Not all monoclonals are the same!

Sometimes I really have a hard time understanding the logic behind some of the clinical trial researchers choose to conduct.  It is not as if we don’t have enough open questions - lord knows there are a lot of interesting drugs and combinations that are still open to exploration.  But more often than not, it seems to me the decisions are made without first putting brain into gear, to the detriment of good scientific logic and patient safety.

You are all familiar (I hope!) with the success enjoyed by FCR (fludarabine, cyclophosphamide and Rituxan) as the present day “gold standard” in the treatment of of previously untreated (“chemo naive”) patients.  So, if FC + Rituxan is so good, how about substituting the other FDA approved monoclonal Campath in place of Rituxan?  If FC + Rituxan is good, would FC + Campath be even better - since Campath packs more punch and is also thought to work in 17p deleted high risk patients?

This might seem a good concept - for about 5 nano-seconds.  Then, if brain was properly in gear, you would start worrying about the fact that both fludarabine and Campath (also known as alemtuzumab ) are extremely immune suppressive.  Of all the drugs you are likely to encounter in your CLL journey, these two drugs are most justly infamous for destroying T-cell counts. And not having sufficient number of T-cells leaves people wide open to opportunistic infections and even secondary cancers - just think of the health issues associated with advanced AIDS patients and you get the picture.  Using both of these drugs (Campath and fludarabine) at the same time would be doubling down on the risk of extreme immune suppression. Patients would be at significantly higher risk of infections and even secondary cancers, when their immune defenses are down for a prolonged period of time.

It is not as if we have no information available on what combination of fludarabine and Campath can do.  We have published several articles on the topic of Campath consolidation.  When Campath was administered too soon after completion of FCR - as a way of mopping up remaining CLL cells and bringing patients closer to a MRD (minimum residual disease) negative status - there was a big spike in toxicity.  A German trial (we wrote about this one all the way back in 2004) using this approach had to shut down because of unacceptable number of infections and even deaths.  CFAR clinical trial at M. D. Anderson (combination of FCR+Campath in one massive drug combination) proved the point once more - very high toxicity when Campath is combined with fludarabine. You would think these lessons have been learned in many different ways and would not have to be learned all over again:

  • Don’t use Campath consolidation too soon after fludarabine based therapy.
  • Substituting Campath in place of Rituxan in regimens such as FCR or FR is not such a good idea, likely to result in heavy duty immune suppression and increased risk of infections, secondary cancers.
  • Piling on Campath on top of FCR (as in the “CFAR” combination) may be more toxicity than most patients can absorb. You guys with me so far?

So, I have a hard time understanding why this group of researchers in France and Belgium  thought that using the same deadly combination - FC + Campath - in previously untreated patients is such a terrific idea.  Mind you, this is not a small scale clinical trial.  This is a full fledged phase-III trial, conducted at many centers in France.  Patients were randomized to get either FC + Rituxan or FC + Campath.  We are not talking about a small group of patients either - a whopping 165 patients were randomized to either group in this study.

Excess mortality following FCCam treatment in previously untreated patients with CLL: safety and efficacy in a randomized, multicenter, phase III trial

Stephane Lepretre1, Therese Aurran2, Beatrice Mahé3, Bruno Cazin4, Olivier Tournilhac5, Herve Maisonneuve6, Olivier Casasnovas7, Alain Delmer8, Veronique Leblond9, Bruno Royer10, Bernadette Corront11, Sylvie Chevret12, Roselyne Delépine13, Sandrine Vaudaux1, Eric Van Den Neste14, Marie Christine Béné15, Remi Letestu16, Florence Cymbalista16, and Pierre Feugier17

A French and Belgian multicenter phase III trial was conducted in medically fit patients with untreated chronic lymphocytic leukemia (CLL). Of 178 patients enrolled in the study, 165 were randomly assigned to receive six courses of oral fludarabine and cyclophosphamide (FC) in combination with rituximab (R; 375 mg/m2 in cycle one, 500 mg/m2 in all subsequent cycles) or alemtuzumab (Campath; 30 mg subcutaneously injected on cycle days 1-3); each cycle was 28 days. Recruitment was halted prematurely because of excess toxicity; eight patients died in the FCCam group: three from lymphoma and five from infection. Overall response (OR) rates were 91% with FCR and 90% with FCCam (P=0.79). Complete remission (CR) rates were 33.75% with FCR and 19.2% with FCCam (P=0.04). Three-year progression-free survival (PFS) was 82.6% with FCR and 72.5% with FCCam (P=0.21). Three-year overall survival (OS) was similar between the two arms at 90.1% in the FCR arm and 86.4% in the FCCam arm (P=0.27).These results indicate that the FCCam regimen for the treatment of advanced CLL was not more effective than the FCR regimen and was associated with an unfavorable safety profile, representing a significant limitation of its use. This study is registered with www.ClinicalTrials.gov, number NCT00564512.

I do not have the heart to summarize the full details of this study.  They are too shocking and depressing.  I described some of the details when this study was first discussed as an ASH 2011 abstract. If you are in the mood for it, or if you are considering the combination of FC + Campath and therefore need a swift kick in the backside to stop you from doing it, please send me a personal email and I will be happy to help you find the full text of this horrific article, just published in all its glory in “Blood”.

Here are the sad details / results in a nutshell.

  • 165 patients recruited for this two arm trial.  Half got FCR, other half got FC + Campath
  • While the patients recruited were indeed a relatively high risk group needing to start therapy of some kind, all of them were previously untreated.  Not what I would call the walking dead, by any means.
  • Things got so bad that even this group of “brave” researchers halted recruitment prematurely.  I guess we have to be grateful for small mercies.
  • Eight patients died in the FC + Campath group.  That is a massively large number!
  • Cause of death was infection in five patients and secondary cancer (lymphoma) in three patients.  This should not come as a surprise to anyone even remotely familiar with the high risk of immune suppression associated with a combination of fludarabine and Campath.
  • So, did the patients in the FC + Campath get a lot better overall responses compared to FC + Rituxan?  Did they get more bang for the very high price they paid for the FC + Campath combination?  You be the judge.  FCR got 90% overall response, while those in the  FC+ Campath arm got 91%.  Absolutely no difference in response rate.
  • How about overall survival?  Once again, no difference between the two groups.
  • Here is the bottom line.  Not my words, this is a direct quote from the article and the abstract above.  “These results indicate that the FCCam regimen for the treatment of advanced CLL was not more effective than the FCR regimen and was associated with an unfavorable safety profile, representing a significant limitation of its use”.

Editorial

Where do I start?

Perhaps a good place to start is raise my concerns with mix-and-match style drug combinations, just changing the alphabet soup of drug combinations.  How about getting a bit more creative, something other than doing yet another me-too style clinical trial?

Is it reasonable to expect that there was sufficient data already available regarding the risks of combining fludarabine and Campath?  I think so.  Many patients had already paid dearly to prove that Campath consolidation too soon after FCR (or FR) was risky business, as far back as our review of it in 2004.  The same concerns were also evident in the results of CFAR combination. Which part of this immune suppression risk  did these researchers not get?

Guess who paid for this trial.  I will give you just one guess.  That’s right, the trial was paid for by Genzyme and Schering - the two pharmaceutical giants that own marketing rights to Campath.  Do you honestly think anyone else would have been interested in paying for this particular deadly combination?

I mourn for the 83 patients who were unfortunate enough to be randomized to the FC + Campath arm of this deadly trial.  Their participation in this clinical trial got them  higher rates of infection, secondary cancers and even premature death - with no increase in response rates or overall survival.  And here is the bit that really sticks in my craw.  The researchers thanked the pharma companies that own Campath and paid for this trial - but they had not one word of thanks for the patient volunteers.  Heck, in this case, thanks would not have been sufficient. How about abject apologies?

What blows my mind is that the terrible outcome of this clinical trial cannot even be dismissed as a case of 20:20 hindsight.  The lessons were there already, provided anyone was willing to look at the outcomes of similar trials in the past and willing to learn from them.  This trial provided nothing more than remedial education as it were, for researchers only too willing to conduct a trial just because they got the funding for it, not because it was a good idea to begin with or one that had high probability of helping the patients who participated in it.  I can (sort of) understand dug companies wanting to improve their market share by pushing the drugs they own.  But what is the excuse of researchers and physicians with a sworn duty to protect patients?  Whatever happened to the “Do no harm” pledge?

Last but not least:  where were the local oncologists who funneled patients into this trial?  On what basis did they guide their patients into this obviously flawed approach?  Is there an active patient advocacy effort available in France and Belgium that could have short-circuited this disasterous trial before it recruited even a single patient?

I guess that last point is the one that hits close to home for me.  We have thousands of members, all around the world.  But there is no question the vast majority of our members come from English speaking countries.  We have a few volunteers translating CLL Topics and Updates articles into German and other languages.  Not enough, it seems.  I am only too aware of the limitations of my own efforts.  Our reach is limited to computer savvy and English speaking patients.  An even bigger hurdle is mind-set.  Too many patients are still timid about getting personally involved in their own healthcare, too many doctors are offended / intimidated by patient advocacy or empowerment, too many inappropriate clinical trial designs getting approved based mostly on availability of funding rather than good science.  Until these mindsets changes, we will continue to have tragedies like this.

What can you do?  Please get the word out.  Preach patient advocacy and personal choice in therapy decisions and clinical trial participation.  If you “get it”, try and convince a few others who may not be quite as far up the learning curve as you are.  We are all our brothers’ keepers.

On a very different subject, my sincere and heartfelt thanks to all the kind readers who wrote and expressed their condolences on the death of my beloved dog Jasper.  Please forgive me for not writing back to thank you personally.  I am still having a hard time coping with this loss.