Consolidation radioimmunotherapy of follicular lymphoma: a step towards cure?

Abstract

Radioimmunotherapy (RIT) of non-Hodgkin’s lymphoma was pioneered at the end of the 1980s [1, 2]. This clinical indication was chosen because of the availability of appropriate antibodies and of the relative radiosensitivity of lymphoma cells: Even moderate absorbed doses were expected to translate into some tumor response. In the meantime, rituximab, a naked chimeric anti-CD20 antibody, became a real clinical and commercial success and is now part of the standard treatment of CD20 positivediffuse large B cells and follicular non-Hodgkin’s lymphoma. However, it is clear that rituximab administered in combination with chemotherapy is not a curative treatment of follicular lymphoma. Thus, radiolabelled anti-CD20 antibodies have been introduced with the aim of improving the efficacy of naked antibodies. Multiple clinical studies were performed first with tositumomab/iodine-131 tositumomab (Bexxar; GlaxoSmithKline, Philadelphia, PA, USA) then with rituximab/yttrium-90 ibritumomab tiuxetan (Zevalin; Biogen Idec, Cambridge, MA, USA), which demonstrated both their safety and efficacy with overall response rates between 50% and 80% and complete response (CR) rates between 20% and 40% in patients with relapsed, refractory or transformed follicular nonHodgkin’s lymphoma. Subsequently, both products have been approved in the US (tositumomab/iodine-131 tositumomab and rituximab/yttrium-90 ibritumomab tiuxetan) and one in Europe (rituximab/yttrium-90 ibritumomab tiuxetan). In the absence of randomised trials, it is difficult to compare the safety and efficacy of both products. Nevertheless, it appears from the literature that they are roughly comparable in terms of response rates and progression-free survival (PFS) even if tositumomab/ iodine-131 tositumomab using a patient-specific dosing regimen seems to induce less bone marrow toxicity than rituximab/yttrium-90 ibritumomab tiuxetan using weightbased dosing regimen [3]. However, from the time of approval, their routine use has not been very successful, with sales showing a much slower progression than expected. Several reasons to this limited commercial performance have been put forward. First, RIT needs a close coordination between haematologists and nuclear medicine physicians. Some referring physicians or haematologists have certainly considered that such coordination was too difficult and RIT too cumbersome even if it is quite simple in a routine practice in most institutions [4]. A stronger reason of the limited success was probably the nonsignificant difference of time to progression (TTP) between patients treated with RIT and those treated with rituximab, making haematologists rather disappointed [5]. In routine clinical practice, both radiopharmaceuticals have been mainly used as a last-line, salvage treatment in patients who had often high tumor burden and had been heavily pretreated, whereas clinical trials had clearly shown that TTP was significantly longer when RIT was used at an earlier stage, after only one prior therapy [6]. There is a relative consensus to consider that the best indication of RIT is the treatment of residual disease characterised by small-sized or microscopic tumors, which are still rather well vascularised and consequently accessible to circulating radiolabelled antibodies. Moreover, the small size of the tumors fits well with the short path length of electrons emitted by iodine-131 (<2 mm) and by yttrium-90 (<5 mm). This favourable situation of residual disease prompted investigators to use RIT as a consolidation Eur J Nucl Med Mol Imaging (2008) 35:1236–1239 DOI 10.1007/s00259-008-0727-z