Saturday, October 09, 2010

The ultimate FCR advice

After all those sleepless nights fueled by dexamethasone working on CLL8 I think it right that I should put FCR into context. In this I am helped by an editorial by Zenz, Mertens and Stilgenbauer from the German group published in Haematologica. It is available by open access so everybody can read it.

The first thing to say is that FCR requires an intact p53 pathway to work and if this is impaired and a patient needs treatment. FCR should not be used. I have already been involved in one court case where a hospital ignored this advice and the patient received substantial damages. I would be prepared to act as an expert witness if such a thing occurred again. Here's what the Germans say about this issue: "Cases with 17p deletion have a very poor prognosis (median survival of less than 2 years from first treatment indication) with alkylator and nucleoside-based chemo(immuno)therapy (chlorambucil, fludarabine, fludarabine + cyclophosphamide, or fludarabine + cyclophosphamide + rituximab). Since a number of agents have been shown to act independently of functional p53 in CLL, current treatment approaches in clinical trials use these agents upfront with early allogeneic stem cell transplantation as consolidation after remission has been achieved in eligible patients."

Those agents include high dose steroids, Alemtuzumab, flavopiridol, possibly revlimid and some of the second and third generation anti-CD20 antibodies.

"In addition to CLL with 17p deletion, the group of patients with TP53 mutations (even in the absence of 17p deletion) is a subgroup gaining increasing attention. TP53 mutations are found in 8–12% of patients with an indication for first-line treatment. The incidence increases during the course of disease and was 37% in a cohort of fludarabine-refractory cases. In a recent study within the German CLL4 study (which compared fludarabine and fludarabine + cyclophosphamide treatment), the incidence of TP53 mutations in the absence of 17p deletion was similar to that of 17p deletions and the clinical course of patients with these forms of CLL was very similar. These data –as well as information from a number of retrospective cohort studies – suggest that TP53 mutation should be added to the diagnostic work-up of patients with CLL in need of treatment"

This is certainly the German view, though there is not yet international consensus on this. Certainly there are extra refractory cases with TP53 mutations in the absence of 17p deletions, but others have found these to be sometimes quite benign. We will have to await further developments on this. But CLL8 does tell us that patients without del 17p who have stable or progressive disease after three courses of FCR should be treated in the same way as the del 17p groups - which means getting them into remission by one of the non-p43 dependent cocktails and then if at all feasible doing an allograft as soon as possible.

How about the rest of the patients? This is the slide that the Germans have produced for risk adapted treatment. Click to enlarge.

"Based on a number of studies including prospective trial data, patients with unmutated IGHV, 11q deletion, V3-21 usage and high levels of serum markers (e.g. β-2 microglobulin) form a high-risk group with a median survival in the range of 53 months following an indication for first-line treatment. These patients are now generally treated with the combination of fludarabine + cyclophosphamide + rituximab (if fit and younger), but future trials may consider maintenance strategies in such patients"

Chris is absolutely right to stress that these trials were conducted in younger, fitter individuals and the results cannot be applied to older unfit patients. It is also important to recognise that CLL8 did include some fit older patients (even up to 80-years olds) who did no worse than the younger patients. However, most older patients will find it hard to manage FCR and dose reduction (as occurred for stage C patients) seems to subtract from the overall survival advantage. It is also wise to remember the results of the REACH trial in which there was no overall survival advantage (as yet) for giving FCR over FC as a second or third line treatment and which was accompanied by problems of long term and late neutropenia (for which we looked for but couldn't substantiate MDS as the cause). The message is that if FCR looks to be an option for your disease, it is better to get it in sooner rather than later, while your still young enough and fit enough to manage it, and before you begin to suffer marrow failure. If you are already stage C disease, you may have to dose-reduce at first, but this should eventually lead to the marrow recovering, and my personal advice is that you should then get back up to full doses. I agree with the Germans that this is the group that we need to see maintenance trials with.

It is important to recognize that the del 11q patients now fall into this intermediate group. CLL8 has removed indecision as to whether they should be intermediate or high risk. If they are getting FCR they are at intermediate risk.

What should happen to intermediate risk patients who are less well or have co-morbidities? I know many people opt for bentamustine-rituximab for this group, but I favor chlorambucil-rituximab as a less toxic and equally effective regimen, but the dose of chlorambucil has to be a proper one, not a 'Smarties' dose (fill in your own national children's sweet instead of 'Smarties' if you don't have them).

AS the Germans say: "While risk-adapted treatment approaches are generally used interchangeably with different treatments for certain prognostic risk groups, future risk-adapted treatment strategies will undoubtedly also have to integrate the patient’s performance status, co-morbidities and age, which is of particular importance considering that the median age at diagnosis is over 70 years old"

This is an interesting suggestion:
"The group of patients with none of the above aberrations and mutated IGHV status have a very favorable outcome and could even be considered for de-escalation studies."

This suggestion is one that I have made in the UK Clinical trials group and we are implimenting trials involving chlorambucil-rituximab and chlorambucil-ofaftumumab in this group.

"In spite of this clinically relevant risk hierarchy, the decision to treat is currently not based on the risk profile but on symptomatic disease. This is important and further supported by the observation that in some subgroups of patients, such as those with 17p deletion (and mutated IGHV), the disease may have an indolent course."

I agree.


Tom said...

Dr. Hamblin,
Thank you very much for the breakdown of the CLL8 study and your own opinions throughout.

Is this study available to the public anywhere. I did a search but just found summaries. I'm interested in more information about maintenance therapy after FCR for younger patients. Is the recommendation every 6 months? Is there any fear of becoming allergic to R or is that not a big worry anymore with the new CD20 anti bodies?

If maintenance is indeed recommended, would this still hold true if the patient had Bexxar consolidation after FCR? Would the use of Bexxar negate the usefulness of maintenance with Rituxan (I wouldn't think it would)?

Sorry for all the questions. Your insomnia was definitely our gain. Thanks again.


Terry Hamblin said...

Write directly to me and I will send you a copy. Bexxar and maintenance would be regarded as experimental therapies and should only be undertaken as part of a clinical trial. No sound advice can be given so far.

Anonymous said...

Unlike Dr. Hamblin, I don't think FCR should be used as a first-line therapy. Why? Because when the patient relapses (and he will relapse), he will be in a precarious situation indeed. Fludarabine-refractory disease means that the patient has a poor prognosis.

My opinion is that there are many treatments now available that are more benign than FCR. These include HDMP+Rituximab, Revlimid+R, flavopiridol, EGCG and others. Clinical trials using such agents as CAL-101, ABT-263, Perixifor+R and others could be considered as well.

When you use FCR, you shoot the whole wad. Why not try something less toxic to start?

Terry Hamblin said...

None of the treatments you mention has ever been compared to FCR so you are asking people to buy a pig in a poke.

It is true that we don't yet know where to go after FCR, but that is the time for all your experimental treatments.

I'd rather buy my pigin a poke after I'd been eating roast turkey for 10 years.

Chaya Venkat said...

EGCG as a therapy option compared to FCR? Lets get real. And I am the woman that spent a lot of time raising money for the EGCG green tea trial at Mayo clinic.

For people with very indolent CLL and those that are lucky enough to have true-blue best of the best prognostic indicators, it is nice to be able to play with EGCG. But for not so lucky patients with 11q or 17p defects / deletions, it is important to get a good strong dose of reality. Time spent chasing low impact and low probability approaches is time lost, the window of opportunity may not be open for long.

By the way, flavopiridol is hardly an easy drug to tolerate. To date, it is only available as part of a clinical trial at OSU - to the best of my knowledge. Tumor lysis risk is still an issue.


~chris said...

I think it is important to note that FC may be a wiser choice over FCR in patients where Hep B or Hep C viruses reactivation may become a problem, post CLL treatment.

The FDA recommends that patients at high risk of HBV infection be screened before initiation of rituximab therapy. Hepatitis B carriers should be closely monitored for clinical and laboratory signs and symptoms of active HBV infection during rituximab therapy and for several months thereafter.

Also see:


Terry Hamblin said...

Good point.

Anonymous said...

So, what type of maintenance therapies exist? Thanks for your posts.

Terry Hamblin said...

rituximab, revlimid, CAL-101 newer antibodies - enzyme inhibitors of various sorts, green tea?. Lots of possiblities.

Anonymous said...

Well, since it would have been John Lennon's 70th, I say:

Never knew a better man
He helps you to understand
He does everything he can
Dr. Hamblin

Richard said...

You quote from the report:-

"The group of patients with none of the above aberrations and mutated IGHV status have a very favorable outcome and could even be considered for de-escalation studies."

Could you please explain what is meant by a de-escalation study?

The OS for treatment with FC shown in Fig 3b (for the above group) appears longer than OS for treatment with FCR shown in Fig3c? Should patients with no abnormalities therefor be using FC or is it a statistical fluke, as the PFS seems better for treatment with FCR for this same group?

Many thanks

Terry Hamblin said...

De-escalation means that some patients may be overtreated with FCR if they have good prognosis markers and we need to do clinical trials comparing a less aggressive regimen such as chlorambucil/rituximab for this group.

Yes it is a statistical artefact of small numbers.

ms said...


Related to your post, I wonder who the top CLL researchers and practioners are? I don't think those names are known to the patient community. I'm into my seventh year of CLL, and can only identify M.D. Anderson, Sloan-Kettering, Rai and Hamblin.


Terry Hamblin said...

Byrd at Ohio, Chiorazzi at North Shore, Kipps at San Diego, Kay and Zent at the Mayo, Flinn at ? Nashville, Hallek and Stilgenbauer in Germany, Hillmen in England, Dreger for transplants in Germany, Mckinnon for transplants in England, Gribben in England and lots more.

Burke said...

Doc, you wrote,

"If you are already stage C disease, you may have to dose-reduce at first, but this should eventually lead to the marrow recovering,..."

I thought that the marrow damage done by FCR was permanent, but this comment suggests that's wrong. Also, for those of us who got a good CR with only 4 cycles and reduced fludarabine, can we expect better results with FCR the second time (than usual) because we didn't get so much the first time.

Terry Hamblin said...

'Expect' is too optimistic. 'Hope for' is more realistic.

Grateful said...

Thank you for your well-written explanation.

Would you consider "FCR-lite" protocols in the de-escalation category?

Terry Hamblin said...

Yes, but they are still relatively untested.

maronedp said...

Dr. Hamblin,

For high risk patients (p53 mutated etc.) are you still advocating getting the CLL under "control" and then allograft?


Terry Hamblin said...

Yes, always assuming that the indications for treatment are present. There is a group of TP53 damaged patients that remain benign.