Click here to view next page of this article

New Advances in Bone Marrow Transplantation

The hematopoietic stem cells are usually produced in the bone marrow and they circulate in the peripheral blood and in the cord blood. So they can be harvested either from the blood, the bone marrow, or the umbilical cord blood. Still for autologous transplantation, peripheral blood stem cells account for the majority of transplants. In the allogeneic setting stem cells from the bone marrow account for most of these transplants. If you look at the number of autologous and allogeneic transplantations over the years you can see that since 1985 there has been bone marrow transplantation.

If you look - this is important - if you look at the causes of death after an HLA-identical sibling transplant, you can see that still the primary disease accounts for the majority of death after an allogeneic transplant from an identical HLA-matched sibling, followed by infection, followed by graft-versus-host disease. So it’s very important that still the number one cause of death after transplant is the primary disease, and that brings up the question that we need to have better ways of controlling the disease and preventing it from recurring.

A few words about the HLA system. As you know, the human leukocyte antigens are the major determinants of histocompatibility between the donor and the recipient, and these antigens are present on the cell surface and they are encoded by a group of genes present on the short arm of chromosome 6. There are two distinct types of HLA genes; the class I, we refer to them as A, B and C. And the class II are the Q, D, P. And any one of you who work in a transplant setting or in a place where they do allogeneic transplant would recognize.

For donor matching, if you look at related donor matching, the likelihood of any sibling of a patient to inherit the same haplotype is 1:4, and if you look at an average family of two children - containing two children or more - in the United States, there is around a 30-40% chance of a patient finding a donor, a sibling donor, who is a match for that patient. If you look at unrelated setting, you can probably find a donor in 15-35% of the cases and that number is increasing because the number of volunteers in the marrow program..

This is a slide showing the chronologic occurrence of complications seen in bone marrow transplantation, and all of them make sense. If you follow somebody after receiving high dose chemotherapy and radiation, for example, and where they infuse the bone marrow or the stem cells, then after that most commonly you see mucositis because of chemotherapy effect and usually neutropenia, hemorrhage because of low platelet count, bacterial and fungal infection because of severe immune suppression and neutropenia, and then reactivation of Herpes simplex virus, presenting as esophagitis or pharyngitis. Then some typical complications that you see in allogeneic transplantation includes venoocclusive disease of the liver.

So the first complication I’ll try to deal with is the immune system deficiencies, and these are both cellular and humoral deficiencies and they occur to some degree in most of your patients after bone marrow transplantation. They are usually more profound and prolonged in patients who have graft-versus-host disease and/or receiving treatment for that disorder. The cellular immune deficiency consists of decreased T-cell responses to alloantigen and mitogens. So these patients tend to be anergic. Decreased helper cell function and decreased activity to intradermal skin tests. The humoral immune deficiency consists of decreased immunoglobulins, mostly IgG2 and IgG4 and this is seen in patients with chronic graft-versus-host disease and recurs in sino-pulmonary infections. So if there is a question about somebody post-transplant with recurrent sinus infections or pneumonias, it is important to recognize that those patients.

Bacterial and fungal infections; during aplasia and the first two to three weeks after transplantation you have all kinds of bacteremias that can happen or fungemias for that purpose, so it’s very important to be careful there and appropriately treat the patient with broad spectrum antibiotics and appropriate antifungal therapy. And then several months after transplantation there are incidents of late fungal infection. Mostly invasive Candidiasis.

Viral infections in the setting of neutropenia; there is a triphasic occurrence of the Herpes virus infection and the first one is the Herpes simplex virus reactivation which you see during the neutropenia period, 1-2 weeks after transplantation. Pharyngitis, esophagitis, most of the time now we don’t see that because all of these patients who test HSV positive get acyclovir prophylactically and usually this complication does not occur. The second type of infection is the cytomegalovirus infection, which is more severe and more difficult.

CMV pneumonitis, a few words on that. Patients present with dyspnea, tachypnea, fever and hypoxemia and it is important to recognize that the auscultatory findings are much less impressive usually than the symptoms or radiologic findings. So if you listen to a patient and most of the time the findings are non-revealing there, if you do a chest x-ray or you do blood gasses or what have you, you will see that the patient has significant radiologic changes.

What do we do to prevent CMV infection? A lot of strategies have been developed to try to control that disease or prevent it to start with, and the first easy thing is to use CMV-negative blood products and CMV seronegative donor/patient pairs. So if the patient and the donor are both CMV-negative that’s the ideal situation, and you try to use CMV-negative blood products. Now these blood products are not readily available. Blood banks have a very hard time trying to find CMV-negative products, so a study from Seattle has looked at the use of leukocyte-proof filters without checking the status of the blood product. And it seems, in that study, that there has been no difference in terms of using leukocyte-proof filters.

The last point is the use of ganciclovir prophylactically, which has been the subject of many studies published in the past several years. The problem with using ganciclovir prophylactically is that it is a myelosuppressive agent. It will delay your bone marrow recovery. It definitely increases the risk of CMV infection, but what happened in those patients is that there has been an increased risk of bacterial infection and fungal infection because of marrow suppression that ganciclovir can induce. So at this point in time, I think most everybody would use ganciclovir outside of a clinical study or research study at the first time that you can identify CMV infection anywhere; in the urine, the saliva or the blood.

Pneumocystis carinii pneumonia is seen usually six months after transplantation, usually in patients who have chronic GVHD and are on steroid therapy and cyclosporine. However, again because of prophylactic Bactrim use in all of these patients we rarely see this complication anymore.

Now a complication that is very peculiar or very characteristic of bone marrow transplantation is the venoocclusive disease of the liver.