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BSc PhD MRCP FRCR
Professor of Targeted Therapy and Oncology
Despite the sensitivity of most lymphomas to initial therapy with chemotherapy or radiotherapy, the majority of patients with advanced non-Hodgkin lymphoma (NHL) eventually relapse and die of their disease.(1) Furthermore, patients with advanced low-grade lymphomas remain incurable, and survival rates have not changed since the early 1960s.(2)
The introduction of monoclonal antibody (mAb)-based therapy, initially with rituximab in the late 1990s and more recently with the conjugation of radioisotopes to mAb as part of radioimmunotherapy (RIT), has provided fresh hopes for NHL patients that their prognosis can be improved.
To date, antibodies directed towards the CD20 antigen on B-cells has dominated the field of mAb therapy and RIT for lymphomas. CD20 is highly expressed on mature B-cells and is present on 95% of B-cell lymphomas.(3) It is neither internalised nor shed from the cell surface and, on binding mAbs, it appears to initiate signalling and trigger cell death through apoptosis.(4)
The anti-CD20 mAb rituximab has become integrated in the treatment of most NHLs and, while the response rates of rituximab as a single agent remain modest, with complete response rates in single figures,(5) associating rituximab with combination chemotherapy (CHOP) has shown a survival advantage when used in the treatment of aggressive lymphomas, as well as dramatic improvements in progression-free survival for indolent lymphomas (follicular lymphoma).(6–8)
(131)I-labelled tositumomab (Bexxar(™)) and (90)Y-labelled ibritumomab tiuxetan (Zevalin(®)) are highly promising therapies with significantly increased overall and complete response rates compared with rituximab. Importantly, both drugs appear able to offer long durable remissions for some patients. As Zevalin is the first and only one of this class of radioimmunoconjugates to have been granted EU approval (in May 2004), this brief article will be limited to describing Zevalin.
Zevalin is composed of mAb ibritumomab covalently bound to tiuxetan, a high-affinity chelator for the radioisotope (90)Y. Ibritumomab is a murine IgG1 kappa mAb that specifically targets the CD20 antigen.(9) The tiuxetan chelator creates a high-affinity, stable, urea-type bond between the antibody and the radioisotope to prevent the radioisotope from dissociating and circulating around the body.(9)
Zevalin treatment first consists of a pretreatment with rituximab. The regimen is delivered over seven days on an outpatient basis. A course of treatment involves intravenous (IV) infusion of rituximab 250mg/m(2) on day 1 and a second IV infusion of the same dose of rituximab on day 7, immediately followed by an IV “slow push” 10-minute infusion of (90)Y-labelled Zevalin.
By labelling mAbs with beta-emitting radioisotopes, radiation can be targeted to the tumour, increasing the potential for clinical response. Lymphomas are highly radiosensitive tumours; furthermore, localised irradiation is the only treatment that offers potentially curative treatment for those patients with early-stage low-grade lymphomas. The potential advantage of RIT over other mAb-directed therapy is that it may kill tumour cells not directly targeted by the mAb via the “crossfire effect”. This can provide cell-kill to adjacent, antigen-negative tumour cells.(9) The unlabelled antibodies may bring about antitumour effects not only by recruiting the host immune system but also through inducing direct cell death.
(90)Y (now licensed for use with Zevalin under the brand name Yttracis(®)) offers a number of advantages over the most commonly used radioisotope in oncology practice, (131)I. (90)Y is a pure beta-emitter delivering higher-energy radiation (2.3MeV vs 0.6MeV) at a longer path length (5.3mm vs 0.8mm). This enhances the crossfire effect and may be advantageous in treating larger, less well vascularised tumour nodules.(9) The physical half-life is 64 hours, which matches the biological half-life of murine mAbs of Zevalin, and the absence of penetrating gamma emissions enables delivery as an outpatient treatment.
Zevalin is dosed according to the patient’s bodyweight and baseline platelet counts. For patients with platelet counts ≥150,000/mm(3), 5MBq/kg bodyweight is given, up to a maximum allowable dose of 1,200MBq. For patients with platelet counts of 100,000–149,000/mm(3), Zevalin is dosed at 11MBq/kg, up to a maximum allowable dose of 1,200MBq.
Clinical experience with Zevalin RIT
There is currently over 10 years’ experience with Zevalin RIT, and it has emerged as a safe, effective and well-tolerated therapy for relapsed “low-grade” NHL.(9) The majority of patients treated in the registration approval studies had relapsed follicular lymphoma. These published studies consistently showed high rates of overall and complete response rates in relapsed follicular lymphoma.
A randomised controlled trial of Zevalin versus rituximab in relapsed or refractory low-grade, or transformed follicular B-cell, NHL demonstrated a superior response rate of Zevalin over rituximab.(10) Seventy-three patients received two doses of rituximab 250mg/m(2) a week apart as predosing, followed by a single dose of Zevalin 0.4mCi/kg (15MBq/kg). Seventy patients in the control arm received rituximab 375mg/m(2) weekly for four weeks. The overall response rate was 80% for the Zevalin group, versus 56% for the rituximab-alone group (p=0.002). Complete responses were 30% and 16% in the Zevalin and rituximab groups, respectively. Both regimens were well tolerated, but, as expected, there was more myelosuppression in the RIT group.
An interesting and potentially important finding that emerged from this study was the relatively high response rates of Zevalin in patients who had become refractory to chemotherapy, which were significantly greater than those seen with rituximab. These data suggest that Zevalin offers hope for meaningful clinical responses, even in patients who have become refractory to chemotherapy.
Perhaps the most impressive finding to emerge from these initial studies was that around 70% of the patients who achieve a complete response remain in remission for years, with some patients treated in the early studies now in remission for more than five years after Zevalin treatment and with a median follow-up of almost four years.(11)
An analysis of prognostic factors has confirmed that this remarkable durability of response is unlikely to be accounted for by patient selection, as most of these durable remissions have been achieved in heavily chemotherapy-pretreated and chemorefractory patients with validated poor prognostic factors such as extensive prior therapy (one to nine regimens), bulky disease, high lactate dehydrogenase levels and extranodal disease. Only disease bulk correlated with the overall response rate, with a highly significant overall response rate of 90% (p<0.001) in patients with masses <5cm.(12)
The dose-limiting toxicity from RIT is myelosuppression, with delayed thrombocytopenia and neutropenia occurring at around four to six weeks after therapy. The extent and duration of the myelosuppression appears to depend upon bone marrow reserve (amount of previous chemotherapy, age of patient and degree of bone marrow infiltration). Around 28% of patients experience grade 4 neutropenia and 8% grade 4 thrombocytopenia in the Zevalin trials (n=261).(9) The nonhaematological toxicity is extremely modest, and even the haematological toxicity can be minimised if appropriate precautions are taken. Patients who have been heavily treated with chemotherapy, such as those with a reduced platelet count (<150 × 10(9)/l), need to be given a reduced dose of radioactivity. With this in mind, Zevalin 0.3mCi/kg (11.1MBq/kg) proved to be both safe and efficacious.(13,14)
Although the results for single-agent RIT are encouraging, the future is likely to involve integrating RIT into chemotherapy protocols, and the current challenge is to determine the optimal approach of integrating Zevalin RIT into chemotherapy schedules. Early data using Zevalin after chemotherapy to improve the quality of clinical responses from partial to complete look extremely promising.(15)
Zevalin RIT offers an excellent treatment alternative in relapsed follicular lymphoma. As Zevalin does not yet have NICE (National Institute for Clinical Excellence) approval in the UK, there is no established funding stream for this new drug and a full economic assessment of this “one-off” drug relative to, for example, eight cycles of R-CVP (rituximab plus cyclophosphamide, vincristine and prednisolone, which was recently given NICE approval) has not yet been performed. Data suggest that a single treatment of Zevalin has the same overall and complete response rates as eight cycles of R-CVP. The establishment of this drug requires an effective team approach between haematologists/oncologists, nuclear medicine physicians, nurses, radiopharmacists and medical physicists. The future for RIT, although extremely promising, will require established health service funding and a key number of centres that can routinely deliver this new drug which offers such great potential in the future treatment of lymphoma.