When is a predose a dose too much?

To the editor:

We read with great interest the review by Sharkey and colleagues¹  that provides a fascinating and informative perspective on the practice of delivering a “cold” or predose of monoclonal antibody (mAb) before the delivery of the radioimmunconjugate in radioimmunotherapy (RIT) of B-cell lymphoma.

This review is important as it raises several clinically relevant questions to the application of RIT in the rituximab era. Predosing with unlabeled or “cold” anti-CD20 mAb has become standard practice in RIT targeting the CD20 antigen.^2,3  The predose has been shown to increase tumor targeting of the labeled mAb by blocking “nonspecific” binding sites such as circulating and splenic B cells and is used in both licensed RIT approaches (⁹⁰Y-ibritumomab tiuxetan [Zevalin] and ¹³¹I-tositumomab [Bexxar]). It is indeed timely to readdress the question of the optimal approach to predose, as in contrast to the pioneering studies, the majority of patients who are currently suitable for RIT have received rituximab.

The recent publication of the FIT study has provided compelling evidence for the efficacy of ⁹⁰Y ibritumomab after induction chemotherapy with patients randomized to RIT enjoying more than a 2-year improvement in progression-free survival.⁴  However, the majority of patients in this study did not receive rituximab containing regimens. Therefore an important question in current clinical practice is whether predose is necessary as part of an RIT consolidation therapy after rituximab containing chemotherapy. This issue comes into sharper focus, if as suggested by Sharkey and colleagues, repeated doses of rituximab may prevent subsequent binding of radiolabeled anti-CD20 antibody to tumor and thus potentially compromise tumor targeting and clinical efficacy. Further uncertainty arises when examining the relative paucity of data on which the current licensed RIT approaches are given.^2,3  The licensed predosing regimen for ⁹⁰Y-ibritumomab was based on just 6 patients with differences observed in the biodistribution between 125 mg/m² and 250 mg/m² of rituximab and the higher dose was selected on the basis of the potential increased clinical activity of large doses of rituximab.³ 

Sharkey and colleagues cite recent preclinical evidence supporting the view that rituximab, if given in high enough doses, blocks the binding of the anti-CD20 radioimmunoconjugate in a Burkitt lymphoma xenograft model.⁵  In such xenograft models there is no cross-reactivity of the predose mAb targeting the normal host B-cell reservoir, leaving a finite antigen sink that is entirely limited to the small human tumors. In this context it is perhaps not surprising the tumors can be saturated with large enough doses of rituximab. Perhaps these important questions must ultimately be addressed in well designed clinical studies?

Currently there is a lack of evidence from clinical studies that prior rituximab compromises subsequent anti-CD20 based RIT. In stark contrast to the preclinical data, recent phase II clinical data using several doses of induction therapy with rituximab alone or as part of Rituximab containing chemotherapy have led to excellent clinical efficacy with high rates of conversion from partial to complete response after RIT.⁶  Our own recently published study attempts to address this predose question. We found that induction therapy with rituximab significantly increases the effective half-life of subsequent ¹³¹I-rituximab and correlated with increased effective half-life of the ¹³¹I-rituximab.⁷  Importantly, we demonstrated that multiple doses of rituximab did not appear to compromise the clinical efficacy or increase the myelotoxicity of subsequent anti-CD20 targeted RIT.

Targeting another antigen such as CD45, as suggested in the review,¹  certainly bypasses the possible CD20 antigen competing effect from rituximab and is potentially an important approach to explore further. However, such an approach does not negate the predose issue, as the same dilemma remains as to how best to improve the targeting of radiolabeled anti-CD45 antibody targeting with a predose of anti-CD45.

The concern over excessive predosing adversely affecting tumor targeting in anti-CD20 based RIT remains an important theoretical concern. However decreased targeting leading to decreased efficacy of RIT has not thus far been observed in the clinic and if there is a deleterious effect with large amounts of mAb predosing, this does not appear to substantially affect the clinical efficacy.⁷  Perhaps of greater concern in improving outcomes for patients with follicular lymphoma is the gross under usage of RIT. In an era where immunochemotherapy has substantially improved outcome, it is perhaps easier to become complacent that using such an effective treatment is not required in the treatment algorithm of follicular lymphoma. For those with low risk FLIPI disease that achieve long-lasting complete remission with rituximab containing regimens that may be so; however lest us not forget the heterogeneity of this disease, the toxicity associated with multiple courses of anthracycline based chemotherapy and the increasing number of patients who will in time become refractory to chemotherapy and rituximab. For the latter groups the unique mechanisms of action of RIT have resulted in high activity with durable remissions in both chemotherapy and rituximab refractory disease.^8,9  Perhaps what is currently required, as suggested by Sharkey and colleagues, is a “re-examination of radioimmunotherapy in the treatment of non-Hodgkin lymphoma” and an integration of this unique approach for some patient groups with follicular lymphoma. There is little doubt that RIT can be enhanced further by adopting the type of RIT/antibody combinations suggested and that such an approach could provide a viable alternative or enhance the responses for patients receiving immunochemotherapy regimens. By adopting such a considered re-examination this will ensure that the future is radiant for many patients with difficult to treat follicular lymphoma and potentially other NHL as well.