Rituximab-induced tumor cell agglutination

The article by Kunzmann and colleagues1brings 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).

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.