Treatment of T-cell

Good morning. In considering childhood ALL and making comparisons to the common form, pre B cell ALL, you have to think that T cell is different.

Clinically, we all know this, because these are typically older patients, adolescent males, and they present with higher white count, and the majority of patients will actually have a mediastinal mass.

Biologically, although not discernible morphologically as shown here, these T lymphoblasts have been defined by surface markers, T cell gene rearrangements, and can actually be differentiated into stages of thymic maturation. There are also a number of studies that report differences in drug sensitivity, both in vitro and in vivo.

Traditional risk factors, however, have been less predictive and are much less sensitive. Commonly, these patients have unfavorable risk factors at the time of diagnosis.

Consequently, they are over-represented in high risk groups, when you use traditional factors such as age, white count, the presence of CNS disease, or other extramedullary disease.

This table here shows you, when you use NCI risk criteria to define risk in T cell patients, that only 25 percent of them are in the standard risk category defined by the age one to nine, and white count less than 50,000. So, that is in comparison to a 60 percent standard risk population for pre-B.

T cell has also been associated with a poor prognosis.

If you look at the studies reported in the 1980s, as shown here for a POG study, the event free survival, when analyzed by cell lineage, shows that T cell patients here with less than a 40 percent event-free survival.

When you look at the same sort of presentation for a CCG study where, in fact, the majority of T cell patients are going to fall in this lymphomatous presentation for ALL, again, you see event-free survival of 40 percent. I pose the question here, is it really a poor prognosis form of ALL.

These are the long-term results which are showing some success for T cell disease in comparison to B lineage disease.

These are data compiled from the leukemia journal, the volume published in 2000 where all the major cooperative groups put together their data for their series of trials.

I have put them together here and, for each group, I have indicated using NCI risk criteria, standard risk and high risk, and the five-year event-free survival for their group of patients. All of these are T cell patients, the overall survival, and then compared it to the B lineage event free survival that is reported.

You can see that pretty consistently, for the BFM, two serial pilots, CCG, Dana Farber, that event free survival is in the 70-plus percent range, and POG series did not fare as well in their earlier trials, and then also St. Jude’s has a T cell population that they report.

In many of these studies, you can see that the event-free survival is really getting very close to what is being reported for B lineage disease.

This is just to show you that event-free survival isn’t the entire story, because when you look at the Dana-Farber trial — this is actually a cumulative collection of T cell patients treated on their series of trials, in comparison to their pre-B population.

You can see that event free survival is really the same. The thing that is different is the shape of this curve. So, the incidence of induction failures, induction death and then early relapse is much different in the T cell patients.

The BFM have demonstrated the benefit of high dose methotrexate, five gram per meter squared, used in four cycles, in their backbone of therapy. This slide just shows you that.

Here on the left is the result of their BFM 83 trial, where in fact they used a low dose of methotrexate, .5 gram per meter squared, and the subsequent trial, BFM86, where they increased the dose of methotrexate to five grams for all patients.

There are four curves here. It represents the non-T, standard risk and high risk, and then the T cell standard risk and high risk. You can see that the benefit was in the T cell patients.

They are the ones who had improved event free survival, both their standard risk and high risk patients, when high dose methotrexate was added to the regimen.

POG also has demonstrated the benefit of high dose methotrexate when used in a backbone of intensive chemotherapy for T cell ALL.

In 9404, high dose methotrexate was randomized, plus or minus five grams per meter squared for four cycles, onto the Dana-Farber backbone.

This slide shows you the results of that study, dividing patients into groups based on their treatment assignment, and also standard risk by NCI criteria versus high risk.

You can see, for both groups of patients, that there was benefit to the high dose methotrexate, and you also can see that the standard risk group, by NCI criteria, did do better than the high risk group.

So, here, a more traditional risk group can be defined, although the treatment was identical for both groups. Treatment was not stratified. This is a retrospective observation.

So, the high risk group, treated with high dose methotrexate, have an 82 percent event free survival. If you look at all comers, it is about 84, 85 percent, and the standard risk group had the best, at 92 percent.

So, I have shown you some improved outcomes. The common elements to treatment that resulted in these improved outcomes really is the same therapy that is being used as for precursor B ALL. There is nothing really very different about it.

Typically, these patients are treated on the high risk regimens because they have high risk features at the time of diagnosis, but the treatment includes a backbone of vincristine, prednisone, 6-MP, methotrexate.

Then, variations are what the use of anthracycline is, what the use of cytoxan might be, asparaginase and how that is given, and whether there is VP-16, other alkylating agents that are included in the regimen or not. None of these treatments have been T cell specific.

So, the challenges in treatment of T cell disease remain that there is still a high rate of induction failure, early relapse, and CNS relapse in particular, that traditional prognostic factors have not been helpful, and treatment has been very intensive.

There are a number of potentially very significant complications from this treatment, which often includes cranial radiation.

So, I want to tell you about compound 506-U78, which is a pro drug of ARA-G. The active metabolite for this drug, ARA-GTP, actually accumulates in T lymphoblasts to a higher level than in pre-B cells or even mature T cells. That is due to the decreased degradation of the ARA-GTP.

So, this appears to be a drug that will actually have T cell specificity. It will work better for T lymphoblasts than it will for the pre-B lymphoblasts.

This next slide shows you the activity of 506U, as a single agent. A phase II study was conducted by POG and CCG in patients with refractory T ALL for lymphoblastic lymphoma.

They used a dose range between 400 and 900 milligrams per millimeter squared per day. This was given times five days.

Here you see the results by stratum. Stratum one were ALL patients in first relapse or induction failures, and the results, when you look at 650 milligrams per meter squared, in a group of 34 patients total, there was a 53 percent response rate.

This really seems quite remarkable. When you look at some of the other strata, again, very refractory patients, ALL in greater than second relapse or second remission.

The response rate is still 27 percent. Again, this is a single agent. It is being given in a five-day course and the course if repeated before activity and remission is assessed.

So, these results were just reported at the COG meeting, and we also looked at toxicity, since that has been a major concern with the use of this agent.

CNS toxicity, which consisted of seizures or somnolence syndrome, was nine percent overall, and peripheral nervous system toxicity, which was primarily a Guillain-Barre type syndrome or peripheral nerve weakness, also occurred in about nine percent of patients.

There was some overlap, in that some patients had both types of neurotoxicity. The neurotoxicity was reversible in almost all cases.

So, based on these response rates, again, 53 percent response rates in a group of relapsed T cell ALL patients or induction failures, obviously very high risk patients, is very encouraging and actually quite exciting.

So, in looking at opportunities that we have for treatment of T cell ALL, compound 506U, and developing for use in the front line of T cell ALL therapy, is the primary task that faces the T cell disease working group within COG.

We look to our colleagues in bone marrow transplant to help us develop the role of stem cell transplantation for patients that are identified as very high risk, as not responding early on, perhaps with very high levels of minimal residual disease.

We also need to learn how to use MRD within the T cell population because, within the POG and CCG group, we do not have that data as yet.

We also look for other therapies, targeted therapies, perhaps, based on the genotypes that were described this morning by Dr. Look and Dr. Willman, and to look to see if we can’t develop other therapies that will be a little bit less intensive, less toxic and better over all. Thank you. I will end there.