Monday, February 13, 2006

Fludarabine Combinations

Today I want to evaluate an important new paper published in Cancer by Bill Wierda.

It is important because it deals with overall survival rather than length of remission. It compares overall survival in relapsed and refractory patients who were treated with one of the following: fludarabine, fludarabine plus cyclophosphamide (FC) or FC plus rituximab (FCR). This information has been available on the lecture circuit for some time, but Bill has been very helpful in publishing it in a form that enables us to scrutinize it carefully. He is to be commended in publishing it without trying to hide any details and even pointing out himself some of the flaws of this kind of study.

I want to go straight to the bottom line. The median overall survival for the fludarabine group was 20 months; for the FC group it was 31 months; for the FCR group it was 49 months. The difference between F and FC had only a 1% risk of having occurred by chance, and the difference between FC and FCR had only a 5% risk of occurring by chance.

Although these figures are impressive and mean that the idea that FCR is better than FC which is better than F alone should certainly be listened to, the way that the data were collected means that the concept is not proven.

The first thing to say is that this was not a randomized trial. Randomization is a great device for ensuring that you are comparing like with like. Scientists who dissect physiological mechanisms prefer to work in inbred strains of mice. All the mice are identical, but humans have so many variables. It is usually impossible to find people who match each other. Even if you choose people with say, Stage 3 or 4, unmutated VH genes, high CD38 levels, high ZAP-70 levels, del 11q, high LDH, high serum CD23 levels, high beta-2 microglobulin levels; even then there will be considerable variation within that group. Patients are all different. Randomization means that the good and poor risk characteristics will tend to cancel each other out is the sample is large enough.

The second thing to say is that these drugs were not tested at the same time. The 241 patients given F were treated between 1984 and 1993; the 111 patients treated with FC were treated between 1995 and 1999; and the 143 patients treated with FCR began treatment between 1999 and 2001. Even if treatment of the disease had not improved in the past 20 years, there is little doubt that supportive care is better. It is admirable that the paper has given so much detail about this. For the F group, there was no routine use of prophylactic antibiotics or growth factors. In contrast some 35 of the FC group were given GM-CSF and 13 amifostine, but again prophylactic antibiotics were not used. For the FCR group Bactrim was given twice weekly and valacyclovir daily. Routine G-CSF was not given, but of course, as time passed G-CSF became much more routinely available in the community, as did better antibiotics and better antifungals.

The third thing is that these patients were not really matched. True, there were no significant differences between the FC and FCR groups in terms of them in terms of age, WBC, Hb, Platelets, beta-2M or albumin, but the F group were 2-3 years older, and had a slightly higher (10K) WBC, and lower HB (1g/dL), though the platelet count was higher (20K). Perhaps more important is what prior treatment the patients had received. 45% of the F group had received 3 or more types of treatment, compared with 31% of the FC group and 29% of the FCR group. In addition 75% of the F group were resistant to alkylating agents, compared to 46% of the FC group and 27% of the FCR group.

We know very well that outcome in CLL is chiefly determined by which ‘bucket’ the CLL falls in. The ‘gold standard’ for determining this is the VH gene mutational status. Unfortunately this was not done in any of these patients. The prognostic test that was done was beta-2M, and the median beta-2M was the same for all three groups. However, beta-2M is influenced not only by the rate of progression of the CLL, but also by the tumor mass, and simply having a lot of CLL is not life threatening.

So, what can we learn from this paper?

First, if you need treatment, and you have already had treatment previously and relapsed or failed to get even a partial remission, then FCR is better than FC in producing remissions, in producing complete remissions, in how long the remission will last and in overall survival. Although, the studies were not contemporaneous and not randomized, the two groups were very similar and the most likely explanation for the difference in outcome is that rituximab really does make a difference.

Second, the addition of cyclophosphamide to fludarabine is still an open question. The F group was more heavily treated than the other two groups, and were treated at a time when supportive care was not so good and significantly at a time when there were no rituximab-containing regimens to rescue them with. We know from another historical comparison (Byrd et al Blood 2005;105:49-53) that rituximab adds similar benefit to fludarabine alone. Although the recent German study shows that FC gives more and better remissions than F alone, so far there has been no difference in overall survival. Therefore the possibility remains that the less toxic FR is no worse than FCR in this situation.

Third, this paper does not address the question of what should be given as first line treatment for CLL. My considered view is still that treatment should be delayed as long as possible and begun with the treatment that does the least harm. But it is still possible that early effective treatment might be most beneficial in certain subgroups.


Anonymous said...

A few equivocations in Dr. Hamblin's post!

I agree that comparing different regimes at different time periods leads to considerable problems. The reason the paper is useful at all is there are no better data out there, so we have to make due with studies with some pretty large problems with them.

As far as early, first-line treatment, Dr. Hamblin is certainly at odds with some of his colleagues. Many oncologists do treat prior to a CLL emergency.

And now Dr. Hamblin admits that there may be some value in treating some patients early.

Common sense would suggest that treating CLL at diagnosis with relatively benign treatments (rituximab as a single agent or with some other 'mild' drugs such as steroids or GM-CSF or similar) might be helpful in patients with aggressive markers.

If and when a 'cure' is found, it would make no sense to wait to treat CLL. Wipe it out when it is early and there is less of a chance of further mutations in an unstable CLL genome.

Some patients have said, with what I consider some legitimacy, that they underwent treatment later than they should have. These patients were using less dangerous therapies such as gene therapy or HDMP+rituximab. It didn't work as well in these patients who had waited for profound symptoms to occur.

It's a crapshoot, but my feeling is that treatment and re-treatment with rituximab with a complement-enhancing agent such as beta glucan or plasma, may be a way to modulate the disease for a significant period of time.

Terry Hamblin said...

I think I am at odds with nearly all my colleagues on the treatment of CLL! When we have a treatment that cures CLL I will endorse its early use as long as it doesn't kill more than it cures. I have never denied that there may be some value in treating patients early, just that there is no evidence to support it. I can think of many reasons why it might be the right thing to do and I have even written protocols to test the hypothesis in randomized controlled trials. But outside an RCT it is too early to jump.

Rituximab alone or with ADCC enhancing agents (G-CSF, GM-CSF, Beta-Glucan) can be given earlier in the course of the disease than chemotherapy because they don't make either marrow failure or the immunodeficiency worse. There is some small risk of allergy to rituximab, and the new fully humanized anti-CD20 might be a better bet.

Exactly when to start treatment is a matter of judgement in every individual patient. There is a risk that treatment will start to late. It has been suggested that delaying treatment allows drug resistant clones to develop; on the other hand there is some evidence that drugs like fludarabine enhance the development of drug resistant clones - either by classic cell selection procedures or by T-cell suppression allowing virally (especially EBV) infected clones to appear

Anonymous said...

When referring to a published paper please include a web link to the original documentation, either full text or abstract.

It is considered to be polite blogger protocol.

Anonymous said...

Dr. Hamblin says, "...this paper does not address the question of what should be given as first line treatment for CLL. My considered view is still that treatment should be delayed as long as possible and begun with the treatment that does the least harm."

It seems to me this is a reasonable application of the Hippocratic dictum, "first, do no harm."

There's hardly any question that harsh chemotherapy such as with Fludarabine may aggravate a CLL patient's condition and cause more problems than it solves.

Until there is solid evidence to the contrary, it may be preferable not to rush treatment.

Michele said...

Thank you for drawing our attention to this paper. Of course, this information has been out there for a while but as you say, it is one thing to see a power point presentation and another to read a peer-reviewed article. It seems with so many "new" markers for CLL progression, researchers will have to start doing RCTs. Of course, if the results of the work they have been doing at MDAnderson is really true, it looks like it will now be unethical randomize subjects to just Fludarabine or even Fludarabine and Cyclophosphamide. Survival data is also tough with CLL; it would be helpful to me if we could start using 5-year survival instead of medians. Anyway, thank you Dr.Hamblin; this is a great blog!

Anonymous said...

I made the original 'anonymous' post.

I have read Dr. Hamblin's comments, as well as others.

What I take away from those comments is that it certainly may not be a bad idea to be treated while the disease is progressing, but not with fludarabine or an alkylating drug such as chlorambucil or cyclophosphamide.

It's important to identify those patients who are unfortunate enough to have an aggressive or even an intermediate-risk form of CLL.

Those patients who are at low risk should not be treated unless the disease progresses.

Perhaps that will be the deciding factor in using less harmful drugs such as rituximab, gene therapy, vaccines, or other agents.

Although the newish markers for determining the aggressiveness of the disease are still controversial, ZAP-70, CD38 and mutational status should alert the clinician that the patient needs to be monitored closely.

Terry Hamblin said...

To all those who add comments, try to think of a nom-de-plume rather than just "anonymous". If you don't want to be identified that's OK, but it would help me to tell one anonymous from another.

tom masik said...

I was trying to read the paper but cannot find anymore. Any advice on where I could find it?