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New Treatments for Acute Myeloid Leukemia

Acute myeloid leukemia is a remarkably heterogeneous disease. What it is is a halt in differentiation. It’s an acquired mutation which, by mechanisms that are still not understood, puts a halt in cell differentiation. So you have continued proliferation but with the buildup of cells at a particular level of maturation. So instead of having a society in which you have the proper number of infants, children, adolescents and adults, you sort of have a society that’s composed entirely of adolescents and children with all of the problems that we recognize that that might become acute myeloid leukemia.

Now a couple of years ago I had the opportunity to summarize a whole series of CALGB-AML studies done over about two, or now almost three decades. The point on this slide is not to necessarily prove that things are getting better in the more recent studies, although they are, but to demonstrate that these studies which aren’t to be compared , some are in younger patients, some are just in older patients, some had APL, some didn’t, etc. but that there is a remarkable similarity in the shape of these curves and those from every other group. What they show is a real cure rate but they also show a very rapid failure rate, a rapid fall-off in the first six months in people who relapse quickly. Lower hazard rate the second six months, much lower the next year, much lower the second to third year, and by three to four years those curves.

Now why doesn’t therapy always work? Or even often? The major reason is inherent resistance of the leukemia cell or for this you could read "cancer". And these could be biochemical, these could be cytokinetic particularly for agents that have to be incorporated into DNA to have its cytotoxicity. They could be pharmacokinetic or wrong doses or intolerable doses of cells and of course the inability of patients to tolerate the dose that you have chosen. I will go through some examples of this. Now I just used this slide to make one important point.

These are different antibodies, that doesn’t really matter. But for example take this patient; 50% of this patient’s blasts express this particular antigen 50%, yet they all look the same under the microscope. Over here we are accustomed to calling cells positive for a particular antigen and whatever properties go along with that antigen if 20% of the cells are positive above background. So that leads you to the biological absurdity that at 21%, you have the disease, at 19% you don’t. Whatever you are measuring by immuno-phenotyping or anything else is something that occurs in only a small population of cells, you are very likely to miss.

Now in my years of watching the treatment of AML and trying to improve it, I think you can sort of divide the series of studies that have been done this way; how to use ara-C, how to use growth factors, the role of transplantation, more recently the role of manipulation of the multi-drug resistance phenotype. There was compelling in vitro evidence for increasing the dose of ara-C that would have enabled the drug to partially escape deamination by very potent enzymes in the plasma and liver, to rapidly cross the cell membrane and eventually to compete with endogenous cellular nucleotides so that it can be incorporated into DNA, result in a false nucleotide, a chain terminator and death of the cell. Lots of good in vitro evidence to support the role of high dose ara-C in all of these steps.

Unfortunately in older patients … and I might add, the word "elderly AML" has crept into the lexicon, something that more and more of us are beginning to find offensive and makes us nervous. The proper phrase is "older people with AML". For older people with AML there was unfortunately no benefit from dose intensification and an appreciable increase in toxicity. In fact, we do not know what the proper post-remission therapy is for older people with AML. If they are older but the small percentage who have a more favorable cytogenetic translocation.