KhalilUllah Hashmi  ( Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan. )

Allogeneic stem cell transplantation (SCT) has significant therapeutic benefit for many patients with haematopoeitic disorders. Unfortunately the benefits of SCT are limited by significant morbidity and mortality related to graft versus host disease. GvHD remains one of the major complications of allogeneic SCT and a major determinant of outcome.1

The acute form occurs within 100 days from HSCT, whereas chronic form develops beyond day+100. Acute GvHD develops in approximately 30% to 60% of patients. Acute GvHD results from an interaction of donor T lymphocytes with recipient antigens. Variety of lymphokines (TNF-a, IL-1, IL-12, IFN-a) are released, which activate both donor and recipient monouclear cells. These activated cells produce non-specific tissue destruction of target organs especially skin, gut and liver.2

Chronic graft versus host disease GvHD is the most important cause of late transplants related morbidity and mortality. Between 30 and 50% of patients surviving 6 months or longer after an HLA identical sibling transplant, develop evidence of chronic GvHD. The major manifestations of chronic GvHD resemble several naturally occurring autoimmune disorders.3

Two basic approaches for GvHD prophylaxis after stem cell transplantation are either treatment of the recipient with pharmacologic agents (Cyclosporine, Prednisolone, Methotrexate, ALG) or in vitro purging of donor T lymphocytes from the marrow. Despite state of art prophylaxis, acute GvHD develops in about 50% of all HLA identical transplants. When the donor and recipient are unrelated or histo incompatible, the incidence of acute GvHD is much higher (40% to 90%) and in nearly 100% of non identical transplants.4

Initial treatment for acute GvHD routinely consists of intensifying the dose of corticosteroids and cyclosporin. Furthermore, steroid-resistant (SR) acute GvHD develops in 30-60% of patients, necessitating secondary intervention. Anti thymocyte globulin (ATG) is commonly used as first line therapy in this setting. Chronic GvHD remains a significant cause of late morbidity and mortality following allogenic stem cell transplantation. However, patients with chronic GvHD are very heterogeneous, making evaluation and treatment difficult. Corticosteroids remain the most effective primary treatment of this condition.5

The transplant related mortality, defined as death without relapse has been found to be significantly high in patients with acute GvHD (grade-II or more). The morbidity and mortality associated with acute GvHD correlate with the severity of the organ involvement. The mortality as a direct or indirect consequence of acute GvHD may be as high as 50%. EBMT working party analysis shows 25% mortality in patients with grade 0-I acute GvHD. The mortality related to Grade-II-IV GvHD ranged from 65% to 93%.6

The incidence of transplant related mortality due to chronic GvHD depends upon the progressive type, onset, extensive stage of GvHD and thrombocytopenia (<100x109/L). The accumulative incidence of transplant related mortality due to chronic GvHD has been reported to be 7-8%. Prolonged immunosuppression to treat severe chronic GvHD results in a potential increase in the risk of opportunistic fatal infection.7

A recent analysis of 4174 HLA identical sibling transplants shows that early and long term outcome is influenced by severity of acute GvHD and at 3 years survival was 74, 64, 37 and 10% respectively for patients with grade-I, II, III and IV acute GvHD respectively.8
There are two major bone marrow transplant centers in Pakistan namely Bismillah Taqee Institute of Health Sciences and Blood Disease Centre, Karachi and Armed Forces Bone Marrow Transplant Centre, Rawalpindi. Uptill now both the centers have carried out more then 250 allogeneic bone marrow transplants for various haematological disorders. The initial results are quite encouraging. However post transplant complications are the main causes of transplant related morbidity and mortality. Graft Versus Host Disease remains one of the major post transplant complications.

Author has reported 50% acute GvHD (Grade II-IV) in allogeneic stem cell transplantation in b-Thalassaemia and Chronic Myeloid Leukaemia in his initial series of transplant. The incidence of chronic GvHD was 5.2% in b-Thalassaemia and 18.1% in Chronic Myeloid Leukaemia.9,10 Author has also reported 44.2% acute GvHD and 14% chronic GvHD in a series of eighty six patients, transplanted for various haematological disorders. A retrospective analysis of acute GvHD in one hundred twenty five patients subjected to allogeneic stem cell transplantation for various haematological disorders at Armed Forces Bone Marrow Transplant Centre, showed 34% acute GvHD and 13% chronic GvHD. (To be presented in APBMT- 2005 Congress in China).

In this issue of JPMA Tahir Shamsi et al. have given a very low incidence of acute GvHD (29%) and chronic GvHD (24.3%) in a series of hundred patients under going allo - SCT for various haematological disorders. This shows the excellent GvHD prophylaxis strategy in their transplant setup. However the incidence of mortality was high in Grade III-IV acute GvHD and chronic extensive GvHD which is comparable to other international studies.

In a developing country the performance of these two transplant centers is excellent and are providing state of art transplant facility to the nation. Though the transplant programme in Pakistan is still in evolution, sooner of later the transplant facility will be available to majority of the critically sick patients at a much cheaper rate as compared to USA, European and other neighboring countries.

1. Vogelsang GB, Arai S. Mycophenolate mofetil for the prevention and treatment of graft versus host disease following stem cell transplantation: preliminary findings. Bone Marrow Transplant. 2001;27:1255-62.

2. Ringden O. Management of graft-versus-host disease. Eur J Haematol 1993;51:1-12.

3. Sullivan KM, Mori M, Sanders J, Siadak M, Witherspoon RP, Anasetti C, et al. Late Complications of allogeneic and autologous marrow transplantation. Bone Marrow Transplant. 1992;10:127-34.

4. Lazarus HM, Vogelsang GB, Rowe JM. Prevention and treatment of acute graft-versus host disease the old and the new. A report from the Eastern Cooperative Oncology Group (ECOG). Bone Marrow Transplant 1997;19:577-600.

5. Khoury H, Kashyap A, Adkins DR, Brown RA, Miller G, Vij R. Treatment of steroid resistant acute graft versus host disease with anti thymocyte globulin. Bone Marrow Transplant 2001;27:1059-64.

6. EBMT News Chronic Leukaemia Working Party Treatment of Acute GvHD 1994;4:1-12.

7. Hsu B, May R, Carrum G, Krance R, Przepiorka D. Use of antithymocyte globulin for treatment of steroid refractory acute graft versus host disease: an international practice survey. Bone Marrow Transplant 2001;28:945-50.

8. Gratwohl A, Brand R, Appereley J, Biezen Av A, Bandini G, Devergie A, et al. Graft - versus-host disease and outcome in HLA-identical sibling transplantation for chronic myeloid leukemia. Blood 2002;100:3877-86.

9. Ullah K, Khan B, Ahmed P, Hussain I, Rasul S, Hanif E, et al. Allogeneic Bone Marrow Transplantation in - Thalassaemia - Single Centre Study. J Pak Med Assoc 2004;54:449-503.

10. Ullah K, Khan B, Ahmed P, Hussain I, Raza S, Naeem M, et al. Allogeneic stem cell transplantation in chronic myeloid leukemia two and a half year experience. Turk J Haematol 2005;22:79-86.