Click here to view next page of this article

 

New Treatments for Myelodysplasia

Myelodysplastic syndromes are characterized by pancytopenia with a hypercellular bone marrow. This is found in about three-quarters of patients myelodysplasia. This is much more common than AML, tends to occur in older people and in the vast majority - around 80% - we don’t have a clue as to what’s causing it. But in around 15% of patients, 10 or 15%, there is some exposure history that we can implicate. Whether it is an environmental factor, some chemotherapy.

What does one do in the initial evaluation of the patient with MDS? Well, obviously careful history and physical, particularly looking for exposure history, CBC, other cell counts, differential and a reticulocyte count, a bone marrow and biopsy with iron stain, cytogenetics, a serum erythropoietin level prior to transfusion and, if you really aren’t quite sure whether this is true MDS or not, you might get a folate or B-12 level. Some other things that are helpful are HLA typing for patients who might be transplant candidates.

As I mentioned, ara-C has been the most widely studied and particularly at low doses. Not those 100 mg or 200 or grams of the stuff that we use for acute leukemia, but in fact in doses of around 10 mg per liter squared once or twice daily. This was based on some early data suggesting that not only could you get responses with those doses, but it might induce cellular or differentiation, which turned out not to be true on the second count, at least. But if you look at an amalgam of the world’s experience up to about 10 years ago or so, the response rate in myelodysplasia was about a 17% complete remission and about a 35% overall response rate.

Another drug which has recently engendered considerable enthusiasm in some camps, certainly a lot of controversy, has been 5-azacitidine. This drug has been around for decades, initially for the treatment of acute leukemia, but it was too toxic. The doses that are used for myelodysplasia are significantly lower. I’ve shown you the three phase II trials that have appeared in the literature. Only the first in a full article, the others in abstract form. The second two are ones of particular note, from the CLGB. The first one using a continuous intravenous infusion, the second subcutaneous administration.

One of the more intriguing sets of results came from Dr. Baran and Kontargen and their co-workers at M.D. Anderson with a topoisomerase I topotecan. And these were data that were most recently published in 2006 in patients with MDS, particularly the bad histologic subtypes. A lot of old people and patients with cytogenetic abnormalities. Half had MDS, half had CMML, they tended to be older. They got complete remissions in about 30% of patients and in fact eight patients became cytogenetically normal.

Well we’ve talked mostly about single agents today. What about aggressive, intensive antileukemic combinations? There have been a number of studies through the years and they are kind of hard to interpret. For one thing, the number of patients is small and variable. The patients within these groups are very heterogeneous. What they suggest is complete remission rates vary anywhere from 15% to 40, 50, 60% but the treatment-related death rate is higher than one would see when you use these sorts of regimens for AML. But some patients do well, particularly those with the RAB histologic subtype. Of course they are like leukemia so you treat them like leukemia. And some of them respond like leukemia. Now the only curative therapy that has been clearly demonstrated to be curative in MDS is allogeneic bone marrow transplant. And I picked just those trials up until a couple of years ago that had 20 or more patients. There are a lot of anecdotal things.

Once the patients fail bone marrow transplant, there has been a lot of enthusiasm for the concept of donor leukocyte infusions and there are minimal data in myelodysplasia. This paper by Dr. Collins and co-workers a couple of years ago only included five patients with MDS.

Now probably the drug that has been talked about considerably more than others recently is amaphostine. Also known by WR27-21. It’s been called a chemo-protectant or radio-protectant and a bone marrow stimulant, all in one. And these are some updated data from Dr. Lizst which was most popularized, and there were 78 patients. As of this publication, only 32 were evaluable. This just shows some demographics of these patients and the dosing schedule of the agent; 200 mg per meter squared three times a week for three weeks. And if they respond, you just keep on keeping on. The updated data are not quite as promising as the earlier data.

Another bit of interesting data are based on the in vitro observation that there may be an autoimmune component leading to myelodysplasia. So Dr. Barrett at the NIH conducted a series of trials - and this is some of the more up-to-date data presented last year at ASH - and

Now anemia is probably the hallmark of MDS and what do we do about it? Well, you need to first evaluate it with the various tests; CBC’s, iron studies and EPO levels. Then if you can identify a cause you treat that cause and transfusions where needed. You design treatment in part on the basis of whether ring sideroblasts are present or absent, and the serum EPO level.

So the treatment of anemia, according to the National Cancer Center Network guidelines; for patients who have no ring sideroblasts, a serum EPO of less than 500, give them EPO at the dose at the schedule mentioned there. And if they respond you continue to treat them. If they don’t respond, then you might consider adding GCSF. If that doesn’t work, then they need to get standard supportive care. For patients who have ring sideroblasts and a serum EPO of less than 500, EPO at this schedule. They recommend immediately giving GCSF. I think that’s a bit of a leap of faith. If they respond you continue, if they don’t then red cell transfusions. Patients

So the NCCN recommendations as published in Oncology in November, I believe, of last year; if you have patients who are low risk or intermediate I and are stable, if they are older, supportive care or some low intensity therapy. Whether that’s some form of growth factor or low dose of some form of chemo. If they are younger and good performance status, then their

Now there are a lot of therapeutic options, a lot of new therapeutic possibilities. These should all be conducted in the context of peer reviewed clinical research studies. How do you find out about those studies? You can always call your local cancer center or your