The addition of rituximab(Drug information on rituximab) (Rituxan) to systemic chemotherapy has improved the response rates, progression-free survival, and overall survival of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) compared to chemotherapy alone. In the front-line setting, the use of rituximab is changing the biology and clinical behavior in DLBCL patients who fail to respond or relapse following chemoimmunotherapy. As noted in last month’s ONCOLOGY, in part 1 of this two-part article, it is becoming evident that the subset of patients with rituximab immunotherapy–relapsed/refractory DLBCL represents a different clinical entity with a higher degree of chemotherapy resistance compared to DLBCL patients receiving upfront chemotherapy alone.
Several novel agents are being evaluated in patients with relapsed/refractory DLBCL, and we have selected some of the most promising agents emerging from early phase I/II clinical trials to discuss here. Each of these agents represent a new class of drug or pathway targeted for the treatment of relapsed/refractory DLBCL: monoclonal antibodies, including drug conjugates and radioimmunoconjugates; immunomodulatory drugs (lenalidomide [Revlimid]); and small molecules targeting cellular pathways (eg, proteasome inhibitors and histone deacetylase inhibitors).
Monoclonal Antibodies, Drug Conjugates, and Radioimmunoconjugates
Advances in molecular biotechnology and tumor immunology have led to the development of chimeric and humanized monoclonal antibodies with longer half-lives and decreased immunogenicity.[1] In addition, improvements in the antibody structure design, large-scale production, and the development of stable linkers used for drug or radioisotope conjugation have resulted in the generation of novel and more potent biologically active agents. Moreover, a better understanding of the biology of B-cell differentiation and B-cell lymphoma has lead to the identification of novel targets for antibody development. These novel agents are being actively studied preclinically and in a large number of clinical trials.
Radioimmunoconjugates
Monoclonal antibodies carrying radioisotopes such as the humanized 90Y-ibritumomab tiuxetan (Zevalin) and murine tositumomab/131I-tositumomab (Bexxar) target the CD20 antigen and deliver cytotoxic radiation into the tumor bed. The antitumor activity of radioimmunoconjugates has been demonstrated in patients with indolent lymphomas, and to a lesser degree, in patients with DLBCL. The major barrier for the use of radioimmunoconjugates in the treatment of DLBCL is myelosuppression, which is of significant concern in patients with rapidly growing and symptomatic disease requiring repeated bouts of chemotherapy. As a result, radioimmunoconjugates have been primarily used either as a palliative option for highly refractory DLBCL patients or evaluated in clinical trials as part of a bone marrow transplant conditioning regimen to replace total-body irradiation.[2-5]
90Y-ibritumomab tiuxetan was evaluated in the palliative setting in 104 patients with relapsed/refractory DLBCL. The patients enrolled in this study were ineligible for high-dose chemotherapy with autologous stem cell support (HDC-ASCS). Response rates to 90Y-ibritumomab tiuxetan were higher in patients without prior rituximab exposure (58%) than in patients with rituximab-treated relapsed/refractory lymphomas (19%).[2]
Several earlier clinical trials had evaluated myeloablative doses of 131I-tositumomab followed by ASCS in elderly DLBCL patients, or the incorporation of 90Y-ibritumomab tiuxetan or 131I-tositumomab into various conditioning regimens in the ASCS or allogeneic bone marrow transplant setting—for example, CyVP16 (cyclophosphamide and etoposide(Drug information on etoposide)) followed by ASCS, or BEAM (carmustine [BCNU], etoposide, cytarabine(Drug information on cytarabine), melphalan(Drug information on melphalan) [Alkeran]) followed by ASCS—in patients with DLBCL. The addition of either 90Y-ibritumomab tiuxetan or 131I-tositumomab to currently available conditioning regimens did not result in additional significant toxicity, and the relapse-free and overall survival at 2 or 3 years was 74% and 93% for 90Y-ibritumomab tiuxetan plus CyVP16–treated patients, and 39% and 55% for patients receiving the 131I-tositumomab plus BEAM regimen, respectively.[3,5]
The results of radioimmunoconjugates are promising, and the benefits and toxicities are challenging clinicians to optimize the use of these novel agents as further data are obtained from clinical trials. Further studies are necessary to better define their role in the management of patients with DLBCL.
Dacetuzumab
Dacetuzumab is a humanized monoclonal antibody that targets CD40, which is expressed on B-cell hematologic malignancies, as well as some solid tumors. CD40 ligand (CD40L), also known as CD154, is the natural ligand of CD40 and a member of the tumor necrosis factor (TNF) family of receptors. The interaction between CD40 and CD40L/CD154 plays an essential role in the contact interactions between antigen-presenting cells and T-cells.
In contrast, the role of CD40 and CD40L in cancer cells remains to be fully defined. There is considerable evidence to suggest that ligation of CD40 on malignant cells by CD154 or agonistic anti-CD40 monoclonal antibodies lead to growth inhibition and apoptosis.[6-9] However, the opposite effect has been demonstrated by other investigators. CD40 signaling may be antiapoptotic or proapoptotic on malignant B cells, depending on the type of malignancy studied and the specific monoclonal antibody or ligand used. In vitro exposure to CD40L of some low-grade B-cell neoplastic cells, such as chronic lymphocytic leukemia cells, promotes cell survival. On the other hand, high-grade lymphoma B-cell lines respond to CD40 signaling and undergo rapid growth arrest and apoptosis. The expression pattern of CD40 on a broad range of malignancies and the role of CD40-CD40L in vivo/in vitro make CD40 an important target for antibody immunotherapy. Preclinical studies demonstrate potential antitumor activity in multiple myeloma and other B-cell lymphoma histologies.[10,11]
