IDEC-C2B8 (Rituximab) Anti-CD20 Monoclonal Antibody Therapy in Patients With Relapsed Low-Grade Non-Hodgkin's Lymphoma

Abstract

IDEC-C2B8 is a chimeric monoclonal antibody (MoAb) directed against the B-cell–specific antigen CD20 expressed on non-Hodgkin's lymphomas (NHL). The MoAb mediates complement and antibody-dependent cell-mediated cytotoxicity and has direct antiproliferative effects against malignant B-cell lines in vitro. Phase I trials of single doses up to 500 mg/m2 and 4 weekly doses of 375 mg/m2 showed clinical responses with no dose-limiting toxicity. We conducted a phase II, multicenter study evaluating four weekly infusions of 375 mg/m2 IDEC-C2B8 in patients with relapsed low-grade or follicular NHL (Working Formulation groups A-D). Patients were monitored for adverse events, antibody pharmacokinetics, and clinical response. Thirty-seven patients with a median age of 58 years (range, 29 to 81 years) were treated. All patients had relapsed after chemotherapy (median of 2 prior regimens) and 54% had failed aggressive chemotherapy. Infusional side effects (grade 1-2) consisting of mild fever, chills, respiratory symptoms, and occasionally hypotension were observed mostly with the initial antibody infusion and were rare with subsequent doses. Peripheral blood B-cell depletion occurred rapidly, with recovery beginning 6 months posttreatment. There were no significant changes in mean IgG levels and infections were not increased over what would be expected in this population. Clinical remissions were observed in 17 patients (3 complete remissions and 14 partial remissions), yielding an intent to treat response rate of 46%. The onset of these tumor responses was as soon as 1 month posttreatment and reached a maximum by 4 months posttreatment. In the 17 responders, the median time to progression was 10.2 months (5 patients exceeding 20 months). Likelihood of tumor response was associated with a follicular histology, with the ability to sustain a high serum level of antibody after the first infusion, and with a longer duration of remission to prior chemotherapy. One patient developed a detectable but not quantifiable immune response to the antibody that had no clinical significance. IDEC-C2B8 in a dose of 375 mg/m2 weekly for 4 weeks has antitumor activity in patients with relapsed low-grade or follicular NHL. Results with this brief, outpatient treatment compare favorably with results with standard chemotherapy, and IDEC-C2B8 has a better safety profile. Further studies evaluating IDEC-C2B8 in other types of lymphoma either alone or combined with chemotherapy are warranted.

Delayed‐onset neutropenia associated with rituximab therapy

“…The frequency with which neutropenia of this type was observed was greater than that observed in a parallel cohort of patients with NHL in CR after completion of treatment with chemotherapy alone, suggesting that an additional factor was involved in the development of delayed-onset neutropenia following treatment which included, or consisted only of, rituximab. The incidence of delayed-onset neutropenia in our patients was also relatively high compared with the values ranging between 0AE6% and 5AE4% reported in previous studies on NHL patients treated with rituximab (Maloney et al, 1997;McLaughlin et al, 1998;Davis et al, 2000;Ghielmini et al, 2000). One possible explanation is that the lower limit of the 95% confidence interval for the value obtained in our series overlapped the upper limits of the 95% confidence intervals for the values in the previously reported studies, suggesting a potential difference of sampling variation.…”

“…Grade 4 neutropenia is commonly observed after the administration of rituximab in combination with chemotherapy, but the transient nature and degree of neutropenia is comparable to that produced by the chemotherapy component alone (Czuczman et al, 2000;Vose et al, 2001;Coiffier et al, 2002). Development of neutropenia with a different pattern of onset has been reported to occur sporadically after a delay of up to many months following completion of rituximab administration (Maloney et al, 1997;McLaughlin et al, 1998;Davis et al, 2000;Ghielmini et al, 2000). Other delayed-onset adverse haematological events include haemolytic anaemia (Ghielmini et al, 2000) and pure red cell aplasia (McLaughlin et al, 1998).…”

Low-dose rituximab is effective in pemphigus

“…[11][12][13] The most common dose in pemphigus is adopted from haematology, namely 375 mg m )2 once a week for four consecutive weeks, as dose-finding studies are sparse. [14][15][16][17] As the antibody-producing B cells in pemphigus are not malignant, and a single dose as low as 100 mg m )2 can deplete B cells, 17 we hypothesized that a lower dose of rituximab might be sufficient for pemphigus. Here we report the surprisingly good and safe effect of 2 · 500 mg rituximab in pemphigus, which is just 39% of the haematological dose for an individual with a body surface of 1AE7 m 2 .…”

Rituximab in non‐haematological disorders of adults and its mode of action

“…Rheumatoid arthritis patients are less likely to develop an infusion reaction than patients with lymphoma. Between 29% and 45% of RA patients suffer a reaction compared to 67% of lymphoma patients during the first infusion (Maloney et al, 1997;Edwards et al, 2004;Cohen et al, 2006). Following one course of therapy total immunoglobulin levels usually remain within the normal range (Edwards et al, 2004;Cohen et al, 2006).…”

“…The half-life of rituximab in patients on dialysis is 12 d (Vieira et al, 2004) compared to 2-9 d in malignancy (Maloney et al, 1997;Berinstein et al, 1998). Rituximab does not appear in the dialysate of patients on haemodialysis (Jillella et al, 2002).…”