Interestingly IDPH had to halt the Rit plus Fludara trial because of toxicity.
Interesting indeed, but does not seem to make sense in a linear world. I think we can all agree that Rituxan by itself is a less toxic agent than Bexxar. Then adding a constant toxicity, fludarabine, is not expected to reverse the comparison. That is, if the effects were simply additive; maybe they are not.
One thing that I believe is right, but have not looked into in detail, is that the amount of antibody required in Rit therapy is quite a bit larger than in Bex. Also, the former being chimeric has serum half-life of weeks instead of very few days like Bex. What am I driving at? I know little (nothing really, but see below) of how the Rit+flu study was conducted, but one can imagine some problems due to the above if the two agents did get to coexist inside the patient for some extended period. In Bex+flu, as I understand it, they really never do as the administration is sequential and akin to a 1-2 punch. Here is a link for easy reference:
nycornell.org
Patients received three cycles of fludarabine (25 mg/m2 x 5 d every 5 weeks) followed six to eight weeks later by tositumomab, iodine I 131 tositumomab
I found this protocol for Rit+flu for BCCL, not sure if still going on, but looks backwards from the above:
cancer.ucsd.edu
INDUCTION:
Rituximab:
week 1, days 1 and 4
day 1 of weeks 5, 9, 13, 17, and 21
Fludarabine IV for 5 days on Weeks 1, 5, 9, 13, 17, and 21
...
So yes, they are given pretty much concurrently.
And here is Rit+flu in NHL:
pslgroup.com (dated May 19, 1999)
Eighteen of the 40 patients planned have been enrolled to the R & F study at RPCI. Of the first 10 patients treated: seven have completed all therapy (six complete remissions and one partial remission); three patients were taken off late in the study due to toxicity. The last eight patients are currently on therapy. No serious or opportunistic infections have been observed and mean quantitative immunoglobulin levels and natural killer cells are preserved. Non-hematologic toxicities have been minor. The study has been amended to allow the dose of fludarabine to be reduced in cases of prolonged cytopenia. Combination chemoimmunotherapy of R & F appears to have significant antitumour activity in patients with low-grade B-cell NHL and study accrual to 40 patients will continue as planned.
Prolonged cytopenia? Hmm, maybe there is something here.
On a related topic, I found this version of Peter's economics-toxicity abstract that contains a bit more detail:
ex2.excerptamedica.com
Do note that this is not "one data point" but rather a retrospective analysis of many data points. Also Fludara leads to about as many adverse effects as CHOP (111 in 50 patients for FLU versus 119 in 48 for CHOP), but the latter's ones are more expensive to treat, probably because they are more serious.
Here, more economics:
208.240.92.166
For now, let's see if they can get that BLA filed.
PB
P.S. berblady, we do read your stuff here -g- |
