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.