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Extended interval between enzyme therapy infusions for adult patients with Gaucher's disease type 1. J Perez-Calvo1, P Giraldo2, GM Pastores2, M Fernandez-Galan1, G Martin-Nunez1, M Pocovi11 Department of Internal Medicine, Hospital Clinico Universitario 'Lozano Blesa', Zaragoza, Spain. , Spain 2 Department of Internal Medicine, Hospital Clinico Universitario "Lozano Blesa", Zaragoza, Spain. , Spain
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 12867687
BACKGROUND: Enzyme replacement therapy (ERT) for Gaucher's disease with alglucerase or imiglucerase is efficacious, well-tolerated and safe. However, cost considerations, visits to medical facilities, potentially duration of theray for life, are issues of major concern to a proportion of treated patients and has, in some cases, led to the withdrawal of therapy. AIMS: To elucidate whether an extension of the interval between enzyme infusions to once every three weeks is as effective in maintaining the clinical responses achieved with the bi-monthly regimen. MATERIALS AND METHODS: Four patients with an optimal response to ERT (at 30 units/kg every two weeks for an average of 27 months), were subjected to enzyme dose/frequency changes that essentially constituted a reduction in cumulative dose over the treatment period. Patients were assessed every 6 months for alterations in haematological parameters, plasma chitotriosidase levels, liver and spleen size, and bone symptoms. RESULTS: All patients had to resume the previous infusion schedule of once every two weeks; one because of new bone marrow infiltrates, two because of visceral enlargement, and the fourth due to progressive anaemia. CONCLUSIONS: This limited experience suggests that a reduction in enzyme dose associated with an extended interval between infusions may lead to variable disease control, and underscores the need for individualization of enzyme therapy.
Over a decade ago the first two reports were published on the treatment of Gaucher’s disease (GD) patients through intravenous supplementation of the deficient enzyme, acid ?-glucocerebrosidase (OMIM *606463).[1],[2] Since then, it has been clearly shown that enzyme replacement therapy (ERT), with either the placental-derived alglucerase (Ceredase®), or the recombinant formulation imiglucerase (Cerezyme®), is an efficacious, well-tolerated and safe treatment modality. However, there are several important issues associated with the current treatment regimen that pose difficulties in administering ERT to all patients. The cost of the drug is much higher than that of most drugs currently used in other clinical situations. In addition, repetitive injections necessitate patients to attend medical facilities periodically, thereby limiting their independence, and in some cases, their life-style. In a recent report, the costs and the required commitment to regular, frequent intravenous infusions were cited as the two main reasons behind the withdrawal of ERT.[3] A less frequent administration of the enzyme, i.e. one infusion every 3 or 4 weeks, as suggested by Brady in 1994,[4] has the potential benefit of simultaneously reducing the cost and improving quality of life. However, to date no studies on the efficacy of such a schedule have been reported. In the present report, we discuss the results of the follow-up of a group of four adult GD patients treated with a conventional ERT schedule (once every 2 weeks), followed by a less frequent regimen, consisting of one infusion every 3 weeks.
The clinical characteristics of the patients, all diagnosed with type 1 GD, are presented in [Table - 1]. The dosage of 30 U/kg every two weeks is the most commonly used regimen in Spain, given the demonstrated efficacy and lower associated costs.[5] The study patients had been on ERT with alglucerase (Ceredase ? Genzyme Therapeutics, Cambridge, MA, USA) at a dose of 30 units/kg every two weeks for an average of 27 (range 18-42) months, and a significant positive clinical and haematological response had been achieved in all of them. In two cases (patients 1 and 2) the dose of alglucerase administered per infusion was unchanged; however, the infusion interval was increased to once every three weeks. In the other 2 patients (patient, 3 and 4), treatment continued to be administered once every two weeks with a reduction in the dose of alglucerase to 15 U/kg/2 weeks and 20 U/kg/2 weeks, respectively. In both patients, at 30 and 36 months respectively, the administration interval was then increased to one infusion every 3 weeks with no changes in the previous amount of alglucerase given per infusion [Table - 2]. Thus, all patients essentially had reductions in their cumulative enzyme dose during the latter course of treatment. All patients underwent physical examination, routine blood tests, measurement of plasma chitotriosidase level and abdominal ultrasonography every 6 months. Other specific tests (i.e. MRI) were performed as needed.
The data on clinical, analytical and major parameters that were monitored for each patient under the different dosage schedules are shown in [tables:2] to [Table - 4]. After a variable period of time, all patients receiving every-3-week infusions had to resume the former every-2-weeks regimen since some sign/s of deterioration had developed [Table - 2]. Patient 1: After 18 months of receiving 30 U/kg every 3 weeks her liver regained its initial (pre-treatment) size. Her infusions were then switched back to 30 U/kg every 2 weeks with no further complaints. Patient 2: After 18 months of receiving 30 U/kg every 3 weeks, an increase in spleen size to values similar to those at baseline prompted us to resume the previous regimen of 30 U/kg every 2 weeks. This treatment schedule has been maintained for an additional 4-year period without any further signs of disease progression. Patient 3: This female patient started enzyme infusions at a dose of 30 U/kg of alglucerase every 2 weeks. After the first year of therapy, alglucerase was tapered, at 6 months interval, to a minimum of 15 U/kg every 2 weeks. This schedule was maintained for 30 months. Thereafter, she was given 15 U/kg every 3 weeks for 24 months. No liver or spleen enlargement was detected and her haematological parameters remained stable throughout this period. However, at the end of the second year on an every 3-weekly infusion regimen she complained of mild arthralgia localised in the right knee and both ankles without any signs of inflammation. An MRI of the spine showed a subtle increase in the degree of marrow infiltration within the body of the 4th and 5th lumbar vertebrae, without any changes in the long bones. Her enzyme infusions were increased to 15 U/kg every 2 weeks followed by relief of symptoms. A year later, the MRI was repeated and showed that marrow infiltration of the vertebral bodies had cleared. She has been maintained on this regimen for about 3 and half years without any new findings. Patient 4: This female patient started ERT with 30 U/kg of alglucerase every 2 weeks, and was maintained on this regimen for 3 years. Subsequently, her dose of alglucerase was reduced to 20 U/kg every 2 weeks for one year, followed by a change in infusion frequency to 20 U/kg every 3 weeks. Finally, after 24 months of the extended infusion regimen, a bi-monthly schedule was again implemented due to progressive anaemia.
A decade after the introduction of ERT in GD, it is possible to state that this modality of treatment is efficacious, safe and well tolerated.[6],[7] However, there are certain issues that remain to be resolved. Whatever regimen is used to start therapy - whether high-dose low-frequency or low-dose high-frequency - the minimum effective dose after an initial response is obtained tends to be about 30 U/kg per month.[8],[9] This still represents a significant financial burden. A low-dose high-frequency regimen was proposed as an attempt to mitigate the financial burden of ERT without loss of efficacy,[10] but this leads to greater interference in the patients’ life-styles, which can be so inconvenient that some patients actually prefer to give up therapy. Furthermore, there is heterogeneity in clinical response to therapy and a low-dose regimen may not be adequate to control or reverse disease symptoms.[11],[12] The fact is that, whether due to financial concerns or to a variety of personal reasons, withdrawal of ERT is a relatively common issue for some patient groups.[3] Currently, there are no guidelines for the long-term treatment of patients with GD after they have responded to and have been on ERT for several years. The usual practice is to reduce the total amount of the drug but keeping the dose interval and the rate of infusions ongoing indefinitely. Brady suggested in 1994 that it was conceivable that less frequent injections of the enzyme, i.e. once every 3 to 4 weeks, may be efficacious in patients who had been “normalized” after the initiation of treatment.[4] This is an attractive approach since it would reduce the financial burden and lifestyle adjustments associated with the current treatment regimen. Although the recommended changes appear reasonable and the fact that one splenectomized adult patient has been stabilized on single monthly injections,[13] this treatment schedule has not been introduced to a larger cohort of patients, and no further data relating to this issue have been reported. In this report, we have explored the efficacy of extending the interval between infusions of alglucerase in GD patients, and have considered either a reduction of the amount of the enzyme given and then subsequently increasing the interval of administration, or alternatively extending the infusion interval without any changes in the amount of alglucerase given per infusion. All of the patients in our study had a protective N370S allele and started treatment after full skeletal growth had been achieved. These patients had previously responded to the conventional ERT schedule and were subsequently kept on an every three weeks infusion regimen for as long as 27 months. Follow up evaluation revealed that all four patients had developed findings suggestive of an active disease process. Two patients had significant visceral enlargement, one developed progressive anaemia and another, presented with abrupt skeletal complications and new vertebral marrow infiltrates that prompted us to return to the often-used schedule of infusions every 2 weeks. Elstein and colleagues reported the clinical course of 15 patients with interruption of therapy after an initial positive response. Although they found no major clinical complications over a variable length of follow-up monitoring, 6 of the patients required the re-institution of treatment because of a clinical relapse.[3] In addition, other authors have found that cessation of ERT is usually followed by the recurrence of GD-related symptoms that requires reinstitution of ERT.[14],[15] The heterogeneity in clinical responses suggests that some especially sensitive (i.e., highly responsive) patients may achieve a sustained response on less frequent infusion schedules. However, it is possible that the amount of enzyme administered after delaying the infusion for an extra week is too low to reach the therapeutic threshold[9] necessary to elicit a long-term response. On the other hand, the lack of efficacy could also be explained by the delay of treatment administration irrespective of dose. As a consequence, in our experience, increasing dose interval appears to lack the effectiveness of the commonly used regimen (i.e., an infusion once every two weeks). It is possible that disease control may be effectively maintained during less frequent infusion intervals if the administered dose is increased. However, this issue has not been examined systematically and maintenance on a high dose would not address concerns regarding treatment costs. Larger, prospective controlled studies are still needed to draw broadly applicable guidelines for the optimal management of patients with Gaucher’s disease.
This study was supported by a grant from Fondo de Investigaciones Sanitarias Ministerio de Sanidad y Consumo (FIS n0 00/0546) and by the “Fundación Española para el Estudio y Terapéutica de la Enfermedad de Gaucher” (FEETEG).
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5]
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