Clinical monitoring after cessation of enzyme replacement therapy in M. Gaucher.

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In a recent paper, Elstein et al (2000) described the course of haematological parameters and liver/spleen volume as assessed by ultrasound in 15 Gaucher patients after cessation of enzyme replacement therapy (ERT). The authors concluded that patients can be withdrawn from therapy for circumscribed periods of time, i.e. several years. We would like to emphasize that more suitable parameters for therapeutic monitoring exist in Gaucher's disease, i.e. plasma chitotriosidase, magnetic resonance imaging (MRI) and the blood levels of serum ferritin, acid phosphatase and angiotensin-converting enzyme (ACE). These parameters allow a more precise clinical judgement of an impending exacerbation of the disease than blood cell counts and ultrasound alone. In a representative German patient population admitted for ERT between 1991 and 2000 (n = 69, mean age at initiation of therapy 46 years, men:women 37:32), only two patients, both non-splenectomized, completely discontinued therapy. One 23-year-old female patient had been on enzyme replacement therapy for 34 months with 40 IU of alglucerase (Ceredase®, Genzyme, Cambridge, MA, USA) per kg body weight (b.w.) every other week, and she discontinued therapy because of an excessive weight gain of > 20 kg since the advent of ERT. Her 15-year-old brother had 8 months of therapy with alglucerase (20 U/kg b.w. every other week) and discontinued therapy for personal reasons. Both patients were reviewed 24 months after discontinuation of ERT. At this time, the female patient complained of bone pain in both knees. Within this time period, the laboratory parameters of the female patient showed a decline of haemoglobin (Hb) and platelets, and a more pronounced increase of serum ACE, ferritin and acid phosphatase levels (Fig 1). The most sensitive blood parameter was plasma chitotriosidase (Hollak et al, 1994; Hollak & Aerts, 1997), which had increased more than threefold. MRI showed a deterioration of bone marrow findings in the female patient (Fig 2). Her brother's Hb decreased from 13·7 to 12·6 g/dl and the platelet levels dropped from 255 to 145 × 109/l. Serum acid phosphatase, ACE and serum ferritin increased from 4·5 to 8·3 U/l, from 89 to 154 U/l and from 54 to 163 μg/l respectively. Plasma chitotriosidase increased from 3373 to 11448 nmol/ml/h. MRI of this patient did not reveal Gaucher-associated bone marrow changes. In both patients, a reinstallation of ERT was recommended. Blood parameters in a 25-year-old female Gaucher patient who discontinued therapy for 24 months because of excessive weight gain. ACE, acid phosphatase and ferritin were determined from serum and chitotriosidase from blood plasma. MRI findings in the same Gaucher patient before (A) and after (B) a 24-month period of discontinuation of enzyme replacement therapy with alglucerase. T1-weighted images in coronal plane showed a typical bone manifestation of Gaucher's disease with an abnormal low signal intensity of both proximal and distal femora, whereas the femoral diaphyses appeared normal (A, white arrows). On follow-up, 2 years after cessation of therapy (B), the femoral diaphyses appeared with a decreased signal intensity (white arrows), indicating a deterioration of the disease. Bone infiltration is found in 70% of Gaucher patients (Rosenthal et al, 1995) and MRI can be used to pick up a deterioration of bone findings. Serum ACE, acid phosphatase and ferritin levels change much earlier and are more sensitive than other blood parameters such as Hb and platelet count (Niederau et al, 1994). Further, our findings show that plasma chitotriosidase can be used to detect early relapses of Gaucher's disease after cessation of ERT. Activation of macrophages is reflected by increased plasma chitotriosidase levels (Hollak & Aerts, 1997). Anaemia, thrombocytopenia and bone disease represent the manifest damage induced by macrophage activation. Gaucher-associated bone disease is reversible only to a limited extent. Clinical monitoring of the Gaucher patient by determination of plasma chitotriosidase and other ‘lysosome-related’ activity parameters must therefore be performed to detect an impending exacerbation of the disease. In our opinion, the purpose of ERT is to avoid irreversible organ damage by decreasing macrophage activation. There is little doubt that, after induction therapy with relatively high doses of the enzyme, stable chitotriosidase levels can be maintained with lower doses of the enzyme, but a complete cessation of therapy will inevitably endanger the patient. Currently, there is no alternative to continuous ERT in the symptomatic Gaucher patient.