In the current issue of Clinical Lymphoma and Myeloma are articles by Daniel Catovsky and Kanti Rai about the relative merits of chlorambucil and fludarabine. I won't go into Kanti's article except to quote this "We do not by any means suggest that chlorambucil as a therapeutic agent should be abandoned."
Daniel's article goes much further. He suggests that clinical trials using chlorambucil have been unfairly biased against it. (Why would that be, I wonder? Could it be that there is no money to be made from chlorambucil?)
He presents evidence to show that the dose of chlorambucil needs to be at least 70 mg/sq meter/month and that the duration of treatment needs to exceed 6 months, preferably up to 12 months. I have already written about this until I am blue in the face, but here is additional evidence that I have not previously mentioned.
I had often puzzled over the fact that the French version of CHOP did so much better than other versions. The answer is now clear: they used double the dose of alkylating agent (cyclophosphamide) and half the dose of anthracycline (doxorubicin) as other people. The Jaksic trial of 1997 had impressive overall response rates of 89.5%. He pushed chlorambucil to toxicity at a dose of between 150-180 mg/sq m/month.
Catovsky comments that the chlorambucil arm of the bendamustine trial was a real outlier, with a response rate of only 31% and a PFS of only 7 months. This compares with the CLL4 trial which had a response rate of 72% and a PFS of nearly 2 years. What he doesn't realise is that the dose of chlorambucil in this trial was calculated according to 'ideal weight'. How many of us (especially we older ones) are at our ideal weight. And if you delve into the small print you find that 'ideal weight' is a function of height. So the dose of chlorambucil in that trial was calculated according to the patient's height! Who ever heard of such a thing? I cannot believe that anything other than obfuscation was intended. And to show Bendamustine in a more favorable light.
Chlorambucil is considerably less toxic than fludarabine, even when given in full doses. My spies tell me that Bendamustine is a lot more toxic than it is claimed to be. There is still life in the old dog, yet.
Unfortunately we live in an era of promotion (mostly not a solid enough ground) of expensive medicines, and even worse, I can't see a way out of it....
ReplyDeleteThere's a pile of examples, from thrombopoietin receptor agonists outperforming every other comparator, sophisticated antiXa inhibitors doing the same with the cheap and old fashioned warfarin and the story goes on with Azacytidine, newer proteasome inhibitors, newer TKIs inhibitorsinn CML and so on...
Admittedly drug companies put massive money into drug discovery and are not allowed to miss market entry, but this tale leaves me a with a sour taste and a bit suspicious. Is it without a reason? I'm not to tell, but I'm really in a need for a super duper statistician to shed some light into all these trials which lead to approvals....
I am grinning and pleased that you are feeling better!
ReplyDeleteFCR versus Bendamustine+Rituxan.
ReplyDeleteIt is possible to say which get better results and are less toxic for untreated symptomatic CLL patients or
it is necessary wait for more trial results?
Thank you Dr. and the best recovery.
Jorge
Whether the "old dog" is Chlorambucil or Dr. Hamblin, I'm glad there is life in it yet.
ReplyDeleteAll the best,
Lynn S.
Glad you are back Dr. H
ReplyDeleteWhen consider chlorambucil treatment for first line who would you consider to be the ideal patient?
In other words what in a patient's CLL profile would make you recommend chlorambucil over fludarabine or FCR for example...
Age, comorbidities, genetic markers or something else?
I have always wondered why Roche chose chlorambucil for the 'CLL11: A Study of RO5072759 With Chlorambucil' trial.. or is this simply more of the chlorambucil as the comparator 'whipping boy'?
More trial results necessary.
ReplyDeleteFor comparison with chlorambucil the best dose of chlorambucil and the longest durations should be chosen. If it's not you will know that it has been set up as a whipping boy. Patients for whom FCR is going to be too toxic should be offered chlorambucil + R in my opinion.
ReplyDeleteDear Dr Hamblin,
ReplyDeleteVery sorry that you not feeling well. My thoughts are with you. Hopefully my question will distract you from your discomforts. I am a physician.
Is there enough data in the literature to compare the short and medium to long term complication rate of optimal dose chlorambucil vs FCR, and could you approximate those percentages off the top of your head. I am referring to non elderly patients (for example 55 year old male)
For example, the rates of severe cytopenias both in the acute stage and in the 2 years following treatment (up to 20% with FCR if I understand the literature correctly), infections requiring hospitalization, , detrimental change in FISH profile (sp conversion to 11q-), Richter syndrome, MDS, and any other you may think of. Thank you and all my best, Roy
FCR as in CLL8 gives a longer overall survival on average compared with FC, which is probably superior to optimum dose chlorambucil. But it comes with a cost of higher risk of both early and late neutropenia. The risks of chromosomal evolution, MDS and Richter's are greater with FCR also, but the better overall survival takes account of all these possible complications. I have had some very good results with FCR as well as the few poor results. I am afraid that the probabilities are not certain enough to make a good judgment. I would still recommend FCR in the young fit patient
ReplyDeleteFCR as in CLL8 gives a longer overall survival on average compared with FC, which is probably superior to optimum dose chlorambucil. But it comes with a cost of higher risk of both early and late neutropenia. The risks of chromosomal evolution, MDS and Richter's are greater with FCR also, but the better overall survival takes account of all these possible complications. I have had some very good results with FCR as well as the few poor results. I am afraid that the probabilities are not certain enough to make a good judgment. I would still recommend FCR in the young fit patient
ReplyDeleteglad to hear you are up to being you. wishing you the very best; so good to hear a true scientist who believes, truly being both.
ReplyDeleteDr. Hamblin,
ReplyDeleteIt may be of interest for Roy to read your 21 January 2009 titled posting "Side Effects in easier language".
IF he has a high WBC count, your 7 September 2008 posting titled "Rituxin and high white counts".
Since my quantitative model of my own ALC growth shows possible treatment c. Mar. '12, this past July I spoke with Drs. Rai & Barrientos about the thrice weekly low dose R regimen of Ron Taylor's you've addressed & as he published in The Journal of Immunology, 2006, 177: 7435-7443, as well as NIH's Dr. Wiestner subsequently in Haematologica. 2010 Feb;95(2):329-32.
Based in large part on your writings, among my other alternative initial treatment courses is chlorambucil.
Incidentally, how much weight would you put on adverse event stats issued within each drug's prescribing information?
I pray you're recovering your health.
Drug companies feel forced to include every reported side effect on their insert sheets. I pay no attention to them unless I have a side effectthat I don't expect. We are conduction a low-dose rituximab trial in the UK but there are no results in yet.
ReplyDeleteFor Jorge,
ReplyDeleteDr. Bruce Cheson championed BR for a frontline TX at the LRF Brooklyn, NY Conference this past weekend.
Most of the data has been gathered from relapsed/refractory patients so it looks like he will be the man to go to for data on frontline TX down the road.
What bothered me was his curt denial when I asked about the low Chlorambucil dosing comparison to Bendamustine. Cheson said "not true" and took another audience question. Caveat Emptor!
Terry - glad to hear you are sounding like your "younger" self again.
WWW
Sounds like Bruce has fallen for the drug company's subtle subterfuge.
ReplyDeleteThank you Waine and Dr. Terry Hamblin.
ReplyDeleteDr. wish you quicker recovery.
Jorge
Dear Dr Hamblin,
ReplyDeleteVery sorry to hear that you are under the weather again. I have read all your posts from the beginning of your blog.
In a young (in 50s) fit patient candidate for FCR because of disease progression and no urgent complication (no hemolytic anemia for example), what are your arguments against a trial period of chlorambucil +R before trying FCR? Because of FCR toxicity and because of the possibility that standards of care change in the next few years. If it is an option, how long a trial period and what end points would you be looking at ? My thoughts are with you for a prompt improvement in your well being, Roy
There are no data to support it. There are data that say that overall survival is longer with FCR than with FC and that Fc give a longer PFS than chlorambucil.
ReplyDelete