Follicular Lymphoma: Expanding Therapeutic Options

By
APAR KISHOR GANTI, MD
Clinical Fellow
Section of Oncology/Hematology
Department of Internal Medicine

R. GREGORY BOCIEK, MD
Assistant Professor
Section of Oncology/Hematology
Department of Internal Medicine

PHILIP J. BIERMAN, MD
Associate Professor
Section of Oncology/Hematology
Department of Internal Medicine

CHARLES A. ENKE, MD
Professor and Chair
Department of Radiation Oncology

JULIE M. VOSE, MD
Neumann M. and
Mildred E. Harris Professor
Chief, Section of
Oncology/Hematology
Department of Internal Medicine

JAMES O. ARMITAGE, MD
Professor
Section of Oncology/Hematology
Department of Internal Medicine
University of Nebraska,
Omaha, Nebraska | February 1, 2005

Future Directions Vaccines
The B-cell lymphomas express a tumor-specific clonal immunoglobulin (idiotype). This is composed of the unique antigenic determinants in the variable regions of the clonal immunoglobulin expressed by the tumor cells. This can be recognized by the immune system and can serve as a target for active immunotherapy. Hsu et al treated 41 patients with B-cell NHL using a vaccine consisting of tumor immunoglobulin protein coupled to keyhole limpet hemocyanin. In their series, 20 patients generated specific immune responses against the idiotypes of their tumor immunoglobulin. Patients who mounted an immune response had increased progression- free survival (7.9 vs 1.3 years) and overall survival (median survival not reached vs 7 years), as compared to those who did not mount an immune response.[129] Timmerman et al vaccinated 35 patients with dendritic cells pulsed with tumor-derived idiotype protein. Of the 23 patients who completed the vaccination schedule, 15 mounted an immune response, either T-cell- mediated or immune-mediated. At a median of 43 months after chemotherapy, 16 of 23 patients showed no tumor progression. Six patients who experienced progression received booster doses of the vaccine, and three of them had a response.[130] Newer Monoclonal Antibodies
The success of the monoclonal antibody rituximab and the radioimmunoconjugates tositumomab and ibritumomab has spurred research into the development of newer targeted therapies directed toward NHL. Epratuzumab (anti-CD22) and apolizumab (Hu1D10) seem most promising in this regard. Epratuzumab is a humanized monoclonal antibody directed against the CD22 determinant RFB4, which is present on 75% of B lymphocytes.[131] In a phase I/II trial, Leonard et al treated 55 patients with escalating doses of epratuzumab and obtained objective responses in 24% of patients with follicular lymphoma. A 43% objective response rate was seen in follicular lymphoma patients treated at 360 mg/m²/wk, suggesting that this dose should be explored further.[132] Postema et al tried to determine the maximum tolerated dose of a new radioimmunoconjugate created by a combination of epratuzumab with rhenium (Re)-186 in a phase I study. They found that Re-186 epratuzumab at a dose of 2.0 GBq/m² was well tolerated. Five out of 15 patients with NHL of diverse histology showed objective responses following a single dose of Re-186 epratuzumab.[133] Apolizumab is a humanized IgG1 monoclonal antibody that binds to a variant (likely posttranslational modification) of the HLA-DRB chain.[134] Apolizumab induces antibody- dependent cellular cytoxicity and complement-mediated lysis as well as signaling via tyrosine phosphorylation in lymphoma cell lines, and hence, it is being evaluated in NHL.[135] In a phase I study conducted at the NCI, 20 patients were treated at various dose levels. The toxicity observed was mainly grade 1 and 2, and occasionally grade 3. The investigators found clear evidence of antitumor effects, especially in follicular lymphoma, where four of eight patients demonstrated an objective response.[136] Galiximab is a macaque-human chimeric antibody directed against CD80. CD80 is an immune costimulatory molecule expressed on the surface of a wide variety of hematologic malignancies, including follicular lymphoma.[ 137] Czuczman et al conducted a phase I/II trial evaluating the efficacy of galiximab in the treatment of relapsed/ refractory follicular lymphoma. They treated 37 patients with escalating doses of galiximab and found that the agent was well tolerated with no major adverse effects. They observed two complete responses and one partial response in 34 evaluable patients, for an overall response rate of 9%.[137] In another phase I study, Gordon et al combined escalating doses of galiximab with rituximab in patients with relapsed/refractory follicular lymphoma. They enrolled 12 patients into this phase of their study, and at 50 days, they observed three complete and four partial responses. They also found no major adverse effects or dose-limiting toxicities.[138] These results show that galiximab is a potentially safe and effective treatment for relapsed/refractory follicular lymphoma. Antisense Therapy
The bcl-2 gene is commonly overexpressed in NHL.[139] More than 85% of patients with follicular lymphoma and t(14;18) overexpress bcl-2.[140] This leads to resistance to apoptosis, thereby promoting tumorigenesis.[ 139] Waters et al conducted a phase I study to evaluate the efficacy and toxicity of an antisense oligonucleotide targeting bcl-2 in patients with NHL. Among the 21 patients they treated with the oligonucleotide, there was one complete response, two minor responses, nine cases of stable disease, and nine cases of progressive disease, thereby demonstrating that antisense therapy was feasible and potentially effective in NHL.[141] Proteasome Inhibitors
The proteasome is a multienzyme complex that is present in all eukaryotic cells. It degrades proteins that regulate cell-cycle progression and causes proteolysis of the endogenous inhibitor of nuclear factor (NF)- kappaB.[142] Bortezomib (Velcade) is a boronic acid derivative that is a highly selective, potent, reversible proteasome inhibitor. The initial demonstration of in vivo antitumor activity of a proteasome inhibitor used a human lymphoma xenograft model,[ 143] leading to an interest in the use of this agent in lymphoid malignancies. O'Connor et al administered bortezomib to 21 previously treated patients with relapsed or refractory indolent lymphomas (small lymphocytic lymphoma/chronic lymphocytic leukemia type [n = 3], follicular lymphoma [n = 9], mantle cell lymphoma [n = 8], and nodal marginal zone lymphoma [n = 1]). They found that six of the eight evaluable patients with follicular lymphoma achieved a major response, with one patient obtaining a durable complete response.[144] CpG Oligonucleotides
Bacterial DNA and synthetic oligodeoxynucleotides containing unmethylated cytosine-guanine dinucleotides known as cytosine phosphorothioate guanine (CpG) oligodeoxynucleotides can activate immune-cell subsets, including cells that participate in antibody- dependent cell-mediated cytotoxicity. Through these effects, CpG oligonucleotides could potentially augment the antitumor effects of monoclonal antibodies. Indeed animal studies have shown that CpG oligonucleotides enhance the efficacy of antitumor monoclonal antibody therapy in the 38C13 murine B-cell lymphoma.[145] Friedberg et al conducted a phase I study combining escalating doses of an immunostimulatory CpG oligonucleotide (1018 ISS) with rituximab in 16 patients with relapsed/refractory NHL (13 patients with follicular lymphoma). The regimen was well tolerated with no major toxicities, producing one complete response, five partial responses, and two cases of progressive disease. Interestingly, these investigators also found an increase in the expression of several interferon-inducible genes. This provides a rationale for further investigation of combination immunotherapy approaches in NHL.[146] Nonmyeloablative Stem Cell Transplantation
The biggest drawback to the routine use of allogeneic stem cell transplantation in the management of follicular lymphoma is the increased incidence of transplant-related mortality. The success of donor lymphocyte infusion in treating relapses following allogeneic HSCT has led to the thinking that a graft-vs-lymphoma (GVL) effect, mediated by lymphocytes, is at least partly responsible for the efficacy of allogeneic stem cell transplantation. Also supporting the existence of the GVL effect is the fact that patients who develop chronic GVHD after allogeneic HSCT have a lower probability of relapsing than patients who do not develop chronic GVHD.[147] In a study at the M. D. Anderson Cancer Center, Khouri et al treated 20 patients with indolent NHL with the combination of fludarabine, cyclophosphamide, and rituximab. They achieved a 2-year overall and relapsefree survival rate of 84%.[148] This study demonstrates the feasibility and efficacy of a relatively nontoxic, nonmyeloablative conditioning regimen for the treatment of follicular lymphoma. Conclusions In conclusion, long-term diseasefree survival is possible in select groups of patients with follicular lymphoma. Patients who have early-stage disease and those who achieve a complete response following initial chemotherapy tend to have long-term disease-free survival. The introduction of newer therapeutic modalities such as immunotherapy, radioimmunotherapy, and advances in stem cell transplantation has improved outcomes in follicular lymphoma over those seen with conventional chemotherapy and RT alone. However, because follicular lymphoma is an indolent disease, watchful waiting is still a good option in elderly asymptomatic patients with a low tumor burden. For patients who relapse following a complete or partial response, salvage chemotherapy followed by auto-HSCT improves outcomes as compared with conventional therapy. For younger patients with chemoresistant disease, allogeneic HSCT must be considered if patients have an HLAidentical sibling, as this strategy probably offers the best chance for cure in this subgroup. There is reason for excitement about the prospects for effective vaccine therapies for lymphoma, as randomized vaccine trials commence and newer cell-based vaccine trials enter the clinic. With such promising new prospects on the horizon, follicular lymphoma-long thought to be incurable- may soon have curative options, at least in a subset of patients.

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FERNANDO CABANILLAS, MD
MICHEL VAN GELDER, MD and HARRY C. SCHOUTEN, MD
DAN L. LONGO, MD

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