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Improved Management of Graft-Versus-Host Disease

New drugs are available to treat graft-versus-host disease (GVHD). Combined with early detection and advances in understanding the underlying mechanisms of the disease, it may be possible to reduce the morbidity and mortality of this major complication of allogeneic transplantation.

Although severe GVHD remains a significant cause of post-transplant morbidity and mortality, mild acute and chronic GVHD are associated with a beneficial anti-tumor effect that can reduce the rate of relapse in patients transplanted for hematologic malignancies. [1] In addition, a 2006 study of 584 transplants found that patients who had chronic GVHD that later resolved had similar long-term health status compared to patients who never developed chronic GVHD. [2]

The National Marrow Donor Program® (NMDP) has produced long-term survival guidelines, Recommended Post-Transplant Care, with screening recommendations for chronic GVHD that include a photo atlas to aid in early detection of chronic GVHD.  See Clinical Guidelines for Transplant Consultation and Post-Transplant Care for more information. (The NMDP operates Be The Match®.)

Acute and chronic GVHD defined
Acute GVHD usually occurs before day 100 post-transplant. Chronic GVHD has somewhat different presentation and often occurs later. However, an "overlap" syndrome has recently been recognized in which diagnostic or distinctive features of chronic GVHD and acute GVHD appear together. [3]

Prevention of acute GVHD

Several successful strategies are being used to reduce the risk of developing acute GVHD. These include:

  • Prophylaxis with immunosuppressive drugs
  • Selective depletion of alloreactive T lymphocytes from the donor graft
  • Using umbilical cord blood as the source of donor cells
  • Choosing more closely HLA-matched donors  

Prophylaxis with immunosuppressive drugs

Intensive prophylaxis with immunosuppressive drugs is standard practice for all patients undergoing allogeneic transplantation. Standard drugs in use include cyclosporine, tacrolimus, methotrexate, mycophenolate mofetil, corticosteroids or antithymocyte globulin (ATG). The decrease in the incidence and severity of acute GVHD is in large part due to the widespread prophylactic use of these drugs, particularly cyclosporine and methotrexate.

New combinations including sirolimus might even be more effective. A 2007 report of 83 transplants showed good outcomes when using sirolimus and tacrolimus, without methotrexate, as prophylaxis for acute GVHD. The incidence of grade II-IV and III-IV acute GVHD in this study were 20.5% and 4.8%, respectively, and there were only two deaths (2.4%) due to GVHD. [4]

Selective depletion of alloreactive T lymphocytes

GVHD is a manifestation of alloreactive donor T cells acting against the patient. Depleting donor T cells prior to infusion into the patient is an effective method of reducing the risk of developing GVHD. However, doing so raises the risk of graft failure, infection and relapse.

In addition, T-cell depletion can reduce the beneficial graft-versus-malignancy effect that can act to eradicate residual disease in the patient. Newer techniques to selectively deplete only alloactivated donor T cells from donor grafts are being tested. [5] 

Using umbilical cord blood as the source of donor cells

Because of the immunological immaturity of the T cells in umbilical cord blood, transplants using this source of cells have a reduced incidence and severity of GVHD. [6,7] Although more commonly used in pediatric patients, cord blood transplantation has been successfully used in adults when sufficient nucleated cell doses are used. [7,8,9] See Hematopoietic Cell Sources Tailored to the Patient for more information.

Closer HLA matching between donor and patient

DNA-based tissue typing has increased the accuracy and specificity of HLA typing, which allows for more precise HLA matching between donors and transplant patients. Because the alloreaction of donor T cells against the patient's cells is reduced as the degree of HLA match is increased, closer HLA matching can significantly reduce the risks of GVHD. [10]

Treatment of acute GVHD

If acute GVHD does develop after transplantation, immunosuppressive drugs are administered, typically corticosteroids along with cyclosporine or tacrolimus. Satisfactory responses to this steroid treatment are observed in only 50% of patients. New drugs and new strategies are also available that can supplement standard treatment, including:

  • Monoclonal antibodies (e.g., anti-CD3, -CD5, and -IL-2 antibodies)
  • Mycophenolate mofetil
  • Alemtuzumab (Campath)
  • ATG
  • Sirolimus

Prevention and Treatment of chronic GVHD

Primary therapy for chronic GVHD is administration of steroids, including cyclosporine and prednisone. Agents such as mycophenolate mofetil, sirolimus, and rituximab have also led to response rates of more than 60% in patients with steroid-refractory chronic GVHD. [1]

A randomized prospective study of 109 transplant patients demonstrated that patients receiving pre-transplant ATG experience significantly less chronic GVHD than patients who did not receive ATG.

After a median follow up of 5.7 years, 60% of non-ATG patients experienced chronic GVHD compared to 37% of patients who received ATG (p=0.05). Extensive chronic GVHD was present in 41% of non-ATG patients and in 15% of ATG patients (p=0.01). [11] See Advances in Conditioning Regimens for more information.

In 2006, a National Institutes of Health (NIH) Consensus Conference established guidelines for diagnosis, ancillary therapy and supportive care in chronic GVHD. The Conference reports outlined proposed treatments for symptoms and gives recommendations for patient education, preventive measures, and appropriate follow-up.

Also developed were standard criteria for the diagnosis of chronic GVHD and a proposed new clinical scoring system that describes the extent and severity of chronic GVHD for each organ or site.

In all, six consensus documents were produced, and they are excellent resources for physicians wishing to learn more about chronic GVHD. [3,12-16]

References

  1. Cutler C, Antin JH. Chronic graft-versus-host disease. Curr Opin Oncol. 2006; 18:126-131.
    http://www.co-oncology.com/pt/re/cooncology/
    abstract.00001622-200603000-00005.htm     
  2. Fraser CJ, Bhatia S, Ness K, et al. Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study. Blood. 2006; 108(8):2867-2873.
    http://bloodjournal.hematologylibrary.org/cgi/content/full/108/8/2867 
  3. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and Staging Working Group Report. Biol Blood Marrow Transplant. 2005; 11(12):945-956.
    http://www.bbmt.org/article/PIIS1083879105006312/fulltext 
  4. Cutler C, Li S, Ho VT, et al. Extended follow-up of methotrexate-free immunosuppression using sirolimus and tacrolimus in related and unrelated donor peripheral blood stem cell transplantation. Blood. 2007; 109(7):3108-3114.
    http://bloodjournal.hematologylibrary.org/cgi/content/full/109/7/3108 
  5. Chen BJ, Cui X, Sempowski GD, Liu C, Chao NJ. Transfer of allogeneic CD62L- memory T cells without graft-versus-host disease. Blood. 2004; 103(4):1534-1541.
    http://bloodjournal.hematologylibrary.org/cgi/content/full/103/4/1534 
  6. Grewal SS, Barker JN, Davies SM, Wagner JE. Unrelated donor hematopoietic cell transplantation: marrow or umbilical cord blood? Blood. 2003; 101(11):4233-4244.
    http://www.bloodjournal.org/cgi/content/full/101/11/4233 
  7. Laughlin MJ, Barker J, Bambach B, et al. Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med. 2001; 344(24):1815-1822.
    http://www.nejm.org/doi/full/10.1056/NEJM200106143442402# 
  8. Ballen KK. New trends in umbilical cord blood transplantation. Blood. 2005;105(10):3786-3792.
    http://www.bloodjournal.org/cgi/content/full/105/10/3786 
  9. Brunstein CG, Barker JN, Weisdorf DJ et al. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood. 2007; 110(8):3064-3070.
    http://bloodjournal.hematologylibrary.org/cgi/content/full/110/8/3064 
  10. Morishima Y, Sasazuki T, Inoko H. The clinical significance of human leukocyte antigen (HLA) allele compatibility in patients receiving a marrow transplant from serologically HLA-A, HLA-B, and HLA-DR matched unrelated donors. Blood. 2002; 99(11):4200-4206.
    http://www.bloodjournal.org/cgi/content/full/99/11/4200 
  11. Bacigalupo A, Lamparelli T, Barisione G, et al. Thymoglobulin prevents chronic graft-versus-host disease, chronic lung dysfunction, and late transplant-related mortality: Long-term follow-up of a randomized trial in patients undergoing unrelated donor transplantation. Biol Blood Marrow Transplant. 2006; 12(5):560-565.
    http://www.bbmt.org/article/PIIS1083879105014163/fulltext 
  12. Shulman HM, Kleiner D, Lee SJ, et al. Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. Pathology Working Group Report. Biol Blood Marrow Transplant. 2006; 12(1):31-47.
    http://www.bbmt.org/article/PIIS1083879105007226/fulltext 
  13. Schultz KR, Miklos DB, Fowler D, et al. Toward biomarkers for chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: III. Biomarker Working Group Report. Biol Blood Marrow Transplant. 2006; 12(2):136-137.
    http://www.bbmt.org/article/PIIS1083879105007834/fulltext 
  14. Pavletic SZ, Martin P, Lee SJ, et al. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant. 2006;12(3):252-266.
    http://www.bbmt.org/article/PIIS108387910600070X/fulltext 
  15. Couriel D, Carpenter PA, Cutler C, et al. Ancillary therapy and supportive care of chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant. 2006; 12(4):375-396.
    http://www.bbmt.org/article/PIIS1083879106001613/fulltext 
  16. Martin PJ, Weisdorf D, Przepiorka D, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: VI. Design of Clinical Trials Working Group report. Biol Blood Marrow Transplant. 2006;12(5):491-505.
    http://www.bbmt.org/article/PIIS1083879106002503/fulltext