Radioimmunotherapy of non-Hodgkin’s lymphoma: a critical appraisal

Radioimmunotherapy is a unique form of radiation therapy that uses antibodies to specifically target radionuclides for systemic cancer treatment. While chemotherapy remains the frontline treatment for non-Hodgkin’s lymphoma, two radioimmunotherapy agents are approved for use in certain follicular and transformed forms of recurrent non-Hodgkin’s lymphoma as a second- or third-line treatment option. However, there are number of clinical trials underway that will likely lead to a more expanded use of this treatment modality in the future. New agents and approaches for radioimmunotherapy are also being developed that could offer an even greater potential for this new form of therapy.     

A review of tositumomab and I131 tositumomab radioimmunotherapy for the treatment of follicular lymphoma

The CD20 antigen has become a major therapeutic target in the management of follicular and other Bcell non-Hodgkin’s lymphomas. The murine monoclonal antibody, tositumomab, on binding CD20, is able to induce antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and apoptosis. In addition, when radioiodinated, the antibody exploits the tumour’s sensitivity to ionising radiation by direct targeting of the malignant cell. Tositumomab and Iodine (I¹³¹) tositumomab (Bexxar^®, GlaxoSmithKline, Philadelphia, PA, USA) is administered in two steps. The dosimetric step determines individual patient pharmacokinetics, allowing a patient- specific dose to be calculated. This is followed by the therapeutic step, with administration of the therapeutic dose between 7 and 14 days after the dosimetric dose. Over a decade’s worth of experience in clinical trials has determined the efficacy and safety of the regimen in a variety of clinical ci-rcumstances; establishment of exactly where the regimen fits amongst the algorithm for the management of follicular lymphoma continues.     

Radioimmunotherapy (RIT) in non-Hodgkin lymphoma

Radio-labeled anti-CD20 antibodies are a relatively novel technique that uses monoclonal antibodies to target CD20-positive cells and administer complex antibody-mediated and/or complement-dependant cytotoxicity in combination with systemic radiotherapy to targeted cells and adjacent cells via the “crossfire” effect. There are currently two main agents in clinical practice—yttrium-90 (⁹⁰Y) ibritumomab tiuxetan (Zevalin) and iodine-131 (¹³¹I) tositumomab (Bexxar)—with other agents in clinical development. Studies have been performed looking into the use of radioimmunotherapy (RIT) in indolent non-Hodgkin lymphoma (NHL), initially in patients with relapsed, treatment-refractory and transformed disease (overall response rates [ORR] 74–92% with complete response [CR] 15–51%), and also in patients not suitable for transplant (i.e., the elderly population [CR 23%]) and in isolation in the first-line setting (comparable response rates to RCHOP) and combination with chemotherapy in the first-line setting (ORR 90–100%). The use of RIT in diffuse large B cell aggressive (DLBC) NHL has been assessed initially in patients with relapsed disease, both rituximab naïve (ORR 44%) and refractory (ORR 19%), and more recently as consolidative treatment following primary chemotherapy (early results 5-year overall survival 60% vs 37%), or in combination with primary chemotherapy. The main side effects are infusion related and hematological with a delayed nadir (4–6 weeks in DLBC NHL, 6–8 weeks in indolent disease) and correlate with bone marrow reserve.     

I-131 tositumomab

Importance of the field: Follicular lymphoma (FL) is a subgroup of B-cell Non-Hodgkin's lymphomas (NHL) that account for 15 – 30% of all lymphomas. I-131 tositumomab is a radiommunoconjugate of ¹³¹I and the anti-CD20 monoclonal antibody tositumomab. It is one of two available radioimmunoconjugates for the treatment of recurrent, refractory, or transformed FL.

Areas covered in this review: This review describes the clinical pharmacology of I-131 tositumomab, dosing and administration guidelines, and the key clinical trials providing evidence of its efficacy and safety in patients with FL, transformed, or other aggressive B-NHL, in combination with chemotherapy, or its incorporation in transplant conditioning regimens. This review also covers safety and regulatory concerns regarding the use of I-131 tositumomab.

What the reader will gain: This review critically appraises the clinical trials behind approval of I-131 tositumomab as a second-line agent for FL and also outlines the data supporting its use in the upfront setting.

Take home message: I-131 tositumomab is a safe and effective option for patients with recurrent, refractory, or transformed FL and carries promise in the upfront treatment of FL, aggressive B-NHL, and as a transplant conditioning regimen.     

Radioimmunotherapy of B-cell lymphoma with radiolabelled anti-CD20 monoclonal antibodies

Abstract CD20 has proven to be an excellent target for the treatment of B-cell lymphoma, first for the chimeric monoclonal antibody rituximab (Rituxan™), and more recently for the radiolabelled antibodies Y-90 ibritumomab tiuxetan (Zevalin™) and I-131 tositumomab (Bexxar™). Radiation therapy effects are due to beta emissions with path lengths of 1–5 mm; gamma radiation emitted by I-131 is the only radiation safety issue for either product. Dose-limiting toxicity for both radiolabelled antibodies is reversible bone marrow suppression. They produce response rates of 70%–90% in low-grade and follicular lymphoma and 40%–50% in transformed low-grade or intermediate-grade lymphomas. Both products produce higher response rates than related unlabelled antibodies, and both are highly active in patients who are relatively resistant to rituximab-based therapy. Median duration of response to a single course of treatment is about 1 year with complete remission rates that last 2 years or longer in about 25% of patients. Clinical trials suggest that anti- CD20 radioimmunotherapy is superior to total body irradiation in patients undergoing stem cell supported therapy for B-cell lymphoma, and that it is a safe and efficacious modality when used as consolidation therapy following chemotherapy. Among cytotoxic treatment options, current evidence suggests that one course of anti-CD20 radioimmunotherapy is as efficacious as six to eight cycles of combination chemotherapy. A major question that persists is how effective these agents are in the setting of rituximab- refractory lymphoma. These products have been underutilised because of the complexity of treatment coordination and concerns regarding reimbursement.     

Pharmacotherapy of large B-cell lymphoma

Background: Constituting approximately 30% of lymphoid malignancies, diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma in adults worldwide. The clinical and biologic heterogeneity that exists in DLBCL suggests that this entity might actually be comprised of several distinct neoplasms that could require different therapeutic approaches. DLBCL was considered incurable until combination chemotherapy became available. Objective: Current treatment strategies for the treatment of untreated and relapsed advanced-stage DLBCL are reviewed; novel treatments for DLBCL are discussed. Methods: Relevant literature was identified using the PubMed search engine and by reviewing abstracts from major conference proceedings. Results/conclusion: Recently, novel therapeutic strategies, including the incorporation of immunotherapy to combination chemotherapy, have improved outcome for patients with DLBCL with cure rates exceeding 50%, especially in younger patients.     

Radioimmunotherapy with iodine-131 tositumomab in patients with low-grade non-Hodgkin's B-cell lymphoma does not induce loss of acquired humoral immunity against common antigens.

Thirty-one previously untreated patients with follicular low-grade B-cell non-Hodgkin's lymphoma expressing the CD20 antigen were treated with iodine-131 tositumomab therapy between 1996 and 1998. The therapy led to a temporary depletion of peripheral blood B-lymphocytes. Recovery of B-cells occurred in most cases by 3 to 6 months and in all patients by 12 months posttherapy. A temporary decline in T-cell subpopulations, but no reduction in serum immunoglobulin levels, could be observed. ELISA techniques were used to detect specific antibodies against rubella, mumps, varicella zoster, measles, and tetanus. Almost all patients remained seropositive against the different antigens during the 1- to 2-year follow-up. No significant reduction in antibody concentrations to tetanus or measles could be detected. The data show that acquired humoral immunity against common antigens appears to be preserved despite a temporary loss of B-lymphocytes.     

Membrane microdomain sphingolipids are required for anti-CD20-induced death of chronic lymphocytic leukemia B cells

Background

Chronic lymphocytic leukemia remains incurable, despite the addition of rituximab to chemotherapy as an available means of treatment. The resistance of certain patients to this monoclonal antibody prompted us to set up in vitro studies of another CD20-specific monoclonal antibody, B1 (later termed tositumomab). We hypothesized that the membrane lipid organization of leukemic B cells might be instrumental in the cells’ sensitivity to the B1 monoclonal antibody.

Design and Methods

B lymphocytes from 36 patients with chronic lymphocytic leukemia and 13 patients with non-Hodgkin’s lymphoma were investigated for B1-triggered cell death. Membrane components, such as sphingomyelin and ganglioside M1, were investigated by flow cytometry, immunofluorescence and co-immunoprecipitation, together with the Csk-binding protein.

Results

Chronic lymphocytic leukemia patients segregated into two groups: B cells from one group were sensitive to B1, whereas those from the second group were not. Further results ascribed the resistance of these latter cases to a defective recruitment of Csk-binding protein, resulting in a lack of sphingomyelin and ganglioside M1 at the outer leaflet of the plasma membrane of their malignant B cells. Sphingolipids were indeed retained in the cytoplasm, because of lowered activity of P-glycoprotein. Supporting this mechanism, rifampicin, an inducer of P-glycoprotein, improved the activity of this transmembrane efflux pump, normalized the quantity of sphingomyelin within the membrane, and thereby restored the efficacy of the B1 monoclonal antibody in the formerly B1-resistant cases of chronic lymphocytic leukemia.

Conclusions

The lipid organization of membranes of B cells from patients with chronic lymphocytic leukemia differs from one patient to another. In practice, given the relevance of the membrane lipid distribution to the efficacy of biotherapies, this observation is of potential importance.     

Anti-CD20 monoclonal antibody therapy in multiple myeloma

CD20 is a particularly appealing target that is expressed on the surface of almost all B cells, with no significant shedding, secretion or internalization. In contrast to the demonstrated efficacy of anti-CD20 strategies in various B-cell lymphoproliferative disorders, the role of such therapy in multiple myeloma is undetermined and controversial. The expression of CD20 by myeloma cells is heterogeneous, and can be detected only in 13–22% of patients. However, there is increasing interest in testing anti-CD20 therapy in myeloma because of recent studies suggesting the existence of clonogenic CD20-positive precursor B cells in the disease. This article reviews the rationale, preclinical and clinical activity of anti-CD20 therapy in myeloma. Clinical trials show that anti-CD20 therapy with rituximab elicits a partial response in approximately 10% of CD20⁺ patients with multiple myeloma. In addition, there is preliminary evidence of disease stabilization in 50–57% of CD20⁺ patients for a period of 10–27 months. Further large-scale clinical trials are therefore needed to establish the role of this promising strategy in the treatment of myeloma.