ONCOLOGY Vol 16 No 3

Currently, patients with early-stage chronic lymphocytic leukemia (CLL) without active disease are observed. However, those patients with elevated beta-2-microglobulin levels appear to have a shorter median survival (6 years vs 10+ years).

Recruitment for a challenging breast cancer trial has begun at sites in more than 40 countries. It is hoped that more than 3,000 patients from approximately 600 sites will participate in a study designed to determine whether earlier use of trastuzumab (Herceptin) increases disease-free survival in women with early breast cancer.

Front-line treatment for previously untreated follicular B-cell lymphoma with the iodine-131-labeled anti-CD20 antibody tositumomab (Bexxar) has been reported to result in a 97% response rate and a 74% complete response rate.

Pure red cell aplasia is a rare occurrence in patients with chronic lymphocytic leukemia (CLL). This report is based on two cases-CLL patients with documented pure red cell aplasia who responded remarkably to anti-CD20 or rituximab (Rituxan

Autoantibodies against factor VIII are rare but may cause life-threatening bleeding. Up to 30% of inhibitors may resolve spontaneously, but immunosuppressive drugs with possible serious adverse effects and costly factor replacement are usually required. Rituximab (Rituxan), a humanized monoclonal antibody against CD20-positive B cells, has been reported to be beneficial in certain antibody-mediated autoimmune diseases. We describe here four consecutively treated patients whose acquired factor VIII inhibitors responded rapidly to immunosuppressive regimens that included rituximab administered at 375 mg/m² weekly for 2 to 4 weeks.

The humanized monoclonal antibody apolizumab (Remitogen, Hu1D10), directed against a polymorphic determinant of HLA-DR expressed on normal and malignant B cells, is capable of inducing antibody-dependent cellular cytotoxicity, complement-mediated lysis, and direct apoptosis of lymphoma cell lines (Int J Cancer 93:556-565, 2001).

The Medicare Payment Advisory Commission (MedPAC) has agreed that Medicare’s physician-fee formula needs to be overhauled. Medicare cut physician fees this year by 5.4% because of an "update" in the formula that MedPAC agreed is seriously flawed.

The optimal therapy for advanced-stage follicular lymphoma is unknown. Combination chemotherapy usually induces remissions in most patients; however, nearly all patients eventually progress and there is no clear plateau on disease-free survival analysis. Single-agent treatment with the monoclonal anti-CD20 antibody rituximab (Rituxan) at 375 mg/m² weekly × 4 doses induces response rates of approximately 50% to 60% in patients with relapsed follicular non-Hodgkin’s lymphoma. In some patients, the molecular detection of disease by polymerase chain reaction assay may be eliminated following antibody therapy.

The FM (fludarabine [Fludara], mitoxantrone [Novantrone]) combination is an effective strategy in follicular lymphoma. From October 1999, patients from 12 Italian centers were randomized for a comparative study of FM vs CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone) chemotherapy with the addition of rituximab (Rituxan) in selected cases.

Anew treatment for small-cell lung cancer holds promise of dramatically improving survival for patients with the disease, said Dr. Alan Sandler, director of Vanderbilt-Ingram Cancer Center’s Thoracic Oncology Program, and leader of a large US study to further evaluate the treatment’s ability to prolong survival in patients with small-cell lung cancer.

Yttrium-90 ibritumomab tiuxetan (Zevalin) has been shown to be an effective and well-tolerated therapy for patients with relapsed B-cell non-Hodgkin’s lymphoma (NHL), with a response rate significantly higher than that seen with rituximab (Rituxan).

At the 2000 American Society of Hematology meeting, we reported the successful treatment of a patient with acquired hemophilia using rituximab (Rituxan). This patient has required no therapy over the past year and has suffered no further hemorrhages. A June 2001 factor VIII level was 35%, and a factor VIII inhibitor level could not be analyzed due to the high level of factor VIII. Since then, three more patients with acquired factor VIII deficiency have received rituximab therapy at the University of Iowa, and are discussed below.

Lorus Therapeutics announced recently that it has initiated a phase III trial to evaluate the macrophage activator Virulizin for the treatment of advanced pancreatic cancer. The company will present the results of this trial to the US Food and Drug Administration (FDA) in a new drug application at the completion of the study.

Alemtuzumab (Campath), a CDR-grafted monoclonal antibody, recognizes the CD52 antigen which is expressed on normal B and T cells as well as on leukemic B-cell chronic lymphocytic leukemia (B-CLL) cells.

Immune thrombocytopenic purpura (ITP) in adults is a chronic autoimmune disease characterized by antiplatelet antibody (APA)-mediated thrombocytopenia.

The antiapoptotic protein bcl-2 is associated with chemotherapy failure in untreated large B-cell lymphomas, and with the recently described poor-prognosis large B-cell lymphoma subtype displaying an activated B-cell genotype (Nature 403:503, 2000).

Current evidence suggests that rituximab (Rituxan) works in vivo mainly through complement-dependent cytotoxicity (CDC) and/or antibody-dependent cellular cytotoxicity (ADCC). Here we have investigated the sensitivity of freshly isolated cells obtained from 33 B-cell chronic lymphocytic leukemia (B-CLL), 5 prolymphocytic leukemia (PLL), and 6 mantle cell leukemia (MCL) patients to be lysed by rituximab and complement in vitro.

Hairy cell leukemia (HCL) is an indolent B-cell neoplasm that strongly expresses CD20. Despite initial very high response rates with cladribine (Leustatin), many patients ultimately relapse.

Rituximab (Rituxan), a chimeric anti-CD20 antibody, is effective as a single agent in chronic lymphocytic leukemia (CLL), down-regulates antiapoptotic proteins in CLL cells in vivo, and is minimally immunosuppressive.

Front-line treatment of chronic lymphocytic leukemia (CLL) with single-agent fludarabine (Fludara) achieves complete remission in 35% of patients.

Tositumomab/iodine-131 tositumomab (Bexxar) is a novel active agent against CD20-positive lymphoma. There is a paucity of data examining the tolerance and outcome of hematopoietic stem cell transplantation (HSCT) for relapse after tositumomab/iodine-131 tositumomab.

Both rituximab (Rituxan) and fludarabine (Fludara) have individual antitumor activity against low-grade lymphoma (LGL). The combination of rituximab plus fludarabine has been shown to have synergistic activity against resistant lymphoma cell lines in vitro. We have recently completed a single-institution clinical trial of rituximab plus fludarabine in 40 patients with either treatment-naive or previously treated LGL.

The patient is a 58-year-old woman (AA genotype) who was found to have a prolonged activated partial thromboplastin time (aPTT) of 65.7 seconds during a preoperative evaluation for spinal stenosis surgery and mild rectal bleeding. Her aPTT test repeatedly remained abnormally prolonged. The patient had an aPTT mixing study that did not correct immediately or at 2 hours (56.4 seconds vs control 29.7 seconds). Her bleeding time was also abnormally prolonged at 11 minutes.

Wyeth-Ayerst Laboratories announced recently that thousands of patients affected by acute myeloid leukemia (AML) may benefit from the new National Comprehensive Cancer Network (NCCN) guidelines for the appropriate treatment of AML, including the use of gemtuzumab ozogamicin (Mylotarg) in specific clinical situations. The only antibody-targeted chemotherapeutic agent approved by the US Food and Drug Administration, gemtuzumab is indicated for patients with CD33-positive AML in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy. The safety and efficacy of this agent in patients with poor performance status and organ dysfunction has not been established.

Advanced follicular lymphomas are incurable with conventional chemotherapy regimens. The Southwest Oncology Group (SWOG) investigated the safety and efficacy of a novel treatment approach by administering six cycles of standard CHOP chemotherapy (cyclophosphamide [Cytoxan, Neosar] at 750 mg/m², doxorubicin HCl at 50 mg/m², vincristine [Oncovin] at 1.4 mg/m², and oral prednisone at 100 mg for 5 days), given at 3-week intervals, followed by radioimmunotherapy. Four weeks after completion of the last cycle of CHOP, patients with a partial (PR) or complete remission (CR) to chemotherapy underwent dosimetry with 450 mg of unlabeled tositumomab (anti-CD20) antibody and 35 mg of trace-labeled iodine-131 tositumomab (Bexxar).

Wild-type bcl-2 protein is normally found within the bilaminar membrane of the mitochondrion, where it is believed to negatively regulate the release of cytochrome C into the cytoplasm after an apoptotic signal has triggered dimerization of bax protein.

Rituximab (Rituxan) has shown high activity in relapsed follicular lymphomas when given alone, and phase II studies indicate that its addition to chemotherapy may further improve response rates substantially. Because prospective randomized studies have not been available so far, the German Low Grade Study Group (GLSG) started a multicenter national trial in patients with relapsed or refractory follicular cell lymphoma (FCL) or mantle cell lymphoma (MCL). As patients were treated for first-line therapy with CHOP (cyclophosphamide [Cytoxan, Neosar], doxorubicin HCl, vincristine [Oncovin], prednisone), the FCM (fludarabine [Fludara], cyclophosphamide, mitoxantrone [Novantrone]) combination was chosen for salvage chemotherapy.

Failure of treatment in chronic lymphocytic leukemia (CLL) is often characterized by increased expression of the antiapoptosis protein bcl-2. High levels of bcl-2 protein block the apoptotic death machinery at the mitochondrial level by maintaining the permeability transition pore (PTP) in the closed position.

At the 24th Annual San Antonio Breast Cancer Symposium, researchers reported a 78% overall response rate in a phase II trial of vinorelbine (Navelbine) plus trastuzumab (Herceptin) in women with HER2-positive metastatic breast cancer. According to FDA-approved labeling, vinorelbine is not indicated for metastatic breast cancer.

It is amazing how, over the past 5 years, the world of clinical research in the lymphoid malignancies has been totally redirected by one molecule called rituximab (Rituxan).