SLIDES & TRANSCRIPTS
Monday, May 12, 2003

Working Group A: Minimal Residual Disease

Michael Borowitz, M.D., Ph.D.
Wendy Stock, M.D.

DR. BOROWITZ: What I would like to do is just sort of summarize in broad strokes some of the things that we talked about.

This is a slide that Wendy showed this morning, kind of outlining the questions to be addressed. We addressed these.

I won't go so far as to say that we answered all of them, but we kind of had some discussion about some of them.

TOP

So, as to the first one, should MRD be used for treatment assignment. I think the first thing that was very clear is that there were philosophical approaches that differed between adults and children.

It is pretty clear that there are opportunities to intensify therapy in MRD positive children, and virtually all of the pediatric groups are now employing, or planning to employ some kind of intensification of at least some subsets of children who are MRD positive.

In adults, I think the one consensus position was that bone marrow transplant was clearly going to be the method of choice in MRD positive adults who had an available donor, but beyond that, the questions became a little bit more complicated.

There was a proposal by Tony, who offered a proposal to study a question in adults with a donor who are MRD negative, to study bone marrow transplant versus chemotherapy.

Wendy will talk a little bit more about some of the adult options, particularly for patients who didn't have a donor.

I think the issue of reduction in therapy, for patients who are MRD negative, that still is a controversial area.

Some pediatric groups are now planning to incorporate this into therapy, but this is by no means universal even in the pediatric world, and I think in the adult world that is not even being considered.

TOP

As to the issue of methodology, this isn't exactly a methodological issue, but there is now general consensus that looking at MRD early in the course of therapy is clearly the most important for purposes of planning therapy, planning intervention.

The important principle is that the sensitivity that is needed depends upon how you are going to use MRD, what interventions you plan, what questions you are asking.

Flow cytometry may methodologically be sufficiently sensitive for the purpose of identifying patients for the intensification of therapy, but clearly, molecular methods are needed if your goal is to identify patients who are truly negative, or if you are going to be using MRD to assess the effectiveness of new agents.

TOP

Now, as to the issue of the level of MRD detected, I think here there isn't very clear consensus about a specific number that is associated with an intervention for MRD, but there are a lot of issues, one of which has to do with correlations among methods, particularly expression-based methods compared to cell-based methods or DNA-based methods.

Clearly, there are other things that this depends upon, what intervention you are planning. The level may be different, depending upon the intervention.

The specific level is probably going to be dependent upon the therapeutic context in which these data have been acquired.

So, it is still very difficult to generalize as to MRD at a level of such and such should cause this intervention, independent of therapy.

There was some discussion about whether blood could substitute for bone marrow. There is some data in the literature that suggests, at least in B precursor ALL it could not, but we heard some other data that suggested that maybe in some settings, it can. Obviously this would have some implications about levels as well, if it is the same, or if it is different.

I think several people raised the point that, rather than worrying about a specific level of MRD, it is really the kinetics of clearance that may be important.

Particularly with the early kinetics of clearance, there was a lot of discussion about moving MRD assessment up earlier in therapy, to even during induction therapy.

TOP

Finally, there is a lot of interest in using MRD as a surrogate marker to evaluate the effectiveness, particularly, of new agent or any therapeutic modalities.

There are several trials ongoing, and Wendy mentioned some of those in her talk this morning. It is really an ideal modality, potentially, for the evaluation of novel therapies but, again, the choice of method will depend upon a number of things.

If the planned therapeutic intervention is during an up front window when there is a lot of disease burden, then low sensitivity methods like flow cytometry may be appropriate for monitoring.

On the other hand, if you are trying to evaluate a new agent which is given in remission, when there is no bulk disease, then we will actually have to have methods of higher sensitivity, and that is maybe one of the major roles for high sensitivity molecular methods as we go on.

The other point that really wasn't raised, but Wendy and I were talking and we really want to make this point, and that is, that this idea of using MRD as a surrogate marker really needs validation. At least in the early stages, this all needs to be linked to outcome studies, and maybe, at some point, we won't have to do that.

Wendy wanted to say a little bit about the discussion, which was extensive, about how to use MRD in the adult trials.

TOP

DR. STOCK: This is a slide, actually, from Dr. Goldstone's proposal, that he thought it is a direction that they may be exploring, and based upon the availability of a sibling and MRD status at six months into treatment.

The MRD negative patients who have a sibling, he thought it would be interesting to randomize them between an allo and shorter course chemotherapy. So, here we talk a little bit about the beginning of reduction of therapy based on MRD.

The MRD positive patients with a matched sib would go to an allo very quickly. If they did not have a sibling, MRD negative patients, again, the same question as here, except for short versus longer course chemotherapy. MRD positive patients, more extensive choice of transplants, using the six-month time point.

TOP

For the U.S. data that we have been looking at, we were thinking that maybe an earlier time point, at least one very early time point, would be the basis upon which we would begin to perhaps think about a phase II study where the MRD positive patients would go early on, as quickly as we could find any kind of a donor, to an allo transplant in first remission, MRD levels, perhaps, at a level of greater than 10-4 after induction therapy. Whether we use PCR or flow, that still remains to be debated.

The MRD positive patients, we thought that this was also a very good group for very early introduction of novel agents for assessment of novel agents, if we have some in the near future, and then going on to late intensification therapy.

Also, there was some discussion about whether intensifying methotrexate, as has been successful in pediatric ALL, especially for the T cell patients, whether MRD assessments could be done at some point during post-remission therapy for that, in terms of monitoring its benefit.

So, that was sort of where we left it. There was no thought to reducing therapy, sort of, in a later discussion. We did not think that was a particularly good goal.

TOP

[No text is associated with this slide.]

TOP

[No text is associated with this slide.]

TOP

PARTICIPANT: So, you won't even test it at 12 weeks?

DR. STOCK: We wouldn't test MRD at 12 weeks? Yes, you could test it. We were talking about at least one really early time point to begin to make the determination.

Then there was another question, too, if two time points were important, if the patient was positive but then negative at 12 weeks, whether one would go straight on to the transplant. That is a question that could be addressed in a phase II study. It is not known.

One of our concerns about waiting more than 12 weeks, of course, is the early relapses, but that was another point brought up, that perhaps two time points, fairly early, maybe at four weeks or even earlier than four weeks, based upon the kinetics, and then a slightly later time point would be appropriate.

PARTICIPANT: Was there any discussion of sample quality? I think I heard someone say that if you compare the first draw and the third draw, there can be a lot of difference in the level of MRD.

DR. BOROWITZ: That point was raised. Again, these are critical questions when you are dealing with identifying negatives for making decisions about reduction in therapy, something like that.

It may mean that you won't intensify or you won't transplant some patients who are positive. I think when you get into production level, those are real questions that have to be dealt with, and you are right, there are some data that later draws give you a lot of hemodilution.

That is why it is really critical to address this question of whether blood can substitute or under what circumstances it can substitute, because then it becomes less of an issue.

PARTICIPANT: What is the recommendation for pediatrics?

DR. BOROWITZ: I think everyone in pediatrics is using some kind of early time point of MRD assessment. Exactly when may vary a little bit, but it may be therapy dependent, to identify bad actors who can benefit from intensification of therapy.

Persistent MRD positivity may be grounds for consideration for transplant and things like that. I think the issue of what you do with patients who are MRD negative with high sensitivity assays is controversial.

We heard that people in Europe are approaching this differently from the way people are doing it here. I don't think that there is a consistent recommendation.

I know that we are not planning to act on that right now, but to continue to study it, but I don't think that there is consistency around the world about that issue.

PARTICIPANT: How much longer do you think this can just be studied? This has been going on for 20 years. Unless somebody is going to do something, like intensify or something --

DR. BOROWITZ: Intensification, I think that is the done deal. It is the reduction question, I think, that people are nervous about.

DR. STOCK: There are two studies going on.

[The following passage from Dr. Borowitz was added during revision and is not in the audio portion]

DR. BOROWITZ: Every study that is going on or is planned in pediatrics will be intensifying on the basis of MRD. In the BFM, MRD PCR will be used to identify both low and high risk patients, with the low risk group defined by those who are MRD negative at both end induction and 3 months, and the high risk group by those who are positive at 3 months, with other patients constituting intermediate risk. In the St. Jude protocols, flow is used to define a very high risk group of patients, and to upgrade standard risk patients to a high risk group, but is not used to identify a low risk group. In the upcoming UK ALL trials, both NCI standard risk and high risk patients who are MRD positive by PCR will undergo randomization among more intensive regimens than if they are MRD negative. Finally, in the new COG trials, levels of MRD of greater than 0.1% by flow will exclude patients from the low risk trial, and will result in assignment to the most intensive therapeutic arm on other trials.

Thus, it is the reduction of therapy for MRD-negatives that there is a question about, with only the BFM currently using absence of MRD as a criterion to define a good risk group.

DR. CARROLL: We debated that about six million years in the group. It is a good question. At some point you have to just do it. Let's move on to immunotherapeutic approaches, antibiotics, Deborah Thomas and John Leonard.

TOP