Graft Versus Host Disease Following Bone Marrow Transplantation - Essay Example

Bone Marrow Transplant and Graft vs Host Disease Bone Marrow Transplant and Graft Versus Host Disease Graft versus host disease (GVHD) happens when immunologically competent cells are transplanted into a recipient who is immunologically compromised. Although GVHD occurs most often in people who have undergone allogeneic bone marrow transplant, it may also follow other tissue transplant. The usefulness of hematopoietic stem cell transplantation (SCT) for the treatment of malignant hematopoietic disease is well known. The occurrence of acute graft vs host disease in such patients is closely related to overall survival after SCT, decreasing the incidence and severity of acute GVAD is very important (Toda, Takatsuka, Nahajima, et.al., 2005). This paper will discuss GVHD in relation to its diagnosis and treatment at this time. There are three basic requirements to cause GVHD to develop. Those are the transplant must have a functional cellular immune component, the recipient tissue must bear antigens foreign to the donor tissue and the recipient immunity must be compromised to the point that it cannot destroy the transplanted cells (Porth & Matfin, 2008). The primary agents of GVHD are the donor compromised T-cells and the recipient tissue that they recognize as foreign and react against it. The greater the difference in tissue antigens between the donor and recipient, the greater the likelihood of GVHD (Toda, et.al.,2005). The mechanism in which inflammatory cytokines are involved in acute graft vs host disease (GVHD) after hematopoietic stem cell transplantation has only been studied for a short period of time. GVHD, it is known however, can occur as an acute or chronic reaction. Acute GVHD develops within days of the graft and usually affects the skin, liver and gastrointestinal tract. The organ most commonly affected is the skin. There is usually a development of a pyritic, maculopapular rash, which begins on the palms of the hands and soles of the feet and then can extend to involve the whole body. The GI part of the disease includes symptoms such as nausea, bloody diarrhea, and abdominal pain. GVHD of the liver includes jaundice, hyperbilirubinemia, and abnormal liver function tests. Veno- occlusive disease may very well follow. Chronic GVHD occurs in about 50% of long term survivors that have not had acute GVHD. Major risk factors for developing major GVHD are mismatched tissues, older age donor, subacute GVHD detected by skin biopsy, administration of unirradiated donor buffy coat transfusions, previous splenectomy, cytomegalovirus seropositivity, primary diagnosis of chronic myeloid leukemia, and total body irradiation containing regimen (Higman, 2004). Other factors that might be predictive are secondary transplant, preceding herpes virus infection, and underlying malignancy (Ozawa, Nakeseka, Nashimora, 2007). The skin manifestations which are seen most often in both acute and chronic resemble lichen planus or coetaneous manifestations of scleroderma. Histologys done on the localized forms reveal hyperkeratosis and epidermal hypertrophy. Later on the dermis becomes atrophic and the inflammatory changes are less striking. In the localized form more generalized erythema, plaques, and waves of desquamation are found with underlying erythema. Photoactivation may be a problem (Chao, 2009). Autoantibodies are found in these patients with chronic GVHD and they are similar to those seen in system lupus erythematosus and other rheumatologic disorders, implicating autoimmunity and autoimmune disease-related gene polymorphism as important components in the formation of GVHD. An increase in suppressor T cells is noted in chronic GVHD. T cells are able to prevent proliferation of a mixed leukocyte reaction and prevent GVHD in some studies. However, in treatment and trials, there is still conflicting data (Toda, et.al, 2007) Develop of moderate or severe acute GVHD after marrow transplant is associated with a significant decrease in survival. Worse, once it occurs, it may not be treatable. Most of the intensive study, because of this has been directed at preventing it from occurring. It appears that prophylaxis is effective but it may also affect the graft versus leukemia effect. All studies so far, have shown that there is a significant increase in relapse of leukemia in patients who have AML versus CML (Chao, 2009). There are presently two major approaches to prophylaxis. They are pharmacologic therapy, and T cell depletion. The most widely used treatment at this time are a combination of methotrexate and cyclosporine. The efficiency of this combination has been shown in a series of random control trials. Patients who received this combination of drugs had significantly lower incidence of gradeII-IV acute GVHD. There have been trials testing the efficacy of the addition of glucocoricoids to the prophylaxis and the effect is still uncertain. There seems to be some positive result but no change that can be seen in overall survival at this time (Chao, 2009).There is also some positive results noted for the addition of tacrolimus but there may also be some renal failure in relation to the combination of these drugs (Chao, 2009). Sirolimus (rapamycin) is a lipophilic macrolide that has been identified for use some years ago. It binds to the same family of intracellular receptors as tacrolimus. Sirolimus reacts differently however, in the fact that it inhibits cytokine driven growth of these cells. This is a study that is being used quite often recently. There are some severe toxicities from this drug such as severe hypertriglyceridemia, a decrease in platelets and leukocytes, epistaxis, blood pressure changes, headaches, nausea and mucous membrane irritation. Testicular atrophy and liver function abnormality may also occur (Higman, 2004). In the case of those patients that fail prophylaxis and a treatment needs to be tried, there are several being used but the disease is still known to have a very high mortality once it forms. Glucocorticoids are the first line of therapy if prophylaxis is failed and acute GVHD develops. Other modalities that have been used are antithymocyte globulin, tacrolimus, monoclonal antibodies, and extracorporeal photochemotherapy(Ozawa, 2007). It is unknown at this time how glucocorticoids work but they seem to be the best line at this time. Methylprednisolone is the most commonly used of the glucocorticoids. Beclomethasone in combination with prednisone shows some promise in some of the studies noted. In one randomized study 60 patient with anorexia and poor oral intake because of intestinal GVHD were treated and 55% had a reasonable response by day 30. In a second trial 129 patients were treated for 10 days and they had 67% reduction in some symptoms (Chao, 2009). Anti-T cell antibodies have been given some primary scrutiny because of the primary role of the T cells in the pathogenesis of GVHD. There have been several studies showing some improvement in progressive disease. There has not been enough to know whether the treatment is truly effective however and there is definitely a need t do subsequent studies. Some of the other treatments that have shown promise and are being used by some are monoclonal antibodies, OKT3 and andtiCD3 antibodies, AntiCD3 antibodies and CD5 immunotoxins, anti-interleukin-2 receptor antibodies, anti-tumor necrosis factor-alpha antibodies, Thalidomide, and many others. Many of these are showing promise in the studies that are being done and there are many documented, well done studies as noted during the research for this paper. Many are not yet definitive, however. With all of these treatments being studied and some satisfaction in prophylactic treatment, the prognosis at this time is still poor. Patients with limited chronic GVHD have a favorable prognosis even without treatment while those patients that have extensive disease, particularly with multiorgan involvement, have very poor long term outcomes. There is and has been good tracking of those who have had poor outcomes and the studies have concentrated on the symptomology that has been presented. Knowledge of those clinical characteristics and the poor outcomes that come with them may help the clinician to identify more aggressive treatment for the disease. In conclusion, GVHD is a frightening disease and it comes on the heels of the treatment of another disease with bone marrow transplant. There are several good treatments at this time for prophylaxis but even those do not always work. Treatment of the disease itself, if not prevented can be difficult treatment and at this point may not be effective. There are many trials in process now in an attempt to find a trusted treatment that works more often for at this point mortality from the disease is still great. References Chao, N. (2009). Clinical manifestations and diagnosis of chronic graft-versus-host disease. UpToDate. www.uptodate.com Chao, N. (2009). Prevention and treatment of acute graft-versus-host disease: recommendations UpToDate. www.uptodate.com Chao, N., (2009). Treatment of chronic graft-versus-host disease. UpToDate. www.uptodate.com Chao, N. (2009). Treatment of acute graft-versus-host disease: clinical trials UpToDate www.uptodate.com Higman, MA, Vogelsang, GB.(2004). Chronic graft versus host disease. BR J Haematrol 125. 435. Ozawa, S., Nakaseka, C., Nishimura, M. et.al.(2007) Chronic graft-versus-host disease after allogeneicbone marrow transplantation from an unrelated donor: incidence, risk factors and association with relapse. A report from the Japan Marrow Donor Program. 17-142 Porth, C & Matfin, G. (2008). Pathophysiology, concepts of altered health states. 8th ed. Lippincott: New York, New York. Toda, A. Takatsuka, H. Nakajuma, T. Nomura, K., Wakae, T., Okada, M. Misawa, M. (2005). Serum elastase and antithrombin 3 in patients with acute graft vs host disease after bone marrow transplant. Clinical Transplant 19. 466-469. Article can be found at: http://search.ebscohost.com/login.aspx?direct=true&db=aph&AN=17519357&site=ehc Read More