Radioimmunotherapy: A New Treatment Modality for B-Cell Non-Hodgkin’s Lymphoma

Yttrium-90 (Y-90) ibritumomab tiuxetan (Zevalin) radioimmunotherapy was approved by the US Food and Drug Administration (FDA) in February 2002 and tositumomab/iodine-131 (I-131) tositumomab (Bexxar) was approved by the FDA in June 2003 for the treatment of patients with relapsed or refractory low-grade, follicular, or CD20-positive transformed B-cell non-Hodgkin's lymphoma (NHL), and rituximab(Drug information on rituximab) (Rituxan)-refractory follicular NHL. In this excellent review, Drs. Ghobrial and Witzig describe the rationale for radioimmunotherapy and the relevant clinical trials that formed the basis for FDA approval. The rationale for radioimmunotherapy in lymphoma is compelling.[1] Kaminski et al introduced I-131-labeled anti-B1 antibody, a murine anti- CD20 monoclonal antibody.[2] Press studied tositumomab/I-131 tositumomab with high-dose chemotherapy and autologous stem cell transplant in patients with recurrent lymphoma.[3] Witzig et al reported on a multicenter phase I/II trial of ibritumomab tiuxetan.[ 4] The development of successful yttrium-labeled radioimmunoconjugates was dependent upon the chelation chemistry developed by Quadri et al, which allowed for stable binding of the yttrium to the DPTA conjugate by altering the 2- and 3-carbon moieties, resulting in a urea(Drug information on urea) bond.[5] The high response rates reported by Witzig and summarized in this review are intriguing and provide proof of principle for this novel therapy. In studies reported to date, the overall response rate to radioimmunotherapy is > 80%, with complete response rates between 20% and 30% for patients with refractory NHL. Furthermore, it is becoming apparent that a significant minority of patients (about 20% to 25%) have durable remissions that last longer than 5 years.[6] It remains to be seen if any of these patients are cured of their disease. Late Toxicity
One of the anticipated difficulties with radioimmunotherapy is late toxicity. The toxicity seen in radioimmunotherapy trials thus far has been minimal, mostly hematologic and reversible. Less than 2% of patients in ibritumomab tiuxetan trials developed a human antimurine antibody (HAMA) or human antichimeric antibody (HACA) response.[6] We believe this low incidence of HAMA/ HACA is related to the use of chimeric antibody for pretreatment, the small dose of parent mouse antibody (between 2 and 10 mg), and the extensive prior therapy received by most patients (with resulting immunosuppression). Thus far, the incidence of secondary malignancy, myelodysplastic syndrome, or acute myeloid leukemia, is estimated to be 1% to 2%.[7] A review of the literature in patients who have not undergone transplantation but have had conventional-dose chemotherapy for low-grade lymphoma reveals that the rate of secondary malignancy is between 4% and 8%, developing over the course of 2 to 9 years after the initiation of treatment.[ 8] We believe that second malignancies may be a long-term complication of lymphoma treatment in general and not necessarily associated with either rituximab or radioimmunotherapy. However, it is critical that these patients are followed long-term. Other late effects such as gonadal toxicity need to be investigated. We recently initiated a trial to prospectively study the fertility of men and women receiving ibritumomab tiuxetan therapy. Role of Radioimmunotherapy
Many other questions remain regarding the efficacy of radioimmunotherapy. For example, what is the appropriate role and best integration of radioimmunotherapy into bone marrow transplant preparative regimens and the activity of such treatment in less common forms of NHL, such as mantle cell lymphoma? Radioimmunotherapy has been studied in the setting of hematopoietic transplantation for relapsed NHL. Ibritumomab tiuxetan and tositumomab/ I-131 tositumomab have been examined in phase I/II trials in combination with standard autologous transplant regimens (carmustine [BCNU]/etoposide/cytarabine/melphalan [Alkeran] and cyclophosphamide(Drug information on cyclophosphamide) [Cytoxan, Neosar]/etoposide) and has proven to be feasible.[3,9] Phase III trials need to be developed to study the role of radioimmunother- apy in autologous transplantation. Furthermore, studies of radioimmunotherapy with allogeneic transplantation are needed, where the radioimmunoconjugate is part of a preparative regimen for patients with lymphoma who are undergoing nonmyeloablative therapy. The early phase I/II data, which suggested minimal activity in mantle cell lymphoma,[4] might have been influenced by the massive splenomegaly seen in the first three patients treated. These patients' spleens responded, but their indicator lesions did not, lending support to the "sink phenomenon," whereby the bulk of radioactivity concentrates at the bulkiest sites of disease. Conversely, very little information exists regarding the biodistribution of the radioisotope in patients with minimal residual disease, as most studies to date have only included patients with measurable nodal disease. This concept will be studied in an Eastern Cooperative Oncology Group study, which will investigate the use of ibritumomab tiuxetan following R-CHOP chemotherapy (rituximab plus cyclophosphamide, doxorubicin(Drug information on doxorubicin) HCl, vincristine [Oncovin], prednisone(Drug information on prednisone)) in patients with mantle cell lymphoma. This question can also be investigated in stem cell transplant studies where patients receive radioimmunotherapy when the disease burden is low. Radiation Enhancement
There have been attempts to take advantage of radiation sensitizers with external-beam radiation, but to date there have been no studies with radioimmunoconjugates. We have been interested in the redox-active agent motexafin gadolinium (MGd), which has shown activity when combined with external-beam radiation in patients with lung cancer and brain metastases.[ 10] We have started a phase I/II trial combining MGd with ibritumomab tiuxetan for the treatment of patients with relapsed/refractory NHL. MGd is a tumor-selective redox mediator that generates reactive oxygen species such as hydrogen peroxide[11] and enhances the efficacy of ionizing radiation. Moreover, MGd induces apoptosis in various lymphoma cell lines and is additive to rituximab.[Personal communication, Richard Miller, Pharmacyclics, Inc] Combination ibritumomab tiuxetan (0.4 mCi/kg) and MGd (2.5 mg/kg) therapy has been well tolerated by the first cohort treated. Therapeutic Combinations
Although there has been much debate in the academic, private practice, and pharmaceutical communities regarding the relative merits of ibritumomab tiuxetan and tositumomab/ I-131 tositumomab, investigators should put marketing questions aside and take advantage of the different physical properties that characterize Y-90 and I-131. Because the bulk of the energy is distributed along a short path with I-131 and a long path with Y-90, the possibility of combined radioimmunotherapy in NHL is not farfetched, with ibritumomab tiuxetan given for initial bulky disease and tositumomab/ I-131 tositumomab for minimal residual disease. Clinical trials to evaluate this strategy should be planned. The exact sequence of radioimmunotherapy in the treatment algorithm for low-grade lymphoma has not yet been defined. Radioimmunotherapy should have a major role as second- or third-line therapy (depending on sequencing with rituximab), following monoclonal antibody and alkylating agents, but prior to purine analog-based treatment such as fludarabine. Exposure to purine analogs before ibritumomab tiuxetan will delay blood count recovery and may result in prolonged cytopenias. Recent reports indicate that radioimmunotherapy does not preclude subsequent treatment for NHL.[12] Chemotherapy and other NHL therapies (including stem cell transplant and immunotherapy) can be administered following radioimmunotherapy.[ 6,12] It is important that clinical investigation of this novel modality continues, to see if the early successes can be duplicated and to better assess the role of radioimmunotherapy in the treatment of lymphoma.