Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an Anti-CD20 monoclonal antibody (Rituximab, IDEC-C2B8)

Eleven patients with relapsed fludarabine-resistant B-cell chronic lymphocy tic leukemia (CLL) or leukemic variants of low-grade B-cell non-Hodgkin's l ymphoma (NHL) were treated with the chimeric monoclonal anti-CD20 antibody rituximab (IDEC-C2B8). Peripheral lymphocyte counts at baseline varied from 0.2 to 294.3 x 10(9)/L, During the first rituximab infusion, patients with lymphocyte counts exceeding 50.0 x 10(9)/L experienced a severe cytokine-r elease syndrome. Ninety minutes after onset of the infusion, serum levels o f tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) peaked i n all patients, Elevated cytokine levels during treatment were associated w ith clinical symptoms, including fever, chills, nausea, vomiting, hypotensi on, and dyspnea. Lymphocyte and platelet counts dropped to 50% to 75% of ba seline values within 12 hours after the onset of the infusion. Simultaneous ly, there was a 5-fold to 10-fold increase of liver enzymes, d-dimers, and lactate dehydrogenase (LDH), as well as a prolongation of the prothrombin t ime. Frequency and severity of first-dose adverse events were dependent on the number of circulating tumor cells at baseline: patients with lymphocyte counts greater than 50.0 x 109/L experienced significantly more adverse ev ents of National Cancer Institute (NCI) grade III/IV toxicity than patients with less than 50.0 x 109/L peripheral tumor cells (P = .0017). Due to mas sive side effects in the first patient treated with 375 mg/m(2) in 1 day, a fractionated dosing schedule was used in all subsequent patients with appl ication of 50 mg rituximab on day 1, 150 mg on day 2, and the rest of the 3 75 mg/m(2) dose on day 3. While the patient with the leukemic variant of th e mantle-cell NHL achieved a complete remission (9 months+) after treatment with 4 x 375 mg/m2 rituximab, efficacy in patients with relapsed fludarabi ne-resistant B-CLL was poor: 1 partial remission, 7 cases of stable disease , and 1 progressive disease were observed in 9 evaluable patients with CLL. On the basis of these data, different infusion schedules and/or combinatio n regimens with chemotherapeutic drugs to reduce tumor burden before treatm ent with rituximab will have to be evaluated. (C) 1999 by The American Soci ety of Hematology.