SLIDES & TRANSCRIPTS
Monday, May 12, 2003

Working Group D: Ph+ ALL

Marty Tallman, M.D.
Bruce Camitta, M.D.

DR. CAMITTA: I think I can summarize our session by saying that everyone agreed that having PH positive ALL was a bad thing and they don't want to have it. It is even worse if you are an adult rather than a child.

These are some of the issues that we brought up and what we think could be done about them.

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The first issue is that we need a better understanding of the pathogenesis of the disease. Clearly, the Philadelphia chromosome alone doesn't explain all the features of the disease.

We need to know, from array studies or from other studies, such as the SCID mouse model, what changes are actually important for the development of the disease.

TOP

The second area has to do with prognostic factors. Clearly, the BFM group has shown that a poor response to seven days of prednisone before other chemotherapy is a very predictive factor.

However, the question is, are the factors that we can find also prognostic. For example, MRD, most patients with Philadelphia chromosome positive ALL have a high level of MRD immediately after induction.

However, how about asking the inverse of that question? Are patients who are negative at day 28 or day 56, do they have a good prognosis and can they be managed with less aggressive therapy.

Similarly, from array data, can we prognosticate which patients with Philadelphia chromosome positive ALL are going to fail induction therapy or are going to relapse early, and therefore, are going to relapse early or, the converse, which patients are going to survive.

TOP

We need better drugs. Right now Imatinib is being investigated. There are at least six different trials, some of which are randomized, some of which are not, which are going to look at Imatinib in patients in the first complete remission, both with and without bone marrow transplantation.

However, the questions that need to come out of these trials are several. What is the optimum dose?

I am not sure we are going to get that answer from these trials, because almost all the trials are using the same dose.

Secondly, what is the optimal schedule? Should the drug be given by itself, should it be given simultaneously with chemotherapy? Should it be alternated, or what other schedule might be effective?

The next thing is, is the drug actually going to be curative? I don't think we want to shift the curve to the left. I think we want to shift the curve to the right. So, are we going to cure patients or are we just going to postpone the inevitable relapse that we see these days.

Finally, what is the role of post-bone marrow transplant chemotherapy or immunotherapy or other therapy in improving the outcomes.

Drugs which were discussed which might be helpful in some patients based upon some in vitro data currently include arsenic, farnesyl transferase inhibitors, and perhaps we will get some hints from some of the work of Dr. Willman and others about other molecular targets that we can develop drugs for.

TOP

In terms of stem cell transplants, we have heard data today that both matched sibling and unrelated donor transplants are indicated for adults with Philadelphia chromosome positive ALL.

In children, clearly, matched sibling transplants are indicated, but the paper of Arico et al suggested that unrelated donor transplants, at least up until several years ago, were not indicated, did not improve the prognosis.

However, recent data suggests that at least at selected centers, that unrelated donor bone marrow transplant could be almost as effective as related matched sibling donor transplants, but this needs to be looked at again in a cooperative group setting.

What is the role of MRD in predicting the outcome of bone marrow transplantation? We have heard this discussed by other investigators.

Finally, as mentioned above, what is the role of post-bone marrow transplant treatment, either based upon MRD or just based upon a randomized study.

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Finally, immunotherapeutic approaches should be considered for PH positive ALL using lymphocytes. You could either have so-called non-specific cells, which are reacting to antigens that are found on all types of ALL cells, or they could be targeted as Dr. Forman was suggested for, for example, the CD19 antigen, if we could find an antigen that was specific for PH positive ALL, and we could also develop monoclonal antibodies, if we could find such a target.

So, these are the challenges we face. I think the challenges are shared by both adults and pediatrics. That is why I am standing here, instead of having two people doing a tag team match. Any questions?

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PARTICIPANT: So, what is the current strategy? What is the state of the art in bone marrow transplant?

DR. CAMITTA: The state of the art is that it is being looked at in at least three or four different studies, and until we have the answer to those studies, we don't have a state of the art.

I think that several of the studies are using the same dose post-transplant that is used in the patients that are not getting transplants, and other studies are starting with a lower dose, about 50 percent of the dose and, if there is no toxicity, will be using the full dose.

PARTICIPANT: I am a bit concerned about the studies. I know that there are many studies, but in most of them the dose that is used is 400.

There are many interruptions for the treatment to allow for autologous transplant and so on. So, if those studies come out to be negative, there is going to be the question of the dose intensity, that you have the selective drugs that you are using not being the best dose scheduled, while non-selective approaches like autologous transplant are compromising the dose.

I think it is very important to go back and look at the design of those studies and try to use them more and more frequently and for the longest period of time.

You have to extrapolate when patients with CML are interrupted, they come back with their disease very quickly, and I think it may be the same for the patients with ALL.

DR. CAMITTA: I think we all agree that we don't have the information on the optimal dosing schedule. After transplant, once counts have recovered, all the studies are going to be using continuous dosing of STI for four to eight months.

Before transplant, there are different ways of doing it, but most are using three week blocks, off for a week or two to give the chemotherapy and then giving it again.

Perhaps if there is no toxicity with that approach, then a continuous dosing will be tried, but there are concerns about overlapping toxicities with some of the drugs.

PARTICIPANT: Four to eight months of maintenance may not be enough. Some of the studies say until PCR negativity for three months. That may not be enough.

DR. CAMITTA: I think that all these studies, I should have mentioned, are being accompanied by measurement of minimal residual disease, by sensitive techniques, in an attempt to answer just that question.

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