ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) patients who are not eligible for high-dose chemotherapy may benefit from an increasing number of regimens integrating novel agents with promising activity and manageable toxicity. Advances in biotechnology have led to the development and validation of novel biomarkers used for categorization or risk stratification in patients with DLBCL. Simultaneously, novel agents are being developed to target cellular pathways that are important in the initiation, growth, and progression of DLBCL. These agents are undergoing clinical testing, and early data are encouraging. This two-part review, which begain in last month’s issue of ONCOLOGY, summarizes treatment options for patients with relapsed/refractory DLBCL and stresses the emerging therapeutic challenges for patients who were previously exposed to rituximab.
The addition of 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. 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.
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%).
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) followed by ASCS, or BEAM (carmustine [BCNU], etoposide, cytarabine, 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 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]
The first phase I dose escalation clinical trial of dacetuzumab in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) was led by Dr Advani et al. The primary objectives of this study were to assess the safety, pharmacokinetics, and antitumor activity of dacetuzumab. Toxicity reported in the first 35 patients enrolled in this study were primarily infusion-related events; most of them were grade 1 or 2 and included fatigue (31%), headache (26%), chills (17%), pyrexia (17%), elevated hepatic transaminases (11%), and hypotension (11%). Antitumor activity was observed in this heavily pretreated group of patients. Responses were more evident in patients with DLBCL. At least eight patients with DLBCL completed one cycle and had received up to a 3-mg/kg dose of dacetuzumab. The response rate in this subgroup of patients was 37.5%, with one patient achieving a complete remission (CR) and two patients, a partial remission (PR).
To further investigate the safety and efficacy of dacetuzumab, researchers conducted a phase II multicenter, open-label study in patients with relapsed CD40+ DLBCL (de novo or transformed histologies). Enrolled patients had failed prior rituximab/chemotherapy regimens or HDC-ASCS. The first cycle of dacetuzumab was administered over a period of 5 weeks, and each patient underwent treatment according to the same dose-escalating schema. Dacetuzumab was given intravenously at 1 mg/kg on day +1, and then escalated to 2 mg/kg on day +4, and to 4 mg/kg on day +8. Subsequently, patients received the full dose of dacetuzumab at 8 mg/kg per weekly dose. Patients showing no evidence of progressive disease were continued on 28-day cycles of dacetuzumab at 8 mg/kg/wk until disease progression or up to 12 cycles.
Preliminary results from this study were presented at the 2008 annual meeting of the American Society of Hematology (ASH) and included 46 patients enrolled from 10 different centers in the United States. The overall response rate was 10%, half of them being CRs and the other half PRs. In addition, 24% of the remaining patients had stable disease on treatment. Reductions in the tumor size of measurable lesions were seen in approximately one-third of patients. Dacetuzumab was well tolerated and the toxicity profile was very similar to what had been observed in phase I studies.[12,13]
Further exploring the capacity of the CD22 antigen-antibody complex to internalize following antibody biding, the use of anti-CD22 to deliver toxins inside lymphoma cells has been investigated in preclinical models and clinical trials.[14,15] Inotuzumab ozogamicin (CMC-544) is an antibody-targeted chemotherapy agent composed of a humanized CD22 antibody, conjugated to calicheamicin, a potent cytotoxic antitumor agent. The antitumor activity of inotuzumab was demonstrated in preclinical models.
Fayad et al conducted a phase I clinical trial of inotuzumab in combination with rituximab in patients with follicular lymphoma and DLBCL. The study included patients with relapsed or refractory B-cell lymphomas who progressed after one or two therapies. Rituximab-resistant patients, defined as those with disease progression within 6 months of the first dose of rituximab, were excluded. Patients received rituximab at 375 mg/m2 on day 1 of each 28-day cycle and inotuzumab on day 2 at doses of 0.8 mg/m2 (n = 5), 1.3 mg/m2 (n = 3), and 1.8 mg/m2 (n = 7) for a maximum of eight cycles. The maximum tolerated dose of inotuzumab was 1.8 mg/m2; additional patients were enrolled at this dose level. At the time of the preliminary analysis, 61 patients had been treated, 30 of whom were assessable for antitumor response.
Toxicities were manageable, and the most common were thrombocytopenia (41%), nausea (38%), fatigue (36%), elevation of liver function test (26%), and neutropenia (25%). Grade 3/4 hematologic toxicities were rare and occurred in 5% of patients. Tumor responses (including 6 CRs) were seen at all dose levels of inotuzumab, and the 6-month progression-free survival in patients with DLBCL was 66%. These data support the continuing development of inotuzumab ozogamicin in combination with rituximab for the management of aggressive NHL. In addition, radiolabeled anti-CD22 monoclonal antibodies in development have significant potential for antitumor activity in CD22-positive B-cell neoplasms.
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