Eleven patients with relapsed fludarabine-resistant B-cell chronic lymphocytic leukemia (CLL) or leukemic variants of low-grade B-cell non-Hodgkin’s lymphoma (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 × 109/L. During the first rituximab infusion, patients with lymphocyte counts exceeding 50.0 × 109/L experienced a severe cytokine-release syndrome. Ninety minutes after onset of the infusion, serum levels of tumor necrosis factor- (TNF-) and interleukin-6 (IL-6) peaked in all patients. Elevated cytokine levels during treatment were associated with clinical symptoms, including fever, chills, nausea, vomiting, hypotension, and dyspnea. Lymphocyte and platelet counts dropped to 50% to 75% of baseline values within 12 hours after the onset of the infusion. Simultaneously, 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 time. 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 × 109/L experienced significantly more adverse events of National Cancer Institute (NCI) grade III/IV toxicity than patients with less than 50.0 × 109/L peripheral tumor cells (P= .0017). Due to massive side effects in the first patient treated with 375 mg/m2 in 1 day, a fractionated dosing schedule was used in all subsequent patients with application of 50 mg rituximab on day 1, 150 mg on day 2, and the rest of the 375 mg/m2 dose on day 3. While the patient with the leukemic variant of the mantle-cell NHL achieved a complete remission (9 months+) after treatment with 4 × 375 mg/m2 rituximab, efficacy in patients with relapsed fludarabine-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 combination regimens with chemotherapeutic drugs to reduce tumor burden before treatment with rituximab will have to be evaluated.

In this report we present a patient with B-cell chronic lymphocytic leukemia who developed an acute tumor lysis syndrome after administration of the human anti-CD20 antibody IDEC-C2B8 (RITUXIMAB) in standard dose of 375 mg/m2. IDEC-C2B8 has been demonstrated to have only mild and tolerable side effects in patients with follicular lymphoma. In these trials patients with lymphocytosis >5000/microl were excluded. Physicians must be aware of this hitherto unreported phenomenon in patients with high CD20-positive blood counts.

Immunotoxins (ITs) consisting of a cell-binding component and a potent toxin were developed as a new class of biological anti-tumor agents to improve adjuvant therapy. Hodgkin's lymphoma (HL) has been demonstrated to be an excellent target for ITs because high concentrations of lymphocyte activation markers such as CD25 and CD30 are expressed on Hodgkin and Reed-Sternberg (H-RS). Several ITs against these antigens have shown potent antitumor effects against H-RS cells in vitro and in different HL animal models. On the basis of its superiority in preclinical models, the anti-CD25 IT RFT5-SMPT-dgA was subsequently evaluated in a phase I study in patients with refractory Hodgkin's lymphoma. The IT was constructed by linking the monoclonal antibody (Moab) RFT5 via a sterically hindered disulfide linker (SMPT) to deglycosylated ricin A-chain (dgA). All 15 patients enrolled in this trial were heavily pretreated with a mean of five different prior therapies. The IT was administered intravenously over four hours on days 1-3-5-7 for total doses per cycle of 5, 10, 15, or 20 mg/m2. Side effects were reversible and related to the vascular leak syndrome (VLS), i.e. decrease in serum albumin, edema, weight gain, hypotension, tachycardia, myalgia, and weakness. In all three patients receiving 20 mg/m2 NCI toxicity grade III was observed. Thus, 15 mg/m2 is the maximal tolerated dose (MTD) of RFT5-SMPT-dgA. 50% of the patients developed human anti-ricin A-chain antibodies (HARA) and/or human anti-mouse antibodies (HAMA). Clinical results included two partial remissions (PR), one minor response (MR), three stable disease (SD) and nine progressive disease (PD). In an extension of the phase I trial, five additional patients have been treated at the MTD.

To evaluate the effects of deglycosylated ricin A-chain (dgA) immunotoxins against disseminated Hodgkin's lymphoma, we used RFT5.dgA (CD25) and IRac.dgA (70 kD) to treat L540Cy Hodgkin cells in severely immunodeficient SCID mice. In this model, more than 90% of the animals developed multiple lymphomas in various organs such as the lymph nodes, liver, bone marrow, and extranodal sites that killed untreated animals after a mean survival time (MST) of 36.3 days. A single intraperitoneal injection of 8 micrograms of either immunotoxin rendered 95% (RFT5.dgA) and 93% (IRac.dgA), respectively, of mice tumor-free when applied 1 day after tumor challenge. The MST of the RFT5.dgA-treated group was extended by more than 80 days (P < .00001). SCID mice treated 12 days after tumor challenge had lower remission rates (46%), suggesting that the antitumor effect of the immunotoxins depends on the number of tumor cells present. We conclude that ricin A-chain immunotoxins have potent antitumor effects against disseminated Hodgkin's tumors in SCID mice and that this model is ideally suited for the evaluation of different immunotoxin treatment modalities.

The treatment options for chronic lymphocytic leukemia (CLL) beside standard therapy with chlorambucil or other alkylating agents have dramatically increased in the last few years. Promising results have been reported with new cytotoxic agents such as the purine analogues fludarabine and 2-chlordeoxyadenosine, either at first diagnosis or at relapse. Nevertheless, all patients with CLL relapse after initial response. Since residual lymphoma cells are very likely to be the origin of the clinical relapse, there is a need for new therapeutic approaches with different mechanism of action to eliminate these residual cells. These approaches include allogeneic or autologous stem cell transplantation as well as immunotherapeutic strategies. Monoclonal antibodies, either alone or conjugated to toxins or radioisotopes, are thus being actively investigated. In clinical trials the genetically engineered chimeric unconjugated anti-CD20 antibody Rituximab and the humanized unconjugated anti-CD52 antibody Campath-1H achieved the most promising results in the treatment of patients with relapsed or refractory low-grade non-Hodgkin’s lymphoma. Thus far there is only little clinical experience with Rituximab in patients with CLL, and the exact role of these agent in the treatment of CLL has still to be determined in ongoing and future trials. As a single agent Campath-1H showed more clinical activity in previously treated CLL patients than Rituximab, with response rates of up to 33% in a multicenter pivotal study. Furthermore, the potential risks of tumor lysis and anaphylaxia for both antibodies and immunosuppression particularly for Campath-1H must be taken into account. The present review will compare the development and the basic principles of these unconjugated monoclonal antibodies and consider their present and potential role in the treatment of patients with CLL.