1. Healthcare

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Home Treatment With Intravenous Enzyme Replacement Therapy for Gaucher
Disease: An International Collaborative Study of 33 Patients
By A. Zimran, C.E.M. Hollak, A. Abrahamov, M.H.J. van Oers, M. Kelly, and E. Beutler
Intravenous enzyme replacement therapy (Alglucerase;
Ceredase; Genzyme Corp, Boston, MA) is an effective and
safe treatment for patients with type 1 Gaucher disease. In
an attempt to reduce its high cost, a ”low-dose high-frequency” protocol (30 U/kg/mo, 3 times a week) was introduced and found to be as effective as the original high-dose
protocol (60 U/kg every 2 weeks). Because receiving frequent infusions creates a burden for many patients, we
have implemented a program of home treatment for our
patients. W e now report the safety and feasibility of lowdose/high-frequency home intravenous enzyme-replacement therapy in 33 patients with Gaucher disease. The
chronic nature of the treatment, its safety, lack of adverse
effects, the stable condition of most patients, and the need
to reduce the high cost make enzyme replacement for
Gaucher disease a good candidate for intravenous home
therapy.
0 1993 by The American Society of Hematology.
I
Instructions and performance of home treatment. Instructions
for the safe and sterile administration of the drug were given to all
NTRAVENOUS ENZYME replacement therapy (Alglucerase; Ceredase; Genzyme Corp, Boston, MA) has
been introduced recently as an effective treatment for patients with type l Gaucher disease.‘ It has been shown to
produce reversal of symptoms and signs of the disorder.’-’
The treatment has been found to be generally safe, and there
are no contraindications to its administration. However,
this treatment is enormously expensive and, therefore, cannot be available for many patients with Gaucher disease. In
an attempt to reduce its cost while maintaining full therapeutic effectiveness,one of us (EB) has proposed the administration of a lower dose of the enzyme at a higher frequency.*,’ The experience of the investigators from three
medical centers, using this low-dose/high-frequency protocol has been very g~-atifying.~,’,~
However, this altered treatment protocol creates a burden for some patients who need
to come to the hospital 3 times a week with additional costs
associated with each visit. In an attempt to reduce the
disruption of the quality of life of our patients and to further
reduce the cost ofthe administration of enzyme therapy, we
have conducted a program of home treatment for our patients. We now report the feasibility, safety, and advantages
of low-dose/high-frequency home intravenous enzyme-replacement therapy in 33 patients with Gaucher disease.
PATIENTS AND METHODS
Patients studied: Diagnosis and indications for treatment. All
study patients had been diagnosed by at least two of the three diagnostic methods: histologic demonstration of typical Gaucher cells
in a bone marrow specimen,low leukocyte acid @-glucosidase
activity, and molecular diagnosis of a defined genotype associated with
Gaucher disease.
All patients suffered from symptomatic disease and had at least
one of the following indications for enzyme therapy: moderate to
massive organomegaly,symptomatic cytopenia, moderate to severe
bone involvement and pulmonary involvement. A severity score
index was assigned to each patient based on age at diagnosis and
extent of organ involvement, as described previously.’
Treatment protocols. All patients received the low-dose/highfrequency protocol that usually consisted of 30 U/kg body weight
per month, divided into equal doses given 3 times a week. Three
patients received the 30 U/kg divided into daily equal doses for 6
months (2 patients) and 3 months; 4 patients received 50 U/kg/
month (3 times a week); and 4 other patients received a “very lowdose protocol” of 15 U/kg/month (3 times a week). All patients
received the first infusions in the hospital before starting home
treatment. Venous access devices (mainly Port-a-cath; Pharmacia,
St Paul, MN) were surgically implanted into 24 of our patients; 9
patients received the infusion through a peripheral vein.
BOCI~,
VOI 82,NO4 (August 15).1993:pp 1107-1 109
patients during the initial in-hospital therapy. After this period,
they were usually able to perform an infusion either into a peripheral vein or into the Port-a-cath system by themselves or with the
help of another person. Although most of the Dutch patients were
trained to perform the insertion ofthe needles by themselves, many
of the Israeli and American patients received help from either a
family member or a visiting nurse (Table 1). Most of the patients
received Ceredase vials containing 50 U of the enzyme (10 U/mL).
In other cases, when 50 U vials were not available, strict guidelines
for the preservation of undiluted enzyme (in the standard 400 U/
mL vials) were given. The appropriate quantity of the enzyme was
diluted aseptically in 100 mL of saline (0.9%),followed by administration by gravity or infusion-pumps either immediately or within 1
week. The enzyme, diluted in 100 mL of physiologic saline for
administration, was stable for several weeks (Fig 1).
RESULTS
Our patient population included 17 women and 16 men,
ranging in age from 4 to 53 years old, with a mean age of
29.5. Their mean seventy score index was 15.7 (range, 5 to
30), indicating moderate-to-severe phenotypic expression
of the disease. They received a total of approximately 4,500
infusions during a period that ranged between 13 and 82
weeks per patient.
Side effects. One patient complained of some abdominal discomfort after Ceredase infusion. Another patient reported 2 episodes of a visual disturbance occuring during
From the Gaucher Clinic, Shaare-Zedek Medical Center, Jerusalem Israel; the Department of Internal Medicine and Hematology,
Academic Medical Center, Amsterdam, The Netherlands; and the
Department of Molecular and Experimental Medicine, Scripps
Clinic and Research Foundation. La Jolla, CA.
Submitted February 1, 1993; accepted April 13. 1993.
Supported by the Helen Manuel Foundation (A.Z.), by National
Institutes of Health Grants No. DK36639 and RR00833, and the
Sam Stein and Rose Stein Charitable Trust Fund (E.B.). This is
manuscript 7474-MEMfom the Scripps Research Institute.
Address reprint requests to E. Beutler, MD, Department ofMolecular and Experimental Medicine, The Scripps Research Institute,
10666 N Torrey Pines Rd, La Jolla, CA 92037.
The publication costs of this article were defayed 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 1993 by The American Society of Hematology.
0006-4971/93/8204-0032$3.00/0
1107
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ZIMRAN ET AL
1108
Table 1. Person Performing the Infusion
Person Performing Infusion
No. of Infusions
Patient
Parent
Brother/Sister
Son/Daughter
Spouse
Nurse
19
8
1
1
2
4
In 3 patients the infusions were performed by more than one person.
early infusions in the course of his treatment. These were
diagnosed by an opthalmologist as “ocular migraine.” Subsequent infusions were not associated with any symptoms.
There were no reports of side effects among any of the other
patients during home therapy.
Complications. There have been no serious complications associated with either the insertion of the needles or
with the infusions ofthe enzyme itself. Phlebitis of a peripheral vein without systemic symptoms occurred in a single
case. In another case, infection of a central line required a
brief hospitalization and was resolved by intravenous antibiotics without the need to remove the line. Replacement of
the Port-a-cath device was performed in a single case, because initially it had been placed on a painful spot on the
chest. In another case, repositioning of the Port-a-cath line
into the subclavian vein was required shortly after the implantation.
Patient satisfaction. Patient satisfaction was not specifically addressed in this study. However, because all the patients received the treatment at home by choice, the patients, in general, reported satisfaction with the home
treatment and preferred it to frequent visits to the hospital.
There were no reports of fears or anxiety associated with the
fact that the treatment was administered at home.
Therapeutic responses. Every patient experienced a satisfactory response to treatment as judged by changes in
blood counts and of organomegaly, measured either by ultrasound scanning or by quantitative magnetic resonance
imaging. Indeed, as had been reported previously, the results of low-doselhigh-frequency therapy were indistinguishable from the much more costly low-frequencylhigh-dose
therapy usually recommended by Genzyme Corp and by
some investigators. Details of the responses of the patients
treated are presented elsewhere. lo,
Costs. When the treatment is performed in a hospital,
the approximate costs of hospital visits three times a week in
Israel, the United States, and the Netherlands are, in United
States dollars, $1,700, $4,810, and $2,750, respectively, per
month. The costs of home treatment plus a monthly visit to
the hospital for follow-up are estimated to be $240, $500,
and $320, respectively, representing approximately a 90%
reduction in the costs (excluding the cost of the enzyme).
antibiotics, y-globulin, chemotherapy, blood, parenteral
nutrition, heparin, and factor VIII.’*-I9Although these
treatments are associated with some risk of complications,
they were still found suitable for home therapy. Among the
major advantages of home therapy are the ability to maintain a near-normal lifestyle, including work or school attendance, in a comfortable and private environment; the patient’s choice of the most convenient time for therapy; and
cost-effectiveness. With a proper selection of patients, basic
education, and periodic monitoring and with the advent of
various access devices that provide an easy way to insert a
needle, intravenous home treatment has become feasible for
very sick patients who otherwise would be hospitalized for
long periods of time. Although originally used mainly by
adults, recent reports have shown the applicability of this
approach to children.”
Low-dose enzyme-replacement therapy for Gaucher disease seems to be an ideal candidate for intravenous home
therapy. The treatment, administered over a long period of
time with high frequency, is very safe and practically free of
significant complications. Most of the patients are clinically
stable and, therefore, do not require frequent examinations
by a physician. In some of the patients, especially children,
contact with other patients with various hematologic and
malignant disorders may create additional fears. The lowering of the cost of the treatment is particularly important,
because alglucerase is presently one of the most expensive
drugs in the world.
Because, safety is a major consideration, after a single
report of a putative anaphylactic reaction in a patient
treated by the high-dose protocol in hospital (G. Pastore,
Mount Sinai Medical Center, New York, NY, personal com-
a
60 --
9’
DISCUSSION
Increasing numbers of patients suffering from different
major diseases are receiving intravenous therapy at home.
These home treatments include hemodialysis, intravenous
20
40
60
80
Days of Storage
Fig 1. The stability of Alglucerase diluted to a concentration of
approximately 1 U/mL in preservative-free isotonic sodium chloride
solution for infusion into a patient with Gaucher disease. The residual enzyme from the IV tubing was stored at 4°C and assayed for
acid @-glucosidaseactivity using 4-methyl umbelliferyl @-glucoside
as substrate accordingto the method of Raghaven et aL9 Even after
60 days of storage, over 70%of the enzyme activity was still present.
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CEREDASE HOME THERAPY
munication), we reviewed the course of our population of
6 1 Gaucher patients treated with Ceredase (both in the hospital and at home) and found 1 patient with a single minor
episode of hives and pruritus that did not reoccur during
later infusions. Combining the minimal adverse effects with
the large number of infusions (-9,000 to date), we suggest
that the safety profile of low-dose Ceredase compares very
favorably with that of other medications that are administered at home. The absence of severe infectious complications is also remarkable in this population of Gaucher
patients, which includes some who are relatively immunocompromised because of splenectomy or defective neutrophil function.’’ Thus, we find that home intravenous enzyme-replacement therapy for Gaucher disease is safe,
feasible, and well accepted by the patients and their families.
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From www.bloodjournal.org by guest on February 6, 2015. For personal use only.
1993 82: 1107-1109
Home treatment with intravenous enzyme replacement therapy for
Gaucher disease: an international collaborative study of 33 patients
A Zimran, CE Hollak, A Abrahamov, MH van Oers, M Kelly and E Beutler
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