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Years after marrow graft

Figure 5 Survival after allogeneic transplant at Pesaro for ß-thalassemia using HLA-identical sibling donors. (A) Probability of survival, event-free survival and graft rejection in all patients. (B) Event-free survival according to disease stage based on extent of liver damage (due to iron overload from multiple transfusions and ineffective erythropoiesis). Early stage (class 1) patients have >90% rejection-free survival. Patients received conditioning regimens containing BU/CY and GVHD prophylaxis with MTX/CSP. Class 1, no hepatomegaly, no portal fibrosis; class 2, hepatomegaly or portal fibrosis; class 3, + hepatomegaly, + portal fibrosis. (Reprinted by permission of Blackwell Science, Inc. from Lucarelli G (1994) Bone Marrow Transplantation in Thalassemia In; Forman SJ, Blume KG and Thomas ED (eds) Bone Marrow Transplantation, 833-835, Blackwell Scientific Publications, Boston, USA.)

HLA-nonidentical stem cell marrow grafts

To extend the available donor pool and thereby offer potentially life-saving treatment, studies using HLA-nonidentical family members and phenotypically HLA-matched unrelated donors have been performed. A high incidence of acute and chronic GVHD and increased risk of graft rejection have been observed. The use of one-HLA-antigen mismatched donors and HLA-matched unrelated donors have been associated with acceptable results. In patients with chronic phase CML, who underwent unrelated donor marrow transplantation in Seattle, an impressive 70% 3-year disease-free survival has been achieved.

Complications of transplant

Factors influencing outcomes of transplant include age, type of transplant, disease type and stage, and pre-existing medical problems. The principal complications that adversely affect outcome include toxicity of conditioning regimens, immunologic deficiency, poor graft function, GVHD and relapse of disease.

Regimen-related toxicities

To achieve maximum antitumor effects, regimens have been intensified such that significant nonhematopoietic toxicities are seen (Table 5). The main life-threatening toxicities are veno-occlusive disease (VOD) of the liver and interstitial pneumonitis. Serious VOD is seen in 15-28% of patients, and severe idiopathic pneumonia in approximately 3% of patients. Long-term side-effects include endocrine dysfunction, infertility, cataracts and, in chil-

Table 5 Major toxicities caused by conditioning regimens Early Late

Infertility3

Endocrine insufficiencies Secondary malignancy Cataracts

Leukoencephalopathy Myelodysplasia syndromeb

Erythroderma Alopecia3

aAlmoct invariable side-effects of conditioning regimens currently used for treatment of malignancy.

"Associated with autologous transplants, may be due to pretransplant therapies.

dren, impaired growth, impaired sexual function and reduced intellectual function. Late secondary malignancy is also a significant problem. Unique to autologous transplant recipients is the development of myelodysplastic syndromes, occurring in up to 20% of patients. The only cure for this life-threatening side-effect is a second transplant.

Hematologic and immune recovery

Recovery of granulocytes and platelets is usually complete by 40-50 days after transplant. Recovery of natural killer (NK) cells, monocytes and macrophages occurs early. However, functional defects, including defective immune function and chemo-taxis, may persist for many months. Lymphocyte dysfunction is often prolonged and characterized by diminished humoral and cell-mediated response to antigen. Peripheral blood B cell numbers and function are depressed, and the T cells show depressed CD4 counts, increased CD 8 suppressor activity and inverted CD4:CD8 ratios. Immune reconstitution is often complete by 1 year, but in patients with chronic GVHD sustained clinical and laboratory evidence of immune deficiency persists.

Infectious complications

Early in the post-transplant period there is severe neutropenia of 2-3 weeks duration and, although bacterial infection is common, the availability of potent antibiotics means that death from bacterial sepsis is uncommon. More difficult problems are viral and fungal infections and, in particular, cytomegalovirus (CMV) infections. Reactivation of CMV from host or transfused cells in the early post-transplant months can cause life-threatening pneumonia, previously fatal in approximately 15% of those receiving allografts for malignancy. Effective preventative measures have included use of CMV-seronegative blood products in CMV-seronegative transplant recipients, and more recently prophylaxis with ganciclovir. Fungal infections due to Candida or aspergillosis are increasingly seen and are often resistant to drug therapy. Herpes simplex is seen commonly after transplant and is prevented with acyclovir. Varicella zoster reactivation occurs in about 40% of cases and is treated effectively with acyclovir. Pneumocystis carinii infection, which previously caused about 10% of post-transplant pneumonias, is prevented with prophylactic trimethoprim-sulfamethoxazole.

Graft-versus-host disease

Acute GVHD is caused by alloreactive T cells directed at non-MHC (major histocompatibility

Mucositis3 Nausea/vomiting3 Enterocolitis Acute myocarditis Veno-occlusive disease of the liver

Interstitial pneumonia Leukoencephalopathy Hemorrhagic cystitis Acute renal failure

Table 6 Major risk factors for the development of GVHD

Acute GVHD

Chronic GVHD

HLA disparity Unrelated donor Advanced malignancy Sex-mismatched donor/recipient pair Parous female donor Increasing patient/donor age Irradiation dose >1200 cGy

HLA disparity Unrelated donor Preceding acute GVHD Increasing patient age complex) antigens recognized on host antigen-presenting cells, or against MHC antigens when MHC disparity exists. A complex series of cellular interactions that generates a cascade of cytokine release appears to be important in pathogenesis. Target organs for inflammation are the skin, liver and gastrointestinal tract. Principal risk factors for GVHD are summarized in Table 6. Between 20 and 50% of patients receiving HLA-identical sibling-donor transplants develop significant acute GVHD, and this is associated with significantly increased risk of transplant-related mortality, primarily as a result of infectious complications due to immune suppression.

Attempts to prevent GVHD are necessary and usually involve administration of immunosuppressive agents (Table 7), most commonly cyclosporine, methotrexate and corticosteroids. Indefinite im-

Table7 Agents currently used or under investigation for prophylaxis and treatment of GVHDa

Agent

Prophylaxis Treatment

Methotrexate Cyclosporine Corticosteroids T cell depletion FK506

Antithymocyte globulin

Anti-T-cell monoclonal antibodies

Mycophenolate mofetilb

Rapamycinb

CTLA4-lgb

Azathioprine0

Thalidomide0

Psoralen ultraviolet A range

(PUVA) therapy Topical corticosteroids (skin, gastrointestinal tract)

Combination therapy is commonly given for prevention of acute GVHD. bPhase I or preclinical studies currently being performed. cMainly used for treatment of chronic GVHD.

munosuppression is not required and transplant tolerance usually develops by 3-6 months. The combination of cyclosporine and methotrexate is better GVHD prophylaxis than either agent alone and leads to improved survival in patients with less advanced malignancy and nonmalignant disorders (Figure 4).

With aggressive malignancy, improved GVHD control may be associated with relapse rates, suggesting a loss of graft-derived antitumor effect. Newer, promising agents include FK506 and mycophenolate mofetil. A highly effective alternative approach to GVHD prevention involves removing T cells from the graft. However, this results in greater risks of graft rejection and relapse, with no survival gain. Treatment of established GVHD primarily involves the use of corticosteroids, antithymocyte globulin (ATG), cyclosporine and, increasingly, other agents listed in Table 7.

Chronic GVHD, defined as GVHD occurring after 100 days post transplant, clinically resembles autoimmune diseases such as scleroderma, Sjogren's syndrome and primary biliary cirrhosis. Severe immune deficiency persists and infection is the most frequent cause of death. Chronic GVHD of some degree occurs in 30-50% of patients receiving HLA-matched sibling transplants, usually within 2 years of transplant, and is associated with reduced probability of survival. The most effective therapy involves use of prednisone plus or minus cyclosporine. Other drugs with an increasing role include FK506 and thalidomide.

A relationship between relapse rates and previous GVHD has been established. Development of clinically significant acute or chronic GVHD provides some protection against relapse (graft-versus-leuke-mia effect), and for patients with advanced leukemia may lead to improved overall survival. In practice, it has not been possible to control GVHD with any precision to exploit this benefit during the transplant process. However, it has been possible to treat some cases of relapsed leukemia, most notably patients with CML, with infusions of donor buffy coat cells and induce second complete remissions, including possible cure.

Graft failure

Poor graft function is common after transplant but often resolves after contributing factors such as infection and drugs are dealt with. Persistent poor graft function is associated with a high mortality and the use of recombinant hematopoietic growth factors improves survival. True immunologic graft rejection is uncommon after the use of TBI-based conditioning regimens, except when HLA-mismatched donors are used and/or the graft is T cell depleted. The addition

Storb R, Anasetti C, Appelbaum F et al (1991) Marrow transplantation for severe aplastic anemia and thalassemia major. Seminars in Hematology 28: 235-239.

Sullivan KM and Koppa SD (eds) (1995) Marrow Transplantation Reviews 1991-1994: Biology and Clinical Practice of Hematopoietic Transplantation. Charlottesville, VA: Kluge Carden Jennings.

Sullivan KM, Agura E, Anasetti C et al (1991) Chronic graft-versus-host disease and other late complications of bone marrow transplantation. Seminars in Hematology 28: 250-259.

Thomas ED, Storb R, Clift RA et al (1975) Bone-marrow transplantation. New England Journal of Medicine 292: 832-843 and 895-902.

Treleaven J and Wiernik P (eds) (1995) Color Atlas and Text of Bone Marrow Transplantation. London: Mosby-Wolfe.

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