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Stamford
Novartis Pharmaceuticals UK Ltd, Camberley, UK
Correspondence: Dr L. R. Dunk, Histopathology Department, Leicester Royal Infirmary, Infirmary Square, Leicester LE1 5WW, UK. E-mail: louisa.dunk{at}btinternet.com
Declaration of interest L.D. has undertaken consultancy for Novartis UK and Novartis Australia and received a fee from Novartis Australia for the preparation of this paper; she was formerly employed by Novartis UK.L.A. and C.A. are employed by Novartis UK.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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Aims To investigate the results of such a rechallenge in 53 patients.
Method An analysis was made of the demographic, haematological and outcome data of patients in the UK and Ireland who were rechallenged with clozapine following leucopenia or neutropenia during previous clozapine therapy.
Results Of 53 patients who were rechallenged, 20 (38%) experienced a further blood dyscrasia. In 17 of these 20 patients (85%) the second blood dyscrasia was more severe (P<0.001), in 12 (60%) it lasted longer (P=0.0368) and in 17 (85%) it occurred more quickly on rechallenge (P<0.001). Of the original 53 patients, 55% (29 patients) are still receiving clozapine.
Conclusions No clear risk factor for repeat blood dyscrasias was identified. Despite this, after risks and benefits have been considered, rechallenge may well be justified in some patients.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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METHOD |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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Study method
Patients in the UK and Ireland who, between 1998 (when a formal rechallenge
process was instituted) and 2003, were rechallenged with clozapine following
leucopenia or neutropenia during previous clozapine therapy were identified
from the CPMS database. Patients were required to have had a break of at least
1 week between their two courses of treatment in order to be classified as
rechallenge patients. Information on demographic factors (age, gender and
ethnic origin), clozapine treatment and haematolgical history and outcome of
these patients was gathered from the CPMS database. Clinical information,
particularly information concerning any other possible causes for the blood
dyscrasias, was obtained from clinician correspondence and notes made at the
time by the CPMS following discussions with healthcare teams.
Statistical analysis
In the analysis of our results we considered the following three main
groups of patients:
We further considered the group that experienced agranulocytosis on rechallenge.
Statistical analysis was carried out using SAS version 8.2 for Windows (SAS Institute Inc., Cary, North Carolina, USA). Comparisons were made between patients who experienced a second dyscrasia v. those who did not, using the Wilcoxon two-sample test or chi-squared test (categorical variables). Within-subject comparisons for characteristics of first and second dyscrasias were made using the Wilcoxon signed ranks test. Time to occurrence of dyscrasia was analysed using the Kaplan–Meier product-limit method with between-group differences tested using the log-rank test. All reported P values are two-sided.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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Patients experiencing a further blood dyscrasia
Of the 53 patients, 20 (5 women, 15 men) (38%) experienced a further blood
dyscrasia on rechallenge. The median age of these patients was 36 years (range
25–60) and the ethnicity of the group was 17 (85%) White, 2 (10%)
African—Caribbean and 1 (5%) ‘Asian’.
Table 1 summarises the data
available for the original blood dyscrasia for the three main groups: all 53
patients, the 20 patients who developed a blood dyscrasia on rechallenge and
the 33 patients who did not. There was no statistically significant difference
between those who developed dyscrasia on rechallenge and those who did not in
duration of clozapine treatment at the time of the original blood dyscrasia
(P=0.50), number of patients in whom no alternative explanation for
the original blood dyscrasia was recorded (P=0.054) or duration of
clozapine treatment break (P=0.93).
Nine (45%) of the second blood dyscrasias were neutropenias, 2 (10%) were leucopenias and 9 (45%) were agranulocytoses. Data on these second blood dyscrasias are presented in Table 3. The median time for the blood dyscrasias to develop from the time of restarting clozapine was 5.5 weeks and in 80% (n=16) of the 20 patients the second blood dyscrasia occurred within 10 weeks of restarting clozapine (Fig. 1). Sixteen (80%) patients had no alternative explanation for this second blood dyscrasia. Two (10%) reported a concurrent infection, 1 (5%) was receiving a concomitant medication recognised to cause neutropenia and 1 (5%) had both these risk factors (Table 4). Five patients received G-CSF as treatment for the second blood dyscrasia. In all of the 20 patients the blood dyscrasia remitted when they again stopped taking clozapine; there was no fatality. None of the 20 patients subsequently restarted clozapine.
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Comparison of first and second blood dyscrasias
In all but 3 of the 20 patients (85%) the second blood dyscrasia occurred
more quickly than the first, and overall the time to the second blood
dyscrasia was much less than the time to the first (median time 5.5 weeks for
the second dyscrasia compared with 81.5 weeks for the first dyscrasia in these
20 patients; P<0.001). This is strikingly illustrated by the
Kaplan–Meier plot in Fig.
2. Again in all but 3 (85%) – but in different patients
– the second blood dyscrasia was more severe than the first (nadir
neutrophil count lower than during the first blood dyscrasia;
P<0.001), and in all but 8 (60%) the second blood dyscrasia lasted
longer than the first (one of the patients whose second blood dyscrasia was
shorter was treated with G-CSF); P=0.0368. Figures
3,
4,
5 compare the time to onset,
severity and duration of the first and second blood dyscrasias in the 20
patients who experienced a blood dyscrasia on rechallenge. The patients
identified by the numbers 1–9 are those who developed agranulocytosis on
rechallenge.
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Table 6 provides the data available for the repeat-exposure blood dyscrasia for the same nine patients. The median age is still 38 years (range 29–60). The speed of onset (all dyscrasias occurred 4–6 weeks after rechallenge), duration (in all but one case the dyscrasia lasted more than 3 days) and severity of the blood dyscrasias are notable. The median dosage at the time of the second blood dyscrasia was 300 mg per day (range 0–700); for 2 patients dosage was not recorded.
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Patient rechallenged after agranulocytosis during first treatment
The patient who had an agranulocytosis on first exposure did not develop a
blood dyscrasia on second exposure during the period of data collection.
However, he developed neutropenia, which resolved when clozapine
administration was stopped, after the cut-off point for data collection, 4
weeks after he restarted clozapine. At the time of this second blood dyscrasia
the patient had a cough, a shadow on chest X-ray, and was prescribed
antibiotics.
Patients who did not develop a blood dyscrasia on rechallenge
Thirty-three patients (62%) (11 women, 22 men) did not develop a second
blood dyscrasia during rechallenge with clozapine. The median age of these
patients was 33 years (range 20–61), and the ethnicity of this group was
24 (73%) White, 5 (15%) African–Caribbean, 2 (6%) ‘Asian’, 1
(3%) ‘Oriental’ and 1 (3%) mixed ethnicity. The median daily
dosage of clozapine at the study cut-off point or at the time the patient
discontinued clozapine was 400 mg (range 200–800); in 3 patients dosage
was not recorded. Twenty-nine (88%) of these 33 patients were still receiving
clozapine at the time of writing. The median duration of the second exposure
in these 29 patients was 24 months (range 1–58);
Fig. 6. Of the four patients no
longer receiving clozapine, two died: the first 2.5 months after restarting
clozapine, from chronic obstructive airways disease and ischaemic heart
disease due to coronary artery atheroma; the second 6.5 months after
restarting clozapine, from acute pulmonary oedema, bilateral pleural effusions
and ascites, presumed toxic effect of pneumococcal pneumonia,
glomerulosclerosis or pseudomembranous colitis. One patient discontinued
clozapine owing to the occurrence of chest pain 29 months after restarting,
and the fourth patient stopped clozapine 1 month after restarting in view of
an overdue blood test. Thus, of the original 53 patients, more than half (55%;
n=29) were still receiving clozapine in February 2005.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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Clozapine-induced agranulocytosis
Agranulocytosis associated with clozapine is an idiosyncratic (type B)
reaction and is not dose-related, as previous analysis of the CPMS cohort has
shown (Munro et al,
1999). The toxicity mainly affects the myeloid (neutrophil)
precursor cells, although the mature neutrophil may also be affected
simultaneously (Pirmohamed & Park,
1997). Seventy per cent of cases occur 6–18 weeks after the
start of treatment (Munro et al,
1999). Although the risk of agranulocytosis decreases with time,
some cases are reported after a number of years of continued therapy. The
mechanism of clozapine-induced agranulocytosis is not known but some evidence
favours an immune-mediated mechanism that may involve a toxic metabolite
(Pirmohamed & Park, 1997).
The disorder is reversible in the vast majority of cases if clozapine is
withdrawn promptly. Supportive care, such as reverse isolation and treatment
with G-CSF or granulocyte–macrophage colony-stimulating factor (GM-CSF),
antibiotics and antifungals as appropriate, may be required. The CPMS data
indicate an increased risk of agranulocytosis with increasing age and Asian
ethnicity (Munro et al,
1999). Additionally, some authors have suggested an increased risk
in women (Alvir & Lieberman,
1994), although this was not seen in the UK CPMS cohort, and in
people of Ashkenazi Jewish descent with the haplotype HLA-B38, DR4, DQw3
(Lieberman et al,
1990). Concomitant treatment with other drugs reported to cause
leucopenia may also increase the risk of agranulocytosis
(Idänpään-Heikkilä
et al, 1977; Povlsen
et al, 1985;
Lindström, 1988;
Gerson et al, 1991; Gerson & Meltzer, 1992;
Junghan et al, 1993;
Valevski et al, 1993;
Chengappa et al, 1996;
Sénéchal et al,
2002), as perhaps does a history of drug-induced blood dyscrasias
(Idänpään-Heikkilä
et al, 1977; Valevski
et al, 1993).
Previous rechallenge experience
We identified 12 published reports (37 patients) providing information on
outcome in patients rechallenged with clozapine after previous leucopenias,
neutropenias or agranulocytoses during clozapine treatment
(Idänpään-Heikkilä
et al, 1977; Povlsen
et al, 1985;
Lindström, 1988;
Grohmann et al, 1989;
Safferman et al,
1992,
1993;
Frankenberg et al,
1994; Barrons et al,
1996; Chengappa et al,
1996; Sperner-Unterweger
et al, 1998;
Sénéchal et al,
2002; Ahn et al,
2004). Five reports (14 patients) described unsuccessful clozapine
rechallenge. We are defining successful rechallenge as re-exposure that does
not result in leucopenia, neutropenia or agranulocytosis or re-exposure where
the patient is maintained on clozapine and ultimately has a normal white cell
and neutrophil count. Five of the eight reports of successful rechallenge were
of unconventional procedures: one described a clozapine overdose after
clozapine discontinuation, and in four clozapine was not discontinued despite
low white cell or neutrophil counts. All 12 reports are summarised in
Table 7.
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Two types of clozapine-induced neutropenia?
It has been postulated that clozapine can induce two clinically distinct
types of neutropenia (Gerson,
1993,
1994); the first type is a mild
to moderate neutropenia (neutrophil count below 1.5 x 109/l
but not lower than 0.5 x 109/l), which occurs in 1.8% of
treated patients. When clozapine is discontinued, recovery is rapid (2–8
days). The second type of neutropenia is more severe with a neutrophil count
below 0.5 x 109/l (agranulocytosis) and an incidence of
0.78%. In the second type, even if clozapine is stopped when the neutrophil
count is just below 1.5 x 109/l, agranulocytosis none the
less develops in some patients, usually within 2–5 days and generally
lasting for 14–21 days. In such patients, monitoring allows the early
detection and treatment but not the prevention of neutrophil suppression. Bone
marrow from these patients demonstrates an absence of myeloid precursors, only
occasional promyelocytes and myeloblasts, and relative erythroid hyperplasia
(Gerson & Meltzer, 1992).
In contrast, in the milder clozapine-induced neutropenia, it has been reported
that there is evidence of myeloid maturation in the bone marrow, suggesting
peripheral destruction of neutrophils
(Gerson, 1993). The theory is
compatible with the fact that, despite a considerable decrease in the
incidence of fatal clozapine-induced agranulocytosis since the onset of white
cell count monitoring – from 0.26% in Finland in 1975
(Idänpään-Heikkilä
et al, 1977) to 0.01% in the UK and Ireland with
monitoring – the incidence of agranulocytosis has remained fairly
constant and has not decreased: a cautious estimate of 0.5% in Finland in 1975
(Idänpään-Heikkilä
et al, 1977; as there was no routine monitoring some
cases are likely to have missed identification), 0.78% in the UK and Ireland
with monitoring. However, it does not seem compatible with the results we have
presented, as one would not expect patients who had experienced only
neutropenia or leucopenia on first exposure to clozapine to develop
agranulocytosis on second exposure, unless they had somehow become more
sensitive to clozapine bone-marrow toxicity. It also implies that patients who
develop only neutropenia or leucopenia on first exposure to clozapine can be
relatively safely rechallenged, and our results demonstrate that this is not
the case, with nine patients who experienced a neutropenia on first exposure
developing agranulocytosis on repeat exposure.
Mechanism of clozapine-induced agranulocytosis
The exact mechanism of clozapine-induced agranulocytosis is unknown; it
could be immune-mediated or involve a toxic mechanism, or even a combination
of both. In the group of nine patients unsuccessfully rechallenged with
clozapine by Safferman et al
(1992), blood dyscrasias
recurred after a number of weeks, with an average time to onset of 14.6 weeks.
These authors concluded that their data favoured an immune-mediated mechanism,
because the blood dyscrasias recurred in all nine patients and did so more
quickly on repeat exposure. The single case report by Frankenberg et
al (1994) also documents a
more rapid blood dyscrasia on rechallenge. Our findings differ from those of
Safferman et al
(1992) as blood dyscrasias
recurred in only 38% of the 53 patients rechallenged in our study, and we
found that the median time to onset of the rechallenge dyscrasia was 5.5
weeks, with 80% of cases, including all the cases of agranulocytosis,
occurring before 10 weeks. However, we did find that when blood dyscrasias
occurred on rechallenge they tended to happen more quickly, last longer and be
more severe. Our results, therefore, also suggest an immune-mediated
mechanism, but as the blood dyscrasias occurred weeks rather than days after
rechallenge, a simple immunological toxicity cannot be the mechanism. It might
be that a certain concentration of metabolite needs to accumulate in order to
stimulate an immunologically mediated toxicity. Whatever the mechanism, it is
clear that extreme caution is required when rechallenging a patient with
clozapine.
Implications of our findings
The results we have described represent the first published report of a
well-documented cohort of patients who have been rechallenged with a good
degree of success. This is due in part to the careful selection of patients on
the basis that their initial blood dyscrasia might well have had a cause other
than clozapine and/or that they had experienced a ‘mild’ episode.
Despite this, 38% (n=20) of our patients did experience a second
blood dyscrasia and 45% (n=9) of these patients developed
agranulocytosis, which represents a 22-fold increase in risk of
agranulocytosis in our rechallenge group compared with clozapine-naïve
patients (in clozapine-naïve patients, 2.8% of patients would be expected
to develop a blood dyscrasia, of whom 28% would be expected to develop
agranulocytosis). Furthermore, in the majority of our unsuccessfully
rechallenged patients, the second blood dyscrasia occurred more rapidly,
lasted longer and/or was more severe than the first blood dyscrasia. Our data
demonstrate that even patients in whom the indications are that clozapine was
not causative in their blood dyscrasia (e.g. patients who develop blood
dyscrasias after lengthy treatment) can experience agranulocytosis on
rechallenge. Our results demonstrate how difficult it is to identify with any
certainty patients whose blood dyscrasias are unrelated to clozapine, and the
need for extreme vigilance when rechallenging any patient. However, we also
demonstrated that patients who do not develop a blood dyscrasia on rechallenge
are likely to continue with clozapine treatment: indeed, the majority of all
the rechallenged patients continued clozapine treatment, many for a number of
years. Therefore, in a carefully selected group rechallenge may well be
justified if it is considered that the risks of withholding treatment are
greater than the risks of rechallenge.
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Clinical Implications and Limitations |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMETHODRESULTSDISCUSSIONClinical Implications and...ACKNOWLEDGMENTSREFERENCES |
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Sperner-Unterweger, B., Czeipek, I., Gaggl, S., et al
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Received for publication October 19, 2004. Revision received February 8, 2005. Accepted for publication February 12, 2005.
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) and second (----) blood
dyscrasias (n=20).
) and second (
)
blood dyscrasias (n=20).
