SLIDES & TRANSCRIPTS
Monday, May 12, 2003

Treatment of Burkitt ALL

Mitchell S. Cairo, M.D.

So, Burkitt leukemia is usually easy to pick up undiagnosed. It is characterized by these L3 looking cells with large basophilic cytoplasm and large vacuoles, and commonly has an 8q24 c-myc translocation, predominantly with the immunoglobulin heavy chain, and sometimes translocated to chromosome 2 and 8 as well.

TOP

So, the prognosis for Burkitt's lymphoma and Burkitt's leukemia has increased dramatically over the past 25 years.

This is a review from the Children's Cancer Study Group, looking at all patients who were treated on the last CCG studies, that included disseminated stage II, IV and BAL disease, that had Burkitt's or Burkitt's-like disease.

In our most recent study, which was CCG-5591, with using much more intense fractionated alkylator therapy and higher doses of methotrexate, we were able to achieve a much improved prognosis compared to our previous studies.

TOP

In 1996, we began an international study for the treatment of B cell non-Hodgkins lymphoma in children, which also included Burkitt's leukemia. It was a cooperative group study between the CCG, the SWOG and the UK CCSG.

TOP

In that study, which closed in June of 2001, which will be presented formally at ASCO later this month, there were approximately 241 patients that had B ALL as defined by greater than or equal to 25 percent L3 blasts.

In the breakdown in that group, there were 53 percent of patients who had pure B ALL. There were 28 percent of patients who were considered what we call group C disease, that had both B ALL as well as CNS disease, and then 19 percent who did not have B ALL, but had central nervous system disease alone.

As usual, it was a male to female dominant ratio, and most of the patients had elevated LDHs defined by greater than two times the upper institutional limits.

The therapy that they received in the study was one that they did not get cranial radiation for the patients who had CNS disease. That was deleted in this particular study.

They received the like therapy, which we call the reduction phase, of low dose cyclophosphamide, vincristine and prednisone at 300 milligrams per meter squared of cyclophosphamide.

Then, on day seven, they started their first induction, which is nicknamed COPADM1. In that, they received fractionated alkylating therapy in this course of 250 per meter squared, twice for three days.

The adriamycin was at 60 milligrams per meter squared, and the methotrexate was given as very high dose therapy, as eight grams per meter squared, with leucovorin rescue.

In the second induction phase, the drug doses were the same, except the fractionated alkylating dose was increased to 500 milligrams per meter squared, twice a day for three days, or a total of three grams per meter squared.

They then went on and received intensification with two CYVE courses that consisted of both a high dose ARA-C at three grams per meter squared, each day for four days, followed by each day, as a continuous infusion, ARA-C at 50 milligrams per meter squared per hour, for the remainder of the 23 hours, and they received VP-16 as well for each of those days.

Then they went on in the standard arm to receive four maintenance courses, the COPADM3 also had the eight grams per meter squared of methotrexate, although the doses of cyclophosphamide were less than they were in these courses.

Then there were three other courses. One was a CHOP-based course that was another ARA-C VP-16 in lower doses.

That was essentially the study. It was a randomized study, which I am not going to show you the randomization, but there was a second arm where there were reduced doses of ACA-C and VP-16 and a deletion of the three courses here of maintenance.

Now, the patients who had CNS positive disease also received a third course of high dose methotrexate that occurred between the two CYVE courses as just eight grams per millimeter squared without any other chemotherapy. This was given over about a four-and-a-half to five month period. It was very intense.

TOP

This is the outcome on the standardized arm for those patients who were randomized to the standard arm, was that the two-year event-free survival was about 94 percent with a fairly long median follow up now of probably about two and a half or three years.

TOP

There was, however, a subgroup of patients that didn't fare as well as those that had pure bone marrow disease here.

This is, again, taking all patients including the randomization. So, the curves are looking a little bit different because I am including the reduced arm here.

You see here the patients that had both bone marrow and CNS disease had a significantly inferior outcome than those that just had bone marrow disease.

TOP

These results are better than what has been published before by the French and the German groups, at least in terms of the standardized arm.

Now, in terms of adult B ALL, I am just going to briefly review four studies that have been published. The data is not as clean because many of the patients had stage IV disease that were included in the publications, and the numbers are smaller, and the therapy is a little bit, for a couple of these earlier studies, a little bit outdated from what is currently being used.

This first study was from Villejuif, the group at Institut Gustav Roussy, that utilized the pediatric SWOG type protocols, some of the older protocols, LMB84 and 86. There were 22 patients in this original study that was reported in Blood in 1995.

For those with stage IV disease, which included some stage IVs and some B ALLs, and it wasn't sorted out, the three year overall survival was 57, plus or minus, 8 percent.

The Germans, using Alfred Reiter’s BFM 83 and 86 studies, again, older studies but reported in 1996, had 59 adults.

Now, both of these studies utilized younger adults. The median age in this study was 26 years and the median age in here was 34 years. So, they are what I would call young adult patients. Again, using the older regimens, the three year overall survival was 50 percent.

The group from M.D. Anderson, from Hagop and Deborah, using the hyper CVAD regimen, they were reported -- and they could probably give me more updated information -- there were 26 patients.

The remarkable thing is that this had an older population. The median age in this group was 58 years old, so a somewhat different population in these two groups.

Using the hyper CVAD alternating with methotrexate, and here the methotrexate was given at one gram per meter squared alternating with ARA-C, alternating with the CVAD regimen, and somewhat lower doses of cyclophosphamide, the three-year overall survival.

They noted in this report that patients over 60 years of age, and patients with poor performance and a number of other laboratory abnormalities, had a worse outcome.

Then, the group from NCI -- and the numbers are very small here -- that Ian Magrath reported several years ago, was a combined pediatric adult study, although the adults patients, again, the median age here was 24 years of age. So, not a very old group.

While I listed 14 patients, there were really only three patients who got the 89 C41 study, so the numbers are very small. Of those three patients with stage IV, it wasn't clear how many of them had B ALL.

This study used CODOX-M, which is cyclophosphamide vincristine, adriamycin and methotrexate, although the methotrexate was given as about 6.7 grams per meter squared per day, given both as a bolus and continuous infusion, alternating with IVAC, which was ifosfamide, VP-16 and ARA-C, but the numbers are way too small to determine whether this was effective or not.

TOP

Lastly, the future plans in the pediatric oncology group is to try to test the feasibility of adding Rituximab into this regimen.

This study is about to open up. It will use the same standard reduction, although recombinant urokinase will be given for patients with hyperuricemia.

We will then be incorporating two doses of Rituximab with each of the regimens. They have now been changed in name to COMRAP1 and COMRAP2, and then they will be getting one course of the Rituximab in the CYVE regimens each, and they will receive the four maintenance courses based on the results of our randomized study.

The idea here is to test the feasibility of adding Rituximab and then, in the future randomized study, for those subgroups that look like they are not doing as well, we will be potentially asking a Rituximab plus or minus chemotherapy question. Thank you.

TOP