodney H. Falk, and Martha Skinner
The morbidity and lethality of AL amyloidosis is caused by
the deposition of Ig light chains as fibrillar amyloid protein
in vital organs, disrupting their function, and not by the generally low burden of clonal plasma cells that produce the
paraproteins. Survival of patients with AL amyloidosis is no
more than 1 t o 2 years from the time of diagnosis with
current management approaches. Clearly, more effective
therapies are needed for this rapidly lethal disease. Five patients were treated with dose-intensive melphalan and
blood stem cell support and followed for a period of 1 year.
Patients were diagnosed with AL amyloidosis by tissue biopsy and categorized by performance status and organ
involvement. Their plasma cell dyscrasias were evaluated
with immunofixation electrophoresis of serum and urine
specimens, quantitative serum Igs, and immunohistochemical staining of bone marrow biopsy specimens. After treatment with dose-intensive intravenous melphalan followed
by infusion of autologous growth-factor-mobilized blood
stem cells, clinical evaluations and plasma cell studies were
repeated at 3 and 12 months. Three men and 2 women aged
38 t o 53 years were treated. Median performance status
(SWOG) was 2 (1 to 3). and clinical presentations included
L AMYLOIDOSIS is a plasma cell dyscrasia that results
from an excess production of Ig light chains which
form insoluble amyloid fibrillar deposits in the kidneys,
heart, liver, autonomic and peripheral nerves.'.' Eighty-five
percent of patients have evidence of a plasma cell dyscrasia
with serum andor urine monoclonal proteins and with lowlevel bone marrow (BM) plasmacytosis showing clonal dominance by either K or A light-chain i ~ o t y p e s . ~ . ~
For patients with AL amyloidosis death usually occurs in
1 to 2 years from diagnosis despite current standard treatment
with oral melphalan and prednisone?,6 By comparison, patients with stage I multiple myeloma or monoclonal gammopathies of undetermined significance, whose neoplastic
plasma cell burdens are roughly equivalent to those in AL
amyloidosis, have median survivals twofold to sevenfold
10nger.~These differences in survival highlight the lethal
consequences of systemic amyloid deposition. Elimination
of the plasma cell clone producing amyloidogenic proteins
is a rational therapeutic goal.
The use of myeloablative therapy with allogeneic or
autologous BM infusions in patients with multiple myeloma has become an important area of investigation, and
complete response rates of 10% to 30% in patients with
recurrent or resistant multiple myeloma have been
achieved with this approach.8-'' The mortality and morbidity of this form of treatment have been decreased substantially because of the availability of myeloid growth factors
and mobilized blood stem ~ e 1 l s . Cognizant
l~
of these advances, we used dose-intensive intravenous (IV) melphalan with autologous mobilized blood stem cell support as
therapy for AL amyloidosis. We report on the efficacy of
this approach in the initial five patients treated, at 12 or
more months after treatment.
A
Blood, Vol 88, No 7 (October l), 1996: pp 2801-2806
nephrotic syndrome (n = I),
symptomatic cardiomyopathy
(n = 1). gastrointestinal involvement with polyneuropathy
(n = 2). and hepatomegaly (n = 1). With a median followup of 13 months (12 t o 17 months), all five patients are well
and have shown stable or improved performance status and
clinical remission of organ-related dysfunction, including a
50% reduction in daily proteinuria with no change in creatinine, reversal of symptoms of cardiomyopathy and reductions of posterior wall and septal thickening, reversal of
polyneuropathy and gastric atony, and resolution of hepatomegaly by computed tomographic scan. In3 of the 5 patients
(60%) at 12 months after treatment, plasma cell dyscrasias
could not be detected. Dose-intensive chemotherapy with
intravenous melphalan and growth-factor-mobilized blood
stem cell support is feasible therapy for patients with AL
amyloidosis, even when there is clinical evidence of cardiac
involvement. At least some patients with AL amyloidosis
achieve complete remission of their plasma cell dyscrasia,
improvement in performance status, and clinical remission
of organ-specific disease after this form of treatment.
0 1996 by The American Society of Hematology.
PATIENTS, MATERIALS, AND METHODS
Patients
Beginning in January 1994, patients 18 to 61 years old with AL
amyloidosis diagnosed by tissue biopsy (defined as the presence of
apple-green birefringence on Congo red-stained specimens) were
evaluated as previously described, and considered for dose-intensive
IV melphalan with blood stem cell support on a clinical trial approved by our institutional review board for human studies, requiring
written informed consent.'4.15Melphalan at 200 mg/m' was offered to
patients younger than 61 years with adequate cardiac (left ventricular
ejection fraction >50%), pulmonary (diffusion capacity >50% predicted), hepatic (bilirubin <2.0 g/dL), and renal function (creatinine
< 1.5 mg/dL).
At baseline, patients were evaluated clinically and with studies
that included blood counts and chemistries, 24-hour urinary protein,
From the Transfusion Medicine Service, the Department of Pathology and Laboratory Medicine; the Sections of HematologyOncology, Cardiology, and Rheumatology, the Department of
Medicine; the Neurological Unit, Boston City Hospital and the Department of Neurology; the Department of Nursing; the Autologous
Stem-Cell Transplant Program in the Cancer Research Center; Boston University Medical Center Hospital, and Boston University
School of Medicine, Boston, MA.
Submitted February 26, 19%; accepted May 30, 1996.
Supported in part by a grant from Amgen.
Address reprint requests to Raymond L Comenzo, MD, Director,
Transfusion Medicine, H-303, 88 E Newton St, 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.
0 19% by The American Society of Hematology.
OOO6-4971/96/8807-OO41$3.00/0
2801
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
2802
COMENZO ET AL
Table 1. SWOG Patient Performance Status Grading Scale
Grade
Scale
0
Fully active; able to carry on all predisease activities without
restriction. (Karnofsky 90% to 100%)
Restricted in physically strenuous activity but ambulatory
and able to perform work of a light or sedentary nature,
eg, light housework or office work. (Karnofsky 70% to
80%)
Ambulatory and capable of all self-care but unable to
perform any work activities. Up and about more than 50%
of waking hours. (Karnofsky 50% to 60%)
Capable of only limited self-care; confined to bed or chair
more than 50% of waking hours. (Karnofsky 40% to 50%)
Completely disabled. Cannot perform any self-care. Totally
confined to bed or chair. (Karnofsky 10% to 20%)
Dead
1
2
3
4
5
electrocardiogram, echocardiogram, gastric emptying scan, and computed tomographic scan, as indicated by symptoms and clinical findings. Each patient’s systemic amyloidosis was categorized by extent
and predominance of organ-system involvement, and each patient’s
performance status was assessed according to Southwestern Oncology Group (SWOG) criteria (Table 1).
Presence of a monoclonal plasma cell dyscrasia was assessed by
serum and urine immunofixation electrophoresis (IFE-S and IFE-U),
and by BM biopsy with standard immunohistochemical staining for
light-chain isotypes. Quantitative serum Ig levels, and, after July
1995, quantitative urinary light chains, were measured. Amyloid
deposits in BM biopsy specimens stained with Congo red were
graded as 0 (none detected), 1 (in vessels only), 2 (moderate interstitial deposits), and 3 (massive interstitial deposits).
Using these studies, patients were evaluated at baseline, and again
at 3 and 12 months after treatment, and responses to therapy were
categorized in terms of (1) changes in performance status, (2)
changes in clinical findings and organ-related symptoms of amyloidosis, and (3) persistence or undetectability of a monoclonal
plasma cell dyscrasia by serum and urine immunofixation electrophoresis and by marrow biopsy with immunohistochemical staining
for light-chain isotypes.
Blood Stem Cells
Hematopoietic stem and progenitor cells were mobilized with
granulocyte colony-stimulating factor (G-CSF, filgrastim; AMGEN,
Thousand Oaks, CA) by subcutaneous injection for 4 to 6 days.’’
Daily large-volume leukapheresis was performed between days 4
and 7, and the leukapheresed mononuclear cells were evaluated,
cryopreserved, and subsequently infused as previously described.16
Briefly, evaluation of stem cell collections included flow cytometric
studies to determine the fraction of cells that were CD34’ and standard progenitor cell assays to calculate the number of colony-forming units granulocyte-macrophage, scored at 14 days of culture. The
target dose of CD34+ cells was 5 X 106/kg.
Chemotherapy
Dose-intensive melphalan was administered 1V over 2 days, 100
mg/m*/d, for a total of 200 mg/m*, and stem cells were infused
72 hours later. Postinfusion cytokine support consisted of G-CSF.
Patients received antibiotic prophylaxis with oral ciprofloxacin and
intravenous 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 x 109/Land of platelets >20
sion.
X
10y/Lwithout platelet transfu-
RESULTS
Patients
Between January 1, 1994 and December 31, 1994, three
men and two women with a median age of 46 years (range,
39 to 53) were treated on this trial. All patients gave written
informed consent. We report the 1 year follow-up results in
these five consecutive patients who had multiple biopsies
from separate sites positive for amyloid (range, 2 to 4) and
who were treated at a median of 5 months from diagnosis
(range, 2 to 18 months). All of these patients had evidence
of amyloid depositions in blood vessels in BM biopsies.
All patients tolerated stem cell mobilization and leukaphereses without significant complications. Per kilogram of
patient weight, the five patients received a median of 8.3 X
lo6 CD34+ cells (3.4 to 12.5) containing 100 X IO4 CFUGM (33 to 133). All patients tolerated dose-intensive melphalan and stem cell infusion (days -4 to 0) without significant complications, and became pancytopenic after
dose-intensive melphalan. Hematopoietic reconstitution occurred in all patients by a median of 10 days for neutrophils
(range, 9 to 10) and for platelets (9 to 12). At 12 months in
these five patients, median complete blood count values were
white blood cell count 5.0 x 109/L(4.6 to 5.6), hemoglobin
13.8 gm/dL (13.3 to 15.6) and platelet count 156 X 10y/L
(1 18 to 208).
All patients had nausea, vomiting, and grade I1 mucositis
by the Common Cancer Toxicity Criteria.” One patient became febrile requiring IV antibiotics; blood cultures were
negative. Two patients had peripheral and pulmonary edema
requiring diuresis. Other toxicities included hypematremia
and hyponatremia and increased creatinine. All toxicities
resolved within 30 days of therapy.
Patient Responses at 12 Months
Case one. Patient 1, a 42-year-old man, had gastrointestinal symptoms and peripheral polyneuropathy, and was
treated 2 months from diagnosis, having received no prior
oral therapy. He had presented with a painful peripheral
polyneuropathy, was orthostatic by vital signs with symptoms, and had gastrointestinal symptoms that included dysgeusia, loss of appetite, nausea, and vomiting. Biopsy specimens of stomach, rectum, BM (1 +), and abdominal fat were
positive for amyloid. Sural nerve biopsy was negative. He
required total parenteral nutrition (TPN) for profound (25%)
weight loss due to gastric atony as documented by a gastric
emptying scan showing 0% emptying at 2 hours. Opiates
were required for discomfort associated with his peripheral
neuropathy.
At 12 months he had regained all lost weight, was eating
a normal diet without TPN, and had a gastric emptying scan
in the supranormal range. A dramatic improvement in performance status was noted, from 3 to 0, and he had returned
to full-time employment. He required no medications. As
shown in Fig 1, depicting the neurologic exams of this patient across the top, the polyneuropathy had remitted at 3
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
HIGH-DOSE MELPHALAN FOR AL AMYLOIDOSIS
2803
-
Baseline
3 Months
Y
.0)
Y
L
I
Baseline
n
3 Months
Y
J1
Legend
Temp. Loss
Pain Loss
Touch LOSS Hyperaesthesia
Fig 1. Patient 1 had experienced the transition from pain to numbness in the weeks before treatment. After therapy, the numbness remitted
with a brief period of pain in the feet. Currently the patient's only symptom at 12 months is numbness in his toes. Patient 3 had pain, sensory
losses, and weakness which largely resolved after therapy. Currently his only symptom at 12 months is mild discomfort of his soles.
months, resulting in improved overall function. Resolution
of orthostatic and gastrointestinal symptoms occurred 3 to 9
months after dose-intensive melphalan.
At baseline, this patient had serum and urine findings of
a plasma cell dyscrasia with a monoclonal IgAA in his serum
and A light chains in his urine, as well as suppressed noninvolved Ig levels, and a BM biopsy showing 10% plasma
cells uniformly staining for A. At 12 months, his BM showed
less than 5% plasma cells with staining for both light-chain
isotypes, and he had negative IFE-S and IFE-U.IgA and
IgM were normal but IgG was 630 mg/dL (normal, 700 to
1,600 mg/dL).
Case two. Patient 2, a 46-year-old man with amyloid
cardiomyopathy and a myocardial biopsy sample positive
for amyloid, was treated 5 months after diagnosis having
received a single course of oral melphalan and prednisone
containing 32 mg of melphalan. BM (1+) and abdominal
fat biopsies were also positive for amyloid. At 12 months
of follow-up, performance status over the year improved
from 2 to 0, New York Heart Association (NYHA) class
improved from III to I, diuretics were no longer needed, and
the patient was able to work full-time and exercise strenuously.
A comparison of echocardiograms from baseline and 12
months posttherapy showed reductions in the thickness of
both the posterior wall and interventricular septum from 1.5
and 1.4 cm to 0.93 and 0.98 cm, respectively, although left
ventricular ejection fraction decreased from 56% at baseline
to 44% at 12 months. Baseline IF%-S was negative while
baseline IFE-U showed A light chains. Baseline BM studies
showed 10% plasma cells uniformly staining for A. Although
the BM findings at 12 months follow-up had normalized,
showing less than 5% plasma cells staining for both lightchain isotypes; although the IFE-S remained negative and
the serum IgG level had normalized, increasing from 544 to
960 mg/dL; and, although quantitative urinary A light chains
were not detectable, IFE-Ushowed a faint band suggestive
of A light chains, a band that had not been detected at 3
months of follow-up. In addition, 24-hour urinary protein
increased from 256 mg at baseline to 601 mg at 12 months
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
2804
with unchanged albumin and creatinine, and alkaline phosphatase increased also, from 104 to 277 U/L. The significance of these findings is not clear at this time, in view of
the patient’s excellent performance status. (Author’s note:
At 2 years posttherapy, IFE-U, IFE-S, and BM were normal
and complete remission maintained.)
Case three. Patient 3, a 38-year-old man treated 3
months after diagnosis, presented with a painful peripheral
polyneuropathy, orthostasis, nausea, abdominal pain, and
profound weight loss (55 lb) because of gastric atony. Biopsy
specimens of an axillary lymph node, abdominal fat, and
BM (2+) were positive for amyloid. He had a performance
status of 3 and had received no prior therapy. Opiates were
required to treat pain due to his peripheral neuropathy. He
had A light chains in both serum and urine and 5% plasma
cells in his BM.
As was the case for patient 1, the peripheral polyneuropathy, gastrointestinal, and autonomic symptoms resolved over
the 12 months after dose-intensive melphalan and no medications were needed or prescribed. The pattern of resolution
of his neuropathic symptoms is depicted in the lower panels
of Fig 1. Initially the patient required total parenteral nutrition for several months, but by 1 year’s time he was eating
a normal diet, had regained 30 lb, and returned to full-time
employment. Performance status had improved from 3 to 0.
BM biopsy sample was normal and IFE-U and IFE-S were
negative.
Case four. Patient 4, a 46-year-old woman with hepatomegaly and AL amyloidosis confirmed by liver biopsy specimen, was treated 11 months after diagnosis having received
oral therapy including 264 mg of melphalan. At 12 months’
follow-up, performance status improved from 2 to 0 and
cranio-caudal liver span by CT scan decreased from 20 cm
at baseline to 14.5 cm, demonstrating resolution of hepatomegaly. This patient’s formal abdominal girth measurements
over the same period showed a 3-cm decrease without weight
change, and alkaline phosphatase decreased from 184 to 136
U L
Baseline BM findings showed 12% uniformly K-staining
plasma cells, and, although baseline IFE-S was negative,
baseline IFE-U showed K light chains. At 12 months’ followup, BM studies were normal, IFE-S remained negtive, and
previously noted urinary light chains were not detected by
IFE-U. Serum IgG and IgA levels had been suppressed at
baseline, whereas, at 12 months, the IgG level had increased
to 911 mg/dL but the IgA level remained below normal.
With respect to other organ systems, 24-hour urinary protein
was reduced from 645 to 90 mg with creatinine unchanged
at 1.3 mg/dL, and echocardiogram remained normal.
Casefive. Patient 5, a 53-year-old woman with nephrotic
syndrome, had had a monoclonal gammopathy of undetermined significance for 15 years before being diagnosed with
multiple myeloma and AL amyloidosis. Renal and abdominal fat biopsy specimens were positive for amyloid. At diagnosis, serum IgGA was 3.5 g/dL, IFE-U contained monoclonal IgGA, and BM biopsy had 25% A-staining plasma
cells in sheets. After treatment with oral therapy, including
468 mg of melphalan, a reduction in monoclonal paraprotein
to 1.3 g/dL was observed. She was treated with dose-inten-
COMENZO ET AL
sive IV melphalan and stem cell support 18 months after
myeloma and amyloidosis were diagnosed. At 1 year posttherapy, her performance status remains a 1 with no evidence
of progressive amyloidosis.
Of note, the daily urinary protein has decreased from
11,370 mg at the time of stem cell mobilization to 5,040 mg
12 months later, with a creatinine of 1.0 versus a baseline
of 1.1 mg/dL. The serum albumin has increased to 3.4 from
a baseline of 2.0 g/dL. However, the monoclonal IgGA remained detectable by IFE-S and IFE-U; serum Ig levels were
otherwise normal.
DISCUSSION
AL amyloidosis is a rapidly lethal disease, and therapies
currently in use have modified its dismal prognosis only
marginally. In a recent trial, 100 patients with AL amyloidosis were prospectively randomized to receive colchicine
alone or melphalan, prednisone, and colchicine.l4 Median
survival from the time of study entry to end-organ failure in
those treated with three drugs was 12.2 months, compared
with 6.7 months for those treated with colchicine alone ( P
= .087). In an earlier study of 101 patients, the progressionfree median survival for those receiving melphalan and
prednisone was 16 months whereas for controls receiving
colchicine it was 6 months.6 Moreover, evaluation of patient
subsets in this study showed differences in response to chemotherapy.
Of particular note, none of the 15 patients with polyneuropathy that were studied were found to respond to treatment
with oral melphalan and prednisone. Each of these patients
experienced progression of their disease without enhanced
survival. In contrast, survival for patients with congestive
heart failure was significantly longer for those receiving melphalan and prednisone, a median survival of 12 months,
versus 5 months for controls. Among patients with nephrotic
syndrome there was no survival difference based on regimen.
It is against the backdrop of these two prior clinical trials
that the significance of this report can be best appreciated, for
these trials indicate that oral melphalan, despite its variable
bioavailability, is part of a modestly useful treatment regimen and that clinical responses to this oral regimen vary
with the type of organ involvement in AL amyloidosis.
Although patients with AL amyloidosis usually have minimal burdens of neoplastic plasma cells and limited prior
exposure to chemotherapy, they have been excluded from
clinical trials of dose-intensive chemotherapy because of
treatment-related deaths during autologous marrow transplantation attributed to cardiac
The preliminary results we report herein show that the exclusion of
patients with AL amyloidosis from such trials may not be
warranted; however, the risks should not be minimized, and,
therefore, the application of this new therapy must be in the
context of appropriately designed clinical trials at centers
with extensive experience in the evaluation and treatment of
patients with this rare disease and expertise in stem cell
transplantation.
Eligible patients with AL amyloidosis tolerated stem cell
mobilization, leukapheresis, dose-intensive IV melphalan,
and its short-term hematologic and gastrointestinal toxicities,
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
2805
HIGH-DOSE MELPHALAN FOR AL AMYLOIDOSIS
with minimal morbidity, despite prior evidence of amyloid
cardiac disease. In this regard, clinical trials using doseintensive chemotherapy with mobilized blood stem cells for
patients with AL amyloidosis should be designed so that the
toxicities of the stem cell mobilization regimen do not prevent patients from being treated with dose-intensive melphalan. Our results support the advisability of using growth
factor mobilization of stem cells and of dispensing with
cyclophosphamide-based mobilization regimens, and their
potential infectious and myocardial side effects.
In view of prior clinical trials, it is notable that three
of five patients experienced durable complete remissions of
plasma cell dyscrasias and that all patients experienced improved organ function in the predominant organs of involvement. It is particularly notable that two patients with painful
polyneuropathy experienced remissions of neuropathic
symptoms after treatment, for the polyneuropathy associated
with amyloidosis has been recalcitrant to alternative treatment approaches.2’,22Indeed, a treatment-associated improvement in sensory and motor function has never been
reported previously in patients with this disease. The rapid
reversal of neuropathic signs and symptoms that we observed
questions the commonly held belief that infiltration and compression of vascular and neural elements by amyloid depositions underlie its pathophysiology. Rather, remission of polyneuropathy with a reduction of amyloidogenic plasma cells
supports the conclusion that a readily reversible metabolic
derangement associated with Ig aggregation into amyloid
fibrils may be the pathophysiological mechanism that underlies the polyneuropathy in this disease.
Although allogeneic transplantation in select patients with
AL amyloidosis may be
the organ compromise of
patients with AL,amyloidosis may increase the risk of this
approach. However, allogeneic BM would be free of contaminating clonal cells whereas mobilized autologous blood stem
cell preparations may contain clonal plasma cell
Ex vivo treatment of autologous stem cell preparations to remove contaminating neoplastic cells may prove important for
maximizing efficacy of this treatment approach.2sHence, ex
vivo purging procedures, combined with polymerase chain
reaction assays for molecular markers of clonal cells, may be
useful in the development of future clinical trial^.^^.^'
In conclusion, AL amyloidosis, often a rapidly lethal
plasma cell dyscrasia, is amenable to treatment with doseintensive IV melphalan, followed by growth-factor-mobilized blood stem cell support for hematopoietic rescue,
Remissions of both the plasma cell dyscrasia and clinical
symptoms and signs of amyloidosis occur with this treatment
approach; furthermore, objective amelioration of amyloidrelated organ dysfunction may occur despite persistence of
the plasma cell dyscrasia. The durability of the clinical remissions achieved by this treatment approach remains to be
determined, as does the impact of this approach on resorption
of amyloid deposits and patient survival. Nevertheless, our
results indicate that this therapy can be conducted safely
in patients with AL amyloidosis and that dramatic clinical
improvements can be achieved.
ACKNOWLEDGMENT
We are grateful for the efforts of Rebecca Brown, Rita Galvin,
and the oncology nurses in the F3 Hematology-Oncology Clinic
(Boston, MA) and on Atrium 7 East; and for those of Kate Murphy
and the apheresis staff in the BUMCH Blood Bank (Boston, MA).
We also thank Ceit McCaleb, Sharon Olsen, Virginia Banis, and
Charles Breen for patient coordination.
REFERENCES
1. Isobe T, Osserman E F Patterns of amyloidosis and their association with plasma-cell dyscrasia, monoclonal immunoglobulins
and Bence-Jones proteins. N Engl J Med 290:473, 1974
2. Glenner GG: Amyloid deposits and amyloidosis: The betafibrilloses. N Engl J Med 302:1283, 1980
3. Skinner M, Benson MD, Cohen AS: Amyloid fibril protein
related to immunoglobulin light chains. J Immunol 114:1433, 1975
4. Buxbaum J: Mechanisms of disease: Monoclonal immunoglobulin deposition. Hematol Oncol Clin North Am 6:323, 1992
5. Kyle RA, Greipp PR: Amyloidosis (AL): Clinical and laboratory features in 229 cases. Mayo Clin h o c 58:665, 1983
6. Kyle RA, Greipp PR, Garton JP, Gertz MA: Primary systemic
amyloidosis: Comparison of melphaladprednisone versus colchicine. Am J Med 79:708, 1985
7. Kyle RA: “Benign” monoclonal gammopathy-After 20 to
35 years of follow-up. Mayo Clin Proc 63:26, 1993
8. McElwain TJ, Powles RL: High-dose intravenous melphalan
for plasma-cell leukemia and myeloma. Lancet 12322, 1983
9. Barlogie B, Hall R, Zander A, Dicke A, Alexanian R: Highdose melphalan with autologous bone marrow transplantation for
multiple myeloma. Blood 67: 1298, 1986
10. Barlogie B, Alexanian R, Dicke KA, Zagars G, Spitzer G,
Jagganath S, Horwitz L: High-dose chemotherapy and autologous
bone marrow transplantation for resistant multiple myeloma. Blood
70:869, 1987
11. Jagganath S, Barlogie B, Dicke K, Alexanian R, Zagars G,
Cheson B, Lemaistre FC, Smallwood L, m i t t K, Dixon DO: Autologous bone marrow transplantation in multiple myeloma: Identification of prognostic factors. Blood 76:1860, 1990
12. Jagganath S, Vesole DH, Barlogie B, Tricot G: Peripheral
blood stem cell transplantation in multiple myeloma. Ann HematoV
Oncol 2:53, 1994
13. Comenzo RL, Berkman EM: Hematopoietic stem and progenitor cells from blood: Emerging uses for new components for transfusion. Transfusion 35:335, 1995
14. Skinner M, Anderson JJ, Simms R, Falk R, Wang M, Libbey
CA, Jones LA, Cohen AS: Treatment of 100 patients with primary
amyloidosis: A randomized trial of melphalan, prednisone, and colchicine versus colchicine only. Am J Med 100:290, 1996
15. Cohen AS, Skinner M: The diagnosis of amyloidosis, in Cohen AS (ed): Laboratory Diagnostic Procedures in the Rheumatic
Diseases (ed 3). Orlando, FL, Grune and Stratton, 1985, p 377
16. Comenzo RL, Vosburgh E, Weintraub LW, Tansan S, Arkin
CF, Wright DG: Mobilized peripheral blood stem and progenitor
cells for hematopoietic rescue collected by large-volume leukapheresis. Transfusion 35:493, 1995
17. Investigator’s Handbook: A Manual for Participants in Clinical Trials of Investigational Agents Sponsored by the Division of
Cancer Treatment, National Cancer Institute, Revised Edition. Washington, DC, Government Printing Office, 1993 (NIH publication no.
93-2770)
18. Mehta J, Nagler A, Slavin S: Marrow transplantation in multiple myeloma (letter). N Engl J Med 326:1087, 1992
19. Gharton G: Marrow transplantation in multiple myeloma (letter). N Engl J Med 326:1087, 1992
20. Barlogie B: Marrow transplantation in multiple myeloma (letter). N Engl J Med 326:1088, 1992
21. KeIly JJ, Kyle RA, O’Brien PC,Dyck PJ: The natural history
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
2806
of peripheral neuropathy in primary systemic amyloidosis. Ann New
rol 6:1, 1979
22. Dustin MA, Skinner M, Anderson J, Cohen AS: Peripheral
neuropathy as an early marker of AL amyloidosis. Arch Intern Med
149:358, 1989
23. Gahrton G , Tura S, Ljungman P, Belanger C, Brandt L, Cavo
M, Facon T, Granena A, Gore M, Gratwohl A, Lowenberg B, Nikoskelainen J, Reiffers JJ, Samson D, Verdonck L, Volin L: Allogeneic bone marrow transplantation in multiple myeloma. N Engl J
Med 325:1267, 1991
24. van Buren M, Hene RJ, Verdonck LF, Verzijlbergen FJ, Lokhorst HM: Clinical remission after syngeneic bone marrow transplantation in a patient with AL amyloidosis. Ann Intern Med
122508, 1995
2.5. Brugger W, Bross KJ, Glatt M, Weber F, Mertelsman R,
Kanz L: Mobilization of tumor cells and hematopoietic progenitor
cells into peripheral blood of patients with solid tumors. Blood
83:636, 1994
26. Ross AA, Cooper BW, Lazarus HM, Mackay W, Moss TJ,
Ciobanu N, Tallman MS, Kennedy MJ, Davidson NE, Sweet D,
Winter C, Akard L, Jansen J, Copelan E, Meagher RC, Herzig RH,
Klump TR, Kahn DG, Warner NE: Detection and viability of tumor
cells in peripheral blood stem cell collections from breast cancer
COMENZO ET AL
patients using immunocytochemical and clonogenic assay techniques. Blood 82:2605, 1993
27. Moss TJ, Ross AA: The risk of tumor cell contamination
in peripheral blood stem cell collections. J Hematotherapy 1 :22.5.
I992
28. Gazitt Y, Reading CC, Hoffman R, Wickrema A, Vesole DH,
Jagganath S, Condino J, Lee B, Barlogie B, Tricot G : Purified
CD34+ Lin-Thy+ stem cells do not contain clonal myeloma cells.
Blood 86:381, 199.5
29. Gribben JG, Freedman AS, Neuberg D, Roy DC, Blake KW.
Woo SD, Grossbard ML, Rabinowe SN, Coral F, Freeman GJ, Ritz
J, Nadler LM: lmmunologic purging of marrow assessed by PCR
before autologous bone marrow transplantation for B-cell
lymphoma. N Engl J Med 325:1525, 1991
30. Negrin RS, Pesando J: Detection of tumor cells in purged
bone marrow and peripheral-blood mononuclear cells by polymerase
chain reaction amplification of hcl-2 translocations. J Clin Oncol
12:1021, 1994
3 I . Schiller G, Vescio R, Freytes C, Spitzer G, Sahebi F, Lee M,
Wu CH, Cao J, Lee JC, Hong CH, Lichtenstein A, Lill M, Hall J ,
Berenson R, Berenson J: Transplantation of CD34+ peripheral blood
progenitor cells after high-dose chemotherapy for patients with advanced multiple myeloma. Blood 86:390, 1995
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
1996 88: 2801-2806
Dose-intensive melphalan with blood stem cell support for the
treatment of AL amyloidosis: one-year follow-up in five patients
RL Comenzo, E Vosburgh, RW Simms, P Bergethon, D Sarnacki, K Finn, S Dubrey, DV Faller, DG
Wright, RH Falk and M Skinner
Updated information and services can be found at:
http://www.bloodjournal.org/content/88/7/2801.full.html
Articles on similar topics can be found in the following Blood collections
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American
Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.