Haematologica 2003 - Supplements

of B and its metabolites, however, was low. Only 20 and 5 % of
the administered B dose were recovered in urine in patients of
Group 1 and 2. B and its metabolites are dialysed in the same
quantities as renally eliminated in non-dialysed patients with endstage
renal disease. By means of anova, no differences were
found between the two patient-groups in plasma kinetics of B and
its metabolites. The toxicities that occurred were salivary gland
dysfunction causing dry mouth and taste disturbances, nausea and
vomiting, moderate myelotoxicity of CTC grade 2/3 leuko-and
thrombocytopenia and worsening of pre-existing
lymphocytopenia. These toxicities are well known and
manageable. With the exception of a higher frequency of
Table 1. Plasma chitotriosidase after frequent plasmapheresis with HES* Not available
Patient
(m/f)
Age Total
HES
(l)
HES
(l/month)
Creatinine
clearance
(ml/min)
Plasma
chitotriosidase
(nmol/h/ml)
Bone
marrow
biopsy
1 (f) 43 130 6.5 61 6130 Foam
cells
2 (m) 54 18 3.6 88 422 n.a.*
3 (m) 68 16 3.2 73 307 Foam
cells
4 (f) 54 14 4.7 84 242 Foam
cells
5 (m) 23 42.5 2.2 120 206 n.a.*
6 (m) 51 33.1 4.1 112 200 n.a.*
7 (f) 54 31.5 1.4 70 165 n.a.*
8 (m) 75 10 10 119 93 Foam
cells
9 (m) 31 67.5 1.6 187 78 n.a.*
10 (m) 66 25.5 1.1 85 60 Foam
cells
11 (m) 34 31.5 4.5 116 59 n.a.*
moderate leuko- and thrombocytopenia in patients with renal
insufficiency, no difference in toxicity was observed between the
two patient groups. Toxic effects of B on liver and kidney
function were not observed.
No dose reductions will be necessary in patients with normal liver
function and end-stage renal disease, including dialysisdependent
patients, thus B can be applied at 120 mg/m² iv over
30 minutes on days 1 and 2 at 4-weekly intervals. This may be an
advantage over melphalan.
395
FREQUENT PLASMAPHERESIS WITH
HYDROXYETHYL-STARCH (HES) IN MONOCLONAL
GAMMOPATHY RESULTS IN TISSUE INFILTRATION
WITH ACTIVATED FOAMY MACROPHAGES
J.J.A. Auwerda1, J.H.P. Wilson2, O.P. van Diggelen3, P.
Zondervan4, P. Sonneveld1
Departments of Hematology1, Internal Medicine2, Clinical
Genetics3 and Pathology4 Erasmus Medical Centre, Dr
Molewaterplein 40, PO-Box 2040, 3015 GD, Rotterdam, the
Netherlands.
Hydroxy-ethyl starch (HES, Fresenius) is a chemically modified
cornstarch. Because of the reported advantages of synthetic
plasma expanders, it has been suggested that HES-products might
emerge as a standard replacement fluid in plasmapheresis. The
kinetics of HES elimination depend on enzymatic degradation (αglucosidases/α-amylases)
in blood, tissues, and the
reticuloendothelial system, followed by urinary excretion.
However, tissue and lysosomal storage in macrophages can
occur. In Gaucher disease, similar foamy macrophages excrete
chitotriosidase (CT) and the level of plasma CT reflects the extent
of tissue infiltration. We have investigated the clinical
applicability of plasma CT concentration as a parameter of tissue
accumulation of HES in patients undergoing chronic
plasmapheresis for monoclonal gammopathy or other reasons.
Eleven patients receiving frequent plasmapheresis with HES were
identified. The cumulative HES dose and renal function
(creatinine clearance) were calculated and plasma CT was
determined (table 1). When available, bone marrow aspirates
were reviewed.
All patients with impaired renal function, who were exposed to a
high dose (liters/month) exhibited an increase in plasma CT
(normal range 4-195 nmol/h/ml). Foamy macrophages were
observed in all available bone marrow biopsies regardless of the
plasma CT. One patient (no-1) even developed a severe acquired
lysosomal storage disease causing malnutrition and weight loss,
myelofibrosis, polyneuropathy, organomegaly and ascitis due to
massive tissue infiltration with foamy macrophages. In this
patient, plasma CT increased after a cumulative dose of 20 liters
and reached the range of Gaucher disease at a cumulative dose of
85 litres. Conventional plasma expanders which had been used
prior to HES exposition had not altered the normal plasma CT
concentration in this patient. After cessation of HES,
plasmapheresis with conventional expanders did not result in a
decrease in plasma CT. This was confirmed by bone marrow
biopsies performed a year later, which still revealed massive
foamy macrophage infiltration. Based on these results we
conclude that in patients with impaired renal function, frequent
plasmapheresis with HES results in tissue infiltration with
activated, CT secreting foamy macrophages. We believe that the
level of plasma CT can be used to monitor tissue storage of HES.
Furthermore, excessive administration of HES will result in a
severe acquired lysosomal storage disease.
396
APOMINE, a Novel Inhibitor of the
Mevalonate/isoprenoid Pathway, Promotes Apoptosis
of Myeloma Cells In Vitro and Is Associated with a
Modulation of Myeloma Disease In Vivo
Claire M. Shipman (1), Gabrielle Mueller (1), Karin
Vanderkerken (2), Mark Perry (3), Sandy Cordiner-Lawrie
(1), Graham Russell (1), Ben Van Camp (2), Eric Niesor
(4), Craig Bentzen (4), Peter I. Croucher (1)
(1) Nuffield Dept. of Orthopaedic Surgery, University of Oxford,
UK(2) Hematology and Immunology, Free University Brussels,
Belgium(3) Medicine, Univeristy of Bristol, Bristol, UK(4) ILEX
Oncology, Geneva, Switzerland
The process of isoprenylation plays an important role in
regulating the function of proteins that are critical in the growth
and survival of myeloma cells. Inhibiting the pathways
responsible for this process therefore represents a novel approach
to controlling the growth of myeloma cells. APOMINE, a novel
1,1 bisphosphonate ester, increases the rate of degradation of
HMGCoA reductase, thereby inhibiting the mevalonate pathway
and preventing protein prenylation. The aim of the present study
was to determine whether APOMINE could induce apoptosis in
myeloma cells, influence osteoclast formation and bone
resorption in vitro and modulate the myeloma disease in vivo.
Treatment of the human myeloma cell lines NCI H929, RPMI
8226 and JJN-3 with 2-20µM APOMINE induced a dosedependent
increase in apoptosis, as identified by characteristic
changes in nuclear morphology and by an in situ nick translation
assay (p < 0.001). APOMINE had no effect on the accumulation
of cells in the S phase of the cell cycle; which we have previously
seen with bisphosphonic acids. To investigate the effect of
APOMINE in vivo, 5T2MM murine myeloma cells were injected
intravenously into C57BL/KaLwRij mice. After 8 weeks all
animals injected with tumour cells had detectable serum
paraprotein and were treated with APOMINE in the diet
(200mg/kg) (n=10), or vehicle (n=10) for a further 4 weeks when
all animals were sacrificed. All animals injected with tumour
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