Peter,
Has CLTR disclosed whether there is in fact significant patient-to-patient variation in the dose they end up using?
Good question - I'm going to dig into some materials (perhaps pay another visit to the invaluable PB shrine ;-) and see what information might be available on actual Bexxar dosing.
There is an interesting ASH abstract from Coulter that supports the importance of their dosimetry, in particular, how extent of disease for each patient impacts the effective half-life of Bexxar (see if you can find the slam against Zevalin and fixed dosing imbedded in the abstract):
EXTENT OF DISEASE IMPACTS THE EFFECTIVE HALF-LIFE OF IODINE I 131 TOSITUMOMAB IN NON-HODGKIN'S LYMPHOMA (NHL). <snip>
BexxarTM (tositumomab and Iodine I 131 tositumomab) has been demonstrated to be safe and effective as a single agent in the treatment of low-grade and transformed low-grade NHL. Dosimetry studies enable the calculation of total body effective half-life (T1/2) of this agent. In bulky disease or in the minimal residual disease setting following chemotherapy, this may be particularly relevant. Patients receive a single dosimetric dose (450 mg of tositumomab IV over 1 hour followed by 35 mg (5 mCi) of Iodine I 131 tositumomab) with 3 total body counts obtained over the next 6 to 7 days. Seven to 14 days after the dosimetric dose, a patient-specific therapeutic dose of Iodine I 131 tositumomab is given, with activity to deliver a 75 cGy total body dose (adjusted to 65 cGy for platelet count 100,000 to 149,000 cells/mm3). To assess the impact of extent of disease on the effective T1/2 of Iodine I 131 tositumomab, we evaluated 53 patients (29 males, 24 females) treated at the New York-Cornell Center for Lymphoma and Myeloma in 4 different studies, one of which included debulking chemotherapy 6-8 weeks prior to Iodine I 131 tositumomab. <snip>
In conclusion, the effective half-life of Iodine I 131 tositumomab in NHL patients was reduced in the presence of splenomegaly and higher tumor burden. Significant patient variability is present, supporting the importance of individualized patient dosing. Administration based on a fixed mCi/m2 dose may lead to significant underdosing for patients with splenomegaly or high tumor burden and overdosing for those with minimal disease. These factors may be even more relevant in the development of new treatment regimens incorporating debulking chemotherapy prior to radioimmunotherapy.
In fairness to the Zevalin researchers, they insist that their 111In dosimetry has not been a useful predictor of marrow toxicity - I would speculate that this might be due to the much shorter radioactive half-life of Zevalin's 90Y (64 hours) versus Bexxar's 131I (8 days). I suppose it becomes more important to tweak the dose when the radiation will be in the body for an addition 4 or 5 days. On the other hand, this may only be an indication that the Zevalin dosimetry process (using 111In-labeled antibody as a dosimetry surrogate for the therapeutic 90Y-labeled antibody) is fundamentally flawed, ie, they've found it's not a useful predictor of marrow toxicity because of subtle differences in pharmacokinetics between 111In-labeled antibody vs. 90Y-labeled.
We don't have this question about Bexxar because they are able to use the same drug for dosimetry and therapeutic dose, due to the 131I emitting both beta and gamma particles. But if Zevalin surrogate dosimetry is really flawed, then they've kind of taken lemons and made lemonade - they say, "we're going to have simplified standard dosing with no dosimetry because we've shown that the dosimetry doesn't help any", but the reality would be that they're just not capable of doing what is done with gamma-emitting Bexxar. If this is so, this would be one of those theoretical reasons that Bob L has been looking for to explain why we might see higher marrow toxicity with Zevalin than with Bexxar.
In looking through the literature on this, I get the impression that the jury may still be out on the extent to which 111In-labeled antibody makes an entirely adequate dosimetry surrogate for 90Y. In the following abstract from a journal article, we see that these researchers (working with a different antibody) found that it was a generally accurate surrogate, but importantly, that it resulted in inaccurate prediction of radiation dose to the marrow:
Monoclonal antibodies (MoAb) labeled with 90Y are being used for radioimmunotherapy. Because 90Y is a beta emitter, quantitative information from imaging is suboptimal. With the concept of a "matched pair" of isotopes, 111In is used as a surrogate marker for 90Y. We evaluated the differences in biodistribution between 111In- and 90Y-labeled murine antiTac MoAb directed against the IL-2Ralpha receptor. <snip>
This study shows that differences typically ranging from 10% to 15% exist in the biodistribution between 111In- and 90Y-labeled antiTac. Thus, it appears that 111In can be used as a surrogate marker for 90Y when labeling antiTac with the 1 B4M chelate, although underestimates of the bone marrow radiation dose should be anticipated.
J Nucl Med, 40(2):268-76 1999 Feb
Not entirely damning to Zevalin, it's a different antibody and receptor target, but certainly raises a question in an area where there is none with Bexxar.
Cheers,
Gordon |
