Report of a European consensus workshop to develop recommendations for the optimal use of (90)Y-ibritumomab tiuxetan (Zevalin) in lymphoma.

BACKGROUND: Non-Hodgkin's lymphoma (NHL) comprises a group of related haematological malignancies, predominantly of B-cell origin, which have been described as indolent or aggressive according to their clinical course. Standard treatment for indolent NHL consists of conventional chemotherapy, but, although long-term remissions may occur, most patients will die of their disease. Radioimmunotherapy (RIT) is a novel modality for treating indolent NHL, using monoclonal antibodies to target tumour cells with systemic, low-dose radiation. (90)Y-Ibritumomab tiuxetan (Zevalin); Schering AG, Berlin, Germany), the first RIT approved for use in relapsed/refractory indolent NHL, comprises the murine anti-CD20 monoclonal antibody ibritumomab, covalently linked to the high-energy beta-emitter, yttrium-90, by the chelator, tiuxetan. MATERIALS AND METHODS: A multidisciplinary consensus workshop of European clinicians who had taken part in clinical trials of (90)Y-ibritumomab tiuxetan was convened to develop recommendations for the clinical preparation and administration of (90)Y-ibritumomab tiuxetan in Europe. The workshop was held in anticipation of European Medicines Agency approval of this agent, which was gained in 2004 for adult patients with rituximab-relapsed or refractory CD20(+) follicular B-cell NHL. RESULTS AND CONCLUSIONS: This article summarises the consensus recommendations developed for hemato-oncologists.     

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.     

Monoclonal antibody therapy for B-cell lymphoma

Treatment strategies and outcomes for patients with non-Hodgkin's lymphoma (NHL) are undergoing rapid and important evolution. We have recently witnessed the advent of novel targeted therapies, such as gene therapies, active immunotherapies, antisense therapies, new small molecules and biologicals, and monoclonal antibodies (MoAbs). The first MoAb approved for the treatment of cancer, rituximab, was approved in 1997 and has been rapidly incorporated into treatment regimens for NHL. In a randomized trial in combination with CHOP chemotherapy (cyclophosphamide, hydroxydaunomycin, vincristine, and prednisone), rituximab showed superiority to CHOP for patients with diffuse large cell NHL (DLCL).The rituximab + CHOP combination has become the gold standard for frontline therapy for DLCL and has shown significant activity in the management of follicular NHL. In February 2002, the first radioimmunotherapeutic agent for the treatment of cancer, ibritumomab tiuxetan (Zevalin), was approved. Ibritumomab tiuxetan, an yttrium-labeled antibody used in conjunction with rituximab, has significant activity in follicular and transformed NHL. Use of rituximab has proved that antibodies are safe and active even as single agents. The results have helped dispel the negativity and biases resulting from many years of disappointing results in this important area of research. Results with rituximab have opened the doors to continued research and have provided the impetus necessary for renewed enthusiasm and optimism in continuing the search for curative regimens for patients with NHL.     

Upfront Consolidation Combining Yttrium-90 Ibritumomab Tiuxetan and High-Dose Therapy with Stem Cell Transplantation in Poor-Risk Patients with Diffuse Large B Cell Lymphoma

We evaluated the safety and efficacy of standard-dose yttrium-90 (Y⁹⁰) ibritumomab tiuxetan combined with high-dose BEAM (carmustine, etoposide, cytarabine, and melphalan) after first-line induction treatment in young patients with poor prognoses diffuse large B cell lymphoma (DLBCL) (clinicaltrials.gov: NCT00689169). Seventy-five high-risk (≥2 International Prognostic Index [IPI] factors) consecutive DLBCL patients (≤65 years old) in complete remission (CR) or partial remission (PR) after rituximab chemotherapy were treated with Y⁹⁰ ibritumomab tiuxetan and BEAM regimen followed by autologous stem cell transplantation (ASCT). The median follow-up was 34 months. Of the 75 patients, 71 underwent ASCT and were eligible for analysis. Median time to reach a neutrophil count of >500/μL and platelet count of >20,000/μL was 11 days. Mucositis ≥3 (51%) occurred in most patients. Other adverse events were similar to those seen with BEAM alone. The overall response rate was 86%; 59 patients (83%) achieved a CR or unconfirmed CR. The 2-year event-free survival (EFS), overall survival (OS), and disease-free survival were 79%, 83%, and 91%, respectively. Disease status (CR/PR) and positron emission tomography (PET) findings before transplantation did not predict treatment failure. The IPI (2 versus >2) and maximum tumor diameter of ≥10 cm at diagnosis appeared to be prognosis factors for OS but not for EFS. Adding Y⁹⁰ ibritumomab tiuxetan to BEAM is safe and does not increase transplantation-related toxicity. First-line consolidation with Y⁹⁰ ibritumomab tiuxetan and high-dose chemotherapy induced high rates of EFS and OS in poor-prognosis patients with DLBCL, regardless of PET status after induction treatment and warrants a randomized study.     

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.     

Consolidation with 90Yttrium‐ibritumomab tiuxetan after bendamustine and rituximab for relapsed follicular lymphoma

Bendamustine and rituximab (BR) are widely used in patients with follicular lymphoma (FL) previously treated with conventional immunochemotherapy, but the role of consolidation radioimmunotherapy in these patients is unknown. This study evaluated the efficacy and safety of consolidation with ⁹⁰Yttrium‐ibritumomab tiuxetan (⁹⁰Y‐IT) after re‐induction therapy with BR in patients with previously treated FL. This study included adult patients with relapsed FL who had undergone one or two prior therapies. Re‐induction therapy with BR was administered every 4 weeks up to 4–6 cycles. If patients achieved at least partial response, ⁹⁰Y‐IT was administered as consolidation therapy. The primary endpoint was 2‐year progression‐free survival (PFS) after consolidation. A total of 24 FL patients (median age 60 years) who had undergone one (n = 17) or two (n = 7) prior treatments received BR. After BR therapy, 22 patients proceeded to consolidation with ⁹⁰Y‐IT, resulting in an overall 88% response rate to the protocol treatment. Within a median observation period of 46.8 months, the estimated 2‐year PFS rate after the consolidation among the 22 patients receiving ⁹⁰Y‐IT was 59% (95% confidence interval [CI], 38%–77%). Patients whose remission after previous treatment had lasted ≥2 years had a significantly higher 2‐year PFS rate than patients whose remission after previous treatment had been <2 years (68% vs. 33%, Wilcoxon p = 0.0211). Major adverse events during the protocol treatment and within 2 years after the consolidation were hematological toxicities, but they were generally acceptable. Consequently, the estimated 2‐year overall survival after the consolidation was 95% (95% CI, 74%–99%). In conclusion, in a subset of patients with previously treated FL, ⁹⁰Y‐IT consolidation after BR re‐induction conferred a durable remission, indicating that consolidation therapy using ⁹⁰Y‐IT may be a novel therapeutic option for patients with relapsed FL (UMIN000008793).     

Current results and future applications of radioimmunotherapy management of non-Hodgkin's lymphoma

Monoclonal antibodies labeled with radionuclides have become an important therapeutic tool in the treatment of patients with non-Hodgkin's lymphomas (NHL). At the present time, their use in the US is approved for patients with rituximab-resistant, low-grade, follicular or transformed NHL. Encouraging responses seen in the relapsed and refractory patients have prompted their evaluation in earlier disease or in other histologic sub-types either alone or in combination with conventional chemotherapy. Additionally, they have been included as preparative regimens for stem cell transplant protocols within the context of clinical trials. This review discusses the latest clinical trials and future directions of radioimmunoconjugates in the treatment of NHL, with emphasis on US Food and Drug Administration (FDA) approved radioimmunoconjugates, namely ¹³¹I-tositumomab and ⁹⁰Y-ibritumomab tiuxetan.     

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.