ALL Leukemia

SLIDES & TRANSCRIPTS
Monday, May 12, 2003

Treatment of Ph+ ALL

Deborah Thomas, M.D.

Slide 1:

Good morning. Today, I am going to discuss some of our data at M.D. Anderson in the most high risk group we have in Philadelphia ALL, particularly the subset where we now have some new agents that can impact the outcome of disease.

I won't belabor the point that this, of course, is a disease with a two-year disease-free survival of less than 15 percent.

The question that faces us now is how best to use Imatinib methylate in the treatment of this disease, and perhaps this presentation will allow some further discussion today in our workshop, to help design clinical trials that will best serve these patients.

As you know, both Dr. Druker and Dr. Ottman have published studies, initially a phase I study looking at a dose ranging from 300 to 1000 milligrams of Imatinib and, again, subsequently a phase II study of either 400 milligrams or 600 milligrams daily dose of Imatinib.

The complete remission rate was fairly similar in both groups of heavily pretreated patients of approximately 20 percent, and a significant hematologic response rate.

However, the unfortunate events were that the patients generally all relapsed, and quite rapidly, and usually with explosive disease.

Clearly, as a single agent in the subset of patients who have been previously treated, this may not be the optimal use of this agent.

There were, around this time, particularly with the interest in CML, in vitro studies looking at potential synergistic or additive agents, and there was demonstrated to be additive effects with anthracyclines and interferon alpha, and potentially synergism with LSC.

The backbone of our treatment of ALL at M.D. Anderson, of course, includes the use of hyper-CVAD, and the traditional outcome in patients who have de novo Philadelphia positive ALL is a relatively good complete remission rate, similar to their counterparts, however, with a very high relapse rate.

Slide 2:

So, in designing a clinical trial using a combination of Imatinib with hyper-CVAD, the question was whether to use concurrent or sequential therapy, and we favor concurrent administration because of the in vitro data with synergism.

We designed the clinical trial in mind using the backbone without any dosage estimate of the particular agents, other than our standard dose reductions for older age, with reduction in RSE and potential reductions for methotrexate in the face of renal failure at presentation.

A course of treatment was designed, usually administered over five to six months. We added the supportive care measure of the protective environment in patients who were older than 60 years of age.

We continued to administer intrathecal therapy, given the information that perhaps Imatinib did not penetrate the CSF adequately to provide CNS prophylaxis.

The Imatinib was given in the front line patients at 400 milligrams daily and, in the salvage setting, it was 600 milligrams daily, for the first 14 days of each cycle.

The week off, with these treatments being given approximately every three weeks, was designed to allow recovery from myelosuppression, which had been seen at a variable rate in the CML study.

Initially, we designed a maintenance phase of approximately one year in duration, utilizing a higher dose of Gleevec, 600 milligrams daily, concurrently with vincristine and prednisone.

We avoided the use of 6-mercapto-purine or methotrexate for the concern of potential hepatotoxicity, and perhaps compromising the dose of Gleevec.

Slide 3:

So, some initial preliminary data on 16 patients who have been treated and reported in ASH last year, showed that the comparison group of 29 patients were fairly similar, except this group had a higher incidence of CNS disease at presentation, and the great majority had a very high white count at presentation.

Slide 4:

When we look at the responses, all patients who entered the study with active disease were able to achieve a complete response, including resolution of all extramedullary disease.

Patients who had previously been treated with one or two induction cycles of therapy without Gleevec were also allowed to enter, either in complete remission or refractory.

The patients who were considered refractory had failed one prior course of therapy. They all responded. Those patients, four out of the five who entered had minimal residual disease detectable prior to study entry, and were not evaluable, however, for complete remission.

In the 11 patients of this group who had been evaluable for evidence of molecular remission, we did see this in a small proportion of patients, also confirmed by nested PCR, and some patients who had a ratio of BCR ABL of ideal less than 0.05, although the clinical significance of this is not yet determined and we have not yet made any adjustments in therapy based on this information except to follow it prospectively.

Slide 5:

All patients who were eligible for stem cell transplant were encouraged to do so, and we were able to do this in approximately 50 percent of the patients after identification of a donor within one to six months.

None of the patients, except for one who entered allogeneic transplant, had achieved molecular complete remission prior to doing so.

However, nearly all the patients, after allogeneic transplant, did achieve molecular complete remission which had been monitored serially.

This shows overall survival rate comparison to the control group with a minimum follow up of not quite one year.

These patients were censored at the time of allogeneic transplant. If you remove the censoring, there is one additional relapse after allogeneic transplant at day 186, in a patient who had received four cycles of hyper-CVAD followed by match-related sibling donor transplant, and no post-transplant Gleevec.

The other relapse patient was a primary refractory patient who relapsed one year later on therapy after refusal of stem cell transplant.

Slide 6:

So, when you look at the concern about potentiation of toxicity, drug interaction and potential treatment delays or excessive mylosuppression, we did not observe this to any significant fashion.

We observed predominantly expected toxicities of neutropenic fever or infection. There were a few patients who had mild elevations in hepatic transaminases, usually occurring immediately after administration of chemotherapy, the methotrexate RSC courses and transient, similar to what we would see with hyper-CVAD and methotrexate RSC alone.

No patient requited cessation of the Gleevec therapy for the potentiation of toxicity.

Slide 7:

Now, the concern about concurrent therapy led to design of other clinical trials, and Dr. Ottman presented this at ASH.
His trial looked at patients who had Philadelphia positive ALL, or CML lymphoid blast crisis. The majority of patients were Philadelphia ALL patients who had received a standard induction therapy and then were enrolled on a subsequent clinical trial looking at minimal residual disease and outcome in patients who were treated sequentially with blocks of Gleevec therapy.

PCR was obtained pre and post Imatinib, which was given for 28 days after the induction course, either at a dose of 400 or 600 milligrams, with the majority receiving the former, followed by stem cell transplant, if feasible.

If stem cell transplant was not available, the patient went on to a consolidation course. Again, at each time point, the patient would proceed to stem cell transplant as soon as feasible. A subsequent block of Imatinib therapy would be given subsequent, if they had not yet proceeded.

The preliminary data presented showed that 90 percent of the patients had achieved complete remission after the first Imatinib course of therapy. There were patients who had only achieved a partial response prior to entering this cycle, and one of these progressed during that course.

The minimal residual disease parameters actually had reduced in a majority of patients, but some also had a rise during the Imatinib cycle, the first that is indicated there.

The concern was potentially that the patients would have, on presentation, prior to entering stem cell transplant, a higher level of minimal residual disease, too.

They had a very high rate of successful allogeneic stem cell transplant. One patient had relapse with overt leukemia prior to doing so.

Although the abstract form does not indicate the additional relapses, when Dr. Ottman presented, he did show that there were patients who relapsed after stem cell transplant.

Slide 8:

So, one of the concerns is potential mechanisms of resistance that need to be studied further in these patients.

Dr. Hofmann has published both on the single point mutation at the ATP binding site, which was acquired and not present prior to therapy, and gene expression profiling, which has indicated high levels of tyrosine kinases and ATP synthesis, and other pro-apoptotic and p15, which are down-regulated.

Of course, perhaps gene expression profiling may be important in selecting these patients for use of Imatinib and best use in clinical trials.

Slide 9:

So, one of the potential complications and concerns that has to be addressed is the use of Imatinib in front line Philadelphia positive ALL. What is the optimal dose. Should it be given concurrently or sequentially with therapy? What is the duration?

Does a negative quantitative PCR substantiate the discontinuation of such intervention?

Perhaps the use of biologic modifiers, such as farnesyl transferases, which have been shown to re-institute sensitivity to Gleevec and CML could be utilized in patients who develop mechanisms of resistance.

Perhaps combination therapy with monoclonal antibodies should be incorporated for synergistic potentiation.

Again, probably what will be discussed in the next session and later in the workshop would be the use of Imatinib either in conditioning regimens, as pursing for autologous marrow collection and post transplant, to allow reconstitution of donor chimerism. All need to be explored.

What is the optimal dose? What are the concerns about potential for drug interaction?

Again, mechanisms of resistance and predictive value and minimal residual disease all need to be further delineated. Thank you for your attention.