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New Treatments for Aplastic Anemia and Pure Red Cell Aplasia

The empty bone marrow is the hallmark of this disease. An absolute empty bone marrow biopsy, can be seen in a couple of congenital syndromes; constitutional forms of aplastic anemia that can present in adults. This is just showing you the results of diapoxy butane testing in a patient with Fanconiís anemia, and you can see these very peculiar forms in the mitotic spread that are the hallmark, and in fact the diagnosis of Fanconiís anemia, is based on this test. Which is done, by the way, in peripheral blood lymphocytes. No need to have a bone marrow specimen to do this. Fanconiís anemia has been reported in patients in their 50ís and even early 60ís. Point one and point two is that Fanconiís, although serotypically associated with physical anomalies - short stature, all sorts of urogenital and skeletal problems - Fanconiís anemia can be absolutely without physical anomalies, even with careful examination. Probably the majority of patients only suffer from aplastic anemia.

This is another form of - of course these are just hands - but this is the representation of the hands of a patient with dyskeratosis congenita which also presents with an empty bone marrow. These patients usually do not present beyond the first or early second decade of life, so it is rarer to see them in adulthood. But you can certainly see a teenager and you look for these very misshapen fingernails. Now this is a great teaching bone marrow biopsy because if the fellow had only gone in this far we would have probably just called it aplastic anemia and not had enough tissue to look at. But there obviously are cells here, quite nicely demarcated, and this patient has 5Q minus myelodysplasia. And you should know that about 20% of patients with what we call myelodysplasia have bone marrow hypocellularity. In my mind this is the single most difficult, differential diagnosis to make with aplastic anemia. Partly because we are not really sure what to do with cytogenic abnormalities.

This shows you again in a different patient. Hereís a nice big early erythroid form and you see that myeloid elements really are without granules. This is a slide from Upjohn, It's not one of my patients. But hereís a Pelger-Huett anomaly which also can be seen. In this patient there are a number of early myeloid cells. Okay, hereís another empty-appearing bone marrow, though there is a little bit of hematopoiesis going on here. This is a very unfortunate woman who actually had an aleukemic form and an aplastic form of acute leukemia. So again looking very carefully at the aspirate smear you sometimes have to look right in the spicula. You can appreciate that there are blasts here.

Now the next to last thing I want to mention; these are not hematopoietic cells at all. This is a myelophthisic bone marrow. There is some fibrosis on the biopsy but this is breast cancer in the bone marrow and this can also produce pancytopenia. This woman in fact had a recurrence of breast cancer diagnosed on a bone marrow that was performed for falling blood counts. Finally, this is myelofibrosis. This is the one diagnosis in addition to cancer in which you may have trouble actually aspirating cells. In some of the medical textbooks they will tell you that itís hard to aspirate from aplastic anemia. Thatís not true. You aspirate. Itís just a very watery specimen but if you really have trouble aspirating after doing a biopsy, thatís almost always myelofibrosis or bad technique, but mostly itís myelofibrosis. So this is a VEN diagram but it indicates what I think is a fundamental relationship - although the exactitude of the relationship is not really of import - among.

This is a patient with aplastic anemia who has got very pronounced bleeding symptoms and signs. As you can see, these ecchymoses, petechiae; she is actually oozing from the mouth and other organs as well. Sheís actually doing very well five or six years after this gruesome picture was taken. She is a little bit atypical in that she is older and aplastic anemia is a disease of younger individuals. This is very similar to the data that you can get from Seattle or other large centers that see aplastic anemia patients. There is a marked age, the history shows a marked peak among late teen years and the early 20ís and 30ís. This nadir in early middle age and then a secondary peak among older patients.

Now aplastic anemia has a lot of clinical associations which you should know, although they are not terribly helpful in terms of actually dealing with the patient, with a few rare exceptions. Of course the most common form of aplastic anemia is iatrogenic. I mean weíve all produced it in this room. You give a patient with cancer - or more recently with a collagen vascular disease - very heavy doses of cytotoxic chemotherapy or irradiation and you can produce transient aplasia, which is identical to all intents and purposes pathological to acquired aplastic anemia. But this is not obviously a cause of community acquired aplastic anemia. With very rare exceptions.

So clearly, benzene has a strong relationship. I think itís really the only chemical in which we have very good evidence that there is a relationship to this type of bone marrow failure. But because of the tight regulation of benzene in industry in the United States, this is a very infrequent historical fact in patients. You do sometimes get a patient who will give you a history of benzene exposure that is indirect. For example, Iíve had patients who have cleaned their toupees with benzene or patients who have used gasoline repeatedly to wash their hands. Gasoline is a good solvent. It contains benzene, so you can get it indirectly in that sort of history. Medical drugs, of course chloramphenicolís.

Iím going to talk a little bit about the hepatitis syndrome, because thatís one in which we do have a very good objective marker of a preceding event. Iíll discuss that in a few moments. And then there are some immunological syndromes. Remember, eosinophilic fasciitis, itís a rare collagen vascular disease with these painful indurated lesions and a very characteristic biopsy appearance when you look at the fat. Pregnancy has a peculiar association. There are well documented cases of women who develop bone marrow failure with pregnancy. It gets better if the uterus is evacuated naturally, or artificially, and then gets worse with subsequent pregnancies. Then weíll talk a little bit about PNH and MDS.

Now the natural history of aplastic anemia untreated is rapid death from one of the elements of pancytopenia. If you read the case histories from the early part of the century itís remarkable how many patients simply succumb from anemia. I mean, children would die of congestive heart failure in their beds at home, kind of in Dickens style, and with the introduction of blood transfusion that obviously made an impact on the cause of death. Although not very much on prolonging life, I think. Nowadays most patients die of infectious complications, especially a fungal infection. Sometimes a very ordinary Pseudomonas-type bacterial infection, but itís generally fungal infections. So we can make an estimate that there is about an 80-90% mortality with just supportive care. This is in the era of androgens, these studies were done in the era of androgens, red cell transfusions, some platelet transfusions and of course some antibiotics. Nonetheless, patients died at a high rate. We know that the only important predictive factor, in terms of death - at least under these circumstances - are the blood counts. Age is not important, putative etiology is not important, where you live is not important, itís just how severely the blood counts are affected. There are a lot of different criteria that have been adopted. These are those of Bruce Kemit and they are the ones that most people remember them easily. So if you have two of these three blood counts low, that marks you as severe. That means you have to get treatment.

Now there are basically two ways of treating severe aplastic anemia. Now we are restricting ourselves to those patients who have the poor prognosis with just supportive care. One of them is bone marrow transplant, and somewhere along the line you will hear about transplant, but itís worth just reviewing the overall statistics. This was published in an article that Iíve referenced to you that summarized the results of treatment in aplastic anemia, a couple of years ago. And itís still quite accurate. So looking at both individual centers and also registry data mainly from Europe, but also the International Bone Marrow Transplant Registry, survival - at whatever time you talk about - you can see that the median survival is usually three, four, five years. This is assumed to reflect long term survival but people really arenít certain. Itís somewhere between 65% and 90% depending on which study you believe. The overall data, most recent but are unpublished, would suggest that 75-80% of patients who undergo bone marrow transplant for aplastic anemia will survive to five years.

So the first point in terms of rejection; this is clearly related to alloimmunization, although I think it is also related to the intrinsic biology of aplastic anemia. Weíll talk in a few minutes about the qualities of this disease as an autoimmune process. But it is related to alloimmunization. However the old dogma that you should absolutely not transfuse patients, aside from the fact that it is difficult to ignore a bleeding young kid with a platelet count of 3,000 and say "Iím not going to transfuse him and wait for the bone marrow transplant", it just doesnít work. But in fact data from the International Bone Marrow Transplant Registry a few years ago indicated that the risk of graft failure or graft rejection.

However graft-versus-host disease - especially in older patients - is. This slide looks like a Miro painting, but what itís trying to show is that if you look at older patients the rate of death is higher, and this is almost exclusively due to the occurrence of chronic graft-versus-host disease and the concurrent infections that occur. So you have rates in these various studies - thereís one thatís pretty low - but in general they have run between 40-70% in older patients. These are survivals. So the survivals can be as low as 10%, as good as 70% but this is based on where you take the cut- off. Whereas in children, survival is usually on the order of 75-95%.

Now the problems I mentioned with bone marrow transplant is that you have to have a sibling donor. Obviously there are huge registries out there now that allow - at least most Caucasians with the right HLA types - to find an alternative donor in the community. And the best results with this sort of procedure have been obtained at Childrenís Hospital in Milwaukee. But I think it is worth pointing out that this is still not a cure in every patient and their data are pretty much the same. About half of the patients do well and with this very intensive conditioning regimen and with T-cell depletion, they do well without very much in the way of graft-versus-host disease, which is terrific. But the procedure or the disease is lethal in the other 50%. So obviously going to an alternative donor is a big step because there is no going back and