Saturday, November 07, 2009

Who now should get FCR?

The German CLL8 trial continues to give us useful information. For the first time one treatment arm has lead to an improvement in overall survival. Previously, in, for example, the British CLL4 trial, while one of the arms (FC) showed a higher response rate and longer progression-free survival, the overall survival for the different arms was exactly the same. However, in CLL8, FCR gives a statistically longer overall survival than FC. Another gem to come from the trial is the evidence that achieving minimal residual disease (MRD) negativity is associated with longer survival no matter how it is achieved. In other words, if you got MRD negativity from FC you did just as well as if you got it from FCR - it's just that you are more likely to get it from FCR.

The third gem is that while other trials have shown the deleterious effect of having del 11q23 or an ATM mutation, FCR abolishes the ill-effect and such patients have the same survival curve as those with trisomy 12 or no karyotypic abnormality.

What does all this mean for the CLL community? I think it is now clear that if you of an age where a 10 year survival is important to you then your best chance of getting one is to be treated with FCR - provided you are robust enough to withstand the side effects. Rather than decide who should get FCR we are now trying to decode who should not.

If you are aged over 70, then FCR may not to be the way to go. It is unlikely that you will be able to withstand the whole 6 courses that give the best effect and you are likely to have co-morbidities that will make FCR too toxic. The sort of co-morbidities that I am talking about would be a degree of impairment of kidney, heart or liver, any evidence of bone marrow failure, and a history of unusual infections, in particular fungal pneumonias.

Co-morbidity is not confined to the over-70s, but it is commoner at this age.

If you have FCR you should be aiming at MRD negativity. If you don't achieve it then you should think about further treatment - likely to be one of three drugs at present: high dose steroids, alemtuzumab or Revlimid. Ideally this should be in the context of a clinical trial, because their utility in this setting is still in doubt.

The group with del 17p13 or a p53 mutation, while only 5% of those needing treatment for the first time will almost certainly fail to respond to FCR and these should have a different approach.

For the very elderly, many find that a gentler approach gives a better quality of life. Remember, that not everybody who meets the IWCLL Guidelines indications for treatment will feel ill. A lowish platelet count, a biggish spleen, a fast lymphocyte doubling time, may all be without symptoms. Even a large lymph node may cause no problems other than the fact that you notice that it is there. If you are 82 years old and quite well, why would you need a treatment that certainly involves trips to hospital and will probably make you feel unwell? At that age your life probably won't be shortened by CLL, so what benefit will you get from the treatment?

The only cure of CLL is a bone marrow transplant, but most centers would be unwilling to enroll a patients for the program who has not had FCR - unless they had del 17p13.

You may see this as a change in attitude on my part. Well when the evidence changes, I change my mind. Don't you?


Randy Shannon said...

Thanks Dr. Hamblin. Coming up on year six with CLL- I have changed my mind several times. I appreciate that you base your minds changes on new data...and of course your contribution to our community.

God Bless,

Burke said...

Doctor Hamblin,

You mention 10 year survival above, and there is a Blood paper linked below that states that 72% of the frontline patients receiving FCR get CR's lasting a median of 7 years. Previously you explained here that these CR's are CR's as defined in the '96 guidelines.

Would you hazzard a guess as to what the median would be for CR's that are MRD negative?

Terry Hamblin said...

who knows? Is a cure possible?

Burke said...


Weren't the MD Anderson people claiming cures with FCR a while back?

Have you changed your mind about that too?

Terry Hamblin said...

No. Note the ironic question mark.

Anonymous said...

Which patients do you think are likely to be suitable for single agent ofatumumab?

Terry Hamblin said...

WE don't have an answer for that. Ofatumumab trials are still immature.