Bob,
Whoops - if I ever did see a statement about *results* of a lower fludarabine dose in the Rituxan combo trials, I certainly can't find it now. Looks like a faulty recollection, thanks for keeping me honest... ;-)
FWIW, it seems that the investigator who reported on this at ASCO (the reference I saw) put a finer point on the dose adjustment than the Medscape writer whose piece you saw. The Medscape piece said:
"However, unexpectedly severe hematologic toxicity has been seen, necessitating a 40% reduction of the fludarabine dose (25 mg/m2 x 3 days) in future protocols."
medscape.com
whereas the investigator in the 1999 ASCO abstract stated more specifically that the dose would be lowered only for those with "prolonged cytopenia" or something to that effect.
(for those who might not know where to find ASCO abstracts, search the last three years at
asco.org
So, since we don't know at this point how much efficacy we might lose from lowering the Fludara dose, and exactly what percentage of people will require it to be lowered, and indeed whether or not they've run into this in the Bexxar trials (my suspicion is they have, but only because both Rituxan and Bexxar are similar in that they are MAbs that bind CD20), it looks like we have to keep this in mind as a factor that has the potential to cause the results from either or both Fludara combo trials to disappoint somewhat. Not mixing well with fludarabine is perhaps a bigger risk for Bexxar than Rituxan here, as Bexxar presumably becomes a better first-line option when combined with the fludarabine-induced immunosuppression exerting a likely limiting effect on HAMA.
A question about your personal opinion on optimal first-line treatment, as well as Bexxar vs. Rituxan efficacy - you wrote:
"In any event, I will modify my question to "why Bexxar+fludarabine instead of Rituxan+(CHOP or fludarabine) for first-line treatment?" Obviously this can't be answered now, but it will be very interesting to see how this unfolds."
As regards optimal first-line treatment - I agree with you that it is certainly impossible to know with any certainty what this will turn out to be, only final trial results and an FDA stamp can tell us that, but of course some investing success may accrue to those who gauge the existing data better than others and place the appropriate bets (in retrospect, my statement that "the most powerful combination is obvious" is poorly stated, my real feeling is that the *best bet* for the most powerful combination is obvious here). So, I'd be interested to know whether you have an opinion on which combination is the better bet to dominate first-line treatment (if indeed either one succeeds in doing so). Sounds like you may be content on the fence right now, but I may be misreading you...
In the simplest terms, my preference for Bexxar+fludarabine as best bet for optimal first-line therapy is grounded in the idea that we start by choosing Bexxar over Rituxan for the anti-CD20 component of the combination, owing to Bexxar's superior treatment results (although some will still argue those). I approach the chemo component second since the literature seems to suggest that we can get comparable efficacy from Fludara/Fludara combinations versus CHOP. So if you are indeed on the fence, did you diverge with me on the belief that Bexxar provides superior treatment to Rituxan?
I think that V1 recently stated the superiority argument very well, that regardless of squabbles over complete response criteria (in which category I still believe Bexxar is superior), the most crucial issue here given the nature of this disease is durability of response, and that's where Bexxar is extraordinary. As we know from the pivotal trial data, Bexxar has reversed the natural course of the disease, providing patients with longer duration of remission than their last treatment more often than not. I have seen no such claims from IDEC about Rituxan, and if they had such data, I think they would be shouting it. V1 posted some Rituxan data awhile back that showed on average shorter duration of response with Rituxan vs. last chemo. Because the natural course is for each remission to be shorter in duration than the last, it seems patients will gravitate toward the treatment that offers longest first remission with at least comparable potential side effects. Seems you have best odds of getting the largest total remission time if the first one is very long.
So when we go on to consider that the *early* first-line results from Bexxar *by itself* look comparable to Rituxan+CHOP in terms of response rates (I'm planning to post some more on that, and some good reasons for why we can know these particular results are comparable regardless of criteria squabbles), add to that what we know about durability of Bexxar remissions, then add to that the *much* milder side effects of Bexxar vs. Rituxan+CHOP, not to mention a much easier dosing schedule for Bexxar, then we see that Bexxar is already clearly in the lead here (assuming the early data holds up), except for the HAMA issue. I'd prefer to bet that we can add the right amount of Fludara to provide immunosuppression along with some added possible *supra-additive* anti-neoplastic synergy without upsetting the side-effects applecart, than bet that Rituxan+CHOP wins because HAMA is still too big of an issue regardless of our efforts. Still a bet though - as you say, how this plays out will be very interesting indeed.
One tidbit on potential CHOP side effects - for anyone who's not familiar, they're not a picnic, and that may limit the prospects for CHOP ending up in the preferred first-line combination absent some clear benefits to overall survival or duration of remission (CVP is standard of care for indolent lymphoma first-line chemo rather than CHOP right now due to the harsher CHOP regimens not having shown overall survival benefits to CVP). From the 1998 Rituxan+CHOP ASCO abstract, here's just the severe and life-threatening toxicities encountered:
"Toxicity included grade 4 neutropenia in 13 pts (17 cycles). Grade 3 toxicities included neutropenia (16 cycles), dehydration (4 cycles/2 pts), asthenia (3 pts), abdominal pain/back pain (2 pts each), intestinal obstruction (1 pt), hypersensitivity (1 pt), arthralgia/arthritis (1 pt each), anorexia (1 pt), diarrhea (1 pt), nausea/vomiting (1 pt each), anemia (1 pt)."
Seems the Rituxan was not implicated in this, they indicate this is par for the course with CHOP.
Bob - Glad you found my post interesting. I've enjoyed following your posts hereabouts, and your contributions to this discussion have been very helpful to me.
Cheers!
Gordon |
