Thursday, July 24, 2008

New Trials

No blogging yesterday as I was at the UK CLL group's clinical trials meeting. This was a good chance to review what was happening in the UK. Currently we are without a major change. LRF CLL4 has been analyzed and published with its concusion that the combination of fludarabine and cyclphosphamide gives more responses and longer remissions than either fludarabine of chlorambucil as single agents, and rather more surprisingly that these two drugs cannot be distinguished by their performance. However, none of these drugs gives a longer overall survival compared to the others when used as first line treatment. There are 5 of 6 other spin-off papers due from that trial, mainly about the prognostic factors, but also about the comparison of oral and iv fludarabine.

The next trial has been a long time in coming because the Germans have rather stolen a march on us, and have already asked the next major question, which is does the addition of ritiuximab improve results. Although this will be the subject of a major paper at ASH, we know from heavy hints from the Roche website that the answer will be a very high response rate (perhaps 95%) much longer remissions (4-5 years?) and no improvement in overall survival.

So what is there left to do with conventional drugs? There is the Ron Taylor question: do we need such large doses of rituximab? And there is the Spanish question: is there a place for mitoxantrone?

Our next trial is going to address these, starting, we hope, early next year. The randomization will be between FCR and FCMr. F=Fludarabine, C=Cyclophosphamide, M=mitoxantrone (at a small dose, 6mg/sq m), R=full dose rituximab, r=minidose rituximab (100mg). At the same time we will conduct a randomized phase II study comparing FCR with FCMR.

We currently have a randomized phase II study looking at chlorambucil versus chlorambucil plus rituximab in patients though unfit for fludarabine and are looking at a randomized phase III study looking at chlorambucil with or without ofatumumab.

Several centers are also taking part in the international study comparing FCR with FCR plus lumiliximab.

The consolidation study with Campath is continuing but is recruiting poorly perhaps because of the 6 dearths in the American study. It is clear that eradication of minimal residual disease should only be undertaken in centres experienced with the problem.

The 17p- trial (Campred) is almost complete and it is touch and go whether it will be ready for ASH. A new trial adding Revlimid is being designed. Revlimid is also the drug of choice for early stage, poor risk patients.

On the horizon are some Treanda trials: R-Bendamustine v R-chlorambucil might be attractive as long as they chose a proper dose of chlorambucil. An SMZL comparing splenectomy and FR might have difficulty recruiting even if it were pan-Europe. We might join the CALGB mini-allo trial.


Anonymous said...

Dr. Hamblin,

Were there any early results or discussions from trials using single agent Revlimid with CLL patients?

Terry Hamblin said...

The two area where revlimid might offer an advantage is in the treatment of drug resistant CLL and in the treatment of early stage CLL where yuou don't want to expose the patients to cytotoxic drugs.

Anonymous said...

A couple of things.

The chlorambucil and rituximab study reminds one of an American who liked the low toxicity of the combination. However, he passed away after using the combination.

Is FCR available in the UK, and covered by the NHS?

Has there been any results on the mini-dose of rituximab? That is of interest to many, yet I've seen no results as of yet.

Also, you mention the campath consolidation. Is this worthwhile? I know of two people who have done it, survived it, and are doing extremely well. This was consolidation after HDMP+R (high dose methylprednisolone plus regular strength rituximab (375 mg/m2, I think).

And how can we tell if a clinic is experienced enough using Campath? Thanks for the interesting post.

Terry Hamblin said...

Chlorambucil + rituximab is a low tosicity regime, but it is not suitable for everybody. FCR has not yet been considered by NICE. The trouble is that there is no evidence yet published that it is any better than say FC (though we know on the grapevine that it is better than FC in the German CLL8 trial) Hence in certain centers you can get it, Some trials offer free FCR (the lumiliximab trial for example where both arms get FCR). However, we have to remember that even the German trial shows no overall survival advantage for FCR and the extended follow-up of FCR from MD Anderson shows a worse outcome for the over 65s who comprise two-thirds of patients.

There are no results from any low dose rituximab studies yet, though Dr Hillmen has confirmed Ron taylor's observation that after the first 50mg there are no circulating cells with CD20 on them and these take several days to recover.

I am encouraged by Campath consolidation, though it has to be done properly. At the moment I recommend that it is confined to big centers that have been publishing on CLL, and kept out of the hands of office oncologists.

Anonymous said...

Dr. Hamblin --

Have you seen Chaya Venkat's alert about the encouraging results of a small Greek/Israeli trial of Rituxan with complement? Does that suggest that single-agent Rituxan might be effective (at least for some cases) as a first-line treatment after all?

Terry Hamblin said...

I've only seen it second hand. This is not a new phenomenon - I first described it in "Barriers to successful immunotherapy with anti idiotype antibody. J Gordon, A Abdul Ahad, TJ Hamblin, FK Stevenson and GT Stevenson. British Journal of Cancer,1984,49: 547-557"

There is evidence that complement is consumed by antigen/antibody reactions - it is this reaction that causes the infusion reactions to rituximab which are mediated by the complement components C3a and C5a. Without complement the killing of CLL cells is impaired, so adding fresh complement in the form of fresh frozen plasma would enhance the effect.

Anonymous said...

I don't understand why there is no improved survival after using FCR.

I know of several patients who where somewhat sick (rising WBC, enlarging nodes, declining performance) who improved after FCR. I can't believe that if they took nothing they would have lived as long as they have with FCR.

Don't CLL drugs extend life? If not, why use them?

Terry Hamblin said...

Nobody said that there is no improved survival with FCR. Very probably all CLL drugs lead to improved survival (over no treatment at all). What trials show is that there is no evidence that you live any longer if you start out with FCR first line, than if you have it third line, having frst had remission with chlorambucil and FC. What we do know is that 18% of patients who get FCR have long term neutropenia when it is given first line and that FCR is perhaps a bit too much for the over-70s who comprise more than half of all patients.

At present doctors tend to choose the regimen that gives the longest first remission for first line treatment. This is a strategy that has paid dividends in acute leukemia, but there is absolutely no evidence that it is the best strategy in CLL. If we wait another 10 years or 20, evidnece may emerge, but it may turn out quite the other way round. To choose FCR first line is not necessarily wrong, but it not necessarily right either. It is still a matter of faith.