SLIDES & TRANSCRIPTS
Monday, May 12, 2003

Allogeneic and autologous SCT

Charles Linker, M.D.
Slide 1:

It has been very difficult to determine the place of autologous transplant in the treatment of ALL.

At the present time, I don't think that there is any clear patient group for whom autologous transplant is the treatment of choice.

What I want to share with you today is a pilot experience that we have at UCSF in collaboration with Stanford and the City of Hope.

The first curve, when the slides come up, will show our outcome of chemotherapy at UCSF and show that we can characterize a group of patient with very high risk, for whom the two year event-free survival with standard chemotherapy is zero.

You can see, with our patients, excluding the very high risk, our five year event-free survival is 64 percent, and there is a poor risk group in which the curve plummets.

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Slide 2:

So, in collaboration on the west coast, we decided to target those high risk patients who we felt, even in the absence of seeing the MRC data, were candidates for allogeneic transplant as their primary therapy.

The question, what do you do for patients who you think need an allogeneic transplants and for whom you do not have an available donor?

We used a strategy which said, we ought to use intensive, pre-transplant cytoreduction to get the patients in better disease shape prior to transplant, and we used a very intensive high dose AraC plus an etoposide regimen. We collected peripheral blood stem cells, we did in vitro purging using technology that Rod Negrin had developed at Stanford for lymphoma patients.

Then, most important, I think, we maximized the intensity of the preparative regimen, thinking that, just to use an autologous transplant regimen which has acceptable toxicity in the allogeneic setting is not using your maximal tool.

The patients with rapid engraftment with stem cells can tolerate higher doses. They are not immunosuppressed.

Since you know you are dealing with a fairly chemo and radiation resistant set of diseases, you ought to try to maximize your regimen.

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Slide 3:

So, the patients who were eligible for this pilot trial were either those in second remission or higher risk patients in first remission defined either by adverse cytogenetics that we could all agree on.

They did not achieve remission after four weeks of therapy and that is with a DVP ASP regimen with 240 milligrams per meter squared of daunorubicin, and 72,000 units per meter squared of asparaginase. So, a fairly front loaded induction regimen.

If you were not in remission after that, but subsequently went into remission, you were eligible. If you had B lineage disease where there was some negotiation between the groups, we consider high risk over 100,000 in B lineage, but there was a patient that got on it with 94,000.

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Slide 4:

So, simply, four days of twice daily high dose AraC with etoposide, collect stem cells, and the transplant dose is 1320 of TBI, 60 per kilo of a etoposide, and 100 per kilo of cyclophosphamide, doses which are probably too much at least in adults, in the allogeneic setting, but we thought might be tolerable in the autologous setting.

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Slide 5:

These patients were up to age 60, the median age close to 40, 18 high risk first remission, as indicated there, including seven Ph positives, and seven patients in second remission. So, a group of patients, I think we could agree, that would be at fairly high risk.

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Slide 6:

We had one death in consolidation. There are some early relapses, mostly in the Ph positive patients before the availability of Gleevec.

Ten of these 24 patients remain in remission. The median follow up is now 3.1 years. The minimum follow up is 1.4 years.

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Slide 7:

So, the data is not mature and it doesn't project very well either, but the bottom curve there is all the patients from study entry, from the start of consolidation, showing a 34 percent five-year event-free survival. It is, of course, higher if you look only at the patients who made it to the transplant.

We were a little bit surprised to have a relapse at three, and one at four years. We thought that, in this very high risk group, once you made it to two years, you would be home free, but that, at least so far, was not the case.

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Slide 8:

What can we learn from this pilot experience? I think the treatment is feasible. There are relatively few deaths and one was an air embolus, which was very preventable.

I think that there is some efficacy of this program. I don't think we would have had 30 to 40 percent event-free survival in this group of patients, and we have enough follow up to say that at least some of those patients are salvageable.

There is other data, particularly from Dieter Hoelzer's group. Hans Martin has a program which is very similar in design to ours, with a high DAC base, cytoreduction, a very aggressive transplant regimen.

He has data in 40 Ph positive patients with long follow up, showing 20 percent long-term salvage.

What the in vitro purging did, of course, we don't know, and we are not going to be able to use it in the future because the docs at Stanford are not pursuing these home grown antibodies.

So, to me, I think that there is enough going on here that the role of autologous transplant needs to be explored further.

There is a CALGB SWOG study that Wendy Stock alluded to, looking at Ph positive ALL, in which patients with donors will have an allo, those without will have auto, intercalate Gleevec into this schema.

I can mention, the two Ph positive patients we have treated since the availability of Gleevec who have been on maintenance, both of those remain in remission more than two years.

I think it is going to be critical to define what is going on in the stem cell product using some o the MRD techniques that have been talked about.

If purging has a role, we need to come up with a way to do this and it is not at all clear what that should be.

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