Radioimmunotherapy: A New Treatment Modality for B-Cell Non-Hodgkin’s Lymphoma
Radioimmunotherapy: A New Treatment Modality for B-Cell Non-Hodgkin’s Lymphoma
Yttrium-90 (Y-90) ibritumomab
tiuxetan (Zevalin) radioimmunotherapy
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 (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
The rationale for radioimmunotherapy
in lymphoma is compelling.
Kaminski et al introduced I-131-labeled
anti-B1 antibody, a murine anti-
CD20 monoclonal antibody. Press
studied tositumomab/I-131 tositumomab
with high-dose chemotherapy
and autologous stem cell transplant in
patients with recurrent lymphoma.
Witzig et al reported on a multicenter
phase I/II trial of ibritumomab tiuxetan.[
4] The development of successful
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 bond.
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. It remains
to be seen if any of these patients
are cured of their disease.
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. 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%. 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 [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, 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 HCl, vincristine [Oncovin], 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 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. 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.
2. Kaminski MS, Zasadny KR, Francis IR, et al: Radioimmunotherapy of B-cell lymphoma with [131I]anti-B1 (anti-CD20) antibody. N Engl J Med 329:459-465, 1993.
3. Press OW, Eary JF, Gooley T, et al: A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas. Blood 96:2934-2942, 2000.
4. Witzig TE, White CA, Wiseman GA, et al: Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin’s lymphoma. J Clin Oncol 17:3793-3803, 1999.
5. Quadri SM, Vriesendorp HM, Leichner PK, et al: Evaluation of indium-111- and yttrium-90- labeled linker-immunoconjugates in nude mice and dogs. J Nucl Med 34:938-945, 1993.
6. Gordon LI, Molina A, Witzig T, et al: Durable responses after Ibritumomab Tiuxetan radioimmunotherapy for CD20+ B=cell lymphoma: Long term follow-up of a phase I/II study. Blood. In press.
7. Witzig TE, White CA, Gordon LI, et al: Safety of yttrium-90 ibritumomab tiuxetan radioimmunotherapy for relapsed low-grade, follicular, or transformed non-Hodgkin’s lymphoma. J Clin Oncol 21:1263-1270, 2003.
8. Travis LB, Curtis RE, Stovall M, et al: Risk of leukemia following treatment for non- Hodgkin’s lymphoma. J Natl Cancer Inst 86:1450-1457, 1994.
9. Winter JN, Inwards D, Erwin W, et al: Phase I trial combining 90Y Zevalin and high-dose BEAM chemotherapy with hematopoietic progenitor cell transplant in relapsed or refractory B-cell NHL (abstract). Blood 98:2835a, 2001.
10. Mehta MP, Rodrigus P, Terhaard CH, et al: Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases. J Clin Oncol 21:2529-2536, 2003.
11. Magda D, Lepp C, Gerasimchuk N, et al: Redox cycling by motexafin gadolinium enhances cellular response to ionizing radiation by forming reactive oxygen species. Int J Radiat Oncol Biol Phys 51:1025-1036, 2001.
12. Ansell SM, Ristow KM, Habermann TM, et al: Subsequent chemotherapy regimens are well tolerated after radioimmunotherapy with yttrium-90 ibritumomab tiuxetan for non- Hodgkin’s lymphoma. J Clin Oncol 20:3885- 3890, 2002.