Who should have prognostic markers done and when?

Why should I get my prognostic markers done? Many people have decided not to get their markers tested for very good reasons. They just want to get on with their lives and the future will come soon enough. However, just like we watch the weather forecasts many of us do want to know something about the future so we can plan for it.

I think it goes without saying that anyone who needs treatment should have his TP53 status established. Response to conventional drugs in CLL is severely impaired in TP53 deficient patients and why suffer the toxicity of fludarabine if it isn't going to work? Generally this means a FISH test for del 17p. In my opinion knowing that you are del 13q, or trisomy 12 isn't going to give you any extra information and unless these come as a cheap package, I wouldn't bother with them at this stage.

The other markers that matter of IGHV mutations, CD38, ZAP-70, beta2M and del 11q. These will not affect the response to treatment, at least not when judged by rate of CR and PR, though they might affect MRD negativity. What they do affect is length of remission and overall survival. The IGHV mutation status affects these things from the time of diagnosis, and ZAP-70 expression done by the Crespo method or the Orchard method is a close correlate of that. ZAP-70 done by the Rassenti method is an independent prognostic factor and when done by commercial labs is so unreliable as not to be recommended.

CD38 is changeable, so at diagnosis it may be low but as the disease progresses it tends to increase. The same is true to some extent of Beta2M.

A lot of thought is spent on whether to choose FR or FCR, or between FCR and PCR and even if Bendamustine might not be a better bet, but what influences outcome most is not which treatment is chosen but whether or not the IGHV genes are mutated or unmutated. This does not change during the course of disease and only needs to be done once, at diagnosis.

In about a third of cases the markers are uniformly bad and in about a third they are uniformly good. It is the middle third where confusion lies. In my experience these patients have an intermediate prognosis. This is often because the CD38 is low and will be raised later in the course of the disease, but sometimes it is because the CLL cell has found another way of signaling through to second messengers in the cell that by-pass the B-cell receptor's usual pathway.

Del 11q was always thought of as a poor prognostic marker, but the addition of rituximab to therapeutic mixtures has meant that remissions have been just as long as for those without del 11q. However, a caveat: on the grapevine I hear that this may not remain true as the trials become more mature. We wait and see.

This is what I recommend for patients who have CLL.

Group 1. Those patients with MBL and those who truly do not want to know, do not do any but the diagnostic markers (CD5, CD19, CD20, CD23, CD79b, surface Ig, FMC7).

Group 2. Those who do want some idea of the future, IGHV mutations, Beta2M and CD38. In certain circumstances (if you are lucky enough to be under a Consortioum Center) ZAP-70. Don't be content with just the mutated/unmutated result; ask which gene is being used and whether it belongs to one of the stereotypes.

Group 3. If you have unmutated IGHV genes and low CD38 and Beta2M, get these measured every year. There is no need to repeat the IGHV mutations; these will not change.

Group 4. If you are about to start treatment either for the first or subsequent time you must have FISH for Del 17p and preferably at the moment for Del 11q. At the moment there is no need to test for trisomy 12 or del 13q, but if these are available in a cheap package you may as well since I do believe that as more knowledge accumulates they will be useful. With del 13q it is likely to be the size of the deletion that is important. It is always better to get the markers done at research labs rather than at commercial labs, because they often obtain more information than you pay for and as time passes that information becomes useful. I am still waiting to see what becomes of the information that those with trisomy 12 often have trisomy 16 and sometimes 18 or 19 as well. They may all belong to a single stereotype.

There is evidence that mutated and unmutated respond equally well to PCI32765 and CAL101. Yes, but they respond equally well to fludarabine. It is length of remission and overall survival where things differ.