The activity of radio-immuno conjugate in Non-Hodgkin Lymphoma (NHL) has resulted in FDA approval of two antibodies, Y(90) Ibritumomab tiuxetan and I(131) tositumomab. Both these agents target CD20, a receptor widely expressed in B-Cell NHL. These immunoconjugates deliver their radioactive payload to the malignant clone in the bone marrow and lymph node. Their use has been associated with modest improvement in survival end points among several lymphoma histologies. The promising effect on disease control as well as their efficacy in disease relapse is encouraging in low grade lymphoma. Radioimmunotherapy (RIT) is increasingly being explored in the setting of consolidation as well as conditioning regimens prior to stem cell transplantation. Here, we summarize the clinical use, complications and future applications of RIT in NHL.

Radioimmunotherapy (RIT) is a safe and effective therapeutic option for patients with indolent B-cell non-Hodgkin lymphomas (NHL), in both up-front and relapsed/refractory settings. Two approved agents (90Y-ibritumomab tiuxetan and 131I-tositumomab) are available in the United States. Both target CD20 with similar clinical outcomes but with unique clinical considerations and radiation precautions due to the use of varying radioisotopes.This paper reviews the available evidence for these approved RIT agents and examines the recently published and ongoing clinical trials of potential novel indications for aggressive B-cell NHL.A pretreatment biodistribution evaluation required before administering the 90Y-ibritumomab tiuxetan therapeutic dose has been removed, which once limited its usage. The potential clinical applications of RIT include relapsed/refractory indolent B-cell NHL, diffuse large B-cell lymphoma, indolent lymphoma in the front-line setting, and mantle cell lymphoma. Multiple novel RIT agents are in preclinical and clinical development, and the addition of radiosensitizers or external-beam radiotherapy may act in synergy with RIT for both indolent and aggressive lymphomas. The risk of treatment-related myelodysplastic syndrome does not appear to be higher in patients treated with RIT over those receiving chemotherapy alone.RIT is a safe, effective, and significantly underutilized therapy for patients with B-cell NHL, and many studies have demonstrated the efficacy of 90Y-ibritumomab tiuxetan and 131I-tositumomab for relapsed/refractory indolent B-cell lymphomas. Continued research to establish its efficacy for other lymphoma subtypes is warranted.

Mantle cell lymphoma (MCL), though characterized by the chromosomal translocation t(11; 14) (q13; q32), is a heterogeneous disease. Often termed an aggressive lymphoma in the U.S., but included in indolent lymphoma trials in Europe, MCL is not curable with standard immuno-chemotherapy. There is no single standard initial therapy for this disease. Although standard lymphoma therapies yield high response rates, relapse is inevitable. Unmet needs in MCL include better induction therapy, consolidation treatments to prolong first remission and better therapeutic options for relapsed disease. In this review, we evaluate the role of radioimmunotherapy (RIT) in MCL, a novel strategy combining monoclonal antibodies with radioisotopes to deliver radiation directly to tumour tissue, both in the frontline and relapsed setting.

To exploit the B-lymphocyte antigen-CD20 binding capacity of the Ibritumomab tiuxetan (IBTN) monoclonal antibody (mAb) for imaging, the over-expression of B cells in non-Hodgkin's lymphoma (NHL) (a myeloproliferative disorder of the lymphatic system) was investigated. In the current investigation, we present the labeling of the IBTN with technetium-99m ((99m)Tc) through [(99m)Tc(CO)(3)](+) precursor for radioimmunoimaging (RII) of the tumor prior to its treatment with (90)Y labeled IBTN. Labeled IBTN was radiobiologically characterized in terms of radiochemical purity, in vitro stability in human plasma, immunoreactivity, binding with Raji and Ramos cells and biodistribution in a female nude mouse (FNM) model. It was observed that the reduced IBTN (rIBTN) showed more promising radiobiologic characteristics than the nonreduced IBTN. Significantly higher transchelation was seen in excess cysteine compared with histidine. The radioconjugate showed higher saturated binding affinity with CD20 antigen. Significantly higher target (tumor) to background ratios were observed 1 h post-injection (p.i.). Based on radiochemical purity, in vitro stability, immunoreactivity, binding and biodistrubtion in the FNM model, we recommend the radiolabeling of the rIBTN using tricarbonyl technique as a potential RII agent.

Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has long been a standard treatment for lymphoma. Improvements to the efficacy of this regimen can be made by increasing the doses of doxorubicin and cyclophosphamide, as in the chemotherapeutic regimen of doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP), and by reducing the standard dosing interval, as seen with the CHOP-14 regimen. Adding the immunotherapeutic agent rituximab (R) to either CHOP or ACVBP has been shown to improve outcomes significantly, such that six cycles of R-CHOP plus two cycles of ritux-imab are as effective as eight cycles of R-CHOP, and R-CHOP-21 appears to be at least as effective as the more dose-intense R-CHOP-14. In patients who have several adverse prognostic factors, R-ACVBP plus autologous stem-cell transplantation has been shown to produce good treatment outcomes. The use of positron emission tomography scanning before and early in treatment should allow prediction of long-term outcomes, and therefore the adaptation of treatment to individual prognosis and treatment needs. In patients with follicular lymphoma, rituximab has been shown to improve the efficacy of conventional chemotherapies. In addition, rituximab alone or yttrium-90-ibritumomab tiuxetan are effective maintenance therapies in this condition.

In 2008, we reported favorable 5-year outcomes of nonmyeloablative allogeneic stem cell transplantation after fludarabine, cyclophosphamide, rituximab (FCR) conditioning for relapsed and chemosensitive follicular lymphoma. However, innovative strategies were still needed to treat patients with chemorefractory disease. We therefore subsequently performed a trial in which (90)Y-ibritumomab tiuxetan (0.4 mCi/kg) was added to the fludarabine, cyclophosphamide conditioning regimen ((90)YFC). Here, we report updated results of the FCR trial and outcomes after (90)YFC. For the FCR group (N = 47), since the last update, one patient developed recurrent disease. With a median follow-up of 107 months (range, 72-142 months), the 11-year overall survival and progression-free survival rates were 78%, and 72%, respectively. For the (90)YFC group (N = 26), more patients had chemorefractory disease than did those in the FCR group (38% and 0%, P < .001). With a median follow-up of 33 months (range,17-94 months), the 3-year progression-free survival rates for patients with chemorefractory and chemosensitive disease were 80% and 87%, respectively (P = .7). The low frequency of relapse observed after a long follow-up interval of 9 years in the FCR group suggests that these patients are cured of their disease. The addition of (90)Y to the conditioning regimen appears to be effective in patients with chemorefractory disease. This trial was registered at www.clinicaltrials.gov as NCT00048737.

The immunotherapy of cancer has made significant strides in the past few years due to improved understanding of the underlying principles of tumor biology and immunology. These principles have been critical in the development of immunotherapy in the laboratory and in the implementation of immunotherapy in the clinic. This improved understanding of immunotherapy, enhanced by increased insights into the mechanism of tumor immune response and its evasion by tumors, now permits manipulation of this interaction and elucidates the therapeutic role of immunity in cancer. Also important, this improved understanding of immunotherapy and the mechanisms underlying immunity in cancer has fueled an expanding array of new therapeutic agents for a variety of cancers. Pegylated interferon-α2b as an adjuvant therapy and ipilimumab as therapy for advanced disease, both of which were approved by the United States Food and Drug Administration for melanoma in March 2011, are 2 prime examples of how an increased understanding of the principles of tumor biology and immunology have been translated successfully from the laboratory to the clinical setting. Principles that guide the development and application of immunotherapy include antibodies, cytokines, vaccines, and cellular therapies. The identification and further elucidation of the role of immunotherapy in different tumor types, and the development of strategies for combining immunotherapy with cytotoxic and molecularly targeted agents for future multimodal therapy for cancer will enable even greater progress and ultimately lead to improved outcomes for patients receiving cancer immunotherapy.

A total of 20 patients enrolled in a multicenter phase II dose escalation study of radioimmunotherapy (RIT) using yttrium-90-ibritumomab tiuxetan at two dose levels (22 and 30 MBq/kg) in 10 patients, combined with reduced intensity conditioning (RIC) using fludarabine, melphalan and alemtuzumab followed by allogeneic hematopoietic cell transplantation (HCT) from either matched-related (n=5) or matched-unrelated donors (n=15). Postgrafting immunosuppression with cyclosporine was administered. Diagnoses were diffuse large B-cell lymphoma (n=13), transformed CLL (n=4), blastic mantle cell lymphoma (n=2) and follicular lymphoma grade 3 (n=1). Median age was 51 (range, 29-69) years. All patients were high risk with relapsed/refractory disease or relapse after preceding autologous HCT. Median follow-up of patients alive was 1115 (range, 1006-1252) days. No directly RIT-related toxicities were observed. The cumulative incidence of non-relapse mortality was 30%. Incidences of grade II-IV acute and chronic GvHD was 45% and 70%, respectively. Kaplan-Meier estimated 3-year OS and EFS were 20% for both dose levels. In conclusion, dose escalation of RIT and combined use with RIC is feasible with no additional toxicity due to dose escalation. This study is registered on http://clinicaltrials.gov as NCT00302757.