Blood, 1 October 2002, Vol. 100, No. 7, pp. 2672-2672
CORRESPONDENCE
To the editor:
Rituximab-induced tumor cell agglutination
The article by Kunzmann and colleagues1
brings attention to a potential complication of rituximab
therapy, known as rituximab-induced tumor cell agglutination
(RITCA), in patients with a high number of circulating
lymphoma/leukemia cells. Although it is not clear whether the figures
included in the report represent leukostasis secondary to high
leukocyte count or true tumor cell agglutination (TCA), it is,
nevertheless, an important observation and should alert clinicians who
are undertaking such treatment of this potential untoward effect of
rituximab therapy.
Severe infusion-related toxicities during treatment with
rituximab have been reported in patients with a high number of
circulating tumor cells and this complication has hitherto been
attributed to cytokine release. It is conceivable that, at least in
some cases as pointed out by Kunzmann and colleagues, the above
phenomenon (ie, TCA) may either induce or contribute to the
pathogenesis of various infusion-related toxicities. One of the
important sequelae of this syndrome is peripheral circulatory failure.
The management of such a hemodynamic disturbance routinely includes
administration of intravenous fluids, either crystalloids (eg, normal
saline) or various colloidal preparations such as gelofusin. Although these preparations are effective in restoring peripheral circulation and blood pressure, their effect on the coexisting pathologic process
(ie, TCA) is not known.
I would like to present some observations made during rituximab
therapy in 2 patients with high circulating tumor (leukemic) cell
counts (120 × 109/L and 256 × 109/L).
Both patients were given prerituximab hydration therapy with normal
saline followed by the drug at standard dose (375 mg/m2).
Both patients experienced mild to moderate hypotension following the
first dose of rituximab, but blood pressure was promptly restored by
further administration of intravenous fluids (normal saline). Blood
samples from these 2 patients were collected 6 hours after the first
dose of rituximab infusion into RPMI medium and divided into 6 aliquots
and incubated at 37°C for 2 hours with 1 mL of one of the following:
normal saline, Hartman solution, hydroxy ethyl starch, dextran-40
(6%), dextran-70 (6%), or gelofusin. Aliquots of these
suspensions were collected for light microscopy and scanning
electron microscopy (SEM). Smears were prepared from the samples,
stained with May-Grünwald-Giemsa (MGG) stain, and examined by
light microscopy. The results show that none of the samples incubated
in normal saline or Hartman solution exhibited TCA (Figure 1A) while
varying degrees of TCA were noted with all colloid solutions.
The most profound TCAs were observed with dextran-70 and gelofusin
(Figure 1B,C).
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| Figure 1.
Ex vivo agglutination of in vivo antibody-coated chronic
lymphocytic leukemia cells (CLLs).
Cells incubated in normal saline (control) are shown in panel A, cells
incubated in gelofusin showing TCA are shown in panel B, and SEM
appearance of agglutinated CLL cells is shown in panel C. Original magnification: × 500.
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Although this observation was made ex vivo, it nevertheless
raises an important question whether similar changes (ie, TCA) may be
induced in vivo by the above colloid preparations. It may, therefore,
be reasonable to make a suggestion that colloids such as gelofusin, a
commonly used intravenous preparation to restore blood pressure in
patients with cardiovascular collapse, may induce or aggravate TCA in
patients with a high number of circulating tumor cells and,
therefore, should be used with caution during or soon after rituximab
infusion. Further in vivo studies are needed to confirm the above ex
vivo observations.
Muttuswamy Sivakumaran
Correspondence: Muttuswamy Sivakumaran, Department of
Haematology, Peterborough District Hospital, Thorpe Road, Peterborough,
United Kingdom; e-mail: m.sivakumaran{at}pbh-tr.nhs.uk
References
1.
Kunzmann V, Ruediger T, Hallek M, et al.
Tumor cell agglutination and not solely cytokine release as mechanism of adverse reactions during anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) treatment.
Blood.
2001;98:1991-1992[Free Full Text].
Response:
Reinvestigation of colloid administration's role in
rituximab-induced tumor cell agglutination recommended
In a recent report of the fatal course of a rituximab-treated
patient, we have demonstrated that tumor cell agglutination (TCA) might
be a key mechanism of rituximab-induced adverse reactions. The pattern
of intravascular leukostasis shown by histopathologic examinations was
clearly different from findings in other patients with high leukocyte
counts.1
Dr Muttuswamy Sivakumaran reports an interesting ex vivo finding
regarding rituximab-induced tumor cell agglutination (RITCA). He
suggests that various colloid preparations may induce or aggravate TCA
in patients with a high number of circulating tumor cells, based on ex vivo observations in blood samples collected from 2 patients 6 hours after their first rituximab infusion.
In the course of his severe infusion-related syndrome, our reported
patient also experienced hypotension, which was treated with hydroxy
ethyl starch (250 mL 10% HES), after the administration of
intravenous crystalloids (normal saline) did not increase blood pressure. Since HES was among the colloid preparations
which induced TCA in Dr Sivakumaran's ex vivo experiments, we
cannot exclude the possibility that the administration of this
colloid preparation aggravated infusion-related toxicities in our
patient and finally contributed to the fatal course.
The induction of blood cell agglutination after administration of HES
has not been described before, even in patients with abnormally high
blood cell numbers. However, it has been shown that HES can preserve
rather than induce platelet agglutination during and after
cardiopulmonary bypass surgery.2 The in vivo effect of
colloid preparations after infusion of therapeutic monoclonal antibodies such as rituximab are not known. Therefore, we recommend a
reinvestigation concerning the administration of colloids in all
rituximab-related fatalities that have been reported to date to further
evaluate their role in RITCA.
The ex vivo observations by Dr Sivakumaran confirm our results
suggesting that TCA may play a role in the pathogenesis of rituximab-related toxicities, especially in patients with a high number of circulating tumor cells. Until the exact
function of colloids in this syndrome has been elucidated, we support
Dr Sivakumaran's suggestion that colloids should be avoided in
the management of peripheral circulatory failure after
rituximab infusion.
Volker Kunzmann and Martin Wilhelm
Correspondence: Martin Wilhelm, Medizinische Poliklinik
Wuerzburg, Julius-Maximilians Universitat Wurzburg, Klinikstrase 6-8, 97070 Wurzburg, Germany; e-mail:
wilhelm{at}medizin.uni-wuerzburg.de
References
1.
Kunzmann V, Ruediger T, Hallek M, Mueller-Hermelink H-K, Wilhelm M.
Tumor cell agglutination and not solely cytokine release as mechanism of adverse reactions during anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) treatment.
Blood.
2001;98:1991-1992[Free Full Text].
2.
Tigchelaar I, Gallandat Huet RC, Korsten J, Boonstra PW, van Oeveren W.
Hemostatic effects of three colloid plasma substitutes for priming solution in cardiopulmonary bypass.
Eur J Cardiothorac Surg.
1997;12:678-680[CrossRef][Medline]
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