After Evaluation & Diagnosis: Following the Patient

Dr. Kalaycio: I agree. We have fully evaluated our patient and we've made the diagnosis. Now, we start therapy with a TKI based on patient risk profile and side effect potentials. It's time to follow the patient and determine next steps.

Current guidelines^3,4 suggest monitoring quantitative PCR after 3 months of therapy and to gauge response. Dr. Deininger, how do you interpret and act on those results following the first 3 months of therapy?

Dr. Deininger: I think what you're getting at is the 10% mark that is a highly predictive value in terms of subsequent achievement of major molecular response and also overall progression free and overall survival.

We'll certainly get this data point. Then we'll put it in a clinical context. I think this context needs to take into account the initial BCR-ABL transcript level. I think Dr. Mauro mentioned that they always determine that. I think that is really good advice, so you can make a comparison with the diagnostic value.

One scenario, of course, is the patient is well below 10% and then things are just in the green range and you would wave people through and reassess in 3 months. If people are very high, I think then you have to ask yourself why that's the case.

Some people have a lot of toxicity issues. For example, they may not have been able to take the required amount of medication. It's not always easy to clearly distinguish between resistance and intolerance.

No matter what, I think it's going to be critical to consider a potential change in treatment if people are in the 70%—80% range. In my mind, there's a gray area.

These are the people who are maybe between 10%—20%. Here, I think this initial value can really help. If there's a significant reduction compared to baseline, I would not necessarily change at that point.

If there is literally no change compared to baseline, I would strongly consider a change unless I am concerned about other issues like noncompliance or drug interactions. What I'm trying to say in a rather long-winded way is that the 10% value shouldn't be seen as a dogma.

It still needs to be placed in a clinical context. One should not rush to any conclusions. Ten percent, 11%, and 9% are identical values in the world of PCR testing. One should not over-interpret that.

Dr. Kalaycio: I think that you're making an important point about absolutes in the interpretation of these tests. Dr. Mauro, how do you interpret the 3-month data that comes back?

Dr. Mauro: I agree with my colleague on the approach that it has to be put in a clinical context. I think what we've learned is the importance of the starting value and relative reduction and to not consider response milestones as black and white guides.

I think there are certain scenarios that require some caution. The patient who is on imatinib who is close but has not reached the landmark may be different that a similar patient on dasatinib or nilotinib who has not had significant reduction—that's probably a more pressing situation.

It's ironic that guidelines—maybe because of lack of options—don't encourage us to think about changing therapy early in someone who hasn't met milestones in 3 months when they've been put on a more potent agent.

I also think that careful consideration is needed regarding treatment intensity and the impact of interruptions, in conjunction with all the other facets—the rate of change, the absolute change from the patient's baseline, the starting response level and the timing of the PCR. We need to look at the actual day it's performed. If it's really not 3 months of therapy, we can misjudge.

Dr. Kalaycio: Right. Now, as you're monitoring patients, Dr. Mauro, at what point would you consider testing for kinase domain mutations?

Dr. Mauro: I think we have pretty good guidance from studies to date regarding when mutation testing is indicated and of higher yield. It's generally earlier on into treatment when we have clinical scenarios that are of greater risk, namely failure to achieve cytogenetic responses. In such scenarios if mutation testing informs treatment decision making it is very helpful.

Patients who have defined themselves as not achieving early molecular response—which we discussed earlier—especially someone who's had a second-generation TKI, warrants mutation testing in my view. Patients who don't achieve classical cytogenetic response landmarks at 6 and 12 (or 18) months, who thus have a higher residual volume of disease and perhaps as a function more clonal instability, I think also warrant attention.

I think we run into trouble when we start to, in an overly critical manner, assess patients’ longer term and deeper molecular response trajectories. Mutation testing becomes difficult or impossible for patients who are at or near major molecular remission (MMR). Mutation yield is generally very low for patients who have not lost MMR and also likely those with small volume of change around the MMR threshold. Looking ahead, I think further investigation into early time points and the setting of minimal residual disease may yield data to be able to predict potential resistance earlier than observing it clinically.

Dr. Kalaycio: Right. Dr. Deininger, if you're monitoring a patient and he’s missing milestones and you do obtain a mutation analysis and find a T315I mutation, do you offer that patient an opportunity to see how well they're going to do with ponatinib, or do you refer that patient to your transplant team for consideration of transplant as soon as a donor is available?As a transplanter, even I would not suggest transplant upon the recognition of the T315I. I would wait until all available TKIs have been tried and have either not worked or weren't tolerated.  – Matt Kalaycio, MD

Dr. Deininger: I think we do the first and half of the second. We would certainly offer a trial of ponatinib or, if possible, a clinical trial unless there are insurmountable contraindications.

I don't really think there are any such circumstances with optimized cardiovascular management at the same time, and we may involve a cardiologist at that point to help us if there are cardiovascular risk factors.

We would also do a referral to a transplant center unless the patient is as per performance status, just not a transplant candidate or is too old. Otherwise, we would always make a referral, but we would not pursue a transplant as the first modality, provided that the patient is in chronic phase. Progression to accelerated phase or blastic phase would be looked at totally differently. Here we would certainly put people on a transplant course.

Dr. Kalaycio: I agree. As a transplanter, even I would not suggest transplant upon the recognition of the T315I. I would wait until all available TKIs have been tried and have either not worked or weren't tolerated.

As the two of you know, we're doing fewer and fewer transplants for CML these days. The results we're getting in folks who are failing all of these agents are not as good as they used to be when we were transplanting in the first 3 months of a new diagnosis. Bone marrow transplant is something to defer for as long as possible, at least in my mind.