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Indian Pediatr 2011;48:
779-784 |
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Recombinant Macrophage
Targeted Enzyme Replacement Therapy for Gaucher Disease in India |
*A Nagral, *P Mewawalla, #S Jagadeesh,
†M Kabra, $SR Phadke,
#IC Verma, #RD Puri,
#N Gupta, ##PS Kishnani And **PK
Mistry
From *Department of Gastroenterology, Jaslok Hospital and
Research Centre, Mumbai, India; #Department of Genetics, Mediscan systems,
Chennai, India; †Division of Clinical Genetics, Department of Pediatrics,
All India Institute of Medical Sciences, New Delhi, India; $Department of
Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical
sciences, Lucknow, India;#Centre for Genetic Medicine, Sir Ganga Ram
Hospital, New Delhi, India; ##Division of Medical Genetics, Duke
University Medical Center, Durham, USA; and **Section of Pediatric
Hepatology and Liver Transplantation; Yale University School of Medicine,
New Haven, USA.
Correspondence to: Dr. Aabha Nagral, 7, Snehasagar,
Prabhanagar, Prabhadevi, Mumbai 400 025, India.
Email: [email protected]
Received: August 25, 2009;
Initial review: September 18, 2009;
Accepted: March 29, 2010.
E Pub ahead of Print: PII: S097475590900598-1
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Objective: Gaucher disease in India has been reported only in a few
case reports from India. The aim of the study was to assess the response
to enzyme replacement therapy in Indian patients with Gaucher disease.
Design: Retrospective analysis of patients
receiving CHO-derived recombinant macrophage-targetted glucocorebrosidase.
Setting: Five centers from India with experience in
treating lysosomal storage disorders.
Patients: The diagnosis of Gaucher disease was
confirmed by low glucocerebrosidase levels, though it was first made on
splenectomy in 8 and on bone marrow examination in 9 patients. Twenty five
of 52 patients diagnosed with Gaucher disease (17 Type I, 8 mild Type III)
received treatment for >6 months. Indications for treatment included
symptomatic anemia, thrombo-cytopenia, organomegaly, bone disease or mild
neurological symptoms leading to impairment of quality of life. Patients
with significant neurological involvement were excluded. The drug
infusions were given intravenously every 15 days.
Main Outcome measures: Hemoglobin, platelet counts,
liver and spleen volumes and growth parameters.
Results: 22 of the 25 children who survived were
analyzed. After 6 months of treatment, the mean (range) increase in
hemoglobin was 1.5 (-3.4 to 6.1) g/dL (P=0.01) and in platelet
count was 32 x 109/L (-98.5 x 109 to 145.5 x109) /L (P=0.02). The
mean (range) increase in weight was 3 kg (-5.6 to 10.5) (P=0.04)
and in height was 7.1 cm (0 to 26.5) (P=0.0003). Liver size
decreased by a mean (range) of 38.5% (- 5.5 to 86.7) (P=0.0003) and
the spleen size by 34.8% (0 to 91.7) (P=0.004). All patients had
improvement in bone pains and in 2 patients, neurological symptoms
improved with others remaining static.
Conclusions: This is the first reported cohort of
patients in India reporting our experience with imiglucerase enzyme
replacement therapy for treatment of Gaucher Disease in India.
Key words: Children, Gaucher disease, Imiglucerase, India,
Lysosomal storage disorder, Treatment.
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G aucher disease (GD) is the most prevalent lysosomal
storage disorder and has served as a prototype for genetic/phenotypic
delineation as well as therapeutic innovation. The metabolic defect is an
inherited deficiency of lysosomal acid β-glucosidase
due to mutations in the GBA1 gene [1]. The result is an accumulation of glucocerebroside in the lysosomes of macrophages and a complex
multisystemic phenotype involving the liver, spleen, bone marrow, skeleton
and the lungs. Gaucher disease is classified into three broad phenotypic
categories depending on the absence or presence of neurological
involvement; although overall it represents a continuum of disease
spectrum [2-5].
Gaucher disease is pan-ethnic but type 1 GD is most
prevalent in Ashkenazi Jews [2]. An increased incidence of neuronopathic
Gaucher disease has been reported from other countries [6,7] but the
frequency and phenotypic spectrum of Gaucher disease in India is currently
unknown. There have been isolated case reports of GD in India [8-11].
Recently, we have been able to treat patients in India with Gaucher
disease with recombinant macrophage-targeted enzyme replacement therapy (ERT)
through the Humanitarian Program of Genzyme Corporation. We herein report
our experience of 25 patients with GD in India. This is also the first
description of the phenotypic spectrum of GD in India.
Methods
Fifty-two patients were diagnosed with GD over a period
of 10 years at the recruiting centers across India. Examination of
patients included a general systemic examination with neurological
evaluation including an ophthalmologic examination. Forty-three of the 52
patients were evaluated for enzyme replacement therapy (ERT). Nine
patients had mild, stable disease that did not require immediate ERT. The
indications for enzyme replacement therapy were symptomatic anemia (i.e.,
requiring blood transfusion), symptomatic thrombocytopenia (mainly
manifesting as epistaxis and easy bruisability), organomegaly or
symptomatic bone disease and/or failure to thrive and/or significant
impairement of quality of life. Patients with significant neurological
involvement were excluded.
The enzyme replacement therapy consisted of CHO-derived
recombinant macrophage-targeted glococerebrosidase (Imiglucerase, Cerezyme,
Genzyme Coroporation). Freeze-dried recombinant enzyme was diluted in 0.9%
NaC1 to a total volume of 100 mL and infused through a blood transfusion
filter over 1 to 2 hours. An initial test dose of 5 mL was given.
Initially, patients received enzyme dose of 60U/kg every 15 days.
Subsequently, the dose was adjusted based on response to therapy.
The candidacy of patients to receive ERT was evaluated
by the IMAB (Indian Medical Advisory Board) that included six expert
physicians from centers across India, international experts on the
disease, and representatives of Genzyme corporation. Enzyme therapy was
initiated after informed consent was obtained. Before initiating enzyme
therapy, patients had physical examination, laboratory studies including
complete blood count, and a liver profile. Radiological studies included
ultrasonography or CT scan of the abdomen to determine liver and spleen
volumes, and long bone surveys to study bone deformities and densities.
Patients who were enrolled in the previous one-year, also underwent chest
X-ray and 2D echo to rule out lung parenchymal involvement and
pulmonary hypertension, respectively. Patients were monitored every 6
months for their height, weight, hemoglobin, platelet count, liver and
spleen sizes, and subjective assessment of bone pains, neurological
symptoms and quality of life.
The hemoglobin, platelet, height and weight changes
were analyzed using the paired student t test. The spleen and liver
volumes were calculated in terms of percentage changes and their means
were analyzed using the paired student t test.
Results
Of the 22 patients currently receiving ERT for > 6
months, 16 exhibited Type I and six had Type III Gaucher disease. There
were 15 males and 7 females, median age was 3.6 years (range, 1.6 to 26
years). The diagnosis of GD was first suspected on pathology of
splenectomy specimens in 8 patients, in 9 patients on bone marrow
examination showing typical Gaucher cells and in the remaining 5 patients,
by direct determination of acid glucosidase activity in peripheral blood
leucocytes. All patients underwent confirmation of diagnosis by demons-tration
of low glucosidase activity in peripheral blood leucocytes. The mean
enzyme level was 10% (0-75%) of the lower limit of the normal range. There
was history of consanguinity in parents of 11 patients (50%).
Of the 43 patients deemed suitable for ERT, 25 patients
received treatment for ≥6
months. Three of these 25 patients died within mean period of 22 months
(range 15 to 36 months) of start of ERT in spite of receiving therapy and
have been described separately.
Response to treatment was analyzed retrospectively from
the data available of patients who were treated for more than or equal to
6 months. All patients had severe splenomegaly and/or hepatomegaly, as
well as variable degrees of anemia and thrombocytopenia. Six patients
(27%) had mild neurological involvement consistent with Type III Gaucher
disease.
Hematological responses: Anemia was noted in all
patients at the initiation of treatment (100%). The mean (range) baseline
hemoglobin was 8.4 (3.8 to 11.2) g/dL. 11 patients had received blood
transfusions prior to the start of treatment.
Thrombocytopenia was noted in 18 out of 22 patients at
the initiation of treatment (82%) and the mean (range) baseline platelets
were 116×109 (50-400×10 9)/L.
The platelet levels of 11 patients completely normalized during the course
of treatment. In 8 patients treated for more than a year, for an average
of 2.5 years (1.5-10 years), the mean (range) increase in hemoglobin was
3.75 g/dL (P=0.005) and the mean (range) increase in platelets was
183×109/L (P=0.0007).
The mean change in hemoglobin and platelets is shown in the Table
I.
TABLE I Change in Hemoglobin and Platelets with Enzyme Therapy
|
Hemoglobin (g/dL) |
Platelets (102/L) |
|
mean (range) |
mean (range) |
6 months post ERT |
1.5 (3.4, 6.1) |
32 (-98.5, 145.5) |
(n=22) |
(P=0.01) |
(P=0.02) |
1 year post ERT |
2.2 (-0.6, 6.4) |
133 (-22, 313) |
(n=8) |
(P=0.002) |
(P=0.003) |
*ERT- Enzyme replacement therapy. |
Weight and height changes: Two patients reported a
loss of weight. The changes in weight and height are shown in the
Table II.
TABLE II Change in Weight and Height with Enzyme Therapy
|
Weight (kgs) |
Height (cm) |
|
Mean (range) |
Mean (range) |
6 months post ERT |
3 (-5.6 to 10.5) |
7.1 (0 to 26.5) |
(n=22) |
(P=0.04) |
(P=0.0003) |
1 year post ERT |
5.3 (-4.4 to 23.5) |
8 (1 to 32.5) |
(n=8) |
(P=0.02) |
(P=0.0004) |
*ERT- Enzyme
replacement therapy. |
In 8 patients who were treated for more than a year,
for a mean of 2.5 years (1.5-10 years), the mean (range) increase in
weight was 12.9 kg (-4.4 to 23.5) (P=0.006), and the mean (range) increase
in height was 34.1 (1-67) cm (P=0.0003).
Liver size decreased over a mean period of 2.5 years
(range 6 months to 10 years) by 38.48% (-5.47 to 86.67) (P=0.0003)
in comparison to the baseline. Spleen size in the non-splenectomised
patients showed a mean (range) decrease of 34.75% (0 to 91.67) (P=0.004).
Bone manifestations: Ten patients showed Erlenmeyer
flask deformity of the femur. 9 had osteopenia and one had osteoporosis.
One patient also developed avascular necrosis of the femur head and
underwent osteotomy for abduction deformity. There was a subjective
improvement in bone pains in all those who received ERT.
Neurological manifestations: Neurological
manifestations were seen in 6 patients (Type III GD). There was
ophthalmoplegia in 5 patients, occulomotor apraxia in 1 patient,
retroflexion of the neck in 1 patient and difficulty in swallowing in 1
patient. The patients with neck retroflexion and swallowing difficulty
showed improvement and the other neurological symptoms remained static and
did not progress further. None of the patients had mental retardation or
any history of seizures.
Mortality
Three patients (not included in the 22 analyzed
patients) succumbed to the illness despite ERT. The first patient with
type 1 GD, had presented with growth retardation and recurrent epistaxis
since 3 years of age. At 9 years of age GD was diagnosed and splenectomy
was performed. A year later, he had a variceal bleed, which was treated
endoscopically. He was also diagnosed to have hepato-pulmonary syndrome
with clubbing and cyanosis, which was proven on a Tc 99m macroaggregated
albumin scan. He was started on ERT. During the treatment over one and a
half years, he showed remarkable improvement with his hemoglobin
increasing from 8.8g/dL, his platelet counts increased from 34×109/L
to 230×10 9/L and serum albumin
increased from 1.4 g/dL to 3.5 g/dL. His height increased by 10 cm and
weight by 5 kg. After one and half years of being on treatment, he
succumbed to respiratory distress after developing pneumonia. This was as
unusual as patients with good response on ERT do well in the long term.
The second patient had type III GD and had presented
with anemia and abdominal distension due to massive hepatosplenomegaly.
She was dependent on blood transfusions for severe anemia. Her hemoglobin
was 4.7 g/dL and platelets of 80,000/cmm. She was initially diagnosed as
Type 1 GD. She received ERT for a period of 3 years. During the course of
her treatment, her hemoglobin increased to 9.5 g/dL, platelets increased
to 430×10 9/L. Her height
increased by 10 cm and weight by 1.96 kg. Three months prior to her death,
her hemoglobin fell to 5 g/dL and the hepatosplenomegaly increased.
Ultrasonography of the abdomen revealed enlarged abdominal lymph nodes and
she was also found to have a lateral gaze palsy (when the diagnosis was
revised to Type III GD). She died due to respiratory distress associated
with bronchospasm, after 3 years of treatment. This patient is similar to
the one described by Burrrow, et al. [12], who developed
progressive mesenteric and mediastinal lymphadenopathy over 12 months,
despite enzyme replacement therapy.
The third patient was enrolled at the age of 6 years
with failure to thrive, abdominal distension secondary to severe
hepatosplenomegaly, epistaxis and bone pains. His hemoglobin was 8.6 g/dL
and platelets of 137×10 9/L.
His parameters did not improve and after a period of 1 and half years on
ERT, he developed acute respiratory infection and breathlessness and died.
Adverse effects: One patient developed fever and
breathlessness after the first enzyme infusion, but did not have the any
further adverse effects when the infusions were given at a slower rate.
None of the patients were administered any pre-medications.
Discussion
Gaucher disease is believed to be extremely rare in
India; however, its prevalence is not known. It is very likely that the
prevalence is severely underestimated in part due to lack of access to
diagnostic testing as well as a lack of awareness. In the majority of our
patients (17/22), the diagnosis was not initially suspected but only made
after either splenectomy or bone marrow biopsy. Unfortunately, very few
centers in India have the facility to perform leukocyte acid glucosidase
assay. Prior to the large series reported herein, there have been isolated
case reports of GD from India [8-11] with only one patient receiving
enzyme replacement therapy [8]. With the availability of leukocyte acid
glucosidase testing and increasing awareness of the disease, we are
beginning to diagnose Gaucher disease with an increasing frequency. Fifty
percent of our patients had history of consanguinity. Also, the
availability of enzyme therapy through the India Charitable Access Program
of Genzyme Corporation, USA should stimulate clinicians to consider GD in
the differential diagnosis in order not to miss this treatable lysosomal
storage disorder.
This article presents the largest experience of enzyme
replacement therapy in Gaucher disease in India. We document clinical
response in terms of improvements in height, weight, hemoglobin,
platelets, spleen and liver volumes. There was excellent response in all
disease domains, including improvement of hematological parameters,
reversal of organomegaly and improvement of growth parameters. Several
patients were blood transfusion dependent and with ERT, they did not
require further transfusions. One patient with advanced liver disease
associated with hepatopulmonary syndrome showed a poor response and
eventually succumbed. This underscores the importance of early diagnosis
before irreversible complications of Gaucher disease occur.
Before the introduction of enzyme therapy [13],
treatment for Gaucher disease was supportive, with splenectomy, blood
transfusions, analgesics and orthopedic surgeries for bone pain. In
selected patients, cure was possible with bone marrow transplantation, but
the risk of the transplantation are high [14,15]. Enzyme replacement
therapy has transformed the management of Gaucher disease. Lifelong
therapy is recommended unless alternative therapies like gene therapy
become available in the future.
Side effects related to Imiglucerase injection
administration have been reported in less than 15% of patients. Reported
side effects include nausea, vomiting, abdominal pain, diarrhea, rash,
fatigue, headache, fever, dizziness, chills, backache, and rapid heart
rate. At the site of injection, discomfort, itching, burning swelling or
uninfected abscess can occur. Approximately 15% of patients have developed
antibodies though all patients tolerate treatment [17]. Antibody levels
were not monitored in our patients. One of our patients had side effects,
during the first injection, which did not recur again. It could also have
been a pyrogenic reaction.
Andersson, et al. [18], in a large series of 884
patients, documented normalization of hemoglobin, height and weight over a
period of 8 years and significant improvement in the first 2 years. The
liver and spleen volumes also reduced significantly within the first 2
years. Though we do not have comparative long term data, our medium term
follow up of 1 year in the Indian patients revealed that the hemoglobin
increased by 2.2g/dL, 50% of patients achieved normal platelet counts and
the liver and spleen volumes decreased by about 1/3rd the original volumes
over a mean period of 2.5 years.
This article should help improve awareness of GD when a
patient presents with organomegaly and/or cytopenia and/or bone pain. This
cohort of GD patients reported excellent outcomes of imiglucerase enzyme
replacement therapy.
Acknowledgments: We thank Tomye Tierney and the
Humanitarian Program of Genzyme Corporation, USA for providing
Imiglucerase to treat our patients. We are grateful for advice from Drs
Ashok Vellodi, Atul Mehta and Richard Moscicki in the Expert Committee. Dr
Pramod K Mistry is supported by NIH NIDDK K24DK066306 mid-career clinical
investigator grant. Dr Priya S Kishnani is a member of the North American
Gaucher Registry Advisory Board.
Contributors: AN contributed to conceptualization
and design of the study with interpretation of data and revising and
approving the final draft of the manuscript; PM analyzed and interpreted
the data with approval of the manuscript; SJ, MK, SP, ICV, RDP, NG
contributed to the data with approval of the manuscript; PSK and PKM
contributed to the drafting of the manuscript and revising it critically
for important intellectual content.
Funding: None.
Competing interests: Dr Pramod K Mistry and Dr
Priya S Kishnani have received research grants from Genzyme Corporation.
What is Already Known?
• Gaucher disease is treatable with enzyme
replacement therapy but diagnosis and treatment was not possible
or affordable for most patients with the disease in India.
What this Study Adds?
• Imiglucerase enzyme replacement therapy showed satisfactory
outcomes in majority of the treated children.
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